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WO2002002553A1 - Compositions pharmaceutiques destinees au traitement de la nephropathie diabetique - Google Patents

Compositions pharmaceutiques destinees au traitement de la nephropathie diabetique Download PDF

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Publication number
WO2002002553A1
WO2002002553A1 PCT/JP2001/005743 JP0105743W WO0202553A1 WO 2002002553 A1 WO2002002553 A1 WO 2002002553A1 JP 0105743 W JP0105743 W JP 0105743W WO 0202553 A1 WO0202553 A1 WO 0202553A1
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WIPO (PCT)
Prior art keywords
compound
diabetic nephropathy
diabetic
nephropathy
methyl
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PCT/JP2001/005743
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English (en)
Japanese (ja)
Inventor
Atsuo Tahara
Takeshi Suzuki
Takeyuki Yatsu
Yuichi Tomura
Junko Tsukada
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU2001267911A priority Critical patent/AU2001267911A1/en
Publication of WO2002002553A1 publication Critical patent/WO2002002553A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a therapeutic agent for diabetic nephropathy, particularly a therapeutic agent for overt diabetic nephropathy and early diabetic nephropathy.
  • Diabetic nephropathy is a type of microangiopathy caused by a chronic hyperglycemic state, which causes microalbuminuria to show signs of proteinuria, renal dysfunction, hypertension, edema, etc., leading to renal failure.
  • the disease progresses through five stages: early nephropathy, early nephropathy, overt nephropathy, renal failure, and dialysis therapy.
  • diabetic nephropathy progresses relatively slowly in the early stages, and its lesions are also reversible.However, in the overt period in which proteinuria is positive, the lesions become irreversible and rapidly decrease renal function. End-stage renal failure (Di abetes, 46, S104-S111, 1997).
  • Characteristics of changes in renal function in the early stages of diabetes include microalbuminuria and glomerular hyperfiltration (Am. J. Med., 72, 375-380, 1982 / Br. Med. J., 4, 257-259, 1972).
  • an increase in glomerular pressure is thought to be deeply involved in the progression of nephropathy, and it is well known that the glomerular hyperfiltration theory that diabetic nephropathy is caused by abnormal glomerular hemodynamics. ing. That is, glomerular hyperfiltration caused by a rise in glomerular pressure caused by changes in glomerular import arteriole and export arteriole resistance precedes renal tissue damage, which causes albuminuria and diabetic nephropathy. It is considered to trigger the onset of the disease (Am. J. Med., 80, 443-453, 1986b).
  • overt nephropathy is a stage in which proteinuria is clinically recognized, and in many cases, renal function (glomerular filtration value) has already started to decrease.
  • the appearance of proteinuria in diabetic patients was considered to progress to renal failure over the course of a few years, making the disease difficult to treat, that is, difficult to treat.
  • Treatment of diabetic nephropathy is based on three basic treatments: (1) strict blood sugar control, (2) blood pressure control, and (3) protein restricted diet.
  • Angiotensin converting enzyme (AC) is used for blood pressure control.
  • Inhibitors and calcium antagonists are used.
  • vasopressin receptor antagonists have been synthesized.
  • clinical expectations of vasopressin receptor antagonists have been diminished due to the following problems.
  • the problem has a ®V 1A V 2 antagonism, not found pure V 1A antagonist or V 2 antagonists, it is impossible to orally administered for having 2 peptide structure, (3) When administered chronically, the antagonistic effect disappears, leaving only the agonist effect. (4) The species difference is large and extremely effective in rats, but almost no antagonistic effect in dogs, monkeys and humans, etc. (Therapy, Vol.81, extra number, pp.309-314, 1999).
  • the inventor considers a compound having extremely high affinity and selectivity for the human V1A receptor to be at least as high as that of a rat without being affected by species differences, if it is overt diabetic nephropathy and Z or early We thought that it could be a therapeutic drug for diabetic nephropathy, and conducted intensive research with the aim of searching for a compound having such a profile.
  • this compound has an excellent ameliorating effect on evening proteinuria and renal glomerular lesions in rats with overt diabetic nephropathy without affecting blood pressure. Confirmed and completed the invention.
  • this compound reduces urinary albumin excretion and suppresses renal glomerular hyperfiltration in early-stage diabetic nephropathy rats without affecting systemic blood pressure
  • the invention has been completed after confirming that the present invention has the effect.
  • the present inventors have completed the invention by finding that only 1Z2 fumarate stably forms a single crystal form in the process of studying the industrial production of compound A or a salt thereof as a pharmaceutical raw material. . That is, the present invention relates to a pharmaceutical composition for treating overt diabetic nephropathy comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to an agent for improving proteinuria or an agent for improving renal function in patients with overt diabetic nephropathy.
  • the present invention relates to the use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for overt diabetic nephropathy.
  • the present invention relates to a method for treating overt glycemic nephropathy, which comprises administering to a patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition for treating early-stage diabetic nephropathy comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and more particularly, an agent for improving albuminuria in patients with early-stage diabetic nephropathy Or an agent for improving renal glomerular hyperfiltration in patients with early-stage diabetic nephropathy. Furthermore, the present invention relates to the use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for early-stage diabetic nephropathy. Furthermore, the present invention relates to a method for treating early-stage diabetic nephropathy, comprising administering to a patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition for inhibiting the progress of diabetic nephropathy, comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to the use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of an agent for suppressing the progress of diabetic nephropathy. Furthermore, the present invention relates to a method for suppressing the progress of diabetic nephropathy, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a patient. Furthermore, the present invention relates to a novel compound A ⁇ 1/2 fumarate.
  • Compound A is a compound having a vasopressin receptor antagonistic activity, and a method for producing its hydrochloride is disclosed in Published Technical Report No. 97-9952.
  • V 2 receptor has an antagonistic action, renal diseases based on these findings prevention (nephrosis, nephritis, diabetic nephropathy, chronic or acute renal failure) and many other diseases and Z or Osamu Although it is suggested that it may be useful for treatment, no specific experiment is described for each disease. Further, Compound A or a salt thereof is not specifically disclosed.
  • the present inventor has, among the myriad of compounds included in the above formula (I), especially of compound A or salt thereof affinity-selectivity for V 1 A receptor of human is extremely excellent Was found to be an antagonist.
  • Compound A or a salt thereof is effective in overt diabetic nephropathy at an extremely low dose of about 1% of the dose at which OPC-21268 reduced urinary protein excretion in STZ-induced diabetic nephropathy rats. It has been confirmed that proteinuria and renal glomerular lesions in rats are improved, and albuminuria and glomerular hyperfiltration in rats with early-stage diabetic nephropathy are improved, and the present invention has been completed based on the results.
  • the medicament of the present invention is a remarkably excellent therapeutic agent for overt diabetic nephropathy, a therapeutic agent for early diabetic nephropathy, and an agent for inhibiting the progress of diabetic nephropathy.
  • the 1Z2 fumarate of compound A does not form a polymorph in crystallization from a water-ethanol system of less than 10%, it is considered that there are few problems concerning stability and solubility.
  • a compound having a crystalline polymorph free form or salt
  • the stability and solubility will vary, so the drug substance will not be dispersed. Standards cannot be guaranteed. It may also affect the pharmacokinetics of the drug and even its efficacy as a drug. Therefore, the 1/2 fumarate salt of compound A, which does not have a crystalline polymorph, is excellent as a pharmaceutical raw material in that a stable drug effect can be expected.
  • Compound A can form pharmaceutically acceptable acid and base addition salts with a wide variety of inorganic and organic acids or bases.
  • Such salts also form part of the invention.
  • salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid
  • salts with organic acids such as fumaric acid, malic acid, citric acid, succinic acid, and mesylic acid
  • salts with alkali metals such as sodium and potassium
  • calcium And salts with alkaline earth metals such as magnesium
  • salts with organic bases such as diethanolamine.
  • the compound A or a salt thereof, which is an active ingredient of the medicament of the present invention includes a mixture of various isomers and all of its isolated, hydrated, and solvated forms.
  • the compound A or a salt thereof, which is an active ingredient of the medicament of the present invention includes a compound having a crystalline polymorph (free form or salt), and includes all such crystalline forms.
  • Preferred as an active ingredient of the medicament of the present invention is a 1/2 fumarate of compound A.
  • Compound A or a salt thereof can be easily obtained by the production method described in the above-mentioned published technical report No. 97-9952, or by the production method of Example 1 described later, or according thereto.
  • the drug of the present invention is prepared as an oral solid preparation, an oral liquid preparation or an injection using an organic or inorganic carrier, excipient, and other additives suitable for oral or parenteral administration according to a conventional method. be able to. Most preferred are oral solid dosage forms that can be easily taken by patients and that are easy to store and carry.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminate metasilicate. Mixed with magnesium.
  • the composition may be prepared in accordance with conventional practice with additives other than inert diluents, for example, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), magnesium stearate, polyethylene glycol, starch, talc.
  • the pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose or the like, or a film of a gastric or enteric substance.
  • a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose or the like, or a film of a gastric or enteric substance.
  • Oral liquid preparations include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water, ethanol, etc.
  • the composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for intravenous injection, intramuscular injection, subcutaneous injection and the like include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • Diluents for non-aqueous solutions and suspensions include, for example, vegetable oils such as propylene glycol, polyethylene glycol and olive oil, alcohols such as ethanol, and polysorbate 80 Etc.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose), and solubilizing agents (eg, glutamic acid, aspartic acid). .
  • the dose of the compound A or a salt thereof, which is the active ingredient of the present invention is appropriately determined depending on the individual case in consideration of the administration route, the symptoms of the disease, the age, sex, etc. of the administration subject.
  • the active ingredient per adult is about 1 to 50 Omg Z days, preferably 10 to 20 Omg / day, and this is orally administered once or in 2 to 4 times. .
  • the drug of the present invention is an insulin preparation, a sulfonylurea drug, a sulfonamide drug, a biguanide drug, an aldose reductase inhibitor, an ⁇ -dalcosidase inhibitor, an insulin sensitizer, a somatomedin C drug, and other hypoglycemic drugs.
  • Prostanoid-related drugs, AEC inhibitors, angiotensin ⁇ receptor antagonists, tropoxane synthase inhibitors, vitamin ⁇ preparations, Kampo preparations, calcium antagonists, diuretics, etc. Can be used together after a while You.
  • Insulin preparations include insulin, neutral insulin, amorphous insulin zinc aqueous suspension, biphasic isophen insulin aqueous suspension, isophen insulin aqueous suspension, insulin zinc aqueous suspension, prominin insulin zinc aqueous suspension Aqueous suspension of crystalline zinc insulin; Toluptamide, glicloviramide, acetohexamide, tolazamide, chlorpropamide, dalipenclamide, daliclazide as sulfonylureas; dalibazole as sulfonamide; metformin hydrochloride as biguanide Buformin hydrochloride; epalrestat as an aldose reductase inhibitor; pogliose and acalcose as hypoglycosidase inhibitors; troglitazone and pioglitazone as insulin sensitizers; Medincerin as a medin C preparation; nateglinide as a hypoglycemic drug; beraprost, alprostadil
  • FIG. 1 is a multiplex recording diagram of a powder X-ray diffraction spectrum of a crystal of compound A ⁇ 1/2 fumarate under various crystallization conditions.
  • FIG. 2 shows a thermogravimetric analysis of TG-DSC of crystals of compound A ⁇ 1/2 fumarate.
  • FIG. 3 shows the protocol of STZ-induced diabetic nephropathy rat test protocol showing overt proteinuria of Test Example 2.
  • FIG. 4 shows the effect of Compound A on urinary albumin excretion.
  • FIG. 5 shows the effect of Compound A on urinary protein excretion.
  • FIG. 6 shows the effect of Compound A on systolic blood pressure.
  • FIG. 7 shows the effect of Compound A on renal glomerular lesions.
  • FIG. 8 shows the protocol of the diabetic overt nephropathy rat test protocol with hypertension in Test Example 3.
  • FIG. 9 shows the effect of compound A on urinary albumin excretion.
  • FIG. 10 shows the effect of Compound A on urinary protein excretion.
  • FIG. 11 shows the effect of Compound A on systolic blood pressure.
  • FIG. 12 shows the effect of Compound A on renal glomerular lesions.
  • FIG. 13 shows the STZ-induced diabetic early nephropathy rat test protocol showing microalbuminuria of Test Example 4.
  • FIG. 14 shows the effect of Compound A on urinary albumin and type 4 collagen excretion.
  • FIG. 15 shows the effect of Compound A on systemic and renal hemodynamics.
  • FIG. 16 shows the effect of Compound A on glomerular hemodynamics.
  • FIG. 17 shows the STZ-induced diabetic early nephropathy rat test protocol showing microalbuminuria of Test Example 5.
  • FIG. 18 shows the effect of Compound A on urinary albumin and type 4 collagen excretion.
  • FIG. 19 shows the effect of Compound A on creatinine clearance and systolic blood pressure.
  • FIG. 20 shows the effect of Compound A on renal glomerular lesions.
  • FIG. 21 shows the effect of compound A on tubular lesions.
  • FIG. 1 shows a powder X-ray diffraction spectrum diagram of the compound A ⁇ 1Z2 fumarate obtained using the Cu—Ko; line of the crystal under the crystallization conditions shown in Table 1.
  • Example 2 (5) Lot 15 ethanol stirring blade The measurement conditions are as follows.
  • Sample amount about 10mg Sample cell; Aluminum open cell,
  • a capsule having the following formulation was produced.
  • the test was conducted in the same manner as in the receptor binding test in (1).
  • the experimental protocol is shown in FIG. Sixteen weeks after the administration of STZ to induce diabetes, urinary albumin excretion, urinary protein excretion, blood pressure, and blood glucose levels were measured, and diabetic rats were treated to equalize the parameters. Divided into groups.
  • the urinary albumin concentration and urine protein concentration were measured from the obtained urine sample, and the amount of urinary albumin excretion and the amount of urinary protein excretion were calculated by multiplying the urine volume.
  • the urinary type 4 collagen concentration was also measured, and the amount of urinary type 4 collagen excreted was calculated by correcting the urinary creatinine level at the same time.
  • Urine glucose was measured based on a standard method.
  • kidney For renal tissue fixation and pathological examination, the kidney was perfused and fixed with saline and 10% formalin in 10% phosphate buffer under ether anesthesia. It was immersed and fixed in 10% buffered formalin solution. A paraffin section was prepared from this kidney fixing material, and subjected to H & E staining and PAS staining for microscopic examination. Glomerular lesions were classified into 100 glomeruli per rat according to the following grades. Normal No abnormality
  • Urinary albumin excretion and urinary protein excretion were significantly increased in the diabetic control group as compared with the normal group. Urinary albumin excretion and urinary protein excretion both showed an improvement effect in the compound A (3 mg / kg / day) administration group and in the enalapril (10 mg / kg / day) administration group. Urinary type 4 collagen excretion was also significantly increased in the diabetic control group as compared to the normal group, and a significant improvement effect was observed in the compound A administration group, but not in the enarabril administration group, although a significant improvement was observed. Admitted.
  • FIG. 6 shows the results of the systolic blood pressure 8 weeks after continuous administration of the drug. Blood pressure was significantly increased in the diabetic control group compared to the normal group. The compound A administration group had no effect on blood pressure, but the enalapril administration group showed a significant hypotensive effect.
  • Fig. 7 shows the incidence of glomerular lesions for each grade. Diabetes control compared to normal group In the group, the incidence of lesion and its grade increased significantly. Compound in drug administration group
  • Test Example 3 STZ-induced overt diabetic nephropathy rat test showing hypertension
  • diabetic rats with hypertension were prepared by performing STZ administration after uninephrectomy on spontaneously hypertensive rats.
  • Enalapril maleate was used as a control.
  • FIG. 8 shows an experimental protocol.
  • urinary albumin excretion, protein excretion, systolic blood pressure, and blood glucose level were measured, and diabetic rats were divided into three groups so that each parameter became equal.
  • the non-diabetic group gained weight over time, but the diabetic control group did not gain weight, and the weight of the diabetic control group was significantly lower than that of the non-diabetic group.
  • Blood glucose and urine glucose levels were also significantly increased in the diabetic control group, and they continued to exhibit high blood glucose and high urine glucose throughout the test period.
  • a marked increase in urine volume and drinking water was always observed throughout the test period.
  • Compound A and enalabril had no effect on weight loss, hyperglycemia / urinary glucose, or polydipsia in these diabetic controls.
  • Urinary albumin excretion and urinary protein excretion 8 weeks after continuous drug administration are shown in FIGS. 9 and 10.
  • Urinary albumin excretion and urinary protein excretion were significantly increased in the diabetic control group compared to the non-diabetic group.
  • Urinary albumin excretion The urinary protein excretion was improved in the compound A and enalapril treatment groups.
  • Urinary type 4 collagen excretion was also significantly increased in the diabetic control group compared to the non-diabetic group, and a significant improvement was observed in the compound A and enalapril administration groups.
  • Fig. 12 shows the glomerular lesion occurrence rates for each grade.
  • the incidence and grade of lesions were significantly increased in the diabetic control group compared to the non-diabetic group.
  • lesion ameliorating effects were observed for each grade.
  • the results of Test Examples 2 and 3 show that Compound A improves urinary albumin Z excretion and creatinine clearance at a lower dose than the control compound enalapril.
  • the blood urea nitrogen level in the drug-administered group did not change from that in the normal group, suggesting that this improvement in creatinine clearance did not cause an excessive decrease in renal function.
  • Compound A exhibited a nephropathy improvement effect equal to or higher than that of enalapril despite having no antihypertensive effect, indicating that it has a kidney-specific mechanism of action independent of the antihypertensive effect It was suggested.
  • renal glomerular lesions in the diabetic control group, lesions that could be clearly differentiated from those in the non-diabetic group were observed in this study, and the significant improvement effect of Compound A was observed.
  • the effect of Compound A on the increase in urinary albumin / protein excretion is considered to be the result of lowering glomerular pressure by reducing elevated creatinine clearance and improving glomerular hyperfiltration.
  • Compound A is lower than enalapril maleate, the most commonly used therapeutic agent, in diabetic nephropathy rats with overt proteinuria and in hyperglycemic diabetic nephropathy rats. It was confirmed that the dose can improve proteinuria, renal function and glomerular lesions. Furthermore, since it does not affect blood pressure, it was suggested that combination treatment with conventionally used antihypertensive drugs is also possible.
  • Test Example 4 STZ-induced diabetic early nephropathy rat test showing microalbuminuria (4 Weekly oral administration)
  • Rats Male Wistar rats (Nippon Charles' River, 10 weeks old) were used for the experiment.
  • Figure 13 shows an outline of the protocol. Rats measured urinary albumin excretion before STZ administration and were equally divided into four groups.
  • STZ 50 mg / kg was dissolved in citrate buffer and administered via rat femoral vein to induce diabetes.
  • the normal group received the same volume of saline intravenously instead of STZ.
  • each drug was suspended in a 0.5% methylcellulose solution, and oral continuous administration was started once daily at a liquid volume of 5 ml / kg.
  • urine was collected in a metabolic cage for 24 hours while awake, and urinary albumin, type 4 collagen, and creatinine excretion were determined from the obtained urine samples.
  • the rats continued to administer the drug once a day thereafter, and a renal clearance experiment was performed in the same week.
  • a polyethylene catheter for blood pressure measurement and blood collection was inserted into the right femoral artery of the rat under anesthesia with inactin (100 mg / kg).
  • catheters for drug administration were inserted into the left and right femoral veins.
  • inulin clearance measurement 1.5 ml / kg of 1 inulin solution dissolved in physiological saline from the force fenus of the right femoral vein After the administration, continuous injection was performed at a volume of 0.1 ml / min in the normal group and 0.2 ml / min in the diabetic group.
  • a probe for measuring renal blood flow was attached and connected to an electromagnetic flowmeter.
  • the distal side was ligated, a polyethylene catheter was inserted, and urine was collected over time. Blood pressure was continuously recorded via a polygraph system with a catheter inserted into the artery connected to a pressure transducer.
  • Heart rate was measured by driving evening rice from the blood pressure pulse. Renal blood flow was also continuously recorded via a polygraph system, as was blood pressure. After a stable period of about 1 hour after the start of continuous inulin infusion, a 20-minute urine collection was started after confirming that hemodynamics and urine volume were stable. At an intermediate point 10 minutes after the start of urine collection, mean blood pressure, heart rate and renal blood flow were measured and used as basal values. At the same time, arterial blood was collected for immediate measurement of blood inulin concentration and hematocrit value, and immediately the same amount of saline was intravenously replaced.
  • the left kidney was carefully detached from the surrounding tissues, and the capsule on the outer part of the kidney, where blood vessel control was small, was incised (diameter 1 awake, depth 0.3 mm). Then, the tip of the pencil-type CCD biological microscope mounted on the micromanipulator was guided obliquely to the kidney surface so as not to damage the tubule. By manipulating the micromanipulator, 2 to 6 glomeruli were observed per animal without obstruction of blood flow due to invasion of the experiment and showing glomerular import / export arterioles and glomerular circumference. The glomerular images were recorded continuously on tape by a video cassette recorder and used for measuring glomerular import, export arterioles and glomerular diameter. After the measurement of glomerular hemodynamics, blood for measuring blood creatinine concentration was collected from the abdominal aorta, and the left kidney was excised and the wet weight was measured.
  • Fig. 14 shows urinary albumin and collagen type 4 excretion at 4 weeks after continuous drug administration in each group.
  • Urinary albumin and type 4 collagen excretion were significantly increased in the diabetic control group compared to the normal group.
  • a significant improvement effect was observed in both the compound A and enarabril administration groups.
  • FIG. 15 shows the values of each parameter at 4 weeks after continuous administration of each group.
  • Mean blood pressure did not change significantly between the normal group and the diabetic control group, and renal blood flow tended to increase but was not significant in the diabetic control group.
  • creatinine clearance showed an increasing tendency in the diabetic control group as compared to the normal group, and a significant increase in glomerular filtration rate was observed.
  • mean blood pressure and renal blood flow did not show significant changes, but creatinine clearance and glomerular filtration rate tended to decrease.
  • the mean blood pressure was significantly lower in the group receiving enalapril than in the diabetic control group.
  • renal blood flow significantly increased, creatinine clearance tended to decrease, and glomerular filtration rate showed a slight increase.
  • FIG. 16 shows the values of each parameter overnight at 4 weeks of continuous drug administration in each group.
  • the diameter of imported arterioles was significantly increased in the diabetic control group compared to the normal group, the diameter of imported arterioles was not significantly changed, and the ratio of imported Z exported arterioles was significantly increased. did.
  • the glomerular diameter was significantly increased in the diabetic control group as compared to the normal group.
  • the compound A administration group no significant change was observed in the diameter of the imported arteriole, but an increase in the diameter of the exported arteriole was observed.
  • the increase in the ratio of the imported arteriole to the exported arteriole was significantly improved.
  • the glomerular diameter was also a tendency for the glomerular diameter to decrease.
  • FIG. 17 shows an outline of the protocol. Under anesthesia with pentobarbital (50 mg / kg), STZ (50 rag / kg) was dissolved in citrate buffer and administered from rat femoral vein to induce diabetes. The normal group received the same volume of saline intravenously instead of STZ.
  • each drug was suspended in 0.5% methylcellulose solution and administered orally once daily for 16 weeks at a volume of 5 ml / kg, and blood was collected and urine collected every 4 weeks (24-hour urine collection) , Body weight, urine output, water intake, and systolic blood pressure were measured.
  • the obtained blood was immediately subjected to slow protein, and blood glucose was measured based on a standard method.
  • the amount of albumin excreted in urine was calculated from the obtained urine sample.
  • urinary type 4 collagen concentration was also measured, and the amount of urinary type 4 collagen excreted was calculated by correcting the urinary creatinine level at the same time.
  • the urinary sugar level was measured based on a standard method.
  • Creatinine clearance, systolic blood pressure, blood glucose, urine in the same manner as in Test Example 1.
  • the amount of medium 4 collagen excreted and the amount of urinary albumin excreted were measured, and renal tissue fixation and pathological examination were performed.
  • Tubular lesions were classified according to the following score 1 according to the appearance frequency of urinary casts in the tubules.
  • Score — 0 No urinary cast
  • Z score 1 1: Small number of small casts in the cortex or extramedullary zone (less than 10 spots on section)
  • Z score 1: 2 Small number of cortical and extramedullary zones Large urinary casts scattered in tubules (10 or more sections)
  • Scorer 3 Large urine casts scattered in cortical and extramedullary tubules (10 or more sections)
  • Fig. 18 shows the results of the excretion of urinary albumin and type 4 collagen 16 weeks after continuous administration of the drug.
  • Urinary albumin excretion and urinary type 4 collagen excretion were significantly increased in the diabetic control group as compared with the normal group.
  • the compound A administration group, the enalapril administration group and the compound A + enalapril administration group all showed a significant improvement effect on the increase in urinary albumin and type 4 collagen excretion.
  • Fig. 19 shows the results of creatinine clearance and systolic blood pressure 16 weeks after continuous drug administration.
  • the glomerular and tubular lesion occurrence rates are shown in FIG. 20 and FIG.
  • the incidence of lesions in the normal group was about 5% of the total, and most showed only mild lesions with a score of -1.
  • the incidence and extent of lesions in the diabetic control group were significantly worse than in the normal group.
  • no clear difference was observed in any group from the diabetic control group.However, when focusing on scorer 3 showing a glomerular sclerosis image, compound A and compound A + enalapril were administered. There was an improvement trend in the group.
  • the incidence and incidence of tubular lesions tended to be worse in the diabetic control group than in the normal group.
  • Compound A has three problems with pasopressin receptor antagonists (1 It has V 1 A V 2 antagonistic activity, and no pure V 1 A antagonist or V 2 antagonist has been found. Antagonism disappears when administered, only agonist action remains.
  • Dosage regimen The study should be performed in a double-blind, multicenter, placebo-controlled, dose-escalating fashion. All patients receive the three doses of the test drug and placebo, and the placebo treatment period is randomly assigned during the test drug treatment period. The total treatment period for each patient is 24 weeks, with two weeks before and after the run-in period and a four-week period.
  • Evaluation index (Primary index) Changes in albumin excretion from the start of administration to after treatment (24 weeks). (Secondary index) Albumin excretion from the last dose during the treatment period until the next treatment period change of. Changes in urine osmotic pressure, type 4 collagen, urinary N-acetyl / 3-D-glucose-aminidase and TGF-] 3 excretion, and intravenous arginine vasopressin.
  • Albumin excretion and urine osmolality should be assessed at baseline at the end of the run-in period using 24 hours x 3 urine collection samples.
  • Albumin excretion and urine osmotic pressure should be reassessed at the end of each treatment period and at the beginning of the next treatment using 24 hours x 3 urine samples.
  • Patients are hospitalized for at least 8 hours on the first day of each treatment period (Visits 4, 7, 10, and 13) and patients receive the first dose of each treatment period at the hospital.
  • Patients are hospitalized for 24 hours on the last dosing day (Visit 4, 7, 10, and 13), and patients receive the last dose of each treatment period at the hospital.
  • the amount of type 4 collagen, creatinine, N-acetyl-i3-D-darco-aminidase and TGF-j8 in urine was measured before randomization at Visit 1 and at 4, 7, 10, 13, and 14 before randomization. At this time, a small amount of urine is measured to evaluate the therapeutic effect of the biomarker. Intravenous arginine vasopressin is measured at visits 1, 4, 7, 10, 13, and 14. Industrial applicability
  • proteinuria in patients with overt diabetic nephropathy a therapeutic agent effective for improving reduced renal function and renal glomerular lesions, and Z or albuminuria in patients with early diabetic nephropathy
  • the present invention can provide a therapeutic agent effective for improving renal glomerular hyperfiltration and suppressing the progress of disease.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Urology & Nephrology (AREA)
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Abstract

L'invention concerne des compositions pharmaceutiques destinées au traitement de la néphropathie diabétique patente et/ou précoce, qui contiennent comme ingrédient actif (Z)-4'-{4,4-difluoro-5-[2-oxo-2-(4-pipéridino-pipéridino)éthylidène]-2,3,4,5-tétrahydro-1H-1-benzazépine-1-carbonyle}-2-2méthyl-3-furanilide ou des sels de celui-ci pharmaceutiquement acceptables.
PCT/JP2001/005743 2000-07-04 2001-07-03 Compositions pharmaceutiques destinees au traitement de la nephropathie diabetique WO2002002553A1 (fr)

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AU2001267911A AU2001267911A1 (en) 2000-07-04 2001-07-03 Pharmaceutical compositions for treatment of diabetic nephropathy

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JP2000-201818 2000-07-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0716083A1 (fr) * 1993-08-26 1996-06-12 Yamanouchi Pharmaceutical Co. Ltd. Derives de la benzazepine, composition pharmaceutique le contenant, et ses intermediaires
JP2000063363A (ja) * 1998-08-12 2000-02-29 Yamanouchi Pharmaceut Co Ltd 新規なトリアゾール誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0716083A1 (fr) * 1993-08-26 1996-06-12 Yamanouchi Pharmaceutical Co. Ltd. Derives de la benzazepine, composition pharmaceutique le contenant, et ses intermediaires
JP2000063363A (ja) * 1998-08-12 2000-02-29 Yamanouchi Pharmaceut Co Ltd 新規なトリアゾール誘導体

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BARDOUX PASCALE ET AL.: "Vasopressin contributes to hyperfiltration, albuminuria and renal hypertrophy in diabetes mellitus: study in vasopressin-deficient brattleboro rats", PROC. NATL. ACAD. SCI. USA, vol. 96, no. 18, 1999, pages 10397 - 10402, XP002945530 *
NISHIKAWA TESUO ET AL.: "Short-term clinical trial of 1- (1-(4-(3-acetylaminopropoxy)-benzoyl)-4-piperidyl)-3,4-dihydro-2 (1H)-quinolinone in patients with diabetic nephropathy", ARZNEIM-FORSCH/DRUGRES, vol. 46, no. 9, 1996, pages 875 - 878, XP002945529 *
YAMANOUCHI PHARMACEUTICAL CO. LTD., JOURNAL OF TECHNICAL DISCLOSURE (HATSUMEI KYOKAI KOUKAI GIHO), vol. 097, no. 9952, 15 December 1997 (1997-12-15), HATSUMEI KYOUKAI, pages 1 - 2 *

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