TW200538154A - Combination of organic compounds - Google Patents

Abstract

The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising (i) a renin inhibitor or a pharmaceutically acceptable salt thereof, and (ii) the diuretic amiloride or triamterene or a pharmaceutically acceptable salt thereof, and (iii) a further diuretic (e.g. HCTZ) or a pharmaceutically acceptable salt thereof.

Description

200538154 IX. Description of the invention: Such as a combination preparation or a pharmaceutical combination respectively [Technical Field to which the Invention belongs] The present invention relates to a composition comprising: (i) a renin inhibitor or a pharmaceutically acceptable salt thereof; and ( π) amine chloride or amphetamine or a pharmaceutically acceptable salt thereof; and (iii) thiazide diuretic or a pharmaceutically acceptable salt thereof. [Prior art] 1 Renin inhibitors contain compounds having different structural characteristics. For example, mention may be made of compounds selected from the group consisting of: ditekiren (chemical name: ns-HRMRMRwjR *)]] Koyamayama dimethylethoxy) carbonylproline L_phenylpropylaminomethyl_N_ [2_hydroxy-5-methyl-1- (2-methylpropyl) _4 _ [[[2_methyl "— [[(孓 .pyridylmethyl)) Moon female] Ik group] Butyl] Amine] Amino] Hexyl] _N_a (aifa) _Methyl-histamine (Moon female), Terlakiren (Chemical name · [r_ (r * , S *)]-N- (4-Morylyl) -L-phenylpropylaminofluorenyl (cyclohexylmethylhydroxymethylethoxy) -3-oxopropyl > s-methyl- L-Cysteine), zankiren (chemical name: [Bu (cyclohexylmethyl) -2,3-dihydroxy-5_methylhexyl] -α _ [[2-[[ (4-methyl-1-piperazinyl) sulfofluorenyl] methyl] -1-oxo-3_phenylpropyl] amino] thiazolepropanthine) 'especially its hydrochloride, respectively , The following formulas of r〇66-1132 and RO-66-1 168, 99159.doc 200538154

Especially preferred are compounds of the formula:

It is chemically defined as 2 (s), 4 (S), 5 (S), 7 (S) -N- (3-y ^ a >-, --oxypropyl) _2,7-diU -Methylethyl) -4-hydroxy-5-amino-8- [4-methoxyf 3 (3-methoxy_propoxy) phenyl] _octylamine (common name ·· Aliceji

(klren)) 'is specifically disclosed in EP 6785403 A; or a pharmaceutically acceptable salt thereof, especially a hemi-fumarate. ..... =: The preferred pharmaceutically acceptable salt is the hydrochloride. 〇 The thiazide diuretics are selected from the group consisting of chlorothiazine, < chlorothiazine and chlorothiazide%-, /, lice thiazide, 曱, preferably a small group. Most preferred is hydrochloropyrazine. Yue 〃 ", σ, such as a combination preparation or a pharmaceutical composition, a lunarin inhibitor or its pharmacological M σ, respectively, and / or (ii) amine chloride- 脒 or a pharmaceutically acceptable salt thereof ' · And (iii) Ammonia chloride or its medically accessible :::; and the best is a combination, which is the salt of the text. It contains: ⑴Alice Gillen or: and D preparation or pharmaceutical composition 99159.doc M medically acceptable salts, and 200538154 (ii) amine chloride hydrochloride; and (iii) hydrochlorothiazide. [Summary] The structure of the active agent identified by the common name or trademark name can be Taken from the current version or library of the standard outline "1 dirty others", such as Life Cycle

Patents International (e.g., Ron) n, IMS World Pubhcaticms. Relevant content is incorporated by reference. Anyone familiar with this technology will be able to recognize other active agents such as j-Hai and based on these documents, it is also possible to manufacture and test pharmaceutical indications and characteristics from in vitro and in vivo standard test models. The corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used for crystallization in the form of a solvate such as a hydrate or including other solvents. The compounds to be combined may exist as a pharmaceutically acceptable salt. For example, if these compounds have at least one diagnostic center, they can form acid addition salts. If required, a corresponding acid addition salt with additional presence of the test center can also be formed. Compounds with acid groups (such as COOH) can also be tested to form salts. ^ Diuretics amine tritium or amine benzene "or their pharmaceutically acceptable salts in each case inhibit the test channel in the distal tubule and increase sodium and chloride ions by reducing potassium excretion To collect the excretion tube. Thiazine diuretics are known to reduce electrolyte resorption from junior officials, thereby increasing the excretion of sodium and gas ions and subsequent water. The excretion of potassium can also be Increased by applying, for example, lice sputum. Separately, amine chloride d is higher than hydrazine, (especially its hydrochloride) or a combination of ㈣R and ㈣ diuretics (such as hydroxazine), which increases sodium and milk ions The amount of excretion, while reducing the excretion of urinary potassium. 99159.doc 200538154 The following experiments were found to be more surprising ... that is, a combination of the following (0 month inhibitor or a pharmaceutically acceptable salt; And (Π) amiprodil or amphetamine or a pharmaceutically acceptable salt thereof; and (iii) other diuretics or pharmaceutically acceptable salts, which not only lead to a surplus (especially enhanced, better For synergistic) treatment effects, sub-treatments have additional benefits, And apply only as disclosed in this article

The combination of the medicament compound compound used as a single treatment, which leads to further surprising beneficial effects. Surprise, that is, the combination of the present invention is different), and the following experimental findings of the detailed set of results are more palatable and only lead to benefits (especially enhanced, preferably synergistic treatment, and additional benefits, such as unexpected effects) Prolongation, wider changes in therapeutic treatments, and unexpected beneficial effects on debilitating conditions as described below. In addition, 'the unexpected effect of the combination of the present invention is the fact that higher blood dust will follow with each of the triple treatments— The dosage of the components is reduced and reduced.-Better potassium treatment and automatic balance.-Better due to the kinetic effects of three independent ingredients and the protection provided by Aliceamine Chloride: Ammonium or Ammonium. : Myocardial compliance. Beijishang 'Alice Jiyu protects myocardial ischemia from renin by inhibiting renin during perfusion and reconstruction, and amine chloride or amine benzene is determined by resistance Of sclerosis in local defect reperfusion injury

Na + boat exchange agents protect myocardium from repetitive ischemia and acute myocardial infarction. 99159.doc 200538154 Established test models and especially it ’s, these test models described in this article can be conspicuous that the combination of therapeutic agents consisting of ⑴ to 会 will lead to the disease that is expected below More effective prevention or better treatment. For a large number of groups described in this article, A σ and & if absorbed simultaneously, it will not only enhance the effect of the treatment (especially synergistic), but also lead to additional benefits obtained by the same treatment, such as efficacy Unexpected lengthening, extensive changes in therapies, and accidents associated with diabetes-related diseases and conditions have consequences such as a small increase in weight. In addition, for human patients, serving = Lao Guang: it is more convenient and easier to remember (for example, before meals) taking three tablets at the same time than staggering (ie, according to a more complicated treatment schedule) ^ In all cases described herein, all three activities are administered as a fixed combination (meaning as a single bond). Taking single spin W is even easier than taking three spins at the same time. In addition, packaging can be accomplished with less effort. As used herein, the term " synergy " means that the effects achieved by the methods and compositions of the present invention are greater than the combined effects of the methods of the present invention and the compositions comprising the active ingredients of the present invention. [Embodiment] Those skilled in the art can completely choose relevant and standard animal test models to prove the above and the following treatment of hypersensitivity and beneficial effects. For example, the medical activity caused by the administration of AT1 receptor antagonists or diuretics or a representative of the combination of active agents used according to the present invention can be achieved by the use of corresponding pharmacological models known in the related art. Confirmed. Those skilled in the art can completely choose relevant animal test models to prove the therapeutic indications and beneficial effects of 99159.doc 200538154 above and below. For example, the beneficial effects on blood pressure can be confirmed by a test model as disclosed by RL Webb et al. In 丄 Hypertension, 16. 843-852, 1998. • Method: '/ The combination according to the invention comprises a compound of formula ⑴ or a pharmaceutically acceptable salt thereof, which can be administered by various routes of administration, however in this example a continuous microosmotic pump is used via a subcutaneous implant Inculcate to test it. Multiple doses of each agent can be tested to determine the optimal drug content of each agent in the combination that gives the greatest response. For such studies, it is best to use a treatment group consisting of at least 6 animals per group. When conducting each study, it is best to evaluate the effects of the combined treatment group while evaluating the individual components. Although it is possible to observe the effect of the drug in an acute dose (such as 1 day), it is best to observe the response in a chronic setting as shown below, where the experiment is completed during a two to three week observation period. Long-term studies have sufficient time to allow compensatory responses to full development and therefore the effects observed will best describe the actual response to the call-test system that represents a sustained or lasting effect. The effects on blood day described below represent synergistic antihypertensive effects when two agents are used in combination. Statistical analysis: "", oral / 0 treatment can be measured by the maximum change in blood pressure in each treatment group or the area under the curve of blood ^ ^ time change (AUC) to the treatment of the single treatment group: compared with the average value of the 5 Hai group Soil SEM indicates all values. When ρ < 0 · 05, 2 full accountability can be obtained. Using a single factor AN0VA, followed by appropriate after-effects such as the Dukascopy test to perform the value of each treatment group Statistical comparison. 99159.doc 200538154 Results: When the components are provided in combination, the blood pressure can be reduced to a similar degree using fewer component doses than when the individual single treatment is administered. In addition, it was unexpectedly found that the combination was administered. High doses of individual compounds of formula (I) or their pharmaceutically acceptable salts can significantly reduce blood pressure. For example, such beneficial effects can be obtained by, for example, G. Jeremic et al., J. Cardiovasc. Pharmacol. 27: 347-354 , The test model disclosed in 1996 was confirmed. For example, using the following test model, the combination of the present invention can be found to prevent and treat myocardial infarction (including delayed myocardial infarction after expansion into congestive heart failure) In the study to be performed, permanent coronary artery occlusion (CAO) in rats (normal Sprague Dawley rats or Dahl salt-sensitive rats on a high-salt diet) was used as a separate study. Models of acute myocardial infarction in normotensive or hypertensive animals. These experiments were performed by 5 treatment groups with the following characteristics: I · Virtually operated animals; • CAO + vehicle; • CAO + Alice Gillen (al) Or its pharmaceutically acceptable salt; • CAO + amine gas σ than moon rice (ami); • CAO + hydrogen thiazine (HCTZ); • CAO + Alice Gillen or its pharmaceutically acceptable salt + amine Pyridoxine + hydrothiazide. The following variables were measured during the study: • infarct area; 99159.doc -11-200538154 • LV chamber volume; • density of interstitial and perivascular collagen in the remaining LV myocardium; Western blot method to measure COL-I and COL-III protein content in remaining LV myocardium; • Cross-sectional area and length of cardiomyocytes in LV myocardial sections; • Plasma concentrations of renin and aldosterone; • Sodium and potassium Urone • Blood pressure in conscious animals; • LV and carotid blood pressure in paralyzed animals Methodology: Infarct size · 6 μm thick lateral tissue sections of the left ventricle stained with Schottky tetrazolium blue and B / W XC -77CE CCD camera (Sony, Sony) to obtain images. The specially developed software (Porzio et al., 1995) was used to process the obtained images by the KS 300 image analysis system (Carl Zeiss Vision). A single operator who was blind to the therapeutic effect interactively defined the boundaries of the ventricular septum and semi-automatically identified the infarcted area on each slice as the unstained ventricular tissue area. The software automatically calculates a set of geometric parameters defined as the components of the ventricle section of the cavity, septum, infarct area, infarcted LV wall, and living LV wall (Porzio et al., 1995). Histology: After diastolic stagnation by intravenous injection of 0.5 M KC1, the heart was fixed in situ by retrograde perfusion with buffered 4% formaldehyde. After fixation, the free walls of the left ventricle (LV) and right ventricle were weighed independently; the longer diameter of the LV was measured with a caliper. LV tissue sections were stained with hematoxylin and eosin for qualitative testing and a semi-automated image analysis routine 99159.doc 12 200538154 was used to quantify the cross-sectional area of myocardial cells. The semi-automated image analysis example sequence (Masson et al., 1998) was used to assess interstitial collagen deposition in LV on Sirius red-stained sections. Collagen content in LV remaining myocardium: The LV tissue in the remaining myocardium was subjected to PAGE-SDS electrophoresis and electrolysis on a nitrocellulose membrane, thereby homogenizing it. The breach point was exposed to a primary antibody, meaning rabbit anti-rat collagen type I or type III antiserum (Chemicon). The identification of primary antibodies ranges from co-enzymatic acid filling enzymes (for collagen type I) or peroxidases (for collagen type III). Left ventricular chamber volume: The LV chamber volume is determined by the heart remaining in diastolic phase (KCL) and fixed in formalin at a hydrostatic pressure equivalent to the measured end-diastolic LV diastolic pressure. Insert a metric rod into the LV to measure the internal length of the LV. The lateral diameter of the LV cavity was measured in two 1-mm-thick lateral slices near the base and apex of the ventricle (Jeremic #mic, 1 996). The cavity volume is calculated from the integral equation of the transverse diameter and the internal length. Systemic and left ventricular hemodynamics: A microend pressure transducer (Millar SPC-320) connected to a recorder (Windograf, Gould Electronics) was inserted into the right carotid artery to record systolic and diastolic blood pressure. Move the pressure transducer forward to the LV to measure LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), the first derivative of LV pressure over time (+ dP / dt), and heart rate. Non-Invasive Blood Pressure · The systolic blood pressure and heart rate of conscious rats were measured by tail cuff manometry (Letica LE 5002). Urine electrolytes, hormones: Rats were individually placed in metabolic cages and 24-h urine was collected in 1 ml HC1 6 N. Measure water intake. In Bondelut C18 99159.doc -13- 200538154 Materials and Methods 20-24 week old male SHR purchased from RCC Ldt (Fullingsdorf, Switzerland) were stored in a temperature- and light-controlled room with feeding rats (Nafag 9331, Gossau, Switzerland) and free passage of tap water. The experiment was performed according to the NIH guidelines and approved by the Canton Veter inary office (Bew 161, Kantonales Veterinaramt, Liestal, Switzerland). All rats were treated with NO synthesis inhibitor L-NAME (Sigma Chemicals) in drinking water (50 mg / 1) for 12 weeks. The average daily dose of L-NAME calculated from the water consumed was 2.5 mg / kg / d (range 2.1-2.7). The rats were divided into 5 groups: group 1, control group (n = 40); group 2, aliskiren (al; n = 40); group 3, amine gas (ami; n = 30) ); Group 4, hydrochlorothiazide (HCTZ; n = 30); group 5, combination (al_ami-HCTZ) (n = 30). These drugs can be administered in the form of drinking fluids or mixed with food. The dose to be used was selected from the work of Sweet et al. (1987), which showed that the survival rate of rats with cured myocardial infarction was significantly increased. After treatment with the compound of formula (I) in the form of hemi-fumarate, the pressurization effect of 1 mg / kg Ang II obtained in normal blood pressure rats in the control group can be reduced (Gervais et al., 1999 ). Measure your weight weekly. The systolic blood pressure and heart rate were recorded by tail cuff plethysmography 3 and 2 weeks before the start of the study and 2 weeks after administration. One week before the start of treatment, the urine of rats placed in individual (metabolic) cages was collected for 24 hours, and the volume and protein, creatinine, sodium, and sodium were measured using standard laboratory methods at 4 and 12 weeks. Potassium. At the same time, blood samples were taken from the posterior orbital plexus (maximum 1 ml) for the determination of creatinine, Na +, and K +. Ten rats in each group were sacrificed at 4 weeks to collect kidneys and hearts for use at 99159.doc 15 200538154. Therefore, the present invention further relates to a method for preventing, delaying, and treating at least one disease or condition selected from the group consisting of: (a) blood pressure, congestive heart failure, percutaneous blood vessels Restenosis after angioplasty and restenosis after coronary artery bypass surgery; (b) Atherosclerosis, antitumor and syphilis syndrome "type diabetes, obesity, nephritis, low thyroid function τ, money infarction (Mi ) Post-survival, coronary heart disease, senile hypertension, familial lipid abnormal hypertension, increased collagen formation, fibrosis, and reconstruction after hypertension (the combination's anti-biotic effect) 'all of these diseases Or conditions are related or unrelated to hypertension; ⑷endothelial dysfunction related or unrelated to hypertension; ⑷hyperlipidemia, hyperlipoproteinemia and hypercholesterolemia; (e) glaucoma; (f) independent contraction Stage hypertension (ISH); (g) diabetic retinopathy; and (h) peripheral vascular disease; comprising administering a combination therapeutically effective dose of a combination of each of the following to a warm-blooded animal in need thereof Including humans) .. ⑴-type renin inhibitor or a pharmaceutically acceptable salt thereof containing at least one of the following: chloramine or amine benzene bite or pharmaceutically acceptable salt thereof ; And ㈣ other diuretics (such as HCTZ) or a pharmaceutically acceptable salt thereof. 99159.doc -18 · 200538154 In addition, the present invention relates to the use of a combination comprising: (0 renin inhibitor or a pharmaceutically acceptable salt thereof; and (i) amine chloride tolidine or amine phenylhydrazone Pyridine or a pharmaceutically acceptable salt thereof, and (iii) other diuretics (such as HCTZ) or a pharmaceutically acceptable salt thereof; which are used for the manufacture of at least one selected from the group consisting of prevention, delay expansion or treatment; Diseases or conditions of the following groups: ⑷ hypertension, congestive heart failure, restenosis after percutaneous transluminal angioplasty and restenosis after coronary artery bypass surgery; (b) atherosclerosis, Anti-insulin and syndrome, type 2 diabetes, obesity, nephritis, heart, myocardial infarction, survival after coronary heart disease, elderly hypertension, familial lipid abnormal hypertension, increased collagen formation, fibrosis and Reconstruction after hypertension (the antiproliferative effect of the combination), all of these diseases or conditions are related or unrelated to hypertension; (C) Endothelial dysfunction related or unrelated to hypertension, which includes the administration of the medicine of the present invention Compounds; (d) hyperlipidemia, hyperlipoproteinemia, and hypercholesterolemia; (e) glaucoma; ⑴ independent systolic hypertension (ISH); (g) diabetic retinopathy; and (h) Peripheral vascular disease. The present invention further relates to a pharmaceutical composition for preventing, delaying, and treating a disease or condition selected from the group consisting of: (a) hypertension, congestive heart failure, percutaneous cavity Restenosis after angioplasty and restenosis after coronary artery bypass surgery; 99159.doc -19- 200538154 力 " Power: atherosclerosis, insulin resistance and x syndrome, type 2 diabetes, obesity, thyroid function Hypoxia, survival after myocardial infarction (MI), coronary: arterial heart disease, senile hypertension, familial lipid abnormal hypertension, increased formation of neutropenin, fibrosis, and reconstruction of hypertensive blood vessels (the combination of ) All diseases or conditions such as $ HAI are related or not related to high blood dust

内皮 Endothelial dysfunction associated with or unrelated to hypertension, which comprises administering the pharmaceutical composition of the present invention; () is known to be hypoxemia, lipoproteinemia, and hypercholesterolemia; (e) glaucoma; (f) Independent systolic hypertension (ISH); (g) diabetic retinopathy; and (h) peripheral vascular disease; the composition comprises: (1) a renin inhibitor or a pharmaceutically acceptable salt thereof; and ⑻ Amine gas or phenanthrene bite or a pharmaceutically acceptable salt thereof; and (iii) other diuretics (such as HCTZ) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. Another benefit of administering the composition of the present invention is that the dosage can be reduced by using smaller doses of the individual drugs to be combined according to the present invention, for example,%. These dosages are not only always smaller, but also do not need to be frequently or Can be used to reduce the occurrence of side effects. This is based on the needs and requirements of the patient to be treated. A preferred ' combinationally effective dose of the active agent of the combination according to the invention can be administered at the same time or in any order continuously or independently in the form of a fixed combination 99159.doc -20-200538154. As described above and below, the pharmaceutical composition according to the present invention can be used for simultaneous use or continuous use in any order, for independent use or in a fixed combination. ° Another complaint by Ben Maoming is a set for preventing, delaying expansion, treating a disease or condition according to the present invention, comprising: U)-some Alice Gillen in a first unit dosage form or a pharmaceutically acceptable Accepted salts; ㈨ some therapeutic agents in second (and other) unit dosage forms ⑴) and ㈣ or their pharmaceutically acceptable salts as appropriate in each case; and (C) containing the first, the second (Etc.) Containers for unit dosage forms. "The present invention also relates to a" component set "in a variant. For example, in this sense, the β-Aiwait combination component can be administered independently or by using a specific amount group Different doses are given at the same time, which means that they are given at the same time or at different points in time. For example, the components of the M 邛 kit can then be dosed at the same time or Γ, that is, at different points in time. Dosing and talking to this component:: 饤. ": At the same or different time intervals. Preferably, the mouth / specific time interval is selected so that the combination of these imp # ° and the combined use has a greater effect on the disease or condition being treated than using only these groups. The effect obtained by any one of these is even more so. The present invention is further related to packaged, independent or continuous use = a combination according to the present invention and a commercial package for the same purpose. These medicinal preparations are related to those which contain common active compounds or medical active ingredients for medical use, including intestines (such as oral) and rectal or 99159.doc 200538154 times, Start with, for example, the dose of Alice Gillen. For example, the mouth, "take the appropriate dose in the morning, noon or evening. It is preferably administered twice a day. The hydrochlorothiazide will be supplied in a suitable unit dosage form, such as in the form of a capsule, and the dosage form contains a therapeutic agent that can be applied to a patient's agent θ sigma effective agent ΐ, for example, about 5 mg to about 50 mg. The preferred dosage per unit dosage form is 6 a mg, 12.5 mg or 25 mg. The doses of the active ingredient that can be used up to two times per day are the same doses that are usually used for monotherapy, and the lower limit is the most preferred. The active ingredient can be applied up to three times a day. Particularly preferred is a low-dose combination. 99159.doc 23-

Claims (1)

200538154 10. Scope of patent application: 丨 .-Species: Combined, such as combination preparation or pharmaceutical composition, which contains: (Octoline inhibitor or its pharmaceutically acceptable salt; and (: diurea amine chloride) ° amiloride or terene or a pharmaceutically acceptable salt thereof; and (π〇 other diuretics or a pharmaceutically acceptable salt thereof. 2) If the combination of claim 1, It includes: (iskiren) or a pharmaceutically acceptable salt thereof; and (11) Amlodipine or a pharmaceutically acceptable salt thereof; and (II) Hydrochlorothiazide or a pharmaceutically acceptable salt thereof 3. The combination as claimed in claim 1, comprising: G) 乂 risitine hemi-tetrabufonate; and (11) amitriprolidine hydrochloride; and (iii) hydrochlorothiazide. T -A substance, which includes a combination of any one of the elements of the claim, 5.-a pharmaceutical composition, which is capable of preventing, delaying expansion, treating at least one disease or disorder selected from the group consisting of: a) Hypertension, congestive heart failure, restenosis after percutaneous transluminal angioplasty, and coronary arteries Restenosis after surgery, (b) Survival after atherosclerosis, insulin resistance and recombination syndrome, type 2 diabetes, obesity, nephritis, hypogonadism, myocardial infarction, coronary heart disease, Hypertension in the elderly, familial lipid abnormality hypertension, increased collagen formation, fibrosis, and reconstruction after hypertension (the combination's anti-biotic effect), all these diseases or these conditions are associated with high blood dust 99159.doc 200538154 related or unrelated; ⑷f hyperemia related or irrelevant endothelial dysfunction; (d) hyperlipidemia, ancient daggers, lunioproteinemia and hypercholesterolemia (e) glaucoma; Bloodemia, (0 independent systolic hypertension (ISH); (g) diabetic retinopathy; and (h) peripheral vascular disease; the composition comprises: a renin inhibitor or a pharmaceutically acceptable Salts; & ⑼ diuretics amine clopyridine or amine phenyl pyridine or pharmaceutically acceptable salts thereof; and (111) other diuretics or pharmaceutically acceptable salts thereof; and (iv) adjuvants. 6. A combination of Pathways: (i) a renin inhibitor or a pharmaceutically acceptable salt thereof, and (11) a diuretic amine gas η ratio or amine phenylpyridine or a pharmaceutically acceptable salt thereof; and (m) Other diuretics or their pharmaceutically acceptable salts, which are used in the manufacture of a medicament for the prevention, delay of expansion, treatment of at least one disease or disorder selected from the group consisting of: (a) blood pressure, congestive Heart failure, restenosis after percutaneous transluminal angioplasty, and restenosis after transarticular bypass surgery; (b) Atherosclerosis, insulin resistance and multiple syndromes, type 2 diabetes, obesity, nephritis, thyroid Hypofunction, survival after myocardial infarction (MI), crown 99159.doc 200538154 Heart disease of the arteries, + Zhugu, «« Old blood return day, increase in familial lipid = :: :), fibrosis and high blood-' Related or unrelated diseases: Endothelial dysfunction that is related to or unrelated to hypertensive disease and hypertensive disease; W yueyue bayonetemia, hyperlipoproteinemia, and hypercholesterolemia (e) Glaucoma; ⑴ independent systolic hypertension (ISH), · (g) diabetes Retinopathy; and (h) peripheral vascular disease. 7. A method for preventing, delaying the expansion and treating a disease or condition of at least one group of diseases ... a kind selected from the following facial pressure, congestive heart failure, restenosis after percutaneous transluminal angioplasty And restenosis after coronary artery bypass surgery, iliac artery atherosclerosis [anti-insulin and X syndrome, type 2 diabetes, obesity, nephritis, hypothyroidism, survival after myocardial infarction (MI), coronary, arterial heart disease , Old hyperemia, familial dyslipidemia, high blood dust, increased collagen formation, fibrosis and reconstruction after hypertension (the combination's antiproliferative effect) 'All these diseases or these conditions are related to hypertension Relevant or unrelated; (C) Endothelial dysfunction related or unrelated to blood pressure; (d) Hyperlipidemia, hyperlipoproteinemia, and hypercholesterolemia; (0 glaucoma; ⑺ independent systolic hypertension (iSH ); 99159.doc 200538154 (g) diabetic retinopathy, and (h) I distal vascular disease; the method includes administering the following items to the effective amount / Dish blood animals, including human ... renin inhibitors or pharmaceutically acceptable salts thereof; and (:). Diuretics amine clopipine or amphetamine or pharmaceutically acceptable JHL · 'Salt (111) Other diuretics (such as HCTZ) or its pharmaceutically acceptable 99159.doc 200538154 VII. Designated representative map · (1) The designated representative map in this case is: (none) (II) The representative map Brief description of the component symbols: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: (none) 99159.doc