CN1446084A - Treatment of insulin resistance syndrome - Google Patents

Treatment of insulin resistance syndrome Download PDF

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Publication number
CN1446084A
CN1446084A CN01814039A CN01814039A CN1446084A CN 1446084 A CN1446084 A CN 1446084A CN 01814039 A CN01814039 A CN 01814039A CN 01814039 A CN01814039 A CN 01814039A CN 1446084 A CN1446084 A CN 1446084A
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ethyl
dihydro
pyrazolo
pyrimidin
ones
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D·A·弗里伯格
E·M·吉布斯
N·P·考比克
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SmithKline Beecham Ltd
Pfizer Ltd
Pfizer Inc
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SmithKline Beecham Ltd
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Priority claimed from GB0030649A external-priority patent/GB0030649D0/en
Priority claimed from GB0106468A external-priority patent/GB0106468D0/en
Priority claimed from GB0106465A external-priority patent/GB0106465D0/en
Priority claimed from GB0117134A external-priority patent/GB0117134D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of CN1446084A publication Critical patent/CN1446084A/en
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Abstract

Use of a selective cGMP PDE5 inhibitor or a pharmaceutical composition thereof in the preparation of a medicament for the curative, palliative or prophylactic treatment of the insulin resistance syndrome wherein the insulin resistance syndrome means the concomitant existence in a subject of two or more of: dyslipidemia; hypertension; type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes; hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal obesity wherein said use can occur alone or in combination with other agents to treat the insulin resistance syndrome or individual aspects of the insulin resistance syndrome.

Description

The treatment of insulin resistance syndrome
The present invention relates to the purposes of selectivity cGMP PDE5 inhibitor, specifically the present invention relates to be used for the treatment of the selectivity cGMP PDE5 inhibitor compound such as the chemical compound former times De Nafei (sildenafil) of insulin resistance syndrome.
The insulin resistance syndrome meaning of this paper definition is to follow to have two or more following symptoms in the patient: dyslipidemia, hypertension, type ii diabetes or glucose tolerance reduce (IGT) or type ii diabetes family history, hyperuricemia and/or gout, procoagulant state, atherosclerosis, trunk obesity.The type ii diabetes family history meaning of this paper definition is its close relative, and promptly compatriot, father and mother or grand parents suffer from type ii diabetes.At the center of insulin resistance syndrome, the common feature of organizing resistance of insulin action also is referred to as " syndrome X " and " metabolic syndrome " in biomedical document.This damaging biological effect to insulin can either can obtain proof in the blood vessel induction at insulin again in the metabolism induction of insulin.Although there is the monogenic syndrome of insulin resistance (IR), identified that wherein one determines that gene is the reason (for example short evil spirit's looks syndrome) of insulin resistance, rare relatively.The IRS of opposite more common existence is relevant with obesity (particularly abdominal part) and to present be polygenic.
Early stage adaptation response to insulin resistance in suffering from many individualities of insulin resistance syndrome is to produce the compensatory hyperinsulinemia.As the patient with insulin resistance syndrome gradually during glucagon, their proofs have variation in various degree aspect clinical parameter, comprise blood pressure and/or serum glucose and/or cholesterol and/or triglyceride and/or uric acid and/or promote the level increase of the factor of solidifying.In case these clinical parameters change enough greatly, the patient with IRS may differently present the clinical symptoms or the diagnosis of easy identification.These symptoms comprise:
1. hypertension (hypertension);
2. glucose tolerance reduces (IGT) or type ii diabetes (DM);
3. hyperlipemia or dyslipidemia, particularly (but being not limited to) HTC;
4. hyperuricemia or gout;
5. Hypercoagulability (be defined as unusual, the trend that forms grumeleuse increases, particularly in the blood vessel);
6. atherosclerosis.
These clinical symptoms are confirmed as the risk factor of cardiovascular (coronary artery and cerebrovascular) disease.
Because the multiformity of the common peril factor relevant with this syndrome, and may be many be subjected to individualities that insulin resistance syndrome influences because they may not present external symptom and do not have the medical history of coronary heart disease and undiscovered, therefore be difficult to estimate the universality of insulin resistance syndrome in general crowd.Yet can suppose that the patient crowd who presents the danger of insulin resistance syndrome at least comprises obese individuals, special (abdominal part) obesity.Because obesity is the extremely common problem in the industrialization world and is attended by above-mentioned clinical symptoms that the universality of IRS is very high probably.This potential patient group of single consideration forms the potential very big crowd who presents the danger of insulin resistance syndrome complication.For example in the U.S., there was age of 23% suffer from hypertension in 1994 at the population between 20-74 year, per 100,000 philtrums have 5 people's death (1997).Estimate at 154,392 in the whole world in 2000,000 diabetics.Wherein, 15,000,000 people is in the U.S., and 934,000 in Britain.Two kinds of sexes are suffered from ischemic heart desease and were estimated it is 51,948 in 1998 in WHO zone, and 000 people is dead 7,375,000, account for total death toll 13.7% and in dead score, arrange the highest.That suffers from diabetes in two kinds of sexes in the WHO zone estimated it is 11,668 in 1998,000.Therefore the needs that exist very big effective and safe oral medication insulin resistance syndrome and prevention insulin resistance syndrome and clinical effectiveness thereof to occur.
The resistance of insulin action also can be observed the biological effect of the induced minimizing of blood vessel of insulin by endothelium.That is, insulin to small part impels blood vessel lax by The Effect of Nitric Oxide.The nitric oxide that produces in endothelium stimulates then in the blood vessel and to produce cGMP and to make their lax or expansions.Blood vessel this opened and made more blood flow, works as vitals, and this was a particular importance when for example heart needed more blood flows.Confirmed to reduce from the nitric oxide (NO) that the endothelium of suffering from insulin resistance discharges.The release of nitric oxide production this minimizing is not only because insulin, and owing to other important vessel diastole agent such as acetylcholine.This so-called " endothelial dysfunction " belongs to the risk factor of the cardiovascular disease that is caused by insulin resistance syndrome.Think that the blood vessel function of insulin regulates metabolic effect owing to insulin, particularly, but not necessarily be limited to glucose metabolism.
Except nitric oxide production blood vessel function, NO also has direct influence to the glucose absorption of skeletal muscle.That is, the treatment of NO-donor substance (Nitroprusside) or cGMP analog external treatment make glucose absorption increase (by the transportation of GLUT4 glucose transport device).This vasodilation dependent/non-dependent path description is at the Diabetes of G.J.Etgen, D.A.Fryburg and E.M.Gibbs, 46, 1997 pp.1915-1919 add this paper with its content by reference.This paper proposes in a word, and nitric oxide and cGMP have the gentle blood vessel function of direct tissue water of influence, mediation or imitation insulin action.
The further influence of the damaging NO release of endothelium comprises: vascular smooth muscle cell (VSMC) growth, propagation and mobile increasing, and it may be the committed step that causes the blood vessel scleratheroma speckle formation of apoplexy; Platelet aggregation and degree of adhesion increase (these also are that cGMP orders about to hematoblastic influence); Lipid peroxidation and to comprising that adhesion molecule (ICAM) and E-in the vascular cell adhesion molecule (VCAM-1), born of the same parents select the increase of influence of the inhibition of proteic cell adhesion molecule expression.Damaging endothelial NO discharges activity influence inflammatory cytokine such as the activity of tumor necrosis factor-alpha and the generation of mononuclear cell chemokine of also passing through the reduction of transcriptional activation agent nuclear factor k B.
Example is to belong to the treatment of the factor of IRS (for example fat) or the treatment of IRS itself, for example with troglitazone or auspicious pearl woods (Rezulin), improves many these clinical symptoms.For example, only induce that the diet of weight saving or rem will bring high blood pressure down, blood glucose and triglyceride.The medicament that design improves insulin sensitivity also can advantageously change blood pressure, lipid and blood glucose.
This paper proposes, successful diagnosis and with selectivity PDE5 inhibitor, particularly former times De Nafei treatment has the insulin resistance syndrome patient of (as defined above), can obtain the clinical relevant improvement of blood pressure and/or blood glucose and/or lipid and/or uric acid and/or clot-promoting factor.This treatment can take place separately or take place with other therapeutic combination of improving IRS.The improvement of these clinical symptoms should reduce cardiovascular disease and these individual disorderly other complication (include, but are not limited to diabetic neuropathy, nephropathy and the retinopathy) danger that takes place of a part among these patients.
The present invention relates to research to the Drug therapy of individuality with insulin resistance syndrome defined above.
Although insulin resistance syndrome has many demonstrations, an important Mechanical Fundamentals of this symptom is the blood vessel of insulin and the resistance of metabolic effect.It will also be appreciated that the basic pathology in insulin resistance syndrome medium vessels resistance is to reduce by the NO amount that endotheliocyte response insulin produces.In this insulin path of insulin resistance individuality, may there be the damaging signal (from phosphatidyl-inositol 3-kinase, P13K, path) of insulin to glucose absorption, it may cause invalid GLUT-4 transportation mechanism.Although do not wish to be bound by any particular theory, path and cGMP-NO mechanism path that this paper proposes GLUT-4 transportation mechanism interlink somehow.
With regard to the insulin signaling path of glucose absorption (through GLUT-4 transportation mechanism) best movable, preferably has the NO-cGMP path of a normal activity.
This paper also proposes, and uses cGMP specific PDE 5 inhibitor that the cGMP signal is enlarged in having the patient of insulin resistance syndrome, will help making insulin glucose absorption signal optimization and improve insulin action in critical tissue.By making tissue more responsive to insulin, the improvement that this paper also proposes the clinical parameter of IRS thus will make and include, but are not limited to following improvement:
1. glycemic control: in suffering from the patient that diabetes or glucose tolerance reduce (IGT), this paper supposes that the improvement of insulin resistance should make plasma glucose concentration reduce (perhaps fasting or at oral glucose tolerance test or after the meal).In relevant mode, regulate as pathophysiology by the patient, or during fasting state or at edible glucose or after the meal, may exist serum insulin concentration to improve.These improvement of glycemic control if the patient has type ii diabetes, in long-term glycemic control for example will confirm, but be not limited to, and improve on the mensuration of HbA1 c (glycosylated hemoglobin) or fructosamine; And/or
2. blood pressure: this paper supposes that the improvement of insulin resistance also can obtain the improvement of systolic pressure and diastolic pressure; And/or
3. lipid: this paper supposes that the improvement of insulin resistance also can obtain serum lipid, includes, but not limited to the improvement of serum cholesterol and triglyceride; And/or
4. uric acid: this paper supposes that the improvement of insulin resistance also can obtain the improvement of serum uric acid; And/or
5. coagulation factors: this paper supposes that the improvement of insulin resistance also will make the factor of coagulant blood state deteriorating towards normal recovery.
These of insulin resistance improve the component that (sensitivity of improvement) may be attended by or may not be attended by the improvement of compensatory hyperinsulinemia and therefore improve insulin resistance syndrome.
CGMP PDE5 inhibitor prevention phosphodiesterase 5 enzymes are converted into the influence that therefore non-activity GMP increases the accumulated amount of cGMP with cGMP.CGMP gathers vasodilation, metabolism and the anti-arteries and veins gruel type that activates that will enlarge obtainable nitric oxide and insulin to be influenced.This paper supposes that this expansion effect (blood plasma cGMP's) will alleviate the side effect that is caused by IRS and improve one or more related symptoms.
Former times De Nafei (Viagra ) be a kind of cyclic guanosine monophosphate ester (cGMP) specific phosphodiesterase enzyme 5 types (PDE5) for the main PDE5 isozyme in the human body cavernous body of penis Orally active, effectively and selective depressant.Therefore, shown that former times De Nafei can treat male erectile dysfunction effectively.This paper proposes by suppressing the conversion pathway of cGMP to GMP, selectivity cGMP PDE5 inhibitor and specifically former times De Nafei increase derive from the intracellular concentration of the nitric oxide (NO) of cGMP.This vasodilation, metabolism and the anti--actuating arteries and veins gruel type that will enlarge obtainable nitric oxide and insulin of gathering influences.
Therefore according to a first aspect of the invention, a kind of method for the treatment of insulin resistance syndrome is provided, comprise: with selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition treatment patient of effective dose, wherein the insulin resistance syndrome meaning is to follow the following symptom that has two or more in the patient: dyslipidemia, hypertension, type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to the individuality with IRS, one or more symptoms that this method can cause the IRS of this paper definition have the benefit influence.So basis on the other hand, and the present invention provides a kind of treatment type ii diabetes or glucose tolerance to reduce (IGT) in addition; Or the method for dyslipidemia or hyperuricemia and/or gout or coagulant blood state, comprise with cGMP PDE5 inhibitor or its Pharmaceutical composition of effective dose and treat this patient.According to another aspect, the present invention also provide a kind of in the patient of other risk factor that does not cause because of IRS treatment type ii diabetes or glucose tolerance reduce the method for (IGT), comprise that selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor that this paper with effective dose defines later or medicinal acceptable salt or its Pharmaceutical composition treat this patient.According to another aspect, the present invention also provides a kind of prevention patient to reduce the method that (IGT) is developed to type ii diabetes from glucose tolerance, comprises that PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor that the selectivity this paper with effective dose defines later or medicinal acceptable salt or its Pharmaceutical composition treat the patient of this treatment of needs.
According to second aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise with cGMP PDE5 inhibitor or its Pharmaceutical composition of effective dose and treat this patient that wherein the insulin resistance syndrome meaning is to follow to have three kinds or multiple following symptom: dyslipidemia in the patient; Hypertension; Type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to the third aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise with cGMP PDE5 inhibitor or its Pharmaceutical composition of effective dose and treat this patient that wherein the insulin resistance syndrome meaning is to follow to have four kinds or multiple following symptom: dyslipidemia in the patient; Hypertension; Type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to fourth aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise with cGMP PDE5 inhibitor or its Pharmaceutical composition of effective dose and treat this patient that wherein the insulin resistance syndrome meaning is to follow to have five kinds or multiple following symptom: dyslipidemia in the patient; Hypertension; Type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to the 5th aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise with cGMP PDE5 inhibitor or its Pharmaceutical composition of effective dose and treat this patient that wherein the insulin resistance syndrome meaning is to follow to have: dyslipidemia in the patient; Hypertension; Type ii diabetes or glucose tolerance reduce (IGT); With the trunk obesity.
According to the 6th aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise with the cGMP PDE5 inhibitor of effective dose or the treatment of its Pharmaceutical composition have type ii diabetes, glucose tolerance reduces (IGT) or bran is urinated at least a patient in disease family history and the following symptom: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to a seventh aspect of the invention, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise that having type ii diabetes, glucose tolerance with the cGMP PDE5 inhibitor of effective dose or the treatment of its Pharmaceutical composition reduces (GT) or bran and urinate in disease family history and the following symptom at least two kinds patient: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to eight aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise that having type ii diabetes, glucose tolerance with the cGMP PDE5 inhibitor of effective dose or the treatment of its Pharmaceutical composition reduces (IGT) or bran and urinate in disease family history and the following symptom at least three kinds patient: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to the 9th aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise that having type ii diabetes, glucose tolerance with the cGMP PDE5 inhibitor of effective dose or the treatment of its Pharmaceutical composition reduces (IRS) or bran and urinate in disease family history and the following symptom at least three kinds patient: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to the tenth aspect, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise that having type ii diabetes, glucose tolerance with the cGMP PDE5 inhibitor of effective dose or the treatment of its Pharmaceutical composition reduces (IGT) or bran and urinate in disease family history and the following symptom at least four kinds patient: dyslipidemia; Hypertension; Hyperuricemia; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According to the tenth on the one hand, the invention provides a kind of method for the treatment of insulin resistance syndrome, comprise with the cGMP PDE5 inhibitor of effective dose or the treatment of its Pharmaceutical composition have type ii diabetes, glucose tolerance reduces (IGT) or bran is urinated at least a patient in disease family history and the following symptom: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
According on the other hand, the present invention also provides a kind of and has been accredited as the method with the danger that reduces the cardiovascular disease generation among the patient that insulin resistance syndrome danger takes place, wherein said method comprises with the cGMP PDE5 inhibitor of effective dose or its Pharmaceutical composition treats this patient, wherein has the patient that insulin resistance syndrome danger takes place to be defined as and has individuality at least a in the following symptom: dyslipidemia; Hypertension; Type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity and next analyze to find to have at least two kinds of described symptoms.
According to another aspect, the invention provides a kind of method of in polygenes insulin resistance individuality, treating the previously defined insulin resistance syndrome of this paper, comprise with cGMP PDE5 inhibitor or its Pharmaceutical composition of effective dose and treat this individuality.
The suitable PDE5i that is used for Pharmaceutical composition of the present invention is the cGMPPDE5i that this paper defines later.Preferred especially effectively and optionally cGMP PDE5i is used for this paper.
Being used for suitable cGMP PDE5 inhibitor of the present invention comprises:
Disclosed pyrazolo among the EP-A-0463756 [4,3-d] pyrimidin-7-ones class; Disclosed pyrazolo among the EP-A-0526004 [4,3-d] pyrimidin-7-ones class; Disclosed pyrazolo in the International Patent Application WO 93/06104 [4,3-d] pyrimidin-7-ones class; Disclosed isomerism pyrazolo [3,4-d] pyrimidin-4-one class in the disclosed International Patent Application WO 93/07149; Disclosed quinazoline-4-one class in the disclosed International Patent Application WO 93/12095; Disclosed pyrido in the disclosed International Patent Application WO 94/05661 [3,2-d] pyrimidin-4-one class; Disclosed purine-6-one class in the disclosed International Patent Application WO 94/00453; Disclosed pyrazolo in the disclosed International Patent Application WO 98/49166 [4,3-d] pyrimidin-7-ones class; Disclosed pyrazolo in the disclosed International Patent Application WO 99/54333 [4,3-d] pyrimidin-7-ones class; Disclosed pyrazolo among the EP-A-0995751 [4,3-d] pyrimidin-4-one class; Disclosed pyrazolo in the disclosed International Patent Application WO 00/24745 [4,3-d] pyrimidin-7-ones class; Disclosed pyrazolo among the EP-A-0995750 [4,3-d] pyrimidin-4-one class; Disclosed chemical compound in the disclosed International Patent Application WO 95/19978; Disclosed chemical compound in disclosed chemical compound and the disclosed International Patent Application WO 93/07124 in the disclosed International Patent Application WO 99/24433.
Disclosed pyrazolo in the disclosed International Patent Application WO 01/27112 [4,3-d] pyrimidin-7-ones class; Disclosed pyrazolo in the disclosed International Patent Application WO 01/27113 [4,3-d] pyrimidin-7-ones class; Disclosed chemical compound among disclosed chemical compound and the EP-A-1092719 among the EP-A-1092718.
Being used for preferred selectivity V-type phosphodiesterase inhibitor of the present invention comprises:
5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (former times De Nafei), also be referred to as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfonyl]-4-methyl piperazine (referring to EP-A-0463756);
5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to EP-A-0526004);
3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO98/49166);
3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO99/54333);
(+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also be referred to as 3-ethyl-5-{5-[4-ethyl piperazidine-1-base sulfonyl]-2-([(1R)-and 2-methoxyl group-1-Methylethyl] the oxygen base) pyridin-3-yl }-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO99/54333);
5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also be referred to as 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-4-ethyl piperazidine (referring to WO 01/27113, embodiment 8);
5-[2-isobutoxy-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113, embodiment 15);
5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113,
Embodiment 66);
5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO01/27112, embodiment 124);
5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO01/27112, embodiment 132);
And medicinal acceptable salt, polymorph and solvate.
Therefore according to a preferred aspect; the invention provides the selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors or its Pharmaceutical composition is used for the treatment of in preparation; alleviate or the prophylactic treatment mammal in the purposes of medicine of insulin resistance syndrome; wherein said selectivity cGMPPDE5 inhibitor is selected from: former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones and 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-guanamine-yl)-4-ethoxyl phenenyl also] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt; solvate; prodrug or polymorph.
More particularly; the invention provides the method that a kind of treatment has the patient of insulin resistance syndrome; comprise with the following selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors of being selected from of effective dose and treat this patient: former times De Nafei; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
The present invention also provides selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor; especially former times De Nafei, 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-1-(2-methoxy ethyl)-1; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones is used for the purposes of the compositions of production for treating or prevention insulin resistance syndrome.
According on the other hand, the present invention also provides former times De Nafei or its medicinal acceptable salt or Pharmaceutical composition to be used for the treatment of to have type ii diabetes, glucose tolerance reduces (IGT) or has bran and urinates in disease family history and the following symptom at least a: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or the purposes of the insulin resistance syndrome among the patient of trunk obesity.
According to another aspect, the present invention also provides former times De Nafei or its medicinal acceptable salt or Pharmaceutical composition to be used for the treatment of to have type ii diabetes, glucose tolerance reduces (IGT) or have bran urinates in disease family history and the following symptom one or more: dyslipidemia; Hypertension; Or the purposes of the insulin resistance syndrome among the patient of trunk obesity.
According to another aspect, the present invention also provides former times De Nafei or its medicinal acceptable salt or Pharmaceutical composition to be used for the treatment of to have type ii diabetes or glucose tolerance to reduce (IGT) or have the purposes that bran is urinated the insulin resistance syndrome among the patient of disease family history and dyslipidemia and hypertension and trunk obesity.
The medicinal acceptable salt of preferred former times De Nafei used herein is former times De Nafei citrate and former times De Nafei mesylate.
The cGMP PDE5 inhibitor of this paper definition; especially effectively and selectivity cGMP PDE5 inhibitor; former times De Nafei, 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2 most preferably; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-1-(2-methoxy ethyl)-1; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones can be used for the compositions of production for treating or prevention endothelial dysfunction in addition.
Other V-type PDE inhibitor that is applicable to this paper purposes comprises:
(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine [2 ', 1 ': 6,1] pyrido [3 also, 4-b] indole-1,4-diketone (IC-351), embodiment 78 and 95 chemical compound in the promptly disclosed International Application No. WO 95/19978, and the chemical compound of embodiment 1,3,7 and 8;
2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (vardenafil), also be referred to as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-guanamine-yl)-4-ethoxyl phenenyl also] sulfonyl]-the 4-ethyl piperazidine, the embodiment 20,19,337 of promptly disclosed International Application No. WO 99/24433 and 336 chemical compound; With
The chemical compound of the embodiment 11 of disclosed International Application No. WO 93/07124 (EISAI); With
Rotella D P, J.Med.Chem., 2000,43,1257 chemical compound 3 and 14.
The cGMP PDE5 inhibitor of other type that is used in combination with the present invention comprises: 4-bromo-5-(pyridylmethyl amino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H) 2H-Pyridazin-3-one; 1-[4-[(1,3-benzo dioxo-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidines-carboxylic acid a, sodium salt; (+)-cis-5,6a, 7,9,9,9a-six hydrogen-2-[4-(trifluoromethyl)-phenyl methyl-5-methyl-ring penta-4,5] imidazo [2,1-b] purine-4 (3H) ketone; The prazocillin; Cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro ring penta [4,5]-imidazo [2,1-b] purine-4-ketone; 3-acetyl group-1-(2-benzyl chloride base)-2-propyl indole-6-carboxylate; 3-acetyl group-1-(2-benzyl chloride base)-2-propyl indole-6-carboxylate; 4-bromo-5-(3-pyridylmethyl amino)-6-(3-(4-chlorphenyl) propoxyl group)-3-(2H) 2H-Pyridazin-3-one; 1-methyl-5 (5-morpholine acetyl group-2-positive propoxy phenyl)-3-n-pro-pyl-1, and 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones; 1-[4-[(1,3-benzo dioxo-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidine carboxylic acid a, sodium salt; No. 4516, Pharmaprojects (Glaxo Wellcome); No. 5051, Pharmaprojects (Bayer); No. 5064 (Kyowa Hakko of Pharmaprojects; Referring to WO 96/26940); No. 5069, Pharmaprojects (Schering Plough); GF-196960 (GlaxoWellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 and 38-9456 (Bayer) and Sch-51866.
It should be understood that the content of top disclosed patent application, particularly the general formula of the therapeutical active compound of claims wherein and illustration chemical compound are added herein by reference by reference in full.
The adaptability of any specific cGMP PDE5 inhibitor can use literature method by estimating its effectiveness and selectivity, then estimates its toxicity, absorbability, metabolism, pharmacokinetics etc. according to the medicinal time of standard and easily determines.
Preferred these cGMP PDE5 inhibitor have the IC of the anti-PDE5 enzyme that is lower than 100 nMs (preferably being lower than 50 nMs) 50
According on the other hand; the invention provides selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor or its Pharmaceutical composition is used for the treatment of in preparation; alleviate or the prophylactic treatment mammal in the purposes of medicine of type ii diabetes or IGT; wherein said selectivity cGMP PDE5 inhibitor is selected from: former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones and 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-guanamine-yl)-4-ethoxyl phenenyl also] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt; solvate; prodrug or polymorph.
More particularly; the invention provides a kind of treatment and have type ii diabetes; the patient's of IGT or IR method; comprise with the following selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor for treating patient of being selected from of effective dose: former times De Nafei; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
According on the other hand; the present invention also provides selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor; especially former times De Nafei, 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-1-(2-methoxy ethyl)-1; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones is used for the purposes of the compositions of production for treating or prevention type ii diabetes, IGT or IR.
According on the other hand, the present invention also provides former times De Nafei or its medicinal acceptable salt or its Pharmaceutical composition to be used for the treatment of the purposes of type ii diabetes, IGT or IR.
The IC of cGMP PDE5 inhibitor 50Value can use the PDE5 in the test method part of this paper back to measure to determine.
The cGMP PDE5 inhibitor that is preferred for Pharmaceutical composition of the present invention has selectivity to the PDE5 enzyme.Preferred they to big by 100 to PDE3 of the selectivity ratios of PDE5, more preferably big 300.More preferably this PDE5 has the selectivity than PDE3 and PDE4 big 100, more preferably big 300.
Those skilled in the art can easily determine selectivity ratios.The IC of PDE3 and PDE4 enzyme 50Value can be used definite literature method to learn and measure, referring to S A Ballard etc., and Journal of Urology, 1998, the 159 volumes, 2164-2171 page or leaf and describe in detail as this paper back.
According on the other hand, the invention provides the purposes of described according to any aspect of this paper front or this paper back, as to be applicable to oral administration medicinal drug, described medicine comprises IC 50PDE5 inhibitor less than 100 nMs and selectivity ratios PDE3 big 100.Wherein said oral use is used for the treatment of insulin resistance syndrome; or type ii diabetes or IGT or IR; of the present invention any aspect according to this paper detailed earlier herein; described PDE5 inhibitor is PyrazolopyrimidinonecGMP preferably; more preferably former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones and 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole also [5; 1-f]-guanamine-yl)-the 4-ethoxyl phenenyl] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt; solvate; prodrug or polymorph; and former times De Nafei especially; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-1-(2-methoxy ethyl)-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones, and former times De Nafei particularly.
Wherein said oral administration PDE5 inhibitor is used for the treatment of insulin resistance; Type ii diabetes; Glucose tolerance reduces (IGT); Dyslipidemia; Hyperuricemia and/or gout; Or coagulant blood state; and described PDE5 inhibitor is a PyrazolopyrimidinonecGMP; be more preferably former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones and 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole also [5; 1-f]-guanamine-yl)-the 4-ethoxyl phenenyl] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt; solvate; prodrug or polymorph; especially former times De Nafei; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-1-(2-methoxy ethyl)-1; 6-dihydro-7H-pyrazolo [4; 3-pyrimidin-7-ones, particularly former times De Nafei.
Propose previously as this paper, in having the patient of insulin resistance syndrome, use cGMP specific PDE 5 inhibitor to enlarge the cGMP signal and will help to make insulin glucose absorption signal optimization and improve the effect of insulin in critical tissue.By making tissue more responsive to insulin, this paper has also proposed to make the clinical parameter of IRS to improve thus.Therefore, according on the other hand, the present invention also provides a kind of method of improving insulin action (treatment insulin resistance), wherein said method comprises that treatment has the patient of insulin resistance syndrome, and it is that selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor (this paper detailed earlier herein) treatment with effective dose has the patient of insulin resistance.
Therefore the present invention also provides a kind of method for the treatment of insulin resistance; comprise the patient who has insulin resistance with the following selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor for treating of being selected from of effective dose: former times De Nafei; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
According to the individuality with IRS, one or more symptoms that any method of this paper detailed earlier herein can cause the IRS by this paper definition have beneficial effect.So basis on the other hand, and the present invention also provides a kind of treatment type ii diabetes or glucose tolerance to reduce (IGT); Or the method for dyslipidemia or hyperuricemia or coagulant blood state, wherein said method comprises that selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor (as this paper detailed earlier herein) treatment with effective dose has the method for the insulin resistance of hiding.
Therefore the present invention also provides a kind of treatment type ii diabetes or glucose tolerance to reduce (IGT); Or dyslipidemia; or hyperuricemia; or the method for coagulant blood state; comprise with the following selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor for treating patient of being selected from of effective dose: former times De Nafei; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
The medicinal acceptable salt that contains the selectivity cGMP PDE5 inhibitor compound disclosed herein that is used for the treatment of insulin resistance syndrome of basic nuclear core according to the present invention for example is with mineral acid example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid and phosphoric acid, use carboxylic acid, perhaps the non-toxic acid addition salts that forms with the organic sulfonic acid class.Example comprises its HCl, HBr, HI, sulfate or disulfate, nitrate, phosphate or hydrophosphate, acetate, benzoate, succinate, saccharate (saccarate), Rhizoma Corydalis carboxylate, maleate, lactate, citrate, tartrate, gluconate, camsilate (camsylate), mesylate, esilate, benzene sulfonate, tosilate and pamoate.Be used for selectivity cGMP PDE5 inhibitor compound of the present invention and also can provide medicinal acceptable slaine, particularly non-toxic alkali and alkali salt with alkali.Example comprises sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salt.Evaluation Berge to suitable pharmaceutical salts Deng, J.Pharm, Sci., 66, 1-19,1977.
The cGMP PDE5i chemical compound, its medicinal acceptable salt and the medicinal acceptable solvent thing that are applicable to any aspect of the present invention disclosed herein can be individually dosed, but in human therapy usually with according to the suitable pharmaceutical excipient of required administration path and the medicinal choice of practice of standard, the mixture administration of diluent or carrier.
For example, be applicable to cGMP PDE5i compound or its salt of the present invention or solvate can following form per os, cheek or sublingual administration: tablet, capsule (comprising soft capsule), multiparticulates, gel, thin film, ovulum, elixir, solution or suspension, can contain flavoring agent or coloring agent, be used at once-, postpone-, improve-, continue-, dual-, control-release or the delivery applications of pulsing.These chemical compounds also can be through the form of quick dispersion or rapid-dissolve dosage form or high energy dispersions or as the coated granule administration.Suitable pharmaceutical formulation can be as being required to be coating or coating form not.
This solid pharmaceutical composition, for example tablet can contain excipient such as microcrystalline Cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine and starch (preferred corn, Rhizoma Solani tuber osi or tapioca), disintegrating agent such as Explotab, cross-linked carboxymethyl cellulose sodium and some composition silicate and particle binders such as polyvinylpyrrolidone, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and arabic gum.Can contain lubricant such as magnesium stearate, stearic acid, glycerol behenic acid ester and Pulvis Talci in addition.
The solid composite of similar type also can be used as the filler in gelatine capsule or the HPMC capsule.The preferred excipient of this respect comprises lactose, starch, cellulose, lactose or high molecular weight polyethylene glycol.With regard to aqueous suspensions and/or elixir, these cGMP PDE5i chemical compounds can with various sweeting agents or flavoring agent, coloring agent or dyestuff, with emulsifying agent and/or suspending agent and with diluent such as water, ethanol, propylene glycol and glycerol and combined hybrid thereof.
Improve to discharge and on equipment body and/or in being included in those of the pulsation release dosage form can contain that excipient describes in detail as release dosage form at once those and other excipient, coating of playing the effect of rate of release improver.The rate of release improver comprises, but never be limited to hydroxypropyl emthylcellulose, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyoxyethylene, xanthan gum, carbomer, ammonio methacrylate copolymer, castor oil hydrogenated, Brazil wax, paraffin, cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phathalate, methacrylic acid copolymer and composition thereof.Improve release and pulsation release dosage form and can contain a kind of or its combination in the rate of release improvement excipient.Rate of release improves excipient and can appear in the dosage form, promptly in the substrate, and/or on the dosage form, promptly on surface or coating.
Disperse or dissolve dosage particles (FDDF) fast and can contain following component: aspartame; acesulfame-K; citric acid; cross-linked carboxymethyl cellulose sodium; crospovidone; two anti-hematic acid (diascorbic acid); ethyl acrylate; ethyl cellulose; gelatin; hydroxypropyl emthylcellulose; magnesium stearate; mannitol; methyl methacrylate; the Herba Menthae flavoring agent; Polyethylene Glycol; fused silica; silicon dioxide; Explotab; stearyl Rhizoma Corydalis carboxylic acid sodium; Sorbitol; xylitol.This paper describes the used term of FDDF and disperses or dissolves the dissolubility that depends on used medicine, can prepare the fast-dispersing type when promptly medicine is insoluble, can prepare rapid-dissolve dosage form when medicine is solubility.
Be applicable to that cGMP PDE5i chemical compound of the present invention also can be without intestinal canal administration, for example in lung, in the intravenous, intra-arterial, intraperitoneal, sheath, in the ventricle, in the ureter, in the breastbone, intracranial, intramuscular or subcutaneous, perhaps they can pass through infusion or the administration of needleless technology.With regard to this parenterai administration, they preferably use with the form of aseptic aqueous solution, and this aqueous solution can contain other material, thereby for example enough salt or glucose ooze solution and blood etc.If necessary, this aqueous solution should be cushioned (preferably to pH be 3-9) aptly.By well known to a person skilled in the art that the standard pharmaceutical technology can be readily implemented in the suitable parenteral formulation of preparation under the aseptic condition.
With regard to regard to patient's per os and parenterai administration, the selectivity cGMP PDE5 inhibitor compound that the present invention disclosed herein uses any aspect or the dosage level of its salt or solvate be 5-500mg (with single dose or separate doses) normally.With regard to the treatment insulin resistance syndrome, this dosage can be through continuous (chronic) daily dose of single dose, separate day dosage, a plurality of daily dose, acute dose, specific period, and they can be more than 1-5 days or 5 days, for example up to 10 days or longer.The treatment of insulin resistance syndrome may be subjected to the influence of successive administration in addition, for example through the sustained release dosage form, wherein these continuous dosage form can the sky be that the basis continues administrations in many days, and perhaps wherein these successive doses can carry out through slow delivery formulations, and each administration is lasting more than 1 day.With regard to chronic sympton, can carry out through Consecutive Days dosage or through recurring rule administration control or extended release preparation etc.The reference of all these form of therapy can be used for others of the present invention as herein described equally, for example with regard to the treatment of type ii diabetes, IGT or insulin resistance.
Therefore, with regard to each administration one or two or a plurality of with regard to, for example be applicable to the tablet of cGMP PDE5i compound or its salt of the present invention or solvate or the reactive compound that capsule can contain 5mg-250mg, depend on the circumstances.In any case the doctor will determine the actual dose of any single patient of optimum, and it will be with the reactions change of age, body weight and particular patient.Top dosage is the average case of enumerating.Certainly, existence or high or low dosage range are individual cases preferably, and this situation also within the scope of the invention. The example tablet
Tablet typically can contain the 0.01mg-500mg that has an appointment and be used for selectivity cGMP PDE5 inhibitor compound of the present invention (or its salt) in general, and the tablet filling weight can be 50mg-1000mg simultaneously.The example preparation of describing is the 10mg tablet:
Preparation 1 Component %w/wFormer times De Nafei citrate 10.000* lactose 64.125 starch 21.375 cross-linked carboxymethyl cellulose sodium 3.000 magnesium stearate 1.500
* this amount is typically adjusted according to pharmaceutically active.
Preparation 2
Use following component to prepare tablet:
Amount (mg/ tablet)Former times gets those non-250 microcrystalline Cellulose, 400 fused silica, 10 stearic acid 5 and adds up to 665mg
The tablet that these components is mixed and suppressed each heavy 665mg of formation.
Preparation 3
Can be prepared as follows iv formulation: former times gets that non-100mg etc. and oozes normal saline 1,000ml
Be applicable to cGMP PDE5i chemical compound of the present invention also can through intranasal or by inhalation and send with the form of dry powder inhalation (inhalatio) easily or from pressurizing vessel, pump, spraying or nebulizer with suitable propellant, for example dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, alkane hydrofluoride are as 1,1,1, the 2-tetrafluoroethane (HFA 134A[trade mark] or 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227EA[trade mark]), carbon dioxide or other suitable gas aerosol spray are presented.When being pressurized aerosol,, a valve that discharges metering can determine this dosage unit by being provided.This pressurizing vessel, pump, spraying or nebulizer can contain the solution or the suspension of this reactive compound, and the mixture that for example uses ethanol and propellant can contain lubricant, for example sorbitan trioleate in addition as solvent.The capsule and the cartridge case (for example preparing with gelatin) that are used for inhaler or insufflator can contain The compounds of this invention and the powder binder that suits such as the mixture of powders of lactose or starch through preparation.
Aerosol or dry powder goods preferably discharge The compounds of this invention to the patient through preparation so that each dosing or " spray " contain 1-50mg.Aerocolloidal whole day dosage will be in the scope of 1-50mg, and it can the single dose administration, perhaps more through the whole day of being everlasting with the separate doses administration.
Be applicable to that cGMP PDE5i chemical compound of the present invention also can discharge by nebulizer through preparation.The preparation that is used for atomizer device for example can contain the following component as solubilizer, emulsifying agent or suspending agent: water, ethanol, glycerol, propylene glycol, low molecular poly class, sodium chloride, fluorocarbon, Polyethylene Glycol ethers, sorbitan trioleate, oleic acid.
Perhaps, be applicable to that cGMP PDE5i compound or its salt of the present invention or solvate can suppositorys or the form administration of pessulum, perhaps they can gel, the form of hydrogel, lotion, solution, unguentum, ointment or dusting applies partly.Be applicable to that cGMPPDE5i compound or its salt of the present invention or solvate also can for example use skin patch through skin or transdermal administration.They also can pass through lung or the administration of rectum path.
These chemical compounds also can be by eye path administration.With regard to ophthalmic applications, these chemical compounds can be mixed with etc. ooze, pH is through micronization suspension that adjust, Sterile Saline, perhaps preferably be mixed with wait ooze, pH is through solution that adjust, Sterile Saline, choose wantonly and mix with antiseptic such as zephiran chloride alkane.Perhaps they can be formulated in ointment such as the vaseline.
With regard to local coating is to the skin, be applicable to that cGMP PDE5i compound or its salt of the present invention or solvate can be mixed with the suitable ointment that contains this reactive compound, these chemical compounds suspend or are dissolved in and for example have in following one or more the mixture: mineral oil, liquid petrolatum, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene chemical compound, emulsifing wax and water.Perhaps, they can be mixed with suitable lotion or unguentum, for example suspend or are dissolved in and have in following one or more the mixture: mineral oil, sorbitan monostearate, Polyethylene Glycol, liquid paraffin, polysorbate 60, cetyl ester type waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Be applicable to that cGMP PDE5i chemical compound of the present invention also can mix use with cyclodextrin.Known cyclodextrin can form with drug molecule and comprise and do not comprise complex.The formation of drug-cyclodextrin complex can improve dissolubility, dissolution velocity, bioavailability and/or the stability of drug molecule.The drug-cyclodextrin complex is useful to most of dosage forms and route of administration.As with direct compound a kind of replacement form of medicine, cyclodextrin can be used as auxiliary additive, for example as carrier, diluent or solubilizer.The most frequently used α-, β-and gamma-cyclodextrin and suitable case description at WO-A-91/11172, WO-A-94/02518 and WO-A98/55148.
Usually, in the people, oral administration is a preferred path, is most convenient.When the receiver suffer from dysphagia or oral after under the drug absorption situation about descending, medicine can be through non-intestinal, Sublingual or cheek administration.
With regard to the veterinary uses, chemical compound or its acceptable salt for animals or its acceptable solvent thing for animals or prodrug, according to the acceptable goods administration of normal veterinary practice with the veterinary, and doctor for animals will determine the dosage and the path of the administration of optimum particular animals.
Therefore, the tablet or the capsule of selectivity cGMP PDE5 inhibitor compound for example used according to the invention or its salt or solvate can contain once, twice or the each reactive compound of 5mg-250mg aptly of multiple dosing.The doctor will determine the actual dose of optimum individual patient and will change with the reaction of age, body weight and particular patient in any case.Top dosage is giving an example of average case.Certainly, individual cases can be higher or be low is favourable, and these all within the scope of the invention.
All comprise healing, alleviate with prophylactic treatment and comprise acute treatment (taking as required) and chronic treatment (being long-continued treatment) with reference to the treatment that relates to should to understand this paper.
The present invention comprises in addition with the cGMP PDE5 inhibitor compound of this paper definition and the combined therapy insulin resistance syndrome of one or more following additional medical active agent:
1) one or more natural existence or synthetic prostaglandin or its ester.The prostaglandin that is applicable to this paper comprises following chemical compound: Alprostadil, prostaglandin E 1, prostaglandin E 0, 13,14-dihydro prostaglandin E 1, prostaglandin E 2, eprazinol, natural, synthetic and semisynthetic prostaglandin and derivant thereof, comprise the US 6,037 that WO-00033825 and/or on March 14th, 2000 authorize, those described in 346 (all adding this paper by reference), PGE 0, PGE 1, PGA 1, PGB 1, PGF 1α, 19-hydroxyl PGA 1, 19-hydroxyl-PGB 1, PGE 2, PGB 2, 19-hydroxyl-PGA 2, 19-hydroxyl-PGB 2, PGE 3α, U-32921E dinoprost, trometamol, dinoprostone, fat prostatitis element (lipoprost), gemeprost, meteneprost, Nalador, tiaprost and thymoxamine; And/or
2) one or more alpha-adrenergic aceptor antagonist chemical compounds, α-Zu Zhiji.The chemical compound that is applicable to this paper comprises: the alpha-adrenergic receptor blocker described in disclosed PCT application on June 14th, 1998 WO99/30697.The publication that will be referred to alpha-adrenergic receptor is added herein by reference and comprises selectivity α 1-adrenoceptor or α 2-adrenoceptor blocker and non-selective adrenoceptor blocker, suitable α 1-adrenoceptor blocker comprises: phentolamine, phentolamine mesylate, trazodone, aldehydase matter, indoramine, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaroxan, Yohimbine (α 2-blocker), rauwolfia alkaloids, Rui Kaoda are for (Recordati) 15/2739, SNAP 1069, SNAP 5089, RS17053, SL89.0591, doxazosin, terazosin, abanoquil and prazosin; Be disclosed in US6,037,346[2000 March 14] α 2-blocker, dibenamine, tolazoline, trimazosin and dibenamine; Alpha-adrenergic receptor described in the following United States Patent (USP): 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000, each adds this paper by reference with them; α 2-adrenoceptor blocker comprises: clonidine, papaverine, papaverine hydrochlorate, and optional have cardiac tonic such as pyrrole bright (pirxamine) to exist; And/or
3) one or more NO-donors (NO-agonist) chemical compound.The NO-compound donator that is applicable to this paper comprises organic nitrate, for example single-, two or three-nitrate or organic nitrates class, comprise glycerol trintrate (also being referred to as nitroglycerin), isosorbide 5-Mononitrate, Iso-bid, pentaerythritol tetranitrate, cardilate, sodium nitroprusside (SNP), 3-morpholine sydnonimine molsidomine, S-nitroso-group-N-acetyl group penicillamine (SNAP), S-nitroso-group-N-glutathione (SNO-GLU), N-hydroxyl-L-arginine, the amyl group nitrate, linsidomine, linsidomine hydrochlorate (SIN-1), S-nitroso-group-N-cysteine, two oleic acid diazene (NONOates), 1,5-pentane dinitrate, the L-arginine, Radix Ginseng, date fruit, molsidomine, Re-2047, nitrosylation maxisylyte derivant such as NMI-678-11 and NMI-937 described in disclosed PCT application WO 0012075; And/or
4) one or more potassium channel openerses or regulator.The suitable potassium channel opening agent/regulator that is used for this paper comprises nicorandil, cromakalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glibenclamide, 4-amino (amini) pyridine, BaCl 2And/or
5) one or more dopaminergic reagent, preferred apomorphine or selective d 2, D3 or D2/D3 agonist, for example pramipexole and ropinirole (as claimed among the WO-0023056), L-DOPA or carbidopa, PNU95666 (as claimed among the WO-0040226); And/or
6) one or more vasodilation.The vasodilation that is applicable to this paper comprises nimodipine, pinacidil, cyclandelate, isoxsuprine, chlorpromazine, haloperidol, Rec15/2739, trazodone, and/or
7) one or more coagulation dioxane A2 agonist; And/or
8) one or more peptides; Suitable peptide is described in the United States Patent (USP) 6 of authorizing on March 14th, 2000,037,346 and comprise acetergamine, brazergoline, bromerguride, cianergoline, delergotrile, disulergine, Cornocentin, gynergen, etisulergine, Lergotrile, lysergic acid diethylamine, mesulergine, Ergota metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride, terguride; And/or
9) one or more regulate the inhibitor of natriuretic factor, the particularly chemical compound of the effect of atrium natriuretic factor (also being referred to as atrium natruresis peptide), Type B and C type natriuretic factor such as neutral endopeptidase; And/or
10) one or more angiotensin receptor antagonists such as Losartan; And/or
11) substrate of one or more NO-synzyme, for example L-arginine; And/or
12) one or more calcium channel blockers such as amlodipine; And/or
13) antagonist of one or more endothelin receptors and inhibitor or endothelin converting enzyme; And/or
14) one or more cholesterol reducing agents such as inhibin (for example atorvastatin/Lipitor-trade mark) and fibrate; And/or
15) one or more antiplatelets and antithrombotic agent, for example tPA, uPA, warfarin, hirudin and other thrombin inhibitor, heparin, Thrombokinase activity factor inhibitor; And/or
16) the sensitive agent of one or more insulins such as auspicious pearl woods (Rezulin), Ah ten thousand ground (Avandia) or Acker holder (Actos) and hypoglycemia medicine for example but are not limited to glipizide (sulphanylureas), metformin, acarbose; And/or
17) one or more acetylcholinesteraseinhibitors inhibitors such as donezipil; And/or
18) one or more estrogenic agents and/or estrogen agonist and/or estrogen antagonist, preferred raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol and medicinal acceptable salt (following compd A) thereof, its preparation is specified in WO 96/21656.
23) one or more other PDE inhibitor, more preferably PDE 2,4,7 or 8 inhibitor, preferred PDE2 inhibitor, described inhibitor preferably have the IC of enzyme relatively separately that is lower than 100nM 50: and/or
24) one or more NPY (neuropeptide tyrosine) inhibitor, more particularly NPY1 or NPY5 inhibitor, preferred NPY1 inhibitor, preferred described NPY inhibitor (comprising NPYY1 and NPY Y5) has the IC that is lower than 100nM 50, more preferably less than 50nM, suitable NPY, especially the NPY1 inhibitor compound is described in EP-A-1097718; And/or
25) one or more vasoactive intestinal peptide (VIP), VIP analogies, more particularly by one or more VIP receptor subtype VPAC1, the VPAC or (pituitary gland thuja acid cyclase activating peptide), one or more VIP receptor stimulating agents or the VIP analog (for example Ro-125-1553) or the VIP fragment of PACAP mediation, one or more alpha-2-adrenoceptor antagonists and VIP combination (for example Invicorp, Aviptadil); And/or
26) one or more melanocortin (melanocortin) receptor stimulating agent or regulator or melanocortin intensifier; claimed chemical compound among melanotan 11, PT-14, PT-141 or WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, the WO-09954358 for example, and/or
27) one or more serotonin receptor agonist, antagonist or regulator, especially the agonist of 5HT1A, antagonist or regulator (comprising VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptor comprise described in WO09902159, WO-00002550 and/or the WO-00028993 those; And/or
28) one or more testosterone substituting agent ((inc) dehydrogenation androstanedione of fusion), testosterone (Tostrelle), dihydrotestosterone or testosterone implant; And/or
29) one or more estrogen, estrogen and medroxyprogesterone or Medroxyprogesterone Acetate (MPA) (promptly as a combination) or estrogen and methyltestosterone hormone replacement therapy agent (for example HRT, particularly Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, tibolone); And/or
30) regulator of the transport protein of one or more epinephrine, dopamine and/or serotonin, for example amfebutamone, GW-320659
31) one or more purinergic receptor agonists and/or regulator; And/or
32) one or more neurokinin (NK) receptor antagonist comprises described in the WO-09964008 those; And/or
33) one or more opioid receptor stimulating agent, antagonist or regulator, the agonist of preferred ORL-1 receptor and/or;
34) agonist or the regulator of one or more oxytocin/vassopressin receptor, preferred selectivity oxytocin agonists or regulator; And/or
35) regulator of one or more Cannabined receptor.
36) one or more CNS activating agent; And/or
37) composite restrainer such as the omapatrilat of the chemical compound of one or more inhibition angiotensin converting enzyme such as enalapril (enapril) and one or more angiotensin converting enzyme and neutral endopeptidase; And/or
38) L-DOPA or carbidopa; And/or
39) one or more steroid or non-steroidal anti-inflammatory agent; And/or
40) one or more Protein kinase C-beta inhibitor such as LY333531; And/or
41) activator of one or more AMP-activated protein kinase such as 5-amino-4-imidazoles carbamyl ribonucleotide; And/or
42) insulin; And/or
43) lose weight agent such as sibutramine or orlistat; And/or
44) one or more inhibitors of dipeptidyl IV such as NVP DPP728 or P32/98; And/or
45) one or more glucagon antagonist such as NNC25-2504
46) reagent such as the PTP112 of one or more inhibition PTP1B; And/or
47) one or more use antisense technology reduces the medicament of PTP1B level; And/or
48) one or more glycogen synthase kinase-3 inhibitor such as Chir98014; And/or
49) one or more GLP-1 agonist such as GLP1, NN-2211 or exendin4; And/or
50) one or more PPAR-gamma agonist such as auspicious pearl woods, Ah ten thousand ground, Acker holder or CS011; And/or
51) one or more PPAR-alfa agonists such as fenofibrate; And/or
52) one or more dual PPAR-α/PPAR-gamma agonist such as Fa Gelietazha (farglitazar), Luo Sigelietasong (rosiglitasone), pioglitazone, GW1929, DRF2725, AZ242 or KRP297; And/or
53) one or more SODH inhibitor such as CP-470711; And/or
54) one or more aldose reductase inhibitor such as zopolrestat, zenarestat or fidarestat.
55) one or more growth hormone goods or growth hormone succagoga; And/or
56) one or more nep inhibitor, preferred wherein said NEP is EC3.4.24.11, more preferably wherein said nep inhibitor is the selective depressant of a kind of EC 3.4.24.11, more preferably selective N EP inhibitor is the selective depressant of a kind of EC 3.4.24.11, and it has the IC that is lower than 100nM 50(for example ompatrilat, sampatrilat), suitable nep inhibitor chemical compound be described in EP-A-1097719 and/or;
According on the other hand; the present invention includes with cGMP PDE5 inhibitor compound and one or more other medical active agent treatment type ii diabetes or IGT or IR; wherein said other reagent comprises the medicament among one or more this paper (1) defined above-(56); described cGMP PDE5 inhibitor compound is a PyrazolopyrimidinonecGMP; more preferably former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole also [5; 1-f]-guanamine-yl)-the 4-ethoxyl phenenyl] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt; solvate; prodrug or polymorph; and former times De Nafei particularly; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-1-(2-methoxy ethyl)-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones, particularly former times De Nafei.
Preferred compositions according to the use of any aspect of the present invention as herein described comprises cGMPPDE5i, particularly the combination of other medicament that is selected from (16), (40) that this paper describes in detail above, (41), (42), (43), (50), (51), (52), (53) or (54) of former times De Nafei and one or more. Pharmacokinetics Bioavailability
Preferably, be used for PDE5 inhibitor compound of the present invention (and compositions) but the oral administration biological utilisation.Oral bioavailability is meant the peroral administration ratio that arrives systemic circulation.The factor of the oral bioavailability of decision medicine is dissolubility, membrane permeability and metabolic stability.Typically, use at first external, the per os bioavailability is decided in the screening level translocation of technology in vivo then.
Dissolution, medicine can be in predictions in the extracorporeal dissolution-ability test under the suitable pH of imitation GIT by the solubilization of the moisture inclusions of gastrointestinal tract (GIT).The PDE5 inhibitor compound that preferred the present invention uses has the minimal solubility of 50mcg/ml.Dissolubility can be measured by standard step known in the art, as Adv.Drug Deliv.Rev.23, and 3-25, described in 1997.
Membrane permeability is meant that chemical compound passes through the ability of the cell of GIT.Lipophile is to evaluate this key performance and with an organic solvent pass through external Log D with buffer agent 7.4Measure definition.Preferred chemical compound of the present invention has-2 to+4, more preferably-1 to+3 Log D 7.4This log D can be by standard step known in the art such as J.Pharm.Pharmacol.1990, the mensuration described in the 42:144.
Basically add cell monolayer test as Caco-2 and evaluate useful membrane permeability under the situation that backflow transport protein such as p-glycoprotein are arranged, so-called Caco-2 flux.The chemical compound that preferred the present invention uses has greater than 2 * 10 -6Cms -1, more preferably greater than 5 * 10 -6Cms -1The Caco-2 flux.This Caco-2 amount of flux can be by standard step known in the art such as J.Pharm.Sci, and 1990,79, measuring described in the 595-600.
Metabolic stability has been represented the ability of in absorption process GIT or hepatic metabolism chemical compound: first pass effect.Test system such as microsome, hepatocyte etc. have determined the metabolism tendency.Compound exhibits metabolic stability in this mensuration system in preferred these enforcements is lower than 0.5, and this is consistent with the liver extraction.The example of mensuration system and date processing are described in Curr.Opin.Drug Disc.Devel., and 201,4,36-44, Drug Met.Disp., 2000,28, among the 1518-1523.
Because the interaction of top method, so medicine can be by animal in the biological available further support of human body per os In the bodyTest obtains.In these researchs by oral independent or with the absolute bioavailability of this compound determination of mixture administration.With regard to absolute determination (% absorbs), also use the intravenous path.The example of the evaluation of per os bioavailability can be at Drug Met.Disp., 2001,29,82-87 in animal; J.Med Chem, 1997,40,827-829, Drug Met.Disp., 1999,27,221-226. and J.Pharm.Sci79,7, described in the p595-600 (1990) and Pharm.Res.vol 14, no.6 finds in (1997). PDE5 inhibitor-test method It is active that phosphodiesterase (PDE) suppresses
Be applicable to that preferred PDE chemical compound of the present invention is effective and selectivity cGMP PDE5 inhibitor.The external PDE of anti-cyclic guanosine 3 ', 5 '-Monophosphate (cGMP) and ring gland glycosides 3 ', 5 '-Monophosphate (cAMP) phosphodiesterase suppresses activity can be by measuring its IC 50Value is determined (enzymatic activity suppresses 50% required compound concentrations).
Required PDE enzyme can comprise in people's cavernous body of penis, people and rabbit platelet, people's ventricle, people's skeletal muscle and the bovine retina and separating from each provenance, mainly by W.J.Thompson and M.M.Appleman (Biochem., 1971, 10, 311) method.Specifically, cGMP-specific PDE (PDE5) and cGMP-inhibition cAMP PDE (PDE3) can obtain from people's corpus cavernosum tissue, human blood platelets or rabbit platelet; CGMP-zest PDE (PDE2) can obtain from people's cavernous body of penis; Calcium/calmodulin, CaM (Ca/CAM)-dependency PDE (PDE1) can obtain from people's ventricle; CAMP-specific PDE (PDE4) can obtain from people's skeletal muscle; And light receptor PDE (PDE6) can obtain from bovine retina.Phosphodiesterase 7-11 can become total length people's recombinant clone of SF9 cell to produce by transfection.
Perhaps can use W.J.Thompson etc. (Biochem., 1979, 18, 5228) improved " criticizing " method or the flicker approximate test that can use Amersham plc directly to measure AMP/GMP with the improvement of the described scheme of production code member TRKQ7090/7100 measure.Generally speaking, by under the situation that different inhibitor concentration and low substrate are arranged (at the about 1/3K of concentration mFollowing cGMP or cAMP with 3: 1 unmarked with [ 3H]-ratio of labelling) so that IC 50≈ K i, the enzyme of measuring fixed amount is investigated the effect of PDE inhibitor.With measuring buffer [20mM Tris-HCI pH7.4,5mM MgCl 2, the 1mg/ml bovine serum albumin] will finally measure volume and be supplemented to 100 μ l.Reaction causes with enzyme, cultivates down in 30 ℃ to obtain in 30-60 minute＜30% substrate conversion and stopping with 50 μ l yttrium silicate SPA pearls (the unlabelled separately cyclic nucleotide that PDE9 and 11 is contained 3mM).Plate was sealed once more and shakes 20 minutes, in the dark make these pearl precipitations 30 minutes afterwards, (Packard, Meriden CT) go up counting at TopCount plate count device then.Acitivity unit is converted into the % activity that does not suppress contrast (100%), and inhibitor concentration is drawn and is used " Fit Curve " Microsoft Excel extension to obtain inhibitor IC relatively 50Value. The function activity
This can induce lax ability to measure by measuring the sodium nitroprusside that chemical compound of the present invention strengthens preshrinking rabbit corpus cavernosum tissue bar external, as S.A.Ballard etc. (Brit.J.Pharmacol., 1996, 118(suppl.), abstract153P) described in. Activity in vivo
Use with Trigo-Rocha etc. (Neurourol. and Urodyn., 1994, 13, 71) and described method is the basis, chemical compound strengthens the ability that the inductive penis sponge internal pressure power of intracavitary administration sodium nitroprusside raises and comes SCREENED COMPOUND after anesthesia is determined at intravenous administration in the Canis familiaris L..
Specific selectivity PDE5 inhibitor is to the influence of the insulin resistance syndrome of animal-to the influence of plasma glucose in the ob/ob mice and S-TG level
Biological data
Testing program
Measure chemical compound:
Selectivity PDE5 inhibitor compound to be measured is dissolved in 10% DMSO/0.1% poly alcohol and uses Mus oral cavity feed pin (20gauge, Popper ﹠amp; Sons, Inc., New HydePark, NY) oral gavage metering.The volume of each metering administration 4ml/kg body weight.In the 1-50mg/kg dosage range, measure chemical compound.Perhaps, this mensuration selectivity PDE5 inhibitor compound administration and find plasma glucose and triglyceride reduces with the observed reduction when the administration of through port gavage of same compound similar in drinking water.
Experimental animal:
In these researchs, use (Bar Harbor, the male ob/ob mice in the 6-10 that ME) obtains age in week from Jackson Laboratories.Put 5 mices in each cage and make the free pickuping food of D11 mice (Purina, Brentwood, MO) and water.
Testing program
Before beginning one's study, make mice adapt to Pfizer animal 1 week of equipment.At the 1st day, obtain behind the eye socket blood sample and as mensuration plasma glucose as described in this paper back.Then mice is divided into 5 groups, so that the average blood plasma concentration of glucose of each group does not have difference.At the 1st day, give mice with carrier or selectivity PDE5 inhibitor only to be measured in the afternoon.Then, 2-4 days every days 2 times in the morning with give mice afternoon.At the 5th day, mice accept the morning dosage and after 3 hours blood-letting prepare blood plasma, be used for glucose as described below and triglyceride analysis.Perhaps, selectivity PDE5 inhibitor compound to be measured begins administration and continuously to the 5th day, then the mice blood-letting is prepared as follows the blood plasma of described glucose and triglyceride analysis usefulness in the 1st day the afternoon in drinking water.Collected final plasma sample at the 5th day according to eye socket posterior vein hole blood-letting as described below.In the 1st day and the 5th day mensuration body weight of research, and estimate this food consumption of 5 days.
Final blood-letting and tissue collecting:
Research last day morning the morning about 8 clockwise mices give subject composition or carrier.After the administration 3 hours, obtain 25 μ L blood and it is joined in the Denville science microtubule of 0.025% heparinized saline of 100 μ L through eye socket posterior vein hole.These pipes rotated 2 minutes with the highest being arranged among the Beckman Microfuge12.Collect blood plasma and be used to measure plasma glucose and triglyceride.By broken end these mices are put to death then and with Lithium acid heparin will about 1ml blood collecting in Becton-Dickinson Microtainer trade mark plasma collection pipe.These pipes are provided with rotation 5 minutes with maximum in Beckman Microfuge12.With plasma collection quick freezing in the 1.5ml Eppendorf pipe and in the liquid nitrogen.Plasma sample is preserved under-80 ℃ up to analysis.
Metabolite and hormone assay:
Use Alcyon clinical chemistry analyzer (Abbott laboratory, Abbott Park, IL) kit measurement plasma glucose and the triglyceride of supplying with Abbott.Use Amersham (Piscataway, Biotrak enzyme immunity test system measurement blood plasma cGMP NJ).By similar techniques can (Uppsala, MercodiaELISA insulin test kit Sweden) be estimated plasma insulin by ALPCO.All tests all are to carry out according to the guide that manufacturer provides.
Statistical analysis:
The t-check of passing through Student ' s is to comparing between Drug therapy and the suitable carrier.
Result's (summary):
Proved that according to the foregoing biological test method of this paper selectivity PDE5 inhibitor has reduced the plasma glucose of ob/ob mice generation and the level of S-TG.
The result
Table 1 has been described the variation of using the observed plasma glucose levels of selectivity PDE5 inhibitor compound in 5 day time.Selectivity PDE5 compd A: 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulphonyl
Base)-2-positive propoxy phenyl]-2-(pyridine-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-d] is phonetic
Pyridine-7-ketone selectivity PDE5 compd B: 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-first
Base-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo
[4,3-d] pyrimidin-7-ones
Table 1
The variation of plasma glucose concentration (mg/dl)
Carrier -9±22
PDE5?A-10mg/kg -115±34*
PDE5?A-50mg/kg -105±25*
PDE5?B-25mg/kg -97±32*
The data of table 1 are to represent with the standard error of meansigma methods ± meansigma methods.These numerals have been reacted the absolute reduction of plasma glucose levels.Indicate with * p＜0.05 with the significant difference of vehicle Control.
Table 2 has been described the variation with blood plasma cGMP and plasma triglyceride level in the ob/ob mice of selectivity PDE5 inhibitor compound A to be measured and B observation.
Table 2
Blood plasma cGMP level (mg/dl) Plasma triglyceride level (mg/dl)
Carrier ?9.8±0.5 ?178±16
?PDE5?A-10mg/kg ?48.3±19.0^ ?163±10
?PDE5?B-25mg/kg ?30.7±3.3** ?143±7^
Data in the table 2 are to represent with the standard error of meansigma methods ± meansigma methods.Indicate with ^p＜0.1, * p＜0.05, * * p＜0.01 with the significant difference of vehicle Control.
Table 3 has been described the reduction that gave the observed plasma glucose levels of mice selectivity PDE5 inhibitor compound in 5 day time with drinking water.
Selectivity PDE5 Compound C: former times De Nafei
Table 3
The variation of plasma glucose concentration (mg/dl)
Carrier 25±25
?PDE5?C-9mg/kg -27±34
?PDE5?C-22mg/kg -15±27
?PDE5?C-45mg/kg -36±22^
Data in the table 3 are to represent with the standard error of meansigma methods ± meansigma methods.Reducing in this table on the occasion of the reaction plasma glucose levels.Indicate with ^p＜0.1 with the significant difference of vehicle Control.
Table 4 has been described with drinking water and has been given triglyceride level in the ob/ob mice of mouse assay selectivity PDE5 inhibitor compound C treatment.
Table 4
Plasma triglyceride level (mg/dl)
Carrier ?204±13
?PDE5?C-9mg/kg ?163±14*
?PDE5?C-22mg/kg ?212±20
?PDE5?C-45mg/kg ?151±10**
Data in the table 4 are to represent with the standard error of meansigma methods ± meansigma methods.Indicate with * p＜0.05, * * p＜0.01 with the significant difference of vehicle Control.
In a word, these result of the test hint selectivity PDE5 inhibitory action in hyperglycemia, insulin resistance ob/ob mice have been improved the metabolizing parameters that causes because of IRS.
And these results hint with selectivity PDE5 inhibitor for treating plasma glucose concentration is reduced.As this paper detailed earlier herein, the reduction of plasma glucose concentration is consistent with the improvement of insulin resistance of clinical parameter that is IRS, and be described in further detail previously as this paper, these improvement will confirm for example improvement of HbA1 c in the patient who suffers from type ii diabetes.
These results have hinted that also the treatment with selectivity PDE5 inhibitor can make the serum lipids level improve.As this paper detailed earlier herein, the improving of serum lipids level (for example triglyceride level) is consistent with the improvement for the insulin resistance of the clinical parameter of IRS.This improvement will confirm for example improvement of dyslipidemia (high triglyceride blood) in the patient's (just as defined herein) who suffers from IRS.
These results in pancreas hyperglycemia, the insulin resistance ob/ob mice also hint and can or still less improve the metabolizing parameters that causes because of IRS in the time at 5 days with selectivity PDE5 inhibitor for treating continuously.
Clinical testing data 1
With in the clinical trials in 28 days of former times De Nafei, obtaining the S-TG level before ND's administration and when finishing.The dosage that comprises in this research is former times De Nafei or the placebo of 10mg, 25mg and 50gm, administration every day 1 time.These patients suffer from the insulin resistance syndrome of the previously defined risk factor definition of this paper.Thereby data are presented on and describe the evidence that the patient suffers from insulin resistance syndrome in following table 5 and 6.
Table 5 has been described the segmentation of IRS component among the patient who studies.
Coronary artery disease (CAD)/ischemic heart desease (IHD) is a kind of clinical effectiveness of suffering among the patient of insulin resistance syndrome.The existence of CAD/IHD has presented the existence of insulin resistance syndrome among the patient who is supported in the risk factor of only suffering from a kind of definition for this reason.
Table 5
The IRS component Placebo Former times De Nafei Add up to
Dyslipidemia (HTC) ????40 ????74 ????114
Fat (BMI＞26) ????26 ????47 ????73
Hypertension ????10 ????12 ????22
Coronary artery disease (h/o pharyngalgia, arrhythmia, MI, i.e. atherosclerosis) ????8 ????5 ????13
Hyperuricemia ????0 ????2 ????02
BMI-constitutional index table 6 has been described the summation of the quantity of IRS component in the patient organizes.
Table 6
1 component ????114 ?T
2 components ????80 ?73(T+O)；4(T+H)；3(T+I)
3 components ????24 ?6(T+O+I)；14(T+O+H)；2(T+I+H)；2(T+O+U)
4 components ????4 ?T+O+I+H
The triglyceride (dyslipidemia) that T=raises, O=obesity, H=hypertension, I=CAD/IHD, U=hyperuricemia
Below original date was presented on, it had confirmed to have reduced the S-TG level with former times De Nafei treatment.To 10,25 and 50mg former times De Nafei group observe S-TG level (in mg/dl) respectively and reduce by 100.3,67.3 and 23.9, and in placebo group, reduce 19.9mg/dl.Reduce approximately 40%, 31% and 12% above this with former times De Nafei treatment from baseline value (mg/dl) 255,213 and 191 respectively, and placebo is reduced by 10.7% from baseline 185mg/dl.
In former times significant difference on the statistics (p=0.0457) is compared in the reduction of observed S-TG in the De Nafei group with placebo.In HDL, also see trend (p=0.0539).In the ND with many IRS features, these variations are consistent with the improvement of insulin resistance syndrome.
And the ND of these results and many features consistent when the time with former times De Nafei treatment with IRS.So basis on the other hand, and the present invention also comprises with selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor (as mentioned above) treatment insulin resistance.
Clinical testing data 2
In outpatient, multicenter study to the adult patients of suffering from diabetes with citric acid former times De Nafei chronic treatment.The patient takes several different antidiabetic drugs (including, but not limited to metformin, insulin or sulfonylurea) always or only uses dietary therapy.Before treatment, measure glycosylated hemoglobin (HbA1C) when finishing with studying.Glycosylated hemoglobin (HbA1 c) be the means of identification of chronic glucose control.In this research, in suffering from the described patient of type ii diabetes, work as with citric acid former times De Nafei (Viagra TM) treatment the time observes glucose control and significantly improve.In whole patient's group, as one man observe these remarkable improvement, and how treat regardless of its background.
These results are with consistent with the improvement of IRS in former times De Nafei when treatment adult patients.And the glucose when with former times De Nafei treatment is controlled consistent among these results and the patient who suffers from type ii diabetes.Therefore the invention provides a kind of method for the treatment of type ii diabetes, comprise with selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor (previously defined as this paper), particularly former times De Nafei treatment needs the patient of this treatment.Particularly described treatment is undertaken by oral.
The result of clinical trial 2 supports the previously defined selectivity cGMP of this paper PDE5 inhibitor, and particularly former times De Nafei is used for the treatment of the purposes of IGT.
The improvement of IRS when these results and adult patients get the combined therapy of that not sum antidiabetic drug with former times in addition is consistent.Therefore the present invention comprises the combined therapy IRS of selectivity PDE5 inhibitor and antidiabetic drug in addition.Particularly described combined therapy is undertaken by oral.
According on the other hand, the invention provides a kind of treatment IRS that is applicable to, IR, type ii diabetes, glucose tolerance reduces (IGT), hyperuricemia and/or gout, dyslipidemia, the combined therapy of coagulant blood state or trunk obesity, wherein said combination comprises selectivity cGMPPDE5 inhibitor, preferred PyrazolopyrimidinonecGMP, previously defined other activating agent of former times De Nafei and this paper particularly, and preferred (16), (40), (41), (42), (50), (52), (53) and/or (54), more preferably one or more following symptoms: the weight saving agent, sulfonylurea, insulin, auspicious pearl woods, Ah ten thousand ground, the Acker holder, glipizide, metformin, acarbose, Luo Sigelitasong, pioglitazone, Fa Gelietazha, LY333531, CS011, the PPAR-alfa agonists, and/or CP-470711 combination.
According on the other hand, described combined therapy is that through port carries out and can is the form of test kit.
In a word, the improvement of the clinical parameter that all causes with IRS and because of IRS of the result of animal and human test is consistent.That is, the PDE5 inhibitor compound is supported in the improvement of the glucose of those of the improvement of the triglyceride in diabetes and the non-diabetic test and trouble diabetes, includes but not limited to the activity of former times De Nafei to IRS.

Claims (63)

  1. Selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition be used for the treatment of, alleviate in preparation or the medicine of prophylactic treatment insulin resistance syndrome in purposes, the wherein said insulin resistance syndrome meaning is to follow to have two or more following symptoms in the patient: dyslipidemia; Hypertension; Type ii diabetes, glucose tolerance reduce (IGT) or bran is urinated the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  2. 2. purposes as claimed in claim 1, wherein said patient suffers from type ii diabetes, glucose tolerance reduces (IGT) or bran is urinated disease family history and at least a or multiple following symptom: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  3. 3. purposes as claimed in claim 1, wherein said patient suffers from type ii diabetes, glucose tolerance and reduces (IGT) or bran and urinate disease family history and two or more following symptoms at least: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  4. 4. purposes as claimed in claim 1, wherein said patient suffers from type ii diabetes, glucose tolerance reduction or bran and urinates disease family history and at least three kinds or multiple following symptom: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  5. 5. purposes as claimed in claim 1, wherein said patient suffers from type ii diabetes, glucose tolerance reduction or bran and urinates disease family history and at least four kinds or multiple following symptom: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  6. 6. purposes as claimed in claim 1, wherein said patient suffers from type ii diabetes, glucose tolerance reduction or bran and urinates disease family history and at least five kinds or multiple following symptom: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  7. 7. purposes as claimed in claim 1, wherein said patient suffers from type ii diabetes or glucose tolerance reduction and dyslipidemia and hypertension and trunk obesity.
  8. 8. purposes as claimed in claim 1, wherein said patient suffers from three kinds or multiple following symptom: type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  9. 9. purposes as claimed in claim 1, wherein said patient suffers from four kinds or multiple following symptom: type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  10. 10. purposes as claimed in claim 1, wherein said patient suffers from five kinds or multiple following symptom: type ii diabetes, glucose tolerance reduce (IGT) or have bran urinates the disease family history; Dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  11. 11. purposes as claimed in claim 1, wherein said patient suffers from dyslipidemia, hypertension, type ii diabetes or glucose tolerance and reduces (IGT) and trunk obesity.
  12. 12. as claim 1-11 purposes arbitrarily, wherein said selectivity cGMP PDE5 inhibitor is selected from former times De Nafei, 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1, the 4-diketone; 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5; 1-f] [1; 2; 4] triazine-4-ketone and 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-guanamine-yl)-4-ethoxyl phenenyl also] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt, solvate, prodrug, polymorph or Pharmaceutical composition.
  13. 13. as claim 1-12 purposes arbitrarily; wherein said selectivity cGMP PDE5 inhibitor is selected from former times De Nafei, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones.
  14. 14. selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of in preparation, alleviate or the medicine of prophylactic treatment insulin resistance syndrome in purposes, the wherein said insulin resistance syndrome meaning is to follow to have dyslipidemia and hypertension and type ii diabetes or glucose tolerance reduction (IGT) in the patient, with the trunk obesity, and wherein said selectivity cGMP PDE5 inhibitor is former times De Nafei, 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1, the 4-diketone; 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5; 1-f] [1; 2; 4] triazine-4-ketone and 1-[[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-guanamine-yl)-4-ethoxyl phenenyl also] sulfonyl]-4-ethyl piperazidine or its medicinal acceptable salt, solvate, prodrug, polymorph or Pharmaceutical composition.
  15. 15. purposes as claim 14; wherein said selectivity cGMP PDE5 inhibitor is selected from former times De Nafei, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones.
  16. 16. as the purposes of claim 14, wherein said selectivity cGMP PDE5 inhibitor is former times De Nafei.
  17. 17. former times De Nafei or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the prophylactic treatment patient in purposes in the medicine of insulin resistance syndrome, described patient suffers from type ii diabetes, glucose tolerance reduces (IGT) or bran is urinated disease family history and at least a or multiple: dyslipidemia; Hypertension; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  18. 18. former times De Nafei or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the prophylactic treatment patient in the purposes of medicine of insulin resistance syndrome, described patient has: type ii diabetes, glucose tolerance reduce (IGT) or bran is urinated the disease family history; Dyslipidemia; Hypertension; With the trunk obesity.
  19. 19. former times De Nafei or its Pharmaceutical composition and described other agent combination are used for the treatment of, alleviate in preparation or the prophylactic treatment patient in the purposes of medicine of insulin resistance syndrome, described patient has: type ii diabetes, glucose tolerance reduce (IGT) or bran is urinated the disease family history; Dyslipidemia; Hypertension; With the trunk obesity.
  20. 20. a method for the treatment of insulin resistance syndrome in the mammal comprises the selectivity cGMP PDE5 inhibitor from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give.
  21. 21. method for the treatment of insulin resistance syndrome in the mammal, comprise the selectivity cGMP PDE5 inhibitor from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give, wherein said comprise every day dosage and wherein said dosage can be the form of single, a plurality of or separate doses.
  22. 22. a method for the treatment of insulin resistance syndrome in the mammal comprises the selectivity cGMP PDE5 inhibitor from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give.Wherein saidly comprise that administration every day continues 5 days or more days, and wherein said dosage can be the form of single, a plurality of or separate doses.
  23. 23. method for the treatment of insulin resistance syndrome in the mammal, comprise the selectivity cGMP PDE5 inhibitor from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give, wherein saidly comprised successive doses 5 days or more days, wherein said successive doses can single or multiple continuous release dosage forms.
  24. 24. a method for the treatment of insulin resistance syndrome in the mammal comprises to described mammal giving the selectivity cGMP PDE5 inhibitor of effective dose and mix one or more to be selected from other following component: one or more following symptoms: kinases inhibitor; And/or one or more activator or the activated protein kinase of AMP-; And/or one or more weight saving agent; And/or insulin; And/or one or more PPAR-gamma agonist; And/or one or more PPAR-alfa agonists; And/or one or more dual PPAR-α/PPAR-gamma agonist; One or more SODH inhibitor; One or more aldose reductase inhibitor; The sensitive agent of one or more insulin; One or more hypoglycemia agent.
  25. 25. selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the medicine of prophylactic treatment type ii diabetes in purposes.
  26. 26. purposes as claim 25; wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors is selected from former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
  27. 27. purposes as claim 26 or 27; wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor is selected from former times De Nafei, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones.
  28. 28. PyrazolopyrimidinonecGMP selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of in preparation; alleviate or the medicine of prophylactic treatment type ii diabetes in purposes; wherein said cGMP PDE5 inhibitor is selected from former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
  29. 29. as the purposes of claim 28, wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors is former times De Nafei.
  30. 30. former times De Nafei or its medicinal acceptable salt or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the medicine of prophylactic treatment type ii diabetes in purposes.
  31. 31. former times De Nafei or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the medicine of prophylactic treatment type ii diabetes in purposes.
  32. Be used for the treatment of, alleviate or the purposes of the medicine of prophylactic treatment type ii diabetes 32. former times De Nafei or its Pharmaceutical composition and described other agent combination are used for preparing.
  33. 33. a method for the treatment of type ii diabetes in the mammal comprises the former times De Nafei from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give.
  34. 34. method for the treatment of type ii diabetes in the mammal, comprise the former times De Nafei from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give, wherein said administration comprise every day dosage and wherein said dosage can be the form of single, a plurality of or separate doses.
  35. 35. method for the treatment of type ii diabetes in the mammal, comprise the former times De Nafei from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give, wherein said administration comprises that every day, dosage continued 5 days or more days, and wherein said every day, dosage can be the form of single, a plurality of or separate doses.
  36. 36. method for the treatment of type ii diabetes in the mammal, comprise to described mammal giving the former times De Nafei of effective dose or its medicinal acceptable salt, solvate or the wherein said administration of compositions comprise that successive doses continues 5 days or more days, wherein said successive doses can be the form of single, a plurality of or separate doses.
  37. 37. a method for the treatment of type ii diabetes in the mammal comprises to described mammal giving the former times De Nafei of effective dose and one or more are selected from the combination of other following component: one or more following symptoms: kinases inhibitor; And/or one or more activator or the activated protein kinase of AMP-; And/or one or more weight saving agent; And/or insulin; And/or one or more PPAR-gamma agonist; And/or one or more PPAR-alfa agonists; And/or one or more dual PPAR-α/PPAR-gamma agonist; One or more SODH inhibitor; One or more aldose reductase inhibitor; The sensitive agent of one or more insulin; One or more hypoglycemia agent.
  38. 38. selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment glucose tolerance reduction (IGT).
  39. 39. purposes as claim 38; wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors is selected from former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
  40. 40. purposes as claim 38 or 39; wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor is selected from former times De Nafei, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones.
  41. 41. PyrazolopyrimidinonecGMP selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of in preparation; alleviate or the prophylactic treatment glucose tolerance reduces the purposes of (IGT); wherein said cGMP PDE5 inhibitor is selected from former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
  42. 42. as the purposes of claim 41, wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors is former times De Nafei.
  43. 43. former times De Nafei or its medicinal acceptable salt or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of prophylactic treatment glucose tolerance reduction (IGT).
  44. 44. former times De Nafei or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment glucose tolerance reduction (IGT).
  45. 45. former times De Nafei or its Pharmaceutical composition and described other agent combination are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment glucose tolerance reduction (IGT).
  46. 46. a method for the treatment of glucose tolerance reduction (IGT) in the mammal comprises the former times De Nafei from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give.
  47. 47. a method for the treatment of glucose tolerance reduction (IGT) in the mammal comprises to described mammal giving the former times De Nafei of effective dose and one or more the combination that is selected from following other component: one or more following symptoms: kinases inhibitor; And/or one or more activator or the activated protein kinase of AMP-; And/or one or more weight saving agent; And/or insulin; And/or one or more PPAR-gamma agonist; And/or one or more PPAR-alfa agonists; And/or one or more dual PPAR-α/PPAR-gamma agonist; One or more SODH inhibitor; One or more aldose reductase inhibitor; The sensitive agent of one or more insulin; One or more hypoglycemia agent.
  48. 48. selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment insulin resistance (IR).
  49. 49. purposes as claim 48; wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors is selected from former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones, or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
  50. 50. purposes as claim 48 or 49; wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE5 inhibitor is selected from former times De Nafei, 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones or 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones.
  51. 51. PyrazolopyrimidinonecGMP selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of in preparation; alleviate or the purposes of the medicine of prophylactic treatment insulin resistance (IR); wherein said cGMP PDE5 inhibitor is selected from former times De Nafei; 5-(2-ethyoxyl-5-morpholine acetylphenyl)-1-ethyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(2-methoxy ethyl)-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or its medicinal acceptable salt; solvate; prodrug; polymorph or Pharmaceutical composition.
  52. 52. as the purposes of claim 51, wherein said selectivity PyrazolopyrimidinonecGMP cGMP PDE 5 inhibitors is former times De Nafei.
  53. 53. former times De Nafei or its medicinal acceptable salt or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment insulin resistance (IR).
  54. 54. former times De Nafei or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment insulin resistance (IR).
  55. 55. former times De Nafei or its Pharmaceutical composition and described other agent combination are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment insulin resistance (IR).
  56. 56. a method for the treatment of insulin resistance (IR) in the mammal comprises the former times De Nafei from effective dose to described mammal or its medicinal acceptable salt, solvate or the compositions that give.
  57. 57. the method for insulin resistance (IR) in the treatment mammal comprises to described mammal giving the former times De Nafei of effective dose and one or more are selected from the combination of other following component: one or more following symptoms: kinases inhibitor; And/or one or more activator or the activated protein kinase of AMP-; And/or one or more weight saving agent; And/or insulin; And/or one or more PPAR-gamma agonist; And/or one or more PPAR-alfa agonists; And/or one or more dual PPAR-α/PPAR-gamma agonist; One or more SODH inhibitor; One or more aldose reductase inhibitor; The sensitive agent of one or more insulin; One or more hypoglycemia agent.
  58. 58. a method for the treatment of insulin resistance syndrome in the mammal comprises to described mammal giving the selectivity cGMP PDE5 inhibitor of effective dose and one or more are selected from the combination of other following component: one or more following symptoms: kinases inhibitor; And/or one or more activator or the activated protein kinase of AMP-; And/or one or more weight saving agent; And/or insulin; And/or one or more PPAR-gamma agonist; And/or one or more PPAR-alfa agonists; And/or one or more dual PPAR-α/PPAR-gamma agonist; One or more SODH inhibitor; One or more aldose reductase inhibitor; The sensitive agent of one or more insulin; One or more hypoglycemia agent.
  59. 59. method for the treatment of insulin resistance syndrome in the mammal, comprise the selectivity cGMP PDE5 inhibitor that gives effective dose to described mammal, preferred PyrazolopyrimidinonecGMP, particularly former times De Nafei and one or more are selected from the combination of other following component: one or more following symptoms: weight saving agent, sulfonylurea, insulin, auspicious pearl woods, Ah ten thousand ground, the Acker holder, glipizide, metformin, acarbose, Luo Sigelitasong, pioglitazone, Fa Gelietazha, LY333531, CS011, the PPAR-alfa agonists, and/or CP-470711.
  60. 60. selectivity cGMP PDE5 inhibitor or its Pharmaceutical composition are used for the treatment of, alleviate in preparation or the purposes of the medicine of prophylactic treatment insulin resistance syndrome, the wherein said insulin resistance syndrome meaning is to follow to have two or more following symptoms in the polygenes patient: dyslipidemia; Hypertension; Type ii diabetes, glucose tolerance reduce (IGT) or bran is urinated the disease family history; Hyperuricemia and/or gout; Coagulant blood state; Atherosclerosis; Or trunk obesity.
  61. 61. one kind as claim 37,47 or 57 Therapeutic Method arbitrarily, wherein said method comprises that the mammal to this treatment of needs gives selectivity PyrazolopyrimidinonecGMP cGMP the PDE5 inhibitor, particularly former times De Nafei of effective dose and one or more are selected from the combination of other following component: one or more following symptoms: weight saving agent, sulfonylurea, insulin, auspicious pearl woods, Ah ten thousand ground, the Acker holder, glipizide, metformin, acarbose, Luo Sigelitasong, pioglitazone, Fa Gelietazha, LY333531, CS011, the PPAR-alfa agonists, and/or CP-470711.
  62. 62. as claim 1-32,38-45,48-55 or 60 purposes or as claim 33-37,46,47,56-59 or 61 arbitrary method arbitrarily, wherein said purposes or method are carried out through a mouthful administration.
  63. 63. as front claim purposes arbitrarily, wherein said cGMP PDE5 inhibitor has the anti-PDE5 IC that is lower than 100nM 50, and the selectivity ratios of the relative PDE3 of PDE5 is greater than 100.
CN01814039A 2000-08-11 2001-08-06 Treatment of insulin resistance syndrome Pending CN1446084A (en)

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US22492800P 2000-08-11 2000-08-11
US60/224,928 2000-08-11
GB0030649.8 2000-12-15
GB0030649A GB0030649D0 (en) 2000-12-15 2000-12-15 Treatment of the insulin resistance syndrome
US26608301P 2001-02-02 2001-02-02
US60/266,083 2001-02-02
GB0106468A GB0106468D0 (en) 2001-03-15 2001-03-15 Treatment of diabetes mellitus
GB0106468.2 2001-03-15
GB0106465A GB0106465D0 (en) 2001-03-15 2001-03-15 Treatment of the insulin resistance syndrome
GB0106465.8 2001-03-15
GB0117134A GB0117134D0 (en) 2001-07-13 2001-07-13 Treatment of the insulin resistance syndrome
GB0117134.7 2001-07-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108452311A (en) * 2012-11-13 2018-08-28 纽斯尔特科学公司 Composition for enhancing energetic supersession and method

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004527476A (en) * 2001-02-02 2004-09-09 ファイザー・インク Treatment of diabetes mellitus
JP4142356B2 (en) 2001-07-05 2008-09-03 オイクロ ヨーロピアン コントラクト リサーチ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディト ゲゼルシャフト PP2C substrate
DE10135815A1 (en) * 2001-07-23 2003-02-06 Bayer Ag Use of imidazo-triazinone derivative phosphodiesterase 5 inhibitors e.g. for treatment of cardiac insufficiency, psoriasis, diabetes, cancer, glaucoma, bladder disease, Parkinson's disease or pain
US7019010B2 (en) 2001-09-27 2006-03-28 Novertis Ag Combinations
US20030114469A1 (en) * 2001-09-27 2003-06-19 Cohen David Saul Combinations
EP1444009A1 (en) 2001-11-02 2004-08-11 Pfizer Products Inc. Treatment of insulin resistance syndrome and type 2 diabetes with pde9 inhibitors
US20030181461A1 (en) * 2002-01-25 2003-09-25 Lautt Wilfred Wayne Use of phosphodiesterase antagonists to treat insulin resistance
BR0307595A (en) * 2002-02-07 2005-02-01 Pfizer Use of pde5 inhibitors such as sildenafil in the treatment of polycystic ovarian syndrome
JP2004018524A (en) * 2002-06-13 2004-01-22 Eucro European Contract Research Gmbh & Co Kg Method for treating arteriosclerosis
GB0214784D0 (en) * 2002-06-26 2002-08-07 Pfizer Ltd Novel combination
EP1605925A1 (en) * 2003-03-17 2005-12-21 Pfizer Products Inc. Treatment of type 1 diabetes with pde5 inhibitors
UA80871C2 (en) * 2003-04-29 2007-11-12 Pfizer Ltd 5,7-diaminopyrazolo[4,3-d]pyrimidines useful in the treatment of hypertension
ATE433978T1 (en) 2003-04-29 2009-07-15 Pfizer Ltd 5,7-DIAMINOPYRAZOLO 4,3-D PYRIMIDINES FOR USE IN THE TREATMENT OF HYPERTENSION
AU2004269923B2 (en) 2003-09-05 2010-05-13 Takeda Gmbh Use of PDE4 inhibitors for the treatment of diabetes mellitus
US7572799B2 (en) 2003-11-24 2009-08-11 Pfizer Inc Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors
US7569572B2 (en) 2004-04-07 2009-08-04 Pfizer Inc Pyrazolo[4,3-D]pyrimidines
CA2599376C (en) 2005-03-08 2014-05-13 Nycomed Gmbh Roflumilast for the treatment of diabetes mellitus
WO2007010337A2 (en) * 2005-07-15 2007-01-25 Proxomed Medizintechnik Gmbh Use of phosphodiesterase type 5 inhibitors for the prevention and treatment of diseases or health disorders and dispensing system for said inhibitors
NZ574710A (en) 2006-09-07 2012-02-24 Nycomed Gmbh Combination treatment comprising the PDE4 inhibitor Compound A ((2R,4aR, 10bR)6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol) for diabetes mellitus
PL2152663T3 (en) 2007-06-04 2014-09-30 Ben Gurion Univ Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
AT512084A1 (en) 2011-10-20 2013-05-15 Univ Wien Tech DIAZABICYCLO AND DIAZASPIRO ALKAN DERIVATIVES AS PHOSPHODIESTERASE-5 INHIBITORS
WO2013173923A1 (en) 2012-05-25 2013-11-28 Diamedica, Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
PL2854841T3 (en) 2012-06-04 2017-08-31 Diamedica Inc. Human tissue kallikrein 1 glycosylation isoforms
AU2014202625B2 (en) * 2013-05-14 2018-11-08 Scimar Ltd. Hepatic insulin sensitizing substance and test meal for insulin sensitization
EP3065723B1 (en) 2013-11-05 2020-09-23 Ben Gurion University of the Negev Research and Development Authority Compounds for the treatment of diabetes and disease complications arising from same
KR20190122706A (en) 2017-03-09 2019-10-30 다이어메디카 인코포레이티드 Dosage form of tissue kallikrein 1
MX2017016930A (en) * 2017-12-19 2019-06-20 Malesil Research & Tech Llc Method of treatment of diabetic foot ulcers.
KR102068299B1 (en) * 2018-12-21 2020-01-20 한국기초과학지원연구원 A pharmaceutical composition for prevention or treatment of metabolic disease comprising CYP4A inhibitor

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9013750D0 (en) * 1990-06-20 1990-08-08 Pfizer Ltd Therapeutic agents
GB9511220D0 (en) * 1995-06-02 1995-07-26 Glaxo Group Ltd Solid dispersions
ES2244979T3 (en) * 1995-12-28 2005-12-16 Fujisawa Pharmaceutical Co., Ltd. DERIVATIVES OF BENZIMIDAZOL.
NZ338075A (en) * 1997-04-25 2000-10-27 Pfizer Ltd Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PED5) for the treatment of sexual dysfunction
BR9810456A (en) * 1997-06-27 2001-09-25 Fujisawa Pharmaceutical Co Sulfonamide compound, method for obtaining it and its pharmaceutical use
WO1999051574A1 (en) * 1998-04-06 1999-10-14 Fujisawa Pharmaceutical Co., Ltd. Indole derivatives
CN1335847A (en) * 1998-12-04 2002-02-13 藤泽药品工业株式会社 Sulfonamide compounds and uses thereof as medicines
AU765128B2 (en) * 1999-03-22 2003-09-11 Bristol-Myers Squibb Company Fused pyridopyridazine inhibitors of cGMP phosphodiesterase
DE19944161A1 (en) * 1999-09-15 2001-03-22 Bayer Ag New combination for the treatment of sexual dysfunction
PT1088824E (en) * 1999-09-30 2004-04-30 Pfizer Prod Inc BLYCYLIC PYRROLYL-AMIDES AS GLYCOGENE-PHOSPHORYLASE INHIBITORS
CA2323008C (en) * 1999-10-11 2005-07-12 Pfizer Inc. Pharmaceutically active compounds
AU2001257146B2 (en) * 2000-04-19 2006-11-30 Johns Hopkins University Methods for prevention and treatment of gastrointestinal disorders

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108452311A (en) * 2012-11-13 2018-08-28 纽斯尔特科学公司 Composition for enhancing energetic supersession and method

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