Because endothelin is relevant with some morbid state and relate to many physiological roles, therefore can disturb or activity that obstruction is relevant with endothelin, be target compound as endothelin-acceptor interaction and the active chemical compound of vasoconstrictor.Identified the multiple chemical compound of endothelin receptor antagonists that is.For example, the tunning of three rugged streptomycetes (Streptomycesmisakiensis) is named as BE-18257B and has been accredited as ET_AAntagonist.BE-18257B is a kind of ring-type pentapeptide (ring (D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp)), and it suppresses in the cardiovascular organization in concentration-dependency mode¹²⁵The endothelin of I-labelling-1 is in conjunction with (IC₅₀Being 1.4 μ M in the aortal smooth muscle, is 0.8 μ M in the ventricle film, is 0.5 μ M in the aortic smooth muscle cell of cultivating), but before 100 μ M concentration, do not suppressing and ET wherein_BThe combination of receptor in the tissue that is dominant.With BE-18257B, relevant ring-type pentapeptide class has been synthesized and has demonstrated as BQ-123 (ring (D-Asp-Pro-D-Val-Leu-D-Trp)) is ET_AAntagonist (is seen people's such as Ishikawa U.S. Patent No. 5,114,918; Also see BanyuPharmaceutical Co., the EP A1 0 436 189 of Ltd (Oct.7,1991)).Measure these cyclic peptides to endothelin-1 and bonded inhibiting studies show that of endothelin specific receptor, these cyclic peptides are preferentially in conjunction with ET_AOther peptide and non--peptide ET have been identified_AAntagonist (see, for example, United States Patent(USP) Nos. 5,352,800; 5,334,598; 5,352,659; 5,248,807; 5,240,910; 5,198,548; 5,187,195 and 5,082,838).These comprise other cyclic peptide, acyl group tripeptides, six peptide analogues, some anthraquinone derivative, indane carboxylic acid, some N-pyrimidine radicals benzsulfamide, some benzsulfamide and some naphthalene sulfonylamide (people such as Nakajima, J.Antibiot., 44:1348-1356 (1991); People such as Miyata, J.Antibiot., 45:74-78 (1992); People such as Ishikawa, J.Med.Chem., 35:2139-2142 (1992); People's such as Ishikawa U.S. Patent No. 5,114,918; EP A1 0 569 193; EP A1 0 558258; Banyu Pharmaceutical Co., the EP A1 0 436 189 of Ltd (Oct.7,1991); Canadian patent application No.2,067,288; Canadian patent application No.2,071,193; U.S. Patent No. 5,208,243; U.S. Patent No. 5,270,313; People such as Cody, Med.Chem.Res., 3:154-162 (1993); People such as Miyata, J.Antibiot., 45:1041-1046 (1992); People such as Miyata, J.Antibiot., 45:1029-1040 (1992); People such as Fujimoto, FEBSLetters, 305:41-44 (1992); People such as Oshashi, J.Antibiot., 45:1684-1685 (2002); EP A1 0 496 452; People such as Clozel, Nature, 365:759-761 (1993); International patent application No.WO 93/08799; People such as Nishikibe, Life Sci, 52:717-724 (1993); With people such as Benigni, Kidney Int., 44:440-444 (1993)).Generally speaking, the authenticating compound of similar about 50-100mM or lower concentration has ET in the external test method_AAntagonist activities.Shown that many these compounds have activity in the animal model in vivo.

Have realized that outside the standard body of estimating endothelin antagonist or agonist activity in the algoscopy, with similar 10^-4MM or lower IC₅₀Or EC₅₀Concentration show active chemical compound have pharmacology's effectiveness (see, for example, United States Patent(USP) Nos. 5,352,800; 5,334,598; 5,352,659; 5,248,807; 5,240,910; 5,198,548; 5,187,195 and 5,082,838).Because this activity, this compounds is considered to be applicable to treatment hypertension such as peripheral circulation depletion, heart disease such as angina pectoris, cardiomyopathy, arteriosclerosis, myocardial infarction, pulmonary hypertension, vasospasm, vascular restenosis, Raynaud disease, apoplexy such as cerebral vasospasm, cerebral ischaemia, brain spasm in late period behind the subarachnoid hemorrhage, asthma, bronchoconstriction, renal failure, renal failure after the ischemia particularly, cyclosporin nephrotoxicity such as acute renal failure, colitis and other inflammatory diseases, cause or the endotoxin shock relevant and wherein relate to other disease of endothelin by endothelin with endothelin.

Therefore, show the disease of the active chemical compound of endothelin receptor antagonists to being caused by ischemia, for example cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency have prevention and therapeutical effect.

Therefore, consider the related of endothelin and numerous disease, think that endothelin plays a crucial role and (see people such as Saito, Hypertension15:734-738 (1990) in these pathophysiology situations; People such as Tomita, N.Engl.J.Med., 321:1127 (1989); People such as Kurihara, J.Cardiovasc.Pharmacol.13 (Suppl.5): S13-S17 (1989); Doherty, J.Med.Chem.35:1493-1508 (1992); People such as Morel, Eur.J.Pharmacol., 167:427-428 (1989)).

Therefore, the material (being antagonist) that specificity suppresses endothelin and its receptors bind should prevent the various The above physiological effects of endothelin and therefore, is valuable drug.For example, endothelin receptor antagonists of the present invention can be used for treating in hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute renal failure, renal insufficiency, cerebral vasospasm, cerebral ischaemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxin shock, endotoxin-inductive organ failure, the blood vessel condense, hypertension or renal failure that postangioplasty restenosis, benign prostatic hyperplasia, ischemia or poisoning cause, described in international application Nos.WO96/11914 and WO95/26716.

Characterized two types mammal endothelin (ET) receptor, ET_AAnd ET_BET_ATo ET-1 and ET-2 is optionally, and ET_BWith the affinity that equates in conjunction with ET-1, ET-2 and ET-3.ET_AMediation vasoconstriction and cell proliferation, and ET_BFor the release of removing, endotheliocyte survival, nitric oxide and the prostacyclin of ET-1, and the inhibition of ECE-1 for be importantly (to see, Luscher, T. wait the people, Endothelins and EndothelinReceptor Antagonists, Therapeutic Considerations for a Novel Classof Cardiovascular Drugs, Circulation, 2434-2444 (November 7,2000); People such as Wu-Wong, Pharmacology of endothelin receptor antagoinistsABT-627, ABT-546, A-182086 and A-192621:in vitro studies, ClinicalScience, Suppl.48,107-111 (2002)).

Because of having developed endothelin receptor antagonists, in the ET field, obtained major progress.BQ-123 and FR139317, two kinds of peptide ET_A-selective antagonist is the impressive progress in the pathophysiology research of ET-mediation.After the peptide compounds, many non-peptide antagonists have been developed, as Ro 47-0203, SB 21 7242, atrasentan etc. with improved pharmacokinetics.

The example of endothelin receptor antagonists comprises, but be not limited to, BE 1827, BQ-610, ABT 627 (see figure 1)s, ABT 546 (see figure 2)s, Ro 61-1790, ZD1611, BMS-182874, BMS-193884, sitaxentan (TBC 11251) (see figure 3), EMD122946, J-104132, LU 127043, LU 135252, SB 234551, SB 247083 and their derivant etc. (are seen, Doherty, Annual Reports in MedicinalChemistry, 35:73-82 (Academic Press, 2000)).Other ethylene sulfamide derivative (it is endothelin receptor antagonists and is applicable in the method for the present invention) is by people Chem.Pharm.Bull. such as Harada, and 49 (12): 1593-1603 (2001) is open.N- azoles thiophene sulfonamide class (see figure 4) is people such as Wu, Recently discovered sulfonamide-, acylsulfonamide-and carboxylic acid-based endothelin antagonists, Drugs, 6 (3): describe among the 232-239 (2003).Other ET_AAntagonist exists, and for example, describes among the U.S. Patent Application Publication Nos.20030092757 and 20030040534.ET_AOther form of antagonist also can be used in embodiment of the present invention as its isomer (for example, resolved enantiomers or racemic mixture), metabolite, polymorph, salt and complex.

In one embodiment, ET_AAntagonist is a sitaxentan, and it is commercially available, and trade mark is THELIN.United States Patent(USP) Nos. 5,591,761; 5,594,021; 5,962,490; 6,248,767 and 6,458,805 disclose the compositions that comprises sitaxentan, use the method and the pharmaceutical composition that comprises sitaxentan of sitaxentan.U.S. Patent No. 5,783,705 disclose the method for preparing sitaxentan.

THELIN (sitaxsentan sodium; TBC1 1251 Na) be orally active endothelin A receptor antagonist, it has been developed and has been used for the treatment of pulmonary hypertension (PAH).ET-1 is mainly produced by vascular endothelial cell, is the main isoform of finding in cardiovascular system and is to have the potent endogenous vasoconstrictor that propagation and fibrinolysis (profibrotic) act on.ET-1 also influences salt and water body homeostasis and Re-A-A and sympathetic nervous system.A large amount of experimental works show that the major physiological effect of ET-1 in laboratory animal and PAH patient is that remodeling the lung pulse guard system continues vasoconstriction, and this is because the propagation of vascular smooth muscle or loose causing.

Think now that in cardiovascular system ET-1 mainly passes through ET to the effect of vascular smooth muscle cell and myocardial cell_AMediation.ET_AActivation promote the lasting vasoconstriction of vascular smooth muscle, the hypertrophy of the stimulation of vascular smooth muscle cell, propagation and hypertrophy, positivity variable force activity and heart cell.By contrast, ET_BMainly in endotheliocyte, kidney and central nervous tissue, find and participate in ET-1, the particularly removing in the vascular bed of lung and kidney.Endothelium ET_BThe vasodilation that promotion is caused by the release of smooth muscle relaxation agent such as nitric oxide and prostacyclin.The important stimulus thing that ET-1 discharges includes, but not limited to hypoxia, ischemia, catecholamines and Angiotensin II.THELIN is to ET_AHas high specific, as antagonist, to ET_ASelectivity than to ET_BSelectivity high about 6,500 times.

ET of the present invention_AThe alternative cpd of antagonist, generally speaking, if they are only to one of receptor subtype, for example, ET_APlay a role, then should show at least 100, as surpassing 1000, as being 500 greater than 1000 increments, i.e. 1500,2000,2500 etc. receptor relative binding ratio.

Based on extracorporeal receptor affinity ratio, bosentan, it is the unique endothelin receptor antagonists that is approved for the PAH treatment, has 20 ET_A: ET_BSelectivity ratios and be classified as non-selective antagonist.By contrast, sitaxentan has 6500 ET_A: ET_BSelectivity ratios and be classified as ET_A-selective antagonist.Therefore, with regard to the object of the invention, bosentan or any other non--specificity endothelin receptor antagonists are not represented ET_A-specific antagonists.

THELIN is a kind of micromolecule of blocking the endothelin effect, the potent medium of a kind of vasoconstriction and vascular smooth muscle growth.Endothelin receptor antagonists multiple wherein regulate vasoconstriction be in the important treatment of diseases effectively.The side effect of THELIN comprises liver function obstacle (ALT and AST increase), headache, edema, constipation, nasal congestion and flushing.

Because ET_AAs if to endothelin-the 1st, optionally, the example of possible compounds suitable for use comprises, for example, in U.S. Patent No. 5,686,478 and table 1 in the chemical compound of description.

Table 1. endothelin antagonist

Chemical compound	Target	Company	Indication/note
Chemical compound	Target	Company	Indication/note	12m	ET_A	Rhone-Poulenc Rorer	Cardiovascular disease
A-127772	ET_A	Abbott		12m	ET_A	Rhone-Poulenc Rorer	Cardiovascular disease
A-127772	ET_A	Abbott		ABT-627	ET_A	Abbott	CHF; Carcinoma of prostate
BE-18572A/B	ET_A	Banyu		ABT-627	ET_A	Abbott	CHF; Carcinoma of prostate
BE-18572A/B	ET_A	Banyu		BMS-20794	ET_A	Bristol Myers Squibb
BMS-182874	ET_A	Bristol Myers Squibb	CHF	BMS-20794	ET_A	Bristol Myers Squibb
BMS-182874	ET_A	Bristol Myers Squibb	CHF	BMS-193884	ET_A	Bristol Myers Squibb
BQ-123	ET_A	Banyu	Only intravenous uses	BMS-193884	ET_A	Bristol Myers Squibb
BQ-123	ET_A	Banyu	Only intravenous uses	RQ-153	ET_A	Banyu	Only intravenous uses

BQ-162	ET_A	Banyu	Only intravenous uses
BQ-162	ET_A	Banyu	Only intravenous uses	BQ-485	ET_A	Banyu	Only intravenous uses
BQ-610	ET_A	Banyu	Only intravenous uses	BQ-485	ET_A	Banyu	Only intravenous uses
BQ-610	ET_A	Banyu	Only intravenous uses	EMD-122946	ET_A	Mcrck	CHF; Hypertension
EMD-94246	ET_A	Merck	CHF; Hypertension	EMD-122946	ET_A	Mcrck	CHF; Hypertension
EMD-94246	ET_A	Merck	CHF; Hypertension	FR-139317	ET_A	Fujisawa Pharm.Co.
J-104121	ET_A	Merck/Banyu		FR-139317	ET_A	Fujisawa Pharm.Co.
J-104121	ET_A	Merck/Banyu		J-104132	ET_A	Merck/Banyu	Hypertension
L-744453	ET_A	Merck	Cardiovascular disease	J-104132	ET_A	Merck/Banyu	Hypertension
L-744453	ET_A	Merck	Cardiovascular disease	L-749329	ET_A	Merek
L-754142	ET_A	Merck		L-749329	ET_A	Merek
L-754142	ET_A	Merck		LU127043	ET_A	Knoll
LU135252	ET_A	Knoll	CHF; Hypertension (darusentan)	LU127043	ET_A	Knoll
LU135252	ET_A	Knoll	CHF; Hypertension (darusentan)	LU208075	ET_A	Knoll	CHF; Hypertension
LU302146	ET_A	Knoll	Occlusive vascular disease	LU208075	ET_A	Knoll	CHF; Hypertension
LU302146	ET_A	Knoll	Occlusive vascular disease	PD-147953	ET_A	Parke-Davis	Cardiovascular disease
PD-151242	ET_A	Parke-Davis	Cardiovascular disease	PD-147953	ET_A	Parke-Davis	Cardiovascular disease
PD-151242	ET_A	Parke-Davis	Cardiovascular disease	PD-155080	ET_A	Parke-Davis	Cardiovascular disease
PD-156707	ET_A	Parke-Davis	Cardiovascular disease	PD-155080	ET_A	Parke-Davis	Cardiovascular disease
PD-156707	ET_A	Parke-Davis	Cardiovascular disease	RO 61-1790	ET_A	Hoffmann-La Roche	SAH; Only intravenous uses
S-0139	ET_A	Shionogi	Cardiovascular disease	RO 61-1790	ET_A	Hoffmann-La Roche	SAH; Only intravenous uses
S-0139	ET_A	Shionogi	Cardiovascular disease	SB-234551	ET_A	SmithKline Beecham
SB-247083	ET_A	SmithKline Beecham		SB-234551	ET_A	SmithKline Beecham
SB-247083	ET_A	SmithKline Beecham		TA-0115	ET_A	Tanabe Seiyaku Co.，Ltd	Heart failure
TA-0201	ET_A	Tanabe Seiyaku Co.，Ltd	Heart failure	TA-0115	ET_A	Tanabe Seiyaku Co.，Ltd	Heart failure
TA-0201	ET_A	Tanabe Seiyaku Co.，Ltd	Heart failure	TBC11251	ET_A	Texas Biotechnology Company	CHF; Primary pulmonary hypertension
WS-7338B	ET_A	Fujisawa		TBC11251	ET_A	Texas Biotechnology Company	CHF; Primary pulmonary hypertension
WS-7338B	ET_A	Fujisawa		ZD 1611	ET_A	Zeneca	Obstructive pulmonary disease; Primary pulmonary hypertension

Reorganization is from people such as Luscher, Endothelins and Endothelin ReceptorAntagonists:Therapeutic Considerations for a Novel Class ofCardiovascular Drugs, 2434-2340 atHttp:// www.circulationaha.org.

" ET_AAntagonist " be meant in conjunction with ET_AAnd blocking-up or suppress ET-1 or other agonist to any natural existence or the synthetic chemical compound of the function of this receptor.ET_AAntagonist can be peptide or non-peptide compound.Preferably, ET_AAntagonist is to ET_AHave＜1 μ M, more preferably＜100nM, most preferably＜10nM, even＜K of 1nM_dET_AAntagonist comprises, for example, the different  azoles of sulfanilamide, TBC-11251, BQ-123, BQ-610, BQ-745, PD156707, PD151242, TTA-386, JKC-301, JKC-302, BE-18257A, BE-18257B, A-1277722, LU 135252, TAK-044, SB 209670, SB 217242, FR139317 and ABT-627 (table 2; People such as Cheng, Ann.Reports in Medicinal Chemistry, Section II, Ch.7, Endothelin Inhibitors, 61-70, (A.M.Doherty, ed., Academic Press, Inc.1997).

Different ET receptor antagonists of table 2. and ET_AAnd ET_BIn conjunction with K_i(nM)

Chemical compound	Company	ET_A	ET_B	Selectivity	List of references
Chemical compound	Company	ET_A	ET_B	Selectivity	List of references	ABT-627	Abbott	0.034	63.3	1882	[24]
ABT-648	Abbott	0.46	13,000	28,261	[23]	ABT-627	Abbott	0.034	63.3	1882	[24]
ABT-648	Abbott	0.46	13,000	28,261	[23]	BUS-182874	Bristol Myers Squibb	48	＞50,000	＞1000	[25]
FR-139317	Fujisawa	1.0	7300	7300	[12]	BUS-182874	Bristol Myers Squibb	48	＞50,000	＞1000	[25]
FR-139317	Fujisawa	1.0	7300	7300	[12]	J-104132	Merck/Banyu	0.034	0.1	2.9	[26]
LU-135252	BASF/Knoll	1.4	184	130	[27]	J-104132	Merck/Banyu	0.034	0.1	2.9	[26]
LU-135252	BASF/Knoll	1.4	184	130	[27]	PO-156707	Parke-Dayis	0.17	139	818	[28]
Bosentan	Roche	6.5	343	53	[29]	PO-156707	Parke-Dayis	0.17	139	818	[28]
Bosentan	Roche	6.5	343	53	[29]	Ro-61-1790	Roche	0.13	＞130	1000	[30]
S-0 139	Shionogi	1.0	1000	1000	[31]	Ro-61-1790	Roche	0.13	＞130	1000	[30]
S-0 139	Shionogi	1.0	1000	1000	[31]	SB-209670	SmithKline Beecham	0.20	18	90	[32]
SB-217242	SmithKline Beecham	1.1	111	101	[33]	SB-209670	SmithKline Beecham	0.20	18	90	[32]
SB-217242	SmithKline Beecham	1.1	111	101	[33]	T-0201	Tanabe	0.015	41	2700	[34]
TAK-044	Takada	1.3	590	454	[35]	T-0201	Tanabe	0.015	41	2700	[34]
TAK-044	Takada	1.3	590	454	[35]	TBC-11261	Texas Biotechnology	0.43	＞4300	10,000	[36]
ZD-1611	Zeneca	1.3^*	＞2000	1500	[37]	TBC-11261	Texas Biotechnology	0.43	＞4300	10,000	[36]

^*K_iBy IC_∞The value assessment (is seen Wu-Wong, Endothelin Antagonists:Past, Present and Future, Current Opinion in Cardiovascular, Pulmonary﹠amp; Renal Investigational Drugs, 1 (3): 346-351 (1999)).

Some examples of ET receptor antagonist have experienced clinical development (seeing Table 3).

Table 3. has experienced the ET receptor antagonist of clinical development

Chemical compound	Selectivity	Administration	Development phase	Indication
Chemical compound	Selectivity	Administration	Development phase	Indication	ABT-627	ET_A	po	II	Carcinoma of prostate
BMS-182874	ET_A	iv	DX	CHF	ABT-627	ET_A	po	II	Carcinoma of prostate
BMS-182874	ET_A	iv	DX	CHF	BMS-183884	ET_A	po	I	CHF, pulmonary hypertension
FR-139317	ET_A	iv	DX	Hypertension, CHF, ischemia	BMS-183884	ET_A	po	I	CHF, pulmonary hypertension
FR-139317	ET_A	iv	DX	Hypertension, CHF, ischemia	J-104132/L-753037	ET_A/ET_B	po	I	Hypertension, CHF
LU-135252	ET_A/ET_B	po	II	CHF, other cardiovascular indication	J-104132/L-753037	ET_A/ET_B	po	I	Hypertension, CHF
LU-135252	ET_A/ET_B	po	II	CHF, other cardiovascular indication	Bosentan	ET_A/ET_B	po	III	CHF, hypertension, ischemia
RO-48-5895	ET_A	po	II	CHF	Bosentan	ET_A/ET_B	po	III	CHF, hypertension, ischemia
RO-48-5895	ET_A	po	II	CHF	Ro-61-0612	ET_A	po，iv	I	CHF, other cardiovascular diseases
Ro-61-1790	ET_A	iv	I	ARF，SH	Ro-61-0612	ET_A	po，iv	I	CHF, other cardiovascular diseases
Ro-61-1790	ET_A	iv	I	ARF，SH	S-0139	ET_A	iv	I	Acute CHF, hypertension, CI
SB-209670	ET_A/ET_B	iv	II	ARF	S-0139	ET_A	iv	I	Acute CHF, hypertension, CI
SB-209670	ET_A/ET_B	iv	II	ARF	SB-217242	ET_A/ET_B	po	II	COPD, urological
TAK-044	ET_A/ET_B	iv	II	MI, ARF, ACI, liver protection	SB-217242	ET_A/ET_B	po	II	COPD, urological
TAK-044	ET_A/ET_B	iv	II	MI, ARF, ACI, liver protection	TBC-11251	ET_A	iv，po	IIa	CHF, COPD, hypertension, SH
ZD-1611	ET_A	po	I	CHF, pulmonary hypertension	TBC-11251	ET_A	iv，po	IIa	CHF, COPD, hypertension, SH

ACI: acute cerebral ischemia; ARF: acute renal failure; COPD: chronic obstructive pulmonary disease; CHF: congestive heart failure; MI: myocardial infarction; SH: subarachnoid hemorrhage; DX: interrupt.

The discussion that in hypertension, acts on about endothelin, see Krum, people such as H., Role of endothelin in hypertension and therapeutic potential ofendothelin blockade, Cardiovascular, Pulmonary ﹠amp; RenalInvestigational Drugs, 1 (3): 316-329 (1999).Table 4 has outline several biochemistry and the pharmacological property of comparing sitaxentan with bosentan.

Table 4. is compared with bosentan, the biochemistry of sitaxentan and pharmacological property.

Character	Sitaxentan	Bosentan
Character	Sitaxentan	Bosentan	To ET_AThe inherence tire	Ki＝0.45nM	Ki＝4.1nM
t_1/2	10 hours	5 hours	To ET_AThe inherence tire	Ki＝0.45nM	Ki＝4.1nM
t_1/2	10 hours	5 hours	ET_A∶ET_BSelectivity	6500	20
To the effect of bile salts to bilirubinic effect	Do not accumulate not effect of bile salts	Suppress the bile salts rear pump, cause bile salts in hepatocyte, to be accumulated having shown inducing bilirubin in PAH patient, to accumulate	ET_A∶ET_BSelectivity	6500	20
To the effect of bile salts to bilirubinic effect	Do not accumulate not effect of bile salts		Inducing of cytochrome P 450 enzymes	Do not confirm clinically up to now to induce	Cause inhibition, then induce multiple CYP enzyme, comprise 3A4,2C9,2C19
Metabolism	By 3A4 and 2C9	By 3A4 and 2C9	Inducing of cytochrome P 450 enzymes	Do not confirm clinically up to now to induce
Metabolism	By 3A4 and 2C9	By 3A4 and 2C9	The removing approach	Blended liver and kidney	Liver

With regard to the embodiment of respectively enumerating, effective ET described above_AAntagonist.

Conjoint therapy

Using the major defect of sldenafil treatment PAH is that it needs three times high dose every day (more much higher than the dosage that is used for erection disturbance, it is regular 15mg-75mg).At present, the unique endothelin receptor antagonists that has been approved for PAH is a bosentan, and it is a kind of non-selective compound of not only having blocked the A receptor but also having blocked the B receptor.Number of ways is disturbed in the use of non-selective ET receptor, and specificity ET_AThe use of antagonist will play a role with the arbitrary way of number of ways (PDE and/or prostacyclin and/or ET_A), thereby better effect and/or dosage are provided and/or reduce side effect.

For example, ET_ACause vasoconstriction, and ET_BCause vasodilation.Bosentan is by both blocking ET_AReceptor is blocked ET again_BReceptor and playing a role.Sitaxentan is only by blocking-up ET_AAnd maintenance ET_BUnimpaired and playing a role.ET_BCause that vasodilative mechanism is by stimulating the generation of nitric oxide and prostacyclin.Nitric oxide (NO) activates the amidino groups cyclase successively, and it increases the level of cGMP.CGMP is responsible for making blood vessel lax.PDE5 works and decomposes cGMP, so the PDE5 inhibitor also can make the cGMP level raise, and causes vasodilation.Therefore, when using together, pass through ET_BReceptor increases cGMP and prevents its decomposition, causes vasodilation to increase and two kinds of better effects of medicine.Non-selective antagonist will can effectively not play a role, because they have blocked ET_BThe generation of the cGMP that stimulates.In addition, in recent research, tested bosentan (a kind of non-selective antagonist) and sldenafil, but this research is owing to pharmacokinetics drug interaction problem is terminated.

Therefore, the present invention relates to PDE5 inhibitor and ET_A-specific antagonists therapy is suppressing and is preventing purposes among cardiac stress or the PAH.Method and formulation of the present invention provides new Therapeutic Method for treatment and the prevention of animal PAH." treatment " or " treatment " also means former the site and the secondary site that are included in them and keeps heart, comprises that PAH is in dormancy (static) state.In addition, " treatment " or " treatment " be meant and increase effect and prevent or reduce resistance form of therapy." treatment " or " treatment " also mean comprise prevent recurrence, reduce pain, do not accommodate DB (morbidity), and increase quality of life relevant with this situation." increase effect " means and comprises ET_ATiring and/or the minimizing of active increase and/or required dosage of antagonist and/or PDE5 inhibitor.The patient's who receives treatment state can pass through standard evaluation known in the art.For example, the patient who suffers from PAH can test through 6 minutes exercise walking before treatment cycle and afterwards.

" treatment effective dose " is meant the amount of the active agents that causes obtaining required effect.The toxicity of this class active agents and therapeutic efficiency can be measured by the standard pharmaceutical procedures in cell culture or laboratory animal, for example, measure LD₅₀(causing the dosage of 50% death of colony) and ED₅₀(colony 50% in the treatment effective dosage).Dosage ratio between toxic action and the therapeutical effect is a therapeutic index, and it is with LD₅₀With ED₅₀Between ratio represent.Preferred high therapeutic index.The data that obtained by these class data can be used for preparing the dosage range that uses for human.The dosage of active agents preferably drops within the scope of circulation composition, and it comprises having very little toxicity or do not have toxic ED₅₀Dosage can change in this scope, and this depends on used dosage form and used route of administration.

Prescription, route of administration and dosage are determined under the condition of considering status of patient by individual doctor accurately.But dosage and blanking time individuation regulate, so that the level of the active agents that is enough to keep treatment or preventive effect to be provided.

The amount of the pharmaceutical composition that gives depends on the curee that treated, curee's body weight, the painful order of severity, administering mode and prescriber's judgement.One embodiment of the invention have been expected ET_AAntagonist or PDE5 inhibitor dosage successive administration every day to separate, but give for twice a kind of like this every day, and another can once a day or provide for three times.Equally, successive administration means and comprises that therapeutical effect is required to be changed according to reaching, as a kind of medicament every other day treatment and administration every day of another kind of medicament or every day multiple dosing.Conjoint therapy can provide PDE5 inhibitor and ET by the independent dosage form to pack together with the directions for use of dosage regimen_AAntagonist and realizing.

Very preferably with unit-dosage composition, give PDE5 inhibitor and ET as the form of oral dosage_AAntagonist or its pharmaceutically acceptable salt are used for the treatment of and/or prevent obstacle, as pulmonary hypertension.

The PDE5 inhibitor every day consumption will be in the scope of 50mg-250mg, increment that can 5mg is adjusted, thereby comprises the treatment effective range.For example, this scope can be 50mg-225mg, 50mg-215mg, 50mg-200mg etc., or 55mg-250mg, 60mg-250mg, 65mg-250mg or 65mg-215mg, 70mg-210mg etc. and version thereof.ET_AAntagonist every day consumption will be in the scope of 5mg-125mg, increment that can 5mg is adjusted, thereby comprises the treatment effective range.For example, this scope can be 10mg-125mg, 15mg-125mg, 20mg-125mg etc., or 5mg-120mg, 5mg-115mg, 5mg-110mg or 25mg-90mg, 30mg-85mg etc. and version thereof.Preferred PDE5 suppresses and ET_AThe ratio range of antagonist is 5: 1-2: 1.

The preparation of pharmaceutical composition

The administration of any compound of the present invention can be passed through any suitable way, and this mode causes treating compounds effective concentration.This chemical compound can be comprised in any suitable carrier mass by any Sq, and exists with the amount that accounts for composition total weight 1-95% usually.The dosage form that said composition can be suitable for oral route provides.Therefore, said composition can be, for example, and the form of tablet, capsule, pill, powder, granule, suspension, emulsion, solution or gel.Pharmaceutical composition can (be seen Remington:The Scienceand Practice of Pharmacy (20th ed.) for example, ed.A.R.Gennaro, LippincottWilliams﹠amp according to conventional pharmacy practice preparation; Wilkins, 2000 and Encyclopedia of PharmaceuticalTechnology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, MarcelDekker, New York).

Pharmaceutical composition of the present invention can be formulated in a large amount of immediately release of active compounds (medicine) or any scheduled time after administration or time cycle after the administration and discharge.The compositions of latter type is commonly referred to as controlled release preparation, and it comprises that (i) produces the preparation of the drug level of substantial constant in the time cycle of an elongated segment in health; (ii) after predetermined lag time, in the time cycle of an elongated segment, in health, produce the preparation of the drug level of substantial constant; (iii) in the preset time periodic process, keep drug effect by keeping constant relatively, effective levels of drugs in the health, simultaneously with the relevant minimized preparation of undesirable side effect of blood plasma level fluctuation of active drug substance; (iv) pass through, for example, the adjacent or space therein of controlled release composition and illing tissue or organ is placed and is made the preparation of drug effect localization; (v) by using carrier or chemical derivative to deliver drugs into the preparation that the particular target cell type makes the drug effect targeting.The all right different speed of controlled release preparation discharges at least two kinds of active component.In addition, controlled release preparation can in 12 hours or 24 hours, discharge at least a active component in different time spans.In one embodiment of the invention, controlled release preparation discharged at least a active component in 24 hours.

Other embodiment of the present invention comprises a kind of pharmaceutical composition, and it comprises immediate release formulations and controlled release preparation, and wherein immediate release formulations contains ET_AAntagonist, PDE5 inhibitor or this two and controlled release preparation contain ET_AAntagonist, PDE5 inhibitor or this two.In one embodiment of the invention, immediate release formulations contains sitaxentan and controlled release preparation contains sldenafil.

Chemical compound in combination has (i) narrow therapeutic index (that is, cause the plasma concentration of harmful side effect or toxic reaction and cause the difference between the plasma concentration of therapeutical effect little); (ii) narrow absorbing window in the gastrointestinal tract; Or (iii) very short biological half life, so that for blood plasma level is maintained treatment level, need be in one day under the situation of frequent drug administration, the administration of the chemical compound of preferred especially controlled release preparation form.

In order to obtain controlled release, any in practicable many strategies, wherein the rate of release of the chemical compound of Tao Luning is greater than its metabolic rate.In an example, controlled release is by different formulation parameters of suitable selection and composition, comprises, for example, different types of controlled release compositions and coating obtain.Therefore, use suitable excipient compounding pharmaceutical in pharmaceutical composition, this pharmaceutical composition discharges medicine in a controlled manner after administration.Example comprises single or multiple units tablet or capsule composition, oil solution, suspension, Emulsion, microcapsule, microsphere, nano-particle, patch and liposome.

The solid dosage forms that orally uses

The preparation that orally uses comprises the tablet that contains active component and nontoxic pharmaceutically acceptable excipient.These excipient can be, for example, inert diluent or filler (for example, sucrose, Sorbitol, sugar, mannitol, microcrystalline Cellulose, starch based comprise potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); Granulation agent and disintegrating agent (for example, cellulose derivative comprises that microcrystalline Cellulose, starch based comprise potato starch, cross-linking sodium carboxymethyl cellulose, alginate or alginic acid); Binding agent (for example, sucrose, glucose, Sorbitol, arabic gum, alginic acid, sodium alginate, gelatin, starch, pregelatinized Starch, microcrystalline Cellulose, Magnesiumaluminumsilicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, ethyl cellulose, polyvinylpyrrolidone or Polyethylene Glycol); With lubricant, fluidizer and antitack agent (for example magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil or Pulvis Talci).Other pharmaceutically acceptable excipient can be coloring agent, flavoring agent, plasticizer, wetting agent, buffer agent etc.

Tablet not coating or they can pass through the known technology coating, optionally postpones in gastrointestinal tract disintegrate and absorption and continuous action is provided thus in a long time.Coating can be suitable for discharging in a predefined manner active drug substance (for example, in order to obtain controlled release preparation) just or it can be suitable for after by stomach, discharging active drug substance (casing).Coating can be sugar-coat, film-coat (for example based on hydroxypropyl emthylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycols and/or polyvinylpyrrolidone) or casing (for example, based on methacrylic acid copolymer, Cellacefate, Hydroxypropyl Methylcellulose Phathalate, acetic acid succinic acid hydroxypropyl emthylcellulose, poly-acetic acid O-phthalic vinyl acetate, Lac and/or ethyl cellulose).In addition, the up time postpones material, as glyceryl monostearate or glycerol distearate.

The solid tablet compositions can comprise and is suitable for protecting compositions to avoid the coating of undesirable chemical change (for example, the chemical degradation before active drug substance discharges).Can with Encyclopedia of Pharmaceutical Technology, above described similar mode is coated in coatings on the solid dosage forms.

If give more than a kind of medicine simultaneously, medicine can be mixed in tablet, maybe it can be separated.In an example, first kind of pharmaceutical pack is contained in the inboard of tablet, and second kind of medicine is in the outside, and before first kind of drug release, the major part of second kind of medicine discharges like this.

The preparation that orally uses can also chewable tablet or wherein active component and inert solid diluent be (for example, potato starch, lactose, microcrystalline Cellulose, calcium carbonate, calcium phosphate or Kaolin) blended hard gelatin capsule or wherein active component and water or oily medium, for example the form of the Perle of Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil provides.The composition of mentioning under tablet and capsule above powder and granule can use in a usual manner, uses, and for example, blender, fluidized bed plant or spray drying device are prepared.

Controlled release oral dosage form

The controlled release composition that orally uses is passable, for example, is configured to discharge active medicine by the stripping and/or the diffusion of control active drug substance.The all right different speed of controlled release preparation discharges at least two kinds of active component.

Stripping or diffusion controlled release can be by chemical compound the suitable coating of tablet, capsule, pill or granular preparation, or realize by chemical compound being incorporated in the suitable substrate.Controlled release coat can comprise above-mentioned one or more coating substances and/or, for example, Lac, Cera Flava, glycowax, castor wax, Brazil wax, stearyl alcohol, glyceryl monostearate, glycerol distearate, the glycerol palmitostearate, ethyl cellulose, acrylic resin, the dl-polylactic acid, cellulose acetate-butyrate, polrvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylates, the methyl methacrylate, 2-hydroxyl methacrylate, the methacrylate hydrogel, 1,3 butanediol, the ethylene glycol methacrylate, and/or polyethylene glycols.In the controlled release matrix preparation, this host material also can comprise, for example, hydration methylcellulose, Brazil wax and stearyl alcohol, carbopol 934, siloxanes, glyceryl tristearate, methacrylate-methyl methacrylate, polrvinyl chloride, polyethylene and/or halocarbon fluorine compounds.

The controlled release composition that contains one or more chemical compounds in the combination required for protection can also be the form of suspension tablet or capsule (that is, behind the oral administration, at tablet or the capsule of specific time cycle inner suspension at the top of gastric content).The suspension tablet preparation of chemical compound can be by with medicine and excipient and 20-75%w/w hydrocolloid, prepares as the granulating mixture of hydroxyethyl-cellulose, hydroxypropyl cellulose or hydroxypropyl emthylcellulose.Then the gained granule is pressed into tablet.When contacting with gastric juice, tablet around its surface, form basically can not infiltration water the gel barrier.This gel barrier participates in keeping being lower than 1 density, tablet is remained in the gastric juice suspend.

The liquid that is used for oral administration

But being suitable for by adding powder dispersed powders or the granule that entry prepares aqueous suspension is the dosage form that makes things convenient for that is used for oral administration.Suspension formulations provides active component and dispersion or wetting agent, suspending agent and one or more antiseptic.Suitable dispersion or wetting agent are, for example, the phospholipid of natural-existence (for example, lecithin or oxirane and fatty acid, long-chain fatty alcohol or derive from the condensation product of the partial ester of fatty acid) and hexitol or hexitan (for example, polyethylene glycol oxide stearate, polyethylene glycol oxide Sorbitol monooleate, polyethylene glycol oxide sorbitan monooleate etc.).Suitable suspending agent is, for example, and sodium carboxymethyl cellulose, methylcellulose, sodium alginate etc.

Oral liquid can be, for example, the form of moisture or oleaginous suspension, solution, emulsion, syrup or elixir, or with before use, the dry labor thing form of water or other appropriate carrier reconstruct provides.This class I liquid I preparation can contain conventional additives such as suspending agent, for example Sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example lecithin, sorbitan monooleate or arabic gum; Non--water carrier (it can comprise edible oil), for example, almond oil, fractionated coconut oil, oiliness esters such as glycerol, propylene glycol or alcoholic acid ester; Antiseptic, for example, methyl or propyl group be right-hydroxybenzoate or sorbic acid, and if desired, also can contain conventional seasoning or coloring agent.Oral formulations also comprises conventional extended release preparation, as has the tablet or the granule of casing.

Be used for the treatment of and/or prevent the compositions of pulmonary hypertension can the snuffing agent or be used for the solution of aerosol apparatus or aerosol or the attritive powder form that is used to be blown into provides, be used for uniting separately or with inert carrier such as lactose, to respiratory tract administration.In this case, the active ingredient composition granule suitably has less than 50 microns, and preferably less than 10 microns, for example, the 1-5 micron is as the diameter of 2-5 micron.Favourable inhalation dose will be about 0.05mg-2mg, for example about 0.05mg-0.5mg, about 0.1mg-1mg or about 0.5mg-2mg.

As common practice in, said composition is usually with the hand-written or printed instructions that is used for medical treatment concerned.

Embodiment

The following example provide illustrational but not-embodiment of restrictive content of the present invention.

Embodiment 1: the research of pharmacokinetics drug interaction

The research of pharmacokinetics drug interaction is to use 24 individualities to carry out.In this research, one group of 24 normal, healthy volunteer participates in two treatment cycle.In a treatment cycle process, the curee accepts the sldenafil (VIAGRA) that 100mg sitaxsentan sodium (THELIN) was also in the end accepted the 100mg single dose totally in 7 days in a day.In another treatment cycle process, the curee accepted placebo totally 7 days and accepted 100mg VIAGRA at the 7th day.Give 12 curees of each treatment cycle random assortment.When the curee finished a treatment cycle, they were transformed into another treatment cycle.Two curees (every group each one) do not finish this research.

Use EDTA as anticoagulant, extract each curee's blood, to measure the blood plasma level of sitaxentan, sldenafil and N-demethylation sldenafil.For each treatment cycle, the 1st, 3,5 and 6 day (in duplicate) draw samples once; Extracting 15 times and the 8th day on the 7th day extracts once again.Sample stored under-20 ℃ nominal temperature be no more than 38 days persistent period.Use one group of calibration criterion product and low, in and high concentration quality control sample, analyze all samples.

The result shows that the sldenafil administration does not change the sitaxentan level.Table 5 has been summarized healthy curee and has been accepted 100mg sitaxentan or placebo every day after totally 7 days, behind the sldenafil of orally give single 100mg dosage, under the condition that has sitaxentan to exist, the pharmacokinetic parameter of sldenafil and N-demethylation sldenafil.The C of sldenafil_Max(Cmax) increased by 18% and AUC_∞(area under plasma concentration/time graph) increased by 28%.Do not observe to active metabolite the influence of the level of N-demethylation sldenafil.Table 6 shows that healthy curee accepts 100mg sitaxentan or placebo every day after totally 7 days, and behind the orally give single 100mg dosage sldenafil, the statistics of the pharmacokinetic parameter of sldenafil and N-demethylation sldenafil relatively.

Healthy curee accepts 100mg sitaxentan or placebo every day after totally 7 days, behind the orally give single 100mg dosage sldenafil, the mean plasma concentration of sldenafil is described in Fig. 5, and healthy curee accepts 100mg sitaxentan or placebo every day after totally 7 days, behind the orally give single 100mg dosage sldenafil, the mean plasma concentration of N-demethylation sldenafil is described in Fig. 6.

Based on these data, VIAGRA does not demonstrate influences the THELIN pharmacokinetics.THELIN shows that whole VIAGRA pharmacokinetics are had less influence, infers that it is based on Cytochrome P450 3A4 expection, weak that sees in the hepatocyte of cultivation and suppresses.

Table 5: healthy curee accepts 100mg sitaxentan or placebo every day after totally 7 days,

Behind the orally give single 100mg dosage sldenafil, sldenafil and

The general introduction of N-demethylation sldenafil pharmacokinetic parameter

Parameter¹	Sitaxentan	Placebo
Parameter¹	Sitaxentan	Placebo	Sldenafil Cmax (ng/mL) Tmax (h) A UC_0-t(h·ng/mL) A UC_∞(h·ng/mL) λz(h^-1) t1/2 (h) CL/F (mL/min) Vz/F (L) N-demethylation silaenafil Cmax (ng/mL) Tmax (h) A UC_0-t(h·ng/mL) A UC_∞(h·ng/mL) λz(h^-1) t1/2(h) CL/F(mL/min) Vz/F(L)	440±232 1.25 1,575±671 1,648±692 0.2514±0.0364 2.82±0.45 147±56.4 34.8±11.5 104±40.8 1.00 389±105 425±115 0.1544±0.0552 5.14±2.13 529±164 224±76.4	377±208 1.00 1,222±474 1,295±488 0.2584±0.0444 2.76±0.45 1 84±69.0 43.6±18.9 109±53.1 1.00 372±107 440±112 0.1506±0.0569 05.1±1.63 524±234 217±66.2

¹Except that Tmax, meansigma methods ± standard deviation, about Tmax, the report intermediate value.

Table 6: healthy curee accepts 100mg sitaxentan or placebo every day after totally 7 days,

Behind the orally give single 100mg dosage sldenafil, sldenafil and

The statistics of N-demethylation sldenafil pharmacokinetic parameter relatively

Parameter	Than (%)¹
	Than (%)¹		Estimated value	90% confidence interval
	Sldenafil Cmax A UC_0-tA U C_∞CL/F Vz/F N-demethylation sldenafil Cmax A U C_0-tA U C_∞CL/F Vz/F	117.61 124.95 127.69 80.03 81.50 100.70 112.43 105.78 88.95 94.89	Estimated value	90% confidence interval	93.81 → 147.46 113.40 → 137.68 115.46 → 141.22 72.63 → 88.18 70.98 → 93.59 82.72 → 122.60 98.50 → 128.32 96.21 → 116.30 77.93 → 101.53 75.60 → 119.10

¹The GeomETic average specific.Analysis based on natural logrithm-translation data

Embodiment 2: efficacy study

Carry out at random, the research of double blinding, placebo-contrast, it comprises 60 curees that suffer from the pulmonary hypertension that moderate causes to severe, by one of following situation: spontaneous lung Arterial Hypertention (PAH is also referred to as primary pulmonary hypertension); Connective tissue disease (CTD); Or congenital heart disease (CHD).Be assigned randomly to one of following dosage (12 curee/treatments) to the curee:

(i) placebo and placebo;

(ii) placebo and 25mg THELIN;

(iii) placebo and 60mg sldenafil;

(iv) 25mg THELIN and 60mg sldenafil; With

(v) 50mg THELIN and 120mg sldenafil.

Gather blood sample with the level of measuring THELIN in the blood plasma and estimate sldenafil and the pharmacokinetics and the pharmacodynamics of N-demethylation sldenafil.In addition, carry out walking distance test in 6 minutes, to estimate the variation of curee's motor capacity.At last, use the symptom of NYHA/WHP functional classification and clinical deterioration rates grade evaluation PAH.

Minimum drug interaction and side effect are (iv) and (therapeutic effect of success is kept in v) appearance in the combination of Zu THELIN and sldenafil simultaneously during treatment.

Claims

1. method for the treatment of pulmonary hypertension, this method comprises needs a) phosphodiesterase 5 of the curee of this treatment effective dose (PDE5) inhibitor and b) endothelin A receptor (ET_A) antagonist.

2. one kind is reduced ET_AThe two side effect or toxic method of antagonist, PDE5 inhibitor or this, this method comprise and give PDE5 inhibitor and ET_AAntagonist wherein reduces or adjusts the amount of the required PDE5 of treatment disease.

3. one kind is reduced ET_AThe two side effect or toxic method of antagonist, PDE5 inhibitor or this, this method comprise and give PDE5 inhibitor and ET_AAntagonist wherein reduces or the required ET of adjustment treatment disease_AThe amount of antagonist.

4. method that realizes or promote mammal medium vessels treatment of conditions, this method comprises a) ET that treats effective dose_AAntagonist and b) the PDE5 inhibitor.

5. method for the treatment of vascular disorder, this method comprises that the curee who needs this treatment treats a) ET of effective dose_AAntagonist and b) the PDE5 inhibitor.

6. any one method of claim 1-5, wherein said ET_AAntagonist is selected from 12m, A-127772, A-1277722, ABT-627, BE 1827, BE-18257A, BE-18257B, BE-18572A/B, BMS-182874, BMS-193884, BMS-20794, BQ-123, BQ-153, BQ-162, BQ-485, BQ-610, BQ-745, EMD-122946, EMD-94246, FR-139317, J-104121, J-104132, JKC-301, JKC-302, L-744453, L-749329, L-754142, LU127043, LU135252, LU208075, LU302146, PD-147953, PD-151242, PD-155080, PD-156707, RO61-1790, S-0139, SB 209670, SB 217242, SB-234551, SB-247083, sitaxentan, the different  azoles of sulfanilamide, TA-0115, TA-0201, TAK-044, TBC11251, TTA-386, WS-7338B, ZD1611 and composition thereof.

7. any one method of claim 1-5; wherein said phosphodiesterase 5 inhibitor are selected from Vardenafil; tadalafil; zaprinast; Da Shengtafei; MBCQ; MY-5445; dipyridamole; furoyl base and benzo furoyl base pyrrolo-quinolones; 2-(2-picoline-4-yl) methyl-4-(3; 4; the 5-trimethoxyphenyl)-8-(pyrimidine-2-base) methoxyl group-1; 2-dihydro-1-oxo-2; 7-naphthyridines-3-methyl formate hydrochlorate; T-1032 (2-(4-aminophenyl)-1; 2-dihydro-1-oxo-7-(2-pyridine radicals methoxyl group)-4-(3; 4,5-trimethoxy-phenyl)-3-isoquinolin methyl formate sulfate); sldenafil; RX-RA-69; SCH-51866; KT-734; vesnarinone; zaprinast; SKF-96231; ER-21355; BF/GP-385; NM-702 and composition thereof.

8. any one method of claim 1-5, wherein said ET_AAntagonist is selected from ABT-627, sitaxentan, the different  azoles of sulfanilamide, TBC11251, ZD1611 and composition thereof.

9. any one method of claim 1-5, wherein said PDE5 inhibitor is selected from Vardenafil, tadalafil, Da Shengtafei, dipyridamole, 2-(2-picoline-4-yl) methyl-4-(3,4, the 5-trimethoxyphenyl)-8-(pyrimidine-2-base) methoxyl group-1,2-dihydro-1-oxo-2,7-naphthyridines-3-methyl formate hydrochlorate, (2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridine radicals methoxyl group)-4-(3,4,5-trimethoxy-phenyl)-3-isoquinolin methyl formate sulfate), sldenafil, vesnarinone, zaprinast and composition thereof.

10. any one method of claim 1-5, wherein said ET_AAntagonist is a sitaxentan.

11. the method that claim 1-5 is any, wherein said PDE5 inhibitor is a sldenafil.

12. the method that claim 1-5 is any, wherein said PDE5 inhibitor is a tadalafil.

13. the method that claim 1-5 is any, wherein said ET_AAntagonist is that sitaxentan and PDE5 inhibitor are sldenafil.

14. the method that claim 1-5 is any, wherein said ET_AAntagonist is that sitaxentan and PDE5 inhibitor are tadalafil.

15. the method for claim 4 or 5, wherein said vascular disorder are selected from erection disturbance, atherosclerosis, renal failure, hypertension, congestive heart failure, diabetic nephropathy, diabetic neuropathy, interstitial lung disease, obstructive sleep respiratory difficulty, obstructive sleep apnea and resistance hypertension.

16. the method for claim 4 or 5, wherein said vascular disorder is a cardiovascular disorder.

17. the method for claim 15 wherein gives (a) and (b) basically simultaneously.

18. the method for claim 15 wherein gives (a) and (b) continuously.

19. a conjoint therapy, it comprises at least a endothelin A receptor (ET_A) antagonist and phosphodiesterase 5 (PDE5) inhibitor.

20. the conjoint therapy of claim 19, wherein said ET_AAntagonist is selected from 12m, A-127772, A-1277722, ABT-627, BE 1827, BE-18257A, BE-18257B, BE-18572A/B, BMS-182874, BMS-193884, BMS-20794, BQ-123, BQ-153, BQ-162, BQ-485, BQ-610, BQ-745, EMD-122946, EMD-94246, FR-139317, J-104121, J-104132, JKC-301, JKC-302, L-744453, L-749329, L-754142, LU127043, LU135252, LU208075, LU302146, PD-147953, PD-151242, PD-155080, PD-156707, RO61-1790, S-0139, SB 209670, SB 217242, SB-234551, SB-247083, sitaxentan, the different  azoles of sulfanilamide, TA-0115, TA-0201, TAK-044, TBC11251, TTA-386, WS-7338B, ZD1611 and composition thereof.

21. the conjoint therapy of claim 19; wherein said PDE5 inhibitor is selected from Vardenafil; tadalafil; Da Shengtafei; MBCQ; MY-5445; dipyridamole; furoyl base and benzo furoyl base pyrrolo-quinolinones; 2-(2-picoline-4-yl) methyl-4-(3; 4; the 5-trimethoxyphenyl)-8-(pyrimidine-2-base) methoxyl group-1; 2-dihydro-1-oxo-2; 7-naphthyridines-3-methyl formate hydrochlorate; T-1032 (2-(4-aminophenyl)-1; 2-dihydro-1-oxo-7-(2-pyridine radicals methoxyl group)-4-(3; 4,5-trimethoxy-phenyl)-3-isoquinolin methyl formate sulfate); sldenafil; RX-RA-69; SCH-51866; KT-734; vesnarinone; zaprinast; SKF-96231; ER-21355; BF/GP-385; NM-702 and composition thereof.

22. the conjoint therapy of claim 19, wherein said ET_AAntagonist is selected from ABT-627, sitaxentan, the different  azoles of sulfanilamide, TBC11251, ZD1611 and composition thereof.

23. the conjoint therapy of claim 19, wherein said PDE5 inhibitor is selected from Vardenafil, tadalafil, Da Shengtafei, dipyridamole, 2-(2-picoline-4-yl) methyl-4-(3,4, the 5-trimethoxyphenyl)-8-(pyrimidine-2-base) methoxyl group-1,2-dihydro-1-oxo-2,7-naphthyridines-3-methyl formate hydrochlorate, (2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridine radicals methoxyl group)-4-(3,4,5-trimethoxy-phenyl)-3-isoquinolin methyl formate sulfate), sldenafil, vesnarinone, zaprinast and composition thereof.

24. the conjoint therapy of claim 19, wherein said ET_AAntagonist is a sitaxentan.

25. the conjoint therapy of claim 19, wherein said PDE5 inhibitor is a sldenafil.

26. the conjoint therapy of claim 19, wherein said PDE5 inhibitor is a tadalafil.

27. the conjoint therapy of claim 19, wherein said ET_AAntagonist is that sitaxentan and described PDE5 inhibitor are sldenafil.

28. the conjoint therapy of claim 19, wherein said ET_AAntagonist is that sitaxentan and described PDE5 inhibitor are tadalafils.

29. the conjoint therapy of claim 19 wherein gives described ET together or separately_AAntagonist and PDE5 inhibitor.

30. the conjoint therapy of claim 19, wherein this conjoint therapy is a kind of pharmaceutical composition.

31. the conjoint therapy of claim 19, wherein said pharmaceutical composition are immediate release formulations.

32. the conjoint therapy of claim 30, wherein said ET_AAntagonist in controlled release preparation, the PDE5 inhibitor in controlled release preparation, or this two all in controlled release preparation.

33. the conjoint therapy of claim 30, wherein said ET_AAntagonist and PDE5 inhibitor but discharge ET with different speed all in controlled release preparation_AAntagonist and PDE5 inhibitor.

34. a pharmaceutical composition, it comprises ET_AAntagonist, PDE5 inhibitor and pharmaceutical carrier.

35. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist is selected from 12m, A-127772, A-1277722, ABT-627, BE 1827, BE-18257A, BE-18257B, BE-18572A/B, BMS-182874, BMS-193884, BMS-20794, BQ-123, BQ-153, BQ-162, BQ-485, BQ-610, BQ-745, EMD-122946, EMD-94246, FR-139317, J-104121, J-104132, JKC-301, JKC-302, L-744453, L-749329, L-754142, LU127043, LU135252, LU208075, LU302146, PD-147953, PD-151242, PD-155080, PD-156707, RO61-1790, S-0139, SB 209670, SB 217242, SB-234551, SB-247083, sitaxentan, the different  azoles of sulfanilamide, TA-0115, TA-0201, TAK-044, TBC11251, TTA-386, WS-7338B, ZD1611 and composition thereof.

36. the pharmaceutical composition of claim 34; wherein said PDE5 inhibitor is selected from Vardenafil; tadalafil; Da Shengtafei; MBCQ; MY-5445; dipyridamole; furoyl base and benzo furoyl base pyrrolo-quinolinones; 2-(2-picoline-4-yl) methyl-4-(3; 4; the 5-trimethoxyphenyl)-8-(pyrimidine-2-base) methoxyl group-1; 2-dihydro-1-oxo-2; 7-naphthyridines-3-methyl formate hydrochlorate; T-1032 (2-(4-aminophenyl)-1; 2-dihydro-1-oxo-7-(2-pyridine radicals methoxyl group)-4-(3; 4,5-trimethoxy-phenyl)-3-isoquinolin methyl formate sulfate); sldenafil; RX-RA-69; SCH-51866; KT-734; vesnarinone; zaprinast; SKF-96231; ER-21355; BF/GP-385; NM-702 and composition thereof.

37. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist is selected from ABT-627, sitaxentan, the different  azoles of sulfanilamide, TBC11251, ZD1611 and composition thereof.

38. the pharmaceutical composition of claim 34, wherein said PDE5 inhibitor is selected from Vardenafil, tadalafil, Da Shengtafei, dipyridamole, 2-(2-picoline-4-yl) methyl-4-(3,4, the 5-trimethoxyphenyl)-8-(pyrimidine-2-base) methoxyl group-1,2-dihydro-1-oxo-2,7-naphthyridines-3-methyl formate hydrochlorate, (2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridine radicals methoxyl group)-4-(3,4,5-trimethoxy-phenyl)-3-isoquinolin methyl formate sulfate), sldenafil, vesnarinone, zaprinast and composition thereof.

39. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist is a sitaxentan.

40. the pharmaceutical composition of claim 34, wherein said PDE5 inhibitor is a sldenafil.

41. the pharmaceutical composition of claim 34, wherein said PDE5 inhibitor is a tadalafil.

42. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist is that sitaxentan and described PDE5 inhibitor are sldenafil.

43. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist is that sitaxentan and described PDE5 inhibitor are tadalafils.

44. the pharmaceutical composition of claim 34, wherein this pharmaceutical composition is an immediate release formulations.

45. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist in controlled release preparation, the PDE5 inhibitor in controlled release preparation, or this two all in controlled release preparation.

46. the pharmaceutical composition of claim 34, wherein said ET_AAntagonist and PDE5 inhibitor but discharge ET with different speed all in controlled release preparation_AAntagonist and PDE5 inhibitor.