CN1344268A - Use of imidazo [1,5-a]pyrido[3,2-e]-pyrazinones as medicaments - Google Patents
Use of imidazo [1,5-a]pyrido[3,2-e]-pyrazinones as medicaments Download PDFInfo
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- CN1344268A CN1344268A CN00805307A CN00805307A CN1344268A CN 1344268 A CN1344268 A CN 1344268A CN 00805307 A CN00805307 A CN 00805307A CN 00805307 A CN00805307 A CN 00805307A CN 1344268 A CN1344268 A CN 1344268A
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Abstract
The invention relates to the use of imidazo[1,5-a]-pyrido[3,2-e]-pyrazinones of formula (1) as inhibitors for phosphodiesterase 5 for the therapy of erectile dysfunction (impotence). The invention also relates to the use of imidazo[1,5-a]-pyrido[3,2-e]-pyrazinones of formula (1) as dual inhibitors of phosphodiesterase 3 and of phosphodiesterase 5 for the therapy of heart failure, pulmonic hypertonia and vascular diseases which are accompanied by insufficient blood supply. The invention further relates to a method for making the same.
Description
Technical field
Imidazoles [1,5-a] pyrido [3,2-e] the pyrazine ketone that the present invention relates to have formula 1 structure is used for the treatment of application, its preparation method of erectile dysfunction (impotence) as active ingredient and comprises the pharmaceutical preparation of these compounds.
The invention further relates to the pharmaceutical preparation that imidazoles [1,5-a] pyrido [3,2-e] pyrazine ketone with formula 1 structure is used for the treatment of the application of heart failure, pulmonary hypertension and vascular disease relevant with low perfusion as active ingredient and comprises these compounds.
Prior art
Impotence may be defined as impotence, because do not erect and/or do not ejaculate.Erectile dysfunction is an employed term when erecing deficiency aspect sexual intercourse intensity or time length.
About 10% the male sex suffers from erectile dysfunction.The male sex at the 40-70 age in year is influenced by this especially, and affected number is approximately 52%.In the whole world, there are millions of male sex to suffer from this disease (only just having about 7.5 hundred ten thousand) in Germany, most of cases have organic reason, and only a few people is psychological reason.Erectile dysfunction is the elderly, particularly suffers from the ubiquitous problem of the elderly of other chronic disease such as hypertension, atherosclerosis and diabetes.
Although various activeconstituentss can both cause erection, they are only directly injecting penis (in the corpus cavernosum penis, i.c.) or splash into urethra (in the urethra) and play a role.This pharmacological agent form was used more than 10 year and had been comprised that i.c. injects vaso-active substance such as Papaverine, Phenoxybenzamine, phentolamine, carlytene and PGE
1(PGE
1).Yet i.c. gives these materials occur together usually severe side effect such as priapism, pain or penis fibrosis.PGE
1Can be by giving in the urethra, but pannonit and U-10858 transdermal administration (on penis).Yet this can cause side effect between the male sex and companion thereof.
Another kind of pharmacological agent is to carry out the surgery interventional therapy by implanting prosthetic.This form of therapy seldom has patient to accept, because anticipated later complication (infection, blood flow obstacle).
The breakthrough of erectile dysfunction treatment is the sildenafil (Viagra that is dropped at US and European by Pfizer
) beginning.Sildenafil is a kind of orally active phosphodiesterase 5 (PDE5) inhibitor, and it does not directly cause erection, but the effect of the nitrogen protoxide (NO) that the enhancing penis discharges under sexual stimulus.As its second messenger cGMP, in cavernous body (erectile tissue), the effect of NO is vasodilation, and the result can make more blood flow into, and causes erection.
Phosphodiesterase (PDE) is gang's isomerase, up to now, may tell off 10 kinds of different isomerases.The PDE enzyme is created in a large amount of cells 3 ', 5 '-one phosphoric acid cyclic guanosine (cGMP) and 3 ', 5 '-one phosphoric acid ring gland glycosides (cAMP) as the second messenger by hydrolytic cleavage.Phosphodiesterase 5 (PDE5) is that cGMP-is specific and preponderate in people sponge body tissue.Suppress the PDE5 in the people sponge body tissue, cause increasing by the intracellular cGMP level of NO inductive.This causes the cavernous body smooth muscle loosening and therefore causes erection.
Therefore the PDE5 inhibitor is applicable to the therapeutical agent as the erectile dysfunction indication.Relevant therewith, especially need PDE5 inhibitor new, that can be used as the active ingredient orally give.
Imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone still is unknown fully as active ingredient treatment erectile dysfunction.
Cardiovascular disorder is one of modal cause of death in the whole world.In WHO member states, have 30.9% among all dead persons in 1998 owing to cardiovascular disorder and wherein 13.7% by oneself owing to coronary heart disease (world's statement-of-health 1999).Yet cardiovascular disorder not only influences the elderly; On the contrary, since 30 years old, this sick incidence increased to some extent.They not only weaken patient's quality of life but also owing to direct and indirect cost issues, its treatment has huge economic implications.Remove foreign genetic element, the pathogeny of cardiovascular disorder is many-sided, particularly unsuitable diet and obesity, abuse of alcohol and Nicotine and shortage physical activity.
Coronary heart disease is a kind of common pathological state, and it comprises stenocardia and myocardial infarction.Stenocardia is the multifactor pathology state that is caused by coronary atherosclerosis.The coronary stricture of restriction of blood flow causes the heart muscle perfusion deficiency, and manifestation has stable form or unstable angina pectoris, asymptomatic myocardial ischaemia, local asphyxia DHF, worry arrhythmia or Acute Myocardial Infarction.Myocardial infarction is caused by thrombus (blood clot) blocking-up coronary artery.Described thrombus is trapped in the stenosis of coronary vasodilator usually.The cardiac muscle district that is positioned at after this stenosis no longer obtains blood supply.According to the position of infraction, affected zone is changeable.Base therapy comprises to be eliminated known Hazard Factor and by using acetylsalicylic acid or ticlopidine, takes the medical approaches anticoagulant.With vasodilator such as nitric ether, beta-blocker or calcium channel blocker treatment angina pectoris attacks, although the side effect that these may have unwanted effect such as ypotension, blood heavily distributes (stealing flow phenomenon) or heart to suppress.The patient that can find out the coronary stricture position clearly can carry out bypass surgery (index: coronary heart disease/stenocardia.Guideline019/001?of?22?June?1998?of?the?Deutsche?Gesellschaft?furKardiologie-Herz-und??Kreislaufforschung?in?derArbeitsgemeinschaft?der?Wissenschaftlichen?MedizinischenFachgesellschaften)。
Another important disease is in heart failure.The no longer supply of blood and oxygen in the sufficient to guarantee health of the pump output that various factors causes heart.Three kinds of forms of cardiac failure are: right heart failure, left heart failure and heart failure whole-heartedly.In right heart failure, right ventricle no longer can pump into pulmonary circulation with the blood of requirement.Yet because blood continues to arrive the right heart from the body circulation, because left ventricle continues to work incessantly, blood is trailed and is got back to belly, liver and even get back to shank.Left heart failure is an employed term when left chamber no longer provides essential work output.In this case, blood fills in lung.Under the situation of heart failure whole-heartedly, before right heart failure or left heart failure took place, two ventricles all were affected usually.
The treatment of Cardiac Insufficiency always at first concentrates on basic disease, for example in worry arrhythmia (with other heart trouble) or the hypertensive treatment.In addition, use cardiac function enhancing or alleviate the medicine of heart burden (according to the reason of Cardiac Insufficiency) and the medicine (diuretic(s), volume reduce) that anhydrates is treated usually.Usually assert the activity of cardiotonic glycoside (for example digoxin, g-uabain) " saving " heart, and these medicines can be taken for a long time.Phosphodiesterase 3 (PDE3) inhibitor increases the concentration of a phosphoric acid ring gland glycosides (cAMP) in the cardiac muscle, therefore increases convergent force by various cAMP deopendent protein kinases.Show that in various clinical studyes PDE3 inhibitor (amrinone, milrinone) clearly is the convergent force toughener, reduce the trend that life expectancy is worth but use continuously to have.Therefore, this material only can be used for acute phase (time length is for using 2-3 week) treatment.Also can use β-adrenoreceptor agonists such as Dopamine HCL and DOPA butylamine, they have the effect of direct enhancing myocardial contraction, but are only applicable to the treatment of acute heart failure.
By using angiotensin converting enzyme inhibitor (ACE inhibitor, for example captopril, enalapril) or angiotensin receptor antagonist (for example losartan), selectivity α 1-adrenergic receptor blocker (for example Prazosin) or organic nitrates to reduce afterload.
Only under indispensable situation, carry out heart transplantation.This is the last option when all other methods have all been failed.Although transplant, comprise other organ transplantation, become a treatment approach at present, heart transplantation is not no problem.
Pulmonary hypertension appears when above when Ppa pulmonary artery pressure rises to 25mmHg.This causes taking place pulmonary heart disease (right ventricle expansion).The reason of essential hypertension is unclear.Inherited genetic factors or the reason relevant with medicine are possible.Primary pulmonary hypertension especially tends to 30 next years old women.The Secondary cases pulmonary hypertension is impaired that cause and may have a variety of causes by kapillary circulation.Because therefore metarteriole hyperemia take place in pulmonic stenosis when obstructive emphysema, asthmatic crisis, pulmonary fibrosis or embolism.Its treatment comprises that reducing Ppa pulmonary artery pressure therefore also alleviates the right ventricle burden.Obtainable up to now material only is those material (ACE inhibitor with non-selective vasorelaxation action, the Ca channel blocker, dihydropyridines) or only use in test and (suck nitrogen protoxide (NO), prostaglin X (PGI2) or prostacycline, adenosine and PGE1, Medical and Surgical Treatment ofAdvanced Pulmonary Hypertension by Kenneth W. Presberg, Division of pulmonary and Critical Care Medicine, MedicalCollege of Wisconsin, Thoracic Medical and SurgicalManagement, Volume III, Number 2 1996).
Phosphodiesterase (PDE) is gang's isomerase, up to now, may tell off 10 kinds of different isomerases.The PDE enzyme is created in a large amount of cells 3 ', 5 '-one phosphoric acid cyclic guanosine (cGMP) and 3 ', 5 '-one phosphoric acid ring gland glycosides (cAMP) as the second messenger by hydrolytic cleavage.Phosphodiesterase 3 (PDE3) is that cAMP-is specific, and phosphodiesterase 5 (PDE5) is that cGMP-is specific.
Just as has already been described, in known phosphodiesterase inhibitor, have only several selectivity PDE3 inhibitor to find to have limited treatment heart failure effect up to now.
Imidazoles [1,5-a] pyrido [3,2-e] the pyrazine ketone that the present invention relates to have formula 1 structure is as the application of active ingredient in treatment heart failure, pulmonary hypertension and vascular disease relevant with low perfusion, and its simultaneously and suppress PDE3 and PDE5 strongly.PDE3 in the inhibition cardiac muscle causes increasing in a kind of known mode the convergent force (positive inotropic action) of heart.Suppress PDE5 and cause particularly arteries expansion and therefore of blood vessel, for example reduce coronary vasodilator or Pulmonic vascular resistance.
Before also do not disclose and realized utilizing simultaneously two kinds of action principles technically by formula 1 compound of the present invention first, promptly cause the arteries expansion, thereby obtain positive inotropic action and hypotensive activity heart by a kind of with identical active ingredient.
As the double inhibitor of PDE3 and PDE5, imidazoles [1,5-a] pyrido [3,2-e] pyrazine ketone or complete the unknown.
European patent 0 400 583 relates to the imidazoles quinoxaline with following general formula
Wherein A represents 7 or 8 nitrogen-atoms or CH, and B and D represent the carbon atom of nitrogen-atoms or CH or replacement, and other radicals R, R
1, R
2Represent hydrogen or various organic substituting group.These compounds have vasorelaxation action.
Remove outside various imidazos [1, the 2-a] quinazolinone, (J.Med.Chem.34 (1991) 2671-2677) has also described 2-imidazoles [1,5-a] pyrido [3,2-e] the pyrazine ketone with following formula structure to people such as D.D.Davey
R on the one hand wherein
1Represent hydrogen and R
2Represent C
2H
5, R on the other hand
1Represent glyoxal ethyline and R
2Represent CH
3The characteristic of two compounds all is as the PDE3 inhibitor with positive inotropic action.
Patent application W0 93/20077 relates to the imidazo quinazolinone with following formula structure
The 5-unit heterocycle that wherein has 2 or 3 nitrogen-atoms in the A representative ring, R
1Can be NO
2Or CF
3And the X representative has the various chains that are no more than 4 chain members, and some of them comprise nitrogen.
These compounds are described as the glutamate receptor antagonist with treatment psychosis effect and anti-ischemia effect.
Required to have pyrido [3, the 2-e]-pyrazine ketone of following formula structure in the DE patent 195 10 965.
These also comprise imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone.Yet, wherein only work as A and represent N-R
3(R
3=H, C
1-6Alkyl) time, R
1Be hydrogen.The anti-asthma and the antiallergic property of the material that requires have been described.
The present invention describes
The present invention relates to have imidazo [1,5-a] pyrido [3, the 2-e]-pyrazine ketone of formula 1 structure
Wherein
A represents O or NH,
R
1, R
2And R
3Can be identical or different and represent hydrogen and
-C
1-8Alkyl, it is straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl, have 3-14 ring go up member's list-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, have 5-15 ring members and 1-6 heteroatoms, preferably the list of N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocyclic substituted one or many
-C
2-8Alkenyl, it is single-or polyunsaturated, straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl, have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, have 5-15 ring members and 1-6 heteroatoms, preferably the list of N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocyclic substituted one or many
-C
2-8Alkynyl, it is single-or polyunsaturated, straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl, have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, have 5-15 ring members and 1-6 heteroatoms, preferably the list of N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocyclic substituted one or many
-have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, it is unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl replaces one or many,
-have the list of 5-15 ring members and 1-66 heteroatoms, preferred N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocycle, it is unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl replaces one or many.
Element of the present invention is, formula 1 compound has nitrogen-atoms and contains A=O or the NH Segment A at 9, and it is the prerequisite for the treatment of therapeutic agent for erection failure basic structure as the present invention.
Formula 1 compound of A=O of the present invention is new.Formula 1 compound of A=NH of the present invention can know from patent DE 195 10 965 that described patent documentation was quoted in the prior art as a reference.
The present invention also relates to the salt of formula 1 compound that can tolerate on the physiology, it can be by with inorganic or organic acid neutralization bases or by with inorganic or organic bases neutralizing acid or by the quaternized quaternary ammonium salt that obtains of tertiary amine is obtained.
Have under the situation of a unsymmetrical carbon at formula 1 compound, the present invention relates to D type, L type and D, the L mixture having under the above unsymmetrical carbon situation, the present invention relates to diastereomeric form.
The invention further relates to the method for preparing formula 1 compound of the present invention.
According to the present invention, have above-mentioned A, R
1, R
2And R
3General formula 1 compound of implication can prepare by following method: will have identical A, R
1, R
2And R
3The 3-aminopyridine of the formula 2 of implication and cyanate be reaction in the presence of acid in organic solvent,
Subsequently, will be with the preparation of this method have identical A, a R
1, R
2And R
3The urea of the formula 3 of implication heats in organic solvent, being cyclized into formula 1 compound of the present invention,
The changing method of preparation formula 3 ureas comprises the use alkali metal cyanate, and it is that preparation method of the present invention is particularly preferred.
The changing method of preparation formula 3 ureas is included in protonic solvent, particularly preferably in reacting in the acetate, it is that preparation method of the present invention is preferred.
The changing method of preparation formula 3 ureas be included in mineral acid, especially preferably with the blendable dense mineral acid of use solvent, for example in the presence of concentrated hydrochloric acid the reaction, it is that preparation method of the present invention is preferred.
The changing method of cyclisation formula 3 ureas comprises the solvent of use boiling point＞80 ℃, the solvent of boiling point＞100 ℃ especially preferably, and it is that to form the preparation method of the present invention of formula 1 compound of the present invention preferred.
The changing method of cyclisation formula 3 ureas is included in＞80 ℃ temperature of reaction under, particularly preferably in reacting under＞100 ℃ the temperature of reaction, it is that to form the preparation method of the present invention of formula 1 compound of the present invention preferred.
The particularly advantageous part of The compounds of this invention is that they can be used as new erectile dysfunction indication therapeutical agent and pass through orally give.
Further integral part of the present invention is, the solution of the The compounds of this invention described in the embodiment particularly preferably is used for orally give.
The preferred treatment plan of orally give 5-200mg compounds represented before sexual intercourse.Described compound also can be used as solution and uses by non-enteron aisle, oral, cheek (buccally) or hypogloeeis.
Integral part of the present invention also comprises, also comprises the medicament production of one or more formula 1 compounds of the present invention and the preparation method of these medicament production thereof carrier that can tolerate on conventional physiology and/or thinner or the auxiliary agent.
Formula 1 compound of the present invention and comprise the medicine of formula 1 compound of the present invention can be separately be bonded to each other use.
Further composition of the present invention is that The compounds of this invention can be used as therapeutical agent and prevents and treat the buck erectile dysfunction in the animal doctor.Dosage, dosage regimen and the pharmaceutical preparation of selection compound should be considered the requirement of species difference and animal doctor's doctor's advice.
The invention further relates to imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone and as the application of therapeutical agent in treatment heart failure, pulmonary hypertension and vascular disease relevant with low perfusion with formula 1 structure.
Wherein
A represents O or NH,
R
1And R
2Can be identical or different and can represent hydrogen and
-C
1-5Alkyl, it is straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NO
2,-CN ,-COOH ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-S-C
1-6-alkyl replaces one or many, and
R
3Represent hydrogen and
-C
1-5Alkyl, it is straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NO
2,-CN ,-COOH ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-S-C
1-6-alkyl or phenyl replaces one or many.
Element of the present invention is, formula 1 compound has nitrogen-atoms and comprises A=O or the Segment A of NH at 9, it be as the present invention treat heart failure, pulmonary hypertension with the prerequisite of the relevant vascular disease therapeutical agent basic structure of low perfusion.
About described formula 1 compound of the present invention as therapeutical agent treatment heart failure, pulmonary hypertension with the application of the relevant vascular disease of low perfusion, the present invention also relates to the salt that can tolerate on these compound physiology, they can be by with inorganic or organic acid neutralization bases or by with inorganic or organic bases neutralizing acid or by the quaternized quaternary ammonium salt that obtains of tertiary amine is obtained.
About described formula 1 compound of the present invention as therapeutical agent treatment heart failure, pulmonary hypertension with the application of the relevant vascular disease of low perfusion, have under the situation of a unsymmetrical carbon at formula 1 compound, the present invention relates to D type, L type and D, the L mixture, and have under the above unsymmetrical carbon situation, the present invention relates to diastereomeric form.
About described formula 1 compound of the present invention as therapeutical agent treatment heart failure, pulmonary hypertension with the application of the relevant vascular disease of low perfusion, The compounds of this invention can be by the mode of being administered systemically, for example give by intravenously, intramuscular and subcutaneous and oral administration mode.The orally give The compounds of this invention is particularly preferred.
Further integral part of the present invention is, as therapeutical agent treatment heart failure, pulmonary hypertension with the application of the relevant vascular disease of low perfusion in, the solution of the The compounds of this invention described in the embodiment particularly preferably is used for orally give.
Described compound also can use by non-enteron aisle, cheek or hypogloeeis with the solution form.
Integral part of the present invention also comprises, also comprises the medicament production of one or more formula 1 compounds of the present invention and the preparation method of these medicament production thereof carrier that can tolerate on conventional physiology and/or thinner or the auxiliary agent.
Described formula of the present invention 1 compound and comprise the medicine of described formula of the present invention 1 compound can be separately be bonded to each other use.
Described formula of the present invention 1 compound is at external while and more intense inhibition PDE3 and PDE5.
Have been found that described formula of the present invention 1 compound causes that in vivo cardiac contractile force strengthens (positive inotropic action) and causes blood vessel, particularly arteries expansion simultaneously.
Integral part of the present invention is that the dual function principle of described The compounds of this invention makes that suppressing to take place serious change of blood pressure becomes possibility with relevant ARR danger with hypoxgia.
One aspect of the present invention is that formula 1 compound of the present invention especially can be used for treating acute phase heart failure, coronary heart disease and pulmonary heart disease.
Embodiment 8-methoxyl group-3-methyl isophthalic acid-propyl imidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone (1) also
29.6g (0.1mol) 3-amino-6-methoxyl group-2-(4-methyl-2-propyl imidazole-1-yl) pyridine is added in the 165ml acetate, and adds 11.8g (0.14mol) potassium cyanate in the solution of 15ml water.Then, under agitation, add 15.5ml concentrated hydrochloric acid (37% concentration), and this compound was stirred 4 hours down at 25-30 ℃.In this reaction soln, add 400ml water then, and transfer to pH8 with strong caustic.When in cooled on ice, N-[6-methoxyl group-2-(4-methyl-2-propyl imidazole-1-yl) pyridin-3-yl] urea crystallizes out.Separate this intermediate, wash with water and drying under 60 ℃.
With this urea boiling reflux 4 hours in 100ml DMF.By using ice-cooled this reaction soln subsequently, product crystallizes out.Separate, with DMF washing and dry down at 80 ℃.
Yield: 14g (theoretical value 51%)
Fusing point: 294-295 ℃
A large amount of other formula 1 compounds can be by using the suitable variation preparation of pointed method among the embodiment, and wherein, following compounds mode is by way of example listed:
Be used for the preparation of the solution of compound 1 oral administration
| Compound | ????A | ????R 1 | ???R 2 | ????R 3 | Fusing point [℃] |
| ??1 | ????O | ??C 3H 7 | ??CH 3 | ????CH 3 | ??294-295(DMF) |
| ??2 | ????O | ????H | ???H | ????CH 3 | ??314-317(DMF) |
| ??3 | ????O | ????H | ??CH 3 | ????CH 3 | ??321-323(DMF) |
| ??4 | ????O | ???CH 3 | ???H | ????CH 3 | ??309-311(DMF) |
| ??5 | ????O | ??C 3H 7 | ???H | ????CH 3 | ??289-290(DMF) |
| ??6 | ????O | ??C 2H 5 | ??CH 3 | ????H | 320 decompose (DMF) |
| ??7 | ????O | ??C 2H 5 | ??CH 3 | ????CH 3 | ??314-315(DMF) |
| ??8 | ???NH | ??C 2H 5 | ??CH 3 | ????CH 2-C 6H 5 | ??276-278(DMF) |
| ??9 | ????O | ??C 2H 5 | ??CH 3 | ??(CH 2) 3-OH | 303-305 decomposes (DMF) |
| ??10 | ????O | ??C 2H 5 | ??CH 3 | ??CH 2(C＝O)CH 3 | 312-314 decomposes (DMF) |
| ??11 | ????O | ??C 2H 5 | ??CH 3 | ?CH 2-2-pyridyl | ??299-301(DMF) |
| ??12 | ????O | ??C 6H 5 | ???H | ????CH 3 | ??323(DMF) |
| ??13 | ????O | ????H | ?C 6H 5 | ????CH 3 | 326 decompose (DMF) |
Compound 1 for example is dissolved in the 1N hydrochloric acid with the ratio of 10-50mg/ml.Further use distilled water diluting, add 10% (volume ratio) polyoxyethylene glycol 660-12-hydroxy stearic acid ester (Solutol with 1: 9 ratio
HS15), obtain clear soln, it comprises the compound 1 of 1-5mg/ml and is used as drinkable or injectable solution.The biological action of The compounds of this invention in the treatment erectile dysfunction
The compounds of this invention is the potent inhibitor of phosphodiesterase 5.For example, its treatment ability external by strengthen NO to mouse fibroblast cell in the effect and the relax human cavernous body of intracellular cGMP level obtain proof.Phosphodiesterase 5 restraining effect
The activity of PDE5 obtains proof the zymin that obtains from human blood platelets.With human blood Citric Acid anti-freezing.At room temperature, being rich in hematoblastic blood plasma in 700 * g made supernatant liquor in centrifugal 20 minutes separates with white corpuscle with red corpuscle.With thrombocyte by ultrasonic dissolution and be used for PDE5 and measure.The activity of phosphodiesterase can be by carrying out the described method of people such as Thompson (Thompson, the W.J. of some modifications; Appleman, M.M., the fractionation .Adv.Cycl.Nucl.Res.1979 of the mensuration of cyclic nucleotide phosphodiesterase and polymolecular form enzyme, 10,69-92) measure.
Reaction mixture comprises 50mM Tris-HCl (pH 7.4), 5mM MgCl
2, various concentration inhibitor, zymin and mensuration necessary other component of each isomerase PDE5 (as follows).By adding substrate, i.e. 0.5 μ m[
3H[-cGMP (approximately 6000CPM/ measures) begins reaction.Final volume is 100ml.
Substances is mixed with storing solution in DMSO.The concentration of DMSO in reaction mixture is 1%v/v.This DMSO concentration is to the active not influence of PDE5.By adding after substrate begins reaction, sample was cultivated 30 minutes down at 37 ℃.By test tube is heated 2 minutes termination reactions down at 110 ℃.Sample was kept in ice 10 minutes again.Add 30 μ l5 '-phosphonucleases (1mg/ml obtains) from the suspension of crotalus adamanteus venom, cultivated 10 minutes down at 37 ℃ then.On ice, each adds 400 μ l Dowex-water-ethanol (1+1+1) mixtures and after fully stirring, they was cultivated on ice 15 minutes again with sample storage.With reaction vessel under 3000 * g centrifugal 20 minutes.The supernatant liquor of 200 μ l sample aliquot is directly transferred in the scintillator.After adding the 3ml scintillator, sample is measured on beta-counter.When measuring PDE5, the non-specific enzymic activity under the various situations of mensuration in the presence of the 100 μ M IBMX also deducts from measured value.
For The compounds of this invention, the IC of the inhibition phosphodiesterase 5 of its mensuration
50Value is 10
-9-10
-5The M scope.
For example, for selected embodiment, the IC of its mensuration
50Be worth as follows:
Induce inoblast (mouse) to produce NO
| Embodiment | IC 50[μmol/l] |
| ????1 | ????0.01 |
| ????5 | ????0.12 |
| ????7 | ????0.10 |
| ????8 | ????0.07 |
The lung fibroblast of mouse fetus (RFL-6) representative suitable, the effect of cGMP level is subjected to medium people such as (, 1991) Ishii of which factor affecting in the research NO pair cell.This ultimate principle can be applicable to the vascular smooth muscle in the cavernous body.
The compounds of this invention improves by NO donor S-nitroso-group-N-ethanoyl-D in concentration dependence mode, and L-Trolovol inductive intracellular cGMP level increases.
Therefore, for example, compound 1 causes the remarkable rising of cGMP level under 0.010 μ mol/1 concentration.Therefore, active 10,000 times of being to use non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) to obtain of the activity of compound 1.The external relaxation effect of people's cavernous body
Strip people cavernous body in organ bath is shunk with norepinephrine in advance.The relaxation effect of determination test compound is with the function representation of concentration.
The compounds of this invention has relaxation effect, and it depends on concentration, depends on the strip cavernous body that shrinks with norepinephrine in advance.Therefore, for example, for compound 1, the EC of its mensuration
50Be 0.35 μ mol/l.The biological action of The compounds of this invention in treatment heart failure, pulmonary hypertension and vascular disease relevant with low perfusion
Formula 1 compound of the present invention is the double inhibitor of phosphodiesterase 3 and phosphodiesterase 5.For example, its treatment can external by strengthen NO to mouse fibroblast cell in the effect of intracellular cGMP level obtain proof.Phosphodiesterase 3 restraining effect
The activity of PDE 3 obtains proof the zymin that obtains from human blood platelets.With human blood Citric Acid anti-freezing.At room temperature, being rich in hematoblastic blood plasma in 700 * g made supernatant liquor in centrifugal 20 minutes separates with white corpuscle with red corpuscle.With thrombocyte by ultrasonic dissolution and be used for PDE3 and measure.The activity of phosphodiesterase can be by carrying out the described method of people such as Thompson (Thompson, the W.J. of some modifications; Appleman, M.M., the fractionation .Adv.Cycl.Nucl.Res.1979 of the mensuration of cyclic nucleotide phosphodiesterase and polymolecular form enzyme, 10,69-92) measure.
Reaction mixture comprises 50mM Tris-HCl (pH 7.4), 5mM MgCl
2, various concentration inhibitor, zymin and mensuration necessary other component of each isomerase PDE3 (as follows).By adding substrate, i.e. 0.5 μ m[
3H]-cAMP (approximately 6000CPM/ measure) begins reaction.Final volume is 100ml.
Substances is mixed with storing solution in DMSO.The concentration of DMSO in reaction mixture is 1%v/v.This DMSO concentration is to the active not influence of PDE3.By adding after substrate begins reaction, sample was cultivated 30 minutes down at 37 ℃.By test tube is heated 2 minutes termination reactions down at 110 ℃.Sample was kept in ice 10 minutes again.Add 30 μ l, 5 '-phosphonuclease (1mg/ml obtains) from the suspension of crotalus adamanteus venom, cultivated 10 minutes down at 37 ℃ then.On ice, each adds 400 μ l Dowex-water-ethanol (1+1+1) mixtures and after fully stirring, they was cultivated on ice 15 minutes again with sample storage.With reaction vessel under 3000 * g centrifugal 20 minutes.The supernatant liquor of 200 μ l sample aliquot is directly transferred in the scintillator.After adding the 3ml scintillator, sample is measured on beta-counter.When measuring PDE3, the non-specific enzymic activity under the various situations of mensuration in the presence of the 100 μ M IBMX also deducts from measured value.
For The compounds of this invention, the IC of the inhibition phosphodiesterase 3 of its mensuration
50Value is 10
-9-10
-5In the M scope.
For example, for selected embodiment, the IC of its mensuration
50Be worth as follows:
Phosphodiesterase 5 restraining effect
| Embodiment | IC 50[μmol/l] |
| ????1 | ????0.02 |
| ????5 | ????0.04 |
| ????7 | ????0.07 |
| ????8 | ????0.07 |
The activity of PDE5 obtains proof the zymin that obtains from human blood platelets.With human blood Citric Acid anti-freezing.At room temperature, being rich in hematoblastic blood plasma in 700 * g made supernatant liquor in centrifugal 20 minutes separates with white corpuscle with red corpuscle.With thrombocyte by ultrasonic dissolution and be used for PDE5 and measure.The activity of phosphodiesterase can be by carrying out the described method of people such as Thompson (Thompson, the W.J. of some modifications; Appleman, M.M., the fractionation .Adv.Cycl.Nucl.Res.1979 of the mensuration of cyclic nucleotide phosphodiesterase and polymolecular form enzyme, 10,69-92) measure.
Reaction mixture comprises 50mM Tris-HCl (pH 7.4), 5mM MgCl
2, various concentration inhibitor, zymin and mensuration necessary other component of each isomerase PDE5 (as follows).By adding substrate, i.e. 0.5 μ M[
3H]-cGMP (approximately 6000CPM/ measure) begins reaction.Final volume is 100ml.
Substances is mixed with storing solution in DMSO.The concentration of DMSO in reaction mixture is 1%v/v.This DMSO concentration is to the active not influence of PDE5.By adding after substrate begins reaction, sample was cultivated 30 minutes down at 37 ℃.By test tube is heated 2 minutes termination reactions down at 110 ℃.Sample was kept in ice 10 minutes again.Add 30 μ l, 5 '-phosphonuclease (1mg/ml obtains) from the suspension of crotalus adamanteus venom, cultivated 10 minutes down at 37 ℃ then.On ice, each adds 400 μ l Dowex-water-ethanol (1+1+1) mixtures and after fully stirring, they was cultivated on ice 15 minutes again with sample storage.With reaction vessel under 3000 * g centrifugal 20 minutes.The supernatant liquor of 200 μ l sample aliquot is directly transferred in the scintillator.After adding the 3ml scintillator, sample is measured on beta-counter.When measuring PDE5, the non-specific enzymic activity under the various situations of mensuration in the presence of the 100 μ M IBMX also deducts from measured value.
For The compounds of this invention, the IC of the inhibition phosphodiesterase 5 of its mensuration
50Value is 10
-9-10
-5In the M scope.For example, for selected embodiment, the IC of its mensuration
50Be worth as follows:
Induce inoblast (mouse) to produce NO
| Embodiment | IC 50[μmol/l] |
| ????1 | ????0.01 |
| ????5 | ????0.12 |
| ????7 | ????0.10 |
| ????8 | ????0.07 |
The lung fibroblast of mouse fetus (RFL-6) representative suitable, the effect of cGMP level is subjected to medium people such as (, 1991) Ishii of which factor affecting in the research NO pair cell.This ultimate principle can be applicable to the vascular smooth muscle in the cavernous body.
The invention compound improves by NO donor S-nitroso-group-N-ethanoyl-D in concentration-dependence mode, and L-Trolovol inductive intracellular cGMP level increases.
Therefore, for example, compound 1 causes the remarkable rising of cGMP level under 0.010 μ mol/l concentration.Therefore, active 10,000 times of being to use non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) to obtain of the activity of compound 1.The cycle analysis of screech owl short-leg beagle under the narcosis
The screech owl short-leg beagle that 4 body weight are 9.0-15.0kg is used for this research.Give 80mg/kg cloralose with the animal intravenously and the 400mg/kg urethane is anaesthetized.Give the dog intubate, but do not take a breath by manual method.
Then brachial artery is ready for record periphery blood pressure.The conduit of introducing terminal little point by right carotid is used to write down left ventricular systolic pressure/diastolic pressure.Measure cardiac output by thermodilution.For this reason, introduce the Swan-Ganz conduit by femoral vein.A/C like this can be at the Pulmonic blood pressure of its most advanced and sophisticated mensuration.Injection 3.0ml physiological saline (4.0 ℃ of temperature) and the variation of temperature of passing through in the truncus aortae are measured cardiac output.
By four limbs recording surface ECG.This ECG parameter is assessed automatically.
Computer aided system obtains and calculates all blood pressures.
For example, in these researchs, may show, rely on the The compounds of this invention 1 of the dosage range that gives 0.25-3.0mg/kg in the mode stomach with dosage after, the convergent force of heart increases (4 times of left chamber elevations of blood pressure), cardiac output increases by 2 times.Although the heart working amount increases greatly, arteriotony only slightly rises in the early stage, and pressure amplitude increases.High dosage slightly reduces systolic pressure.
Although compound 1 cause cardiac output huge with secular increase, do not observe irregular pulse relevant or premature contraction with hypoxgia, this proof compound 1 have strong coronary artery expansion effect.
Claims (28)
1. imidazo [1,5-a] pyrido [3, the 2-e]-pyrazine ketone that has formula 1 structure
Wherein
A represents O,
R
1, R
2And R
3Can be identical or different and can represent hydrogen and
-C
1-8Alkyl, it is straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl, have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, have 5-15 ring members and 1-6 heteroatoms, preferably the list of N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocyclic substituted one or many
-C
2-8Alkenyl, it is single-or polyunsaturated, straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl, have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, have 5-15 ring members and 1-6 heteroatoms, preferably the list of N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocyclic substituted one or many
-C
2-8Alkynyl, it is single-or polyunsaturated, straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl, have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, have 5-15 ring members and 1-6 heteroatoms, preferably the list of N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocyclic substituted one or many
-have the list of 3-14 ring members-, two-or three ring fillings or single-or polyunsaturated carbocyclic ring, it is unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl replaces one or many,
-have the list of 5-15 ring members and 1-6 heteroatoms, preferred N, O and S-, two-or three ring fillings or single-or polyunsaturated heterocycle, it is unsubstituted or by-OH ,-SH ,-NH
2,-NHC
1-6-alkyl ,-N (C
1-6-alkyl)
2,-NHC
6-14-aryl ,-N (C
6-14-aryl)
2,-N (C
1-6-alkyl) (C
6-14-aryl) ,-NO
2,-CN ,-COOH ,-COOC
1-5-alkyl ,-(C=O) C
1-5-alkyl ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-O-C
6-14-aryl ,-S-C
1-6-alkyl ,-S-C
6-14-aryl ,-OSO
2C
1-6-alkyl ,-OSO
2C
6-14-aryl replaces one or many.
2. the salt that can tolerate on the physiology of formula 1 compound of claim 1 is characterized in that it can be by with inorganic or organic acid neutralization bases or by with inorganic or organic bases neutralizing acid or by the quaternized quaternary ammonium salt that obtains of tertiary amine is obtained.
3. claim 1 and 2 formula 1 compound, under the situation with an asymmetry carbon atom, with D type, L type and D, the L form of mixtures exists, and having under the above unsymmetrical carbon situation, exists with diastereomeric form.
4. a kind of in formula 1 compound, the especially following compounds of claim 1-3:
8-methoxyl group-3-methyl isophthalic acid-propyl imidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone;
8-methoxyl group-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group-1-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group-1-propyl imidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
1-ethyl-8-hydroxy-3-methyl imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone;
1-ethyl-8-methoxyl group-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
1-ethyl-8-(3-hydroxypropyl)-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
1-ethyl-3-methyl-8-(2-oxopropyl) imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone;
1-ethyl-3-methyl-8-(2-pyridylmethyl) imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone;
8-methoxyl group-1-phenylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group-3-phenylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also.
Formula 1 compound of preparation claim 1-4 and wherein A represent NH, R
1, R
2, R
3Can be the method for other formula 1 compound identical or different and that also have the described implication of claim 1, it is characterized in that to have identical A, R
1, R
2And R
3The 3-aminopyridine of the formula 2 of implication is reacted with cyanate in the presence of acid in organic solvent,
Subsequently, have identical A, a R with consequent
1, R
2And R
3The urea of the general formula 3 of implication heats in organic solvent,
Therefore cyclisation generates formula 1 compound of the present invention.
6. by method preparation formula 1 compound of claim 5, especially preferably use alkali metal cyanate to come the intermediate of acquisition formula 3.
7. by method preparation formula 1 compound of claim 5 and 6, especially preferably use protonic solvent to come the intermediate of acquisition formula 3.
8. by method preparation formula 1 compound of claim 5-7, there is the intermediate of acquisition formula 3 down particularly preferably in mineral acid.
9. pass through method preparation formula 1 compound of claim 8, particularly preferably in having the intermediate of acquisition formula 3 down with the blendable dense mineral acid of the employed protonic solvent of claim 7.
10. method preparation formula 1 compound by claim 5-9 especially preferably uses the urea of the solvent cyclisation formula 3 of boiling point＞80 ℃.
11. method preparation formula 1 compound by claim 10 especially preferably uses the urea of the solvent cyclisation formula 3 of boiling point＞100 ℃.
12., especially preferably use the urea of＞80 ℃ temperature of reaction cyclisation formula 3 by method preparation formula 1 compound of claim 5-11.
13., especially especially preferably use the urea of＞100 ℃ temperature of reaction cyclisation formula 3 by method preparation formula 1 compound of claim 12.
14. formula 1 compound of claim 1-4 and wherein A represent NH, R
1, R
2, R
3It can be other formula 1 compound identical or different and that have the described implication of claim 1 is used for the medicine of preparation treatment erectile dysfunction (impotence) as therapeutical agent application.
15. medicament production, comprise the compound of one or more claims 1-4 and wherein A represent NH, R
1, R
2, R
3Can be carrier and/or the thinner or the auxiliary agent that can tolerate on other formula 1 compound identical or different and that also have the described implication of claim 1 and the conventional physiology.
16. the method for medicament production of preparation claim 15 is characterized in that, with the compound of claim 1-4 and wherein A represent NH, R
1, R
2, R
3Can be other formula 1 compound identical or different and that also have the described implication of claim 1 be processed into pharmaceutical preparation or be converted into the form that can use in treatment with conventional pharmaceutically acceptable carrier and/or thinner or other auxiliary agent.
17. general formula 1 compound of claim 1-4 and wherein A represent NH, R
1, R
2, R
3Can be other formula 1 compound identical or different and that also have the described implication of claim 1 and/or claim 15 and 16 pharmaceutical preparation separately or be bonded to each other or use with carrier and/or thinner or other auxiliary agent bonded.
18. the compound of claim 1-4 and wherein A represent NH, R
1, R
2, R
3Can be that other formula 1 compound identical or different and that also have the described implication of claim 1 is used to prepare the treatment erectile dysfunction (impotence) of claim 14, the preferred especially application by oral, non-enteron aisle, cheek or hypogloeeis administered agents product as therapeutical agent.
19. the compound of claim 1-4 and wherein A represent NH, R
1, R
2, R
3Can be that other formula 1 compound identical or different and that also have the described implication of claim 1 is as being used to prevent and treat the application of the animal doctor of boar erectile dysfunction with therapeutical agent.
20. imidazo [1,5-a] pyrido [3, the 2-e]-pyrazine ketone with formula 1 structure as the therapeutical agent active ingredient be used to prepare treatment heart failure, pulmonary hypertension and with the low application that is perfused with the medicine of related disorders,
Wherein
A represents O or NH,
R
1And R
2Can be identical or different and can represent hydrogen and
-C
1-5Alkyl, it is straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NO
2,-CN ,-COOH ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-S-C
1-6-alkyl replaces one or many, and
R
3Represent hydrogen and
-C
1-5Alkyl, it is straight chain or side chain, unsubstituted or by-OH ,-SH ,-NH
2,-NO
2,-CN ,-COOH ,-F ,-Cl ,-Br ,-I ,-O-C
1-6-alkyl ,-S-C
1-6-alkyl or phenyl replaces one or many.
21. the salt that can tolerate on the physiology of formula 1 compound of claim 20 as the therapeutic activity component be used to prepare treatment heart failure, pulmonary hypertension and with the low application that is perfused with the medicine of related disorders, described salt is characterised in that by with inorganic or organic acid neutralization bases or by with inorganic or organic bases neutralizing acid or by the quaternized quaternary ammonium salt that obtains of tertiary amine is obtained.
22. formula 1 compound in claim 20 and 21 has under the situation of a chiral carbon atom, D type, L type and D, L mixture and formula 1 compound in claim 20 and 21 with these compounds have under the situation of a plurality of chiral carbon atoms, with diastereomeric form of these compounds and composition thereof as the therapeutic activity component be used to prepare treatment heart failure, pulmonary hypertension and with the low application that is perfused with the medicine of related disorders.
23. in formula 1 compound of claim 20-22, especially use a kind of in the following compounds:
8-methoxyl group-3-methyl isophthalic acid-propyl imidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone;
8-methoxyl group-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group-1-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-methoxyl group-1-propyl imidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
1-ethyl-8-hydroxy-3-methyl imidazo [1,5-a] pyrido [3,2-e] pyrazine ketone;
1-ethyl-8-methoxyl group-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
8-benzylamino-1-ethyl-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also;
1-ethyl-8-(3-hydroxypropyl)-3-Methylimidazole is [1,5-a] pyrido [3,2-e] pyrazine ketone also.
24. formula 1 compound of claim 20-23 as the therapeutic activity component be used to prepare treatment heart failure, pulmonary hypertension and with the low application that is perfused with the medicine of related disorders, it is characterized in that, these compounds have the double inhibition effect, simultaneously and suppress phosphodiesterase 3 and phosphodiesterase 5 strongly, it causes the arteries expansion by a kind of with identical active ingredient, thereby obtains positive inotropic action and hypotensive activity to heart.
25. medicine comprises carrier and/or the thinner or the auxiliary agent that can tolerate on the compound of one or more claims 20-23 and the conventional physiology.
26. the method for medicine of preparation claim 25 is characterized in that the form that the compound of one or more claims 20-23 is processed into pharmaceutical preparation or can uses with conventional medicine carrier and/or thinner or other auxiliary agent in treatment.
27. general formula 1 compound of claim 20-23 and/or the pharmaceutical preparation of claim 25 and 26 are separately or be bonded to each other or use with carrier and/or thinner or other auxiliary agent bonded.
28. the compound of claim 20-23 as the therapeutic activity component be used to prepare treatment heart failure, pulmonary hypertension and with low be perfused with related disorders, the especially preferably application by oral, intravenously, intramuscular, subcutaneous, non-enteron aisle, cheek or hypogloeeis administered agents.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19902082.5 | 1999-01-20 | ||
| DE1999102082 DE19902082A1 (en) | 1999-01-20 | 1999-01-20 | New and known imidazo(1,5-a)pyrido(3,2-e)pyrazinone derivatives, useful as phosphodiesterase 5 inhibitors for treating erectile dysfunction |
| DE1999161302 DE19961302A1 (en) | 1999-12-18 | 1999-12-18 | Treatment of erectile dysfunction using new or known imidazo(1,5-a)pyrido(3,2-e)pyrazinones as phosphodiesterase inhibitors, some of which are also useful for treating cardiovascular disorders |
| DE19961302.8 | 1999-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1344268A true CN1344268A (en) | 2002-04-10 |
Family
ID=26051406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00805307A Pending CN1344268A (en) | 1999-01-20 | 2000-01-14 | Use of imidazo [1,5-a]pyrido[3,2-e]-pyrazinones as medicaments |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP1144410A2 (en) |
| JP (1) | JP2002535330A (en) |
| KR (1) | KR20010101603A (en) |
| CN (1) | CN1344268A (en) |
| AR (1) | AR022318A1 (en) |
| AU (1) | AU2291200A (en) |
| BG (1) | BG105714A (en) |
| BR (1) | BR0007613A (en) |
| CA (1) | CA2296224A1 (en) |
| CO (1) | CO5190700A1 (en) |
| CZ (1) | CZ20012627A3 (en) |
| EA (1) | EA200100792A1 (en) |
| EE (1) | EE200100377A (en) |
| HU (1) | HUP0105132A3 (en) |
| ID (1) | ID29790A (en) |
| IL (1) | IL144156A0 (en) |
| IS (1) | IS5987A (en) |
| LT (1) | LT2001078A (en) |
| LV (1) | LV12793B (en) |
| NO (1) | NO20013334L (en) |
| SK (1) | SK10322001A3 (en) |
| TR (1) | TR200102121T2 (en) |
| WO (1) | WO2000043392A2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101553491B (en) * | 2006-12-13 | 2013-05-29 | Aska制药株式会社 | Quinoxaline derivative |
| CN104703987A (en) * | 2011-10-10 | 2015-06-10 | H.隆德贝克有限公司 | Pde9i with imidazo pyrazinone backbone |
| US9434733B2 (en) | 2012-01-26 | 2016-09-06 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone |
| US10513524B2 (en) | 2015-07-07 | 2019-12-24 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases |
| US12006319B2 (en) | 2018-05-25 | 2024-06-11 | Cardurion Pharmaceuticals, Inc. | Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6548490B1 (en) * | 1997-10-28 | 2003-04-15 | Vivus, Inc. | Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
| US6403597B1 (en) | 1997-10-28 | 2002-06-11 | Vivus, Inc. | Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation |
| AU2002361417A1 (en) * | 2001-12-17 | 2003-06-30 | Altana Pharma Ag | Use of selective PDE5 inhibitors for treating partial and global respiratory failure |
| US6916345B2 (en) | 2002-02-12 | 2005-07-12 | L'oreal S.A. | 6-alkoxy-2,3-diaminopyridine couplers for dyeing keratin fibres |
| FR2835741B1 (en) * | 2002-02-12 | 2006-05-05 | Oreal | NOVEL 6-ALCOXY-2,3-DIAMINOPYRIDINE COUPLINGS USEFUL FOR DYING KERATIN FIBERS |
| DE10325813B4 (en) | 2003-06-06 | 2007-12-20 | Universitätsklinikum Freiburg | Prophylaxis and / or therapy in portal hypertension |
| WO2006023603A2 (en) | 2004-08-17 | 2006-03-02 | The Johns Hopkins University | Pde5 inhibitor compositions and methods for treating cardiac indications |
| WO2009070583A1 (en) * | 2007-11-30 | 2009-06-04 | Wyeth | Pyrido[3,2-e]pyrazines, process for preparing the same, and their use as inhibitors of phosphodiesterase 10 |
| WO2009070584A1 (en) | 2007-11-30 | 2009-06-04 | Wyeth | Aryl and heteroaryl fused imidazo[1,5-a]pyrazines as inhibitors of phosphodiesterase 10 |
| JP5842640B2 (en) * | 2012-01-31 | 2016-01-13 | 株式会社東洋新薬 | Phosphodiesterase 3 inhibitor |
| US10005789B2 (en) | 2014-08-07 | 2018-06-26 | Intra-Cellular Therapies, Inc. | Organic compounds |
| WO2016022825A1 (en) * | 2014-08-07 | 2016-02-11 | Intra-Cellular Therapies, Inc. | Organic compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5055465A (en) * | 1989-05-31 | 1991-10-08 | Berlex Laboratories, Inc. | Imidazoquinoxalinones, their aza analogs and process for their preparation |
| DE19510965A1 (en) * | 1995-03-24 | 1996-09-26 | Asta Medica Ag | New pyrido / 3,2-e / pyrazinone with anti-asthmatic activity and process for their preparation |
-
2000
- 2000-01-14 SK SK1032-2001A patent/SK10322001A3/en unknown
- 2000-01-14 CN CN00805307A patent/CN1344268A/en active Pending
- 2000-01-14 EA EA200100792A patent/EA200100792A1/en unknown
- 2000-01-14 JP JP2000594808A patent/JP2002535330A/en active Pending
- 2000-01-14 AU AU22912/00A patent/AU2291200A/en not_active Abandoned
- 2000-01-14 BR BR0007613-9A patent/BR0007613A/en not_active Application Discontinuation
- 2000-01-14 CZ CZ20012627A patent/CZ20012627A3/en unknown
- 2000-01-14 IL IL14415600A patent/IL144156A0/en unknown
- 2000-01-14 WO PCT/EP2000/000260 patent/WO2000043392A2/en not_active Application Discontinuation
- 2000-01-14 EP EP00901561A patent/EP1144410A2/en not_active Withdrawn
- 2000-01-14 EE EEP200100377A patent/EE200100377A/en unknown
- 2000-01-14 TR TR2001/02121T patent/TR200102121T2/en unknown
- 2000-01-14 KR KR1020017009112A patent/KR20010101603A/en not_active Application Discontinuation
- 2000-01-14 ID IDW00200101592A patent/ID29790A/en unknown
- 2000-01-14 HU HU0105132A patent/HUP0105132A3/en unknown
- 2000-01-19 CA CA002296224A patent/CA2296224A1/en not_active Abandoned
- 2000-01-19 AR ARP000100246A patent/AR022318A1/en unknown
- 2000-01-19 CO CO00002747A patent/CO5190700A1/en not_active Application Discontinuation
-
2001
- 2001-06-29 IS IS5987A patent/IS5987A/en unknown
- 2001-07-05 NO NO20013334A patent/NO20013334L/en not_active Application Discontinuation
- 2001-07-17 BG BG105714A patent/BG105714A/en unknown
- 2001-07-19 LT LT2001078A patent/LT2001078A/en not_active Application Discontinuation
- 2001-07-19 LV LV010109A patent/LV12793B/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101553491B (en) * | 2006-12-13 | 2013-05-29 | Aska制药株式会社 | Quinoxaline derivative |
| CN104703987A (en) * | 2011-10-10 | 2015-06-10 | H.隆德贝克有限公司 | Pde9i with imidazo pyrazinone backbone |
| CN104703987B (en) * | 2011-10-10 | 2017-05-03 | H.隆德贝克有限公司 | Pde9i with imidazo pyrazinone backbone |
| US9643970B2 (en) | 2011-10-10 | 2017-05-09 | H. Lundbeck A/S | Substituted imidazo [1,5-a]pyrazines as PDE9 inhibitors |
| US9993477B2 (en) | 2011-10-10 | 2018-06-12 | H. Lundbeck A/S | Substituted imidazo[1,5-a]pyrazines as PDE9 inhibitors |
| US9434733B2 (en) | 2012-01-26 | 2016-09-06 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone |
| US9533992B2 (en) | 2012-01-26 | 2017-01-03 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone |
| US9850249B2 (en) | 2012-01-26 | 2017-12-26 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone |
| US10513524B2 (en) | 2015-07-07 | 2019-12-24 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases |
| US11608342B2 (en) | 2015-07-07 | 2023-03-21 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases |
| US12006319B2 (en) | 2018-05-25 | 2024-06-11 | Cardurion Pharmaceuticals, Inc. | Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20013334D0 (en) | 2001-07-05 |
| IL144156A0 (en) | 2002-05-23 |
| BR0007613A (en) | 2001-10-30 |
| AR022318A1 (en) | 2002-09-04 |
| IS5987A (en) | 2001-06-29 |
| CO5190700A1 (en) | 2002-08-29 |
| CA2296224A1 (en) | 2000-07-20 |
| LT2001078A (en) | 2002-08-26 |
| KR20010101603A (en) | 2001-11-14 |
| CZ20012627A3 (en) | 2002-01-16 |
| NO20013334L (en) | 2001-07-05 |
| LV12793B (en) | 2002-05-20 |
| SK10322001A3 (en) | 2002-07-02 |
| EA200100792A1 (en) | 2002-10-31 |
| LV12793A (en) | 2002-02-20 |
| HUP0105132A2 (en) | 2002-05-29 |
| BG105714A (en) | 2002-02-28 |
| EE200100377A (en) | 2002-10-15 |
| AU2291200A (en) | 2000-08-07 |
| WO2000043392A3 (en) | 2000-09-28 |
| JP2002535330A (en) | 2002-10-22 |
| TR200102121T2 (en) | 2002-01-21 |
| ID29790A (en) | 2001-10-11 |
| HUP0105132A3 (en) | 2002-12-28 |
| EP1144410A2 (en) | 2001-10-17 |
| WO2000043392A2 (en) | 2000-07-27 |
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