CN101001630A

CN101001630A - Combination of selective noradrenalin reabsorption inhibitor and PDEV inhibitor

Info

Publication number: CN101001630A
Application number: CN 200580027106
Authority: CN
Inventors: B·休斯
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 2004-08-10
Filing date: 2005-07-29
Publication date: 2007-07-18
Also published as: TW200605895A; AR052522A1; ZA200700129B; GB0417777D0

Abstract

The invention relates to a combination of selective noradrenalin resorbing inhibitor (NRI) and the V type phosphodiesterase inhibitor (PDEV) which is especially used for curing pain.

Description

The combination of selectivity noradrenaline reuptake inhibitor and PDEV inhibitor

Invention field

The present invention relates to the combination of a kind of selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor, and relate to the pharmaceutical composition that comprises this combination, and the purposes that should make up.

Background technology

Norepinephrine (noradrenaline/norpepinephrine) is a monoamines nerve conduction material important among the central nervous system.The norepinephrine of normal amount can be lured driving into, and has the ability of recovery.And the norepinephrine conduction is undesired, especially norepinephrine is lower than normal amount, can cause various mentally, in the behavior and nervous system disease, especially melancholia, it is characterized by multiple symptom, comprise lack cordiality, life power and interest is (referring to R.J.Baldessarini, " Drugs and Treatment of Psychiatric Disorders:Depressionand Mania ", Goodman and Gilman ' sT he Pharmacological Basis ofTherapeutics, McGraw-Hill, NY, pp.432-439,1996).

Norepinephrine passes through the end of protoneuron, by a ditch that is called synaptic space, and is bonded to the lip-deep acceptor molecule of nervus opticus unit.This combination can cause in the cell and change, and causes or activates neuronic reaction of second (postsynaptic) or change.The deactivation of nerve conduction is mainly absorbed by first (presynaptic) neuron by the nerve conduction material again and takes place.Therefore, block this resorbent chemical compound (being called noradrenaline reuptake inhibitor (NRI)) and can improve the amount of norepinephrine, and help to correct the abnormal conditions of norepinephrine conduction in synapse.The example of this noradrenaline reuptake inhibitor is reboxetine (reboxetine) (R, R/S, S)-(2-[(2-ethoxy phenoxy) (phenyl) methyl] morpholine).Known reboxetine can be effectively from short-term (promptly being less than for 8 weeks) or treat the melancholia for a long time (referring to S.A.Montgomery, Reboxetine:Additional Benefits to theDepressed Patient, Psychopharmacol (Oxf) 11:4 Suppl., S9-15 (summary), 1997).WO-A-01/01973 disclose the given enantiomer of using reboxetine (S, S)-reboxetine treatment chronic pain, peripheral neurophaty, incontinence (comprising stress incontinence, congenital stress incontinence and Combination incontinence), fibromyalgia and other physical psychological and migraine.

The PDEV inhibitor is to suppress the active chemical compound of the 5th type ring-type guanosine 3 ', 5 '-one monophosphate monophosphate diesterase (cGMP PDEV).Example has sldenafil (Sildenafil; 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones; Viagra ); it is described as several cardiovascular disease of treatment at first, turns out to be the oral drugs of first effective treatment male erectile disorder (MED) subsequently.EP-A-1129706 and WO-A-01/26659 have described use PDEV inhibitor for treating nervous system disease.People such as nearest Jain, Brain Research, 909,170-178 (2001); People such as Asomoza-Espinosa, Eur.J.Pharm., 418,195-200 (2001); With people such as Mixcoatl-Zecutal, Eur.J.Pharm., 400,81-87 (2001) has described the analgesic effect of sldenafil.

Just needing a kind of better pain therapy method at present, for example, than active higher under the low dosage, the pain condition of illness of wide scope is all being had activity, more can not have side effects, acting on faster and action time is longer.

Unexpectedly, find that at present the selectivity noradrenaline reuptake inhibitor (NRI) and the combined therapy of the 5th type phosphodiesterase (PDEV) inhibitor can provide remarkable result aspect pain therapy, especially with independent use wherein during arbitrary medicament relatively.The beat all synergy of this combination results, produce render a service when using arbitrary medicament separately stronger.

Think that at present the resorption of blocking-up spinal cord pain synapse place norepinephrine can be transmitted along the neuraxon by the inhibition of pain signal and reduce pain.Further think, suppress PDEV and can promote impaired peripheral neural blood vessel perfusion owing to the symptom (as chronic diabetes) that causes pain.Use the combined therapy pain of selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor, observed beat all synergism can reduce the input to central nervous system's pain signal, and weakens the transmission of sort signal simultaneously.Can explain like this these two kinds of bonded benefits of medicine why greater than use separately the resultant benefit of each medicine add and.

Summary of the invention

Therefore, the invention provides the combination of a kind of selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor.

In addition, the invention provides a kind of pharmaceutical composition, it comprises selectivity noradrenaline reuptake inhibitor (NRI), the 5th type phosphodiesterase (PDEV) inhibitor and the acceptable adjuvant of medicine, diluent or carrier.

In addition, the invention provides a kind of combination that is used as selectivity noradrenaline reuptake inhibitor (NRI) with the 5th type phosphodiesterase (PDEV) inhibitor of medicine.

In addition, the invention provides a kind of selectivity noradrenaline reuptake inhibitor (NRI) or the 5th type phosphodiesterase (PDEV) the inhibitor purposes in medicine is made, described medicine is used in treatment of pain simultaneously, in regular turn or individually dosed.

In addition, the invention provides a kind of being used for simultaneously, in regular turn or the combination of individually dosed selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor in treatment of pain.

In addition, the invention provides a kind of method for the treatment of pain, it comprises the selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor of the mammal effective dose that needs this treatment simultaneously, in regular turn or separately.

In addition, the invention provides a kind of test kit, the instrument that it comprises selectivity noradrenaline reuptake inhibitor (NRI), the 5th type phosphodiesterase (PDEV) inhibitor and comprises described compositions.

In addition, the invention provides a kind of product that contains the combination of selective noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor, as simultaneously, be used for the treatment of the combination preparation of pain in regular turn or separately.

Description of drawings

Fig. 1 has shown (S, S)-reboxetine (1-3-10-30mg/kg, IP), compd A (3-10-30mg/kg, SC) and these two kinds of chemical compound ratios be the combination (3 or 10mg/kg of 1: 1 and 3: 1, IP, (S, S)-reboxetine and 3mg/kg, SC, compd A) effect in the CCI rat model in static allodynia.

The specific embodiment

Combination provided by the invention can be used for treating pain, and this is a preferable use.Physiological pain is a kind of important protection mechanism, is used for the noxious stimulus of the environment that may come from the outside is given a warning.System is by the specific main sensory neuron work of a cover, and via peripheral transmission mechanism exclusively activated by destructive stimulus (referring to Millan, 1999, Prog.Neurobiol., 57,1-164, review).These Sensory nerve fibres are called as nociceptor (nociceptor), and the conduction velocity that it is characterized by the minor diameter aixs cylinder is slow.Density, persistent period and the quality of nociceptor coding destructive stimulus, and because their landform are organized and are projected on the spinal cord graphicly, therefore coding stimulates the position that takes place.Nociceptor is found in injury and accepts on the nerve fiber, and two kinds of main types are arranged: A-δ fiber (sheath is arranged) and C fiber (no sheath).After the process through complexity in back of the body angle, hole, the activity that nociceptor produces directly or via the brain stem relay nucleus is transferred to ventral thalamus, to being uploaded to cerebral cortex, has produced pain at this then.

Acutely involve identical path usually, but drive, so pain relieving provides protection mechanism, and can not help to slow down and the wide relevant symptom of scope morbid state by different pathophysiological processes with chronic pain.When body tissue was subjected to grievous injury because of disease or wound, the feature of nociceptor changed.Produce sensibilization at periphery, injured part and nociceptor termination center.So just, the tetchiness that causes injury and near normal structure.In acute pain, these mechanism are quite useful, make repair process to take place, and when the injury recovery from illness, it is normal that the tetchiness situation just can be recovered.Yet under the chronic pain state, the tetchiness state also will be grown more than repair process, this normally because nervous system is injured causes (Woolf and Salter, 2000, Science, 288,1765-1768).Sensitivity in patient's symptom, occurs not accommodating when unusual, will produce pain clinically.The patient tends to the branch variety classes, different pain symptoms can occur.Some kinds of typical pain kinds comprise: 1) spontaneous pain can be slow, scorching hot or twinge; 2) destructive stimulus there is exaggerative pain reaction (hyperpathia); 3) pain that causes by stimulation harmless under the normal condition (allodynia (allodynia), people such as Meyer, 1994, Textbook of Pain, 13-44).Although backache, arthritis are bitterly, CNS is injured or the symptom of neuropathic pain is similar, its mechanism has nothing in common with each other, and therefore needs different therapeutic strategies.Therefore, pain can be distinguished into some different zones, because the pathophysiological mechanism difference comprises nocuity, inflammatory and neuropathic pain.The pain that should be noted that some form has Different types of etiopathogenises, therefore can be subdivided into more than one zone, all has nocuity and neuropathic composition as backache and cancer pain.

Nociceptive pain injuredly may cause that maybe injured intensive stimulation causes by organizing.The stimulation conduction of importing into by the injury nociceptor of pain activates, and makes the spinal cord sensitization of its terminal level.Be passed to brain along the ridge bundle then, this perceive pain (people such as Meyer, 1994, Textbook of Pain, 13-44).The activation of nociceptor activates two kinds of afferent nerve fiber.Have myelin A-δ fiber conduction rapidly, be responsible for the pain sensation sharp-pointed, twinge, then conduction velocity is slower not have marrow C fiber, passes on slow pain or aches.Moderate to severe acute injury pain is the key character of some pain, injure as the central nervous system, pull/sprain, burn, myocardial infarction, acute pancreatitis, postoperative pain (pain after any Surgery Treatment), pain after the wound, renal colic, cancer pain (can be the relevant pain of tumor, as the bone pain, headache, face ache and Encelialgia, or the pain relevant with treatment of cancer, as syndrome after the chemotherapy, operation back chronic pain syndrome, with radiation back syndrome, the perhaps relevant acute pain syndrome of cancer is as by chemotherapy, immunotherapy, the treatment that hormonotherapy and X-ray therapy cause interacts and causes), and backache (may or be broken by intervertebral disk hernia, perhaps joint of lumbar vertebra, the sacrum osteoarthrosis, other muscle of vertebra or posterior longitudinal ligament cause unusually).

Neuropathy degeneration pain is defined as by primary affection in the nervous system or pain that dysfunction caused or caused.Neural injury can be caused by wound or disease, so term " neuropathy degeneration pain " comprises the disease that Different types of etiopathogenises is different.These comprise, but be not limited to: central pain after peripheral neuropathy, diabetes type neuropathy, postherpetic neuralgia, nervi trigeminus neuralgia, backache, cancer neuropathy, HIV neuropathy, false limbs pain, complication of wrist, the apoplexy, and with chronic alcoholism, thyroid function deficiency, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, the epilepsy pain relevant with avitaminosis.Neuropathy degeneration pain is ill, because its any defencive function of tool not.Its still continues existence usually after cause disappears, the common sustainable several years, obviously reduce the patient quality of life (Woolf and Mannion, 1999, Lancet, 353,1959-1964).The symptom of neuropathy degeneration pain is difficult to treatment, even because they are suffering between the patient of same disease also have nothing in common with each other usually (Woolf and Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353,1959-1964).These comprise spontaneous pain, and it can be successional, paroxysmal or the undesired pain that causes, for example hyperpathia (the destructive stimulus sensitivity is increased) and allodynia (to normal non noxious stimulation sensitivity).

Inflammatory process is the biochemistry and the cellular activity of a series of complexity, in response to organizing injured or exotic occurring and activate, cause swelling and pain (Levine and Taiwo, 1994, Textbook ofPain, 45-56).Arthralgia is modal inflammatory pain.Atrophic diseases is one of modal chronic inflammation symptom of developed country, and rheumatoid arthritis is common disability-causing factor.The definite cause of disease of rheumatoid arthritis is not known as yet, but present hypothesis show gene and microbiological factor all very important (Grennan and Jayson, 1994, Textbook of Pain, 397-407).Existing 1,600 ten thousand U.S. common people of expection suffer from symptomatic osteoarthritis (OA) or degenerative joint disease, their major part is more than 60 years old, and estimate to rise to 4,000 ten thousand, make it to become serious public health problem (Houge ﹠amp with this numeral of increase of population ages; Mersfelder, 2002, Ann Pharmacother., 36,679-686; People such as McCarthy., 1994, Textbook of Pain, 387-395).Most patient who suffers from osteoarthritis can be owing to relevant pain is sought medical advice.Arthritis all has a strong impact on psychology and physiological function, is considered to the primary factor that disables old age.Another kind of inflammatory pain is and the relevant pain of inflammatory bowel (IBD).

Visceral pain is and the relevant pain of internal organs (comprising abdominal organs).These organs comprise sexual organ, spleen and part digestive system.The pain relevant with internal organs can be divided into digestibility visceral pain and non-digestibility visceral pain.Usually the intestines and stomach that causes pain (GI) disease that runs into comprises functional intestinal disease (FBD) and inflammatory enteropathy (IBD).These GI diseases comprise very large-scale morbid state, only can suitably be controlled at present, with regard to FBD, it comprises stomach-esophagus backflow, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), with regard to IBD, it comprises Crow engler's disease, ileitis and ulcerative colitis, and all these all produce visceral pain regularly.The visceral pain of other type comprises pain and the pelvic pain relevant with dysmenorrhea, cystitis and pancreatitis.

The pain of other type comprises:

● by the pain that musculoskeletal disease causes, comprise myalgia, fibromyalgia, spondylitis, seronegativity (non-rheumatoid) arthrosis, nonarticular rheumatism, duchenne's type muscular dystrophy (dystrophinopathy), glycogenolysis (glycogenolysis), polymyositis and pyomyositis;

● heart and vascular pain comprise the pain that is caused by angina pectoris, myocardial infarction, mitral stenosis, pericarditis, Raynaud phenomenon (Raynaud ' s phenomenon), scleroderma (scleredoma) and skeleton ischemic muscular atrophy;

● headache, for example migraine (comprising migraine without aura and absence of aura migraine), cluster headache and tension-type headache; With

● mouthful jaw prosopodynia comprises toothache and temporomandibular joint muscular fasciae pain.

Combination of the present invention can be used for treating all pain, especially neuropathy degeneration pain, particularly postherpetic neuralgia, pain diabetes type neuropathy and chronic low back pain.

The present invention's combination also can be used for treating pain symptom in addition.Particularly, combination provided by the invention can be used for treating nervous system disorder, (comprise as the addiction imbalance because ethanol, nicotine or other have the material of psychological impact), withdrawal syndrome, adjustment disorder (comprises the emotion melancholy, anxiety, the Combination anxiety, with the emotion melancholy, behavioral disorder, with Combination behavior and emotional disorder), study relevant and mental disorder (comprising Alzheimer's disease) with the age, nervous anorexia, indifferently, the not enough disease of attention (or other cognition) that causes by the general curative situation, the not enough Attention Deficit Hyperactivity Disorder (ADHD) of attention, bipolar disorder, disease of eating too much at one meal, chronic fatigue syndrome, chronic or acute pressure, behavioral disorder, the cyclothymia, melancholy (comprising that teenager is melancholy and slight melancholy), dysthymia, fibromyalgia, (comprise somatization disease with other health form disease, transform disease, hypochondriasis, physical abnormality imbalance (body dysmorphic disorder), do not break up health form disease and health form disease NOS), frequent anxiety neurosis, incontinence is (as stress incontinence, genuine stress incontinence, urge incontinence, with the Combination incontinence), suck obstacle, poisoning obstacle (alcohol addiction), manic, fat, the vain hope obsession, with relevant pedigree obstacle, oppositional defiant disorder, Panic disorder, damage back stress sexual disorders, through preceding uneasy imbalance (being premenstrual syndrome and back uneasiness luteal phase disease), mental sickness (comprises schizophrenia, division emotion and schizophrenia), seasonal affective disorder, sleep disorder (as the lethargy and the enuresis), social phobia (comprising social anxiety disorder), specificity is grown imbalance, selective serotonin absorbs inhibition (SSRI) again, " tired " syndrome (wherein after the satisfied in the early stage reaction of patient, can't keep the satisfied reaction of SSRI treatment), Parkinson's disease, cognition and dysmnesia, the nerve growth imbalance, lose memory, excessively forgetful, attention disorders, learning disorder, dementia and TIC obstacle (as Du Laideshi disease).

Combination of the present invention can be used for treating urinary incontinence, as true sexual oppression urinary incontinence (GSI), stress incontinence (SUI) or senile urinary incontinence; Overactive bladder (OAB) comprises spontaneous detrusor instability (di), nervous system disease (as Parkinson's disease, multiple sclerosis, vertebra is injured and apoplexy) the detrusor over-activity of secondary, the detrusor over-activity that bladder dysuria (as benign prostatic hyperplasia (BPH), urethral stricture) excites; Enuresis nocturna; Because the bonded urinary incontinence of above-mentioned symptom (as the stress incontinence relevant) with overactive bladder; With the lower urinary tract syndrome, as frequent micturition and urgent micturition.Term OAB is contained OAB that follows urinary incontinence and the OAB that does not follow urinary incontinence.

Combination of the present invention also can be used for treating mammiferous sexual dysfunction, the sexual dysfunction (delaying as ejaculation) that sexual dysfunction that comprise male erectile disorder, sexual impotence, female sexual disorder, clitoris obstacle, women's frigidity obstacle, women's sexual excitation obstacle, women's pain obstacle, female orgasmic disorder, dyspareunia, sickle shaped cell disease patient's priapism, is caused by spinal cord injury and selective serotonin reuptake inhibithors bring out.

Sexual dysfunction (SD) is serious clinical problem, can influence masculinity and femininity.The cause of SD can be organic and psychological.The organic viewpoint of SD is caused by the internal blood vessel disease that usually as relevant with hypertension or diabetes, medication and/or psychosis such as melancholia cause by writing out a prescription.Psychological factor comprises fear, performance anxiety and person-to-person conflict.SD diminishes the sex expression degree, reduces self-respect and influences inter personal contact, thereby causes the personality puzzlement.Clinically, the SD obstacle be divided into female sexual disorder (FSD) and male sexual disorder (MSD) (people such as Melman, J.Urology, 1999, 161, 5-11).

FSD can be defined as the women to be difficult to maybe can't obtain to satisfy in sex expression.FSD is the collective term (Leiblum of multiple women's sexual maladjustment, S.R. (1998) .Definition andclassification of female sexual disorder (definition of women's sexual maladjustment and classification), Int.J.Impotence Res., 10, S104-S106; Berman, J.R., Berman, L.﹠amp; Goldstein, I. (1999) .Female sexual dysfunction:Incidence, pathophysiology, evaluation and treatment options (female sexual disorder: incidence rate, pathophysiology, assessment and treatment are selected), Urology 54, 385-391).The women may have the combination that lacks desire, sexual excitation or orgasm difficulty, dyspareunia or these problems.Several conditions type, medicine, injured or spiritual problem all can cause FSD.Developing Therapeutic Method target is to treat specific FSD hypotype, mainly is libido and sexual excitation obstacle.

The classification best definition of FSD becomes each stage with respect to normal women's reaction: desire phase, excitation period and high-tide period (Leiblum, S.R. (1998) .Definition and classification offemale sexual disorders (definition of women's sexual maladjustment and classification), Int.J.ImpotenceRes., 10, S104-S106).Desire or libido are the driving forces of sexual behaviour.Its form of expression generally includes with interesting companion's one time-out or the sex fantasy when being exposed to other sexual stimulus.Sexual excitation is in response to the vascular reaction of sexual stimulus, and one of them important important document is genitals hyperemia, comprises that the vaginal lubrication degree increases, vagina prolongs and genitals sensation/sensitivity increases.Climax is the tensile release of property of excitation period accumulation.

Therefore, FSD generation when the women has uncomfortable or ungratified reaction in any one stage that (is generally desire, excitement and high-tide period) in these stages.The FSD category comprises libido prestige decay obstacle, sexual excitation obstacle, climax obstacle and property pain obstacle.Although combination of the present invention also can be used for promoting the reaction (in women sexual excitation obstacle) of genitals to sexual stimulus, when realizing this function, also improved ache related, the painful and discomfort relevant, thereby treated other women's sexual disorders with sexual intercourse.

Combination of the present invention also can be used for treatment or the low obstacle of preventative desire, sexual excitation obstacle, climax obstacle and property pain obstacle, more preferably be used for the treatment of or preventative excited obstacle, climax obstacle and property pain obstacle, most preferably be used for the treatment of or preventative excited obstacle.If the women has no stomach for to property or interest is extremely low, there is not or only has a little sex fantasy, libido then takes place hope low obstacle.Such FSD Ke Yi Shi Testis ketone level is low to be caused, itself since natural menolipsis or traumatic menolipsis cause.Other reason comprises disease, medicine, fatigue, melancholy and anxiety.

Being characterized as of women's sexual excitation obstacle (FSAD) do not have sufficient genital response to sexual stimulus.Genitals can not experience the excited distinctive hyperemia of normality.Vaginal wall poor lubrication, so sexual intercourse meeting pain.Climax can be hindered.When the sexual excitation obstacle can be by menolipsis or produce the estrogen reduction of back and age of sucking and cause, and cause by the disease (as diabetes and arteriosclerosis) of blood vessel parts.Other factors may be to cause with diuretic, antihistaminic, antidepressant drug such as SSRI or antihypertensive treatment.The property pain obstacle being characterized as and inserting the pain cause of (comprising dyspareunia and vulvismus), can cause owing to reducing lubricated medicine, endometriosis, pelvic inflammation disease, intestinal inflammation or urethra problem.

The sickness rate of FSD is difficult to metering, has contained several problems because this belongs to, and some is difficult to measure, and just begins for treatment FSD interesting in recent years.Many women's property problem is relevant with the female aging process, and is perhaps relevant with hypertension with chronic disease such as diabetes.

Because FSD is made up of several hypotypes at the sexual response cycle reveal any symptoms, therefore there is not single Therapeutic Method.Treatment to FSD at present mainly concentrates on psychological or issues associated.During the treatment of FSD was developing gradually, the research of this medical problem was devoted in more and more many clinical and basic research.Women's property symptom is not all to be psychological category on the pathophysiology, and especially those suffer from the individuality of the vascular obstacle (as FSAD) that helps all women's discomforts.There is not medicine to get permission to treat FSD at present yet.Experienced Drug therapy comprises estrogen administration (part or Hormone Replacement Therapy), androgen or changes medicine such as the buspirone or the Desyrel (trazodone) of emotion.These treatments are selected usually owing to the bad or unacceptable side effect of effect makes us not satisfied.

TheDiagnostic and Statistical Manual (DSM, the diagnostic ﹠ statistical manual) IV of American Psychiatric Association (alliance of Americanism section) is defined as women's sexual excitation obstacle (FSAD): " a kind of persistence or recurrent ground can't obtain or keep the reaction because the sufficient lubrication that sexual stimulus produces swells in sexual activity whole process.This serious misery and the inter personal contact difficulty of can causing unusually ".Sexual excitation reaction comprises the pelvis congestion of blood vessel, vagina is moistening and the swelling of expansion and internal genitalia.The serious misery of this unusual initiation and/with the inter personal contact difficulty.

FSAD is sexual maladjustment occurred frequently, perplexing menolipsis (± HRT) preceding-, in-, the back-the women.Other imbalance incident with it is closely bound up, as melancholy, cardiovascular disease, diabetes and UG obstacle.The main consequence of FSAD is for lacking hyperemia/expansion, lacking joyful sense lubricated and shortage genitals sensitivity.FSAD to excite consequence be libido reduction, dyspareunia and be difficult to reach a climax.

Male sexual disorder (MSD) (also is called male erectile disorder (MED) and/or penetrates obstacle (as premature ejaculation), frigidity (can't come to orgasm) or libido imbalance relevant as the low obstacle of libido (to property shortage interest) with erection problem usually.

PE is the common relatively sexual dysfunction of male.Existing several different modes are defined this, but the definition of the most well accepted Diagnostic and Statistical Manual of MentalDisorders IV (the diagnostic ﹠ statistical manual IV of mental sickness): " PE be a kind of lifelong continue or recurrent with minimality stimulate before insertion, when inserting or insert in the short time of back and before patient's desired time, ejaculate.Must consider clinically influences persistent multiple factor of excitation period, as the frequency of age, sex partner freshness or stimulation and sexual activity.Misery that this unusual initiation is serious and inter personal contact difficulty ".

Be defined as in The International Classification of Diseases 10 (International Classification of Diseases 10): " can't postpone ejaculation to being enough to enjoy sexual love, show as following several: (1) just ejaculate in the short time before or after sexual intercourse begins (definition time if desired: before sexual intercourse or begin in back 15 seconds); (2) erect and to be not enough to sexual intercourse and just to ejaculate.This problem causes sexual activity sexual repression no thanks to for a long time ".

Other already used definition comprises following standard: relevant with companion's orgasm; Persistent period between insertion and the ejaculation; Push the ability of number of times and Autonomous Control.

PE also may involve psychological factor, and the sex experience of interpersonal problem, anxiety, melancholy, previous failure is all played an important role.

Ejaculation is depended on sympathetic and parasympathetic nervous system.Via sympathetic nervous system output pulse to deferent duct with Fu Testis produces smooth muscle contraction, sperm is moved to the back urethra.The similar contraction of seminal vesicle, prostate and cowper gland can increase the volume and the flowability of seminal fluid.The discharge of seminal fluid is by output pulse mediation (the Coolen ﹠amp that is derived from waist sacrum vertebra middle part of the side spinal cord thalamus population of cells; Truitt, Science, 2002,297,1566), pass through via parasympathetic nervous system, and cause the regular movements contraction of bulbocavernosus muscle, ischiocavernosus and pelvic floor flesh.The cortex control of human ejaculation still in issue.In rat, look district and the as if participation ejaculation action of hypothalamus paraventricular nucleus in the frontal lobe.

Ejaculation comprises two kinds of independent parts---let out essence and ejaculation.Letting out essence is that seminal fluid and Fu Testis of sperm Cong afterbody, deferent duct, seminal vesicle and prostate are disposed to prostate section urethra.After this discharging is that the seminal fluid content per urethram forces discharge.It is different with climax to ejaculate, and the latter is the brain incident sheerly.These two processes take place usually simultaneously.

Combination of the present invention also can be used for treating preeclampsia disease, polycystic ovary disease, the intrauterine undergrowth, infertility, difficult menstruation, dysuria, urine stores obstacle, type ii diabetes, type i diabetes, the glucose tolerance obstacle, insulin resistant disease, metabolic syndrome group, diabetic complication is (as diabetic ulcer, the diabetic ulcer of foot, the diabetic leg ulcer, diabetic neuropathy, the periphery diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, liver insulin sensitiser material (HISS) dependent form insulin resistant disease), premature labor, dysmenorrhea, benign prostatic hyperplasia (BPH), the bladder dysuria, following urethra symptom group, intermittent claudication, angor (comprises stability, unstability and variability Prinzmetal angor), hypertension (comprises essential hypertension, pulmonary hypertension, secondary hypertension, isolate cardiac contractility hypertension, the hypertension relevant with diabetes, the hypertension relevant with arteriosclerosis, and renovascular hypertension), coronary artery disease, congestive heart failure, arteriosclerosis, the disease (building postoperative again through the chamber coronary artery) that vessel open reduces as percutaneous, the periphery angiopathy, apoplexy, the toleration that nitrate brings out, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, the hypoxia vasoconstriction, chronic obstructive disease of lung, bronchitis, cystic fibrosis, the reversibility pulmonary vascular is shunk, lung blood vessel repellence reduces, part and comprehensive respiratory failure, the disease of tool intestinal motility disorder feature (as irritable bowel syndrome IBS), gastroparesis (comprising diabetic gastroparesis), gastric emptying disorder, the BarrettShi esophagus, the anal orifice and rectal intestine obstacle, dysperistalsis (dysperistalsis), spastic esophagus movement obstacle (as over anaphylaxis LES), diffuse spasm, functional dyspepsia, gastropathy (as causes the diabetic gastropathy of feeling sick, vomiting, stomachache, with full too early), chronic tissue's anoxia, preeclampsia, the Kawasaki syndrome, multiple sclerosis, acute respiratory failure, psoriasis (comprising the psoriasis relevant) with renal syndrome, downright bad, the scar scar forms, the acute and chronic skin injury, fibrosis (comprises pulmonary fibrosis, skin and cornea incrustation, infect, wound, fibrosis behind operation or the heat injury, scleroderma, with other connective tissue pathological changes, cardiac fibrosis, meat fiberization, renal fibrosis, chronic skin ulcer, and lipdermatosclerosis), postoperative and the adhesion of sudden property, chafing disease (comprising tinea and associated conditions), the old and feeble degenerative disease (comprise skin aging) relevant with aging with all, the hepatic fibrosis of any cause of disease (comprising viral and non-viral hepatitis and liver cirrhosis), chronic pancreatitis, chronic thyroiditis, calcific deposit disease (any source), morbidity deposits/reinvents relevant disease with connective tissue matrix, acne, cancer is (as the polyp cancer, carcinoma of prostate, breast carcinoma, pulmonary carcinoma, leukemia, renal carcinoma, Crow engler's disease, hepatocarcinoma, chronic lymphatic cancer and tumor), cancerometastasis, bald head, baldness, septicemia, osteoporosis, tinnitus, hearing impairment, HirschsprungShi disease, myasthenia gravis, the Eisenmenger syndrome, the carpenter's pincers esophagus, anal fissure, hemorrhoid, the anoxia vasoconstriction, the CREST syndrome, systemic lupus erythematosus (sle), atrophic diseases (as rheumatic arthritis), thrombosis, systemic sclerosis, thromboembolism, myocardial infarction, coronary insufficiency, ischemic heart desease, platelet aggregation, the unstable blood pressure of hemodialysis session is fixed, ischemia/reperfusion injury, and coronary heart disease.

Combination of the present invention also is used at the hemodialysis session stabilizing blood pressure, and increases birth weight.

Combination of the present invention also can be used for treating ocular disease and symptom, as glaucoma, optic neuropathy, the maincenter retinal vein occlusion, interior intraocular pressure raises, retinal artery occlusion, look circulatory disorders, the optic nerve pathological changes, degeneration of macula (as the degeneration of macula relevant) with the age, optic nerve disease is (as normal the realizing property optic neuropathy of blood pressure, ischemic optic neuropathy, toxic optic neuropathy becomes, traumatic optic neuropathy, sudden optic neuropathy, optic nerve choroid wart, and benign intracranial hypertension), retinal diseases is (as retinal vessel new life, ischemic blood/rheology disease, with the toxic maculopathy), choroidal diseases is (as preceding choroid ischemic imbalance, angiogenesis under the degeneration retina, diabetic choroid ischemia, angiogenesis under the inflammatory retina, with irrelevant choroid ischemia of age, macula lutea degeneration choroid wart, the atrophy of macula lutea retinal pigment epithelium, retinal pigment epithelium comes off, angiogenesis under the degeneration retina, the macular degeneration that wet type is relevant with the age, macular edema, familial choroid wart, the macula lutea disease relevant with hypertension, hemangioma, papillitis optica, retinitis, the pigment retinal degenerative disease, the macular edema of no blood vessel seepage, retinitis pigmentosa, early stage macular hole, choroidal artery new life, branch's retinal vein occlusion, the stage casing uveitis, with sudden retinal telangiectasis), low ocular blood flow, low visual performance, interior intraocular pressure raises, with retina or obstruction of artery.

Under situation of the present invention, " selectivity " noradrenaline reuptake inhibitor is the chemical compound to the resorbent inhibition better effects if of the resorbent inhibition effect comparison serotonin of norepinephrine, refers in particular to the chemical compound to resorbent inhibition effect comparison serotonin of norepinephrine and the resorbent inhibition better effects if of dopamine.By measuring chemical compound serotonin is absorbed the inhibition constant (or Ki value) in site again, and norepinephrine is absorbed the Ki value in site again, can determine this selectivity divided by chemical compound.The resorbent Ki value of norepinephrine is low more, represents high more to the binding affinity of norepinephrine receptor.The ratio of serotonin (Ki)/norepinephrine (Ki) is high more, and expression is high more in conjunction with selectivity to norepinephrine receptor.Preferably, this selectivity (serotonin (Ki)/norepinephrine (Ki)) is at least 10 times, more preferably at least 100 times, more preferably at least 1000 times again, most preferably is at least 5000 times.It is unit that inhibition constant (Ki value) is reported with nanomole (nM) usually, can be according to Y.C.Cheng and W.H.Prusoff, " Relationship Between the InhibitoryConstant (Ki) and the Concentration of Inhibitor Which Causes 50%Inhibition (IC ₅₀) of an Enzymatic Reaction ", Biochemical Pharmacology, the method for describing among the vol.22, pp.3099-3108 (1973) is by IC ₅₀Value is calculated.Suitable experimental detail is disclosed in WO-A-01/01973.

Term " norepinephrine (noradrenaline) " and " noradrenaline (norepinephrine) " are synonyms, and the two all is used for this description.Similarly, term " noradrenaline reuptake inhibitor " and " noradrenaline reuptake inhibithors " are synonyms, term " selectivity noradrenaline reuptake inhibitor " and " selectivity noradrenaline reuptake inhibithors " same meaning.

Preferred selectivity noradrenaline reuptake inhibitor is a disclosed reboxetine among the GB-A-2014981.Reboxetine only demonstrates limited serotonin and absorbs inhibitory action again, does not have the dopamine resorption.From chemically, reboxetine has two asymmetric centers, therefore, can exist by two pairs of enantiotopic diastereomers in theory, a pair of enantiotopic (R, R) and (S, S), a pair of enantiotopic (R, S) and (S, R).But, the reboxetine that is commonly called as be meant commercially available ratio be 1: 1 (R, R) and (S, S) racemic mixture of enantiomer.The commercial goods of reboxetine is called EDRONAX ^TM, PROLIFT ^TM, VESTRA ^TMAnd NOREBOX ^TM

Especially preferred selectivity noradrenaline reuptake inhibitor be among the GB-A-2167407 disclosed reboxetine (S, S)-corresponding isomer.Reboxetine (S, S)-norepinephrine that enantiomer has absorbs inhibition again and absorb inhibiting selectivity again with respect to serotonin and significantly improve, and is disclosed as WO-A-01/01973.Therefore, WO-A-01/01973 discloses the method that a kind of norepinephrine selectivity absorbs inhibition again, this method comprises the step of the compositions that gives the individual treatment effective dose, and pharmacology's selectivity that said composition comprises serotonin (Ki)/norepinephrine (Ki) is at least about 5000 chemical compound.

The example that is applicable to the PDEV inhibitor that the present invention makes up has: pyrazolo [4, the 3-d] pyrimidin-7-ones that is disclosed in EP-A-0463756; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones of EP-A-0526004; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones of WO-A-93/06104; Be disclosed in isomery pyrazolo [3, the 4-d] pyrimidin-4-one of WO-A-93/07149; Be disclosed in the quinazoline-4-one of WO-A-93/12095; Be disclosed in pyrido [3, the 2-d] pyrimidin-4-one of WO-A-94/05661; Be disclosed in the purine-6-one of WO-A-94/00453; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones of WO-A-98/49166; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones of WO-A-54333; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-4-one of EP-A-0995751; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones of WO-A-00/24745; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-4-one of EP-A-0995750; The hexahydropyrazine that is disclosed in WO-A-95/19978 is [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1 also, the 4-diketone; Be disclosed in imidazo [5,1-f] [1,2,4] triazine-ketone of EP-A-1092719 and WO-A-99/24433; With the bicyclic compound that is disclosed in WO-A-93/07124; This paper is incorporated herein by reference all these.

Other example that is applicable to the PDEV inhibitor that the present invention makes up comprises: pyrazolo [4, the 3-d] pyrimidin-7-ones that is disclosed in WO-A-01/27112; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones of WO-A-01/27113; Be disclosed in the chemical compound and the chemical compound that is disclosed in EP-A-1092719 of EP-A-1092718; Be disclosed in the tricyclic compound of EP-A-1241170; Be disclosed in the alkyl sulphone compound of WO-A-02/074774; Be disclosed in the chemical compound of WO-A-02/072586: the chemical compound that is disclosed in WO-A-02/079203; Be disclosed in the chemical compound of WO-A-01/87882; Be disclosed in the chemical compound of WO-A-00/56719, for example BMS-341400; Be described in the chemical compound of WO-A-99/64004, for example BMS-263504; Be described in the chemical compound (Jordanian Pharmaceutical Manufacturing and medicalequipment Company) of EP-A-1057829; Be described in the chemical compound of EP-A-722936; Be described in the chemical compound of WO-A-93/07124; Be described in the chemical compound of WO-A-98/06722; Be described in the chemical compound of WO-A-98/06722; Be described in the chemical compound of EP-A-579496, especially ONO1505 (Ono); Be described in the chemical compound of WO-A-97/03070, especially OPC35564 (Otsuka); With the chemical compound that is described in WO-A-02/074312; This paper is incorporated herein by reference all these.

Other example that also is applicable to the PDEV inhibitor that the present invention makes up comprises: the carboline derivative that is described in WO-A-03/00691, WO-A-02/098875, WO-A-02/064591, WO-A-02/064590 and WO-A-01/08688; The pyrazine that is described in WO-A-02/098877 is [1 ', 2 ': 1,6] pyrido [3,4-B] indole-1 also, the 4-derovatives; Be described in the tetracyclic compound of WO-A-02/098428; Be described in the chemical compound of WO-A-02/088123 and WO-A-02/00656; Be described in the condensation pyrazine derovatives of WO-A-02/38563 and WO-A-02/000657; Be described in the indole derivatives of WO-A-02/36593; Be described in the condensation pyrindole derivant of WO-A-02/28865 and WO-A-02/28859; The hexahydropyrazine that is described in WO-A-02/28858 and WO-A-01/94345 is [1 ', 2 ': 1,6]-pyrido [3,4-B] indole-1 also, the 4-derovatives; Be described in the condensed heterocyclic derivates of WO-A-02/10166; Be described in the ring-type GMP specific PDE inhibitors of WO-A-02/00658; Be described in the Fourth Ring diketopiperazine chemical compound of WO-A-01/94347; Be described in the chemical compound of WO-A-02/98877; With the chemical compound that is described in WO-A-02/19213 application application; This paper is incorporated herein by reference all these.

Other example that also is applicable to the PDEV inhibitor that the present invention makes up comprises the chemical compound that is described in WO-A-01/64129, DE-A-10104800, WO-A-02/59126, DE-A-10104095, WO-A-02/49651, DE-A-10063224, DE-A-10060338, DE-A-10058662, WO-A-02/00660, WO-A-2004/096810 and WO-A-2005/049616, and this paper is incorporated herein by reference all these.

Other also is applicable to that the PDEV inhibitor that is bonded in the present invention's combination comprises: 4-bromo-5-(pyridylmethyl amino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H) 2H-Pyridazin-3-one; 1-[4-(1,3-benzo dioxole-5-ylmethyl amino)-6-chloro-2-quinozolinyl]-the 4-pyridine-3-carboxylic acid, single sodium salt; (+)-suitable-5,6a, 7,9,9,9a-six hydrogen-2-[4-(trifluoromethyl)-phenyl methyl-5-methyl-ring penta-4,5] imidazo-[2,1-b] purine-4 (3H) ketone; Furazlocillin; Suitable-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro ring penta [4,5]-imidazo [2,1-b] purine-4 ketone; 3-acetyl group-1-(2-chlorphenyl)-2-propyl indole-6-carboxylate; 3-acetyl group-1-(2-chlorphenyl)-2-propyl indole-6-carboxylate; 4-bromo-5-(3-pyridylmethyl amino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H) 2H-Pyridazin-3-one; 1-methyl-5 (5-morpholino acetyl group-2-positive propoxy phenyl)-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; 1-[4-[(1,3-benzodioxole-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidines-carboxylic acid, single sodium salt; Pharmaprojects No.4516 (Glaxo Wellcome); Pharmaprojects No.5051 (Bayer); PharmaprojectsNo.5064 (Kyowa Hakko; Referring to WO-A-96/26940); Pharmaprojects No.5069 (Schering Plough); ER-118585, E-8010, E-4021 and E-4010 (Eisai); Bay-38-3045﹠amp; 38-9456 (Bayer); FR181074, FR229934 and FR226807 (Fujisawa); TA-1032, T-0156 and TA-1790 (Tanabe Seiyaku); EMD82639 and EMR6203 (Merck); LAS34179 and LAS35917 (Almirall); Sch-51866; BMS-223131 (Bristol Myers Squibb); NCX911 (Nicox); And ABT-724 and ABT-670 (Abbott).

PDEV inhibitor preferred for the present invention comprises:

(i) 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Sildenafil sldenafil, Viagra ), also be called 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfonyl]-4-methyl piperazine (referring to EP-A-0463756);

(ii) 5-(2-ethyoxyl-5-morpholino acetylphenyl)-1-methyl-3-n-pro-pyl-4,6-dihydro--7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to EP-A-0526004);

(iii) 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-n-pro-pyl phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-98/49166);

(iv) 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2 (2-methoxy ethoxy) pyridin-3-yl)]-and 2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-99/54333);

(v) (+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also be called 3-ethyl-5-{5-[4-ethyl piperazidine-1-base sulfonyl]-2-([(1R)-and 2-methoxyl group-1-Methylethyl] oxygen) pyridin-3-yl }-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-99/54333);

(vi) 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also be called 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-] pyrazolo [4,3-d] pyrimidine-5-yl }-the 3-pyridyl sulfonyl }-4-ethyl piperazidine (referring to WO-A-01/27113, embodiment 8);

(vii) 5-[2-isobutoxy-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-01/27113, embodiment 15);

(viii) 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-01/27113, embodiment 66);

(ix) 5-[(5-acetyl group-2-propoxyl group-3-pyridine radicals)-and 3-ethyl-2-(1-isopropyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-01/27112, embodiment 124);

(x) 5-[(5-acetyl group-2-butoxy-3-pyridine radicals)-and 3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO-A-01/27112, embodiment 132);

(xi) (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1,4-diketone (Tadalafil tadanafil, IC-351, Cialis ), promptly, WO-A-95/19978 embodiment 78 and 95 chemical compound, and the chemical compound of

embodiment

1,3,7,8;

(xii) 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil, Vardenafil, Levitra ), also be called 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f] also)-as-triazine-2-yl]-the 4-ethoxyl phenenyl] sulfonyl]-the 4-ethyl piperazidine, that is, WO-A-99/24433 embodiment 20,19,337 and 336 chemical compound;

(xiii) be disclosed in the pyrazolo [4 of WO-A-00/27848,3-d] pyrimidin-4-one, especially N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and 4-propoxyl group phenyl] sulfonyl]-1-methyl-2-pyrrolidine-propionic acid amide. [DA-8159 (embodiment 68 of WO-A-00/27848)];

(xiv) chemical compound of WO-A-93/07124 embodiment 11;

(xv) 4-(4-benzyl chloride base) amino-6,7,8-trimethoxy quinazoline;

(xvi) 7,8-dihydro-8-oxo-6-[2-propoxyl group phenyl]-1H-imidazo [4,5-g] quinazoline;

(xvii) methyl 1-[3-[1-[(4-fluorophenyl)]-7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazoline-6-yl]-4-propoxyl group phenyl] Methanamide;

(xviii) 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones

(xix) 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-the 4-ethyl piperazidine;

(xx) N-[1-(2-ethoxyethyl group)-5-(N-ethyl-N-methyl amido)-7-(4-picoline-2-base is amino)-1H-pyrazolo [4,3-d] pyrimidine-3-carbonyl] Methanesulfomide (embodiment 115 of WO-A-2005/049616);

(xxi) N-{5-(ethyl-methyl-amino)-7-(4-methyl-pyridine-2-base is amino)-1-[2-(2,2, the 2-trifluoro ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidine-3-carbonyl] Methanesulfomide;

(xxii) N-[5-(2,5-diaza-bicyclo-[2.2.1] heptan-2-yl)-1-(2-ethoxyethyl group)-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-7-yl]-(4-picoline-2-yl)-amine, especially N-[5-(1S, 4S)-(2,5-diaza-bicyclo-[2.2.1] heptan-2-yl)-1-(2-ethoxyethyl group)-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-7-yl]-(4-picoline-2-yl)-amine (embodiment 229 of WO-A-2004/098610); With

(xxiii) the 3-ethyl-5-[(R)-3-methyl-piperazine-1-yl]-1-[2-(2,2, the 2-trifluoro ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7-yl } pyrimidine-4-base-amine (embodiment 249 of WO-A-2004/098610);

With and acceptable salt of medicine and solvate.

The chemical compound that other PDEV inhibitor preferred for the present invention is formula (III):

Wherein:

A is CH or N;

R ¹Be H, C ₁To C ₆Alkyl, C ₃To C ₆Thiazolinyl, C ₃To C ₆Cycloalkyl, C ₃To C ₆Cycloalkenyl group or C ₃To C ₆Perfluoroalkyl, wherein said alkyl can be side chain or straight chain, and wherein said alkyl, thiazolinyl, cycloalkyl or perfluoroalkyl are randomly replaced by one or more substituent groups that are selected from following groups: hydroxyl; C ₁To C ₄Alkoxyl; C ₃To C ₆Cycloalkyl; C ₁To C ₃Perfluoroalkyl; By one or more C that are selected from ₁To C ₃Alkyl, C ₁To C ₄Alkoxyl, C ₁To C ₄Haloalkyl or C ₁To C ₄The phenyl that halogenated alkoxy replaces, wherein said haloalkyl or halogenated alkoxy contain one or more halogen atoms, halogen, CN, NO ₂, NHR ¹¹, NHSO ₂R ¹², SO ₂R ¹², SO ₂NHR ¹¹, COR ¹¹, CO ₂R ¹¹, R wherein ¹¹Be H, C ₁To C ₄Alkyl, C ₂To C ₄Thiazolinyl, C ₁To C ₄Alkanoyl, C ₁To C ₄Haloalkyl or C ₁To C ₄Halogenated alkoxy, and R wherein ¹²Be C ₁To C ₄Alkyl, C ₂To C ₄Thiazolinyl, C ₁To C ₄Alkanoyl, C ₁To C ₄Haloalkyl or C ₁To C ₄Halogenated alkoxy; NR ⁷R ⁸, CONR ⁷R ⁸Or NR ⁷COR ¹¹, R wherein ⁷And R ⁸Be selected from H, C independently of one another ₁To C ₄Alkyl, C ₂To C ₄Thiazolinyl, C ₁To C ₄Alkoxyl, CO ₂R ⁹, SO ₂R ⁹, wherein said alkyl, thiazolinyl or alkoxyl are randomly by NR ⁵R ⁶, C ₁To C ₄Haloalkyl or C ₁To C ₄Halogenated alkoxy replaces, and R wherein ⁹Be H, hydroxyl, C ₂To C ₃Alkyl, C ₁To C ₄Alkanoyl or C ₁To C ₄Alkyl, it is randomly replaced by phenyl, and wherein said phenyl is randomly replaced by one or more substituent groups that are selected from following group: randomly by C ₁To C ₄Haloalkyl or C ₁To C ₄The C that halogenated alkoxy replaces ₁To C ₄Alkyl, C ₁To C ₄Alkoxyl, halogen, CN, NO ₂, NHR ¹¹, NHSO ₂R ¹², SO ₂R ¹², SO ₂NHR ¹¹, COR ¹¹Or CO ₂R ¹¹Het ¹Het ²Or Het ³Or R ₁Be Het ⁴Or phenyl, wherein said phenyl is randomly by one or more C that are selected from ₁To C ₄Alkyl, C ₂To C ₄Thiazolinyl, C ₁To C ₄Alkoxyl, halogen, CN, CF ₃, OCF ₃, NO ₂, NHR ¹¹, NHSO ₂R ¹², SO ₂R ¹², SO ₂NHR ¹¹, COR ¹¹, CO ₂R ¹¹Substituent group replace;

R ²Be H, C ₁To C ₆Alkyl, C ₃To C ₆Thiazolinyl or (CH ₂) _n(C ₃To C ₆Cycloalkyl), wherein n is 0,1 or 2, and wherein said alkyl or alkenyl is randomly replaced by one or more fluoro substituents;

R ¹³Be OR ³Or NR ⁵R ⁶

R ³Be C ₁To C ₆Alkyl, C ₃To C ₆Thiazolinyl, C ₃To C ₆Alkynyl, C ₃To C ₇Epoxy radicals, C ₁To C ₆Perfluoroalkyl or (C ₃To C ₆Cycloalkyl) C ₁To C ₆Alkyl, it is randomly replaced by 1 or 2 substituent group that is selected from following group: C ₃To C ₅Cycloalkyl, hydroxyl, C ₁To C ₄Alkoxyl, C ₃To C ₆Thiazolinyl, C ₃To C ₆Alkynyl, Bian oxygen base, NR ⁵R ⁶, phenyl, Het ¹, Het ², Het ³Or Het ⁴, C wherein ₁To C ₆Alkyl and C ₁To C ₄Alkoxyl can randomly can be randomly by haloalkyl such as CF ₃Be connected on end; C ₃To C ₆Cycloalkyl; Het ¹, Het ², Het ³Or Het ⁴

R ⁴For randomly by OH, NR ⁵R ⁶, CN, CONR ⁵R ⁶Or CO ₂R ⁷The C that replaces ₁-C ₄Alkyl; Randomly by CN, CONR ⁵R ⁶Or CO ₂R ⁷The C that replaces ₂-C ₄Thiazolinyl; Randomly by NR ⁵R ⁶The C that replaces ₂-C ₄Alkanoyl; Randomly by NR ⁵R ⁶The hydroxyl C that replaces ₂-C ₄Alkyl; Randomly by OH or NR ⁵R ⁶(the C that replaces ₂-C ₃Alkoxyl) C ₁-C ₂Alkyl; CONR ⁵R ⁶CO ₂R ⁷Halogen; NR ⁵R ⁶NHSO ₂NR ⁵R ⁶NHSO ₂R ⁸Or all can be randomly by methyl substituted phenyl or heterocyclic radical; Perhaps R ⁴Be pyrrolidinyl sulfonyl, piperidino sulfonyl, morpholinyl sulfonyl, or on piperazinyl 4-position, have R ¹⁰Substituent piperazine-1-base sulfonyl, wherein said piperazinyl is randomly by 1 or 2 C ₁To C ₄Alkyl, C ₁To C ₃Alkoxyl, NR ⁷R ⁸Or CONR ⁷R ⁸Replace, and randomly with the form of its 4-N-oxide;

R ⁵And R ⁶Be selected from H independently of one another and randomly by C ₃To C ₅Cycloalkyl or C ₁To C ₄The C that alkoxyl replaces ₁To C ₄Alkyl perhaps forms azelidinyl, pyrrolidinyl, piperidyl, morpholinyl, 4-(NR with the nitrogen-atoms that they connected ⁹)-piperazinyl or imidazole radicals, wherein said group are randomly replaced by methyl or hydroxyl;

R ¹⁰Be H; C ₁To C ₆Alkyl, (C ₁-C ₃Alkoxyl) C ₂-C ₆Alkyl, hydroxyl C ₂-C ₆Alkyl, (R ⁷R ⁸N) C ₂To C ₆Alkyl, (R ⁷R ⁸NCO) C ₁-C ₆Alkyl, CONR ⁷R ⁸, CSNR ⁷R ⁸, or C (NH) NR ⁷R ⁸, it randomly is selected from hydroxyl, NR by 1 or 2 ⁵R ⁶, CONR ⁵R ⁶, randomly by C ₁To C ₄Alkyl or C ₁To C ₄The phenyl that alkoxyl replaces replaces; C ₂To C ₆Thiazolinyl or Het ⁴

Het ¹Be 4-, 5-or 6-member heterocyclic ring containing nitrogen base that N-connects, it randomly contains other hetero atom of one or more S of being selected from, N or O;

Het ²For containing the 5-unit heterocyclic radical that the heteroatomic C-of O, S or N connects, it randomly contains the hetero atom of one or more O of being selected from or S;

Het ³For containing the 6-unit heterocyclic radical that the heteroatomic C-of O or S connects, it randomly contains the hetero atom of one or more O of being selected from, S or N, perhaps Het ³For containing the 6-unit heterocyclic radical that three heteroatomic C-of N connect;

Het ⁴For containing 1,2 or 3 4-, 5-or 6-unit heterocyclic radical that is selected from the heteroatomic C-connection of S, O or N; Wherein any described heterocyclic radical Het ¹, Het ², Het ³, or Het ⁴All can be saturated, part is undersaturated or armaticity, and wherein any described heterocyclic radical all can be randomly by one or more C that are selected from ₁To C ₄Alkyl, C ₂To C ₄Thiazolinyl, C ₁To C ₄Alkoxyl, halogen, CO ₂R ¹¹, COR ¹¹, SO ₂R ¹²Or NHR ¹¹Substituent group replace, and/or wherein any described heterocyclic radical is benzo-fused;

Perhaps, wherein work as R ¹³Represent OR ³Or R ³NR ⁵R ¹Represent Het, alkyl Het, aryl or alkylaryl, 5 groups in back are all randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³And SO ²NR ¹⁴R ¹⁵Substituent group replace and/or be connected on end; R ²Represent hydrogen, halogen, cyano group, nitro, OR ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, SO ₂NR ¹⁴R ¹⁵, low alkyl group, Het, alkyl Het, aryl or alkylaryl, 5 groups in back are all randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, and SO ₂NR ¹⁴R ¹⁵Substituent group replace and/or be connected on end; R ³Represent hydrogen, low alkyl group, alkyl Het or alkylaryl, 3 groups in back are all randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, and SO ₂NR ¹⁴R ¹⁵Substituent group replace and/or be connected on end; R ⁴Represent H, halogen, cyano group, nitro, halo (low alkyl group), OR ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, NR ¹⁶Y (O) R ¹⁷, SOR ¹⁸, SO ₂R ¹⁹R ²⁰, C (O) AZ, low alkyl group, low-grade alkenyl, low-grade alkynyl, Het, alkyl Het, aryl or alkylaryl, 7 groups in back are all randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, and SO ₂NR ¹⁴R ¹⁵Substituent group replace and/or be connected on end; Y represents C or S (O), wherein when Y is S (O), and R ¹⁶And R ¹⁷In one do not exist; A represents low-grade alkylidene; Z represents OR ⁶, halogen, Het or aryl, 2 groups in back are all randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, and SO ₂NR ¹⁴R ¹⁵Substituent group replace; R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁸, R ¹⁹, and R ²⁰Represent H or low alkyl group separately; R ¹⁰And R ¹¹Represent H or low alkyl group separately, latter's group is randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, and SO ₂NR ¹⁴R ¹⁵Substituent group replace and/or be connected on end, perhaps be randomly by the Het or the aryl of the one or more replacements in described back 7 groups, perhaps R ¹⁰And R ¹¹In one can be lower alkoxy, amino or Het, back 2 groups are all randomly replaced by low alkyl group; R ¹²And R ¹³Represent H or low alkyl group separately, perhaps R ¹²And R ¹³In one can be C (O)-low alkyl group or C (O) Het, wherein Het is randomly replaced by low alkyl group; R ¹⁴And R ¹⁵Represent H or low alkyl group separately, perhaps R ¹⁴And R ¹⁵Form heterocycle with the nitrogen-atoms that they connected; R ¹⁶And R ¹⁷Represent H or low alkyl group separately, perhaps R ¹⁶And R ¹⁷In one can be Het or aryl, back 2 groups are all randomly replaced by low alkyl group; Het represents randomly substituted 4 to 12 yuan of heterocyclic radicals, and it can be an armaticity or nonaromatic, can contain one or more pairs of keys, can be monocycle or bicyclic, can contain the hetero atom of one or more N of being selected from, S and O;

Perhaps acceptable salt of its any medicine or solvate.

In formula (III), the PDEV inhibitor can contain halogen group.At this, " halogen " is meant fluorine, chlorine, bromine or iodine.

In formula (III), the PDE5 inhibitor can contain one or more alkyl, alkoxyl, thiazolinyl, alkylidene and alkenylene group, and it can be straight chain or straight chain.

In formula (III), the preferred group of chemical compound used according to the invention is: R ¹Be H, methyl or ethyl; R ²Be H, the C that randomly replaced by OH ₁-C ₃Alkyl or methoxyl group; R ³Be C ₂-C ₃Alkyl or pi-allyl; R ⁴Be sulfonyl piperidino or 4-N-(R ¹⁰)-sulfonyl piperazine-1-base; R ⁵Be H, NR ⁷R ⁸Or CONR ⁷R ⁸R ¹⁰Be H, C ₁-C ₃Alkyl, hydroxyl, C ₂-C ₆Alkyl, CONR ⁷R ⁸, CSNR ⁷R ⁸Or C (NH) NR ⁷R ⁸R ⁷With R ⁸Represent H or methyl separately.

In formula (III), the preferred group of used according to the invention other is: R ¹Be the C that is randomly replaced by Het ₁To C ₂Alkyl; 2-(morpholine-4-yl) ethyl or benzyl; R ²Be C ₂To C ₄Alkyl; R ¹³Be OR ³Or NR ⁵R ⁶R ³For randomly being selected from cyclopropyl, cyclobutyl, OH, methoxyl group, ethyoxyl, benzyloxy, NR by 1 or 2 ⁵R ⁶, phenyl, furan-3-base, pyridine-2-base and pyridin-3-yl the C that replaces of substituent group ₁To C ₄Alkyl; Cyclobutyl; 1-methyl piperidine-4-base; Oxolane-3-base or oxolane-4-base; R ⁵And R ⁶The C that is selected from H independently of one another and is randomly replaced by cyclopropyl or methoxyl group ₁To C ₂Alkyl perhaps forms azelidinyl, pyrrolidinyl or morpholinyl with unit that they connected; R ⁷And R ⁸Form randomly by 1 or 2 methyl substituted 4-R with the nitrogen-atoms that they connected ¹⁰-piperazinyl is randomly with the form of its 4-N-oxide; R ¹⁰For H, randomly be selected from OH, NR by 1 or 2 ⁵R ⁶, CONR ⁵R ⁶The C that replaces ₁To C ₃Alkyl is randomly by the phenyl of methoxyl group, benzodioxole-5-base and benzodioxole-2-base replacement; Pi-allyl; Pyridine-2-base; Pyridin-4-yl or pyrimidine-2-base; And Het is selected from pyridine-2-base; Pyridine 1-oxide-2-base; 6-picoline-2-base; 2-methoxypyridine-2-base; Pyridazine-2-base; Pyrimidine-2-base and 1-Methylimidazole .-2-base.In this group, those chemical compounds more preferably, wherein: R ¹Be the C that is randomly replaced by Het ₁To C ₂Alkyl; 2-(morpholine-4-yl) ethyl or benzyl; R ²Be C ₂To C ₄Alkyl; R ¹³Be OR ³R ³For randomly by the mono-substituted C of cyclopropyl, cyclobutyl, OH, methoxyl group, ethyoxyl, phenyl, furan-3-base or pyridine-2-base ₁To C ₄Alkyl; Cyclobutyl; Oxolane-3-base or oxolane-4-base; R ⁷And R ⁸Form 4-R with the nitrogen-atoms that they connected ¹⁰-piperazinyl is randomly with the form of its 4-N-oxide; R ¹⁰For randomly by the mono-substituted C of OH ₁To C ₃Alkyl; And Het is selected from pyridine-2-base; Pyridine 1-oxide-2-base; 6-picoline-2-base; 6-methoxypyridine-2-base; Pyridazine-3-base; Pyrimidine-2-base and 1-Methylimidazole .-2-base.

Reorganization chemical compound those chemical compounds more preferably: R wherein ¹Be C ₁To C ₆Alkyl, wherein said alkyl can be side chain or straight chain, perhaps R ¹Be C ₃To C ₆Cycloalkyl is wherein worked as R ¹Be C ₁To C ₃During alkyl, described alkyl is replaced by one or more substituent groups; Work as R ¹Be C ₄To C ₆Alkyl, C ₃To C ₆During cycloalkyl, described alkyl or cycloalkyl is randomly replaced by one or more substituent group; Described substituent group is selected from: hydroxyl; C ₁To C ₂Alkoxyl; C ₃To C ₅Cycloalkyl; NR ⁷R ⁸, NR ⁷COR ¹¹Or COR ¹¹, R wherein ⁷And R ⁸Be selected from H, C independently of one another ₁To C ₄Alkyl or CO ₂R ⁹, R wherein ⁹And R ¹¹Defined previously as this paper; Het ¹Group, the 4-member heterocyclic ring containing nitrogen base that it connects for N-; Het ³Group, it is the 6-unit heterocyclic radical that contains O or the heteroatomic C-connection of S, it randomly contains the hetero atom of one or more O of being selected from, S or N, perhaps Het ³Group is to contain the 6-unit heterocyclic radical that 3 heteroatomic C-of N connect; Perhaps R ¹Be Het ⁴Group, it is to contain 1 4-unit heterocyclic radical, perhaps R that is selected from the heteroatomic C-connection of S, O or N ¹Be Het ⁴Group, it is to contain 1,2 or 3 6-unit heterocyclic radical that is selected from the heteroatomic C-connection of S or O, wherein any described heterocyclic radical Het ¹, Het ², Het ³, Het ⁴Be saturated, part is unsaturated or armaticity, and randomly by one or more C that are selected from ₁To C ₄Alkyl, C ₁To C ₄Alkoxyl ,-CO ₂R ¹¹,-SO ₂R ¹²,-COR ¹¹Or NHR ¹¹Substituent group replace R wherein ¹¹And R ¹²Defined previously as this paper, and/or wherein any described heterocyclic radical is benzo-fused; Perhaps R ¹For by one or more CF that are selected from ₃,-OCF ₃,-SO ₂R ¹²,-COR ¹¹The phenyl that substituent group replaced, R wherein ¹¹And R ¹²Defined previously as this paper; R ²Be C ₁To C ₆Alkyl; R ¹³Be OR ³R ³Be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, it randomly is selected from cyclopropyl, cyclobutyl, hydroxyl, methoxyl group, ethyoxyl, Bian oxygen base, phenyl, benzyl, furan-3-base, oxolane-2-ylmethyl, oxolane-3-ylmethyl, pyridine-2-base, pyridin-3-yl or NR by 1 or 2 ⁵R ⁶Substituent group replace R wherein ⁵And R ⁶Be selected from H and C independently of one another ₁To C ₂Alkyl; R ⁴For having R on the piperazinyl 4-position ¹⁰Substituent piperazine-1-base sulfonyl, wherein said piperazinyl is randomly by 1 or 2 C ₁To C ₄Alkyl replaces, and randomly its form is the 4-N-oxide; R ¹⁰For H, randomly be selected from hydroxyl, NR by 1 or 2 ⁵R ⁶, CONR ⁵R ⁶The C that substituent group replaced ₁To C ₃Alkyl, wherein R ⁵And R ⁶Be selected from H, C independently of one another ₁To C ₄Alkyl and C ₃Thiazolinyl.

In formula (III), the other preferred group of chemical compound used according to the invention is: R ¹(back 4 groups are all randomly by one or more cyano group, low alkyl group, OR of being selected to represent H, low alkyl group, Het, alkyl Het or alkylaryl ⁶, C (O) OR ⁹Or NR ¹²R ¹³Substituent group replace and/or be connected on end); R ²(back 3 groups are all randomly replaced by one or more this paper substituent group defined previously and/or are connected on end, preferably by NR to represent hydrogen, halogen, low alkyl group, Het or aryl ¹²R ¹³Or SO ₂NR ¹⁴R ¹⁵Replace and/or be connected on end); R ³Represent C ₁-C ₄Alkyl or C ₃-C ₄Cycloalkyl, it is randomly by one or more halogen, cyano group, nitro, low alkyl group, halo (low alkyl group), OR of being selected from ⁶, OC (O) R ⁷, C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³And SO ₂NR ¹⁴R ¹⁵Substituent group replace and/or be connected on end; R ⁴Represent halogen, cyano group, nitro C (O) R ⁸, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, N[Y (O) R ¹⁷] ₂, NR ¹⁶Y (O) R ¹⁷, SOR ¹⁸, SO ₂R ¹⁹, C (O) AZ, low alkyl group, low-grade alkynyl, Het or aryl, back 3 groups are all randomly replaced and/or are connected on end as this paper substituent group defined previously by one or more; And wherein Y, A, Z, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁸, R ¹⁹Defined previously with Het such as this paper.More preferably, in this advances chemical compound in one group, R ¹Represent randomly substituted low alkyl group, more preferably low alkyl group, end are the low alkyl group of lower alkoxy, the terminal NR of being ¹²R ¹³Low alkyl group or end be the low alkyl group of N-morpholino.In addition alternatively, R ¹Can represent 4-piperidyl or 3-azelidinyl, its randomly at piperidyl nitrogen-atoms place by low alkyl group or C (O) OR ⁹Replace.In this preferred chemical compound, advance in one group R at this ²Represent C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, randomly by one or more O, S or N disconnect, randomly at N place by low alkyl group or aryl replaces or randomly by the low alkyl group of aryl or Het replacement.More preferably, work as R ²When being the low alkyl group that disconnects, disconnecting atom is one or more O and low alkyl groupization-N, works as R ²When being aryl, it is randomly replaced by phenyl or pyridine radicals.This advances one group of particularly preferred chemical compound is those chemical compounds, wherein R ²Represent C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³, the C that randomly disconnected, randomly replaced by low alkyl group at the N place by O or N _1-4Alkyl, randomly substituted phenyl or randomly substituted pyridine-2-base, pyridin-3-yl, pyrimidine-5-base, pyrazine-2-base, pyrazoles-4-Ji, oxadiazole-2-base, furan-2-base, furan-3-base, oxolane-2-base and imidazo [1,2-a] pyridine-6-base.In this preferred one group of chemical compound, R ³Can represent low alkyl group or cycloalkyl.In addition, X is preferably O.In the preferred chemical compound of this group, R ⁴Represent halogen, low alkyl group, low-grade alkynyl, randomly substituted Het, randomly substituted aryl, C (O) R ⁸, C (O) AZ, C (O) OR ⁹, C (O) NR ¹⁰R ¹¹, NR ¹²R ¹³Or NR ¹⁶Y (O) R ¹⁷Preferred R ⁴Be C (O) R ⁸(as acetyl group), halogen (as iodine), SO ₂R ¹⁹(R wherein ¹⁹Represent low alkyl group) and C (O) NR ¹⁰R ¹¹(R wherein ¹⁰And R ¹¹Represent H and low alkyl group separately, and/or R ¹⁰And R ¹¹In one be lower alkoxy) or NHB, wherein B represents H, SO ₂CH ₃Or C (O) Het.In further preferred chemical compound, R ⁴(back 2 groups are by C (O) OR to represent iodine, low alkyl group, low-grade alkynyl ⁹Replace and/or be connected on end (R wherein ⁹Represent H or C _1-6Alkyl)) N (H) Y (O) R, ¹⁷, N[Y (O) R ¹⁷] ₂, it is randomly by Het or NR ¹²R ¹³Replace (R wherein ¹²And R ¹³Represent together by O or N-S (O) ₂The C of-(the optional aryl that replaces) interruption _3-5Alkylidene).

Be used for the IC of the preferred PDEV inhibitor of the present invention's combination to the PDEV enzyme ₅₀Be lower than 100nM, more preferably less than 50nM, more preferably less than 10nM.This IC ₅₀Value can be used known PDE5 test determination, and this test is described in such as WO-A-01/27113, EP-A-0526004 and EP-B-0463756.

Preferably, PDEV inhibitor used according to the invention has selectivity (with regard to measured IC to the PDEV enzyme ₅₀).More preferably, its selectivity ratios PDE3 for PDEV is high more than 100 times, more preferably more than 300 times.More preferably, the PDEV inhibitor is more than 100 times for the selectivity of PDE3 and PDE4, more preferably more than 300 times.More preferably, its to the selectivity of other all PDE enzymes all more than 10 times, more preferably more than 100 times.Those skilled in the art can determine the selectivity ratio at an easy rate.The IC of PDE3 and PDE4 ₅₀Value can use the literature method of having set up to determine, referring to people such as SABallard, and Journal ofUrology, 1998, vol.159, pp 2164-2171.

The particularly preferred PDEV inhibitor that is used for this component invention is:

5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil) or acceptable salt of its medicine or solvate, especially sldenafil citrate;

(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine is [2 ', 1 ': 6,1] pyrido [3 also, 4-b] indole-1,4-diketone (tadanafil, IC-351, Cialis ) or acceptable salt of its medicine or solvate;

2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil, Levitra ) or acceptable salt of its medicine or solvate;

5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate;

5-[(5-acetyl group-2-butoxy-3-pyridine radicals)-and 3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate;

1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-] pyrazolo [4,3-d] pyrimidine-5-yl }-the 3-pyridyl sulfonyl }-4-ethyl piperazidine or acceptable salt of its medicine or solvate;

N-[1-(2-ethoxyethyl group)-5-(N-ethyl-N-methylamino)-7-(4-picoline-2-base is amino)-1H-pyrazolo [4,3-d] pyrimidine-3-carbonyl] amsacrine or acceptable salt of its medicine or solvate;

3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate; With

The 3-ethyl-5-[(R)-3-methyl-piperazine-1-yl]-1-[2-(2,2, the 2-trifluoro ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7-yl } pyrimidine-4-base-amine or acceptable salt of its medicine or solvate.

Preferably be combined as the combination of selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor according to the present invention, wherein said selectivity noradrenaline reuptake inhibitor (NRI) is selected from:

Reboxetine or acceptable salt of its medicine or solvate, especially reboxetine mesylate; With

(S, S)-reboxetine or acceptable salt of its medicine or solvate, especially (S, S)-the reboxetine succinate;

Described the 5th type phosphodiesterase (PDEV) inhibitor is selected from:

2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil) or acceptable salt of its medicine or solvate;

5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate;

N-[1-(2-ethoxyethyl group)-5-(N-ethyl-N-methylamino)-7-(4-picoline-2-base is amino)-1H-pyrazolo [4,3-d] pyrimidine-3-carbonyl] Methanesulfomide or acceptable salt of its medicine or solvate;

Preferably be combined as (S according to the present invention, S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially, S)-the reboxetine succinate) and the combination of the 5th type phosphodiesterase (PDEV) inhibitor, wherein said the 5th type phosphodiesterase (PDEV) inhibitor is selected from:

1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-4-ethyl piperazidine or acceptable salt of its medicine or solvate;

Preferably be combined as (S according to the present invention; S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially; S)-the reboxetine succinate) and 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1; the combination of 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil) or the acceptable salt of its medicine or solvate (especially sldenafil citrate).

Preferably be combined as according to the present invention (S, S)-reboxetine or the acceptable salt of its medicine or solvate (especially (S, S)-the reboxetine succinate) and (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine also [2,, 1:6,1] pyrido [3,4-b] indole-1,4-diketone (tadanafil, IC-351, Cialis ) or the combination of acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention; S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially; S)-the reboxetine succinate) and 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5; 1-f] [1; 2,4] combination of triazine-4-ketone (Vardenafil) or acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention; S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially; S)-the reboxetine succinate) and 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2; the combination of 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention; S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially; S)-the reboxetine succinate) and 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2; the combination of 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention; S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially; S)-the reboxetine succinate) and 1-{6-ethyoxyl-5-[3-ethyl-6; 7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-combination of 4-ethyl piperazidine or acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention, S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially, S)-the reboxetine succinate) with N-[1-(2-ethoxyethyl group)-5-(N-ethyl-N-methylamino)-7-(4-picoline-2-base amino)-1H-pyrazolo [4,3-d] pyrimidine-3-carbonyl] combination of Methanesulfomide or acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention; S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially; S)-the reboxetine succinate) and 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; the combination of 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate.

Preferably be combined as (S according to the present invention, S)-reboxetine or the acceptable salt of its medicine or solvate ((S especially, S)-the reboxetine succinate) with the 3-ethyl-5-[(R)-3-methyl-piperazine-1-yl]-1-[2-(2,2, the 2-trifluoro ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7-yl } combination of pyrimidine-4-base-amine or acceptable salt of its medicine or solvate.

Be selected to the selectivity noradrenaline reuptake inhibitor (NRI) or the 5th type phosphodiesterase (PDEV) inhibitor of the present invention's combination, especially above listed suitable or preferred chemical compound (hereinafter being referred to as " being used for chemical compound of the present invention ") a kind of, form that can drug acceptable salt is used, as acid-addition salts or alkali salt.

Suitable acid-addition salts is formed by the acid that forms nontoxic salts.Example comprises acetate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, disulfate/sulfate, borate, camsilate, citrate, ethanedisulphonate, ethyl sulfonate, formates, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate (hibenzate), hydrochloric acid/chlorine, hydrobromic acid/bromine, hydroiodic acid/iodine, isethionate, lactate, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate, the 2-naphthalene sulfonate, nicotinate, nitrate, Orotate, oxalates, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, sugar lime, stearate, succinate, tartrate, toluene fulfonate and trifluoroacetate.

Suitable alkali salt is formed by the alkali that forms nontoxic salts.Example comprises the salt of aluminum, arginine, benzyl star, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethane and zinc.

Can also form half salt (semisalt) of bronsted lowry acids and bases bronsted lowry, for example, Hemisulphate and half calcium salt.

The summary of suitable salt can be referring to the Handbook ofPharmaceutical Salts:Properties of Stahl and Wermuth, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

The drug acceptable salt that is used for chemical compound of the present invention can be by one or more preparations of following three kinds of methods:

(i) make chemical compound and required acid or alkali reaction;

(ii) from the suitable precursor of chemical compound, remove acid-or alkali-unsettled protecting group, perhaps use required acid or alkali to make suitable cyclic precursor such as lactone or lactams open loop; Or

(iii) by with suitable acid or alkali reaction, perhaps by suitable ion exchange column, a kind of salt of chemical compound is changed into another kind of salt.

These three kinds of methods are all carried out in solution usually.The salt that generates can be precipitated out, and collects by filtering, and perhaps reclaims by evaporating solvent.The degree of ionization of gained salt can be an extremely almost nonionicization of complete ionizing.

Be used for chemical compound of the present invention not the form of solvation or solvation exist.Term used herein " solvate " is meant and comprises chemical compound and stoichiometric one or more medicine acceptable solvent molecules such as alcoholic acid molecular complex.When being water, uses by described solvent term " hydrate ".

Be used for chemical compound of the present invention and can form complex, clathrate (clathrate) for example, medicine-host forgives complex, and is wherein opposite with aforesaid solvate, and medicine and host's amount can be a stoichiometry or non-stoichiometric.Be used for chemical compound of the present invention and can contain 2 kinds or multiple organic and/or inorganic constituents, its amount can be a stoichiometry or non-stoichiometric.The complex that generates can be ionizing, partial ionization or nonionicization.The summary of this complex is referring to the J.Pharm.Sci. of Haleblian, 64(8), 1269-1288, show (in August, 1975).

Being used for the form that chemical compound of the present invention can prodrug (pro-drug) uses.Therefore, some pharmaceutically active own is extremely low or do not have the compound derivatives of pharmaceutically active to change into can be in donor or on the body time to have required active chemical compound (for example by the hydrolysis cutting).This derivant is called " prodrug ".The out of Memory that prodrug uses can referring to Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T.Higuchi and W.Stella), and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed.E.B.Roche, American Pharmaceutical Association).For instance, prodrug can be by suitable functional group is replaced with the part that some those skilled in the art is called " prodrug fragment (pro-moiety) ", and is for example, of the Design of Prodrugs (Elsevier, 1985) of H.Bundgaard.

Being used for chemical compound of the present invention and can also forming active metabolite when giving the patient, mainly is to pass through oxidation reaction.The hydroxylating particular importance of liver enzyme.

Being used for the chemical compound that contains one or more asymmetric carbon atoms of the present invention can exist by two or more diastereomers.When chemical compound contains thiazolinyl or alkenylene, has the stereoisomer of cis/trans (or Z/E).When constitutional isomer can exchange via low energy barrier, tautomerization (" tautomerism, tautomerism ") can take place.This can take the form of proton tautomerism in containing such as the chemical compound of imines, ketone or oximido, perhaps take the form of so-called valence tautomerism in the chemical compound that contains the armaticity part.A kind of chemical compound can show more than one isomerism.

The cis/trans isomer can separate by well known to a person skilled in the art routine techniques (for example chromatograph and fractional crystallization).

The routine techniques of the single enantiomer of preparation/separation comprises by suitable optical voidness precursor and carries out asymmetric synthesis or by such as chirality high pressure liquid chromatography (HPLC) racemic modification (or racemic modification of salt or derivant) being split.

In addition alternatively, racemic modification (or racemic precursor) can react with suitable optically active compound (for example alcohol), perhaps contains under acid or the alkali situation partly at chemical compound and reacts with alkali or acid (for example 1-phenyl ethyl amine or tartaric acid).The diastereo-isomerism mixture that generates can separate by chromatograph and/or fractional crystallization, by well known to a person skilled in the art method in the diastereomer one or both is changed into corresponding pure enantiomer.

Can use chromatograph (being generally HPLC) obtaining the chipal compounds of the present invention (and chiral precursor) of optical isomer enriched form under the following condition: on asymmetric resin, mobile phase is made up of hydrocarbon (being generally heptane or hexane), and it contains the isopropyl alcohol of 0 to 50% volume (being generally 2% to 20%) and the alkylamine of 0 to 5% volume (be generally 0.1% diethylamine).Concentrate eluate, obtain mixture through enrichment.

Stereomeric aggregation can separate by well known to a person skilled in the art routine techniques, referring to, the Stereochemistry of OrganicCompounds of E.L.Eliel and S.H.Wilen (Wiley, New York, 1994) for example.

It can be isotope-labeled being used for chemical compound of the present invention, and identical but atomic mass or mass number are different from abundance is the highest under the native state atomic mass or the atom of mass number substitutes to wherein one or more atoms by atomic number.

The isotope that these isotopic examples comprise hydrogen (for example ²H, ³H), the isotope of carbon (for example ¹¹C, ¹³C and ¹⁴C), the isotope of chlorine (for example ³⁶Cl), the isotope of fluorine (for example ¹⁸F), the isotope of iodine (for example ¹²³I and ¹²⁵I), the isotope of nitrogen (for example ¹³N and ¹⁵N), the isotope of oxygen (for example ¹⁵O, ¹⁷O and ¹⁸O), the isotope of phosphorus (for example ³²P) and the isotope of sulfur (for example ³⁵S).

Some isotope-labeled chemical compound (for example comprise radioisotopic those) can be used for the tissue distribution research of medicine and/or substrate.Consider its be easy in conjunction with and detection mode ready-made, the radiosiotope tritium is (promptly ³H) and carbon-14 (promptly ¹⁴C) be specially adapted to this purpose.

With higher isotope (deuterium for example, promptly ²H) replace, the advantage in some treatment can be provided, metabolic stability is improved, for example, increase the interior half-life of body or reduce the dosage demand, thereby can be preferred in some cases.

With the isotope that discharges positron (for example ¹¹C, ¹⁸F, ¹⁵O and ¹³N) replace, can be used to detect PET (positron emission tomography) method (PET) research of substrate sensor occupation rate.

Pharmaceutically acceptable solvate comprises that wherein recrystallisation solvent is by for example D ₂O, d ₆-acetone, d ₆The material that-DMSO isotope replaces.

Can the form administration of chemical compound of the present invention with crystallization or amorphous products will be used for.It can be by obtaining such as the method for precipitation, crystallization, lyophilization, jet drying or the evaporation drying form with for example solid suppository, powder or thin film.Microwave or radio-frequency seasoning also can be used for this purpose.

Being used for chemical compound of the present invention can be individually dosed, but more may be with one or more pharmaceutically acceptable excipient as the preparation administration.Any composition except that being used for chemical compound of the present invention described in term used herein " excipient ".The concrete pattern that being chosen in of excipient depended on to a great extent such as administration, excipient are to dissolubility and the influence of stability and the multiple factor of dosage form character.

It is conspicuous to those of ordinary skills that suitable release is used for pharmaceutical composition of chemical compound of the present invention and preparation method thereof.These composition and method of making the sames can be consulted, for example Remington ' s Pharmaceutical Sciences, the 19th edition (Mack PublishingCompany, 1995).

Being used for chemical compound of the present invention can be taken orally.Oral administration can comprise swallows administration, makes chemical compound enter gastrointestinal tract, or buccal or sublingual administration, makes chemical compound directly enter blood flow from mouth.

The preparation that is suitable for oral administration comprises solid preparation such as tablet, contains granule, the capsule of liquid or powder, lozenge (comprise be filled with liquid), chaw, glue, compound and nano-particle, gel, solid solution, liposome, thin film, vesicle (ovules), propellant and liquid preparation.

Liquid preparation comprises suspension, solution, syrup and elixir.This preparation can generally include carrier, for example water, ethanol, Polyethylene Glycol, propylene glycol, methylcellulose or suitable oil and one or more emulsifying agents and/or suspensoid as the filler of soft or hard capsule.Liquid preparation can also prepare by the transformation of solid (for example sachet).

Be used for chemical compound of the present invention and can also be used for quick dissolving, quickly disintegrated dosage form, the Expert Opinion in Therapeutic Patents of Liang and Chen for example, 11(6), 981-986, those dosage forms of describing in (2001).

For Tabules, according to dosage, be used for the 1wt% to 80wt% that chemical compound of the present invention accounts for dosage form usually, more typically be the 5wt% to 60wt% of dosage form.In addition, tablet contains disintegrating agent usually.Examples of disintegrants comprises hydroxypropyl cellulose, starch, pregelatinized Starch and the sodium alginate that sodium starch glycolate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone (crospovidone), polyvinylpyrrolidone, methylcellulose, microcrystalline Cellulose, low alkyl group replace.Usually, disintegrating agent accounts for the 1wt% to 25wt% of dosage form, is preferably 5wt% to 20wt%.

Binding agent is generally used for making tablet to have cohesive.Suitable bonding comprises microcrystalline Cellulose, gelatin, sugar, Polyethylene Glycol, natural and paragutta, polyvinylpyrrolidone, pregelatinized Starch, hydroxypropyl cellulose and hydroxypropyl emthylcellulose.Tablet can also comprise diluent, for example lactose (monohydrate of monohydrate, jet drying, anhydride and analog), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline Cellulose, starch and secondary calcium phosphate dihydrate.

Tablet can also randomly comprise surfactant (for example sodium lauryl sulphate and polysorbate 80) and fluidizer (for example silicon dioxide and Talcum).When having above-mentioned substance, surfactant can account for the 0.2wt% to 5wt% of tablet, and fluidizer can account for the 0.2wt% to 1wt% of tablet.

Tablet also contains lubricant, for example mixture of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and magnesium stearate and sodium lauryl sulphate usually.Lubricant accounts for the 0.25wt% to 10wt% of tablet usually, preferably, accounts for the 0.5wt% to 3wt% of tablet.

Other possible composition comprises antioxidant, coloring agent, flavoring agent, antiseptic and mask agent.

Exemplary tablet contains the medicine up to about 80%, the binding agent of the extremely about 90wt% of about 10wt%, the diluent of about 0wt% to 85wt%, the disintegrating agent of the extremely about 10wt% of about 2wt% and the lubricant of about 0.25wt% to 10wt%.

Tablet mixture can be directly or by roll-in system, forms tablet.Tablet mixture or partially mixed thing can alternately carry out wet granulation, dry granulation or melt granulation before tabletting, fusion is condensed or extruded.Final dosage form can comprise one or more layers, coating can be arranged or do not have coating; Even can be loaded in the capsule.

Tablet formulation is described in Pharmaceutical Dosage Forms:Tablets, the 1st volume, H.Lieberman and L.Lachman work (Marcel Dekker, New York, 1980).

People or consumed oral film for animals generally are the thin-film dosage form that is easy to water solublity or water-swellable, can dissolve fast or mucosa adhesion, generally include and be used for chemical compound of the present invention, film forming polymer, binding agent, solvent, wetting agent, plasticizer, stabilizing agent or emulsifying agent, viscosity modifier and solvent.Some compositions of said preparation can be brought into play more than one effects.

Being used for chemical compound of the present invention can be water solublity or insoluble.Water soluble compound generally includes the 1wt% to 80wt% of solute, more typically is 20wt% to 50wt%.The chemical compound that dissolubility is lower can comprise the larger proportion of compositions, reaches the 88wt% of solute usually.In addition alternatively, the form that the chemical compound of structural formula (I) can the multiparticulates globule exists.

Film forming polymer can be selected from natural polysaccharide, protein or synthetic hydrocolloid, and usually content is 0.01 to 99wt%, more typically is 30 to 80wt%.

Other possible composition comprises antioxidant, coloring agent, spice and flavor potentiator, antiseptic, saliva stimulant, coolant, cosolvent (comprising oil), softening agent, filler, defoamer, surfactant and mask agent.

Thin film is usually by carrying out evaporation drying and prepare being applied to aqueous thin film on peelable backing carrier or the paper.This process can be carried out in drying oven or drying alley (being generally combination type coating exsiccator), is perhaps undertaken by lyophilization or vacuum.

The solid preparation of oral administration can be mixed with immediately and/or modify release.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, targeting release and program discharges.

The suitable modification delivery formulations that is used for the object of the invention is described in United States Patent (USP) the 6th, 106, No. 864.The particular content of other suitable release tech (as high energy dispersion and infiltration and coating granule) can be consulted Pharmaceutical Technology On-line, 25 (2), 1-14, people such as Verma work (2001).Use chewing gum to realize that sustained release is described in WO00/35298.

Be used for chemical compound of the present invention directly administration enter blood flow, muscle or internal.These parenterals comprise in the intravenous, intra-arterial, intraperitoneal, sheath, in the ventricle, in the urethra, in the abdomen, in the intracranial, intramuscular, synovial membrane and subcutaneous administration.The appropriate device of parenteral comprises pin type (comprising microscopic needle) syringe, needleless injector and infusion techniques.

Parenteral administration normally contains the aqueous solution (preferred pH is 3 to 9) of excipient (for example salt, carbohydrate and buffer agent), but, in some applications, it is more suitable for making aseptic non-aqueous solution, perhaps make exsiccant form, use with suitable medium (for example aseptic pyrogen-free water).

Can use the standard drug technology that well known to a person skilled in the art at an easy rate,, under aseptic condition, realize the preparation of parenteral administration for example by lyophilization.

The dissolubility that is used for chemical compound of the present invention that is used to prepare parenteral solution can be increased by using appropriate formulations technology (for example adding solubility enhancing agent).

Release can be made immediately and/or be modified to the preparation of parenteral.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, targeting release and program discharges.Therefore, be used for chemical compound of the present invention and can make solid, semisolid or thixotropic liquid, as the implantation Drug Storage that reactive compound modify to be discharged and administration.The example of this preparation comprises coating support (drug-coated stent) and poly-(dl-lactic-co-glycolic acid) copolymer (PGLA) microsphere.

Being used for chemical compound of the present invention can also be to skin or mucosa topical, that is, and and epidermis or transdermal administration.The preparation that typically is used for this purposes comprises gel, hydrogel, lotion, solution, unguentum, ointment, dusting, dressing, foam, thin film, skin patch, wafer, implant, sponge, fiber, binder and microemulsion.Can also use liposome.Typical carrier comprises alcohol, water, mineral oil, liquid petrolatum, white vaseline, glycerol, Polyethylene Glycol and propylene glycol.Can add penetration enhancer-referring to, J Pharm Sci for example, 88(10), 955-958, Finnin and Morgan work (in October, 1999).

The alternate manner of topical comprise by electroporation, electron ion penetrate, ultrasonicly penetrate, phonophoresis and microscopic needle or needle-free injection device (for example, Powderject ^TM, Bioject ^TMDeng) carry.

Release can be made immediately and/or be modified to the preparation of topical.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, targeting release and program discharges.

Being used for chemical compound of the present invention can also intranasal administration or pass through inhalation, usually as dry powder (single component, or as mixture, for example with the dry mixture of lactose, or, for example mix with phospholipid such as phosphatidylcholine as the blending constituent granule) form from the Diskus administration, or using or do not using suitable propellant (for example 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane) under the situation, from pressurizing vessel, pump, ejector, in nebulizer (preferably making the nebulizer of electricity consumption hydraulic pressure produce mist) or the aerosol apparatus as the aerosol injection administration.For intranasal administration, powder can comprise bioadhesive polymer, for example chitosan or cyclodextrin.

Pressurizing vessel, pump, ejector, nebulizer or aerosol apparatus contain: comprise such as ethanol, ethanol water or be used to make that active matter disperses, dissolving or prolong the solution that is used for chemical compound of the present invention or the suspension of the suitable substituting agent that discharges, as the propellant of solvent, and optional surfactant (for example sorbitan, oleic acid or lact-acid oligomer).

Before using dry powder or suspension formulations,, make size be suitable for sucking and carry (being generally less than 5 microns) the drug products micronization.This can finish by any suitable Ginding process (for example spiral spray grinding, fluidised-bed spray grind, form supercritical fluid method, high pressure homogenize or the jet drying of nanoparticle).

Capsule (by making such as gelatin or hydroxypropyl emthylcellulose), foaming agent and the cartridge case that is used for inhaler or insufflator can be mixed with to contain and be useful on chemical compound of the present invention, suitable powder substrate (for example lactose or starch) and the mixture of powders of outward appearance modifier (for example l-leucine, mannitol or magnesium stearate).Lactose can be anhydrous, or the form of monohydrate, is preferably the latter.Other excipient that is fit to comprises glucosan, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

The suitable pharmaceutical solutions that is used to make electricity consumption hydraulic pressure to produce the nebulizer of mist can whenever be pressed and contain 1 μ g to 20mg and be used for chemical compound of the present invention, and whenever presses volume and can be changed to 100 μ l from 1 μ l.Typical formulation can comprise and is used for chemical compound of the present invention, propylene glycol, sterilized water, ethanol and sodium chloride.Can be used for replacing the selectable solvent of propylene glycol to comprise glycerol and Polyethylene Glycol.

Suitable spice (for example menthol and levomenthol) or sweeting agent (for example glucide or saccharin sodium) can be joined the preparation that those are used for inhalation/intranasal administration.

The preparation that is used for inhalation/intranasal administration can be made and discharge immediately and/or for example use that the modification of PGLA discharges.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, targeting release and program discharges.

Under the situation of Diskus and aerosol, dosage device is determined by the valve of conveying and metering amount.Usually being arranged to give the total daily dose of dosing or " blowing (puff) " according to unit of the present invention can be according to the single dose administration in one day, perhaps more generally, and according to the broken dose administration.

Be used for chemical compound of the present invention and can carry out rectally or vagina administration with form such as suppository, vaginal suppository or enema.Cocoa butter is traditional suppository base, but as long as suitably, can use various substitutes.

The preparation of rectally/vagina administration can be made for immediately and/or modify release.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, targeting release and program discharges.

Be used for chemical compound of the present invention and can also directly deliver medicine to eye or ear, usually ooze, the form administration of the drop of the micronize suspension in the Sterile Saline of pH regulator or solution to wait.Other preparation that is suitable for ophthalmic and in ear administration comprises ointment, gel, biodegradable (for example absorbable gel sponge, collagen) implant and non-biodegradation (for example silicone) implant, wafer (wafer), eyeglass (lense) and microgranule or vesicle system (for example single phospholipid layer vesicle and two phospholipid layer liposome).Can for example cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulosic polymer (for example hydroxypropyl emthylcellulose, hydroxyethyl-cellulose or methylcellulose) or heteropolysaccharide polymer (for example gelan gum) add with antiseptic (for example benzalkonium chloride) with polymer.Said preparation also can penetrate by electron ion and carry.

The preparation of eye drops/in ear administration can be made for immediately and/or modify release.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, targeting release or program discharges.

In order to improve the dissolubility that is used for chemical compound of the present invention that is used for aforementioned any administering mode, rate of dissolution, screening flavor effect, bioavailability and/or stability, the polymer that is used for chemical compound of the present invention and soluble large molecule material (for example cyclodextrin and suitable derivant thereof) or contains Polyethylene Glycol can also be combined use.

For example have been found that the drug-cyclodextrin complex can be used for most of dosage forms and route of administration usually.The two all can use enclose and non-inclusion complex.As with the directly compound optional mode in addition of medicine, cyclodextrin can be used as auxiliary additive, promptly as carrier, diluent or solubilizing agent use.Be most commonly used to these purposes be α-, β-and gamma-cyclodextrin, its example can be consulted international patent application WO91/11172 number, WO94/02518 number and WO98/55148 number.

Two kinds of compositions of this component invention (being selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor) can be simultaneously, in regular turn or individually dosed, to realize the advantage of combination type treatment provided by the invention.Every kind of composition all can be individually dosed, but more generally with one or more excipient as the aforementioned pharmaceutical compositions administration.Usually, two kinds of compositions can be via identical path (as oral) administration.But in some cases, more preferably each component is via different administrations (for example, a kind of composition is via oral administration, and a kind of composition is via the parenteral route administration).For the while administration, two kinds of compositions are preferably formed the part of same pharmaceutical composition, therefore via identical administration.

Oral administration all is preferred to two kinds of components of the present invention.Most preferably, two kinds of compositions are simultaneously via oral route (as the form with tablet) administration.

Two kinds of compositions of the present invention combination can be easily with the form combination of test kit (kit).This test kit comprises selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor (form of each composition be generally in the aforementioned pharmaceutical compositions a kind of), and the instrument (for example container, packing bottle or packing Foilpac) that holds them respectively.The example of this test kit is useful on the domestic blister package of package troche, capsule and analog.

Test kit of the present invention is particularly useful for the administration of different dosage form (for example oral and parenteral), is applicable to compositions independently perhaps is applicable to independently compositions titration each other with different spacing of doses administrations.In order to help to finish administration, test kit generally includes the administration description, and is furnished with so-called memory aid.

Measure the cooperative interaction between one or more compositions, the best scope of validity of each composition and the absolute dosages scope of this effectiveness, can be by the patient who needs treatment different w/w proportions and dosage composition and measure definitely.For the people, the complexity and the cost of carrying out clinical research the patient on one's body can't be implemented the test form of the collaborative pattern in this basis.But, the synergism of observing a kind of species can be predicted the effect of other species and animal model, as described herein, with the prediction synergism, drug application kinetics/medicine dynamic approach, the result of this research can also be used to predict that effective dose that other species are required and plasma concentration are than scope, absolute dosages and plasma concentration.The relatedness of having set up between animal model and the people's Expected Results shows, the synergism of animal preferably uses rodentine static state and dynamic allodynia to measure demonstration, makes rodent suffer the method for operation (injured as chronic contraction) or chemistry (as streptozocin (streptozocin)) to cause allodynia.Because the peak effect of this pattern, its value are estimated best, be convertible into the advantage of saving dosage for neuropathic pain patients with regard to synergism.In other model, the pattern that is used for the treatment of the existing medicament of neuropathic pain only provides partial reaction, is more suitable for the synergistic potential of prediction combination, to promote the maximum drug effect of two kinds of compositions under maximum tolerated dose.

Therefore, the present invention advances to provide on the one hand a kind of synergistic combination that is used for the human body administration, it comprises that selectivity noradrenaline reuptake inhibitor (NRI) is (as (S, S)-reboxetine or acceptable salt of its medicine or solvate, (S particularly, S)-the reboxetine succinate) and PDEV inhibitor or acceptable salt of its medicine or solvate, its w/w combination range is confirmed observed absolute range in the synergistic non-human animal model (being preferably rat model) corresponding to being mainly used in.Suitably, the non-human scope of Ren Lei proportion correspondence be selected from 1: 50 to 50: 1 (weight portion), 1: 50 to 20: 1,1: 50 to 10: 1,1: 50 to 1: 1,1: 20 to 50: 1,1: 20 to 20: 1,1: 20 to 10: 1,1: 20 to 1: 1,1: 10 to 50: 1,1: 10 to 20: 1,1: 10 to 10: 1,1: 10 to 1: 1,1: 1 to 50: 1,1: 1 to 20: 1 and 1: 1 to 10: 1.

When selectivity NRI is (S, S)-reboxetine, and the PDEV inhibitor is when being sldenafil (Sildenafil), the synergist weight range of inhuman (being preferably rat) model of human scope correspondence is about 20: 1 to 1: 10, be preferably 10: 1 to 1: 5, more preferably 5: 1 to 2: 5.

When selectivity NRI is (S, S)-reboxetine, and the PDEV inhibitor is when being Vardenafil (Verdenafil), the synergist weight range of inhuman (being preferably rat) model of human scope correspondence is about 20: 1 to 1: 10, be preferably 10: 1 to 1: 5, more preferably 5: 1 to 2: 5.

When selectivity NRI is (S, S)-reboxetine, and the PDEV inhibitor is when being tadanafil (Tadalafil), the synergist weight range of inhuman (being preferably rat) model of human scope correspondence is about 20: 1 to 1: 10, be preferably 10: 1 to 1: 5, more preferably 5: 1 to 2: 5.

When selectivity NRI is (S; S)-reboxetine; and the PDEV inhibitor is 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] during pyrimidin-7-ones (compd A), the synergist weight range of inhuman (being preferably rat) model of human scope correspondence is about 20: 1 to 1: 10, is preferably 10: 1 to 1: 5; more preferably 5: 1 to 2: 5, most preferably be 4: 1 to 1: 2.In a concrete example, the synergist weight range of inhuman (being preferably rat) model of human scope correspondence is 3: 1.In another concrete example, the synergist weight range of inhuman (being preferably rat) model of human scope correspondence is 1: 1.

With regard to human, some kinds of pain experimental models can be used for the mankind, confirm that to show having synergistic medicament also has the synergism that is complementary in animal body in human body.The example that can meet people's class model of this purpose comprises heat/Fructus Capsici prime modulus model (Petersen, K.L.﹠amp; Rowbotham, M.C. (1999) NeuroReport 10,1511-1516), i.d capsaicin model (Andersen, O.L., Felsby, S., Nicolaisen, L., Bjerring, P., Jsesn, T.S.﹠amp; Arendt-Nielsen, L. (1996) Pain 66 51-62), comprises the model (Witting, N., Svesson, P., Arendt-Nielsen, the L.﹠amp that reuse the capsaicin wound; Jensen, T.S. (2000) Somatosensory Motor Res.17,5-12) and stack or excited (wind-up) reaction (Curatolo, people such as M. (2000) Anesthesiology 93,1517-1530).Adopt these models, the subjective evaluation that can use pain intensity or hyperpathia area is as terminal point, or more objective terminal point, it depends on and can adopt electric physiology or imaging technique (as functional mri) (Bornhovd, K., Quante, M., Glauche, V., Bromm, B., Weiller, C.﹠amp; Buchel, C. (2002) Brain 125,1326-1336).All these models observed combination acts synergistically in the animal experiment of drawing a conclusion also can obtain human trial and confirm all to need objective affirmation evidence before the support.

When the present invention is used for human body, suitable NRI: the proportion of PDEV inhibitor be selected from 1: 50 to 50: 1 (weight portion), 1: 50 to 20: 1,1: 50 to 10: 1,1: 50 to 1: 1,1: 20 to 50: 1,1: 20 to 20: 1,1: 20 to 10: 1,1: 20 to 1: 1,1: 10 to 50: 1,1: 10 to 20: 1,1: 10 to 10: 1,1: 10 to 1: 1,1: 1 to 50: 1,1: 1 to 20: 1 and 1: 1 to 10: 1, be 1: 10 to 20: 1 more suitably, be preferably 1: 1 to 10: 1.

The optimal dose of each composition with regard to synergism can be determined according to disclosed method in animal model.But (even pain experimental model) determines that the research of complete exposure-response relation is that cost is very high under all treatment relevant dose of each composition of combination in the mankind.At least the most at the beginning, determine under the dosage that obtains from the dosage extrapolation of bringing into play synergy in animal body, whether can observe with the corresponding to effect of systemic effect be necessary.With dosage when animal is amplified to human body, need to consider multiple factor, flow into relative absorption, distribution, metabolism and secretion and the relative plasma protein combination of relative body weight/body surface area, each composition, owing to these reasons, the optimal dose ratio of predicting for human body (and patient) is shown as best dose ratio and inequality probably with in the animal body.But the technical staff in animal and human's pharmacokinetics field is appreciated that and calculates relation between these two.The resulting plasma concentration of using in the zooscopy of each component is very important for the bridge of setting up between the effect of animal and human's body, and to estimate to provide the plasma concentration of effectiveness in human body relevant because these are with each composition.When pharmacokinetics/medicine dynamic modeling (comprising for example mimic method of isobologram, action index and reaction surface) and simulation can help to estimate that people intravital collaborative dose ratio, especially one or both in these compositions have been studied in human body.

Therefore, the present invention is according to a kind of human synergistic combination that gives is provided on the other hand, it comprises selectivity noradrenaline reuptake inhibitor (NRI) ((S for example, S)-reboxetine or acceptable salt of its medicine or solvate, especially (S, S)-the reboxetine succinate) and PDEV inhibitor or acceptable salt of its medicine or solvate, wherein each dose of components scope is confirmed observed absolute collaborative scope in the synergistic non-human animal model (being preferably rat) corresponding to being mainly used in.Suitably, dosage range in the human body in the rat of the dosage range correspondence of selectivity noradrenaline reuptake inhibitor is 0.5-50mg/kg, more suitably be 1-30mg/kg, the dosage range of corresponding PDEV inhibitor is 0.1-10mg/kg, more suitably is 1-10mg/kg.

For (S, S)-reboxetine and sldenafil, be used for collaborative scope in the suitably corresponding rat of the dosage range of human body and be 1-30mg/kg (S, S)-reboxetine and 0.5-10mg/kg sldenafil.For (S, S)-reboxetine and Vardenafil, be used for collaborative scope in the suitably corresponding rat of the dosage range of human body and be 1-30mg/kg (S, S)-reboxetine and 0.5-10mg/kg Vardenafil.For (S, S)-reboxetine and tadanafil, be used for collaborative scope in the suitably corresponding rat of the dosage range of human body and be 1-30mg/kg (S, S)-reboxetine and 0.5-10mg/kg tadanafil.For (S; S)-reboxetine and 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones (compd A); collaborative scope in the suitably corresponding rat of the dosage range that is used for human body be 1-30mg/kg (S, S)-reboxetine and 0.5-10mg/kg compd A.

During for the human patients administration, total daily dose of the selectivity noradrenaline reuptake inhibitor (NRI) of the administration according to the present invention and the 5th type phosphodiesterase (PDEV) inhibitor the best will be according to selected particular compound and is greatly different.This optimal dose can be determined according to the medical enforcement method of routine at an easy rate by those skilled in the art.Suitably, the scope that is used for the dosage of human selectivity noradrenaline reuptake inhibitor (NRI) is selected from 0.05-1000mg, 0.1-500mg, 0.2-100mg, 0.5-50mg, 1-25mg, every day 1 to 4 time, suitably be that every day one is to secondary, the dosage range of PDEV inhibitor is selected from 1-200mg, 1-100mg, 1-50mg, 1-25mg, 10-100mg, 10-50mg or 10-25mg, suitably be 10-100mg, every day one, two or three times is suitably for once a day.As an example, when selected selectivity noradrenaline reuptake inhibitor be that (S, S)-during reboxetine, depend on the pattern of administration certainly, total daily dose is generally 0.1mg to 10mg.Preferably, (S, S)-daily dose of reboxetine is 0.1mg to 8mg, more preferably 0.5mg to 6mg.As another example, when selected PDEV inhibitor is sldenafil, dosage be 10 to 100mg (as 25,50 or 100mg), administration in common a day, two or three times is preferably once a day.As another example, when selected PDEV inhibitor is Vardenafil, dosage be 1 to 50mg (as 2.5,5,10 or 20mg), administration one in common a day or secondary are preferably once a day.As another example, when selected PDEV inhibitor is tadanafil, dosage be 1 to 50mg (as 5,10 or 20mg), administration in common a day, two or three times is preferably once a day.

The total daily dose of each composition can be separately or the dosage of gradation give and want, just doctor's angle is considered, can fall into outside the above-mentioned typical doses scope.This typical range is that the average human experimenter of 60kg to 70kg is a benchmark with the body weight.The doctor will can determine the experimenter (as baby and old man) of body weight outside this scope dosage at an easy rate.Preferably, two of this component invention kinds of composition administrations every day one are to secondary.

For avoiding query, alleged " treatment " of this paper comprises therapeutic, appeasing property and prophylactic treatment.

Combination of the present invention comprises selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor.The present invention makes up the PDEV activity of employed chemical compound can be by following test determines.

PDE measures by measuring its IC50 value (suppressing the required compound concentration of 50% enzymatic activity) the vitro inhibition of ring-type guanosine 3 ', 5 '-monophosphate (cGMP) and ring-type adenosine 3 ', 5 '-monophosphate (cAMP) phosphodiesterase is active.

Required PDE enzyme is isolated from multiple source, comprises the platelet of human cavernous body of penis, people and rabbit, human ventricle, human skeletal's flesh and bovine retina, mainly by W.J.Thompson and M.M.Appleman (Biochem., 1971, 10, 311) method.Particularly, the cAMP PDE (PDE3) of cGMP specific PDE (PDE5) and cGMP-inhibition obtains from human corpus cavernosum tissue, human platelet and tame rabbit platelet; The PDE (PDE2) that cGMP-stimulates is obtained by human corpus cavernosum tissue; Calcium/calmodulin (Ca/CAM) dependent form PDE (PDE1) is obtained by human ventricle; CAMP-specific PDE (PDE4) is obtained by human skeletal's flesh; Light receptor PDE (PDE6) is obtained by bovine retina.Phosphodiesterase 7-11 is produced by transfection to the total length people's recombinant clone body in the SF9 cell.

People (Biochem. such as W.J.Thompson are used in test, 1979,18,5228) " batch " method modifies and to carry out, perhaps use the described experimental program of Amersham plc production code member TRKQ7090/7100 to modify and carry out, use the test of concussion nearness that AMP/GMP is directly detected.In brief, investigate the effect of PDE inhibitor by the following method: under the condition that changes inhibitor concentration and a small amount of substrate, detect fixed amount enzyme (cGMP or cAMP unmarked with [ ³H] ratio of labelling is 3: 1, concentration～1/3K _m), make IC ₅₀Approximate Ki.Final test volume is tested buffer [20mM Tris-HCl pH7.4,5mM MgCl up to 100 μ l ₂, the 1mg/ml bovine serum albumin].Reaction causes with enzyme, hatches under 30 ℃ 30-60 minute, gets＜30% substrate conversion rate, with 50 μ l yttrium silicate SPA globules (the ring nucleus thuja acid that contains the 3mM unlabelled PDEs 9 of difference and 11) cessation reaction.Bread board is sealed again, vibrated 20 minutes, make globule sedimentation in the dark 30 minutes then, (Packard, Meriden count on CT) at TopCount plate reader then.Convert radiation active unit to do not suppress contrast (100%) % activity, inhibitor concentration is mapped, use the IC of " Fit curve " agent that is inhibited of the Excelextension of Microsoft ₅₀Value.

Functional activity

By measure chemical compound of the present invention improve sodium nitroprusside-bring out preceding-shrink the ability that rabbit corpus cavernosum tissue bar loosens, this is carried out external test, as people such as S.A.Ballard (Brit.J.Pharmacol., 1996, 118(suppl.), summary 153P) described.

Activity in vivo

Chemical compound screens in the dog of anesthesia, with measure its i.v. administration after, improve in the cavernous body of penis since in the spongy body pressure of injection sodium nitroprusside raise, use based on people such as Trigo-Rocha (Neurourol.and Urodyn., 1994, 13, 71) and described method.

Of the present invention being combined in the pain animal model demonstrates synergism, describes as hypomere.

Method

Animal

Male Sprague Dawley rat (being the 175-200 gram during operation), available from CharlesRiver, U.K. is divided into the 3-6 group.All animals all remain on 12h light/dark circulation (beginning illumination in 7: 00), and quantity-unlimiting food and water are provided.All experiments are undertaken by the blind observer of drug treating.

Chronic contraction injury (CCI) model

Animal places anesthetic room, and with 2% isoflurane (isofluorane) and O ₂Mixture anesthesia.Right back thigh is shaved hair, and with 1% iodine tincture wiping.Then animal is transferred to and in whole process on the constant temperature blanket, in operation process via the omnidistance anesthesia of nasal tube.Skin is downcut along the femur line.It is middle to make general sciatic nerve be exposed to thigh by the blunt dissection along biceps femoris.In ischium trifurcation front side, make the nerve of about 7mm free by subneural insertion tweezers, and nerve is pulled out outside the thigh gently.With tweezers lightly opening and closing for several times help to remove supraneural fascia.Use tweezers that suture is pulled to neural below and beat and simply tie, until feeling slight resistance, and then make a call to second knot.Repeat this process, until near neural, having beaten four loose knots (4-0 is thread), the about 1mm in interval.Otch is successively sewed it up, afterwards local antibiotic on the wound.

The assessment of class pain threshold

Before the allodynia assessment, make animal get used to testing in the cage.(Illinois USA) tests static allodynia for Stoelting, Wood Dale, and strength cumulative (0.7,1.2,1.4,2,4,6,8,10,15 and 26 gram) is to the rear solid end foot bottom surface by applying von Frey hairs.Whenever on pawl, use maximum 6 seconds with von Frey hairs, perhaps until the pawl reaction of contracting occurring.In case set up the pawl reaction of contracting to von Frey hairs, pawl is tested again, begin by the contract myofilament of below, pawl place of generation, all the other myofilaments continue with the gradually low order of strength afterwards, until the pawl that no longer contracts.The highest strength 26g lifts pawl, and induces reaction, and therefore represents cut-out point.Two rear solid ends of every animal all carry out this test.It is the pawl threshold value (PWT) that contracts of unit that the required minimum strength that induces reaction is recorded as with the gram.Static allodynia is defined as animal the stimulation that is equal to or less than 4g (harmless to normal rat) is responded.

Chemical compound

Will (S, S)-the reboxetine succinate is dissolved in the Millipore filtered water, with its with 1,3,10 and the dosage of the free alkali of 30mg/kg pass through intraperitoneal (IP) administration.This corresponding to 1.38,4.13,13.8 and 41.3mg/kg (S, S)-the reboxetine succinate.

PDEV inhibitor 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones (hereinafter being referred to as compd A) is dissolved in the PEG400, and with 3,10 and 30mg/kg subcutaneous administration (SC).

Data analysis

Static allodynia is with the middle number [LQ of logarithm carry mapping; UQ] expression, nonparametric result tests by Kruskall-Wallis and carries out data analysis, and then with the vehicle group of ManN-Whitney ' s U test to each time point, uses Prism Software version 3 (GraphPad ^TM, San Diego, USA).

The result

In CCI rat neuropathic pain pattern will (S, S)-effect of drugs of reboxetine and compd A combination medicament and the specific activity of single medicine itself, to establish the synergism of two kinds of medicines.Under normal circumstances, during with von Frey filament tested static allodynia, original rat shows the pain threshold to the 8-15g of mechanical stimulus.After the CCI of rat sciatic nerve developed into chronic pain, its pawl threshold of reaction (PWT) that contracts obviously was reduced to 2 grams [0; 0].During with vehicle treated CCI rat, do not show that pain threshold changes, but in whole experiment, keep steady state value.

Fig. 1 has shown (S, S)-reboxetine (1-3-10-30mg/kg, IP), compd A (3-10-30mg/kg, SC) and these two kinds of chemical compound ratios be the combination (3 or 10mg/kg of 1: 1 and 3: 1, IP, (S, S)-reboxetine and 3mg/kg, SC, compd A) effect in the CCI rat model in static allodynia.Data are the peak effect (after the administration 1 hour) of each chemical compound, and dosage is with the middle number [LQ of every group of 6 rats; UQ] expression.What dotted line was represented to predict adds and line, as Tallarida before, " Drug synergism:Its detection and application ", and JPET (2001), 298,865-872 is described.In this concrete case, it is corresponding to the dose-response line of compd A.

After single administration, (S, S)-reboxetine and compd A all produce dose-dependent anti-allodynia effect in the preceding clinical model of chronic pain.Particularly, compare with group with vehicle treated, the maximum dose level of two kinds of chemical compounds (30mg/kg) produce counter-rotating ((S, S)-reboxetine and PDEV be respectively 6g[1; 0] and 6g[0; 1]).

(S, S)-effect of Combination of reboxetine and PDEV inhibitor under the ratio of 1: 1 and 3: 1, use 3 or 10mg/kg (S, S)-reboxetine and 3mg/kg compd A study.As shown in Figure 1, two kinds of combinations of two kinds of chemical compounds all produce anti-allodynia effect, and what arbitrary medicine used separately or predicted adds and the excellent effect of effect (shown in dotted line) generation.This shows that two kinds of chemical compounds pharmaceutically have cooperative interaction.

Other advantage of combination provided by the invention can use following pain pattern to understand.

The neuropathy that streptozocin (streptozocin) brings out

For animal gives streptozocin (50mg/kg i.p.) to bring out diabetes.The pain symptom outbreak of two weeks back assessment animal, all experiments are all carried out after this.

The osteoarthritis that MIA-brings out

Animal places anesthetic room, with 2% isoflurane/oxygen mixture anesthesia.Single agent iodo acetic acid list sodium salt (2mg/25 μ l) is carried out the intra-articular injection administration by the Patella ligament.Keep the narcotism of whole injection process via nasal tube.

The thermal hyperalgesia that carrageenin (carrageenan) brings out

Thermal hyperalgesia uses the test of rat sole, and (then with people such as Hargreaves, 1988 described method of modifying carry out for Ugo Basile, Italy) assessment.The rat custom is on the high platform of glass by in three devices that independently the lucite box is formed.The moving radiographic thermal source is positioned under the platform, and focuses on rear solid end, and record is contracted pawl incubation period.22.5 seconds automatic cut-out point is arranged, with prevention tissue damaged.Two rear solid ends of every animal are all noted down 2 to 3 times the pawl incubation period of contracting, and its meansigma methods is represented the baseline of right back pawl and left back pawl.Install calibratedly, obtain about 10 seconds pawl incubation period of contracting.

In these pain models, use other terminal point hereinafter described.

Dynamically pain is super quick

Assess dynamic allodynia by touching the rear solid end foot bottom surface with Cotton Gossypii bud (cotton bud).Must note in this process, will pacifying rat with all strength, it not touched in order to avoid note down the common dynamic activity.Each time point is noted down three times at least, and the representative of its meansigma methods is contracted pawl incubation period.If not reaction in 15 seconds, this process of constipation bundle, animal is distributed into this and contracts the pawl time.Therefore just be enough to represent the pawl that do not contract in 15 seconds.The pawl that contracts reaction is accompanied by pawl usually and shrinks back repeatedly or pat.Dynamically whether allodynia is regarded as representing animal to respond to touching the Cotton Gossypii stimulation in 8 seconds.

Dose-response at first carries out separately with every kind of composition in the combination.Carry out with the combination of fixed proportion more afterwards.The compositions of each fixed dosage ratio is carried out the dose-response test.In each test day, the pawl incubation period of contracting of measuring before Drug therapy that contract pawl threshold value baseline and the Cotton Gossypii bud of von Frey hairs stimulate.After give wanting, the pawl threshold value that contracts and the pawl repeated trials to 5 incubation period hour of contracting.These data represent that with static and dynamic two hours time points this time point is represented the peak of anti-allodynia effectiveness.

The weight tolerance

Use " incapacitance tester " (Linton Instruments, Diss, Norfolk, U.K.) over anaphylaxis of test animal in the test of animal tolerance.Rat is positioned on the lucite swash plate with its limb, by being positioned at the distribution of weight of the power conversion device measurement hind leg under every rear solid end.Every animal places this device, the load-carrying that the record rear solid end applies.The difference of weight tolerance deducts homonymy (injured nerve) pawl by offside (normally) pawl and calculates, and this forms initial data.

Combination of the present invention when treatment pain, can be used in combination with other pharmaceutically active compounds especially, perhaps is used in combination with two or more other pharmaceutically active compounds.Therefore, the wideest scope or the above-mentioned any preferred aspect of being combined in of the present invention can be selected from medicament while, order or the administration respectively of following material with one or more:

● Opium analgesic, for example morphine, heroin, Dilauid, oxymorphone, levorphanol (levorphanol), levallorphan (levallorphan), methadone, methyl piperidine, fentanyl, cocaine, codeine (codeine), paracodin, oxycodone (oxycodone), hydrocodone (hydrocodone), the third oxygen sweet smell (propoxyphene), nalmefene (nalmefene), nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

● NSAID (non-steroidal anti-inflammatory drug) (NSAID), for example aspirin, diclofenac, difiusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin (indomethacin), ketoprofen, ketorolac (ketorolac), meclofenamic acid, mefenamic acid, meloxicam (meloxicam), nabumetone (nabumetone), naproxen, nimesulide, nitroflurbiprofen (nitroflubiprofen), Olsalazine (olsalazine), Ao Shapu piperazine (oxaprozin), BUTE, piroxicam, sulfasalazine, sulindac, Tolmetin or zomepirac;

● Barbiturate tranquilizer, for example amobarbital, allopropylbarbital, neo-barb, butalbital (butabital), mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, quinalbarbitone, talbumal (talbutal), theamylal or thiopental;

● have the benzene phenodiazine (benzodiazepine) of sedation, for example chlordiazepoxide, chlorine nitrogen (clorazepate), stable, flurazepam, lorazepam, oxazepam, temazepam or triazolam (triazolam);

● have the H of sedation ₁Antagonist, for example diphenhydramine, neo-antergan (pyrilamine), promethazine, chlorpheniramine (chlorpheniramine) or chloreyclizine;

● tranquilizer, for example glutethimide, meprobamate, methaqualone or dichloralphenazone;

● skeletal muscle relaxant, for example baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

● nmda receptor antagonist, for example dextromethorphan ((+)-3-hydroxy-n-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-n-methylmorphinan), ketamine, memantine (memantine), the pyrroloquinoline quinine, suitable-4-((phosphonomethyl))-2 piperidine carboxylic acid, budipine (budipine), EN-3231 (MorphiDex , the combination preparation of morphine and dextromethorphan), topiramate (topiramate), neramexane, or perzinfotel, it comprises the NR2B antagonist, ifenprodil for example, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxyl-piperidino]-1-ethoxy-3,4-dihydro-2 (1H)-quinolinone;

● the alpha-adrenergic medicine, for example doxazosin (doxazosin), Tamsulosin (tamsulosin), clonidine, Guanfacine, dexmetatomidine, modafinil (modafinil) or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridine radicals) quinazoline;

● tricyclic antidepressants, for example desipramine, imipramine, amitriptyline or nortriptyline;

● anticonvulsant, for example carbamazepine, lamotrigine (lamotrigine), topiratmate or valproate;

● tachykinin (NK) antagonist, NK-3 particularly, NK-2 or NK-1 antagonist, (α R for example, 9R)-7-[3, two (trifluoromethyl) benzyls of 5-]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] diazocine [2,1-g] [1,7]-naphthyridines-6-13-diketone (TAK-637) also, 5-[[(2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] ethyoxyl-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone (MK-869), A Rui smooth (aprepitant), lanepitant (lanepitant), Dapitant (dapitant) or 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl]-methylamino]-the 2-Phenylpiperidine (2S, 3S);

● muscarine antagonist, for example oxibutynin (oxybutynin), tolterodine (tolterodine), propiverine (propiverine), tropsium chloride, darifenacin (darifenacin), plain Li Fenxin (solifenacin), temiverine (temiverine) and ipratropium (ipratropium);

● COX-2 selective depressant, for example celecoxib (celecoxib), rofecoxib (rofecoxib), parecoxib (parecoxib), valdecoxib (valdecoxib), deracoxib (deracoxib), etoricoxib (etoricoxib) or lumiracoxib;

● coal tar analgesic, particularly acetaminophen;

● neuroleptic, for example droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine (olanzapine), risperidone (risperidone), Ziprasidone (ziprasidone), Quetiapine (quetiapine), Sertindole (sertindole), Aripiprazole (aripiprrazole), sonepiprazole (sonepiprazone), blonanserin (blonanserin), iloperidone (iloperidone), cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl (perospirone), raclopride (raclopride), zotepine, bifeprunox, asenapine, lurasidone, amisulpride (amisulpride), balaperidone, palindore, eplivanserin (eplivanserin), Osanetant (osanetant), Rimonabant (rimonabant), meclinertant, Miraxion  or sarizotan (sarizotan);

● the Rhizoma et radix valerianae receptor stimulating agent (for example, resinferatoxin) or antagonist (for example, capsazepine);

● beta-adrenergic medicine, for example Propranolol;

● local anesthetic, for example mexiletine;

● corticosteroid, for example dexamethasone;

● 5-HT receptor stimulating agent or antagonist, particularly 5-HT _1B/1DAgonist, for example eletriptan (eletriptan), sumatriptan (sumatriptan), naratriptan (naratriptan), Zomitriptan (zolmitriptan) or rizatriptan (rizatriptan);

● 5-HT _2AReceptor antagonist, for example R (+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl ethyl)]-4-piperidine carbinols (MDL-100907);

● cholinergic agent (nicotine) analgesic, for example ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridine)-3-butene-1-amine (RJR-2403), (R)-5-(2-azetidin ylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

●Tramadol；

● alpha-2-delta ligand, gabapentin (gabapentin) for example, lyrica (pregabalin), 3-methyl gabapentin, (1 α, 3 α, 5 α) (3-amino-methyl-bicyclo-[3.2.0] heptan-3-yl)-acetic acid, (3S, 5R)-3-amino methyl-5-methyl-enanthic acid, (3S, 5R)-3-amino-5-methyl-enanthic acid, (3S, 5R)-and 3-amino-5-methyl-sad, (2S, 4S)-4-(3-chlorophenoxy) proline, (2S, 4S)-4-(3-luorobenzyl) proline, [(1R, 5R, 6S)-and 6-(amino methyl) bicyclo-[3.2.0] heptan-6-yl] acetic acid, 3-(1-amino methyl-cyclohexyl methyl)-4H-[1,2,4] oxadiazole-5-ketone, C-[1-(1H-tetrazolium-5-ylmethyl)-suberyl]-methylamine, (3S, 4S)-(1-amino methyl-3,4-dimethyl-cyclopenta)-acetic acid, (3S, 5R)-and 3-amino methyl-5-methyl-sad, (3S, 5R)-3-amino-5-methyl-n-nonanoic acid, (3S, 5R)-and 3-amino-5-methyl-sad, (3R, 4R, 5R)-3-amino-4,5-dimethyl-enanthic acid, (3R, 4R, 5R)-3-amino-4,5-dimethyl-sad;

● cannabinoid;

● metabotropic glutamate salt hypotype 1 receptor (mGluR1) antagonist;

● the five hydroxytryptamine reuptake inhibitor, Sertraline (sertraline) for example, the Sertraline metabolite, the demethyl Sertraline, fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine (fluvoxamine), paroxetine (paroxetine), citalopram (citalopram), citalopram metabolite demethyl citalopram, escitalopram (escitalopram), d, the 1-fenfluramine, femoxetine (femoxetine), ifoxetine (ifoxetine), cyanodothiepin, litoxetine (litoxetine), dapoxetine (dapoxetine), nefazodone (nefazodone), Cericlnmine (cericlamine) and Desyrel;

● two 5-hydroxy tryptamine-NRI, for example venlafaxine (venlafaxine), venlafaxine metabolite O-ODV, clomipramine (clomipramine), clomipramine metabolite demethyl clomipramine, duloxetine (duloxetine), midalcipran (milnacipran) and imipramine;

● can induce nitric oxide synzyme (iNOS) inhibitor, S-[2-[(1-imino group ethyl for example) amino] ethyl]-the L-homocysteine, S-[2-[(1-imino group ethyl)-and amino] ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-imino group ethyl) amino] ethyl]-2-methyl-L-cysteine, (2S, 5Z)-and 2-amino-2-methyl-7-[(1-imino group ethyl) amino]-the 5-heptenoic acid, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl)-butyl] sulfo-]-5-chloro-3-pyridine nitrile, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfo-]-4-chloro-benzonitrile, (2S, 4R)-and 2-amino-4-[[2-chloro-5-(trifluoromethyl) phenyl] sulfo-]-5-thiazole butanols, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfo-]-6-(trifluoromethyl)-3-pyridine nitrile, 2-[[(1R, 3S)-3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfo-]-5-benzyl chloride nitrile, N-[4-[2-(3-benzyl chloride base amino) ethyl] phenyl] thiophene-2-carboxyl amidine, or GE disulphide;

● acetylcholinesteraseinhibitors inhibitors, for example donepezil (donepezil);

● prostaglandin E ₂Hypotype 4 (EP4) antagonist, N-[({2-[4-(2-ethyl-4 for example, 6-dimethyl-1H-imidazo [4,5-c] pyridine-1-yl) phenyl] ethyl } amino)-carbonyl]-4-methyl benzenesulfonamide or 4-[(1S)-1-({ [5-chloro-2-(3-fluorophenoxy) pyridin-3-yl] carbonyl } amino) ethyl] benzoic acid;

● leukotrienes B4 antagonist, for example 1-(3-diphenyl-4-ylmethyl-4-hydroxyl-chromane-7-yl)-Cyclopentane carboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl] the phenoxy base]-valeric acid (ONO-4057) or DPC-11870;

● 5-fat oxidation enzyme inhibitor, for example zileuton (zileuton), 6-[(3-fluoro-5-[4-methoxyl group-3,4,5,6-tetrahydrochysene-2H-pyrans-4-yl]) phenoxy group-methyl]-1-methyl-2-quinolinones (ZD-2138) or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzo quinone (CV-6504);

● sodium channel inhibitor, for example lignocaine;

● 5-HT3 antagonist, for example ondansetron (ondansetron);

And pharmaceutically acceptable salt and solvate.

Claims

1. the combination of a selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor.

2. combination as claimed in claim 1, wherein said selectivity noradrenaline reuptake inhibitor (NRI) be (S, S)-reboxetine or acceptable salt of its medicine or solvate.

3. combination as claimed in claim 1 or 2, wherein said the 5th type phosphodiesterase (PDEV) inhibitor is selected from:

5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sildenafil) or acceptable salt of its medicine or solvate;

(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine is [2 ', 1 ': 6,1] pyrido [3 also, 4-b] indole-1,4-diketone (tadalafil, IC-351, Cialis ) or acceptable salt of its medicine or solvate;

5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-heterocyclic butyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones or acceptable salt of its medicine or solvate;

The 3-ethyl-5-[(R)-3-methyl-piperazine-1-yl]-1-[2-(2,2, the 2-trifluoro ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7-yl }-pyrimidine-4-base-amine or acceptable salt of its medicine or solvate.

4. pharmaceutical composition, it comprises selectivity noradrenaline reuptake inhibitor (NRI), the 5th type phosphodiesterase (PDEV) inhibitor and pharmaceutically-acceptable excipients, diluent or carrier.

5. one kind is used as the selectivity noradrenaline reuptake inhibitor (NRI) of medicine and the combination of the 5th type phosphodiesterase (PDEV) inhibitor.

6. a selectivity noradrenaline reuptake inhibitor (NRI) or the 5th type phosphodiesterase (PDEV) the inhibitor purposes in medicine is made, described medicine be used for treatment of pain simultaneously, in regular turn or separately with two kinds of medicament administrations.

7. method for the treatment of pain, it comprises selectivity noradrenaline reuptake inhibitor (NRI) and the 5th type phosphodiesterase (PDEV) inhibitor that needs the mammal effective dose of this treatment simultaneously, in regular turn or individually.

8. test kit, the device that it comprises selectivity noradrenaline reuptake inhibitor (NRI), the 5th type phosphodiesterase (PDEV) inhibitor and contains described chemical compound.