CN101326163B - Prolinamide derivatives as sodium channel modulators - Google Patents

Abstract

The invention provides a compound of formula (I), a solvate, a salt or prodrug thereof, useful in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels.

Description

Prolinamide derivatives as the sodium channel adjusting control agent

The present invention relates to the alpha-amino group carboxamides derivatives, its salt and prodrug, and relate to this derivative, its salt and prodrug are in the disease that regulation and control mediated of treatment activity-dependent (use-dependent) voltage-gated sodium channel and the purposes in the illness.In addition, the present invention relates to comprise this derivative, the composition of its salt and prodrug and their preparation method.

Voltage-gated sodium channel is responsible for the start-up phase of action potential, and this action potential is the ripple of electric depolarize (electrical depolarisation), and it starts from neuronic somatocyte usually, and propagates to tip along neural axon.At tip, action potential has caused the inflow of calcium and the release of neurotransmitter.The medicine of blocking voltage gated sodium channel such as lignocaine are as local anesthetic.Other sodium channel blockers such as lamotrigine and Carbamzepine, is used for treating epilepsy.Under latter event, the development that the part of voltage-gated sodium channel suppresses to have reduced neuronal excitability and reduced epileptic seizures.Under the situation of local anesthetic, the position of the sodium channel on Sensory neurone has stoped the conduction of painful stimuli.The principal character of these medicines is their the activity-dependent mechanism of action.This medicine is considered to be used for the non-activation configuration (inactivated configuration) of stable channel, and it is that passage is opened a kind of configuration that adopt fast the back.This unactivated state provides refractory phase, and passage returns to its tranquillization (closing) state and prepares to be activated again then.Consequently, the activity-dependent sodium channel blockers has delayed neuronic high frequency bunch to be sent out, and for example responds painful stimuli, and (for example, during epileptic seizures) can help to stop repeatedly and bunch to send out between the neurone depolarizing phase of contingent prolongation.Low frequency, the action potential that for example triggers in heart can not be subjected to the influence of these medicines significantly, although safety margin is all different in each case, this is tranquillization or the opened condition that can block passage because of each these medicine under sufficiently high concentration.

Voltage-gated sodium channel family comprises 10 hypotypes, and wherein four is that brain is specific, NaV1.1,1.2,1.3 and 1.6.In other hypotype, NaV1.4 only appears in the skeletal muscle, and NaV1.5 is that cardiac muscle is specific, and NaV1.7,1.8 and 1.9 mainly appears in the Sensory neurone.For the hypothesis binding site of activity-dependent sodium channel blockers is high conservative between all die moulds.Consequently, medicine such as lignocaine, lamotrigine and Carbamzepine are not distinguished between these hypotypes.Yet because different frequency can be realized selectivity, described frequency is the frequency of passage works better.

In the mode of activity-dependent, the medicine of blocking voltage gated sodium channel also is used for treating bipolar disorder, perhaps alleviates mania or depressed symptom, or as the generation of mood stabilizer with the outbreak of prevention mood.Evidence shows that also the activity-dependent sodium channel blockers can help to alleviate schizoid symptom before clinical and clinical.For example, in healthy people volunteer, lamotrigine has demonstrated and has alleviated by the psychotic symptom of ketamine inductive, and in addition, the medicine that studies show that in the patient can strengthen the antipsychotic effectiveness of some atypical antipsychotic drugs (such as leoponex or olanzapine).Hypothesis is that the effectiveness in these mental disorders can partly be produced by the release that reduces excessive L-glutamic acid.The reduction that L-glutamic acid discharges is considered to be in important brain zone, receives the result that passage suppresses as the activity-dependent in the volume cortex.Yet, also can help the effectiveness of these medicines with the interaction of valtage-gated calcium channel.

International publication application WO05/000309 (Ionix Pharmaceuticals Limited) discloses the purposes of the compound of formula (I), wherein R ₁Be organic substituent, X ₁And X ₂Be directly keyed jointing or compartment, Ar is aryl or heteroaryl, and Y for the aminoalkyl group that replaces or contain heteroaryl-, heterocyclic radical-or phenyl-part:

This compounds is the inhibitor of Sensory neurone specificity sodium channel, and it is said that it is used for the treatment of chronic and acute pain, tinnitus, enteropathy, vesical dysfunction and demyelinating disease.

International publication application WO04/083189 (Merck﹠amp; Co.) disclose the triazole compounds of formula (I), (II) and biaryl substituted (III), it is as sodium channel blockers:

This compounds allegedly is used for the treatment of the illness relevant with sodium channel activity, and this illness for example comprises, acute pain, chronic pain, Encelialgia, epilepsy, irritable bowel syndrome, dysthymia disorders etc.

International publication application WO04/092140 (Merck﹠amp; Co.) disclose the pyrazoles of formula (I), (II), (III) and biaryl substituted (IV), it is as sodium channel blockers:

This compound allegedly is used for the treatment of the illness that comprises acute pain, chronic pain, Encelialgia, inflammatory pain and neuropathic pain.

International publication application WO04/094395 (Merck﹠amp; Co.) disclose the thiazole, oxazole and the imidazoles of the biaryl substituted of formula (I), it is as sodium channel blockers:

This compound allegedly is used for the treatment of the illness that comprises acute pain, chronic pain, Encelialgia, inflammatory pain and neuropathic pain.

International Patent Application WO 04/026826 (F.Hoffman La Roche AG) discloses the 4-pyrrolidone phenyl-benzylic ether derivative of formula (I):

This compound is said to be monoamine oxidase B inhibitors, and allegedly is used for the treatment of illness such as Alzheimer's or senile dementia.

Purpose of the present invention is for determining the compound of regulation and control voltage-gated sodium channel.

In one embodiment, this compound is an activity-dependent sodium channel inhibitor.

In another embodiment, this compound is a hypotype NaV1.3 sodium channel activity-dependent inhibitor.

Another object of the present invention is to determine activity-dependent sodium channel inhibitor, and it has suitable developability matter for oral administration, for example according to exposing (Cmax) and/or bioavailability.

According to first aspect, the invention provides 5-(4-{[(2-fluorophenyl) methyl of formula (I)] the oxygen base } phenyl)-prolineamide,

Or its pharmacy acceptable salt, solvate or prodrug.

Hereinafter, at formula (I) compound of any one definition of the present invention, its pharmacy acceptable salt, solvate and prodrug thereof (except the midbody compound in chemical process) are called " compound of the present invention ".

What person of skill in the art will appreciate that is that formula (I) compound can exist by four kinds of possible diastereomers.In another embodiment, compound of the present invention is selected from:

(5R)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide (Ia),

(5S)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-D-prolineamide (Ib),

(5R)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-D-prolineamide (Ic)

With

(5S)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide (Id)

And (Ia), (Ib), (Ic) or pharmacy acceptable salt (Id), solvate or prodrug.

In another embodiment, compound of the present invention is (5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide (Ia), or its pharmacy acceptable salt, solvate or prodrug.

The diastereomer of formula (I) compound can obtain according to known method in the document, for example by preparing HPLC or passing through chromatography purification.Racemic mixture can use preparation HPLC to separate with the pillar with chiral stationary phase, or uses the method known to those skilled in the art fractionation to obtain single enantiomer.In addition, the chiral intermediate compound can be split, and is used for preparing chipal compounds of the present invention.

Formula (I) compound can form pharmaceutically or veterinarily acceptable salt.Pharmaceutically acceptable or the veterinarily acceptable salt that contains formula (I) compound of basic center is, for example, with mineral acid such as spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid, the nontoxic acid salt that forms with carboxylic acid or organic sulfonic acid.Example comprises HCl, HBr, HI, vitriol or hydrosulfate, nitrate, phosphoric acid salt or hydrophosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactic acid salt, Citrate trianion, tartrate, gluconate, camsilate, mesylate, esilate, benzene sulfonate, tosilate and embonate.For the summary of suitable pharmacologically acceptable salt, can be referring to people J.Pharm such as Berge, Sci., 66,1-19,1977; P L Gould, International Journal ofPharmaceutics, 33 (1986), 201-217; With people such as Bighley, Encyclopedia ofPharmaceutical Technology, Marcel Dekker Inc, New York 1996,13 volumes, 453-497 page or leaf.

Can be understood that by those skilled in the art; the protected derivative of some formula (I) compound; it can form before the stage at last deprotection; it may not have this type of pharmacological activity; but in some cases; can oral or administered parenterally, and after this in vivo metabolism be The compounds of this invention with pharmacological activity.Therefore this analog derivative is also referred to as " prodrug ".All prodrugs of The compounds of this invention all are included in the scope of the present invention.The case description of the prodrug of the The compounds of this invention that function is suitable is in Drugs ofToday, 19 volumes, Number 9,1983, pp 499-538 and Topics in Chemistry, Chapter 31, pp306-316 and " Design of Prodrugs " H.Bundgaard, Elsevier, 1985, Chapter 1 (wherein disclosed content is hereby incorporated by).Can further be understood that by those skilled in the art, some part, be called " preceding-partly (pro-moieties) " by those skilled in the art, (wherein disclosed content is hereby incorporated by) that for example has H.Bundgaard to describe in " Design of Prodrugs " can present suitable function when this type of function is present in the The compounds of this invention.

Technician in the organic chemistry filed is understandable that many organic compound can form mixture with solvent, and these organic compound and described solvent reaction precipitate or crystallization from solvent.These mixtures are referred to as " solvate ".For example, the mixture with water is called " hydrate ".The pharmaceutically acceptable solvate of The compounds of this invention comprises within the scope of the invention.

The pharmaceutically acceptable solvate of compound of the present invention comprises its hydrate.

Its polymorphic form is also included within the scope of The compounds of this invention.

Compound of the present invention can one or more tautomeric forms exist.All tautomer and mixing thereof comprise within the scope of the invention.

The present invention also comprises all suitable isotopic variations of The compounds of this invention.The isotopic variations of The compounds of this invention is defined as at least one atom and is had the ordination number identical with the common atom of occurring in nature but the atom institute alternate compound of different atomic masses.The isotopic example that can incorporate The compounds of this invention into comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as being respectively ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.The isotopic variations of some The compounds of this invention is for example incorporated radio isotope into ³H, ¹⁴The compound of C is used for medicine and/or substrate tissue distribution and measures.Tritium promptly ³H and carbon-14 are promptly ¹⁴The C isotropic substance is particularly preferred, because they prepare and detectability easily.In addition, for example deuterium is promptly with isotropic substance ²H substitutes, and certain treatment advantage can be provided, because metabolic stability is bigger, for example the transformation period increases or the required dosage minimizing in the body, and is preferred in some cases therefore.The isotopic variations of The compounds of this invention can use the suitable isotopic variations of suitable reagent to prepare by exemplary method or the preparation of ordinary method as describing among the embodiment hereinafter.

According on the other hand, the invention provides the method for preparation formula (I) compound, it comprises that formula (II) compound and ammonia solution react in suitable solvent

In one embodiment, this solvent is a methyl alcohol.In another embodiment, the methanol solution of ammonia is a strong solution, for example the solution of 7N or 11.2M.

In another embodiment, reaction is at room temperature carried out.

As mentioned above, can think that The compounds of this invention can be used for the treatment of disease that regulation and control mediated and the illness by voltage-gated sodium channel.

Therefore,, the invention provides The compounds of this invention according on the other hand, as medicine, preferred human medicine.

According on the other hand, the invention provides The compounds of this invention and be used for the treatment of or prevent by the purposes in the medicine of the disease that regulation and control mediated of voltage-gated sodium channel or illness in preparation.

Do not wish to be bound by theory, [numeral in the listed disease bracket refers to the Disorders at Diagnostic andStatistical Manual of Mental can be selected from following listed disease by the disease that regulation and control mediated of voltage-gated sodium channel or illness, the 4th edition, publish and/or International Classification of Diseases the Sort Code in the 10th edition (ICD-10) by American PsychiatricAssociation (DSM-IV)]:

I) depression and mood disorder comprise major depressive episode, manic episode, mixed type outbreak and hypomania; Dysthymia disorders comprises severe depression, evil mood depression of sex (300.4), unspecified dysthymia disorders (311); Bipolar disorder comprises I type bipolar disorder, II type bipolar disorder (following the recidivity major depressive episode of hypomania) (296.89), circulation affective disorders (301.13) and does not indicate bipolar disorder (296.80); Other mood disorder comprises mood disorder that mood disorder (293.83) due to the physical disease (comprise following hypotype follow depressed feature, follow the outbreak of major depression sample, follow manic feature and follow mixed feature), material cause (comprise following hypotype follow depressed feature, follow manic feature and follow mixed feature) and unspecified mood disorder (296.90):

Ii) schizophrenia comprises following hypotype paranoid schizophrenia (295.30), disorganized schizophrenia (295.10), catatonic schizophrenia (295.20), undifferentiated schizophrenia (295.90) and residual schizophrenia (295.60); Schizophreniform disorder (295.40); Schizoaffective disorder (295.70) comprises following hypotype biphasic or bipolar type and depressive type; Vain hope property mental disorder (297.1) comprises following hypotype lagnosis's vain hope, the delusion of grandeur, delusion of jealousy, delusion of persecution, somatic delusion, mixed type vain hope and does not indicate vain hope; Short-term insane (298.8); Shared psychotic disorder (297.3); The mental disorder that physical disease (General Medical Condition) causes comprises that following hypotype follows vain hope (With Delusions) and follow illusion (With Hallucinations); The psychosis that material causes comprises that following hypotype follows vain hope (293.81) and follow illusion (293.82); With unspecified mental disorder (298.9).

Iii) anxiety disorder comprises panic attack; Panic disorder comprises the panic disorder (300.01) of no agoraphobia and the panic disorder (300.21) of agoraphobia is arranged; Agoraphobia; The agoraphobia of panic disorder medical history (300.22), specific phobia (300.29) (claiming simple phobia in the past) (comprises following hypotype animal-type, the physical environment type, blood injection damage type, situation type and other type), social phobia (social anxiety disorder, 300.23), obsessive-compulsive disorder (300.3), posttraumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), anxiety disorder due to the systemic disease (293.84), the anxiety disorder that material causes, separation anxiety obstacle (309.21), adjustment disorder merges anxiety (309.24) and unspecified anxiety disorder (300.00):

Iv) the related disease (substance related disorder) of material comprises material application disease, craves for and substance abuse as substance depilatory, material; The disease that material causes, the persistence perceptual disturbance (flashback) that causes as material is poisoned, material is given up, material causes delirium, persistence dementia that material causes, persistence amnesia that material causes, mental disorder that material causes, mood disorder that material causes, anxiety disorder that material causes, sexual dysfunction that material causes, somnopathy that material causes and halluoinogen; The alcohol relative disease is as alcohol dependence (303.90), alcohol abuse (305.00), alcoholism (303.00), abstinence from alcohol (291.81), alcoholic delirium, alcohol withdrawal delirium, the persistence dementia that alcohol causes, the persistence amnesia that alcohol causes, the mental disorder that alcohol causes, the mood disorder that alcohol causes, the anxiety disorder that alcohol causes, the sexual dysfunction that alcohol causes, somnopathy and the related obstacle of unspecified alcohol (291.9) that alcohol causes; The related disease of Amphetamine (or amphetamine-type), the disease (292.9) that causes as amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine intoxication (292.89), Amphetamine drug withdrawal (292.0), amphetamine intoxication delirium, mental disorder that Amphetamine causes, mood disorder that Amphetamine causes, anxiety disorder that Amphetamine causes, sexual dysfunction that Amphetamine causes, somnopathy that Amphetamine causes and unspecified Amphetamine; The related disease of caffeine, the anxiety disorder that causes as caffeinism (305.90), caffeine, somnopathy and the related disease of unspecified caffeine (292.9) that caffeine causes; The related disease of hemp relies on (304.30), cannabis abuse (305.20), cannabism (292.89), cannabism delirium, the mental disorder that hemp causes, anxiety disorder and the related disease of unspecified hemp (292.9) that hemp causes as hemp; The related disease of Cocaine relies on (304.20), cocaine abuse (305.60), cocaine poisoning (292.89), Cocaine drug withdrawal (292.0), cocaine poisoning delirium, the mental disorder that Cocaine causes, the mood disorder that Cocaine causes, the anxiety disorder that Cocaine causes, the sexual dysfunction that Cocaine causes, somnopathy and the related disease of unspecified Cocaine (292.9) that Cocaine causes as Cocaine; The related disease of halluoinogen is as hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen intoxication (292.89), halluoinogen persistence perceptual disturbance (flashback) (292.89), hallucinogen intoxication delirium, the mental disorder that halluoinogen causes, the mood disorder that halluoinogen causes, anxiety disorder and the related disease of unspecified halluoinogen (292.9) that halluoinogen causes; The related disease of inhalation is as inhalant dependence (304.60), inhalant abuse (305.90), inhalant intoxication (292.89), inhalant intoxication delirium, the persistence dementia that inhalation causes, the mental disorder that inhalation causes, the mood disorder that inhalation causes, anxiety disorder and the related disease of unspecified inhalation (292.9) that inhalation causes; The related disease of Nicotine is as nicotine dependence (305.1), Nicotine drug withdrawal (292.0) and the related disease of unspecified Nicotine (292.9); The related disease of opioid relies on (304.00), abuse of opioid dosage forms (305.50), opioid poisoning (292.89), opioid drug withdrawal (292.0), opioid poisoning delirium, the mental disorder that opioid causes, the mood disorder that opioid causes, the sexual dysfunction that opioid causes, somnopathy and the related disease of unspecified opioid (292.9) that opioid causes as opioid; The related disease of phencyclidine (or Phencyclidines) is as phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine intoxication (292.89), phencyclidine intoxication delirium, the mental disorder that phencyclidine causes, the mood disorder that phencyclidine causes, anxiety disorder and the related disease of unspecified phencyclidine (292.9) that phencyclidine causes; Tranquilizer, the related disease of soporific or antianxiety agent is as tranquilizer, soporific or antianxiety agent rely on (304.10), tranquilizer, soporific or antianxiety agent abuse (305.40), tranquilizer, soporific or antianxiety agent poisoning (292.89), tranquilizer, soporific or antianxiety agent drug withdrawal (292.0), tranquilizer, soporific or antianxiety agent poisoning delirium, tranquilizer, soporific or antianxiety agent drug withdrawal delirium, tranquilizer, soporific or antianxiety agent persistence dementia, tranquilizer, soporific or antianxiety agent persistence amnesia, tranquilizer, the mental disorder that soporific or antianxiety agent cause, tranquilizer, the mood disorder that soporific or antianxiety agent cause, tranquilizer, the anxiety disorder that soporific or antianxiety agent cause, tranquilizer, the sexual dysfunction that soporific or antianxiety agent cause, tranquilizer, somnopathy that soporific or antianxiety agent cause and unspecified tranquilizer, the related disease (292.9) of soporific or antianxiety agent; The related disease of multiple material is as multiple substance depilatory (304.80); With other (or unknown) related disease of material, as anabolic steroids, nitric ether inhalation and Nitrous Oxide:

V) cognitive strengthen (Enhancement of cognition), comprise the cognitive impairment in other disease of treatment, described other disease such as schizophrenia, amphicheirality's obstacle, depression, other mental disorder and follow the mental illness of cognitive impairment, as alzheimer's disease:

Vi) somnopathy, comprise the primary somnopathy, as dyssomnias, as primary insomnia (307.42), primary hypersomnia (307.44), hypnolepsy (347), with breathe relevant somnopathy (780.59), circadian rhythm sleep disorder (307.45) and unspecified dyssomnias (307.47); The primary somnopathy is as parasomnias, as nightmare disorder (307.47), night terror (307.46), somnambulism (307.46) and unspecified parasomnias (307.47); The somnopathy relevant with other mental disorder is as insomnia (307.42) relevant with other mental disorder and the hypersomnia (307.44) relevant with other mental disorder; The somnopathy that physical disease causes, particularly somnopathy are followed spirituality obstacle, neuropathic pain, restless leg syndrome, the heart and lung disease; With the somnopathy that material causes, comprise following hypotype insomnia type, hypersomnia type, parasomnias type and mixed type: sleep apnea and jet lag syndrome:

Vii) eating disorder as anorexia nervosa (307.1), comprises abstain from meat, wine, etc type and eating without restraint/the purgation type of following hypotype; Bulimia nervosa (307.51) comprises following hypotype purgation type and non-purgation type; Obesity; Force eating disorder; Disease of eating too much at one meal; With unspecified eating disorder (307.50):

Viii) the autism spectrum disorder comprises autistic disorder (299.00), A Sipei Ge Shi disease (299.80), thunder Te Shi disease (299.80), childhood disintegrative disorder (299.10) and unspecified ubiquity disease (299.80, comprise atypical autism).

Ix) attention deficit/hyperkinetic syndrome comprises following hypotype attention deficit/hyperkinetic syndrome mixed type (314.01), attention deficit/hyperkinetic syndrome attention deficit principal mode (314.00), the many ejector half of attention deficit/hyperkinetic syndrome (314.01) and unspecified attention deficit/hyperkinetic syndrome (314.9); Hyperkinetic syndrome; The disruptive behaviour obstacle as conduct disorder, comprises following hypotype children's outbreak type (321.81), teenager's outbreak type (312.82) and unspecified outbreak (312.89), oppositional defiant disorder (313.81) and unspecified disruptive behaviour obstacle; And tic disorder, as Tu Leiteshi mental disorder (307.23):

X) personality disorder, comprise following hypotype paranoia's personality disorder (301.0), schizophrenia personality disorder (301.20), schizotypal personality disorder (301,22), antisocial personality disorder (301.7), criticality personality disorder (301,83), histrionic personality disorder (301.50), narcissistic personality disorder (301,81), avoidant personality disorder (301.82), dependent personality disorder (301.6), obsessive-compulsive personalistics's obstacle (301.4) and unspecified personality disorder (301.9): and

Xi) sexual dysfunction comprises dysaphrodisia, as hypothyroid dysaphrodisia (302.71) and sexual aversion disorder (302.79); Sexual arousal dysfunction is as female sexual arousal disorder (302.72) and male erectile disorder (302.72); Orgasm disorder is as female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation (302.75); Sexual pain disorder is as dyspareunia (302.76) and vulvismus (306.51); Unspecified sexual dysfunction (302.70); Sexual perversion is as exhibitionism (302.4), fetishism (302.81), frotteurism (302.89), PEDoPhIlIa (302.2), masochism (302.83), sexual sadism (302.84), eonism (302.3), Voyeurism (302.82) and unspecified sexual perversion (302.9); Gender identity disorder is as children's gender identity disorder (302.6) and teenager or adult's gender identity disorder (302.85); With unspecified sexual dysfunction (302.9).

Xii) impulse control disorder comprises: intermittent explosive disorder (312.34), kleptomania (312.32), pathological gambling (312.31), pyromania (312.33), trichotillomania (312.39), unspecified impulse control disorder (312.3), disease of eating too much at one meal, compulsive buying, compelling sex behavior and force storage.

In another embodiment, can be depression or mood disorder by the disease that regulation and control mediated or the illness of voltage-gated sodium channel.

In another embodiment, can be the related disease of material by the disease that regulation and control mediated or the illness of voltage-gated sodium channel.

In another embodiment, can be that bipolar disorder (comprises I type bipolar disorder by the disease that regulation and control mediated or the illness of voltage-gated sodium channel, II type bipolar disorder (promptly, follow the recidivity major depressive episode of hypomania) (296.89), circulation affective disorders (301.13) or unspecified bipolar disorder (296.80)).

In another embodiment, can be the related disease of Nicotine by the disease that regulation and control mediated or the illness of voltage-gated sodium channel, as nicotine dependence (305.1), Nicotine drug withdrawal (292.0) and the related disease of unspecified Nicotine (292.9).

In one embodiment, The compounds of this invention can be used as anodyne.For example they can be used for treating chronic inflammatory pain (for example, following the pain of rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, urarthritis and juvenile arthritis); Musculoskeletal pain; Low back pain and cervicodynia; Sprain and strain; Neuropathic pain; Sympathetic nerve maintenance pain (sympathetically maintained pain); Myositis; Follow the pain of cancer and fibromyalgia; Follow migrainous pain; Follow the pain of influenza or other virus infection such as common cold; Rheumatic fever; Accompaniment functions bowel disturbance such as non-ucler dyspepsia, the pain of non-cardiac chest pain and irritable bowel syndrome; Follow the pain of myocardial ischemia; Post-operative pain; Headache; Toothache; And dysmenorrhoea.

The compounds of this invention can be used for treating neuropathic pain.Neuropathic pain syndrome can take place subsequently at neuronal damage, even and after original damage has been cured, sustainable several months of this pain or several years.Neuronal damage can occur in the specific region of peripheral nerve, dorsal root, spinal cord or brain.Neuropathic pain syndrome is usually according to causing their disease or incident to classify.Neuropathic pain syndrome comprises: diabetic neuropathy; Sciatica; The low back pain of nonspecific property; The multiple sclerosis pain; Fibromyalgia; The neuropathy that HIV-is relevant; Postherpetic neuralgia; Trigeminal neuralgia; And the pain that causes by health wound, amputation, cancer, toxin or chronic inflammatory illness.These diseases are difficult to treat very much, although more known medicines have limited effectiveness, fully pain management is almost can not realize.The symptom of neuropathic pain is visibly different, and it often is described to spontaneous shooting and lancinating pain, or persistent burning pain.In addition, follow the pain of normal non-pain perception in addition, as the pain perception behind " numb " (paresthesia and insensitive), touch-sensitive increase (oxypathy), the non-noxious stimulation (dynamically, static, thermal anomaly pain), destructive stimulus susceptibility is increased (hot, cold, mechanical hyperalgesia), removes and stimulate the pain sensation (hyperpathia) that the back continues or selectivity to feel the lacking or lack of conduction path (hypalgia).

The compounds of this invention also can be used for the improvement of inflammatory diseases, for example treats tetter (for example, tan severely, burn, eczema, dermatitis, psoriasis); Illness in eye; Tuberculosis (for example, asthma, bronchitis, pulmonary emphysema, allergic rhinitis, non-allergic rhinitis, cough, respiratory distress syndrome, pigeon-fanciers' disease (pigeon fancier ' sdisease), farmer lung, chronic obstructive pulmonary disease (COPD); Gastrointestinal tract disease (for example, Crohn's disease, ulcerative colitis, coeliac disease, Crohn disease, irritable bowel syndrome, inflammatory bowel, gastroesophageal reflux disease); Have other illness of inflammation component such as migraine, multiple sclerosis, myocardial ischemia.

The compounds of this invention also can be used for treating and/or preventing the use anticonvulsive drug and can treat or preventible illness, such as the epilepsy that comprises post-traumatic epilepsy, obsession (OCD), somnopathy (comprising diel rhythm obstacle, insomnia and narcolepsy), tich's (for example Tourette syndrome (Giles de laTourette ' s syndrome)), ataxia, muscular rigidity (spasticity), and temporomandibular joint dysfunction.

The compounds of this invention also can be used for treating vesical reflex hyperfunction (hyperrelexia) after the bladder inflammation.

The compounds of this invention also can be used for treating nerve degenerative diseases and neurodegeneration such as dementia, particularly degeneration dementia (comprising senile dementia, alzheimer's disease, Pick's disease, Huntington chorea, Parkinson's disease and Creutzfeldt-Jakob disease, MND); This compound also can be used for treating amyotrophic lateral sclerosis (ALS) and neural inflammation.

Neurodegeneration after The compounds of this invention also can be used for neuroprotective and is used for the treatment of apoplexy, asystole, lung bypass, traumatic brain injury, Spinal injury etc.

The compounds of this invention also can be used for treating tinnitus, and it is as local anesthetic.

Compound of the present invention also can be used in combination with other therapeutical agent.Therefore on the other hand, the invention provides combination, it comprises The compounds of this invention or its pharmaceutically acceptable derivates and other therapeutical agent.

When The compounds of this invention or its pharmaceutically acceptable derivates and second therapeutical agent were used in combination with opposing same disease state, the dosage the when dosage of every kind of compound can be with this compound of independent use was different.Those skilled in the art can understand appropriate dosage easily.Be understandable that being used for can be along with sanatory character and patient's age and situation in the amount of the required The compounds of this invention of treatment and change, and finally considers decision carefully by care physician or animal doctor.Compound of the present invention can be used in combination [anticoagulant such as thrombin inhibitors, thromboxane receptor antagonist, prostacyclin simulant, phosphodiesterase inhibitor, fibrinogen antagonist with following other medicament, thrombolysis medicine such as tissue plasminogen activator and streptokinase, NSAID (non-steroidal anti-inflammatory drug) is such as Asprin or the like].

Combination refers to for using the mentioned reagent that can exist easily with the form of pharmaceutical preparation, so pharmaceutical preparation comprises combination and pharmaceutically acceptable carrier or vehicle as defined above, and this is also included within another aspect of the present invention.The single component of this type of combination can be by approach order or administration simultaneously in the pharmaceutical preparation that separates or make up of any routine.

When being the order administration, all at first administrations of the The compounds of this invention or second therapeutical agent.When being administration simultaneously, combination can be in identical or different administered in pharmaceutical compositions.

When in identical preparation, making up, be understandable that these two kinds of compounds must stablize, and each other and with other component of preparation be compatible.When separately preparing, they can be with the preparation of any routine, easily in this area the known mode of this compounds is provided.

Compound of the present invention can use with following agent combination, to treat or prevention of psychotic disorders: i) antipsychotic drug; The medicine that ii) is used for EPS, anticholinergic (for example Benzatropine, biperiden, procyclidine and Trihexyphenidyl) for example, antihistaminic (for example diphenhydramine) and dopaminergic (for example amantadine); Iii) thymoleptic; Iv) antianxiety agent; V) cognition enhancer anticholinesterase (for example tacrine, E2020, profit are cut down this bright and lycoremine) for example.

Compound of the present invention can be used in combination with thymoleptic, with treatment or prevention dysthymia disorders and emotional handicap.

Compound of the present invention can use with following agent combination, to treat or prevention two-phase disease: i) mood stabilizer; Ii) antipsychotic drug; Iii) thymoleptic.

Compound of the present invention can use following reagent with following agent combination, to treat or prevention of anxiety disease: i) antianxiety agent; Ii) thymoleptic.

Compound of the present invention can use with following agent combination, to improve nicotine withdrawal and to reduce Nicotine and crave for: i) nicotine replacement therapy, for example sublingual formulation of Nicotine beta-cyclodextrin and Nicotine patch; Ii) Bupropion.

Compound of the present invention can use with following agent combination, gives up and reduces alcohol and crave for to improve alcohol: i) nmda receptor antagonist, for example acamprosate; Ii) GABA receptor stimulant, for example uncle's ammonia ester (tetrabamate); Iii) opiate receptor antagonist, for example TREXUPONT.

Compound of the present invention can use with following agent combination, gives up and reduces opium and crave for to improve opium: i) opium μ receptor stimulant/opium k receptor antagonist, for example buprenorphine; Ii) opiate receptor antagonist, for example TREXUPONT; Iii) vasodilator antihypertensive drug, for example lofexidine.

Compound of the present invention can use with following agent combination, to treat or the prevention somnopathy: i) benzodiazepine

Class, for example temazepam, lormetazepam, estazolam and triazolam; Ii) non--benzodiazepine

Class soporific, for example zolpidem, Zopiclone, Zaleplone and indene (indiplon); Iii) barbiturates, for example somnifen, neo-barb, Sodital, secobarbital and phenylethyl barbituric acid; Iv) thymoleptic; V) other calmness-soporifics, for example Chloral Hydrate and Wy-1485.

Compound of the present invention can use with following agent combination, to treat apositia: i) appetite stimulator, for example Cyproheptadine; Ii) thymoleptic; Iii) antipsychotic drug; Iv) zinc; V) premenstruum medicine, for example Vitamin B6 and progesterone.

Compound of the present invention can use with following agent combination, to treat or the prevention bulimia: i) thymoleptic; Ii) opiate receptor antagonist; Iii) antiemetic ondansetron for example; Iv) testosterone receptor antagonist, for example flutamide; V) mood stabilizer; Vi) zinc; Vii) premenstruum medicine.

Compound of the present invention can use with following agent combination, to treat or the prevention autism: i) antipsychotic drug; Ii) thymoleptic; Iii) antianxiety agent; Iv) stimulant, for example Methylphenidylacetate, amphetamine preparation and pemoline.

Compound of the present invention can use with following agent combination, with treatment or prevention ADHD:i) stimulant, for example Methylphenidylacetate, amphetamine preparation and pemoline; Ii) non--stimulant, for example norepinephrine reuptake inhibitor (for example Tomoxetine hydrochloride), α 2 adrenoceptor agonists (for example clonidine), thymoleptic, modafinil and anticholinesterase (for example lycoremine and E2020).

Compound of the present invention can use with following agent combination, to treat personality disorder: i) antipsychotic drug; Ii) thymoleptic; Iii) mood stabilizer; Iv) antianxiety agent.

Compound of the present invention can use with following agent combination, to treat or the prevention male sexual disorder: i) Phosphodiesterase V inhibitors, for example Vardenafil and Virga; Ii) dopamine agonist/Dopamine HCL transport inhibitors, for example Apomorphine and Bupropion; Iii) alpha adrenergic receptor antagonist, for example phentolamine; Iv) prostaglandin agonists, for example Prostaglandin E1; V) testosterone agonist, for example testosterone; Vi) serotonin transport inhibitors, for example serotonin reuptake inhibitor; V) noradrenaline transporter inhibitor, for example Reboxetine and vii) 5-HT1A agonist, for example Flibaserin.

Compound of the present invention can with specific treatment male sexual disorder same preparation and estrogen agonist for example estradiol be used in combination, with treatment or prevention Female sexual dysfunction.

Antipsychotic drug comprises typical antipsychotic drug (for example chlorpromazine, thioridazine, mesoridazine, Fluphenazine, trilafon, prochlorperazine, trifluoperazine, thiothixene (thiothixine), haloperidol, molindone and loxapine); And atypical antipsychotic agents (for example leoponex, olanzapine, risperidone, Quetiapine, Aripiprazole (aripirazole), Ziprasidone and amisulpride).

Thymoleptic comprise serotonin reuptake inhibitor (for example citalopram, escitalopram, fluoxetine, paroxetine and Sertraline); Dual serotonin/norepinephrine reuptake inhibitor (for example Venlafaxine, duloxetine and Midalcipran); Norepinephrine reuptake inhibitor (for example Reboxetine); Tricyclic antidepressant (for example amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and Trimipramine); Oxidase inhibitor (for example Isocarboxazid, moclobemide, Phenelzine and Tranylcypromine); And other (for example Bupropion, mianserin, mirtazapine, nefazodone and trazodones).

Mood-stabilizing drug comprises lithium, Sodium Valproate/valproic acid/Sodium hydrogen divalproate, Carbamzepine, lamotrigine, gabapentin, topiramate and tiagabine.

Antianxiety agent comprises benzodiazepine

Class, for example alprazolam and lorazepam.

Be understandable that " treatment " cited herein means prevention, the prevention of recurrence and the inhibition or the improvement of symptom (slight, medium or serious), and the treatment of diagnosed disease.

The compounds of this invention can be used as the feed chemicals administration, but is preferably the active ingredient administration that is present in the pharmaceutical preparation.

According on the other hand, the invention provides pharmaceutical composition, it comprises The compounds of this invention, with one or more pharmaceutically acceptable carriers, thinner and/or vehicle.Carrier, thinner and/or vehicle are necessary for " acceptable " and are meant with other component of composition compatiblely, and its receptor are not had injury.

The compounds of this invention can the regular dosage form administration, and this formulation is according to conventional steps as known in the art, and the pharmaceutical carriers or the mixing diluents of The compounds of this invention and standard prepared.These steps can comprise mixing, granulate and suppress or composition is dissolved as suitable required preparation.

Pharmaceutical composition of the present invention can be formulated as any administration, and comprises that those are suitable for oral, part or administered parenterally to the mammiferous form that comprises the people.

Said composition can be with tablet, capsule, powder, granule, lozenge, emulsifiable paste or liquid preparation, as form oral or sterile parenteral solutions or suspension.

Topical formulations of the present invention is passable, for example, ointment, emulsifiable paste or lotion, ophthalmic ointment and eye drops or ear drop, gauze (impregnated dressings) and aerosol, and the additive that can comprise suitable routine helps solvent and the tenderizer in the ointment and the ointment of drug osmotic such as sanitas.

Preparation also can contain compatible conventional carrier, such as emulsifiable paste or ointment base and ethanol or be used for the oil base alcohol of lotion.Examples of such carriers can exist with about 1% to about 98% of preparation.More common they can be formed up to 80% of many about preparations.

The tablet and the capsule that are used for oral administration can be unit dosage, and can contain conventional vehicle such as tackiness agent, for example syrup, gum arabic, gelatin, Sorbitol Powder, tragacanth, or polyethylene base pyrrolidone; Filling agent, for example lactose, sucrose, W-Gum, calcium phosphate, Sorbitol Powder or glycine; Compressing tablet lubricant, for example Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide; Disintegrating agent, for example yam starch; Or acceptable wetting agent is such as Sulfuric acid,monododecyl ester, sodium salt.Tablet can be according to the currently known methods dressing in the common medicinal practice.Oral liquid can be, for example, and the form of water-based or oily suspensions, solution, emulsion, syrup or elixir, or can be used as the dryed product of water before use or other suitable solvent reconstruct.This type of liquid preparation can contain conventional additive, such as suspending agent, as Sorbitol Powder, methylcellulose gum, glucose syrup, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example Yelkin TTS, sorbitol monooleate, or gum arabic; Non-aqueous solvent (it can comprise edible oil), Prunus amygdalus oil for example, oily ester such as glycerine, propylene glycol, or ethanol; Sanitas, for example P-hydroxybenzoic acid methyl ester or P-hydroxybenzoic acid propyl diester or xitix and, optionally, conventional seasonings or tinting material.

Suppository can contain conventional suppository base, for example, and theobroma oil or other glyceryl ester.

For administered parenterally, use compound and aseptic solvent (preferably water) preparation liquid unit dosage.Compound depends on to suspend the solvent and the concentration of use or to be dissolved in the solvent.In preparation during solution, can compound is soluble in water being used for injection, and sterile filtration before being filled to suitable bottle or ampoule and sealing.

Advantageously, reagent such as local anesthetic, sanitas and buffer reagent are dissolved in the solvent.In order to increase stability, can be behind the bottle of packing into frozen composition, and remove water in vacuum.Then should anhydrous freeze dried powder-tight to bottle, thereby and can provide bottle water for injection to be used for reconstituted liquid before use.Non-stomach and intestine suspension is with the preparation of substantially the same method, except the compound suspendible rather than be dissolved in the solvent, and can not pass through filtration sterilization.Compound can be suspended in the sterilization carrier in before, by being exposed to ethylene oxide sterilizing.Advantageously, composition comprises tensio-active agent or wetting agent, distributes with the homogeneous that promotes compound.

Composition can contain from 0.1 weight %, as from 10-60 weight %, active material, it depends on the method for administration.Wherein said composition comprises dose unit, and per unit is as containing the active ingredient of 5-1000mg.Can be for the employed dosage of adult treatment in the 10-3000mg scope of every day, it depends on the approach and the frequency of administration.For oral administration, general dosage can be 50-1500mg every day, for example 120-800mg every day.

To what those having ordinary skill in the art will appreciate that be, the quantity of the best of the single dosage of The compounds of this invention and be at interval by the nature and extent of the disease that will treat, form, approach and the site of administration, and particularly to treat Mammals determined, and this top condition can decide by routine techniques.Those of ordinary skill in the art is understandable that also the best course of treatment, that is, the quantity of the dosage of the The compounds of this invention that gives every day for the fate of determining can utilize the conventional decision test course of treatment to determine by those skilled in the art.

All publications of being quoted in this manual including, but not limited to patent and patent application, are incorporated herein by reference them at this, just as each independent publication is fully set forth at this particularly and individually.

Be understandable that, the present invention includes following aspect.The embodiment of describing for first aspect can be applicable to these other aspects similarly.When it was suitable, above-described disease and illness can be expanded these other aspects:

I) The compounds of this invention is used for the treatment of or prevents disease that regulation and control mediated or illness by voltage-gated sodium channel.

Ii) the treatment or the prevention Mammals in by the disease that regulation and control mediated of voltage-gated sodium channel or the method for illness, comprise the The compounds of this invention of effective dosage.

Iii) The compounds of this invention is used for the treatment of or in advance by the purposes in the medicine of the diseases prevention that regulation and control mediated of voltage-gated sodium channel or illness in preparation.

Iv) The compounds of this invention is being treated or is being prevented by the disease that regulation and control mediated of voltage-gated sodium channel or the purposes in the illness.

Experiment

The present invention illustrates by following embodiment.

In the step below, after each starting raw material, provide the description and the embodiment of corresponding numbering.This provides only for helping the general chemistry worker.Starting raw material not necessarily must be from the method preparation of reference.

Wherein with reference to using " similar " step, understandable as different technologies personnel in this area, this type of step comprises other variation, as temperature of reaction, and agent/solvent amount, reaction times, post-treatment condition or chromatography purification condition.

All compounds of describing among the embodiment hereinafter described all prepare as the first step from stereochemistry pure 5-oxo-L-proline(Pro) methyl ester or 5-oxo-D-proline(Pro) ethyl ester (as 99%ee).Describe and the stereochemistry of the compound of embodiment is being specified under the following hypothesis: this be assumed to be through thereafter any answer under the condition, the pure configuration of 5-oxo-proline ester all remains unchanged.

Following demonstration in the absolute configuration at the three-dimensional center of 2-position according to NOE ¹H NMR tests appointment, by measuring with the stereochemistry with respect to this three-dimensional center for the configuration in the 5-position.

Compound uses ACD/Name PRO 6.02 chemical name softwares (Advanced ChemistryDevelopment Inc., Toronto, Ontario, M5H2L3, Canada) name.

Proton resonance (NMR) wave spectrum usually on the Varian instrument 300,400,500 or 600MHz, or on the Bruker instrument 300 and 400MHz under note down.Use the residual solvent line to report with the chemical shift of ppm (δ) as unit as interior mark.Splitting the branch mode is appointed as: s, and unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak.In 25-90 ℃ temperature range, record NMR wave spectrum.When detecting, provide one maximum chemical shift of content more than a conformer.

HPLC analyzes by R _t(HPLC) indication: x minute, at Agilent 1100 serial equipments, use Luna 3u C18 (2) 100A (50 * 2.0mm) posts (and moving phase: 100%[water+0.05%TFA] to 95%[acetonitrile+0.05%TFA] in 8 minutes, flow velocity=1ml/ minute, the detection wavelength was 220nm.

Mass spectrum (MS) carries out on 4II three quadrupole mass spectrometers (Micromass UK) or Agilent MSD1100 mass spectrograph usually, operate or on Agilent LC/MSD1100 mass spectrograph with ES (+) and ES (-) ionization mode, unite HPLC instrument Agilent 1100 Series operation [LC/MS-ES (+): analyze and analyze (moving phase: 100%[water+0.1%HCO with ES (+) and ES (-) ionization mode at Supelcosil ABZ+Plus (33 * 4.6mm is on the 3 μ m) ₂H], 1 minute, then from 100%[water+0.1%HCO ₂H] to 5%[water+0.1%HCO ₂H] and 95%[CH ₃CN], 5 minutes, under these conditions 2 minutes at last; T=40 ℃; Flow velocity=1mL/ minute; LC/MS-ES (-): analyze and analyze (moving phase: 100%[water+0.05%NH at Supelcosil ABZ+Plus (33 * 4.6mm, 3 μ m) ₃], 1 minute, then from 100%[water+0.05%NH ₃To 5%[water+0.05%NH ₃] and 95%[CH ₃CN], 5 minutes, under these conditions 2 minutes at last; T=40 ℃; Flow velocity=1mL/ minute].In mass spectrum, only reported peak in the molion bunch.

Go up the measurement optically-active at JASCO DIP-360 digital polarimeter (λ=589nm, T=20 ℃, c=1, MeOH solution).

The fast silica gel chromatogram method is carried out (by Merck AG Darmstadt, Germany provides) or is carried out by Varian Mega Be-Si prepacked column or by pre-filling Biotage silicagel column on silica gel 230-400 order.

The SPE-SCX post is the ion-exchange solid-phase extraction column, and it is provided by Varian.The elutriant that the SPE-SCX post uses is methyl alcohol, then the methanol solution wash-out of the ammonia of 2N.

In many preparations, use manual flash chromatography (Flash+) of Biotage or automatic flash chromatography (Horizon) system purifying.These all instruments carry out with Biotage Silica post.

The SPE-Si post is the silica gel solid-phase extraction column, and it is provided by Varian.

Be understandable that wave spectrum and diffraction data can be because slight variation take place the equipment of various factors such as temperature, concentration and use.Those of ordinary skill will appreciate that the XRPD peak position is subjected to the influence of height of specimen.Therefore peak position cited herein changes in+/-0.15 ° of 2 θ scope.

The X-ray powder diffraction

On Bruker D5005, use the Sol-X detector to carry out X-ray powder diffraction (XRPD) analysis.Experiment condition is: emission types: Cu K α, producer voltage: 40kV, producer electric current: 50mA, initial angle: 2.0 ° of 2 θ, end angle: 45.0 ° of 2 θ, step-length: 0.02 ° of 2 θ, per time in step: 1 second.Sample preparation on the no reflection events specimen holder.

Dsc (DSC): should be realized that the endotherm(ic)peak of Ce Lianging is relevant with several factors herein, it comprises the purity of instrument, heating rate, calibration standard, humidity and the use sample of use.

The fusing point of reporting in the experiment is to assess on the basis of the beginning of the endotherm(ic)peak that writes down during the dsc analysis.

Listed the abbreviation of using in the following tabulation:

Two (1, the 1-dimethyl ethyl) pyrocarbonates of BOC2O

DCM-methylene dichloride

DIPEA-diisopropyl ethyl amine

DMAP-4-(dimethylamino) pyridine

DMF-dimethyl formamide

TBTU-O-(benzotriazole-1-yl)-N, N, N ' N '-tetramethyl-urea a tetrafluoro borate

THF-tetrahydrofuran (THF)

The TFA trifluoroacetic acid

MTBE methyl-tertbutyl ether

The Et2O ether

The AcOEt ethyl acetate

MeOH methyl alcohol

The DMSO methyl-sulphoxide

1:(2S is described)-5-oxo-1,2-tetramethyleneimine dicarboxylic acid 1-(1, the 1-dimethyl ethyl) 2-methyl ester (D1):

(20g, 140mmol) (19.6ml, 140mmol), (17.2g 140mmol), drips BOC to DMAP to the adding of the solution in DCM (200ml) triethylamine then to the 5-oxo that is commercially available-L-proline(Pro) methyl ester ₂O (61g, 280mmol) solution in DCM (100ml).The red mixture that obtains was at room temperature stirred 2 hours, under reduced pressure remove then and desolvate, crude product passes through silica gel chromatography, eluent is a cyclohexane/ethyl acetate (7: 3-4: 6), obtain (through in hexane/ether 1: 1, grinding the back) title compound, be white solid (32.4g, 96%); R _f(hexanaphthene: ethyl acetate=65: 35): 0.21; ¹H NMR (300MHz, CDCl ₃) δ (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H).

2:(2S is described)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-oxo-5-{4-[(phenyl Methyl) oxygen base] phenyl } valeric acid methyl ester (D2):

Under-78 ℃ in nitrogen atmosphere, with hexane solution (0.88ml 1.4mmol) drops to the 1-bromo-4-[(phenyl methyl that is commercially available) the oxygen base of 1.6M n-Butyl Lithium] benzene (390mg, 1.48mmol) solution in anhydrous THF (2ml).The suspension that obtains was stirred 40 minutes down at-78 ℃, then it is dropped in advance (the 2S)-5-oxo-1 that is cooled to-78 ℃, 2-tetramethyleneimine dicarboxylic acid 1-(1, the 1-dimethyl ethyl) 2-methyl ester (D1,300mg is 1.23mmol) in the solution in anhydrous THF (2.4ml).This mixture was stirred 40 minutes down at-78 ℃, stirred 1 hour down, then it is used the saturated aqueous ammonium chloride cancellation down at-40 ℃ at-40 ℃.The mixture dilute with water, and use ethyl acetate extraction.Organic phase salt water washing then, Na ₂SO ₄Drying, vapourisation under reduced pressure obtains crude product, and it uses cyclohexane/ethyl acetate (95: 5) wash-out by the silica gel chromatography purifying, therefore obtains title compound, is white solid (170mg, 32%); R _f(hexanaphthene: ethyl acetate=8: 2): 0.30; ¹HNMR (300MHz, CDCl ₃) δ (ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (bs, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H).

3:(2S is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-3,4-dihydro-2 h-pyrrole-2-carboxylic acid methyl Ester (D3):

Under 0 ℃, in nitrogen atmosphere, to (2S)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-oxo-5-{4-[(phenyl methyl) the oxygen base] phenyl } valeric acid methyl ester (D2,323mg, 0.75mmol) solution in dry DCM (4ml) drips trifluoroacetic acid (1ml).The lightpink solution that obtains is warmed to room temperature, and 1 hour time spent, vapourisation under reduced pressure obtains title compound (D7,291mg, 0.68mmol, 91%) then, and it can directly use and need not be further purified at next step for green oily matter; R _t(HPLC): 3.69min; MS:(ES/+) m/z:310[MH ⁺], C19H19NO3 calculated value 309.

4:(5R is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) methyl ester (D4):

5:(5S is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) methyl ester (D5):

To (2S)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-3, (32.4mmol) solution in MeOH (200ml) adds PtO to 4-dihydro-2 h-pyrrole-2-carboxylic acid methyl ester for D3,13.7g ₂(240mg), and this mixture stirred 6 hours down in nitrogen atmosphere (2 normal atmosphere).Remove by filter catalyzer then and, obtain red oil, it is dissolved in the ethyl acetate, and uses NaHCO under reduced pressure except that desolvating ₃Solution washing.The crude product that obtains silica gel chromatography purifying, elutriant be cyclohexane/ethyl acetate (9: 1-8: 2), obtain title compound:

D4,4.15g, 13.3mmol, Y=41%.MS:(ES/+) m/z:312[MH ⁺] .C19H21NO3 calculated value 311.Rt (HPLC): 3.80min.Rf (hexanaphthene: ethyl acetate=7: 3): 0.18. ¹HNMR (300MHz, CDCl ₃) δ (ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.33 (d, 2H); 7.29 (t, 1H); 6.93 (d, 2H); 5.03 (s, 2H); 4.23 (dd, 1H); 4.00 (dd, 1H); 3.71-3.79 (m, 3H); 2.18-2.30 (m, 1H); 2.09-2.18 (m, 2H); 1.67-1.78 (m, 1H). between C2 proton and C5 proton, can observe NOE.

D5,0.6g, 1.9mmol, Y=6%.MS:(ES/+) m/z:312[MH ⁺] .C19H21NO3 calculated value 311; Rt (HPLC): 3.73min.Rf (hexanaphthene: ethyl acetate=7: 3): 0.32. ¹HNMR (300MHz, CDCl ₃) δ (ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.29 (d, 2H); 7.28 (t, 1H); 6.91 (d, 2H); 4.97-5.07 (m, 2H); 4.29 (dd, 1H); 4.09 (dd, 1H); 3.71-3.75 (m, 3H); 2.29-2.42 (m, 1H); 2.09-2.20 (m, 1H); 1.90-2.02 (m, 1H); 1.69-1.82 (m, 1H). between C2 proton and C5 proton, do not observe NOE.

6:(5R is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) (D6):

7:(5R is described)-1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 5-{4-[(phenyl methyl) the oxygen base] benzene Base }-L-proline(Pro) (D7):

To (5R)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) methyl ester (D4,120mg, 0.38mmol) solution in THF (2.3ml) adds LiOH monohydrate in water-soluble (1.1ml) (26mg 0.61mmol), then adds methyl alcohol (1.1ml).The solution that obtains was at room temperature stirred 2.5 hours, under-18 ℃, spend the night then.Under reduced pressure maintain the temperature at 38 ℃ of evaporation organic solvents down then, contain sour intermediate (D6, Rt (HPLC)=3.63min.MS:(ES/+) m/z:298[MH ⁺] .C18H19NO3 calculated value 297) and aqueous solution resistates with being dissolved in BOC among the THF (1.1ml) ₂(168mg 0.77mmol) handles O.Reaction mixture at room temperature stirred 3.5 hours.Evaporate organic solvent, and use 1N HCl acidified aqueous solution to pH=3 down at 0 ℃ alkaline aqueous solution, (2 * 10ml) extract this acidic aqueous solution with ethyl acetate.Organic phase Na ₂SO ₄Drying, and vapourisation under reduced pressure obtain solid, and (3 * 6ml) grind, and obtain title compound, are white powder (D7,137mg, 90%, 2 step) with normal hexane for it; Rt (HPLC): 5.81min; Rf (hexanaphthene: ethyl acetate=1: 1): 0.34; MS:(ES/+) m/z:420[M+Na ⁺] C23H27NO5 calculated value 397; MS:(ES/-) m/z:396[M-H] C23H27NO5 calculated value 397; ¹H NMR (300MHz, CDCl ₃) δ (ppm): 7.5-7.3 (m, 5H), 7.10 (bm, 2H), 6.90 (d, 2H), 5.08 (s, 2H), 4.65 (bm, 1H), 4.50 (bm, 1H), 2.58 (bm, 1H), 2.31 (bm, 1H), 2.11-1.90 (m, 2H), 1.16 (s, 9H).

8:(2S is described, 5R)-2-(aminocarboxyl)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-the 1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D8):

To (5R)-1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-(3.62mmol) solution in dry DMF (20ml) adds DIPEA (1.26ml to the L-proline(Pro) for D7,1.44g, 7.24mmol), add then TBTU (1.23g, 3.98mmol), after 20 minutes, add 1,1,1,3,3,3-hexamethyldisilazane (1,1,1,3,3,3-hexamethyl disilazane) (1.15ml, 5.43mmol).Reaction mixture was at room temperature stirred 2 hours, and it is with 5% NaHCO then ₃The aqueous solution (30ml) is handled, and continues to stir 30 minutes.The mixture dilute with water that obtains, and use ethyl acetate extraction.Organic phase is with salt solution/ice washed twice then, Na ₂SO ₄Drying, evaporation obtains colorless oil.This crude product is by the silica gel chromatography purifying, and (7: 3-5: 5) wash-out obtains title compound (1.25g, 87%) to use cyclohexane/ethyl acetate; R _t(HPLC): 5.51min; R _f(hexanaphthene: ethyl acetate=1: 1): 0.29.MS:(ES/+) m/z:419[M+Na ⁺]; C23H28N2O4 calculated value 396.

9:(2S is described, 5R)-2-(aminocarboxyl)-5-(4-hydroxy phenyl)-1-pyrrolidine carboxylic acid 1,1-dimethyl second Base ester (D9):

To (2S, 5R)-and 2-(aminocarboxyl)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D8,1.2g, 3.02mmol) solution in methyl alcohol (25ml) adds the Pd/C (210mg) of 10 weight %, mixture stirred 6 hours in nitrogen atmosphere (1 normal atmosphere).Remove by filter catalyzer, decompression removes down and desolvates, and obtains title compound, is white solid (870mg, 94%); R _t(HPLC): 3.61min; R _f(hexanaphthene: ethyl acetate=1: 1): 0.18; MS:(ES/+) m/z:329[M+Na ⁺] .C16H22N2O4 calculated value 306; ¹H NMR (300MHz, d ₆-DMSO) δ ppm:9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H); 4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m, 1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).

10:(2S is described, 5R)-2-(aminocarboxyl)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-1-pyrroles Alkane carboxylic acid 1,1-dimethyl ethyl ester (D10):

With 1-(brooethyl)-2-fluorobenzene (30 μ l, 0.220mmol) add to (2S, 5R)-2-(aminocarboxyl)-5-(4-hydroxy phenyl)-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D9,45mg, 0.146mmol) and salt of wormwood (30mg, 0.217mmol) solution in acetonitrile (2ml).Mixture at room temperature stirs and spends the night.TLC adds ethyl acetate and water after showing that reaction is finished.Organic phase salt water washing then, dry (Na ₂SO ₄), filter and evaporation.Crude product uses cyclohexane/ethyl acetate (7: 3-6: 4), obtain title compound (51mg, 85%) by silica gel chromatography; Rt (HPLC): 5.56min; Rf (hexanaphthene: ethyl acetate=1: 1): 0.28; ¹H NMR (300MHz, CDCl ₃) δ (ppm): 7.56-7.48 (m, 1H); 7.37-7.28 (m, 1H); 7.24-7.06 (m, 5H); 6.93 (d, 2H); 5.45-5.37 (br.s, 1H); 5.15 (s, 2H); 4.73-4.60 (m, 1H); 4.53-4.45 (m, 1H); 2.58-2.48 (m, 1H); 2.34-2.25 (m, 1H); 2.09-1.93 (m, 2H); 1.28-1.13 (br.s, 9H).

11:(5S is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) (D11):

According to being similar to the step described in 6 as described before, use (5S)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) methyl ester (D5,600mg, 1.92mmol), synthesising title compound; Rt (HPLC): 3.66min; MS:(ES/-) m/z:296[M-H]; MS:(ES/+) m/z:298[M+H], C18H19NO3 calculated value 297.

12:(5S is described)-1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 5-{4-[(phenyl methyl) the oxygen base] benzene Base }-L-proline(Pro) (D12):

According to being similar to the step described in 7 as described before, use ((5S)-5-{4-[(phenyl methyl) oxygen base] phenyl }-L-proline(Pro) (D11), synthesising title compound (695mg, 90%, 2 step).Crude product can directly need not be further purified in next step use; R _t(HPLC): 5.72min; MS:(ES/-) m/z:396[M-H]; MS:(ES/+) m/z:420[M+Na ⁺], C23H27NO5 calculated value 397, ¹H NMR (400MHz, DMSO-d6) δ (ppm): 12.70-12.42 (br.s, 1H); 7.47-7.42 (m, 2H); 7.42-7.35 (m, 2H); 7.35-7.29 (m, 1H); 7.13-7.07 (m, 2H); 6.98-6.92 (m, 2H); 5.08 and 5.06 (s, s, 2H); 4.96-4.91 and 4.86-4.81 (m, m, 1H); 4.44-4.40 and 4.39-4.34 (m, m, 1H); 2.36-2.13 (m, 2H); 1.90-1.80 (m, 1H); 1.69-1.57 (m, 1H); 1.33 and 1.09 (s, s, 9H).

13:(2S is described, 5S)-2-(aminocarboxyl)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-1-tetramethyleneimine carboxylic Acid 1,1-dimethyl ethyl ester (D13):

According to being similar to the step described in 8 as described before, use (5S)-1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-L-proline(Pro) (D12,690mg, crude product), synthesising title compound (600mg, 87%); R _t(HPLC): 5.23min; MS:(ES/+) m/z:419[M+Na ⁺], C23H28N2O4 calculated value 396.

14:(2S is described, 5S)-2-(aminocarboxyl)-5-(4-hydroxy phenyl)-1-pyrrolidine carboxylic acid 1, the 1-dimethyl Ethyl ester (D14):

According to being similar to the step described in 9 as described before, use (2S, 5S)-2-(aminocarboxyl)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D13,550mg, 1.38mmol), synthesising title compound (400mg, 94%); Rt (HPLC): 3.14min; MS:(ES/+) m/z:329[M+Na ⁺], C16H22N2O4 calculated value 306; ¹H NMR (400MHz, DMSO-d6) δ (ppm): 9.21 (br.s, 1H); 7.40-7.30 (br.s, 1H); 6.96-6.90 (m, 2H); 6.90-6.84 (br.s, 1H); 6.71-6.64 (m, 2H); 4.90 and 4.80 (d, d, 1H); 4.32 and 4.25 (d, d, 1H); 2.37-2.02 (m, 2H); 1.78-1.70 (m, 1H); 1.61-1.46 (m, 1H); 1.32 and 1.09 (s, s, 9H).

15:(2S is described, 5S)-2-(aminocarboxyl)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-1-pyrroles Alkane carboxylic acid 1,1-dimethyl ethyl ester (D15):

With 1-(brooethyl)-2-fluorobenzene (30 μ l, 0.244mmol) add to (2S, 5S)-2-(aminocarboxyl)-5-(4-hydroxy phenyl)-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D14,50mg, 0.163mmol) and salt of wormwood (34mg is 0.244mmol) in the solution of acetonitrile (0.5ml).Mixture at room temperature stirs and spends the night.Add ethyl acetate (20mL) and water (10mL) then.The organic phase dried over sodium sulfate is filtered and vapourisation under reduced pressure.Crude product uses cyclohexane/ethyl acetate (7: 3-6: 4), obtain title compound (65mg, 97%) by silica gel chromatography; R _f(hexanaphthene: ethyl acetate=7: 3): 0.19; MS:(ES/+) m/z:437[M+Na ⁺], C23H27FN2O4 calculated value 414; R _t(HPLC): 5.28min; ¹H NMR (400MHz, DMSO-d ₆) δ (ppm): 7.54-7.44 (m, 1H), 7.40-7.27 (m, 2H), 7.24-7.11 (m, 2H), and 7.06-6.98 (m, 2H), 6.96-6.79 (m, 3H), 5.10-5.00 (m, 2H), 4.91 and 4.81 (d, d, 1H), 4.29 and 4.24 (d, d, 1H), 2.35-2.18 (m, 1H), 2.17-1.97 (m, 1H), 1.78-1.62 (m, 1H), 1.58-1.43 (m, 1H), 1.28 and 1.03 (s, s, 9H).

16:(2R is described)-5-oxo-1,2-tetramethyleneimine dicarboxylic acid 1-(1, the 1-dimethyl ethyl) 2-ethyl ester (D16):

According to being similar to the step described in 1 as described before, use 5-oxo-D-proline(Pro) ethyl ester of being obtained commercially (12g, 75.6mmol), synthesising title compound (14g, 71%); R _f(hexanaphthene: ethyl acetate=7: 3): 0.25; R _t(HPLC) 3.94min; ¹H NMR (400MHz, DMSO-d6) δ (ppm): 4.61 (dd, 1H); 4.25 (q, 2H); 2.58-2.69 (m, 1H); 2.44-2.55 (m, 1H); 2.26-2.38 (m, 1H); 2.00-2.08 (m, 1H); 1.50 (s, 9H); 1.31 (t, 3H).

17:(2R is described)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-oxo-5-{4-[(phenyl Methyl) oxygen base] phenyl } valeric acid ethyl ester (D17):

According to being similar to the step described in 2 as described before, use (2R)-5-oxo-1,2-tetramethyleneimine dicarboxylic acid 1-(1, the 1-dimethyl ethyl) 2-ethyl ester (D16,10.5g 40.8mmol) and 4-iodophenyl phenyl methyl ether (13.34g, 43mmol), synthesising title compound (2.9g, 16%); Rt (HPLC): 6.37min; MS:(ES/+) 464m/z:[M+Na ⁺], C25H31NO6 calculated value 441; ¹H NMR (400MHz, DMSO-d6) δ (ppm): 7.92 (d, 2H); 7.29-7.45 (m, 5H); 6.99 (d, 2H); 5.18 (bs, 1H); 5.12 (s, 2H); 4.29-4.4 (bm, 1H); 4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1H); 2.00-2.15 (m, 1H); 1.39 (s, 9H); 1.28 (t, 3H).

18:(2R is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-3,4-dihydro-2 h-pyrrole-2-carboxylic acid second Base ester (D18):

According to being similar to the step described in 3 as described before, use (2R)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-oxo-5-{4-[(phenyl methyl) the oxygen base] phenyl } valeric acid ethyl ester (D17,2.9g, 6.57mmol), synthesising title compound.Crude product can directly need not be further purified in next step use; R _t(HPLC): 3.80min; MS:(ES/+) 324m/z:[MH ⁺], C20H21NO3 calculated value 323.

19:(5S is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-D-proline(Pro) ethyl ester (D19):

According to being similar to the step described in 4 as described before, use from describing 18 raw materials that obtain, synthesising title compound (1.84g, 86%, 2 step); Rt (HPLC): 4.03min; MS:(ES/+) 326m/z:[MH ⁺], C20H23NO3 calculated value 325; ¹H NMR (500MHz, CHCl3-d) δ (ppm): 7.30-7.47 (m, 7H), 6.96 (d, 2H), 5.06 (s, 2H), 4.23 (q, 2H), 4.15 (dd, 1H), 3.90 (dd, 1H), 2.17-2.28 (m, 1H), 2.07-2.17 (m, 2H), 1.61-1.76 (m, 1H), 1.31 (t, 3H).

20:(5S is described)-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-D-proline(Pro) (D20),

According to being similar to the step described in 6 as described before, use (5S)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-D-proline(Pro) ethyl ester (D19,340mg, 1.045mmol), synthesising title compound; R ^t(HPLC): 3.62min; MS:(ES/+) 298m/z:[MH ⁺], C18H19NO3 calculated value 297.

21:(5S is described)-1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 5-{4-[(phenyl methyl) the oxygen base] benzene Base }-D-proline(Pro) (D21):

According to being similar to the step described in 7 as described before, use (5S)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-D-proline(Pro) (D20), and synthesising title compound (440mg, quantitatively, 2 steps); Rt (HPLC): 5.77min; MS:(ES/+) 420m/z:[M+Na ⁺], C23H27NO5 calculated value 397; ¹H-NMR (500MHz, DMSO-d ₆) δ (ppm): 12.55 (br.s., 1H); 6.65-6.78 (m, 7H); 6.95 (d, 2H); 5.10 (s, 2H); 4.60-4.84 (m, 1H); 4.23 (m, 1H); 2.10-2.30 (m, 2H); 1.63-1.95 (m, 2H); 1.05-1.39 (m, 9H).

22:(2R is described, 5S)-2-(aminocarboxyl)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-1-tetramethyleneimine carboxylic Acid 1,1-dimethyl ethyl ester (D22):

According to being similar to the step described in 8 as described before, use (5S)-1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 5-{4-[(phenyl methyl) the oxygen base] phenyl }-D-proline(Pro) (D21,440mg, 1.11mmol), synthesising title compound (250mg, 56%); Rt (HPLC): 5.52min; MS:(ES/+) 419m/z:[M+Na ⁺], C23H28N2O4 calculated value 396.

23:(2R is described, 5S)-2-(aminocarboxyl)-5-(4-hydroxy phenyl)-1-pyrrolidine carboxylic acid 1, the 1-dimethyl Ethyl ester (D23):

According to being similar to the step described in 9 as described before, use (2R, 5S)-2-(aminocarboxyl)-5-{4-[(phenyl methyl) the oxygen base] phenyl }-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D22,175mg, 0.44mmol), synthesising title compound (135mg, quantitatively); Rt (HPLC): 3.63min; MS:(ES/+) m/z:329[M+Na ⁺].C16H22N2O4 calculated value 306; ¹H NMR (300MHz, d ₆-DMSO) δ (ppm): 9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H); 4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m, 1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).

24:(2R is described, 5S)-2-(aminocarboxyl)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-1-pyrroles Alkane carboxylic acid 1,1-dimethyl ethyl ester (D24):

According to being similar to the step described in 10 as described before, use (2R, 5S)-2-(aminocarboxyl)-5-(4-hydroxy phenyl)-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D23,130mg, 0.44mmol) and 1-(brooethyl)-2-fluorobenzene (166mg, 0.88mmol), synthesising title compound (145mg, 79%); Rt (HPLC) 5.55; MS:(ES/+) 437m/z:[M+Na ⁺], C23H27FN2O4 calculated value 414; ¹H NMR (300MHz, DMSO-d ₆) δ (ppm): 7.48-7.63 (m, 3H); 4.30-4.45 (m, 2H); 4.18-4.29 (m, 2H); 6.90-7.06 (m, 3H); 5.10 (s, 2H); 4.56-4.82 (m, 1H); 4.10-4.18 (m, 1H); 2.12-2.26 (m, 1H); 1.98-2.12 (m, 1H); 1.60-1.95 (m, 2H); 0.98-1.42 (m, 9H).

25:1-[(4-bromine phenoxy group is described) methyl]-2-fluorobenzene (D25)

Method 1: the solution that is dissolved in the acetone (7322mL) to 4-bromophenol (502.08g) adds K ₂CO ₃(570g) and bromobenzyl (523g).This mixture was heated 2 hours under refluxing.Under 25 ℃, reaction mixture cooling is then filtered, and with MTBE (1046mL) washing leaching cake.The filtrate that merges is concentrated into 1000mL and adds MTBE (4184mL).Mixture is used salt solution (1300mL) washing then with the 1M NaOH aqueous solution (1464mL) washing, organic phase is concentrated into dried.Add THF (1300mL), under reduced pressure remove and desolvate, obtain title compound (902.1g); ¹H NMR (400MHz, DMSO-d6) δ (ppm): 7.54 (td, 1H); 7.46 (d, 2H); 7.42 (m, 1H); 7.23 (m, 2H); 7.01 (d, 2H); 5.13 (s, 2H).

D25 also obtains by following:

Method 2: with the 4-bromophenol (19.22g, 111mmol), adjacent fluorine bromobenzyl (20g, 105.8mmol) and salt of wormwood (21.9g, 158.4mmol) heating 6 hours under the stirred mixture of acetone (280ml) is refluxing.Reaction mixture is cooled to room temperature, filters, with TBME (40ml) washing solid.Filtrate that merges and washes are concentrated into final volume under vacuum be about 40ml.The solution that obtains is washed with TBME (160ml), and with 1M sodium hydroxide and salt water washing, be concentrated into oily matter then under vacuum, it solidifies lentamente, obtains title compound (28.9g).

1H?NMR(300MHz，CHCl3-d)δ(ppm)：5.10(s，2H)，6.86(m，2H)，7.10(m，1H)，7.17(m，1H)，7.29(m，1H)，7.35(m，2H)，7.38(m，1H)。

26:(2S is described)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-(4-{[(2-fluorophenyl) Methyl] the oxygen base } phenyl)-5-oxopentanoic acid methyl ester (D26)

Method 1: in nitrogen atmosphere, under room temperature, add iodine (0.3g) to the suspension of magnesium metal (90g) in anhydrous THF (600mL) that stirs.With this mixture heating up to internal temperature is 64+/-2 ℃.With 1-[(4-bromine phenoxy group) methyl]-2-fluorobenzene (D25) (693g) solution in THF (1500mL) add in two batches.First adds 45mL.Second batch drips rest solution (1455mL).After adding, reaction reflux 1 hour.Reaction mixture is cooled to room temperature.Then this reaction mixture is added to lentamente be obtained commercially be chilled to (2S)-5-oxo-pyrrolidine-1 of-60 ℃, 2-dicarboxylic acid 1-tertiary butyl 2-methyl ester (300g) keeps internal temperature to be lower than-60 ℃ in the solution of THF (1500mL).Dropping finished at 2 hours.Dripped afterreaction mixture restir 15 minutes.Drip Virahol (300mL) then, during keep temperature to be lower than-60 ℃.Add saturated aqueous ammonium chloride/saturated sodium-chloride water solution (2/1; Mixture 900mL), during maintain the temperature at-50 ℃.Add entry (600mL) with the dissolving yellow mercury oxide.Separate organic phase, and wash with 13% the NaCl aqueous solution (600mL).Organic phase is concentrated into dried.Add EtOAc (1500mL) then, and the solution vapourisation under reduced pressure is anhydrated to remove.Resistates is by the silica gel chromatography purifying, and (90: 10-8: 2) wash-out obtains title compound (287g) to use cyclohexane/ethyl acetate; ¹H NMR (600MHz, DMSO-d6) δ (ppm): 7.93 (d, 2H); 7.57 (td, 1H); 7.44 (m, 1H); 7.27 (m, 3H); 7.14 (d, 2H); 5.24 (s, 2H); 4.04 (m, 1H); 3.61 (s, 3H); 3.03 (m, 2H); 1.94 (m, 2H); 1.38 (s, 9H).

D26 also obtains by following:

Method 2: under 70-75 ℃, to magnesium chips (12.79g.533mol), a small amount of iodine and 1, the mixture of 2-ethylene dibromide in THF (86.ml), added (4-bromophenyl (2-fluorophenyl) methyl ether) (D25,100g, 355.6mmol) solution in THF (216.25ml) through about 2 hours.Mixture continues other 2 hours of heating down at 70-75 ℃, is cooled to room temperature then, obtains the solution of Grignard reagent.With (2S)-5-oxo-1,2-tetramethyleneimine dicarboxylic acid 1-(1, the 1-dimethyl ethyl) 2-methyl ester (43.25g, 177.8mmol) solution in THF (216.25ml) is cooled to-60 ℃, added the solution of Grignard reagent through 1 hour, under-60 ℃, stirred the mixture 3 hours then.Drip Virahol (43.25ml), then add saturated aqueous ammonium chloride (86.5ml) and salt solution (43.25ml), then mixture is warmed to room temperature.Add entry (173ml) and 50% acetate (50ml) to pH 6-7, then add ethyl acetate (129.7ml).Separate each layer, (2 * 129.7ml) extract water layer with ethyl acetate.The organic layer salt water washing that merges concentrates under vacuum then.Resistates stirs with hexane (216.2ml), crosses filter solid then, and uses hexane wash.To this solid that obtains, add Virahol (432.5ml), mixture stirred 15 minutes down at 45 ℃, was cooled to 5-10 ℃ and stirred 2 hours then.Cross filter solid, use washed with isopropyl alcohol, and dry, obtain title compound, be solid.

1H?NMR(300MHz，CHCl3-d)：δ(ppm)：1.42(s，9H)；2.04(m，1H)；2.28(m，1H)；3.03(m，2H)；3.74(s，3H)；4.37(m，1H)；5.19(b，1H)；5.20(s，2H)；7.02(d，2H)；7.11(t，1H)；7.17(t，1H)；7.33(m，1H)；7.48(t，1H)；7.94(d，2H)。

27:(2S is described)-the 5-{4-[(2-luorobenzyl) the oxygen base] phenyl }-3,4-dihydro-2 h-pyrrole-2-carboxylic acid methyl Ester (D27)

Method 1: under 0 ℃, to (2S)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-5-oxopentanoic acid methyl ester (D26) (243g) drips TFA (461mL) in the solution of anhydrous DCM (2430mL).This mixture is warmed to room temperature and stirred 3 hours.Remove under the vacuum and desolvate and excessive TFA, (place under high vacuum and spend the night by 2 * 1215mL) wash-outs with EtOAc for the brown oil that obtains.Obtain title compound (392g), be red oil, it is directly in next step use, without purifying; ¹H NMR (400MHz, DMSO-d6) δ (ppm): 8.16 (m, 2H); 7.60 (td, 1H); 7.46 (m, 1H); 7.34 (m, 2H); 7.27 (m, 2H); 5.32 (s, 2H); 5.25 (m, 1H); 3.77 (s, 3H); 3.57 (m, 2H); 2.60 (m, 1H); 2.34 (m, 1H).

D27 also obtains by following:

Method 2: under 0-5 ℃, to (2S)-2-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-5-oxopentanoic acid methyl ester (D26,46g, 103mmol) solution in DCM (437ml) drips trifluoroacetic acid (87.4ml) and handles, and is warmed to room temperature then and stirs 3 hours.This solution is cooled to 0-5 ℃, and adding sodium hydroxide solution to final pH is about 7.Separate water layer, and extract with DCM (13ml), the organic layer of He Binging washes with water then, uses dried over sodium sulfate, concentrates under vacuum then, obtains title compound, is solid (33.3g).

1H?NMR(300MHz，CHCl3-d)：δ(ppm)：2.35(m，2H)；2.95(m，1H)；3.12(m，1H)；3.78(s，3H)；4.89(dd，1H)；5.18(s，2H)；7.00(d，2H)；7.10(m，1H)；7.16(m，1H)；7.29(m，1H)；7.5(t，1H)；7.85(d，2H)。

28:(5R is described)-the 5-{4-[(2-luorobenzyl) the oxygen base] phenyl }-L-proline(Pro) methyl ester (D28)

Method 1: in hydrogenation reactor) oxygen base with (2S)-5-{4-[(2-luorobenzyl] phenyl }-3,4-dihydro-2 h-pyrrole-2-carboxylic acid methyl ester (D27) (392g) is dissolved in EtOAc (3160mL).Add 5% palladium carbon (Engelhard numbers 44379, and moisture content is about 50%, 15.8g), reactor is full of hydrogen, to pressure be 2 normal atmosphere, reaction mixture stirred about 1.5 hours.With the reactor decompression, and by the diatomite filtration catalyzer, with EtOAc (2 * 500mL, other then 200mL) washing.With saturated NaHCO ₃The aqueous solution (600mL) adds in this filtrate, then adds 13% w/w Na ₂CO ₃The aqueous solution is (to pH=9,1000mL).Stirred the mixture 10 minutes, and separated each phase then.Remove water, use salt solution (600mL) washing organic layer then.The solution evaporation that obtains is extremely done, and the resistates purified by flash chromatography is used cyclohexane/ethyl acetate (1: 1) wash-out, obtains title compound (133g); ¹H NMR (600MHz, DMSO-d6) δ (ppm): 7.55 (dt, 1H); 7.41 (m, 1H); 7.34 (m, 2H); 7.23 (m, 2H); 6.97 (m, 2H); 5.12 (s, 2H); 4.09 (dd, 1H); 3.83 (dd, 1H); 3.66 (s, 3H); 2.97 (bs, 1H); 2.04 (m, 2H); 1.94 (m, 1H); 1.52 (m, 1H).

D28 is also by following preparation:

Method 2: with (2S)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-3,4-dihydro-2 h-pyrrole-2-carboxylic acid methyl ester (D27,34g, 103.5mmol) solution in ethyl acetate (272ml) places autoclave, and handles with trifluoroacetic acid (7.2ml).The thick slurry of palladium-carbon catalyst with 5% (1.7g) and ethyl acetate (68ml) changes over to, and reacting at room temperature, the 50psi hydrogen pressure stirred 5 hours down.By the Hyflo filtering mixt, with ethyl acetate (272ml) washing, filtrate is used aqueous sodium carbonate and salt water washing then, use dried over sodium sulfate, concentrate the resistates drying then under the vacuum, obtain title compound, be crude product oily matter (also containing some trans-isomer(ide)s).

1H?NMR(300MHz，CHCl3-d)：δ(ppm)：1.7(m，1H)；2.18(m，4H)；3.75(s，3H)；3.91(m，1H)；4.15(m，1H)；5.13(s，2H)；6.96(d，2H)；7.07(m，1H)；7.15(m，1H)；7.30(m，1H)；7.38(d，2H)；7.5(t，1H)。

Embodiment

Embodiment 1:(5R)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide (E1)

Method 1: with (5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-(98.6mmol) solution in methyl alcohol (65ml) is cooled to 0-10 ℃ to L-proline(Pro) methyl ester for D28,32.5g.(175.4ml, 43.8ml 43.8ml.43.8ml) add the methanol solution (approximately 11.2M) of ammonia, and 11 hours times spent are then 15-20 ℃ of following stirring reaction 22 hours in four batches.Remove deammoniation and methyl alcohol under vacuum, add toluene (65ml) then, mixture heating up obtains solution to 60-65 ℃, then it is concentrated under vacuum, and resistates is dry down at 60 ℃.Toluene (130ml) and methyl alcohol (0.32ml) are added in the resistates, and mixture heating up is to 70-75 ℃.Then the solution that obtains is cooled to 15-20 ℃, and stirred 1 hour.Cross filter solid, use toluene wash, and dry under 45-50 ℃, obtain title compound (21.8g), be solid.

¹H?NMR(500MHz，DMSO-d6)δ(ppm)：1.39(m，1H)；1.84(m，1H)；2.04(m，2H)；3.54(m，1H)；4.09(m，1H)；5.12(s，2H)；6.96(d，2H)；7.15(m，1H)；7.25(m，2H)；7.34(d，2H)；7.41(m，2H)；7.55(t，1H)。

E1 is also by following preparation:

Method 2: with (5R)-5-{4-[(2-luorobenzyl) oxygen base] phenyl }-L-proline(Pro) methyl ester (D28) (127g) is dissolved in 7N NH ₃MeOH (1016mL) solution in, this mixture was at room temperature stirred 24 hours.Add other 7N NH again ₃MeOH (63mL) solution, this mixture was stirred other 15 hours.Under reduced pressure remove and desolvate, add MeOH (635mL).Evaporating solns is to doing, and the white solid that obtains was placed weekend under high vacuum.Under 20 ℃, with in this white solid be suspended in MTBE/ toluene mixture of 1: 1 (254mL) and stirred 1 hour.Filter this suspension, solid washs with MTBE (254mL).White solid is dried overnight under 40 ℃ of following vacuum, obtains the product of 122.4g.With in this product flushing be suspended in MTBE/ toluene mixture of 1: 1 (245mL) and at room temperature stirred 1 hour.Filter this mixture, solid washs with MTBE (245mL).The white solid that obtains is dried overnight under 40 ℃ of following vacuum, obtains title compound (109g). ¹H?NMR(600MHz，DMSO-d6)δ(ppm)：7.54(td，1H)；7.41(m，1H)；7.38(m，2H)；7.34(d，2H)；7.24(m，2H)；7.13(bs，1H)；6.96(d，2H)；5.12(s，2H)；4.09(dd，1H)；3.55(dd，1H)；3.24(bs，1H)；2.07(m，1H)；2.00(m，1H)；1.85(m，1H)；1.40(m，1H)。

Embodiment 2:(5R)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide hydrogen chlorate (E2):

Method 1: under 0 ℃, to (2S, 5R)-and 2-(aminocarboxyl)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D10,51mg, 0.123mmol) solution in the mixture of ethyl acetate (0.9ml) and methyl alcohol (1ml) add Acetyl Chloride 98Min. (28 μ l, 2.5eq).Mixture is shaken 1.5 hours, and be warmed to room temperature lentamente.After the solvent evaporated, resistates grinds with ether, obtains title compound, is white solid (42mg, quantitative); Chirality HPLC: post: chiralcel OD 10um, 250 * 4.6mm; Moving phase: A: normal hexane; B: ethanol; Gradient: constant gradient 30%B; Flow velocity: 0.8ml/min; UV wavelength region: 200-400nm; Analysis time: 22min; Retention time: 12.0min.[α] _D=-30.5 ° of .MS:(ES/+) m/z:315[MH ⁺], C18H19FN2O2 calculated value 314; ¹H NMR (400MHz, DMSO-d6) δ ppm 10.19 (br.s., 1H), 8.13 (br.s., 1H), 7.94 (s, 1H), 7.60-7.77 (m, 1H), 7.51 (dt, 1H), 7.43 (d, 2H), 7.34-7.41 (m, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 7.05 (d, 2H), 5.13 (s, 2H), 4.49-4.60 (m, 1H), 4.19-4.28 (m, 1H), 2.17-2.38 (m, 2H), and 2.05-2.16 (m, 1H), 1.92-2.03 (m, 1H).

Embodiment 2 is also by following preparation:

Method 2: will ((5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-the L-prolineamide) (E1 109g) is dissolved in DCM (654mL) and also at room temperature adds Et ₂O (654mL).At room temperature drip the Et of 1N HCl ₂O (380.4mL) solution.This suspension is cooled to 0 ℃, and under this temperature, stirred 1 hour.Cross filter solid, use Et ₂O (2 * 327mL) washings, and under 40 ℃ in vacuum dried overnight, obtain the crystal formation 1 (121.24g) of title compound. ¹H?NMR(600MHz，DMSO-d6)δ(ppm)：10.72(bs，1H)；8.10(bs，1H)；8.08(s，1H)；7.72(s，1H)；7.56(td，1H)；7.49(d，2H)；7.43(qd，1H)；7.25(m，2H)；7.10(d，2H)；5.17(s，2H)；4.61(dd，1H)；4.30(dd，1H)；2.32(m，2H)；2.16(m，1H)；2.02(m，1H)。

Method 3: will ((5R)-5-(4-{[(2-fluorophenyl) methyl] oxygen base } phenyl)-L-prolineamide) (E1,10g 31.8mmol) are dissolved in DCM (50ml) and stir with gac (1g), filter then, with DCM (30ml) washing.Resistates concentrates under vacuum, removes the DCM of about 20ml.Add ether (60ml), (0.84N 40ml), stirs this mixture 30 minutes down at 20-25 ℃ then, is cooled to 0-5 ℃ and stirred 2 hours then then to add the diethyl ether solution of HCl.Cross filter solid, at room temperature dry then with ether washing, obtain the crystal formation 1 (10.25g) of title compound.

¹H?NMR(300MHz，DMSO-d ₆)δ(ppm)：2.04(m，1H)；2.18(m，1H)；2.32(m，2H)；4.34(m，1H)；4.64(m，1H)；5.18(s，2H)；7.10(d，2H)；7.25(m，2H)；7.40-7.60(m，4H)；7.77(s，1H)；8.24(s，1H)；11.03(b，1H)。

Method 4: in round-bottomed flask, under 0 ℃, will ((5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-the L-prolineamide) (E1,1.4g, 4.45mmol) diethyl ether solution (1.1eq, 4.89ml) processing of 1M HCl of the solution in ethyl acetate (14ml) and MeOH (2.5ml).Soon precipitate, mixture stirred 1 hour down at 0 ℃.Then this mixture is diluted with anhydrous diethyl ether (10ml), go up at Gooch strainer (hole 4, diameter 5cm) then and filter.(filter cake on 2 * 20ml) washing filters, therefore the white solid that obtains is transferred in the round-bottomed flask, descends dry 2 hours at room temperature dry 18 hours then under high vacuum at 40 ℃ with anhydrous diethyl ether.Obtain white solid (1.51g), be the crystal formation 1 of title compound.

Method 5: will ((5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-the L-prolineamide) (E1,25g 79.5mmol) is dissolved in ethyl acetate (750ml), and stirs with gac (2.5g), filter then, with ethyl acetate (125ml) washing.In this filtrate and washings, (1N 103ml), stirred this mixture 30 minutes down at 20-25 ℃ then, is cooled to 0-5 ℃ then, and stirs 2 hours through 30 minutes diethyl ether solutions at 20-25 ℃ of following adding HCl.Cross filter solid, (2 * 70ml) wash, at room temperature dry then, obtain the crystal formation 1 (25.5g) of title compound with ethyl acetate.

Identified peak uniqueness and difference of crystal formation 1 of the title compound of embodiment 2, and be presented in the following table:

Fusing point: 230 ℃.

Embodiment 3:(5S)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide hydrogen chlorate (E3):

Synthesising title compound (51mg, 100%) is by embodiment 2, the similar step of describing in the method 1, from (2S, 5S)-2-(aminocarboxyl)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester (D15,62mg, 0.15mmol); R _t(HPLC): 3.54min; Chirality HPLC.Post: chiralpak AD-H 5um, 250 * 4.6mm moving phase: A: normal hexane; B: Virahol.Gradient: constant gradient 30%B. flow velocity: 0.8ml/min.UV wavelength region: 200-400nm.Analysis time: 15min.Retention time: 10.4min; MS:(ES/+) m/z:315[MH+], C18H19FN2O2 calculated value 314; ¹H NMR (500MHz, DMSO-d6) δ (ppm): 9.37-9.13 (br.s., 2H), 8.01 (s, 1H), 7.68 (s, 1H), 7.55 (t, 1H), 7.49 (d, 2H), 7.45-7.37 (m, 1H), 7.29-7.20 (m, 2H), 7.08 (d, 2H), 5.17 (s, 2H), 4.62 (dd, 1H), 4.31 (t, 1H), 2.59-2.50 (m, 1H), 2.37-2.26 (m, 1H), and 2.18-2.03 (m, 1H), 2.01-1.88 (m, 1H).

Embodiment 4:(5S)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-D-prolineamide hydrogen chlorate (E4):

Embodiment 5:(5R)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-D-prolineamide hydrogen chlorate (E5):

Under 0 ℃, to (2R, 5S)-2-(aminocarboxyl)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-1-pyrrolidine carboxylic acid 1, (0.37mmol) solution in DCM (6ml) drips TFA (1.5ml) to 1-dimethyl ethyl ester for D24,145mg.Stirred the mixture with this understanding 1 hour.After the solvent evaporated, the crude product that obtains SCX column purification obtains title compound (100mg, 92%), is the mixture of diastereomer.

Use the chirality preparation HPLC to separate diastereomer: post: chiralpak AD-H; Moving phase: normal hexane: ethanol=70/30; Flow velocity: 13ml/min; UV wavelength region: 225nm; Analysis time: 25min.

Analyze chromatographic condition: chirality HPLC: post: chiralpak AD-H 5um, 250 * 4.6mm; Moving phase: A: normal hexane; B: ethanol; Gradient: constant gradient 30%B; Flow velocity: 0.8ml/min; UV wavelength region: 200-400nm; Analysis time: 30min; R _t: 14.02min (E4); R _t: 16.12min (E3)

E4 (69.5mg): R _t(HPLC): 3.60min. chirality HPLC: post: chiralcel OD 10um, 250 * 4.6mm; Moving phase: A: normal hexane; B: ethanol; Gradient: constant gradient 30%B; Flow velocity: 0.8ml/min; UV wavelength region: 200-400nm; Analysis time: 22min; R _t: 17.6min.[α] _D=+30.7 °. ¹H-NMR (400MHz, DMSO-d ₆) δ (ppm): 10.19 (br.s., 1H); 8.13 (br.s., 1H); 7.94 (s, 1H); 7.60-7.77 (m, 1H); 7.51 (dt, 1H); 7.43 (d, 2H); 7.34-7.41 (m, 1H); 7.23 (d, 1H); 7.18 (dd, 1H); 7.05 (d, 2H); 5.13 (s, 2H); 4.49-4.60 (m, 1H); 4.19-4.28 (m, 1H); 2.17-2.38 (m, 1H); 2.05-2.16 (m, 1H); 1.92-2.03 (m, 1H).

E5 (32mg): R _t(HPLC): 3.55min.Chial HPLC: post: chiralpak AD-H 5um, 250 * 4.6mm; Moving phase: A: normal hexane; B: Virahol; Gradient: constant gradient 30%B; Flow velocity: 0.8ml/min; UV wavelength region: 200-400nm; Analysis time: 15min; R _t: 8.4min.[α] _D=+24.3 °. ¹H-NMR (400MHz, DMSO-d ₆) δ (ppm): 9.25 (br.s., 2H); 8.01 (s, 1H); 7.68 (s, 1H); 7.55 (t, 1H); 7.49 (d, 2H); 7.37-7.45 (m, 1H); 7.20-7.29 (m, 2H); 7.08 (d, 2H); 5.17 (s, 2H); 4.62 (dd, 1H); 4.31 (t, 1H); 2.50-2.59 (m, 1H); 2.26-2.37 (m, 1H); 2.03-2.18m, 1H); 1.88-2.01 (m, 1H).

Embodiment 6:(5R)-and 5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide mesylate (E6):

EtOAc (6ml) is added to (5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base phenyl)-the L-prolineamide (E1,300mg), and with its 60 ℃ down heating 1 hour with dissolved compound.(65 μ l 1.05eq) add in this solution, and acid one adds, and it is muddy that solution becomes at once with methylsulfonic acid then.Then this was placed in the temperature cycle (0-40 ℃) 2 days.The filtering separation compound is white solid, and with the EtOAc washing, it's weekends are past 40 ℃ of following dryings in a vacuum, obtain the title compound of 335mg.

Fusing point: 192 ℃.

Bioassay

The ability of compound regulation and control voltage-gated sodium channel hypotype NaV 1.3 of the present invention can be measured by following test.

Cytobiology

Use (Invitrogen) transfection method of liposome (lipofectamine), by producing the stable cell line of expressing the hNaV1.3 passage with pCIN5-hNav1.3 carrier transfection CHO cell.PCIN5 is for producing the bicistronic mRNA carrier of mammalian cell strain, its tend to make all neomycin resistance cell expressing recombinant proteins (referring to Rees S., Coote J., Stable J., Goodson S., Harris S.﹠amp; Lee M.G. (1996) Biotechniques, 20,102-112), this is to be connected with the Xin Meisu selective marker cDNA in CMV promotor downstream by the cDNA with reorganization (to consult Chen YH in detail, Dale TJ, Romanos MA, WhitakerWR, Xie XM, Clare JJ.Cloning, distribution and functional analysis of the typeIII sodium channel from human brain Eur J Neurosci, 2000Dec; 12,4281-9).Cell is cultivated in the Dulbecco substratum (Invitrogen) of Iscove improvement, described substratum contains 10% foetal calf serum, 1%L-glutamine, 1% penicillin-Streptomycin sulphate (Invitrogen), 1% non-essential amino acid, 2%H-T additive and 1%G418 (Invitrogen), and remains under 37 ℃ at the CO that contains 5% ₂Airborne wet environment in.Cell separates from the T175 culturing bottle and is used to go down to posterity, and uses Versene (Invitrogen) collecting cell.

Cell preparation

Cell is grown to 60-95% in the T75 flask converge.By removing growth medium and (Invitrogen 15040-066) is hatched 6 minutes, with cellular segregation with warm (37 ℃) Versene of 1.5ml.With isolated cells be suspended in 10ml PBS (Invitrogen, 14040-133) in.Then cell suspending liquid is placed the 10-ml centrifuge tube, and under 700rpm centrifugal 2 minutes.After centrifugal, remove supernatant liquor, and the cell precipitation thing is suspended in again among the PBS of 3ml.

Electrophysiology

Under room temperature (21-23 ℃), use IonWorksHT plane formula electrophysiological technique (planar arrayelectrophysiology technology) (Molecular Devices Corp.) record current.Use microcomputer (Dell Pentium 4) to carry out stimulation programs and data gathering.For measurement plane electrode hole resistance (Rp), apply 10mV between each hole, the potential difference of 160ms being separated by.Before adding, cell carries out these measurements.After cell adds, before antibiotic (amphotericin) circulation enters in the cell, carry out the sealing-in test., subtract with before measuring leakage conductance at test pulse by using 160ms hyperpolarization (10mV) prepulsing 200ms in all experiments, to leak.The test pulse step-length is carried out 20ms from command potential-90mV to 0mV, and repeats 10 times under the frequency of 10Hz.In all experiments, there be not (preceding reading) at compound and have under (back reading) execution test pulse program.By adding compound, preceding reading and back reading are distinguished in 3-3.5 minute subsequently hatch.

Solution and medicine

Solution contains (mM) in the cell: K-gluconate 100, KCl 40mM, MgCl ₂3.2, EGTA3, HEPES 5, be adjusted to pH 7.25.Amphotericin 30mg/ml is as storing solution in preparation, and it is diluted to working concentration final in internally buffered liquid is 0.1mg/ml.Outer liquid is the PBS (Invitrogen) of Dulbecco and contains following material (mM): CaCl ₂0.90, KCl 2.67, K ₃PO ₄1.47, MgCl ₂0.50, NaCl 138, Na ₃PO ₄8.10, pH is 7.4.Compound is prepared as the storing solution of 10mM in DMSO, and carries out 1: 3 serial dilution subsequently.At last, with compound outside in the liquid dilution be 1: 100, causing final DMSO concentration is 1%.

Data analysis

Compound not in the presence of, all use sealing-in resistance (＞40M Ω) and peak current amplitude (＞200pA) analyze and filter record, thereby from further analysis, remove inappropriate cell.Use to add before the medicine and add medicine after paired comparisons measure the restraining effect of each compound.By applying mechanically the Hill equation of concentration-response data, measure the concentration (affinity (tonic) pIC50) that suppresses 50% the electric current required compound of drawing by the 1st depolarize pulse.In addition, by compound to the 10th comparison with the 1st time depolarize pulse action, thereby come the activity-dependent inhibition activity of assessing compound.Medicine do not exist and in the presence of, calculate the ratio with the 1st subpulse the 10th time, and calculate the % activity-dependent and suppress.Nest is with use as for affinity pIC ₅₀Identical equation, and calculate generation 15% and suppress (activity-dependent pUD ₁₅) concentration.

In above-mentioned test, 2-5 tests to the embodiment compound, and obtains the pUD greater than 5.0 ₁₅Value.

Claims (13)

1. the 5-of formula (I) (4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-prolineamide,

Or its pharmacy acceptable salt.

2. according to the compound of claim 1, wherein said compound is

Or its pharmacy acceptable salt.

3. according to the compound of claim 1 or claim 2, wherein said compound is (5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-the L-prolineamide.

4. according to the compound of claim 1 or claim 2, wherein said compound is (5R)-5-(4-{[(2-fluorophenyl) methyl] the oxygen base } phenyl)-L-prolineamide hydrogen chlorate.

5. according to the compound of claim 4, it is essentially crystalline form, and be characterised in that the X-ray powder diffraction collection of illustrative plates that has at the characteristic peak of following position: 4.7 ± 0.15 (° 2 θ), 9.5 ± 0.15 (° 2 θ), 12.6 ± 0.15 (° 2 θ), 14.3 ± 0.15 (° 2 θ), 19.2 ± 0.15 (° 2 θ), 20.3 ± 0.15 (° 2 θ), 20.9 ± 0.15 (° 2 θ), 24.0 ± 0.15 (° 2 θ), 26.4 ± 0.15 (° 2 θ).

6. pharmaceutical composition, it comprises as each formula (I) compound or its pharmacy acceptable salt among the claim 1-5, and pharmaceutically acceptable carrier.

7. as each formula (I) compound among the claim 1-5, or its pharmacy acceptable salt is used for the treatment of or prevents by the purposes in the medicine of the disease that regulation and control mediated of voltage-gated sodium channel or illness in preparation.

8. according to the purposes of claim 7, wherein said disease or illness are depression or mood disorder.

9. purposes according to Claim 8, wherein said disease or illness are bipolar disorder.

10. according to the purposes of claim 7, wherein said disease or illness are for forcing eating disorder or disease of eating too much at one meal.

11. according to the purposes of claim 7, wherein said disease or illness are epilepsy.

12. according to the purposes of claim 7, wherein said disease or illness are inflammatory pain or neuropathic pain.

13. preparation is as the method for each formula (I) compound among the claim 1-5, it comprises that the compound of formula (II) and ammonia solution react in suitable solvent