CN101472891A - Crystalline forms of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of neuropathic pain - Google Patents

Abstract

Crystalline forms of 4-[2-(4-methylphenylsulfanyl)-phenyl]piperidine and salts thereof are provided e.g. for the treatment of neuropathic pain.

Description

Treatment of neuropathic is arranged with thrombotonin and the comprehensive inhibiting 4-[2-of norepinephrine reuptake (4-methylbenzene sulfenyl) phenyl] crystallized form of piperidines

The pain sensation is more complicated from the direct transmission of special receptor to brain of bodily injury part than signal, and the pain of wherein feeling is proportional to injury.Or rather, the infringement that the end is organized slightly and may cause the change of the nervus centralis structure that the pain sensation that influences pain sensitivity subsequently is related to the injury of nerve.This neuromechanism changes may cause that central nervous system is in sensitization aspect the reaction of longer destructive stimulus of time length, this may show as such as chronic pain, promptly even at destructive stimulus stopped the back pain sensation still, or hyperpathia, promptly increase the reaction that belongs to the stimulation of normal pain to a kind of.This point more mysterious and be " phantom limb syndrome " to one of play example, promptly in the limbs before it cuts off the lasting pain of existence.About the nearest summary of nervus centralis structural modification and pain, see Melzack et al, Ann.N.Y.Acad.Sci., 933,157-174,2001.

Chronic pain, neuropathic pain for example shows to such an extent that be different from other type pain for example body pain or visceral pain.This pain often is described to thorn, burning, pinprick, fiber crops or cutter and cuts out.The common cause of neuropathic comprises alcoholism, amputation, and back, shank and hip problem, chemotherapy, diabetes, acquired immune deficiency syndrome (AIDS) (HIV), multiple sclerosis, spinal surgery and varicella zoster virus infect.

The nervus centralis of chronic pain part can explain chronic pain for example neuropathic how often to classical anodyne for example nonsteroidal anti-inflammatory agent (NSAIDS) and opium class anodyne poor response.With the amitriptyline is that the tricyclic antidepressant (TCA) that the typical case represents has become the standard medication for the treatment of neuropathic, and its effect believes it is [the Clin.Ther. that carries matter and norepinephrine to carry the comprehensive restraining effect of matter to take place via to thrombotonin, 26,951-979,2004].More closely, there has been the people will all have inhibiting so-called economic benefits and social benefits thymoleptic to be used for the treatment of neuropathic [Human Psychopharm., 19, S21-S25,2004] to thrombotonin and norepinephrine re-uptake clinically.The example of economic benefits and social benefits thymoleptic is Venlafaxine and duloxetine, and these class thymoleptic often abbreviate SNRI as.

Be used for about selective serotonin reuptake inhibitor (SSRI) neuropathic purposes data seldom, but it is generally acknowledged effect limited [Bas.Clin.Pharmacol., 96,399-409,2005].In fact, the someone supposes that the SSRI class itself is faint anti-nociceptive, but the hypothesis thrombotonin carries the restraining effect of matter to increase the antinociceptive effect that norepinephrine reuptake suppresses.This idea obtains the support of a 22 zooscopies and 5 human research's summary, these studies show that the SNRI class is compared with NRI excellent antinociceptive effect, and this is better than SSRI[Pain Med.4,310-316,2000].

About 5-HT ₃The nearest data of antagonistic odansetron show 5-HT ₃Antagonistic has analgesic effect, thereby can be used for treating neuropathic [Anesth.Analg.97,1474-1478,2003].

Yet, the use of tricyclic antidepressant and for example drowsiness of known anticholinergic side effects, anxiety, be on tenterhooks and understanding and memory difficulty etc. interrelate.Therefore, need to find at present the replacement therapy approach of neuropathic in the industry.

Compound 4-[2-(4-methylbenzene sulfenyl) phenyl as free alkali is disclosed as the international patent application of WO 2003/029232 bulletin] piperidines and corresponding HCl salt.It was reported that this compound is that thrombotonin is carried matter and serotonin receptor 2C (5-HT _2C) inhibitor, and it is unusual allegedly to can be used for treating emotionality, for example depression and anxiety.

Brief summary of the invention

The present inventor finds surprisingly, except that the pharmacology performance of having known, 4-[2-(4-methylbenzene sulfenyl) phenyl] piperidines is the potent inhibitor of serotonin reuptake and norepinephrine reuptake, serotonin receptor 3 (5-HT ₃) antagonist, thrombotonin 2A (5-HT _2A) antagonist, and α ₁The inhibitor of adrenergic receptor, and therefore this compound may can be used for treatment such as chronic pain.Therefore, the present invention relates to Compound I, promptly be 4-[2-(the 4-methylbenzene sulfenyl) phenyl of crystallized form] piperidines and pharmaceutical acceptable salt thereof, prerequisite is that this compound is not 4-[2-(4-methylbenzene sulfenyl) phenyl] the piperidinium salt acid salt.

In one embodiment, the present invention relates to the Compound I that is used for the treatment of.

In one embodiment, the present invention relates to a kind of methods of treatment, comprise Compound I patient's drug treatment significant quantity that its needs are arranged.

In one embodiment, the present invention relates to the medical composition of a kind of inclusion compound I.

In one embodiment, the present invention relates to Compound I and be used for the purposes that medicament is made.

Accompanying drawing

Fig. 1: the X-ray diffractogram of the HBr additive salt of Compound I

Fig. 2: the X-ray diffractogram of the HBr additive salt solvate of Compound I

Fig. 3: the X-ray diffractogram of the palmitinic acid additive salt of Compound I

Fig. 4: the X-ray diffractogram of the DL-lactic acid additive salt of Compound I

Fig. 5: the X-ray diffractogram of the hexanodioic acid additive salt (1:1) of Compound I (alpha+beta form)

Fig. 6: the X-ray diffractogram of the hexanodioic acid additive salt (2:1) of Compound I

Fig. 7: the X-ray diffractogram of the fumaric acid additive salt (1:1) of Compound I

Fig. 8: the X-ray diffractogram of the pentanedioic acid additive salt (1:1) of Compound I

Fig. 9: the X-ray diffractogram of the propanedioic acid additive salt of Compound I (alpha-form)

Figure 10: the X-ray diffractogram of the propanedioic acid additive salt of Compound I (beta form)

Figure 11: the X-ray diffractogram of the oxalic acid additive salt (1:1) of Compound I

Figure 12: the X-ray diffractogram of the sebacic acid additive salt (2:1) of Compound I

Figure 13: the X-ray diffractogram of the succsinic acid additive salt (2:1) of Compound I

Figure 14: the X-ray diffractogram of the L MALIC ACID additive salt (1:1) of Compound I (alpha-form)

Figure 15: the X-ray diffractogram of the L MALIC ACID additive salt (1:1) of Compound I (beta form)

Figure 16: the X-ray diffractogram of the D-tartrate additive salt (1:1) of Compound I

Figure 17: with the X-ray diffractogram of the L-aspartic acid additive salt (1:1) of L-aspartic acid blended Compound I

Figure 18: with the X-ray diffractogram of the L-aspartic acid additive salt hydrate (1:1) of L-aspartic acid blended Compound I

Figure 19: with the X-ray diffractogram of the L-glutamic acid additive salt (1:1) of L-glutamic acid monohydrate blended Compound I

Figure 20: the X-ray diffractogram of the lemon acid additive salt (2:1) of Compound I

Figure 21: the X-ray diffractogram of the HCl additive salt of Compound I

Figure 22: the X-ray diffractogram of the phosphoric acid additive salt (1:1) of Compound I

Figure 23: dopamine level in the forehead cortex during The compounds of this invention administration

Figure 24: levels of acetylcholine in the forehead cortex during The compounds of this invention administration

Figure 25 a+b: levels of acetylcholine in forehead cortex and the abdomen hippocampus during The compounds of this invention administration.

Detailed description of the present invention

The present invention relates to be the Compound I of crystal form, i.e. 4-[2-(4-methylbenzene sulfenyl) phenyl] piperidines and pharmaceutical acceptable salt thereof, prerequisite is that described compound is not the salt acid-addition salts. 4-[2-(4-methylbenzene sulfenyl) phenyl] structure of piperidines is

The pharmacology performance of the compounds of this invention is set forth in an embodiment, but can be summarized as follows. This compound is the inhibitor of thrombocytin and norepinephrine reuptake; They suppress serotonin receptor 2A, 2C and 3; And they suppress the alpha-1 adrenergic acceptor.

In one embodiment, described pharmaceutical acceptable salt is the acid-addition salts of non-toxic acid. Described salt comprises the salt of making from following organic acid: maleic acid, fumaric acid, benzoic acid, ascorbic acid, butanedioic acid, oxalic acid, ethanetetrayl salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, malonic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic, p-aminobenzoic acid, glutamic acid, benzene sulfonic acid, theophylline acetic acid and 8-halo theophylline 8-bromine theophylline for example for example. Described salt also can for example hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid be made from inorganic acid. Other useful salt is listed in the table (table 1) of embodiment 1d.

In one embodiment, the compounds of this invention is that formula 1 compound is the HBr addition salts.

In one embodiment, The compounds of this invention is DL-lactic acid additive salt, 1:1 salt especially.

In one embodiment, The compounds of this invention is L-aspartic acid additive salt, 1:1 salt especially.

In one embodiment, The compounds of this invention is L-glutamic acid additive salt, 1:1 salt especially.

In one embodiment, The compounds of this invention is pentanedioic acid additive salt, 1:1 salt especially.

In one embodiment, The compounds of this invention is propanedioic acid additive salt, 1:1 salt especially, has been found that the latter exists with two kinds of polycrystalline modification α and β, and wherein β-formal cause solubleness is lower and it is believed that it is the most stable.

In one embodiment, The compounds of this invention is refining form." refining form " this term intention points out that this compound is gone up substantially and do not contain other compound or other form, i.e. the polymorphic of described compound is as the presumable polymorphic of this situation.

Per os formulation, especially tablet and capsule, because the easily thereby better conformability of administration, what patient and doctor had a preference for often.For tablet and capsule, being preferably this effective constituent is crystalline.

Crystallization of the present invention can be used as solvate and exists, and promptly solvent molecule constitutes the crystal of the part of its crystalline structure.This solvate can generate from water, and this solvate often is called hydrate in this case.Substituting, this solvate can for example ethanol, acetone or ethyl acetate generate from other solvent.The definite quantity of solvate is often different because of condition.For example, hydrate typically can rise or the dehydration with the humidity reduction with temperature.When condition or not or have only the compound of a little change when for example humidity changes, generally be considered as being more suitable in the medicine prescription.Be noted that the HBr additive salt does not generate hydrate when separating out precipitation from water, the compound as succinate, malate and tartrate acid salt is then right.

Some compounds are moisture absorptions, and promptly they absorb water when being exposed to humidity.Water absorbability for will be with the medicine prescription, especially as the compound that tablet or capsule provide, be considered as a kind of undesirable performance to do Formulation Example.In one embodiment, the invention provides the low crystallization of water absorbability.

For the per os formulation of using crystallinity effective constituent,, then also be useful if described crystallization clearly defines.In this paper category, " clearly defining " this term refers to that especially stoichiometry clearly defines, and promptly refers to into ratio between the salt ion and be the ratio between the small integer, for example 1:1,1:2,2:1,1:1:1 etc.In one embodiment, The compounds of this invention is the crystallization that clearly defines.

The solubleness of effective constituent also is significant for the selection of formulation, because it may have a direct impact bioavaliability.For the per os formulation, believe that generally the solubleness of effective constituent is high more useful more, because it has improved bioavaliability.Some patients for example gerontal patient's swallow tablet have difficulty, and a mouthful solution may be needing to avoid a kind of being suitable for of swallow tablet to substitute.For restricted entry drips the volume of solution, the high density that reaches effective constituent in this solution is necessary, and this requires the high-dissolvability of this compound again.As shown in table 3, DL-lactic acid, L-aspartic acid, L-glutamic acid, pentanedioic acid and propanedioic acid additive salt have especially high solubleness.

Crystallized form influences the filtration and the processing characteristics of compound.Needle crystal tends to more be difficult to operation under production environment, become more difficult and time-consuming because filter.The definite crystallized form of a certain given salt may depend on that for example this salts out sedimentary condition.HBr acid salt of the present invention is growth needle-like solvate crystals when separating out precipitation from ethanol, acetate and propyl alcohol, but the crystal of the non-acicular non-hydrated form of growing when the HBr additive salt is separated out precipitation from water provides excellent strainability.

Table 3 has also been set forth crystallization pH, i.e. pH in this salt saturated solution.Why important this performance is, is because lay up period moisture can't be avoided forever fully, and the accumulation of moisture can cause in the tablet that comprises low crystallization pH salt or on pH reduce this and may shorten shelf-life.And then when tablet was made with wet granulation, the salt that crystallization pH is low may cause the processing unit corrosion.Data in the table 3 show that HBr, HCl and hexanodioic acid additive salt may be excellent at this on the one hand.

In one embodiment, The compounds of this invention is to be crystallized form, especially to be the HBr additive salt of refining form.In a kind of further embodiment, the peak position of described HBr salt in X-ray powder diffraction figure (XRPD) is in about 6.08 °, 14.81 °, 19.26 ° and 25.38 ° of 2 θ, and specifically, described HBr salt has XRPD shown in Fig. 1.

In one embodiment, The compounds of this invention is to be crystallized form, especially to be the DL-lactic acid additive salt (1:1) of refining form.In a kind of further embodiment, the XRPD peak position of described DL-lactic acid additive salt is in about 5.30 °, 8.81 °, 9.44 ° and 17.24 ° of 2 θ, and specifically, described DL-lactic acid additive salt has XRPD shown in Fig. 4.

In one embodiment, The compounds of this invention is to be crystallized form, especially to be the L-aspartic acid additive salt (1:1) of refining form.In a kind of further embodiment, described L-aspartic acid additive salt is non-solvate, its XRPD peak position is in about 11.05 °, 20.16 °, 20.60 °, 25.00 ° 2 θ, and specifically, described L-aspartic acid additive salt has XRPD shown in Figure 17 when mixing with the L-aspartic acid.In one embodiment, described L-aspartic acid additive salt is a kind of hydrate, especially is refining form.In a kind of further embodiment, the XRPD peak position of described L-aspartic acid additive salt hydrate is in about 7.80 °, 13.80 °, 14.10 °, 19.63 ° 2 θ, specifically, described L-aspartic acid additive salt hydrate has XRPD shown in Figure 18 when mixing with the L-aspartic acid.

In one embodiment, The compounds of this invention is to be crystallized form, especially to be the L-glutamic acid additive salt (1:1) of refining form.In a kind of further embodiment, the XRPD peak position of described L-glutamic acid additive salt is in about 7.71 °, 14.01 °, 19.26 °, 22.57 ° 2 θ, and specifically, described glutaminate has XRPD shown in Figure 19 when mixing with the L-glutamic acid monohydrate.

In one embodiment, The compounds of this invention is to be crystallized form, especially to be the propanedioic acid additive salt (1:1) of refining form.In a kind of further embodiment, described propanedioic acid additive salt is an alpha-form, its XRPD peak position is in about 10.77 °, 16.70 °, 19.93 °, 24.01 ° 2 θ, or described propanedioic acid additive salt is β-form, its XRPD peak position is in about 6.08 °, 10.11 °, 18.25 °, 20.26 ° 2 θ, specifically, described propanedioic acid additive salt has XRPD shown in Fig. 9 or 10.

In one embodiment, The compounds of this invention is to be crystallized form, especially to be the pentanedioic acid additive salt (1:1) of refining form.In a kind of further embodiment, the XRPD peak position of described pentanedioic acid additive salt is in about 9.39 °, 11.70 °, 14.05 ° and 14.58 ° of 2 θ, and specifically, described pentanedioic acid additive salt has XRPD shown in Fig. 8.

As mentioned above, The compounds of this invention is suitable for the treatment chronic pain particularly well.Chronic pain comprises various indications, for example phantom limb pain, neuropathic, diabetic neuropathy, post herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), the HIV neuropathy, recombination region pain syndrome (CPRS), trigeminal neuralgia/(face) cramp, surgical intervention (for example operation back pain relieving), diabetic angiopathy, the capillary resistance or the diabetic syndrome that interrelate with insulitis, the pain that interrelates with stenocardia, the pain that interrelates with menstruation, the pain that interrelates with cancer, have a toothache, headache, migraine, tension-type headache, trigeminal neuralgia, temporal-mandible joint syndrome, myofascial pain flesh is injured, procerus muscle pain syndrome, bone and arthrodynia (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and oedema that the wound that interrelates with burn causes, because osteoarthritis, osteoporosis, what bone shifted or unknown cause causes sprains or the pain of fracturing, gout, fibrositis, myofascial pain, syndrome of chest outlet, (wherein backache results from general for last backache or back pain, regional, or primary spondylopathy (radiculopathy)), pelycalgia, the ambition pain, non-ambition pain, the pain that interrelates with spinal cord injury (SCI), pain after the nervus centralis apoplexy, the cancer neuropathy, the AIDS slight illness, the sickle cell pain, or it is old ailing.

Specifically, The compounds of this invention can be used for treating mood disorders, for example, and the dysthymia disorders that interrelates with above listed chronic pain indication.

IASP (IASP) is defined as pain " with unhappiness sensation and emotional experience reality or that potential tissue injury interrelates or that describe with this type of infringement " (IASPClassification of Chronic Pain, 2 ^NdEdition, IASP Press (2002), 210).Although pain is always subjective, its reason or syndrome can be classified." neuropathic " is defined as " pain that primary injury or dysfunction cause or cause in the neural system " as a subclass by IASP.

The different subclass of neuropathic obtain IASP and admit that the example is:

Allodynia is defined as " pain that causes owing to a kind of stimulation that does not usually excite pain ".

Cusalgia is defined as " hyperalgesic syndrome after lasting Burning Pain, allodynia and the traumatic nerve injury, often concurrent vasorelaxation and sudomotor function obstacle and alteration in nutrition after a while ".

Oxypathy is defined as " susceptibility to stimulating of raising forecloses feeling ".

Neurodynia is defined as " one or more neural distributivity pain ".

Neuritis is defined as " inflammation that one or more are neural ".

Neuropathy, be defined as " nervous function disorder or pathological change: mononeuropathy in a kind of nerve, mononeuropathy multiplex in some nerves, if dispersivity with two-way then be polyneuropathy ".Neuropathy may with interrelate such as diabetes, be referred to as diabetic neuropathy in this case.

Hyperpathia is defined as " reaction to the stimulation that belongs to normal pain of raising ".

Hyperpathia is defined as " a kind of pain syndrome is characterized in that stimulation, the especially unusual pain reaction of repetitive stimulation, and the threshold value that improves ".

The stimulation that causes this neuropathic can be machinery or hot.

Unique pharmacology performance of The compounds of this invention make its be applicable to treatment not with direct other the relevant disease of chronic pain.5-HT _2CAcceptor is positioned at such as on the dopaminergic neuron, and at this, activation discharges Dopamine HCL and produces the inhibition influence of strengthening, and 5-HT _2CAntagonistic will influence the raising of dopamine level.The data presentation that provides among the embodiment 2E, The compounds of this invention can bring the dose dependent of dopamine level outside the born of the same parents to improve really in brain.Under this background, can suppose 5-HT _2CAntagonistic is specially adapted to treat the dysthymia disorders [Psychopharmacol.Bull., 39,147-166,2006] that is difficult to the treatment of selective serotonin reuptake inhibitor.This hypothesis is supported in some clinical studyes, these studies show that, the combination of mirtazapine and SSRI is better than the patients with depression that SSRI is used for the treatment of does not separately have enough clinical responses (treatment-resistant dysthymia disorders, TRD or refractory depression disease) [Psychother.Psychosom., 75,139-153,2006].Mirtazapine also is a kind of 5-HT ₂And 5-HT ₃Antagonistic, this shows, has both serotonin reuptake and suppresses to use and 5-HT ₂And 5-HT ₃The compound of antagonistic action, for example The compounds of this invention can be used for treating TRD, promptly can improve the patient's who suffers from the treatment-resistant dysthymia disorders alleviation speed.

The data presentation that provides among embodiment 2F and the 2G, The compounds of this invention can improve the outer level of born of the same parents of vagusstoff in forehead cortex and the abdomen hippocampus.Long-standing clinical condition is according to showing, levels of acetylcholine is treatment alzheimer's disease and the damaged a kind of approach of general understanding in the raising brain, with reference to the purposes of acetylcholinesterase in treatment of alzheimer.Under this background, believe that The compounds of this invention can be used for treating alzheimer's disease and the damaged and mood disorders of understanding, for example with alzheimer's disease and the damaged dysthymia disorders that interrelates of understanding.

The part patients with depression can react on the following meaning to using such as the treatment of SSRI: their can for example make moderate progress on MADRD and the HAMD at clinical relevant depressed yardstick, but for example sleep disordered and damaged the remaining unchanged of understanding of other symptom in this case.In category of the present invention, these patients are called partial reaction person.Since the influence to levels of acetylcholine discussed above, The compounds of this invention, and except that dysthymia disorders, it is damaged also to be expected can be used for treatment understanding.Clinical study shows, a kind of alpha-1 adrenergic receptor antagonist of Prazosin compound-be-reduced sleep disordered [Biol.Psychiatry, 61,928-934,2007].And then, the 5-HT of The compounds of this invention _2AAnd 5-HT _2CAntagonistic action is believed also calmness, sleep improves effect [Neuropharmacol.33,467-471,1994], therefore, The compounds of this invention can be used for treating partial reaction person, or in other words reduces with the part of The compounds of this invention to the treatment of the patients with depression person that will make the partial reaction.

Attention-deficient superfunction unusual (ADHD) is that modal neurobehavioral is one of unusual.ADHD is characterised in that following three existence of levying: society is damaged, link up damaged, and restricted, repetition or stereotypy behavior.ADHD starts from childhood or teenager usually, but that symptom may be extended to is adult.Atomoxetine is the unique non-stimulant [Drugs, 64,205-222,2004] that (U.S.) FDA approval at present is used for the ADHD treatment.Atomoxetine is a kind of NRI, and this shows that The compounds of this invention can be used for the treatment of ADHD.In addition, The compounds of this invention is because alpha-1 adrenergic acceptor discussed above and 5-HT ₂Antagonistic action and have sedation effect, this is of value to the treatment of ADHD.

Melancholia is a kind of specific hypotype of dysthymia disorders, often interrelates with severe depression; This of dysthymia disorders type is also referred to as the inhibitable type dysthymia disorders.Melancholia interrelates with anxiety, following fear, insomnia, poor appetite.The compound that suppresses thrombotonin such as both re-uptake of norepinephrine is Venlafaxine for example, the someone to be presented in severe depression and hypochondriacal patient's the treatment be especially effectively [Depres.Anxiety, 12,50-54,2000].As discussed above, produce 5-HT _2CThe compound of antagonistic action can improve Dopamine HCL, thereby such compound is expected to be used for the treatment of effectively melancholia [Psych-pharm.Bull., 39,147-166,2006].In addition, the alpha-1 adrenergic acceptor and the 5-HT of The compounds of this invention ₂Antagonistic action helps to make sleep normalizing, thereby described compound can be used for treating melancholia.

FDA has ratified these two kinds of SSRI of Sertraline and paroxetine recently and has been used for the treatment of stress abnormality (PTSD) after the wound.And then, 5-HT is arranged _2AThe compound of antagonistic activity also is an available, because they are expected to suppress anxiety, insomnia and quick-fried hot-tempered [Curr opinionInvest.Drug, 4,37-41,2003] among the PTSD patient.Therefore, The compounds of this invention is expected to can be used for treating PTSD.

Fever is a kind of symptom of getting in touch with the menopause transition phase.Some women may suffer from this, the degree that reaches its interference sleep or general activity and be necessary to treat.With estrogenic hormone replacement therapy is the ripe way of recent decades, yet people give expression to the concern to side effect, for example mammary cancer and heart trouble recently.Clinical trial with SSRI and SNRI shows that these compounds produce effect to fever, although not as oestrogenic hormon [J.Am.Med.Ass., 295,2057-2071,2006].Yet, fever with the compound that can suppress thrombotonin and/or suprarenin re-uptake for example the treatment of The compounds of this invention can be a kind of replacement therapy that can't accept or can not accept estrogenic women.

It is still to be confirmed unusual of a kind of its active drug Neo-Confucianism that sleep apnea or obstacle sleep apnea-hyponea syndrome or obstacle parahypnosis are breathed.Yet some zooscopies show, 5-HT ₃Antagonistic for example The compounds of this invention can be used for the treatment of intervention [Sleep, 21,131-136,1998 effectively; Sleep, 8,871,878,2001].

The someone shows 5-HT recently ₃Antagonistic odansetron can be used for the treatment of addiction and pure and mild drug abuse [Drug Alc.Depend., 84,256-263,2006 effectively; Pharmacol.Therapeut., 111,855-876,2006].This looks like is to support a kind of like this saying: 5-HT ₃Antagonistic for example The compounds of this invention can be used for the treatment of addiction, for example alcohol, Nicotine or carbohydrate addiction; And pure and mild drug abuse.

5-HT ₃Other suggestion purposes of antagonistic comprises vomiting, especially vomiting, the abnormal food appetite for example voracity and the pungency bowel syndrome (IBS) [Exp.Opin.Ther.Targets, 11,527-540,2007] of chemotherapy induction.

The The compounds of this invention of having given unique pharmacology performance is expected also to can be used for to treat that emotionality is unusual, dysthymia disorders, great depressibility are unusual, post-natal depression, dysthymia disorders, alzheimer's disease, psychosis or the Parkinson's disease, anxiety, the general anxiety that interrelate unusually with the two poles of the earth are unusual, social anxiety is unusual, obsessional idea and dystropy, panic unusually, panic attack, phobia, social phobia, agoraphobia and the stress urinary incontinence.

In one embodiment, the present invention relates to following treatment of conditions method: chronic pain, partial reaction person dysthymia disorders, the treatment-resistant dysthymia disorders, alzheimer's disease is familiar with damaged, ADHD, melancholia, PTSD, fever (hot flushes), sleep apnea, alcohol, Nicotine or carbohydrate addiction, substance abuse, alcohol or drug abuse, vomiting, abnormal food appetite, IBS, emotion is unusual, dysthymia disorders, great depressibility is unusual, post-natal depression, with the dysthymia disorders that the two poles of the earth interrelate unusually, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety is unusual, and social anxiety is unusual, obsessional idea and dystropy, panic unusual, panic attack, phobia, social phobia, agoraphobia or the stress urinary incontinence, and this method comprises the Compound I to patient's drug treatment significant quantity that its needs are arranged.In one embodiment, the described patient who treats because of above listed any disease is that diagnosis has described disease person earlier.

In one embodiment, the present invention relates to a kind of chronic pain methods of treatment, this method comprises the Compound I to patient's drug treatment significant quantity that its needs are arranged.In one embodiment, described chronic pain is selected from phantom limb pain, neuropathic, diabetic neuropathy, post herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), the HIV neuropathy, recombination region pain syndrome (CPRS), trigeminal neuralgia, surgical intervention (for example operation back analgesia), diabetic angiopathy, the capillary resistance or the diabetic symptom that interrelate with insulitis, the pain that interrelates with stenocardia, the pain that interrelates with menstruation, the pain that interrelates with cancer, toothache, headache, migraine, tension-type headache, trigeminal neuralgia, temporal-mandible joint syndrome, the myofascial pain Muscular injuries, fibromyalgia syndrome, bone and arthrodynia (osteoarthritis), rheumatoid arthritis, the rheumatoid arthritis and the oedema that cause by the wound that interrelates with burn, because osteoarthritis, osteoporosis, what bone shifted or unknown cause causes sprains or the pain of fracturing, gout, fibrositis, myofascial pain, thoracic outlet syndrome, (wherein backache is because of general for last backache or back pain, regional, or primary spondylopathy (radiculopathy)), pelycalgia, the ambition pain, non-ambition pain, the pain that interrelates with spinal cord injury (SCI), pain after the nervus centralis apoplexy, the cancer neuropathy, the AIDS slight illness, the sickle cell pain, or it is old ailing.

In one embodiment, described chronic pain is a neuropathic.

In one embodiment, described neuropathic is selected from hyperpathia, hyperpathia, neuropathy, diabetic neuropathy, neuritis, neurodynia, oxypathy, cusalgia and allodynia.

In one embodiment, the dosage of The compounds of this invention is about 0.001～about 100mg/kg body weight/day.

Typical case's oral dosage scope is about 0.001～about 100mg/kg body weight/day, better about 0.01～about 50mg/kg body weight/day, with one or more dosage 1～3 dosed administration for example.Precise dosage depends on administration frequency and mode, the sex of treatment target, age, body weight and overall state, sanatory character and seriousness, any companion's row disease and those skilled in the art the conspicuous other factors that will treat.

Adult's typical oral dosage scope is 1～100mg/ day compound of the present invention, for example 1～30mg/ day or 5～25mg/ day.Typically, once-a-day or twice administration 0.1～50mg, for example 1～25mg, as 1,5,10,15,20 or the 25mg The compounds of this invention, just can accomplish this point.

" the treatment significant quantity " of compound used herein means and is enough to cure, alleviate in a kind of treatment intervention that comprises described compound administration or part stops the quantity of the clinical manifestation of a certain given disease and complication thereof.Be enough to realize that the quantity of this point just is defined as " treatment significant quantity ".This term is also included within and is enough in a kind of treatment that comprises described compound administration to cure, alleviate or part stops the quantity of the clinical manifestation of a certain given disease and complication thereof.The significant quantity of each purpose all depends on this disease or the injured seriousness and the body weight and the overall status of this object.It being understood that determining and can being achieved as follows of suitable dosage: utilize normal experiment, make up the numerical value dot matrix, with test this dot matrix in different points, these are all in well-trained doctor's common skill scope.

" treatment " used herein this term means patient's management and nursing, overcomes a certain illness for example disease or unusual purpose to reach.This term intention comprises the full treatment spectrum of a certain given illness that this patient suffers from; for example this active compound administration is with relief of symptoms or complication, with the progress that delays this disease, unusual or illness, with alleviation or mitigation symptoms and complication and/or to cure or to eliminate this disease, unusual or illness and to prevent this illness; wherein prevention is appreciated that management and nursing for the patient overcome this disease, illness or unusual purpose to reach, and comprises that the active compound administration is to prevent the outbreak of this symptom or complication.But, the treatment of preventative (prevention) and therapeutic (healing) is two independent aspects of the present invention.The patient who treats better is a Mammals, especially human.

In one embodiment, the present invention relates to the present invention and be used for the purposes that following treatment for diseases with medicament is made: chronic pain, partial reaction person dysthymia disorders, the treatment-resistant dysthymia disorders, alzheimer's disease is familiar with damaged, ADHD, melancholia, PTSD, fever (hot flushes), sleep apnea, alcohol, Nicotine or carbohydrate addiction, substance abuse, alcohol or drug abuse, vomiting, abnormal food appetite, IBS, emotion is unusual, dysthymia disorders, great depressibility is unusual, post-natal depression, with the dysthymia disorders that the two poles of the earth interrelate unusually, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety is unusual, and social anxiety is unusual, obsessional idea and dystropy, panic unusual, panic attack, phobia, social phobia, agoraphobia or the stress urinary incontinence.

In one embodiment, the present invention relates to the present invention and be used for for example purposes of treatment of neuropathic with medicament manufacturing of chronic pain.

In one embodiment, the present invention relates to the purposes that the present invention is used as following treatment for diseases with medicament: chronic pain, partial reaction person dysthymia disorders, the treatment-resistant dysthymia disorders, alzheimer's disease is familiar with damaged, ADHD, melancholia, PTSD, fever (hot flushes), sleep apnea, alcohol, Nicotine or carbohydrate addiction, substance abuse, alcohol or drug abuse, vomiting, abnormal food appetite, IBS, emotion is unusual, dysthymia disorders, great depressibility is unusual, post-natal depression, with the dysthymia disorders that the two poles of the earth interrelate unusually, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety is unusual, and social anxiety is unusual, obsessional idea and dystropy, panic unusual, panic attack, phobia, social phobia, agoraphobia or the stress urinary incontinence.

In one embodiment, the present invention relates to be used as for example The compounds of this invention of treatment of neuropathic with medicament of chronic pain.

The compounds of this invention can be used as pure compound separately or with the combination of pharmaceutically acceptable carrier or vehicle, with single dose or multiple dose administration.Can be according to medical composition of the present invention with pharmaceutically acceptable carrier or thinner and any other known adjutant and vehicle according to conventional techniques Remington:The Science and Practice ofPharmacy for example, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, those disclosed preparation in 1995.

This medical composition especially can be for preparing via following any suitable administration: for example per os, per rectum, intranasal, through lung, through local (comprising), transdermal, in the brain pond, through intraperitoneal, transvaginal and non-through intestines (comprise through subcutaneous, through intramuscular, in stndon sheath, through intravenously with through intracutaneous) approach through cheek with through the hypogloeeis, the per os approach is preferably.What know is, preferably approach depend on the overall state of the object that will treat and age, the character and the selected effective constituent of the illness that will treat.

The oral administration medical composition comprises solid dosage for example capsule, tablet, dragee, pill, lozenge, powder and granularity.In the time of suitably, they can be prepared into dressing.

The oral administration liquid dosage form comprises solution, emulsus liquor, suspension liquor, syrup and elixir.

Non-frequent administrable medical composition comprises sterile aqueous and non-aqueous injectable solutions, disperse liquor, suspension liquor or emulsus liquor and use before the sterilized powder agent that will rebuild with sterile injectable solution or dispersion liquid.

Other suitable form of medication comprises suppository, sprays, ointment, emulsifiable concentrate, gelifying agent, inhalation, skin patch, implant etc.

Easily, The compounds of this invention is that its quantity is about 0.1～50mg, for example 1mg, 5mg, 10mg, 15mg, 20mg or 25mg The compounds of this invention with the unit dosage form administration that contains described compound.

For non-through the intestines approach for example through intravenously, in stndon sheath, through intramuscular and similarly administration, dosage is the pact of dosage that oral administration adopts about half typically.

Through enteral administration, can adopt the solution of The compounds of this invention in aseptic aqueous solution, aqueous propylene glycol, water-based vitamin-E or sesame oil or peanut oil for non-.So in case of necessity aqueous solution should be suitable buffered, and liquid diluent is earlier with imbibitions such as enough salt solutions or glucose carry out.The aqueous solution is specially adapted to through intravenously, through intramuscular, through subcutaneous and through the intraperitoneal administration.The sterile aqueous media that is adopted all obtains with those skilled in the art known standard technique easily.

The medical carrier that is suitable for comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.The example of solid carrier is lactose, carclazyte, sucrose, cyclodextrin, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid and Mierocrystalline cellulose lower alkyl ether.The example of liquid vehicle is syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Then, by merging medical composition that The compounds of this invention and pharmaceutically acceptable carrier form easily to be applicable to various formulation administration of disclosed route of administration.

Be applicable to peroral administration prescription of the present invention can be used as separate unit for example capsule or tablet provide, each unit contains the effective constituent of predetermined amount, and can comprise suitable vehicle.And then formula of oral can be the solution in powder or granule, water-based or the non-aqueous liquid or the form of suspension liquor or oil-in-water-type or water-in-oil-type milky liquid liquor.

If solid carrier is used for oral administration, then said preparation can be tablet, places hard gelatin capsule, is powder or piller form, is lozenge or lozenge form etc.The quantity of solid carrier can be different, but normally about 25mg～about 1g.

If the use liquid vehicle, then said preparation can be for example form of water-based or non-aqueous liquid suspension liquor or solution of syrup, emulsus liquor, soft capsule or sterile injectable liquid.

Tablet can be prepared as follows: with effective constituent and common adjutant and/or mixing diluents, be accustomed to the use of normal tabletting machine subsequently and compress this mixture.The example of adjutant or thinner comprises: W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Be usually used in any other adjutant of this type of purpose or additive for example tinting material, rectify smelly correctives, sanitas etc. and also can use, as long as they are compatible with this effective constituent.

The capsule that comprises The compounds of this invention can be prepared as follows: a kind of powder that comprises described compound is mixed with Microcrystalline Cellulose and Magnesium Stearate, and described powder is packed in a kind of hard capsule.Randomly, described capsule can be used suitable pigment coloring.Typically, capsule will comprise 0.25～20% The compounds of this invention, for example 0.5～1.0%, 3.0～4.0%, 14.0～16.0% The compounds of this invention.These intensity can carry 1,5,10,15,20 and the 25mg The compounds of this invention easily with unit dosage form.

The injection solution agent can be prepared as follows: effective constituent and possibility additive are dissolved in part solvent for injection, the better sterilized water, this solution is adjusted to desired volume, make this solution sterilization, and it is filled in suitable ampoule or the phial.The usual in the industry any suitable additive that uses is isotonic agent, sanitas, antioxidant etc. for example.

Compound I prepares can be described in WO 2003/029232.The salt of Compound I can by add suitable acid, subsequently separate out the precipitation prepare.Precipitation can be by carrying out such as cooling off, remove solvent, the another kind of solvent of interpolation or its mixture.

All reference of quoting, comprise that publication, patent application and patent all classify this paper reference as in full with it herein, and reach such degree: point out to classify as reference individually, particularly and list herein every piece of reference of (to the full extent allowed by law) in full in, regardless of do, any specific file include that provides separately in other place herein.

In describing category of the present invention, the use of " ", " a kind of " and " being somebody's turn to do " these terms and similar object of reference is appreciated that to be while encompasses singular and plural number, unless point out in addition herein or context obviously contradicts.For example, " compound " this phrase is appreciated that for meaning various " compound " of the present invention or specifically described aspect, unless point out in addition.

Unless point out in addition, otherwise all exact numerical values recited that provide herein all be corresponding approximation representative (for example, provided, about all definite exemplary numerical value of a certain specificity factor or mensuration, can be interpreted as when also providing suitable corresponding approximate test with " pact " modification).

Use " comprising " with reference to one or more key elements herein, " have ", " comprise ", or " containing " such term is to the description of the present invention any one or many aspects, intention provides " consisting of ", " basic composition is ", or the support of the one or more similar aspect of the present invention of " comprising in fact " these one or more key elements, unless context (for example has explanation or obvious contradiction in addition, the composition that is described as comprising a certain specific factor herein should be understood to also describe a kind of composition of being made up of this key element, unless context has explanation or obvious contradiction in addition).

Embodiment

Analytical procedure

X-ray powder diffraction (XRPD) uses CuK α 1 radiation detection on a PANaly-tical X ' Pert PRO X-ray diffractometer.Sample is to be that 5～40 ° reflection mode uses X ' celerator detector to measure with 2 θ scopes.Elementary composition (CHN) measures on the Elementar Vario EL instrument with Elementar company.Each measure that to use about 4mg sample, result be that mean value as 2 mensuration provides.

The HBr salt of embodiment 1a Compound I

Interpolation 545mL 33wt% HBr/AcOH in oily 4-(2-is to the toluene sulfenyl phenyl) piperidines-1-carboxylic acid, ethyl ester of 442g stirring and heating (about 45 ℃) a little (5.7M, 2.5eqv.).This mixing provides 10 ℃ of heat releases.After final the interpolation, reaction mixture is heated to 80 ℃ and keep 18h.Sampling is analyzed with HPLC, and must add 33wt%HBr/AcOH again if do not finish then.Otherwise, this mixture is cooled to 25 ℃, make product 4-(2-is to toluene sulfenyl phenyl) piperidines hydrobromate separate out precipitation.Behind 25 ℃ of 1h, in thick suspension, add the 800mL diethyl ether.Continue to stir 1h again, then this product filtering separation, wash, spend the night with the 400mL diethyl ether 40 ℃ of vacuum-dryings.The hydrobromate of Compound I is separated as white solid.

The HBr salt of embodiment 1b Compound I

2-(4-toluene sulfenyl) phenyl-bromide

A stirring, have in the reactor that nitrogen covers, (NMP 4.5L) uses nitrogen purging 20min to N-Methyl pyrrolidone.Interpolation 4-methylbenzene thiophenol (900g 7.25mol), adds 1 then, and the 2-dibromobenzene (1709g, 7.25mol).At last, (813g is 7.25mol) as the final reaction thing to add potassium tert.-butoxide.Reaction is heat release, makes the temperature of reaction mixture rise to 70 ℃.In 2～3h, reaction mixture is heated to 120 ℃ then.With the reaction mixture cool to room temperature.Interpolation ethyl acetate (4L) and sodium chloride aqueous solution (15%, 2.5L).This mixture stirs 20min.With aqueous phase separation, extract with another part ethyl acetate (2L).With aqueous phase separation, organic phase merges, with sodium chloride solution (15%, 2.5L) washing.Organic phase is separated, used dried over sodium sulfate, reduction vaporization, provide a kind of red oil that contains 20～30%NMP.This oily matter is diluted to 2 times of volumes with methyl alcohol, and mixture is refluxed.Add methyl alcohol again, until obtaining a kind of limpid red solution.Cool to room temperature blows slowly on this solution edge joint kind limit.Product crystallizes into the canescence crystal, with its filtering separation, with methanol wash, in vacuum drying oven in 40 ℃ of dryings until constant weight.

4-hydroxyl-4-(2-(4-toluene sulfenyl) phenyl) piperidines-1-carboxylic acid, ethyl ester

Have in the stirred reactor that nitrogen covers at one, (600g 2.15mol) is suspended in the heptane (4.5L) with 2-(4-toluene sulfenyl) phenyl-bromide.At room temperature, with the 10min time add 10M BuLi/ hexane (235mL, 2.36mol).Notice and have only small heat release.This suspension stirs 1h at normal temperatures, is cooled to-40 ℃ then.Be no faster than make temperature of reaction remain on speed below-40 ℃ add the 1-ethoxycarbonyl-4-piperidone be dissolved among the THF (1.5L) (368g, 2.15mol).When reaction has reached when finishing, make it go back up to 0 ℃, add 1M HCl (1L), and remain on the temperature below 10 ℃.Sour water is separated, extracts with ethyl acetate (1L).Organic phase merges, with sodium chloride solution (15%, 1L) extraction.Organic phase with dried over sodium sulfate, be evaporated to a kind of hypocrystalline material.(250mL) makes its slurryization, leaches with ether.In vacuum drying oven in 40 ℃ of dryings until constant weight.

4-(2-(4-toluene sulfenyl) phenyl) piperidines-1-carboxylic acid, ethyl ester

With trifluoroacetic acid (2.8kg, 24.9mol) and triethyl-silicane (362g 3.1mol) adds in the reactor that the high-level efficiency agitator arranged.(462g 1.24mol) adds via powder funnel piperidines-1-carboxylic acid, ethyl ester in batches with 4-hydroxyl-4-(2-(4-toluene sulfenyl) phenyl).Reaction is heat release a little.Temperature rises to 50 ℃.After adding end, in 18h, allow reaction mixture rise to 60 ℃.Allow the reaction mixture cool to room temperature.Add toluene (750mL) and water (750mL).Organic phase is separated, and water extracts with another part toluene (750mL).Organic phase merges, (15%, 500mL) dried over sodium sulfate is used in washing with sodium chloride solution.With sodium sulfate leach, filtrate evaporated under reduced pressure, obtain a kind of red oil, the latter further processes at next step.

4-(2-(4-toluene sulfenyl) phenyl) piperidines hydrobromate

In a stirred reactor, allow (40%, 545mL 3.11mol) mixes from the thick 4-of red oily (2-(4-toluene sulfenyl) phenyl) piperidines-1-carboxylic acid, ethyl ester of embodiment 3 and Hydrogen bromide/acetate.This mixture is at 80 ℃ of heating 18h.With the reaction mixture cool to room temperature.In this cooling period, product crystallizes out.At room temperature behind the 1h, ether (800mL) is added in this reaction mixture to mixture restir 1h.With product leach, with ether washing, in vacuum drying oven in 50 ℃ of dryings until constant weight.

The recrystallization of the HBr salt of embodiment 1c Compound I

With the HBr salt of the compound 1 of 10.0g such as above preparation at 100mL H ₂Reflux among the O.This mixture becomes limpid and abundant dissolving at 80～90 ℃.In this clear solution, add the 1g charcoal, continue backflow 15min, filter, make it spontaneous cool to room temperature then.In this cooling period, the precipitation of white solid takes place, and suspension is at stirring at room 1h.Filter, spend the night, the HBr acid salt of 6.9g (69%) compound 1 takes place 40 ℃ of vacuum-dryings.See the XRPD of Fig. 1.Ultimate analysis: 3.92%N, 59.36%C, 6.16%H (theoretical value: 3.85%N, 59.34%C, 6.09%H).

The preparation of embodiment 1d free alkali stock solution

With 500mL ethyl acetate and 200mL H ₂The mixture of O adds in the HBr salt of 50g Compound I, produces a kind of two-phase slurry.Add the dense NaOH of about 25mL in this slurry, this causes generating a kind of limpid two phase liquid (actual measurement pH is 13～14).This solution vigorous stirring 15min separates organic phase.Organic phase 200mL H ₂O washs, uses Na ₂SO ₄Dry, filter, 60 ℃ of vacuum-evaporation, produce the almost colourless buttery free alkali of 38g productive rate (99%).

Use acetic acid ethyl dissolution this oily matter of 10g and volume is adjusted to 150mL, produce 0.235M stock solution in a kind of ethyl acetate, use wherein 1.5mL aliquot sample (100mg) free alkali.

Use 96vol% EtOH dissolving this oily matter of 10g and volume is adjusted to 100mL, produce 0.353M stock solution among a kind of EtOH, use wherein 1.0mL aliquot sample (100mg free alkali).

Embodiment 1e uses the salt of free alkali stock solution to generate

Given aliquot sample is placed test tube, and add appropriate amount of acid pointed in the table 1 while stirring.If this acid is a kind of liquid, then adds its net phase, otherwise it is dissolved in interpolation then in the given solvent.Spend the night in mixing and post precipitation continuation stirring, filter the collecting precipitation thing.Before being 30 ℃ of vacuum-dryings, take out a little, at room temperature dry and do not find time with reference to sample.Why comprising this program, is for the test solvent compound.The results are shown in Table 1 for some.The XRPD diffractogram is shown in Fig. 1～22, and list in the table 2 selected peak position.Table 3 show The compounds of this invention in water solubleness and the pH in the resultant saturated solution." throw out " hurdle shows after this solubility test that isolating throw out is whether identical with institute dissolved compound, and this point is the indication that generates hydrate.

Table 1

Acid (alkali: acid)	MW(g/mol)	Acid amount (mg or μ l)	Solvent	CHN (measured value)	CHN (theoretical value)
						Palmitinic acid, hexadecanoic acid 1:1	256.42	905	EtOAc	75?36 9.77 2?46	75.64 9.9 2.6
DL-lactic acid, DL-2-hydroxy-propionic acid 1:1	901	31.8	EtOAc	66.88 7.26 3.52	67.53 7.29 375
						Hexanodioic acid, 1,6-hexanodioic acid 1:1	146.14	51.6	EtOAc	66?08 7.23 2?98	67?1 7.27 3.26
Hexanodioic acid, 1,6-hexanodioic acid 2:1	14614	258	EtOAc	70?66 7.32 3?82	70.75 7.35 3.93
						Fumaric acid 1:1	116.01	40.9	EtOH	65?71 6.41 3?35	66.14 6.31 3.51

Acid (alkali: acid)	MW(g/mol)	Acid amount (mg or μ l)	Solvent	CHN (measured value)	CHN (theoretical value)
						Pentanedioic acid, 1,5-pentanedioic acid 1:1	132?12	46.6	EtOAc	66.09 6.97 3?2	66?48 7.03 3?37
Propanedioic acid 1:1	104?1	36.7	EtOAc	65?04 6?53 354	65.09 6.5 3?62
						Oxalic acid 1:1	90 1	31.8	EtOH	64?28 6.41 3?61	64.32 6?21 3.75
Suberic acid, 1,8-suberic acid 2:1	202?02	35.6	EtOAc	71.79 7?86 3?58	71?83 7?86 3.64
						Succsinic acid, 1,4-Succinic Acid 2:1	118.1	20.8	EtOAc	65.65 6?86 3?4	65 80 6 78 3 49 (the 1:1 salt that generated)
L MALIC ACID, L-2-hydroxy-butanedioic acid 1:1, α	134.1	473	EtOAc	62?87 6?20 3.22	63?29 6.52 3.36
						L MALIC ACID, L-2-hydroxy-butanedioic acid 1:1, β	134?1	47.3	EtOH	62?99 6?66 3?13	63?29 6?52 3.36
D-tartrate, D-2,3-dyhydrobutanedioic acid 1:1	150.1	53.0	EtOH	60?67 6?4 3?07	60?95 6.28 3?23
						L-aspartic acid 1:1	133?1	47.0	EtOH	59.31 67 71 (containing excess acid)	63?43 6?78 6?73
L-glutamic acid 1:1	165?15	583	EtOH	56 38 688 735 (containing excess acid)	56 46 6.94 7.06 (for 1:1 salt and sour monohydrate 1:1)
						Citric acid 2:1	192.13	33.9	EtOAc	65?93 672 344	66?46 6.64 3?69
HCl/Et 2O1.1	2M	1764	EtOH
						Phosphatase 11: 1	14.7M	24.0	EtOAc	55.79 6.47 3.43	56?68 6.34 3?67

The selected X ray of table 2 peak position (° 2 θ), 2:1 means 2 alkali/1 acid, all values is all ± 0.1 °

					Palmitate	7.00	16.34	22.73	28?21
Stearate	6?70	15?52	21.81	28?91
					Lactic acid salt	5?30	8.18	9?44	17.24
The lactic acid salt hydrate	11?67	16.70	18?25	21?76
					Hydroxyisobutyrate	5?09	16.60	20.38	27?37
Suberate	7?18	12.53	21?11	24.19
					Adipate 2:1	8.03	13.52	17?90	24.60
Adipate 1:1 α	9.33	14.01	18?72	20.63
					Adipate 1:1 β	15.69	21?53	25.81	31.18
Glutarate 1:1	9.39	11?70	14?05	14?58
					Succinate 1:1	11?74	14?33	17.75	26.84
Fumarate 1:1	8?90	11?47	19.25	22.33
					Fumarate 2:1	8?49	12.48	17.78	23?97
Maleate 1:1	12.11	15?51	17?48	22?53
					Maleate 1:1 hydrate	12.81	18?76	20?53	27.31

Malonate α	10.77	16.70	19.93	24.01
					Malonate β	6?08	10.11	18.25	20?26
Aspartate	11.05	20.1	20?60	25?00
					The aspartic acid salt hydrate	7.80	13.80	14.10	19?63
Glutaminate	7.71	14.01	19?26	22?57
					Oxalate	14.68	17.45	19?50	23.90
Malate 1:1 α	8.30	12.04	17.23	20?67
					Malate 1:1 β	10?91	12.87	14.14	26.16
The malate hydrate	12?30	15.56	19.56	23.30
					D-tartrate (from EtOH)	5.08	17.18	19.42	22?10
Hydrochloride	12.44	16.72	19.45	25?02
					Hydrobromate	6.08	14?81	19.26	25?38
Hydrobromate 1-PrOH solvate	657	13.12	19.07	24.77

Table 3

Acid (alkali: acid)	Solubleness (mg/ml)	Crystallization pH	Throw out
				Palmitinic acid, hexadecanoic acid 1:1	0.4	8.6	=beginning
DL-lactic acid, DL-2-hydroxy-propionic acid 1:1	>150	61	=beginning (evaporation back)
				Hexanodioic acid, 1,6-hexanodioic acid 1:1	2.5	4.0	Part 2:1 salt
Hexanodioic acid, 1,6-hexanodioic acid 2:1	1.0	7.8	=beginning
				Fumaric acid 1:1	02	3.3	=beginning
Pentanedioic acid, 1,5-pentanedioic acid 1:1	13	4.6	=beginning
				Propanedioic acid 1:1 (α)	5.2	40	=new form (β)
Oxalic acid 1:1	1.1	2.7	=beginning
				Sebacic acid, 1,8-octane diacid 2:1	0.7	5.5	=beginning
Succsinic acid, 1,4-Succinic Acid 2:1	2.0	40	Hydrate
				L MALIC ACID, L-2-hydroxy-butanedioic acid 1:1, β	2.8	40	Hydrate
D-tartrate, D-2,3-dyhydrobutanedioic acid 1:1	1.8	3.5	Hydrate
				The L-aspartic acid	39	4.3	Hydrate
L-glutamic acid 1:1	>35	4.6	-
				Citric acid 2:1	0.5	47	=beginning
Phosphatase 11: 1	6.0	2.0	？
				HCl	45	6.8	=beginning
HBr	2.4	7.0	=beginning

Embodiment 2A thrombotonin (5-HT) and norepinephrine (NE) re-uptake suppress

The aliquot sample of test compound and rat cortical process contact preparation is cultivated 10min at 37 ℃, add then [ ³H] NE or [ ³H] 5-HT (ultimate density 10nM).The picked-up of non-obligate is to measure in the presence of its Shu Pulun of 10 μ M or citalopram, and total intake is to measure in the presence of buffer reagent.Each aliquot sample is cultivated 15min/37 ℃.After the cultivation, the synaptosome absorption [ ³H] NE or [ ³H] 5-HT is to use a kind of Tomtec cell harvestor program, by via the Unifilter GF/C filtering separation of dipping 30min in 0.1%PEI in advance.Filter wash, on a Wallac MicroBeta counter, count.

To NET, The compounds of this invention demonstrates IC ₅₀Value is 23nM.To SERT, The compounds of this invention demonstrates IC ₅₀Value is 8nM.

Embodiment 2B 5-HT _2A Antagonistic action

Test the affinity of The compounds of this invention, and find that it demonstrates at 5-HT serotonin receptor _2AAffinity (K is arranged on the acceptor ₁Antagonism performance 54nM).This affinity is from Y=100/ (1+10 ^{(X-log IC} ₅₀ ⁾) calculate, Y represents the % combination in the formula, and X represents compound concentration.Use 5 compound concentrations (1,10,30,100,1000nM) calculate IC ₅₀Value.Ki is from Cheng Prusoff equation Ki=IC ₅₀/ (1+ ([L]/Kd)) calculates.Affinity is determined with MDLPharmaservices classification number 271650.

At expressing human 5-HT _2AIn the mammalian cell of acceptor, The compounds of this invention demonstrates the competitive antagonism performance.This compound and 5-HT _2AKi＜the 100nM of receptors bind, and in function test, the interior Ca that preserves of this compound antagonism 5-HT brings out, born of the same parents ²⁺Release, Kb is 67nM.Schild analyzes and disclosed Kb is the competitive antagonism of 100nM.

Experiment is carried out as follows: tested preceding 2 or 3 days, will express 250fmol/mg people 5-HT _2AThe Chinese hamster ovary celI of acceptor is coated on the plate in the density that experiment produced single fused layer the same day being enough to.This cell is at one 5% CO ₂, add dyestuff (Ca in 95% humidity, 37 ℃ of thermostat containers ²⁺Test kit, Molecular Devices company) 60min.Basis fluorescence is the FLIPR with a fluoroscopic image card reader or Molecular Devices company (California, USA Sunnyvale) ³⁸⁴, with the transmitting boundary monitoring of the excitation wavelength of 488nm and 500～560nm.Laser intensity is set to proper level, to obtain the basic value of about 8000～10000 flat fluorescents.The variation of basis fluorescence should＜10% EC50 value is to use the test compound progressive concentration evaluation of containing at least 3 orders of magnitude.Estimated pA ₂Value is to challenge the full dose-response curve of 5-HT with 4 different compound concentrations (150,400,1500 and 4000nM).Also estimated the Kb value, with EC with 5-HT ₈₅2 order of magnitude concentration of challenge substances.Substances 5min before 5-HT adds in this cell.Ki value Cheng-Prusoff Equation for Calculating.

Embodiment 2C 5-HT _3A Receptor antagonism

Expressing the people with number 5-HT _3AIn the ovocyte of acceptor, 5-HT is with EC ₅₀For 2600nM has activated stream.This stream can be used classical 5-HT ₃Antagonistic is the ondansetron antagonism for example.Ondansetron demonstrates the Ki value below the 1nM in this system.The compounds of this invention (demonstrates strong antagonistic action (IC at lower concentration during 0.1nM～100nM) ₅₀～10nm/Kb～2nM), and when (100～100000nM) demonstrate excited performance (EC when using with greater concn ₅₀～2600nM), reach about 70～80% max-flow of max-flow that 5-HT itself brings out.Expressing rat with number 5-HT _3AIn the ovocyte of acceptor, 5-HT has activated EC ₅₀Be the stream of 3.3 μ M.These experiments are carried out as follows.Ovocyte is to take out from the adult female Xenepus laevis with 0.4% MS-222 anesthesia, 10～15min with surgical method.Then, these ovocytes are at OR2 buffer reagent (82.5mN NaCl, 2.0mM KCl, 1.0mM MgCl ₂With 5.0mM HEPES, at room temperature clear up 2～3h with 0.5mg/mL collagenase (1A type, Sigma-Aldrich company) in pH7.6).The ovocyte of folliculus layer is removed in selection, at improved Barth ' s salt solution buffer reagent [88mM NaCl, 1mM KCl, 15mM HEPES, 2.4mM NaHCO ₃, 0.41mMCaCl ₂, 0.82mM MgSO ₄, 0.3mM Ca (NO ₃) ₂] the middle 24h that cultivates, this buffer reagent has replenished 2mM Sodium.alpha.-ketopropionate, 0.1U/L penicillin and 0.1 μ g/L Streptomycin sulphate.Choice phase IV-IV ovocyte, injection 12～48nL contains 14～50pg people 5-HT _3AThe anhydrous nuclease of the cRNA of acceptor coding is used for electrophysiological recording (injection back 1～7 day) 18 ℃ of cultivations until them.People 5-HT will be arranged ₃The ovocyte of expression of receptor is put in the 1mL bath, with woods Ge Shi buffer reagent (115mM NaCl, 2.5mM KCl, 10mM HEPES, 1.8mM CaCl ₂, 0.1mM MgCl ₂, pH7.5) perfusion.Cell with the plug agar 0.5～1M Ω electrode that contains 3M KCl and by GeneClamp 500B amplifier add-90mV voltage transplants.This ovocyte is constantly with the perfusion of woods Ge Shi buffer reagent, and with medicament administration in this perfusion liquid.5-HT stimulant solution was used 10～30 seconds.5-HT ₃The drug effect of receptor antagonist is to investigate by measuring concentration-response that 10 μ M 5-HT are stimulated.

Embodiment 2D α _1A Receptor antagonism

The compounds of this invention is carried out α _1AThe compatibility test of acceptor finds that it demonstrates the antagonism performance, to α _1AAcceptor has medium affinity (Ki=34nM).

The experiment same day (seeing following) about the description of membrane prepare film is thawed, in buffer reagent with a Ultra Turrax homogenizing, and be diluted to desired concentration (5 μ g/ holes～5 μ g/900 μ L, preserve on ice until the use).

Experiment starts from 50 μ L test compounds, 50 μ L[ ³H]-mixing of Prazosin and 900 μ L films, this mixture is cultivated 20min at 25 ℃.Non-obligate combination is to determine in the presence of 10 μ M WB-4101, and total binding is to determine in the presence of buffer reagent.After the cultivation, use Tomtec cell harvesting program (D4.2.4),, the bonded part is separated with unconjugated part by via the Unifilter GF/B filtration of dipping 30min in 0.1%PEI in advance.96 hole strainers add 35 μ L scintillation solution/holes with the ice-cold buffer reagent washing of 1mL 3 times, 50 ℃ of dryings, in this strainer.The bonded radioactivity is counted on Wallac OY 1450 MicroBeta.Affinity is from Y=100/ (1+10 (X ^{-log IC} ₅₀ ⁾) calculate, Y represents the % combination in the formula, X represents compound concentration.The compound concentration that 2 orders of magnitude are contained in use calculates IC ₅₀Value.Ki is from Cheng-Prusoff equation Ki=IC ₅₀/ (1+ ([L]/Kd)) calculates.

In function test, the The compounds of this invention antagonism suprarenin Ca that bring out, storage in the born of the same parents ²⁺Release, it is antagonistic that function test discloses compound.

These experiments are carried out as the following stated basically.

All cells all is in the DMEM substratum of having added 10% BCS, 4mM L-glutaminate (or under the situation at COS-7 2mM) and 100 units/mL penicillin+100 μ g/mL Streptomycin sulphates, at 37 ℃ and 5%CO ₂Cultivate.

In test preceding 24 hours, will express people α _1A-7The Chinese hamster ovary celI of acceptor is inoculated in the black wall microlitre plate in 384 holes that scribble poly--D-Methionin.With substratum suck, each cell in test buffer agent (50 μ L/ hole) at 5%CO ₂In, add dyestuff 1h at 37 ℃ with 1.5 μ M Fluo-4, this test buffer agent consist of Hank ' s balanced salts solution (138mM NaCl, 5mM KCl, 1.3mM CaCl ₂, 0.5mM MgCl ₂, 0.4mM MgSO ₄, 0.3mM KH ₂PO ₄, 0.3mMNa ₂HPO ₄, 5.6mM glucose) add 20mM HEPES pH7.4,10.05%BSA and 2.5mM benemid.Discard after the superfluous dyestuff, cell equals 45 μ L/ holes (for antagonistic test 30 μ L/ holes) with test buffer agent washing, layering, final volume.Under the situation of antagonistic assessment, add antagonistic or supporting agent this moment, as 4 times of 15 μ L aliquot sample in the 4% DMSO buffer reagent of containing, cultivate 20min subsequently to ultimate density (final DMSO=1%).Basis fluorescence is with a fluorometric imaging plate reader or Molecular Devices company (Sunnyvale, FLIPR CA) ^TMWith the excitation wavelength is that 488nm, transmitting boundary are that 500～560nm monitors.Adjust the laser excitation energy, make that basic fluorescence reading is about 8000 relative fluorescence units (RFU).Then, at room temperature with stimulant activated cell with test buffer agent (15 μ L) dilution, in scheduling to last 2.5min with 1.5 seconds interval measurement RFU.Calculate maximum variation of fluorescence in each hole.Analyze from maximum fluorescence variation deutero-concentration-response curve with non-linear regression method (Hill equation).In order to determine antagonistic action, after cultivating 20min, adds (as mentioned above) compound the standard stimulant thrombotonin of fixed concentration.

Embodiment 2E Dopamine HCL improves

The single injected dose of The compounds of this invention has improved the outer DA level of born of the same parents in the rat prefrontal cortex with relying on.8.9mg/kg, for baseline shown in Figure 23, make the DA level improve about 100% and 150% respectively with the hypodermic The compounds of this invention of 18mg/kg.Quantity is calculated as free alkali.

Method

Use the male Sprague-Dawley rat of initial weight 275～300g.These animals isolated with 12 hours bright/dark cycles under the controlled condition of regulation room temp (21 ± 2 ℃) and humidity (55 ± 5%), and bait and tap water can be taken arbitrarily.Treatment experiment in three days is used be the infiltration pony pump (Alzet, 2ML1).The can under aseptic condition of these pumps, and under Sevoflurane anesthesia, implant subcutaneous.Experiment is to carry out with the pony pump of implanting.Blood sample collection when experiment finishes is used to measure the blood plasma level for the treatment of the back test compound in 3 days.

Surgical operation and microdialysis experiment

Experimental animal is implanted in the hippocampus with stereo positioning technique with hypnorm/dormicum (2mL/kg) anesthesia, brain inner catheter (CMA/12), the dialysis probes point is positioned in the abdomen hippocampus (coordinate: 5.6mm before the bregma, side direction-5.0mm, belly is to dura mater 7.0mm); Or be positioned in the prefrontal cortex (coordinate: 3.2mm before the bregma, side direction 3.0mm, belly is to dura mater 4.0mm).Use anchoring screw and acrylic acid or the like cement to fix this conduit.Animal heat.Animal heat is with the rectal prob monitoring and remain on 37 ℃.Allow animal with the rehabilitation from surgical operation of 2 day time, encage separately.Test the same day, microdialysis probe (3mm is long for CMA/12,0.5mm diameter) is inserted via conduit.These probes are connected on the micro syringe pump via a kind of two channels swivel joint.Filtering Ringer's solution (145mM NaCl, 3mM KCl, 1mM MgCl ₂, 1.2mMCaCl ₂) to the perfusion of microdialysis probe start from this probe face insert in the brain before, and continue at whole experimental session with the steady flow dose rate of 1 (1.3) μ L/min.Stablize after the 180min, start experiment.Per 20 (30) min collect the dialysis thing.

After the experiment, slaughter rat,, place with the checking probe with its brain taking-up, freezing, section with the method for beheading.

The dialysis thing is analyzed

The concentration of Dopamine HCL is analyzed with Electrochemical Detection by means of HPLC in the dialysis thing.One amine is isolating with anti-phase liquid chromatography (ODS 150 * 3mm, 3 μ M).Dopamine HCL: mobile phase consists of 90mM NaH ₂PO ₄, the hot sodium sulfonate of 50mM Trisodium Citrate, 367mg/L1-, 50 μ M EDTA and 8% acetonitrile (pH4.0), fluence rate is 0.5mL/min.Electrochemical Detection is to use coulometric detector to finish, potential setting in 250mV (protection battery be set in 350mV) (Coulochem II, ESA).

Embodiment 2F vagusstoff improves

Experimental design is intended to assess the influence of The compounds of this invention to the outer level of born of the same parents of vagusstoff in the movable rat prefrontal cortex of freedom.

Use male Wistar rat (280～350g; Harlan, Zeist, Holland) experimentize.Rat individually is isolated from plastics cage (in 30 * 30 * 40cm), but can at random obtain bait and water.

Rat use isoflurane (2%, 400mL/min N ₂O, 400mL/min O ₂) anesthesia.Use lignocaine (10%m/v) to carry out toponarcosis.Put every animal into a three-dimensional positioning framework (Kopf instrument company, the U.S.), and the rat brain atlas that uses Paxinos and Watson (1982) inserts the I-shape probe (Hospal AN 69 films, 4mm exposed surface) of family manufacture in the central prefrontal cortex (mPFC).The coordinate of probe tip is mPFC[AP=3.4mm, L=-0.8mm, V=5.0mm].Then, this probe uses dental cement and screw retention to skull.Flunixin (1mg/kg, subcutaneous injection) is as the back anodyne administration of performing the operation.

Experiment was carried out after surgical operation in 24～48 hours.Testing the same day, each rat is connected on little filling pump (CMA102) with deflection PEEK tubing, and this dialysis probes contains 147mM NaCl, 3.0mM KCl, 1.2mM CaCl with the fluence rate perfusion of 1.5 μ L/min ₂, and 1.2mMMgCl ₂Woods Ge Shi buffer reagent.With 30min at interval, the microdialysis sample collection in the small-sized phial that contains 55 μ L0.02M formic acid, is used to measure vagusstoff.Sample by a kind of automatic fraction collector (CMA 142) and in-80 ℃ of storages until analysis.After experiment is finished rat is slaughtered.Brain is taken out, solidifies in paraformaldehyde solution (4%m/v).The location of every probe is to carry out the histology checking by the crown section of making brain according to Paxinos and Watson (1982) atlas.

Test compound is dissolved in 10% 2-OH propyl group-beta-cyclodextrin, carries out administration via the subcutaneous injection of 5mL/kg volume with various dose.

The concentration of vagusstoff detects with HPLC and tandem mass spectrometry (MS/MS) to be determined.

Each aliquot sample (25 μ L) is expelled on the HPLC post with automatic sample syringe (Perkin Elmer instrument company, series 200).Chromatographic separation is at anti-phase a 150 * 2.00mm (4 μ m) analytical column (Phenomenex Synergy MAX-RP; Bester) carry out on; the latter is by 4 * 2.0mm guard column (Phenomenex Synergy MAX-RP AJO-6073; Bester) protection, two posts all remain on 30 ℃ temperature.Mobile phase (degree of grade) is formed (UP:ACN:TFA=95.0:0.5:0.1v/v/v%) by super purified water (UP), acetonitrile (ACN) and trifluoroacetic acid (TFA).Mobile phase is with the fluence rate of 0.300mL/min this system that flows through by a HPLC pump (PerkinElmer instrument company, serial 200 micropumps).

This LC/MS analyzes and is to use a kind of API4000MS/MS system to carry out, and this system is by an API4000MS/MS detector and Turbo Ion Spray interface (both are all available from Dutch Applied Biosystem company).Data gathering is carried out in the cationization mode, and ionspray voltage is set in 5.5kV, and the spraying gun gaseous tension is 50psig (on 0～90 a SCIEX yardstick), and probe temperature is 600 ℃.This instrument moves in multiple-reaction monitoring (MRM) mode that is used to detect vagusstoff (precursor 146.1Da, product 86.8Da).Collision energy is 21.0eV, and collision gas (nitrogen) pressure remains on 7 (on 0～12 SCIEX yardsticks).Data Analyst ^TMData system (Applied Biosystem, version 1.2) calibration and quantitative.

Get 2 of aberration rate＜50% in succession the microdialysis sample as baseline values and be set in 100%.The variation of vagusstoff concentration is expressed as the percentage of baseline in the same target body.

Data presentation is in Figure 24.

Embodiment 2G vagusstoff improves

Experimental design gets can assess the influence of The compounds of this invention to the outer level of vagusstoff born of the same parents in the prefrontal cortex of the movable rat of freedom and the abdomen hippocampus.

Use the male Sprague-Dawley rat of initial weight 275～300g.These animals isolated, and can obtain bait and water arbitrarily with 12 hours bright/dark cycles under the controlled condition of regulation room temp (21 ± 2 ℃) and humidity (55 ± 5%).

Surgical operation and microdialysis experiment

Rat is anaesthetized with hypnorm/dormicum (2mL/kg), and brain inner catheter (CMA/12) implanted in the hippocampus with spatial localization method, be intended to the dialysis probes tip is positioned (coordinate: 5.6mm behind the bregma in the abdomen hippocampus, side direction-5.0mm, belly is to dura mater 7.0mm) or be positioned (coordinate: 3.2mm before the bregma in the prefrontal cortex, side direction 0.8mm, belly is to dura mater 4.0mm).Use anchoring screw and acrylic acid or the like cement to fix this conduit.The body temperature of this animal is with the rectal prob monitoring and remain on 37 ℃.Allow rat rehabilitation 2 days after operation, encage separately.Test the same day, microdialysis probe (CMA/12,0.5mm diameter, 3mm length) is inserted via conduit.

These probes are connected on the micro syringe pump via the two channels swivel joint.The filtration Ringer's solution (145mM NaCl, 3mM KCl, the 1mM MgCl that contain 0.5 μ M prostigmin(e) ₂, 1.2mM CaCl ₂) to the perfusion of microdialysis probe start from this probe face insert in the brain before, and continue at whole experimental session with the steady flow dose rate of 1 μ L/min.After stablizing 180min, start experiment.Every 20min collects the dialysis thing.After the experiment animal is slaughtered, taken out its brain, freezing, section is with the checking probe configuration.

The analysis of dialysis thing vagusstoff

The concentration of vagusstoff in the dialysis thing (ACh) is to analyze by means of the HPLC that Electrochemical Detection is arranged, and employed mobile phase consists of 100mM Sodium phosphate dibasic, the hot sulfonic acid of 2.0mM, 0.5mM tetramethylammonium chloride and 0.005%MB (ESA), pH8.0.The preceding enzyme reactor of post that contains the embedding E.C. 1.1.99.1 has been eliminated the choline in the preceding injected sample (10 μ L) of ACh separation on the analytical column (ESA ACH-250); Fluence rate 0.35mL/min, 35 ℃ of temperature.Behind the analytical column, sample has passed through solid phase reactor (ESA) behind the post that contains embedding acetylcholinesterase and E.C. 1.1.99.1.The reactor in back makes ACh change into choline, makes choline change into trimethyl-glycine and H subsequently again ₂O ₂The latter is to use platinum electrode to carry out (analysis cell: the ESA, model 5040) of Electrochemical Detection.

The data statement

In single injection experiment, with compound face administration preceding 3 in succession the mean value of ACh sample data reduction is become the percentage (value is normalized to 100% before the injection of average basis) of basic value as the basal level of each experiment.Data sheet is set forth among Figure 25 a and the 25b.

The accident of the data presentation levels of acetylcholine of explaining among Figure 24 reduces (seeing for example 8mg/kg), this be difficult to explain and also by uncertain owing to experiment.Generally speaking, 2 data sets from embodiment 2F and 2G all show same trend, i.e. the dose dependent raising of the outer levels of acetylcholine of born of the same parents in the brain.Find before this is clinical to be expected to be read as that to can be used for such as treatment be the improvement of being familiar with in the damaged clinical arrangement of disorders such as alzheimer s patient, partial reaction person, the understanding of feature to be familiar with damaged.

The effect of 3 pairs of neuropathic pains of embodiment

In order to demonstrate to the curative effect of neuropathic, The compounds of this invention is tested [Neuro-pharm., 48,252-263,2005 with formalin neuropathic model; Pain, 51,5-17,1992].In this model, mouse is accepted formalin (4.5%, 20 μ L) to the injection on left back pawl sole of the foot surface, puts into subsequently in the single glass beaker (2L capacity) and observes.Two stage of characteristic behavior reaction is brought out in the stimulation that formalin causes, the time quantum that is spent with injured pawl licking is quantized.Fs (on behalf of direct chemical ,～0～10min) stimulate and nociception, and subordinate phase (～20～30min) are considered to represent the pain of neural pathogeny.These two stages return normal stationary phase separately by a behavior.The evaluation of measuring of the time quantum that injured pawl licking is spent in this two stages test compound reduce the validity of pain stimulation.

Every group of test 8 C57/B6 mouse (about 25g).Following table 4 shows that two stages are the time quantum that injured pawl licking is spent among 0～5min and the 20～30min after the formalin injection.The compound administration amount is calculated as free alkali.

Table 4

	Supporting agent	1.0mg/kg	2.5mg/kg	10mg/kg
					0-5min(sec)	42	37	30	37
20-30min(sec)	41	43	26	6

Data presentation in the table 4, on behalf of direct chemical stimulation and nociceptive fs, The compounds of this invention some effects are arranged.More significantly, these data also show the obvious and dose dependent minimizing of time that subordinate phase median claw licking is spent, and show the effect of The compounds of this invention aspect the neurodynia treatment.

Implement 4 capsules

In the first step, allowing 4-[2-(4-methylbenzene sulfenyl) phenyl] the piperidines hydrobromate mixes with Microcrystalline Cellulose.In second step, Magnesium Stearate is sneaked into.Preparation has the capsule-effective constituent of semi-finals degree to be expressed as free alkali.

	1mg	5mg	25mg
				Effective constituent	12.85g	64.25g	321.25g
Microcrystalline Cellulose	2026.55g	2034.55g	1846.85g
				Magnesium Stearate	20.6g	21.2g	21.9g
Capsule 's content weight	206mg	212mg	219mg

From 10000 capsules of each preparing the batch.

Claims (32)

1. the Compound I that is crystallized form, i.e. 4-[2-(4-methylbenzene sulfenyl) phenyl] piperidines and pharmaceutical acceptable salt thereof

Prerequisite is that described compound is not 4-[2-(4-methylbenzene sulfenyl) phenyl] the piperidinium salt acid salt.

2. according to the compound of claim 1, this compound is the HBr additive salt.

3. according to the compound of claim 2, this compound is characterised in that its XRPD peak position is in about 6.08,14.81,19.26 and 25.38 ° of 2 θ.

4. according to the compound of claim 2, this compound is characterised in that the XRPD shown in Fig. 1.

5. according to the compound of claim 1, this compound is a DL-lactic acid additive salt.

6. according to the compound of claim 5, this compound is characterised in that its XRPD peak position is in about 5.30,8.18,9.44 and 17.24 ° of 2 θ.

7. according to the compound of claim 5, this compound is characterised in that the XRPD shown in Fig. 4.

8. according to the compound of claim 1, this compound is pentanedioic acid additive salt (1:1).

9. according to the compound of claim 8, this compound is characterised in that its XRPD peak position is in about 9.39,11.70,14.05 and 14.58 ° of 2 θ.

10. according to the compound of claim 8, this compound is characterised in that XRPD shown in Fig. 8.

11. according to the compound of claim 1, this compound is propanedioic acid additive salt (1:1).

12. according to the compound of claim 11, this compound is characterised in that the XRPD peak position in 10.77 °, 16.70 °, and 19.93 ° and 24.01 ° of 2 θ, or be positioned at 6.08 °, and 10.11 °, 18.25 ° and 20.26 ° of 2 θ.

13. according to the compound of claim 11, this compound is characterised in that XRPD shown in Fig. 9 or 10.

14. according to the compound of claim 1, this compound is L-aspartic acid additive salt (1:1) or L-aspartic acid additive salt hydrate (1:1).

15. according to the compound of claim 1, this compound is L-glutamic acid additive salt (1:1) or L-glutamic acid additive salt monohydrate.

16., be used for the treatment of according to any one compound in the claim 1～15.

17. medical composition comprises according to any one compound and pharmaceutically acceptable vehicle in the claim 1～15.

18. one kind is selected from following treatment of diseases method: chronic pain, partial reaction person dysthymia disorders, treatment-resistant dysthymia disorders, alzheimer's disease, be familiar with damaged, ADHD, melancholia, PTSD, fever (hot flushes), sleep apnea, alcohol, Nicotine or carbohydrate addiction, substance abuse, alcohol or drug abuse, vomiting, abnormal food appetite, IBS, emotion is unusual, dysthymia disorders, great depressibility is unusual, post-natal depression, the dysthymia disorders that interrelates unusually with the two poles of the earth, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety is unusual, and social anxiety is unusual, obsessional idea and dystropy, panic unusual, panic attack, phobia, social phobia, agoraphobia or the stress urinary incontinence, and this method comprises patient's drug treatment significant quantity that its needs are arranged, according to any one compound in the claim 1～15.

19. according to the method for claim 18, wherein said disease is a chronic pain.

20. according to the method for claim 19, wherein said chronic pain is selected from phantom limb pain, neuropathic, diabetic neuropathy, post herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), the HIV neuropathy, recombination region pain syndrome (CPRS), trigeminal neuralgia, surgical intervention (for example operation back analgesia), diabetic angiopathy, the capillary resistance or the diabetic symptom that interrelate with insulitis, the pain that interrelates with stenocardia, the pain that interrelates with menstruation, the pain that interrelates with cancer, toothache, headache, migraine, tension-type headache, trigeminal neuralgia, temporal-mandible joint syndrome, the myofascial pain Muscular injuries, fibromyalgia syndrome, bone and arthrodynia (osteoarthritis), rheumatoid arthritis, the rheumatoid arthritis and the oedema that cause by the wound that interrelates with burn, because osteoarthritis, osteoporosis, what bone shifted or unknown cause causes sprains or the pain of fracturing, gout, fibrositis, myofascial pain, thoracic outlet syndrome, (wherein backache is because of general for last backache or back pain, regional, or primary spondylopathy (radiculopathy)), pelycalgia, the ambition pain, non-ambition pain, the pain that interrelates with spinal cord injury (SCI), pain after the nervus centralis apoplexy, the cancer neuropathy, the AIDS slight illness, the sickle cell pain, with old ailing.

21. according to the method for claim 20, wherein said chronic pain is a neuropathic.

22. according to the method for claim 21, wherein said neuropathic is selected from hyperpathia (hyperpathia), hyperpathia (hyperalgesia), neuropathy, diabetic neuropathy, neuritis, neurodynia, oxypathy, cusalgia and allodynia.

23. be used to make the purposes of disease treatment with medicament according to the compound of any one in the claim 1～15, this disease is selected from chronic pain, partial reaction person dysthymia disorders, the treatment-resistant dysthymia disorders, alzheimer's disease is familiar with damaged, ADHD, melancholia, PTSD, fever (hot flushes), sleep apnea, alcohol, Nicotine or carbohydrate addiction, substance abuse, alcohol or drug abuse, vomiting, abnormal food appetite, IBS, emotion is unusual, dysthymia disorders, great depressibility is unusual, post-natal depression, with the dysthymia disorders that the two poles of the earth interrelate unusually, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety is unusual, and social anxiety is unusual, obsessional idea and dystropy, panic unusual, panic attack, phobia, social phobia, agoraphobia or the stress urinary incontinence.

24. according to the purposes of claim 23, wherein said disease is a chronic pain.

25. according to the purposes of claim 24, wherein said chronic pain is selected from phantom limb pain, neuropathic, diabetic neuropathy, post herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), the HIV neuropathy, recombination region pain syndrome (CPRS), trigeminal neuralgia, surgical intervention (for example operation back analgesia), diabetic angiopathy, the capillary resistance or the diabetic symptom that interrelate with insulitis, the pain that interrelates with stenocardia, the pain that interrelates with menstruation, the pain that interrelates with cancer, toothache, headache, migraine, tension-type headache, trigeminal neuralgia, temporal-mandible joint syndrome, the myofascial pain Muscular injuries, fibromyalgia syndrome, bone and arthrodynia (osteoarthritis), rheumatoid arthritis, the rheumatoid arthritis and the oedema that cause by the wound that interrelates with burn, because osteoarthritis, osteoporosis, what bone shifted or unknown cause causes sprains or the pain of fracturing, gout, fibrositis, myofascial pain, thoracic outlet syndrome, (wherein backache is because of general for last backache or back pain, regional, or primary spondylopathy (radiculopathy)), pelycalgia, the ambition pain, non-ambition pain, the pain that interrelates with spinal cord injury (SCI), pain after the nervus centralis apoplexy, the cancer neuropathy, the AIDS slight illness, the sickle cell pain, with old ailing.

26. according to the purposes of claim 25, wherein said chronic pain is a neuropathic.

27. according to the purposes of claim 26, wherein said neuropathic is selected from hyperpathia (hyperpathia), hyperpathia (hyperalgesia), neuropathy, diabetic neuropathy, neuritis, neurodynia, oxypathy, cusalgia and allodynia.

28. according to any one is used for the compound of disease treatment in the claim 1～15, this disease is selected from chronic pain, partial reaction person dysthymia disorders, the treatment-resistant dysthymia disorders, alzheimer's disease is familiar with damaged, ADHD, melancholia, PTSD, fever (hot flushes), sleep apnea, alcohol, Nicotine or carbohydrate addiction, substance abuse, alcohol or drug abuse, vomiting, abnormal food appetite, IBS, emotion is unusual, dysthymia disorders, great depressibility is unusual, post-natal depression, with the dysthymia disorders that the two poles of the earth interrelate unusually, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety is unusual, and social anxiety is unusual, obsessional idea and dystropy, panic unusual, panic attack, phobia, social phobia, agoraphobia or the stress urinary incontinence.

29. the compound according to claim 28 is used for the treatment of chronic pain.

30. be used for the compound of following disease treatment according to claim 29: phantom limb pain, neuropathic, diabetic neuropathy, post herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), the HIV neuropathy, recombination region pain syndrome (CPRS), trigeminal neuralgia, surgical intervention (for example operation back analgesia), diabetic angiopathy, the capillary resistance or the diabetic symptom that interrelate with insulitis, the pain that interrelates with stenocardia, the pain that interrelates with menstruation, the pain that interrelates with cancer, toothache, headache, migraine, tension-type headache, trigeminal neuralgia, temporal-mandible joint syndrome, the myofascial pain Muscular injuries, fibromyalgia syndrome, bone and arthrodynia (osteoarthritis), rheumatoid arthritis, the rheumatoid arthritis and the oedema that cause by the wound that interrelates with burn, because osteoarthritis, osteoporosis, what bone shifted or unknown cause causes sprains or the pain of fracturing, gout, fibrositis, myofascial pain, thoracic outlet syndrome, (wherein backache is because of general for last backache or back pain, regional, or primary spondylopathy (radiculopathy)), pelycalgia, the ambition pain, non-ambition pain, the pain that interrelates with spinal cord injury (SCI), pain after the nervus centralis apoplexy, the cancer neuropathy, the AIDS slight illness, the sickle cell pain, or it is old ailing.

31. be used for the compound of treatment of neuropathic according to claim 30.

32. according to the compound of claim 31, wherein said neuropathic is selected from hyperpathia (hyperpathia), hyperpathia (hyperalgesia), neuropathy, diabetic neuropathy, neuritis, neurodynia, oxypathy, cusalgia and allodynia.

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