CN1989107A - Pyridine derivatives - Google Patents

Abstract

The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds for the treatment of pain.

Description

Pyridine derivate

Technical field

The present invention relates to pyridine derivate.More particularly, the present invention relates to 6-amino-2-aminocarboxyl-5-phenyl-pyridine derivate and preparation method thereof, be used to prepare this derivative intermediate, contain the purposes of composition and this derivative of this derivative.

Background technology

Pyridine derivate of the present invention is a sodium channel modulators, and it has the purposes in many treatments, especially for treatment pain.

More particularly, pyridine derivate of the present invention is selective N a _V1.8Conditioning agent.It shows Na _V1.8The affinity of passage has surpassed its affinity to tetraodotoxin susceptibility sodium channel (TTX-S).Compare with tetraodotoxin susceptibility sodium channel, the preferred pyridine derivate of the present invention is to Na _V1.8Passage demonstrates at least 5 times selectivity.

Na _V1.8Passage is the valtage-gated sodium-ion channel of expressing in the nociceptor, and Sensory neurone is responsible for changing nociceptive stimulus.This passage of rat and people has been cloned respectively at 1996 and 1998, and (Nature 379 (1996), pp.257-262; Pain 1998 Nov; 78 (2): 107-14).Na _V1.8Be called as SNS (the specificity sensory nerve is former) and PN3 (peripheral nerve type 3) before the passage.Na _V1.8Passage is thought atypically owing to it demonstrates to the opposing of the sealing effect of the toxin tetraodotoxin of filefish, and think that it is the slow voltage-gated channel that records from dorsal root ganglion neurons and the basis of tetraodotoxin opposing (TTX-R) sodium current.Near Na _V1.8That the passage molecule constitutes is Na _V1.5Passage, the latter is a cardiac sodium channel, the two about 60% homology.Na _V1.8The expression of passage in dorsal root ganglion (DRG) " minicell " is the highest.The C-cell of many types of nociceptor that these are considered to generally acknowledge or Pain receptor and A-delta cell.Under normal circumstances, Na _V1.8Passage is not all having an expression Anywhere except that DRG neurone subgroup.Think Na _V1.8Passage works in the hyperexcitability due to DRG sensitizing and the nerve injury.Na _V1.8The purpose that passage suppresses to regulate is to reduce the excitability of nociceptor by stoping it to work in excited process.

There are some researches show Na _V1.8Knocking out of passage causes pain sensation phenotype blunt, cause usually inflammatory activation (inflammatory challenges) (people such as A.N.Akopian, Nat.Neurosci, 2 (1999), 541-548), Na _V1.8The gene of passage is knocked down (knockdown) and has been reduced the pain behavior, is neuropathic pain (people such as J.Lai, Pain, 2002 Jan in this case; 95 (1-2): 143-52).Coward etc. and Yiangou etc. have shown Na _V1.8As if under the pain symptom, expressed (Pain.2000 Mar; 85 (1-2): 41-50 and FEBS Lett, 2000 Feb 11; 467 (2-3): 249-52).

Na _V1.8Passage also demonstrates in back and dental pulp structure and is expressed, evidence suggests it in cusalgia, inflammatory bowel and multiple sclerosis, play a role (people such as Bucknill., Spine.2002Jan 15; 27 (2): 135-40; People such as Shembalker, Eur J Pain.2001; 5 (3): 319-23; People such as Laird, J Neurosci.2002 Oct 1; 22 (19): 8352-6; People such as Black, Neuroreport.1999 Apr 6; 10 (5): 913-8 and Proc.Natl.Acad.Sci.USA 97 (2000), pp.11598-11602).

Known have several sodium channel modulators to be used as anticonvulsive drug or thymoleptic, for example card is smeared Xiping (carbamazepine), amitriptyline (amitriptyline), lamotrigine (lamotrigine) and Riluzole (riluzole), at the bottom of all these medicines all are target with tetraodotoxin susceptibility (TTX-S) sodium channel of brain.These TTX-S medicines all have the side effect (comprising dizziness, ataxia and drowsiness) of dose limitation (dose-limiting), and its reason mainly is that they act on the interior TTX-S passage of brain.

One of target of the present invention provides new outstanding drug candidate Na _V1.8Channel modulators.Preferred compound should with Na _V1.8Passage is combination effectively, and particularly the avidity of TTX-S passage is lower to other sodium channel, and demonstrates as Na _V1.8The functionally active of channel modulators.They should be from gi tract by absorption well, metabolic stability and possess favourable PK (pharmacokinetic) profile.They should be nontoxic, side effect is very little.And the ideal drug candidate will exist with physical form stable, non-hygroscopic, easy preparation.

Particularly, pyridine derivate of the present invention is to Na _V1.8The selectivity of passage is higher than the selectivity to tetraodotoxin sensitivity (TTX-S) sodium channel, thereby improves side effect.

Therefore, pyridine derivate of the present invention can potentially be used for the treatment of the disease of wide range, especially pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, Encelialgia, nociceptive pain (comprising post-operative pain) and and mixed type pain, described mixed type pain relates to internal organ, gi tract, cranium cerebral tissue, musculoskeletal system, backbone, urogenital system, the cardiovascular system central nervous system (CNS) of unifying, and it comprises cancer pain, backache and mouthful jaw prosopodynia.

The disease of other available pyridine derivate treatment of the present invention comprises multiple sclerosis, nerve degenerative diseases, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathic disease, functional bowel disorder, inflammatory bowel, pain (relevant with dysmenorrhoea, pelvic pain, urocystitis, pancreatitis, migraine, gathering together property and tension headache), diabetic neuropathy, peripheral nerve characteristic of disease pain, sciatica, fibromyalgia and cusalgia.

WO-A-96/18616 discloses a kind of pyridine derivate that can be used as nitric oxide synthase inhibitor activity.

6-amino-N-methyl-5-(2,3, the 5-trichlorophenyl) niacinamide is as the conditioning agent of tetraodotoxin sensitivity (TTX-S) sodium channel and disclose (USA, August 2000 for Gordon Conference, New London).

Summary of the invention

Therefore, the invention provides pyridine derivate or its pharmaceutically acceptable salt or the solvate of a kind of structural formula (I):

Wherein

R ¹Be randomly by Het ¹, Het ²Or (C ₃-C ₇) (the C of cycloalkyl substituted ₁-C ₆) alkyl, wherein said Het ¹, Het ²(C ₃-C ₇) cycloalkyl randomly on ring carbon atom by one or more (C that are independently selected from ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group and halo (C ₁-C ₄) substituting group of alkyl replaces;

Each R ²Be independently selected from fluorine, chlorine, bromine and iodine;

N is 1,2 or 3;

Het ¹Be the saturated of 5-unit or 6-unit or part unsaturated heterocycle base, it contains one or two heteroatomic ring composition that is selected from nitrogen, oxygen and sulphur independently of one another, and described theheterocyclic nitrogen atom randomly has (C ₁-C ₄) alkyl substituent, described epithio atom randomly has 1 or 2 Sauerstoffatom; And

Het ²Be 5-unit or 6-unit heteroaryl, it contains (a) 1 to 4 nitrogen-atoms or (b) Sauerstoffatom or a sulphur atom and 0,1 or 2 nitrogen-atoms.

In above-mentioned definition, halogen is meant fluorine, chlorine, bromine or iodine.Alkyl and alkoxyl group contain the carbon atom of desired number, can be unbranched or side chain is arranged.The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.The example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.The example of haloalkyl comprises trifluoromethyl.

Het ¹Object lesson comprise tetrahydrofuran base, pyrrolidyl, THP trtrahydropyranyl, piperidyl, morpholinyl, thio-morpholinyl and piperazinyl, (as indicated above randomly be substituted).

Het ²Object lesson comprise thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oh azoles base, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oh di azoly, thiadiazolyl group, tetrazyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl (as indicated above randomly be substituted).

In an optimal way (A), the invention provides pyridine derivate or its pharmaceutically acceptable salt or solvate, the wherein R of a kind of structural formula (I) ¹As hereinbefore defined, R ²Be chlorine.

In an optimal way (B), the invention provides pyridine derivate or its pharmaceutically acceptable salt or solvate, the wherein R of a kind of structural formula (I) ²As above being defined in the wideest mode or with the optimal way of (A), and n is 3; More preferably, R ²Group is positioned at 2,3 and 5 of phenyl ring.

In further optimal way (C), the invention provides pyridine derivate or its pharmaceutically acceptable salt or solvate, the wherein R of a kind of structural formula (I) ²Defined in the wideest mode or with (A) or optimal way (B) in as mentioned with n, and R ¹Be (the C that is randomly replaced by piperidyl, imidazolyl, morpholinyl, piperazinyl or pyrrolidyl ₁-C ₆) alkyl; More preferably, R ¹Be methyl, ethyl or the propyl group that is randomly replaced by piperidyl, imidazolyl, morpholinyl, piperazinyl or pyrrolidyl; Most preferably, R ¹Be methyl.

Indivedual preferred R ¹Base is a methyl; 2-(piperidines-1-yl) ethyl; 3-(tetramethyleneimine-1-yl) propyl group; 3-(morpholine-4-yl) propyl group; 2-(tetramethyleneimine-1-yl) ethyl; And 3-(imidazoles-1-yl) propyl group.

List concrete preferred pyridine derivate below according to the present invention:

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids methyl nitrosourea;

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids (2-piperidines-1-base-ethyl)-acid amides;

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids (3-tetramethyleneimine-1-base-propyl group)-acid amides;

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids (3-morpholine-4-base-propyl group)-acid amides;

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids (2-tetramethyleneimine-1-base-ethyl)-acid amides;

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids (3-imidazoles-1-base-propyl group)-acid amides; And

Its pharmaceutically acceptable salt and solvate.

Particularly preferred pyridine derivate is 6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids methyl nitrosourea or its pharmaceutically acceptable salt or solvate according to the present invention.

The compound of structural formula (I) is Na _V1.8Channel modulators can potentially be used for the treatment of multiple disease.Be preferably used for treating pain, particularly chronic, struvite, nervosa, nociceptive pain and Encelialgia.

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

Pain is divided into acute or chronic usually.Acute pain takes place suddenly and the time length short (usually within 12 weeks or shorter).It is relevant with specificity inducement (for example specificity damage) usually, usually is sharp pain and more serious.This pain can occur in operation, dental procedure, strains or sprain after the specificity damage that is caused.Acute pain can not cause any psychological sustained reaction usually.On the contrary, chronic pain is a kind of long-term pain, continues usually to surpass 3 months, and causes serious psychology and emotional problem.The common examples of chronic pain is neuropathic pain (for example diabetic neuropathy pain, postherpetic neuralgia), carpal tunnel syndrome, backache, headache, cancer pain, arthritis pain and chronic post-operative pain.

When body tissue was subjected to grievous injury because of disease or wound, the activation feature of nociceptor changed, and produced sensibilized at periphery, injured part and nociceptor termination center.These effects cause pain to strengthen.In acute pain, these mechanism are quite useful, help to promote the protectiveness behavior, thereby can start repair process better.Usually in a single day the expectation damage cures, and susceptibility just returns to normally.But under a lot of chronic pain states, hypersensitivity is lasting more than healing process, and this normally causes by neural system is impaired.This damage causes unusual (Woolf﹠amp in the Sensory nerve fibre relevant with maladjustment and abnormal activity usually; Salter, 2000, Science, 288,1765-1768).

Susceptibility in patient's symptom, occurs not accommodating when unusual, will produce pain clinically.The patient tends to performance and has nothing in common with each other, and can show as various pain symptoms.These symptoms comprise: 1) spontaneous pain can be slow, scorching hot or shouting pain; 2) destructive stimulus there is exaggerative pain reaction (hyperpathia); With 3) and the pain that causes by stimulation harmless under the normal circumstances (allodynia (allodynia), people such as Meyer, 1994, Textbook ofPain, 13-44).Although suffer the acute patient's symptom with chronic pain of various forms can be similar, its potential mechanism can have nothing in common with each other, and therefore needs different therapeutic strategies.Therefore, according to different physiopathology, pain can also be divided into many different hypotypes, comprises nocuity, inflammatory and neuropathic pain.

Nociceptive pain injuredly may cause that maybe injured intensive stimulation causes by organizing.Importing into of pain by the stimulation of injury nociceptor conduction activation, and make neuronal activation in the spinal cord of its terminal level.Be passed to brain along the ridge bundle then, perceive pain (people such as Meyer, 1994, Textbook of Pain, 1344) at this.The activation of nociceptor activates two kinds of afferent neurofibers.Have myelin A-δ fiber conduction rapidly, be responsible for the pain sensation sharp-pointed, shouting pain, then conduction velocity is slower not have marrow C fiber, passes on slow pain or aches.Moderate to severe acute injury pain is the key character of some pain, as central nervous system injure, pull/sprain, pain, renal colic, cancer pain and backache behind the burn, myocardial infarction, acute pancreatitis, postoperative pain (pain after any Surgery Treatment), wound.Cancer pain can be a chronic pain, for example relevant pain (as bone pain, headache, face ache or Encelialgia), or the pain relevant (as syndromes after syndromes, operation back chronic pain syndrome or the radiotherapy after the chemotherapy) with cancer therapy with tumour.Cancer pain can also react on chemotherapy, immunotherapy, hormonotherapy or radiotherapy and take place.Backache may or be broken or the other muscle of joint of lumbar vertebra, sacrum osteoarthrosis, vertebra or posterior longitudinal ligament cause unusually by protrusion of intervertebral disc.Backache can natural remission, but for some patient, it continues to surpass for 12 weeks, becomes chronic disease and especially makes the people weak.

Neuropathic pain is defined as at present by primary affection in the neural system or pain that dysfunction caused or caused.Nervous lesion can be caused by wound and disease, therefore term " neuropathy sex change pain " comprising: central pain after peripheral neuropathy, diabetes type DPN, postherpetic neuralgia, trigeminal nerve neurodynia, backache, cancer DPN, HIV DPN, false limbs pain, carpal tunnel syndrome, the apoplexy, and with chronic alcoholism, thyroid function deficiency, uremia, multiple sclerosis, Spinal injury, Parkinson's disease, the epilepsy pain relevant with vitamin deficiency.Neuropathy sex change pain is ill, because its any defencive function of tool not.Its still continues existence usually after cause disappears, the common sustainable several years, obviously reduce the patient quality of life (Woolf and Mannion, 1999, Lancet, 353,1959-1964).The symptom of neuropathic pain is difficult to treatment, even because they are suffering between the patient of same disease also have nothing in common with each other usually (Woolf and Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353,1959-1964).They comprise spontaneous pain, and it can be successional, paroxysmal or the undesired pain that causes, for example hyperpathia (the destructive stimulus susceptibility is increased) and allodynia (to normal non-noxious stimulation sensitivity).

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

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

The pain that should be noted in the discussion above that some type has Different types of etiopathogenises, thereby can divide in a more than field, and for example, backache and cancer pain all both be nociceptive pain, were again neuropathic pain.

The pain of other type comprises:

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

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

● headache, for example migraine (including the migraine of tendency and the migraine of absence of aura), cluster headache, mixed type headache, tension-type headache and with the related headache of vascular disease; With

● mouthful jaw prosopodynia comprises toothache, otalgia, burning mouth syndrome and temporomandibular joint muscular fascia pain.

The pyridine derivate of structural formula (I) also estimates to can be used for treating multiple sclerosis.

The invention still further relates to the therepic use of the pyridine derivate of structural formula (I) as the medicine of treatment or alleviation nerve degenerative diseases symptom.These nerve degenerative diseases comprise, for example, and Alzheimer's (alzheimer ' s disease), Huntington's disease (Huntington ' sdisease), Parkinson's disease (Parkinson ' s disease) and amyotrophic lateral sclerosis.The present invention comprises that also treatment is called as the nerve degenerative diseases of acute cerebral insult.These include but not limited to: apoplexy, head trauma and suffocate.Apoplexy refers to a kind of cerebrovascular disease, is also referred to as cerebrovascular accident (CVA), comprises the acute thrombus embolic stroke.Apoplexy comprises focus ischemic and whole body ischemic.Also comprise transient ischemic attack and other cerebrovascular problem simultaneously with cerebral ischemia.These vascular disease especially betide the patient who stands carotid endarterectomy, or betide the patient who stands other cerebrovascular or vascular surgery usually, or betide and stand to comprise the patient of the cerebrovascular according to the diagnostic vascular test of shadow or inspection.Other is incident to be head trauma, spinal cord injuries receptor or damage that is caused by whole body anoxic, anoxic, hypoglycemia, ypotension and the similar damage of seeing in embolism, HT and anoxic process.The present invention can also be used for following situation, for example, at the bypass surgery intra-operative, intracranial hemorrhage, accident in perinatal asphyxia, cardiac arrest and the epileptic state.

Skilled doctor can determine suitable situation, and wherein the patient is subject to or is in the danger such as apoplexy, and the patient who suffers apoplexy is carried out administration by method of the present invention.

The pharmaceutically acceptable salt of the compound of structural formula (I) comprises its acid salt and alkali salt.

Suitable acid salt is formed by the acid that forms non-toxic salt.Example comprises acetate, adipate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, camsilate, Citrate trianion, cyclamate, ethanedisulphonate, esilate (esylate), formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate (hibenzate), hydrochloride/muriate, bromate/bromide, iodate/iodide, isethionate, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate (naphthylate), the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate (orotate), oxalate, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, pyroglutamate (pyroglutamate), saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salt.

Suitable alkali salt is formed by the alkali that forms non-toxic salt.Example comprises the salt of aluminium, arginine, benzathine, calcium, choline, diethylamine, glycol amine, glycine, Methionin, magnesium, meglumine, tromethane, potassium, sodium, Tutofusin tris and zinc.

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

For the summary of suitable salt, can be referring to Stahl and Wermuth showed Handbook of Pharmaceutical Salts:Properties, Selection, and Use(Wiley-VCH, 2002).

The pharmaceutically acceptable salt of the compound of structural formula (I) can be by one or more preparations in following three kinds of methods:

(i) make the compound of structural formula (I) and required acid or alkali reaction;

(ii) with acid-or alkali-unsettled protecting group from the precursor of the compound of suitable structural formula (I), remove, perhaps use required acid or alkali to make suitable cyclic precursor (as lactone or lactan) open loop; Or

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

All these three kinds reactions are generally all carried out in solution.Gained salt can be precipitated out and collect by filtering, and perhaps reclaims by evaporating solvent.The degree of ionization of gained salt can be changed to ionization hardly from complete ionization.

Compound of the present invention can be from amorphous fully to the form existence of the solid-state continuum of crystalline fully.Term " amorphous " refers to the state of long-range order on the material want molecular level, depends on temperature, and this state can demonstrate the physical property of solid or liquid.This material can not provide the characteristic X-ray diffractogram usually when showing solid property, therefore more formally be described as liquid.When heating, the transformation from solid property to characteristics of liquids can take place, this transformation is characterised in that the variation of state, is generally second order trnasition (" glassy transition ").Term " crystallization " refers to that material has the solid phase of regular internal structure on molecular level, provides the characteristic X-ray diffractogram with characteristic peak.When abundant heating, this material also will demonstrate the characteristic of liquid, but the transformation characteristic from solid to liquid is phase transformation, is generally first-order transition (" fusing point ").

The form of all right non-solventization of compound of the present invention and solvation exists.Term " solvate " is used for describing the molecular complex that contains compound of the present invention and one or more pharmaceutically acceptable solvent molecules (as ethanol) in this article.When described solvent is water, adopt term " hydrate ".

The categorizing system to organic hydrate of generally acknowledging has defined isolated sites hydrate, channel water compound or metallic ion coordination hydrate at present, shows referring to K.G Morris Polymorphism in Pharmaceutical Solids(H.G.Brittain edits, Marcel Dekker, 1995).The isolated sites hydrate keeps apart water molecules by inserting organic molecule from be in direct contact with one another.In the channel water compound, water molecules is present in the lattice passage, with other water molecules next-door neighbour.In the metallic ion coordination hydrate, water molecules combines with metal ion.

When solvent or watertight cut in conjunction with the time, mixture will have clear and definite stoichiometry and humidity is irrelevant.But if the combination of solvent or water is very weak, as in passage solvate and hygroscopic compound, water/solvent will depend on humidity and drying conditions.In this case, non--stoichiometry is a benchmark.

The multicomponent mixture (beyond salt and the solvate) in addition that is included in the scope of the present invention, its Chinese traditional medicine and at least a other composition exist with stoichiometry or non-stoichiometric amount.Such mixture comprises inclusion compound (medicine-host comprises the type mixture) and cocrystallization thing.The crystalline complex that latter's General Definition becomes neutral molecule to constitute, it combines by noncovalent interaction, but can also be the mixture of neutral molecule and salt.The cocrystallization thing can by fusion-crystallization, by recrystallization from solvent or by composition physical grinding is together prepared-referring to Chem Commun, 17, 1889-1896, O.Almarsson and M.J.Zaworotko (2004).The general summary of multicomponent mixture can be referring to J Phann Sci, 64(8), 1269-1288, Haleblian (in August, 1975).

When being in appropriate condition following time, compound of the present invention can also mesomorphic state (mesomorphic or liquid crystal) exist.Mesomorphic state is the intermediate state (or molten mass, or solution) between real crystal form and real liquid state.The mesomorphism increase that causes because of temperature change is described to " thermic ", and the mesomorphism increase that causes by second kind of composition of adding (as water or other solvent) is described as " lyotropic ".May form the molten compound that causes mesomorphous phase and be described as " amphipathic ", by having ion (as-COO ^-Na ⁺,-COO ^-K ⁺,-SO ₃ ^-Na ⁺) or nonionic (as-N ^-N ⁺(CH ₃) ₃) the molecule of polar head-group constitute.More information can referring to Crystals And the Polarizing Microscope, N.H.Hartshorne and A.Stuart, the 4th edition (Edward Arnold, 1970).

Hereinafter comprise reference, with the reference of solvate, multicomponent mixture and the liquid crystal of relevant its salt about its salt, solvate, multicomponent mixture and liquid crystal all about the reference of compound in structural formula I.

Compound of the present invention comprises the compound as the defined structural formula of preamble (I), comprise polymorphic form and crystal habit that they are all, as hereinafter defined its prodrug and isomer (comprising optical isomer, geometrical isomer and tautomer), and the compound isotopically labelled of structural formula (I).

As shown, the what is called " prodrug " of the compound of structural formula (I) also within the scope of the invention.Therefore, some of the compound of structural formula (I) self pharmacologically actives extremely low seldom or the derivative that does not have change into the compound (for example by the hydrolysis cutting) that possesses required active structures formula (I) at human body after for oral administration or external application.This derivative is called " prodrug ".Can consult about the further information that prodrug uses Pro-drugs as Novel Delivery Systems, the 14th the volume, ACS Symposium Series (T.Higuchi and W.Stella) and Bioreversible Carriers In Drug Design, Pergamon Press, 1987 (E.B.Roche compiles, AmericanPharmaceutical Association).

Can prepare by the following method according to prodrug of the present invention: for example, well known to a person skilled in the art that with some the part that is called " precursor portions (pro-moiety) " is (as H.Bundgaard Design ofProdrug(Elsevier, 1985)) replace the suitable functional group that exists in the compound of structural formula (I).

Some examples according to prodrug of the present invention comprise: when the compound of structural formula (I) contains uncle's ammonia or the (NH of parahelium functional group ₂Or-NHR, wherein when R ≠ H), its acid amides, for example, this situation can be that one or two hydrogen atom of amido functional group of compound of structural formula (I) is all by (C ₁-C ₁₀) alkyl carbonyl replaces and the compound that forms.

Can in aforementioned reference, consult according to substituent other example of previous example and the example of other type prodrug.

And some compound of structural formula (I) itself just can be used as the prodrug of the compound of other structural formula (I).

The metabolite that comprises the compound that also has structural formula (I) within the scope of the invention, that is, and the compound that forms by vivo medicine-feeding.Some examples according to metabolite of the present invention comprise

(i) compound when structural formula (I) contains methyl, methylol, its derivative (CH ₃The CH of-＞- ₂OH);

(ii) the compound when structural formula (I) contains alkoxyl group, hydroxyl, its derivative (OR-＞-OH);

(iii) the compound when structural formula (I) contains secondary amino group, uncle's ammonia, its derivative (NHR ¹The NH of-＞- ₂);

(iv) the compound when structural formula (I) contains phenyl moiety, phenol, its derivative (Ph-＞-PhOH); And

(v) the compound when structural formula (I) contains amide group, carboxylic acid, its derivative (CONH ₂-＞-COOH).

Contain the compound of the structural formula (I) of one or more unsymmetrical carbons can two kinds or the form of steric isomer exist.Compound at structural formula (I) contains under the situation of thiazolinyl or alkenylene, and three-dimensional cis/trans (or Z/E) isomer can be arranged.Under the situation that constitutional isomer can be changed mutually via low energy barrier, tautomerism (" tautomerism ") can take place.In containing the compound of the structural formula of imino-, ketone or oxime (I) for example, show as the form of proton change, perhaps in containing the compound of aromatic portion, show as the form of so-called covalency change.As a result, the simplification compound can show the isomery of more than one types.

All steric isomers, geometrical isomer and the tautomeric form of the compound that also has structural formula (I) that is included in the scope of the present invention comprise the compound that demonstrates isomery more than a type, and one or more mixture.Also comprise sour affixture salt or alkali salt, wherein gegenion is optically active, for example, and d-lactic acid salt or l-Methionin, or racemoid, for example dl-tartrate or dl-arginine.

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

The routine techniques that is used to prepare/separate independent enantiomer comprises that to carry out chirality from suitable optical purity precursor synthetic, perhaps adopts such as chiral high performance liquid chromatography (HPLC) racemic compound (or racemic compound of salt or derivative) is split.

In addition alternatively, can make racemic modification (or racemic precursor) and suitable optically active compound (as alcohol) reaction, perhaps the compound at structural formula (I) contains under the situation of acid moieties or alkali part, with alkali or acid (as 1-phenyl-ethyl amine or tartrate) reaction.The diastereo-isomerism mixture that obtains can separate by chromatogram and/or fractional crystallization, by well known to a person skilled in the art mode in the diastereomer one or both is changed into corresponding pure enantiomer.

Can use chromatogram (being generally HPLC) obtaining the chipal compounds of the present invention (and chiral precurser) of optical isomer enriched form under the following condition: on asymmetric resin, moving phase is made up of hydrocarbon (being generally heptane or hexane), and it contains the Virahol of 0 to 50% volume (being generally 2% to 20%) and the alkylamine of 0 to 5% volume (be generally 0.1% diethylamine).The enriched material that concentrates elutant provides the mixture of enrichment.

When any racemic modification crystallization, may form two kinds of dissimilar crystal.First type is racemic compound (true racemic modification) mentioned above, wherein produces a kind of uniform crystalline form, contains two kinds of enantiomers of equimolar amount.Second type is racemic mixture or aggregation, wherein produces two kinds of crystalline forms that equimolar amount comprises single corresponding isomer separately.

Although two kinds of crystalline form physical propertiess that exist in the racemic mixture are identical, they compare physical property with real racemic modification may be different.Racemic mixture can by well known to a person skilled in the art routine techniques separate-referring to, for example, E.L.Eliel and S.H.Wilen work Stereochemistry of Organic Comrounds(Wiley, 1994).

The present invention includes all pharmaceutically acceptable isotope-labeled compounds of structural formula (I), identical but atomic mass or total mass number are different from abundance is the highest under the native state atomic mass or the atom of total mass number substitutes to wherein one or more atoms by ordination number.

The isotropic substance that the isotopic example that is suitable for being included in compound of the present invention comprises hydrogen (for example ²H, ³H), the isotropic substance of carbon (for example ¹¹C, ¹³C and ¹⁴C), the isotropic substance of chlorine (for example ³⁶Cl), the isotropic substance of fluorine (for example ¹⁸F), the isotropic substance of iodine (for example ¹²³I and ¹²⁵I), the isotropic substance of nitrogen (for example ¹³N and ¹⁵N), the isotropic substance of oxygen (for example ¹⁵O, ¹⁷O and ¹⁸O), the isotropic substance of phosphorus (for example ³²P) and the isotropic substance of sulphur (for example ³⁵S).

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

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

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

Usually, by routine techniques known to a person of ordinary skill in the art, perhaps use suitable isotope labeling reagent to replace the non-marked reagent that adopts before,, can prepare the compound isotopically labelled of structural formula (I) by being similar to appended embodiment and the described method of preparation part.

Pharmaceutically acceptable solvate according to the present invention comprises that recrystallisation solvent is by for example D ₂O, d ₆-acetone, d ₆The material that-DMSO isotropic substance replaces.

Comprise and also have structure formula V as described below, (VI) and midbody compound (VII) within the scope of the invention, its all salt, solvate and mixture, with and all solvates and the mixture of salt, as before to as described in the compound of structural formula (I).The present invention includes all polymorphic forms and the crystal habit thereof of aforementioned species.

In order to select optimal formulation and route of administration indication, should carry out the evaluation of its bio-pharmaceutical characteristic (as solvability and stability of solution (intersection pH), perviousness etc.) to the compound of structural formula (I) with the treatment suggestion.

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

They can be individually dosed, perhaps with one or more other compound combination medicine-feeding of the present invention, perhaps with one or more other medicines (or its arbitrary combination) administration.Usually, they with one or more pharmaceutically acceptable vehicle as the preparation administration.Any composition except that compound of the present invention described in term used herein " vehicle ".The concrete pattern that being chosen in of vehicle depended on to a great extent such as administration, vehicle are to solvability and the influence of stability and the multiple factor of formulation character.

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

Oral administration

Compound of the present invention can be taken orally.Oral administration can comprise swallows administration, makes compound enter gi tract, and/or on the buccal, tongue or sublingual administration, makes compound directly enter blood flow from mouth.

The preparation that is suitable for oral administration comprises solid, semisolid and liquid system, for example tablet; Soft or the hard capsule that contains multiple particle or nanoparticle, liquid or powder; Lozenge (comprise be filled with liquid); Chaw; Glue; The fast-dispersing type; Film; Vesicle (ovules); Propellant; And cheek/mucous membrane adhesion patch.

Liquid preparation comprises suspension, solution, syrup and elixir.This preparation can be as soft or hard capsule (for example, make by gelatin or Vltra tears) weighting agent, generally include carrier, for example water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil and one or more emulsifying agents and/or suspensoid.Liquid preparation can also prepare by the transformation of solid (for example sachet).

Compound of the present invention can also be used for quick dissolving, quickly disintegrated formulation, the Expert Opinion in Therapeutic Patents that for example Liang and Chen showed, 11(6), 981-986, those formulations of describing in (2001).

For Tabules, according to dosage, medicine can account for the 1wt% to 80wt% of formulation, more typically is the 5wt% to 60wt% of formulation.Except that medicine, tablet contains disintegrating agent usually.Examples of disintegrants comprises that sodium starch glycolate, Xylo-Mucine, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpolypyrrolidone (crospovidone), polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, low alkyl group replace hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate.Usually, disintegrating agent accounts for the 1wt% to 25wt% of formulation, is preferably 5wt% to 20wt%.

Tackiness agent is generally used for making tablet to have binding property.Suitable binder comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetic gum, polyvinylpyrrolidone, pregelatinized Starch, hydroxypropylcellulose and Vltra tears.Tablet can also comprise thinner, for example lactose (monohydrate, jet drying monohydrate, anhydride and analogue), N.F,USP MANNITOL, Xylitol, glucose, sucrose, sorbyl alcohol, Microcrystalline Cellulose, starch and secondary calcium phosphate dihydrate.

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

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

Other possible composition comprises oxidation inhibitor, tinting material, seasonings, sanitas and mask agent.

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

Tablet mixture can be directly or by roll-in system, forms tablet.Tablet mixture or partial confounding compound can alternately carry out wet granulation, dry granulation or melt granulation before compressing tablet, fusion is condensed or extruded.Final formulation can comprise one or more layers, coating can be arranged or do not have coating; Even can be loaded in the capsule.

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

People or consumed oral film for animals generally are the thin-film dosage form that is easy to water-soluble or water-swellable, can dissolve fast or the mucous membrane adhesion, generally include compound, film-forming polymer, tackiness agent, solvent, wetting Agent for Printing Inks, softening agent, stablizer or emulsifying agent, viscosity modifier and the solvent of structural formula (I).Some compositions of said preparation can be brought into play more than one effects.

The compound of structural formula (I) can be water-soluble or insoluble.Water-soluble cpds generally includes the 1wt% to 80wt% of solute, more typically is 20wt% to 50wt%.The compound that solvability is lower can comprise the larger proportion of composition, reaches the 88wt% of solute usually.In addition alternatively, the form that the compound of structural formula (I) can the multiparticulates globule exists.

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

Other possible composition comprises oxidation inhibitor, tinting material, spices and flavor potentiator, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oil), tenderizer, weighting agent, defoamer, tensio-active agent and mask agent.

Membrane according to the invention is carried out evaporation drying and is prepared by falling the water-based film that is applied on peelable backing carrier or the paper usually.This process can be carried out in drying oven or drying alley (being generally built-up type coating moisture eliminator), is perhaps undertaken by lyophilize or vacuum.

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

The suitable modification delivery formulations that is used for the object of the invention is described in United States Patent (USP) the 6th, 106,864.The particular content of other suitable release tech (as high energy dispersion and infiltration and coating particles) can be consulted Pharmaceutical Technology On-line, 25 (2), 1-14, people such as Verma work (2001).Use the chewing gum class to realize that sustained release is described in WO 00/35298.

Administered parenterally

Compound of the present invention directly administration enters blood flow, muscle or internal.The suitable method of administered parenterally comprises in the intravenously, intra-arterial, intraperitoneal, sheath, in the ventricle, in the urethra, in the abdomen, in the encephalic, intramuscular, synovial membrane and subcutaneous.The appropriate device of administered parenterally comprises pin type (comprising micro-needle) syringe, needleless injector and infusion techniques.

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

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

The solubleness of compound that is used to prepare the structural formula (I) of parenteral solution can be increased by using appropriate formulations technology (for example adding solubility enhancing agent).

Release can be made immediately and/or be modified to the preparation of administered parenterally.Modify delivery formulations and comprise that postponing to discharge, continue release, pulse release, sustained release, target release and program discharges.Therefore, compound of the present invention can be made suspension, or makes solid, semisolid or thixotropic liquid, as the implantation Drug Storage that active compound modify to be discharged and administration.The example of this preparation comprises coating support (drug-coated stent) and comprises the semisolid and the suspension of poly-(dl-lactic-co-glycolic acid) multipolymer (PGLA) microballoon of medicine carrying.

Topical

Compound of the present invention can also carry out part, epidermis (interior) or transdermal administration to skin or mucous membrane.The preparation that typically is used for this purposes comprises gel, hydrogel, lotion, solution, paste, ointment, dusting, dressing, foam, film, skin patch, wafer, implant, sponge, fiber, bandage and micro emulsion.Can also use liposome.Typical carrier comprises alcohol, water, mineral oil, petrosio, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.

Can add penetration enhancer-referring to, J Pharm Sci for example, 88(10), 955-958, Finnin and Moran work (in October, 1999).

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

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

Inhalation/intranasal administration

Compound of the present invention can also intranasal administration or is passed through inhalation, usually as dry powder (single component, or as mixture, for example with the dry mixture of lactose, or as the mixing element particle, for example mix with phosphatide such as phosphatidylcholine) form from the Diskus administration, or using or do not using suitable propelling agent (for example 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane) under the situation, from pressurizing vessel, pump, injector, in spraying gun (preferably making the spraying gun of electricity consumption hydraulic pressure produce mist) or the atomizer as the aerosol injection administration, perhaps as the nasal cavity drop administration.Be used for intranasal administration, powder can comprise bioadhesive polymer, for example chitosan or cyclodextrin.

Pressurizing vessel, pump, injector, spraying gun or atomizer contain: comprise such as ethanol, aqueous ethanolic solution or be used to make that actives disperses, dissolving or prolong the solution or the suspension of the The compounds of this invention of the suitable substituting agent that discharges, as the propelling agent of solvent, and optional tensio-active agent (for example sorbitanic, oleic acid or lact-acid oligomer).

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

Capsule (by making such as gelatin or Vltra tears), whipping agent and the cartridge case that is used for sucker or insufflator can be mixed with and contain compound of the present invention, suitable powder matrix (for example lactose or starch) and the powdered mixture of outward appearance properties-correcting agent (for example l-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can be anhydrous, or the form of monohydrate, is preferably the latter.Other vehicle that is fit to comprises dextran, glucose, maltose, sorbyl alcohol, Xylitol, fructose, sucrose and trehalose.

The suitable pharmaceutical solutions that is used to make electricity consumption hydraulic pressure to produce the spraying gun of mist can whenever be pressed and contain 1 μ g to 20mg compound of the present invention, and whenever presses volume and can be changed to 100 μ l from 1 μ l.Typical formulation can comprise compound, propylene glycol, sterilized water, ethanol and the sodium-chlor of structural formula (I).Can be used for replacing the selectable solvent of propylene glycol to comprise glycerine and polyoxyethylene glycol.

Suitable spices (for example menthol and l-Menthol) or sweeting agent (for example asccharin or soluble saccharin) can be joined the preparation of the present invention that those are used for inhalation/intranasal administration.

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

Under the situation of Diskus and aerosol, dosage device is determined by the valve of conveying and metering amount.Usually be set to containing the compound of 1 μ g to 20mg structural formula (I) according to unit of the present invention with dosing or " each spray ".Total per daily dose is generally 1 μ g to 100mg, can be in one day according to the single dose administration, perhaps more generally, according to the broken dose administration.

Rectal administration/intravaginal administration

Compound of the present invention can carry out rectal administration or vagina administration with the form such as suppository, vaginal suppository or enema.Theobroma oil is traditional suppository base, but as long as suitably, can use various surrogates.

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

Administration in eye drops/ear

Compound of the present invention can also directly deliver medicine to eye or ear, usually with the micronize suspension or etc. ooze, the form administration of the drops of the sterile saline solution of pH regulator.Other preparation that is suitable for intraocular and Er Nei administration comprises ointment, gel, biodegradable (for example absorbable gel sponge, collagen) implant and non-biodegradation (for example silicone) implant, wafer (wafer), eyeglass (lense) and particulate or vesica system (for example single phospholipid layer vesica and two phospholipid layer liposome).Can for example cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulose polymer compound (for example Vltra tears, Natvosol or methylcellulose gum) or mixed polysaccharide polymkeric substance (for example gelan gum) add with sanitas (for example benzalkonium chloride) with polymkeric substance.Said preparation also can penetrate by electron ion and carry.

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

Other technology

For the solubleness that improves the compound of the present invention that is used for aforementioned any administering mode, dissolution rate, screening flavor effect, bioavailability and/or stability, compound of the present invention and soluble large molecule material (for example cyclodextrin and suitable derivative thereof) or the polymkeric substance that contains polyoxyethylene glycol can also be combined use.

For example have been found that the drug-cyclodextrin mixture can be used for most of formulations and route of administration usually.The two all can use inclusion and non-inclusion complex.As with the other optionally mode of the direct compound of medicine, cyclodextrin can be used as supplementary additive, promptly as carrier, thinner or solubilizing agent use.Be most commonly used to these purposes be α-, β-and γ-Huan Hujing, its example can be consulted international patent application WO91/11172 number, WO94/02518 number and WO98/55148 number.

Pharmaceutical kit (kit-of part)

The combination medicine-feeding that needs to use active compound owing to the purpose of for example treating special disease or situation, therefore scope of the present invention comprises two or more pharmaceutical compositions, wherein at least aly contain with good grounds compound of the present invention, can combine with the form of test kit easily, to be suitable for the co-administered of composition.

Therefore, test kit of the present invention comprises two or more independently pharmaceutical compositions, the wherein at least a compound that contains with good grounds structural formula of the present invention (I), and the instrument that keeps described ancestral's compound respectively, for example container, packing bottle or packing Foilpac.The example of this test kit is useful on the family expenses Blister Package of package troche, capsule etc.

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

Dosage

For being the human patients administration, to depend on administering mode certainly, the total per daily dose of The compounds of this invention is generally at 0.1mg to 1000mg.For example, it is 1mg to 1000mg that oral administration can require total per daily dose, and intravenous dosages can only require to be 0.1mg to 100mg.Total per daily dose can be according to single dose or broken dose administration, and according to doctor's prescription, dosage can exceed general range herein.

This dosage is based on the human experimenter that mean body weight is about 60kg to 70kg.The doctor can exceed experimenter such as the baby and the definite at an easy rate dosage of old man of this scope to body weight.

For averting misconceptions, " treatment " as referred to herein comprises curative therapy, palliative therapy and prophylactic treatment.

Na _V1.8Channel modulators when treatment pain, can be used in combination with the reason active compound of other medicine especially, perhaps is used in combination with two or more other pharmaceutically active compounds.For example, Na _V1.8Channel modulators, the compound of structural formula particularly as indicated above (I), or its pharmaceutically acceptable salt or solvate can be selected from medicament while, order or the administration respectively of following material with one or more:

● opium pain killer, for example morphine, heroine, Novolaudon, oxymorphone, levorphanol (levorphanol), levallorphan (levallorphan), methadone, methyl piperidine, fentanyl, Cocaine, morphine monomethyl ether (codeine), paracodin, oxycodone (oxycodone), hydrocodone (hydrocodone), the third oxygen sweet smell (propoxyphene), Nalmefene (nalmefene), nalorphine, naloxone, TREXUPONT, buprenorphine, butorphanol, nalbuphine or pentazocine;

● NSAID (non-steroidal anti-inflammatory drug) (NSAID), for example acetylsalicylic acid, diclofenac, diflusinal, R-ETODOLAC, fenbufen, fenoprofen, flufenisal, flurbiprofen, Ibuprofen BP/EP, indomethacin (indomethacin), Ketoprofen, ketorolac (ketorolac), meclofenamic acid, vialidon, meloxicam (meloxicam), nabumetone (nabumetone), Naproxen Base, nimesulide, nitroflurbiprofen (nitroflubiprofen), Olsalazine (olsalazine), Ao Shapu piperazine (oxaprozin), BUTE, piroxicam, sulfasalazine, sulindac, Tolmetin or zomepirac;

● barbiturate tranquilizer, for example Amobarbital, somnifen, neo-barb, butalbital (butabital), promind, metharbital, Methohexitone, Sodital, phenylethyl barbituric acid, secobarbital, Talbutal, theamylal or thiopental;

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

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

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

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

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

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

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

● anticonvulsive drug, for example Carbamzepine, lamotrigine (lamotrigine), topiratmate or valproate;

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

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

● COX-2 selective depressant, for example celecoxib (celecoxib), rofecoxib (rofecoxib), parecoxib (parecoxib), valdecoxib (valdecoxib), deracoxib (deracoxib), L-791456 (etoricoxib) or lumiracoxib;

● coal tar pain killer, particularly paracetamol;

● neuroleptic, for example droperidol, chlorpromazine, haloperidol, trilafon, thioridazine, mesoridazine, trifluoperazine, Fluphenazine, W-108, olanzapine (olanzapine), risperidone (risperidone), Ziprasidone (ziprasidone), Quetiapine (quetiapine), Sertindole (sertindole), Aripiprazole (aripiprrazole), sonepiprazole (sonepiprazone), blonanserin (blonanserin), Zomaril (iloperidone), Perospirone (perospirone), raclopride (raclopride), zotepine, bifeprunox, asenapine, lurasidone, amisulpride (amisulpride), balaperidone, palindore, eplivanserin (eplivanserin), Osanetant (osanetant), Rimonabant (rimonabant), Miraxion_ or sarizotan (sarizotan);

● the vanilla receptor stimulant (for example, resinferatoxin) or antagonist (for example, capsazepine);

● beta-adrenergic medicine, for example Proprasylyte;

● local anesthetic, for example mexiletine;

● reflunomide, for example dexamethasone;

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

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

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

●Tramadol_；

● the PDEV inhibitor, 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl-alkylsulfonyl) phenyl for example]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidyl-7-ketone (sildenafil), (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine also [2 ', 1 ': 6,1]-pyrido [3,4-b] indoles-1,4-diketone (IC-351 or tadalafil), 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (vardenafil), 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-(5-ethanoyl-2-propoxy--3-pyridyl)-3-ethyl-2-(1-sec.-propyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-(2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl)-3-ethyl-2-(2-methoxy ethyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[(2S)-2-(methylol) tetramethyleneimine-1-yl]-N-(pyrimidine-2-base methyl) pyrimidine-5-methane amide, 3-(1-methyl-7-oxo-3-propyl group-6, the 7-dihydro-1 h-pyrazole is [4,3-d] pyrimidine-5-yl also)-N-[2-(1-methylpyrrolidin-2-yl) ethyl]-4-propoxy-benzsulfamide;

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

● cannaboid;

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

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

● norepinephrine (nor-epinephrine) reuptake inhibitor, for example maprotiline, Tymelvt, mirtazapine (mirtazepine), oxaprotiline (oxaprotiline), fezolamine (fezolamine), tomoxetine (tomoxetine), mianserin, Bupropion (buproprion), bupropion metabolites hydroxyl Bupropion, nomifensine and viloxazine (Vivalan_), selectivity NRI particularly, Reboxetine (reboxetine) for example, particularly (S, S)-Reboxetine;

● two serotonin-NRI, for example Venlafaxine (venlafaxine), Venlafaxine metabolite O-ODV, clomipramine (clomipramine), clomipramine metabolite demethyl clomipramine, duloxetine (duloxetine), Midalcipran (milnacipran) and imipramine;

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

● acetylcholinesterase depressant, for example E2020 (donepezil);

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

● leukotrienes B4 antagonist, for example 1-(3-phenylbenzene-4-ylmethyl-4-hydroxyl-chroman-7-yl)-Cyclopentane carboxylic acid (CP-105696), 5-[2-(2-propyloic)-3-[6-(4-p-methoxy-phenyl)-5E-hexenyl] the phenoxy base]-valeric acid (ONO-4057) or DPC-11870;

● 5-fats oxidn enzyme inhibitors, for example zileuton (zileuton), 6-[(3-fluoro-5-[4-methoxyl group-3,4,5,6-tetrahydrochysene-2H-pyrans-4-yl]) phenoxy group-methyl]-1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethylammonium-6-(3-pyridylmethyl)-1,4-benzo quinone (CV-6504);

● sodium channel inhibitor, for example lignocaine;

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

And pharmaceutically acceptable salt and solvate.

This composition has remarkable advantages, is included in the synergy in the treatment.

The pyridine derivate of structural formula (I) suppresses Na _V1.8The ability of passage can use the following analysis method to measure.

Embodiment

Na _V1.8The VIPR of compound measures

Summary:

This mensuration is used for determining that compound is to people Na _V1.8(HEK293) effect of tetraodotoxin opposing type (TTX-R) sodium channel in the express cell system, it has used Aurora ' s fluorescence voltage/ion probe reader (VIPR).This experiment is carried out based on FRET (FRET (fluorescence resonance energy transfer)), and has used two kinds of fluorescence molecules.First kind of fluorescence molecule Oxonol (DiSBAC ₂(3)) be a kind of high fluorescence, electronegative hydrophobic nonionic, it can " impression " transmembrane potential.Corresponding to the variation of membrane potential, it can redistribute between two binding sites of plasma membrane opposite side rapidly.This voltage-dependent redistribution is by second kind of fluorescence molecule (tonka bean camphor (CC ₂-DMPE)) and being converted into fluorescence ratio output valve, second kind of fluorescence molecule is combined on the surface of plasma membrane specifically, experiences ionic FRET integral part as wakeup voltage and plays a role.For mensuration can be carried out, passage must keep open state on pharmacology.This can be by (being used for Na with Deltamethrin (deltamethrin) _V1.8) or the veratridine SHSY-5Y of TTX-S passage (be used for measure) handle cell and carry out.

Cell cultures:

People Na _V1.8Cell is grown in the T225 flask, at 5%CO ₂Reaching about 70% in the humidifying incubator converges.Culture media composition is made up of DMEM/F-12,10%FCS and 300 μ g/mlGeneticine.According to the design needs, make its division with 1: 5 to 1: 20 cell decomposed solution, and before division next time, grew 3-4 days.

Standard program:

First day:

Before experiment, move to HEK-Nav1.8 cell (100 μ l/ hole) on the culture plate that scribbles poly--D-Methionin (poly-D-lysine) from culture plate in the following manner: 24 Xiao Shi @3.5 * 10 ⁴Cells/well (3.5 * 10 ⁵Cell/ml) or use the selection technology.

Second day: VIPR measured:

The experiment before, with damping fluid equilibrium at room temperature 2 hours or in 30 minutes balances of 37 ℃ of balances.

2. preparation coumarine dye (seeing below) and preservation in the dark.With no Na ⁺Damping fluid is loaded culture plate washer (plate washer) and washed cell 2 times in advance.Attention: the residual damping fluid of about 30 μ l is deposited in the every hole of culture plate washer.In the hole, add 100 μ l tonka bean camphor (CC ₂-DMPE) solution (seeing appendix) is also at room temperature avoided light cultivation 45 minutes.

3. prepare Oxonol (DiSBAC ₂(3)) dyestuff (seeing below):

4. pass through at no Na ⁺Wash sucking-off tonka bean camphor solution from the hole in the damping fluid.

5. add 30 μ l compounds (referring to additional culture plate).In the hole, add 30 μ l Oxonol solution, cultivate 45 minutes (total pore volume is about～90 μ l) under the room temperature in the dark.

6. in case cultivation is finished, cell is ready, measures sodium with VIPR and adds membrane potential.

Data are analyzed, reported into the normalization method ratio of 460nm and the following intensity of surveying of 580nm passage.The method of calculation of these ratios are as follows.Additional culture plate contains DiSBAC ₂(3) the concentration contrast solution identical with used Tissue Culture Plate, and do not contain cell in the background culture plate.For sample point 5-7 (initially) and 44-49 (finally), the intensity level at each wavelength place is averaged.From all mensuration holes, deduct these mean value through in the average intensity value in the identical timed interval.Be defined as follows from the initial ratio (Ri) of sample 3-8 gained and from the final ratio (Rf) of sample 45-50 gained:

Ri= (intensity 460nm, sample 3-5-background 460nm, sample 3-5)

(intensity 580nm, sample 3-5-background 580nm, sample 3-5)

Rf= (intensity 460nm, sample 25-30-background 460nm, sample 25-30)

(intensity 580nm, sample 25-30-background 580nm, sample 25-30)

Final data all is normalized into the initial ratio in every hole, reports into Rf/Ri.This analysis is carried out with the computer special procedure that is the design data of VIPR generation.

Use Excel Labstats (fitting of a curve) to the mapping of Rf/Ri rate value, perhaps analyze by ECADA, thus the IC50 of definite each compound.

Na ⁺Add pH of buffer 7.4 (regulating)-10 * storing solution with 5M NaOH

Component:	Mwt/ concentration n	Weight/volume	10 * concentration (mM)	1 * concentration (mM)
					NaCl KCl CaCl 2 MgCl 2 Hepes dH 2O	58.44 74.55 1M solution 203.31 238.3	93.5g 3.35g 20ml 2.03g 23.83g 1L	1600 45.0 20.0 10.0 100	160 4.5 2 1 10

No Na ⁺PH of buffer 7.4 (regulating)-10 * storing solution with 5M KOH

Component:	Mwt/ concentration n	Weight/volume	10 * concentration (mM)	1 * concentration (mM)
					Choline CaCl 2MgCl 2Hepes dH 2O	139.6 1M solution 203.31 238.3	223.36g 1ml 2.03g 23.83g 1L	1600 1.0 10.0 100	160 0.1 1.0 10

1 * no Na+ damping fluid :-400ml 10 *+3600ml dH ₂O

2 * no Na+ damping fluid :-100ml 10 *+400ml dH ₂O

1 * Na+ adds damping fluid :-50ml10 * Na ⁺Interpolation+450ml dH ₂O

Tonka bean camphor (CC2-DMPE): 2 culture plates:

At first mix 22 μ l pluronics gram (Pluronic) (20%)+22ml 1 * no Na+ damping fluid in 220 μ l tonka bean camphor (1mM)+test tubes, gentle vortex

Solution C onc. ⁿ: finally measure Conc. ⁿ

Tonka bean camphor (1mM) 10 μ M 10 μ M

Oxonol (DiBAC ₂(3)): 2 culture plates:

48 μ l Oxonol (5mM)+120 μ l Tartrazol yellow (200mM) vortexs

8.0ml 2 * no Na+ damping fluid vortex

1.6 μ l Deltamethrin (5mM) vortex

Solution C onc. ⁿ: finally measure Conc. ⁿ

Oxonol(5mM) 30μM 10μM

Deltamethrin (5mM) 1 μ M 330nM

Tartrazol yellow (200mM) 3mM 1.0mM

TTX-S measures

TTX-S is determined on the natural SHSY-5Y clone and carries out.Several tetraodotoxin susceptibility voltage-gated sodium channels of these cell expressings, it comprises Na _V1.2, Na _V1.3And Na _V1.7Use the Na that is used for that above describes in detail _V1.8The process of measuring is measured, and replaces the opener of Deltamethrin as the sodium channel with veratridine during difference is to measure, and finally measuring concentration is 50 μ M.

All pyridine derivates of structural formula (I) can perhaps pass through embodiment part and the described concrete grammar of preparation part by the process described in the logical method of listing below, or by its conventional modification is prepared.Except any new intermediate used herein, the present invention also comprises any one or the multiple method that is used to prepare the pyridine derivate of structural formula (I).

In following logical method, unless otherwise noted, R ¹, R ²With n as before to as described in the definition done of the pyridine derivate of structural formula (I).

According to first method, the pyridine derivate of structural formula (I) can be from structural formula (VI) or compound (VII), shown in scheme 1.

Scheme 1

Wherein X is suitable leavings group, for example trifyl, fluorine, chlorine, bromine, iodine;

PG is suitable protecting group, for example tertbutyloxycarbonyl, N-carbobenzoxy-(Cbz), tertiary butyl carbonyl or methyl carbonyl;

R ³Be suitable ester group, for example (C ₁-C ₆) alkyl, benzyl;

M is hydrogen or basic metal; And

M ¹Be suitable coupling group, for example stannane, borine or boric acid, metal or metal halide.

The compound of structural formula (III) can be by randomly existing under the condition of acid acceptor, with suitable acyl chlorides or acid anhydrides in appropriate solvent (for example methylene dichloride Huo diox), reaction is 5-18 hour under 25 to 50 ℃ temperature, prepares from the compound of structural formula (II).PG is suitable tertbutyloxycarbonyl, N-carbobenzoxy-(Cbz), tertiary butyl carbonyl or methyl carbonyl, is preferably tertbutyloxycarbonyl or methyl carbonyl, most preferably is the methyl carbonyl.

When PG is the methyl carbonyl, typical condition and Bioorg.Med.Chem.9,2061-2071, the condition of describing in 2001 is similar, comprises 1.0 normal compound (II) and excessive acetic acid acid anhydrides, and in the Zai diox, 50 ℃ are following 18 hours.

The compound of structural formula (IV) can be by in suitable solvent (for example water or water and pyridine), under 65 to 75 ℃ temperature, with suitable oxygenant (for example potassium permanganate or sodium dichromate 99) oxidation 3-18 hour, prepare from the compound of structural formula (III).Typical condition comprises 1.0 equivalent compounds (III) and 2.0-6.0 equivalent potassium permanganate, and in the mixture of water and pyridine, 75 ℃ following 18 hours.

The compound of structure formula V can be as J.Org.Chem.61,4623-4633,1996 described such preparations, or by under the condition that has suitable acid (for example concentrated hydrochloric acid or the vitriol oil), carrying out alkylation in 18-72 hour, from the compound of structural formula (IV) with suitable alcohol reflux heating.Under this condition, remove simultaneously amine protecting group (PG).Typical condition comprises 1.0 equivalent compound (IV) and excessive methanols, has under the condition of the vitriol oil reflux 48 hours.

In addition alternatively, the compound of structure formula V can pass through integrating step ii and iii, from the compound of structural formula (III).Typical condition comprises 1.0 equivalent compounds (III) and 2.0-6.0 equivalent potassium permanganate, and in the mixture of water and pyridine, 75 ℃ following 18 hours.Add the methyl alcohol and the vitriol oil behind the vacuum concentration, reflux 48 hours obtains required product.

The compound of structural formula (VI) can be by compound and the amine NH that makes the structure formula V ₂R ¹At suitable solvent (for example methylene dichloride or tetrahydrofuran (THF)/R ³The OH mixture) to the temperature that refluxes, reacts preparation in 18-72 hour at 25 ℃ in.Typical condition comprises 1.0 equivalent compounds (V) and 5.0-10.0 equivalent NH ₂R ¹, in tetrahydrofuran (THF)/methyl alcohol, 25-80 ℃ following 18-72 hour.

In addition alternatively, reaction can also use microwave to carry out under comparatively high temps.Typical condition comprises 1.0 equivalent compounds (V) and 5.0-10.0 equivalent NH ₂R ¹, in tetrahydrofuran (THF)/methyl alcohol, 130 ℃ following 30 minutes, at room temperature stirred subsequently 72 hours.

The compound of structural formula (VII) can by with the compound of structural formula (VIII) (M wherein ¹Be suitable trialkyl stannane, dihydroxyl borine, dialkoxy borine, lithium, halogen magnesium or halogen zinc, be preferably the dihydroxyl borine) under the condition that has appropriate catalytic system (for example palladium or nickel catalyzator) and excessive appropriate base (for example salt of wormwood, Potassium monofluoride or triethylamine), in suitable solvent (for example diox or tetrahydrofuran (THF)), 25 ℃ to the temperature that reflux crosslinking reaction 1-18 hour, from the compound of structure formula V.Typical condition comprises 1.0 equivalent compounds (V), the suitable boric acid of 1.0-1.1 equivalent (phenylo boric acid or 2 for example, 3,5-trichlorobenzene boric acid), 3.2-3.3 equivalent Potassium monofluoride, three (dibenzalacetones), two palladiums (O) (catalyzer) and two (three-tertiary butyl phosphine) palladiums (O) (catalyzer), in tetrahydrofuran (THF), following 18 hours of envrionment conditions.

Person of skill in the art will appreciate that the catalyst type that is adopted will depend on such as M ¹The character of base, used multiple factors such as substrate are determined.The example of this linked reaction comprises so-called " Suzuki " condition, " Stille " conditioned disjunction " Negishi " condition, as " Metal Catalysedcross-coupling reaction ", F.Diederich compiles, described in Wiley-VCH1998 and the reference thereof.

The pyridine derivate of structural formula (I) can by with the cross-coupling reaction of the compound of structural formula (VIII), from the compound of structural formula (VI).Process step v is described as mentioned for reaction conditions.

In addition alternatively, the pyridine derivate of structural formula (I) can be by compound and the amine NH that makes structural formula (VII) ₂R ¹Prepared in reaction.Process step iv is described as mentioned for reaction conditions.

With reference to above logical method; those skilled in the art will be readily appreciated that: exist under the situation of protecting group; usually can exchange with other kin protecting group, for example under the situation of amine, be easy to exchange with the amine protecting group of any appropriate with the tertbutyloxycarbonyl protection.Suitable protecting group is described in " the Protective Groups in Organic Synthesis " of T.Greene and P.Wuts work (the 3rd edition, 1999, John Wiley and Sons).

For as described in the pyridine derivate of structural formula (I), the invention still further relates to structure formula V, (VI) and the novel intermediate compound (VII) of knot as mentioned above, its all salt, solvate and mixture, and all solvates and the mixture of salt as preamble.The present invention includes the polymorphic form and the crystal habit thereof of all aforesaid kind.

During according to the pyridine derivate of structural formula of the present invention (I), in order to satisfy this purpose, those skilled in the art is the form of choice structure formula V, (VI) or compound (VII) routinely, to bring into play best property combination in preparation.This characteristic comprises the productive rate of fusing point, solubleness, workability and intermediate forms and the easily separated purifying of product.

Following examples are used for the preparation of the pyridine derivate of description architecture formula (I).

Embodiment 1

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids methyl nitrosourea

With two (three-tertiary butyl phosphine) palladium (O) (135mg, 0.27mmol) tetrahydrofuran (THF) (11mL) solution join the product (1.36g of preparation example 4,5.92mmol), Potassium monofluoride (1.14g, 19.55mmol), 2,3, (1.46g is 6.51mmol) with three (dibenzalacetones), two palladiums (O) (81mg for 5-trichlorobenzene boric acid, 0.09mmol) in the mixture in tetrahydrofuran (THF) (27mL), reaction mixture was stirred 18 hours under room temperature, nitrogen.Subsequently mixture is filtered by Arbocel_, and wash with tetrahydrofuran (THF).With the filtrate vacuum concentration, by purification by silica gel column chromatography (with 50: 50 heptane: eluent ethyl acetate), thereby obtain the titled reference compound of white solid, productive rate 80%, 1.57g.

¹H NMR(400MHz，CD ₃OD)δ：2.94(s，3H)，7.33(d，1H)，7.41(dd，2H)，7.68(d，1H)LRMS：m/z APCl 330[M+H] ⁺

Trace analysis: C ₁₃H ₁₀Cl ₃N ₃O requires:C 47.23; H 3.05 N 12.71; Found C 47.15; H3.18, N 12.55

Embodiment 2

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids

(2-piperidines-1-base-ethyl)-acid amides

With 1-(2-amino-ethyl) piperidines (0.60g, 4.71mmol) tetrahydrofuran (THF) (2.4mL) solution join the product (0.16g of preparation example 3,0.47mmol) in the suspension in methyl alcohol (4mL) and tetrahydrofuran (THF) (2mL), with mixture 50 ℃ of heating 72 hours down.Subsequently with the reaction mixture vacuum concentration, with resistates by purification by silica gel column chromatography (with 90: 10 methylene dichloride: methanol-eluted fractions), obtain the titled reference compound of yellow solid shape, productive rate 92%, 0.19g.

¹H NMR (400MHz, CD ₃OD) δ: 1.45-1.54 (m, 2H), 1.60-1.69 (m, 4H), 2.53-2.66 (m, 6H), 3.58 (t, 2H), 7.33 (d, 1H), 7.42 (dd, 2H), 7.69 (d, 1H) LRMS:m/z APCl 427[M+H] ⁺Trace analysis: C ₁₉H ₂₁Cl ₃N ₄O 0.5 H ₂O requires:C 52.25; H 5.08 N 12.83; Found C52.52; H 4.96, and N 12.87

Embodiment 3

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids

(3-tetramethyleneimine-1-base-propyl group)-acid amides

Use method similar to Example 2, prepare titled reference compound from the product and 1-(3-aminopropyl) tetramethyleneimine of preparation example 3.With crude compound by purification by silica gel column chromatography (with 90: 10: 1 methylene dichloride: methyl alcohol: 0.88 ammoniacal liquor wash-out), develop with ether then, obtain required product, productive rate 60%, 61.5mg.

¹H NMR (400MHz, CD ₃OD) δ: 1.81-1.92 (m, 6H), 2.65-2.75 (m, 6H), 3.44-3.50 (m, 2H), 7.33 (d, 1H), 7.42 (dd, 2H), 7.70 (d, 1H) LRMS:m/z APCl 427[M+H] ⁺Trace analysis: C ₁₉H ₂₁Cl ₃N ₄O 0.5 H2O requires:C 52.25; H 5.08 N 12.83; Found C 52.02; H 4.86, N12.61

Embodiment 4

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids

(3-morpholine-4-base-propyl group)-acid amides

(87mg, methyl alcohol 0.6mmol) (0.5mL) solution join the product of preparation example 3, and (20mg in tetrahydrofuran (THF) 0.06mmol) (0.5mL) solution, at room temperature stirred mixture 72 hours with 2-(the 4-morpholine also) propylamine.With the reaction mixture vacuum concentration, resistates by purification by silica gel column chromatography (with 90: 10 methylene dichloride: methanol-eluted fractions), obtain titled reference compound, productive rate 71%, 19mg.

¹H NMR(400MHz，CD ₃OD)δ：1.80-1.88(m，2H)，2.43-2.53(m，6H)，3.45(m，2H)，3.65(m，4H)，7.33(d，1H)，7.42(dd，2H)，7.70(d，1H)LRMS：m/z APCl 443[M+H] ⁺

Embodiment 5

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids

(2-tetramethyleneimine-1-base-ethyl)-acid amides

With the product of preparation example 3 (20mg, 0.06mmol) and 1-(2-amino-ethyl) tetramethyleneimine (69mg, 0.6mmol) mixture in tetrahydrofuran (THF) (0.5mL) and methyl alcohol (0.5mL) places microwave tube, heating 30 minutes in microwave under 130 ℃.Mixture was at room temperature stirred 72 hours, then solvent evaporated under reduced pressure.By purification by silica gel column chromatography (with 90: 10 methylene dichloride: methanol-eluted fractions), obtain titled reference compound, productive rate 88%, 22mg.

¹H NMR(400MHz，CD ₃OD)δ：1.80-1.90(m，4H)，2.65(m，4H)，2.75(t，2H)，3.59(m，2H)，7.34(d，1H)，7.42(dd，2H)，7.69(d，1H)LRMS：m/z APCl 413[M+H] ⁺

Embodiment 6

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids

(3-imidazoles-1-base-propyl group)-acid amides

With 1-(3-aminopropyl) imidazoles (0.28mL, 2.42mmol) join the product (122.6mg of preparation example 3,0.37mmol) tetrahydrofuran (THF) (4mL) and methyl alcohol (0.5mL) solution in, with mixture 65 ℃ of down heating 18 hours, 75 ℃ of heating 72 hours down.Subsequently with the reaction mixture vacuum concentration, and by purification by silica gel column chromatography (with 90: 10: 1 methylene dichloride: methyl alcohol: 0.88 ammoniacal liquor wash-out), in methylene dichloride/ether, develop subsequently, obtain the titled reference compound of white solid, productive rate 70%, 110mg.

¹H NMR (400MHz, CD ₃OD) δ: 2.11 (m, 2H), 3.42 (m, 2H), 4.12 (m, 2H), 6.97 (s, 1H), 7.20 (s, 1H), 7.34 (d, 1H), 7.43 (dd, 2H), 7.69 (d, 1H), 7.72 (d, 1H) LRMS:m/z APCl 424[M+H] ⁺Trace analysis: C ₁₈H ₁₆C _L3N ₅O 0.25 H ₂O requires:C 50.37; H 3.87 N 16.32; Found C 50.36; H 3.84, and N 16.15

Preparation example 1

N-(3-bromo-6-methyl-pyridine-2-yl)-ethanamide

(21mL, (10g 53.46mmol) in De diox (50mL) solution, heats mixture 18 hours down at 50 ℃ 223mmol) to join 2-amino-3-bromo-6-picoline with diacetyl oxide.Subsequently under reduced pressure with solvent evaporation, resistates with saturated sodium bicarbonate solution (150mL) dilution.Throw out is leached, wash with water, and be dissolved in again in the methylene dichloride, filtrate is neutralized to pH 7 with saturated sodium bicarbonate solution, and with dichloromethane extraction (3 * 100mL).Merge organic solution, wash with water, and use dried over mgso, vacuum concentration obtains white solid.By purification by silica gel column chromatography (with 75: 25 ethyl acetate: the heptane wash-out), obtain the titled reference compound of white solid, productive rate 75%, 9.2g.

¹H NMR (400MHz, CD ₃OD) δ: 2.17 (s, 3H), 2.49 (s, 3H), 7.09 (d, 1H), 7.94 (d, 1H) LRMS:m/z APCl 231[M+H] ⁺Trace analysis: C ₈H ₉BrN ₂O requires:C 41.95; H 3.96 N12.23; Found C 41.92; H 3.91, and N 12.16

Preparation example 2

6-amino-5-bromo-pyridine-2-carboxylic acids methyl esters

With potassium permanganate (9.77g, 61.81mmol) be added drop-wise to preparation example 1 product (4.8g, in the solution of water 20.95mmol) (100mL) and pyridine (8), with mixture 75 ℃ of down heating 18 hours.Further (3.31g 61.81mmol) joins in the mixture, continues down to stir 18 hours at 75 ℃ with potassium permanganate subsequently.Subsequently reaction mixture is filtered by Celite_, filtrate washs (6 * 50mL) with ethyl acetate.With aqueous solution vacuum concentration, obtain light yellow solid, (5 * 50mL) at 50 ℃ of following azeotropic, obtain the thick sylvite as intermediate with itself and toluene.Subsequently this intermediate is dissolved in the methyl alcohol (400mL) reflux.(5mL) joins in the mixture with the vitriol oil, and continues heating 2 days.Under reduced pressure with solvent evaporation, and with saturated sodium bicarbonate solution (150mL) resistates is alkalized to pH 8, and with dichloromethane extraction (3 * 50mL).With the organic solution dried over mgso that merges, vacuum concentration obtains the titled reference compound of light yellow solid shape, productive rate 34%, 1.65g.

¹H NMR (400MHz, CD ₃OD) δ: 3.90 (s, 3H), 7.25 (d, 1H), 7.88 (d, 1H) LRMS:m/z ES 233[M+H] ⁺Trace analysis: C ₇H ₇BrN ₂O ₂Requires:C 36.39; H 3.05 N 12.12; Found C 36.24; H 3.08, and N 11.94

Preparation example 3

6-amino-5-(2,3,5-three chloro-phenyl)-pyridine-2-carboxylic acids methyl esters

With two (three-tertiary butyl phosphine) palladium (O) (9.3mg, 0.18mmol) tetrahydrofuran (THF) (2mL) solution join the product (0.21g of preparation example 2,0.90mmol), Potassium monofluoride (0.17g, 2.86mmol), 2,3, (0.21g is 0.95mmol) with three (dibenzalacetones), two palladiums (O) (9.3mg for 5-trichlorobenzene boric acid, catalyzer) in tetrahydrofuran (THF) (4mL) solution, reaction mixture was at room temperature stirred 18 hours in the nitrogen atmosphere.Subsequently mixture is diluted with ether, filter by Arbocel_, and further wash with ether.With the filtrate vacuum concentration, by purification by silica gel column chromatography (with 66: 33 heptane: eluent ethyl acetate), obtain the titled reference compound of white solid, productive rate 83%, 0.25g.

¹H NMR (400MHz, CD ₃OD) δ: 3.94 (s, 3H), 7.35 (d, 1H), 7.48 (m, 2H), 7.70 (d, 1H) LRMS:m/z APCl 331[M+H] ⁺Trace analysis: C ₁₃H ₉Cl ₃N ₂O ₂Requires:C 47.09; H 2.74 N8.45; Found C 47.05; H 2.80, and N 8.51

Preparation example 4

6-amino-5-bromo-pyridine-2-carboxylic acids methyl nitrosourea

With methylamine (2M, in the tetrahydrofuran (THF), 36.8mL, (1.70g in methyl alcohol 7.36mmol) (10mL) suspension, stirred mixture 18 hours at room temperature 73.64mmol) to join the product of preparation example 2.Subsequently with the reaction mixture vacuum concentration, resistates by purification by silica gel column chromatography (with 75: 25 ethyl acetate: the heptane wash-out), obtain the solid state titled reference compound, productive rate 96%, 1.63g.

¹H NMR (400MHz, CD ₃OD) δ: 2.90 (s, 3H), 7.20 (d, 1H), 7.82 (d, 1H) LRMS:m/z APCl231[M+H] ⁺Trace analysis: C ₇H ₈BrN ₃O requires:C 36.55; H 3.50 N 18.26; Found C36.50; H 3.47, and N 18.12

¹H nucleus magnetic resonance (NMR) spectrum is consistent with the structure that provides in all cases.Characterization displacement study (δ) provides with the low field of PPM from tetramethylsilane, uses tradition abbreviation expression main peaks: for example, s, unimodal; D, doublet; T, triplet; Q, quartet; M, multiplet; Br, broad peak.Use electro-spray ionization (ESI) or atmospheric pressure chemical ionization (APCI) record mass spectrum (m/z).Following abbreviation is used for common solvent: CD ₃OD, deuterated methanol; THF, tetrahydrofuran (THF)." ammoniacal liquor " refers to that proportion is 0.88 concentrated ammonia solution.

Emrys Creator or EmrysLiberator supply microwave radiation that use provides by Personal Chemistry Ltd..Energy region is 15-300W under 2.45GHz.Actual energy output changes in reaction process, to keep constant temperature.

The analytical procedure check that the compound of all embodiment is all described through the 34-38 page or leaf finds that it is to Na _V1.8The avidity of passage is less than 10 μ M.Particularly, embodiment 1 and 7 binding affinity are respectively 2.04 and 5.48 μ M.

Use the method for inspection of the 38th page of description, the compound of finding all embodiment is to Na _V1.8The selectivity of passage is its optionally at least 2 times to the TTX-S sodium channel.

Claims (15)

1. the compound of a following formula or its pharmaceutically acceptable salt or solvate:

Wherein

R ¹Be randomly by Het ¹, Het ²Or (C ₃-C ₇) (the C of cycloalkyl substituted ₁-C ₆) alkyl, wherein said Het ¹, Het ²(C ₃-C ₇) cycloalkyl randomly on ring carbon atom by one or more (C that are independently selected from ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group and halo (C ₁-C ₄) substituting group of alkyl replaces;

Each R ²Be independently selected from fluorine, chlorine, bromine and iodine;

N is 1,2 or 3;

Het ¹Be the saturated of 5-unit or 6-unit or part unsaturated heterocycle base, it contains one or two heteroatomic ring composition that is selected from nitrogen, oxygen and sulphur independently of one another, and described theheterocyclic nitrogen atom randomly has (C ₁-C ₄) alkyl substituent, described epithio atom randomly has 1 or 2 Sauerstoffatom; And

Het ²Be 5-unit or 6-unit heteroaryl, it contains (a) 1 to 4 nitrogen-atoms or (b) Sauerstoffatom or a sulphur atom and 0,1 or 2 nitrogen-atoms.

2. compound according to claim 1, wherein each R ²Be chlorine.

3. compound according to claim 1 and 2 is characterized in that n is 3.

4. compound according to claim 3 is characterized in that R ²Base is positioned at 2,3 and 5-position of phenyl ring.

5. according to any described compound among the claim 1-4, it is characterized in that R ¹Be (C ₁-C ₆) alkyl, it is randomly replaced by piperidyl, imidazolyl, morpholinyl, piperazinyl or pyrrolidyl.

6. according to any described compound among the claim 1-5, it is characterized in that R ¹Be methyl.

7. pharmaceutical composition, it comprises as the compound of any described structural formula (I) among the claim 1-6 or its pharmaceutically acceptable salt or solvate and one or more pharmaceutically acceptable vehicle.

8. as compound or its pharmaceutically acceptable salt or the solvate of any described structural formula (I) among the claim 1-6, it is as medicine.

9. as compound or its pharmaceutically acceptable salt or the solvate or the purposes of its composition in medicine is made of any described structural formula (I) in claim 1-6 or 7, described medicine is used for the treatment of Na _V1.8Channel modulators has the disease or the patient's condition of indication.

10. as compound or its pharmaceutically acceptable salt or the solvate of any described structural formula (I) in claim 1-6 and 7, or its composition is used for the treatment of the purposes on the medicine of the disease or the patient's condition in manufacturing, and the described disease or the patient's condition are selected from pain, acute pain, chronic pain, inflammatory pain, neuropathic pain, Encelialgia, nociceptive pain, multiple sclerosis, nerve degenerative diseases, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathic disease, functional bowel disorder, inflammatory bowel, the pain relevant with dysmenorrhoea, pelvic pain, urocystitis, pancreatitis, migraine, gathering together property and tension headache, diabetic neuropathy, sciatica, fibromyalgia and cusalgia.

11. purposes according to claim 10, the wherein said disease or the patient's condition are selected from pain, acute pain, chronic pain, neuropathic pain, peripheral nerve pain and osteoarthritis.

12. a treatment comprises in the human Mammals Na _V1.8Channel modulators has the disease of indication or the method for the patient's condition, and this method comprises compound or its pharmaceutically acceptable salt, solvate or the composition as any described structural formula (I) in claim 1-6 or 7 that needs the Mammals of this treatment significant quantity respectively.

13. method for the treatment of the disease or the patient's condition, the described disease or the patient's condition are selected from pain, acute pain, chronic pain, inflammatory pain, neuropathic pain, Encelialgia, nociceptive pain, multiple sclerosis, nerve degenerative diseases, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathic disease, functional bowel disorder, inflammatory bowel, the pain relevant with dysmenorrhoea, pelvic pain, urocystitis, pancreatitis, migraine, gathering together property and tension headache, diabetic neuropathy, sciatica, fibromyalgia and cusalgia, this method comprise respectively the compound of giving with the Mammals significant quantity of this treatment of needs as any described structural formula (I) in claim 1-6 or 7, or its pharmaceutically acceptable salt, solvate, or composition.

14. method according to claim 13, the wherein said disease or the patient's condition are selected from pain, acute pain, chronic pain, neuropathic pain, peripheral nerve pain and osteoarthritis.

15. as compound or its pharmaceutically acceptable salt or the solvate of any described structural formula (I) among the claim 1-6, and the combination of other kind pharmaceutical activity medicament.