CN1720219A

CN1720219A - Fused bicyclic or tricyclic amino acids

Info

Publication number: CN1720219A
Application number: CNA028084454A
Authority: CN
Inventors: 戴维·C·布莱克莫尔; 贾斯廷·S·布赖恩斯; 索菲·C·威廉斯
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 2001-04-19
Filing date: 2002-04-03
Publication date: 2006-01-11
Anticipated expiration: 2022-04-03
Also published as: GB2374595A; CN100354251C; ZA200307097B; GT200200074A; UA74879C2; ECSP034804A; DOP2002000372A; GB0109635D0

Abstract

The compounds of the instant invention are bicyclic or tricyclic amino acids useful in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, arthritis, neuropathological disorders, sleep disorders, visceral pain disorders, and gastrointestinal disorders. Processes for the preparation of the final products and intermediates useful in the process are included. Pharmaceutical compositions containing one or more of the compounds are also included.

Description

Fused bicyclic or tricyclic amino acids

Invention field

The present invention relates to useful as drug novel cyclic aminoderivative, its preparation method, comprise described compound pharmaceutical composition, with and be used for the purposes of following disease treatment.The present invention also relates to two ring and tricycle kentones compounds, can be used as the intermediate of above-claimed cpd preparation.

Background of invention

Gabapentin (Neurontin ^(R)) for can be used for treating the anticonvulsive drug of epilepsy, show that recently it is the potential medicine of neuropathic pain.It is 1-(the amino methyl)-cyclohexyl acetic acid of following formula structure:

Gabapentin is a kind of in the following formula series compound,

R wherein ₁Be hydrogen or low alkyl group, and n is 4,5, or 6.These compounds are recorded in United States Patent (USP) 4,024,75 and division United States Patent (USP) 4,087,544 in.Its disclosed purposes is: to thiosemicarbazide-the induce protection of spasm; Protection to the cardiazol spasm; Disease of brain, epilepsy, have a syncopal attack, the protection of hypokinesia and head wound; And improve brain function.These compounds can be used for elderly patients.The open of above-mentioned two parts of patents is incorporated herein by reference here.

WO99/21824, it openly also is incorporated herein by reference, cyclic amino acid (amino acids) is further disclosed, can be used for treating epilepsy, have a syncopal attack, nerve degenerative diseases, dysthymia disorders, anxiety disorder, paranoid fears, pain, neuropathic disease, gastrointestinal tract disease irritable bowel syndrome (irritable bowel syndrome for example, IBS) and inflammation, particularly sacroiliitis.Disclosed compound comprises those compounds of following formula:

With and salt, wherein: R is hydrogen or low alkyl group; And R ¹To R ⁸Be selected from independently of one another hydrogen, 1～6 carbon atom straight or branched alkyl, phenyl, phenmethyl, fluorine, chlorine, bromine, hydroxyl, hydroxymethyl, amino, amino methyl, trifluoromethyl ,-CO ₂H ,-CO ₂R ¹⁵,-CH ₂CO ₂H ,-CH ₂CO ₂R ¹⁵,-OR ¹⁵, R wherein ¹⁵Be straight or branched alkyl, phenyl or the phenmethyl of 1～6 carbon atom, R ¹～R ⁸Be not hydrogen simultaneously.

The open WO0128978 of international patent application, corresponding to U.S. Patent application U.S.60/160725, put down in writing following formula serial novel bicyclic amino acid, its pharmacologically acceptable salt, with and prodrug:

Wherein n is 1 to 4 integer, wherein has three-dimensional center, and each center can be R or S independently, and preferred compound is those compounds of (wherein n is 2～4 integer) among the above-mentioned formula I-IV.Disclosed compound can be used to treat multiple disease, comprises epilepsy, has a syncopal attack, hypokinesia, head disease, nerve degenerative diseases, dysthymia disorders, anxiety disorder, paranoid fears, pain, neuropathic disease and somnopathy.Wherein discloseder compounds in the patent are using ³H gabapentin and carry out having the radioligand-binding assay high reactivity (Gee N.S., Brown J.P., Dissanayake V.U.K. from the isolating α 2 δ subunits of pig brain tissue, Offord J., Thurlow R., Woodruff G.N., J.Biol.Chem., 1996; 271:5879-5776).

The some of them compound the results are shown in following table:

Patent application EP01400214.1 discloses above-mentioned formula I～IV compound at prevention and treatment visceral pain, and the application in the gastrointestinal tract disease.

Summary of the invention

Derived from analogue, by 3-or 4-person's ring being condensed with the pentamethylene ring and, showing similar high reactivity by the compound that one or more substituting group replaces as the above-claimed cpd of 1-(amino methyl)-pentamethylene acetate.And,, show high reactivity based on the amino-acid compound of two ring [3.2.0] heptane, two ring [4.2.0] octanes and two ring [5.2.0] nonanes (one of atom of wherein amino and carboxyl composition and four membered ring is connected).

The invention provides bicyclic amino acid-like substance and derivative thereof, prodrug and pharmacologically acceptable salt and solvate, can be used for treating that multiple disease comprises epilepsy, has a syncopal attack, hypokinesia, head disease, nerve degenerative diseases, dysthymia disorders, anxiety disorder, paranoid fears, pain, somnopathy, osteoarthritis, rheumatoid arthritis and nervous system disease.The compound that provides also can be used for treating visceral pain, functional bowel disease, for example for example visceral pain, pelvic pain, urocystitis and the pancreatitis of CrohnShi disease, ileitis and ulcerative colitis and the other types that are associated with dysmenorrhoea of stomach-esophageal regurgitation, maldigestion, irritable bowel syndrome and functional abdominal pain syndrome and inflammatory bowel.Also can be used to treat premenstrual syndrome.It is the compound of any following general formula:

R wherein ¹And R ²Respectively be independently selected from cycloalkyl, phenyl and the phenmethyl of H, straight or branched 1-6 carbon atom alkyl, 3-6 carbon atom, the precondition that must satisfy is: under the situation of formula (XVII) secocubane compound, and R ¹And R ²Be not except the hydrogen simultaneously.

Suitable compound (comprising its salt, solvate and prodrug) is:

((1R, 5S)-the 3-aminomethyl-1,2,5-dimethyl-two ring [3.2.0] heptan-3-yl)-acetate;

((1S, 5R)-the 3-aminomethyl-1,2,5-dimethyl-two ring [3.2.0] heptan-3-yl)-acetate;

((1R, 5S)-3-amino methyl-6,6-dimethyl-two ring [3.1.0] oneself-the 3-yl)-acetate;

((1S, 5R)-3-amino methyl-6,6-dimethyl-two ring [3.1.0] oneself-the 3-yl)-acetate;

((1S, 2S, 5R)-2-amino methyl-6,6-dimethyl-two ring [3.1.0] oneself-the 2-yl)-acetate;

((1R, 2S, 5S)-2-amino methyl-6,6-dimethyl-two ring [3.1.0] oneself-the 2-yl)-acetate;

((1S, 2R, 5R)-2-amino methyl-6,6-dimethyl-two ring [3.1.0] oneself-the 2-yl)-acetate;

((1R, 2R, 5S)-2-amino methyl-6,6-dimethyl-two ring [3.1.0] oneself-the 2-yl)-acetate;

((1R, 5R, 6S)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1S, 5S, 6S)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1R, 5R, 6R)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1S, 5S, 6R)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

Cis-((1S, 2R, 4S, 5R)-3-amino methyl-2,4-dimethyl-two ring [3.2.0] heptan-3-yl)-acetate;

Trans-((1S, 2R, 4S, 5R)-3-amino methyl-2,4-dimethyl-two ring [3.2.0] heptan-3-yl)-acetate;

((1S, 5R, 6S, 7R)-3-amino methyl-6,7-dimethyl-two ring [3.2.0] heptan-3-yl)-acetate;

((1S, 5R, 6R, 7S)-3-amino methyl-6,7-dimethyl-two ring [3.2.0] heptan-3-yl)-acetate;

((1R, 2S, 5S)-and 7-amino methyl-3,3-dimethyl-three ring [3.3.0.0] suffering-7-yl)-acetate;

((1R, 6R, 7S)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1S, 6S, 7S)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1R, 6R, 7R)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1S, 6S, 7R)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1R, 7R, 8S)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate;

((1S, 7S, 8S)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate;

((1R, 7R, 8R)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate; And

((1S, 7S, 8R)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate.

Preferred compound (comprising its salt, solvate and prodrug) is:

[(1R, 5R, 6S)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate;

[(1S, 5S, 6R)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate;

[(1RS, 5RS, 6RS)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate;

[(1RS, 6RS, 7SR)-and 7-(amino methyl) two ring [4.2.0] suffering-7-yls] acetate; And

[(1RS, 6RS, 7RS)-and 7-(amino methyl) two ring [4.2.0] suffering-7-yls] acetate.

Particularly preferred compound (comprising its salt, solvate and prodrug) for [(1R, 5R, 6S)-6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate.

The compounds of this invention can non-solvent compound form and solvate form thereof, comprises that hydrate forms exists.Usually, solvate form thereof comprises hydrate forms, and it can comprise isotropic substance and replace (as D ₂O, d6-acetone d6-DMSO), is equal to non-solvent compound form, and is included within the scope of the invention.

Some compound of the present invention has one or more chiral centre, and each center can exist R (D) or S (L) configuration.The present invention includes its all enantiomorph and epimer form and suitable mixture.Diastereomer or cis are achieved with the trans available routine techniques that separates, as by The compounds of this invention or its suitable salt or derivative stereoisomer mixture are carried out fractional crystallization, chromatogram or H.P.L.C..The single enantiomer of The compounds of this invention also can be from corresponding optical purity intermediate preparation, in the time of suitable, or by splitting, for example by corresponding racemoid being carried out on suitable chirality upholder H.P.L.C. separates or by corresponding racemoid and the suitable optical activity acid or the diastereoisomeric salt of alkali formation are carried out fractional crystallization.

The present invention also comprises all suitable isotopic variations of The compounds of this invention or its pharmacologically acceptable salt.The suitable isotopic variations of The compounds of this invention or its pharmacologically acceptable salt is defined as: wherein at least one atom is had the same atoms number but nucleidic mass and nature are found different atoms usually and replaced.The isotropic substance example that can be incorporated in The compounds of this invention and the pharmacologically acceptable salt thereof comprises hydrogen, carbon, and nitrogen, oxygen, phosphorus, sulphur, the isotropic substance of fluorine and chlorine is respectively for for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.The compounds of this invention with and the isotropic substance form of pharmacologically acceptable salt, for example, wherein radio isotope is for example ³H or ¹⁴Those compounds that C has mixed can be used for the tissue distribution research of medicine and/or substrate.Preferred especially isotropic substance tritium, promptly ³H, and carbon-14, promptly ¹⁴C is because its easily preparation and detection.And, replace for example deuterium with isotropic substance, that is, ²H can provide some treatment advantage owing to have the high metabolic stability of religion, and for example, therefore the dosage demand of transformation period or decline in the body of increase can become preferred character in some cases.The compounds of this invention with and the isotropic substance form of pharmacologically acceptable salt, can use the suitable isotropic substance form of suitable reagent usually, be prepared with for example illustrational method of ordinary method or embodiment and the method hereinafter described in the preparation.

Because amino acid is amphoteric, its pharmacologically acceptable salt can be suitable nontoxicity inorganic or organic acid or base addition salt.Suitable acid salt is hydrochloride/muriate, hydrobromide/bromide, hydriodide/iodide, vitriol, hydrosulfate, nitrate, phosphoric acid salt, acid phosphate, acetate, fumarate, aspartate, besylate, bicarbonate/carbonate, d-camphorsulfonic acid salt (camsylate), D and L-lactic acid salt, D and L-tartrate, edisylate, mesylate (mesylate), malonate, the clear salt of lactic acid, gluceptate, mesylate, stearate, glucuronic acid, 2-naphthalenesulfonate (2-napsylate), tosylate, hibenzate, nicotinate, isethionate, malate, maleate, Citrate trianion, Portugal (grape) sugar lime, succinate, sugar lime, benzoate, esylate, and pamoate salt.Suitable alkali salt is to form non-toxic salts with alkali, example is sodium, potassium, aluminium, calcium, magnesium, zinc, choline, glycol amine, hydramine (olamine), arginine, Padil, tromethamine, N, N '-two benzyl Edamines, Methionin, meglumine and diethyl amine salt.Also can use with the salt that quaternary ammonium ion forms, for example tetramethyl ammonium is prepared.The compounds of this invention also can be zwitter-ion.

The salt that The compounds of this invention is suitable is hydrochloride.The comment of suitable salt is referring to Berge etc., J.Pharm.Sci., 66,1-19,1977.

The The compounds of this invention scope also comprises its polymorphism (polymorphs).

The prodrug of above-claimed cpd comprises in the scope of the invention.The effect of oral pharmaceutical depend on medicine stride the epithelial effective transhipment of film with and stability in enterohepatic circulation.Administered parenterally effectively but the relatively poor medicine of oral result, or its plasma half-life very short medicine, can carry out chemically modified and become prodrug forms.Prodrug is a kind of like this medicine: is through chemically modified, may the abiology activity at its action site, but by one or more zymetology or the degraded of other physiological dispositions or be modified into the parent biologically active form.This chemically modified medicine, or prodrug should have different drug metabolism character to patient, and be easier in the epithelial absorption of film, better salt pref and/or solvability, the whole body stability of improvement (for example the transformation period improves in the blood plasma).These chemically modifieds can be

(1) ester or amide derivatives, it can quilt, for example, esterase or lipase degraded.For ester derivative, ester is with the carboxylic moiety of known method derived from drug molecule.For amide derivatives, acid amides is with known method derived from carboxylic acid part or amine moiety.

2) peptide class can be by special or nonspecific protease identification.Amine or carboxylic moiety with known method and drug molecule form amido linkage, peptide can be coupled on the drug molecule.

(3) derivative, the film selective action of the prodrug forms by prodrug forms or modification accumulates in site of action with it.

Any combination of (4) 1～3.

Those of ordinary skills further will recognize for those of ordinary skills to be some compositions of known " preceding-composition ", for example such as among " Design of Prodrugs " by H Bundgaard (Elsevier) 1985 record, when these functional groups that can form " prodrug " are present in the The compounds of this invention, can give the appropriate functional characteristic.In addition, some compounds of the present invention can be used as the prodrug of other compounds of the present invention.The derivative of all protections of The compounds of this invention and prodrug all comprise within the scope of the present invention.

Studies show that: will be prepared into " soft " quaternary ammonium salt by some drugs increases its oral absorption.Quaternary ammonium salt is called " soft " quaternary ammonium salt because, with conventional quaternary ammonium salt, as, R-N ⁺(CH ₃) ₃Different, its hydrolysis can discharge active medicine." soft " quaternary ammonium salt is compared with alkaline drug or its salt has useful physical character.With other salt hydrochloride for example, comparing to increase water-solublely, but the more important thing is and can increase the absorption of medicine from intestines.The absorption that increases may be because the following fact: " soft " quaternary ammonium salt has surfactant properties and can form micella and form unionized ion equity with cholic acid, and it can more effectively permeate enteric epithelium.After prodrug was absorbed, hydrolysis discharged the reactive precursor compound fast.

Aminoacyl-ethyl glycolate and-lactate be known L-threonine derivatives of high therapeutic index (Wermuth C.G., Chemistry and Industry, 1980:433-435).Amino acid whose carboxyl can carry out esterification with known method.Prodrug and soft medicine are being known (Palomino E., Drugs ofthe Future, 1990 in the art; 15 (4): 361-368).The two pieces of quoted passages in back are incorporated herein by reference here.

The invention still further relates to the therepic use of The compounds of this invention, be used for the treatment of or alleviate the symptom of nerve degenerative diseases as medicine.This nerve degenerative diseases comprises, for example, and AlzheimerShi disease, HuntingtonShi disease, ParkinsonShi disease and amyotrophic lateral sclerosis.The present invention also relates to be called the treatment of the nerve degenerative diseases of acute cerebral insult.These diseases include but not limited to: apoplexy, cerebral trauma and faintness.Apoplexy refers to cerebrovascular disease, also refers to cerebrovascular events (CVA), and comprises acute thrombotic apoplexy.Apoplexy comprises focus and whole ischemic.Other the cerebrovascular problem that also comprises transient ischemic attacks and follow cerebral ischemia.These vascular disease can accepted the operation of carotid artery intima excision or other cerebrovasculars or vascular operation usually particularly, or comprise among the patient of diagnostic blood vessel operations such as cerebral angiography and showing effect.Other incidents have injury of head, chorda dorsalis injury, or because the similar damage of seeing in the damage that general anoxic, histanoxia, hypoglycemia, ypotension cause and embolia, hyperfusion and the histanoxia similar operations.The present invention will be useful to many incidents, for example, and in heart bypass operation, the incident of intracranialing hemorrhage, perinatal period faint, heart attack and epilepsy (epilepticus) outbreak.

Common physician can judge the suitable situation of carrying out administration with the inventive method, and wherein the patient easily suffers from or is in the danger of suffering from following disease, for example, and apoplexy and suffering stroke.

The compounds of this invention also can be used for treating acute and chronic pain.Acute pain is very of short duration usually and enliven relevant with the extreme of sympathetic nervous system.Example is a postoperative pain, for example exodontia back, migraine, headache, trigeminal neuralgia and allodynia.Chronic pain is normally defined and continues 3～6 months pain, comprises somatogenic pain and psychologic pain.The chronic pain example comprises that musculoskeletal disease (for example rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, seronegativity (non-rheumatism) joint disease, non-rheumatic arthritis and all joint diseases) related pain and cancer are ache related, peripheral neurophaty and postherpetic neuralgia.Other pain are that pain reaction is arranged.Other pain are caused by peripheral sensory nerve injury or infection.It includes, but are not limited to be derived from that peripheral nerve injury, herpes virus infection, diabetes, cusalgia, clump are torn, neuroma, limb amputation and vasculitic pain.Neuropathic pain also comprises and is derived from the nervous lesion that chronic alcoholism, human immunodeficiency virus infection, thyroprivia, uremia or vitamin deficiency cause.Neuropathic pain includes but not limited to, the pain that nerve injury causes is as, diabetes pain for example.Psychologic pain is the pain of no organ cause, low back pain for example, atypia face ache and chronic headache.The pain of other types has: inflammatory pain, osteoarthritis pain, trigeminal nerve neurodynia, cancer pain, diabetic neuropathy, unpeaceful legs syndrome, acute bleb and postherpetic neuralgia, cusalgia, brachial plexus are torn, occipital neuralgia, gout, illusion limb (phantom limb), burn and other forms of neurodynia, nervosa and congenital pain syndrome.

The The compounds of this invention expection can be used for treating dysthymia disorders.Dysthymia disorders can be the result of organ disease, is secondary to the anxiety of personal damage (loss), or congenital cause is arranged.There is the strong tendency of family's morbidity in some form dysthymia disorders, and there is mechanistic reason (mechanistic cause) in hint at least some form dysthymia disorders.The diagnosis of dysthymia disorders is mainly by making the quantification of patient's mood change.These mood evaluations are undertaken by the doctor usually or Neuropsychology person quantizes for example Hamilton dysthymia disorders equal or the brief introduction of psychosis equal with the equal of having verified.Developed the emotional change degree that many other criterions quantize and measure depressive patients, for example insomnia, attention are concentrated difficulty, lack spirit, are felt valueless and guilty.The diagnosis that is mentally ill of dysthymia disorders Case definition and institute all is collected in Diagnostic and Statistical Manual of Mental Disease (Fourth Edition) referred to as the DSM-IV-R manual published by the AmericanPsychiatric Association, in 1994.

The The compounds of this invention expection can be used for treating visceral pain and gastrointestinal tract disease.Internal organ comprise abdominal organs.These organs comprise sexual organ, spleen and part Digestive tract.The pain related with internal organ can be divided into Digestive tract visceral pain and non-Digestive tract visceral pain.Common gi tract (GI) disease comprises functional bowel disease (FBD) and inflammatory bowel (IBD).These GI diseases comprise widely, can only obtain at present the morbid state of medium control, comprise-for FBD, stomach-esophageal regurgitation, maldigestion, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and-for IBD, CrohnShi disease, ileitis and ulcerative colitis, and all diseases that often produce visceral pain.Show recently: in the pathology of these diseases, especially irritable bowel syndrome and maldigestion, the visceral pain threshold has reduced, and shows the hypersensitivity of internal organ.The visceral pain of other types comprises pain, pelvic pain, urocystitis and the pancreatitis that dysmenorrhoea is relevant.

The known hypersensitivity (Farthing M.J. (1998) Drugs 56:11-21) of having only drug selectivity ground effect GI disease association seldom.Existing pain therapy is divided into two kinds: (1) non-steroid antiinflammatory drug, be used for the treatment of mild pain, but its therepic use is limited by GI side effect (gastric erosion, ulcer of digestive system formation, duodenum and colonic inflammation); (2) morphine and relevant opium class material, be used for the treatment of moderate to serious pain, but its therepic use is also limited by the side effect of non-expectation, and described side effect comprises constipation, breathes to press down and suppress (respiratory depression), resistance and abuse potential.

The The compounds of this invention expection can be used for treating anxiety disorder and paranoid fears, by being confirmed with the standard pharmacological method.

Therefore, the present invention provides the purposes of the compound of the formula that is selected from (I)-(XXV) as medicine on the other hand.

On the other hand, the present invention also provides the purposes of compound in preparation treatment disease Chinese traditional medicine of the formula of being selected from (I)-(XXV).Described disease is selected from epilepsy, has a syncopal attack, hypokinesia, head disease, nerve degenerative diseases, dysthymia disorders, anxiety disorder, paranoid fears, pain, irritable bowel syndrome, somnopathy, osteoarthritis, rheumatoid arthritis, neuropathic disease, visceral pain, functional bowel disease, inflammatory bowel, pain, pelvic pain, urocystitis and pancreatitis that dysmenorrhoea is relevant.

As the aspect of selecting, the invention provides the method for the following disease of treatment, described disease is selected from epilepsy, have a syncopal attack, hypokinesia, the head disease, nerve degenerative diseases, dysthymia disorders, anxiety disorder, paranoid fears, pain, irritable bowel syndrome, somnopathy, osteoarthritis, rheumatoid arthritis, nervous system disease, visceral pain, functional bowel disease, inflammatory bowel, the pain that dysmenorrhoea is relevant, pelvic pain, urocystitis and pancreatitis, this method comprise the compound to the formula that is selected from (I)-(XXV) of the administration treatment significant quantity of this treatment of needs.

The biologic activity of The compounds of this invention can be used ³H gabapentin and the α that is derived from pig brain tissue ₂The δ subunit is measured (Gee N.S., Brown J.P., Dissanayake V.U.K., Offord J., Thurlow R., Woodruff G.N., ADVANCEADVANCE J.Biol.Chem., 1996 in the radioligand assay method; 271:5879-5776).The result can be expressed as μ M or nM α 2 δ binding affinities.

The compounds of this invention can with one or more other active medicinal matters, dividually, side by side or successively ground carries out administration in combination.Suitable material is used for the treatment of pain especially, comprising:

(i) opium class pain killer can be treated ketone, dihydrocodeinone, Propoxyphene, Nalmefene, Naloxone Hydrochloride, Narlan, naltrexone, buprenorphine, butorphanol, Buna coffee and pentazocine as morphine, heroine, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, dolantin, fentanyl, Cocaine, morphine monomethyl ether, paracodin, hydroxyl;

(ii) nonsteroidal anti inflammatory medicine (NSAIDs) is as Asprin, Diclofenac sodium, diflusinal, R-ETODOLAC, Bufemid, Lilly 53838, flufenisal, flurbiprofen, Ibuprofen, indomethacin, Ketoprofen BP 93, ketone Luo Laike, meclofenamic acid, mefenamic acid, Nabumetone, Naproxen Base, oxaprozine, Phenylbutazone, piroxicam, sulindac, Tolmetin, zomepirac and pharmacologically acceptable salt thereof;

(iii) barbituric acid pain killer is as Amobarbital, alkene ethypropymalum, neo-barb, butabital, prominal, metharbital, methohexital, Sodital, phenylethyl barbituric acid, secobarbital, alkene Butobarbital, theamylal, Barbinarcol and pharmacologically acceptable salt thereof;

The Benzodiazepine that (iv) has analgesic effect is as chlordiazepoxide, chlordiazepoxide, diazepam, flurazepam, lorazepam, oxazepam, temazepam, ALprazolanic and pharmacologically acceptable salt thereof;

(the H that v) has analgesic effect ₁Antagonist is as diphenhydramine, neo-antergan, promethazine, Toldrin, Chlorcyclizine and pharmacologically acceptable salt thereof;

(vi) other pain killers, for example glutethimide, meprobamate, first Kui ketone, Dichloralphenazone and pharmacologically acceptable salt thereof;

(vii) skeletal muscle relaxant, as baclofen, carisoprodol, chlorzoxazone, prohe tatriene, methocarbamol, orphenadinum and pharmacologically acceptable salt thereof,

(viii) nmda receptor antagonist is as Dextromethorphane Hbr ((+)-3-hydroxy-n-methylmorphinan) and the metabolite right side thereof mutter ((+)-3-hydroxy-n-methylmorphinan), ketamine, Memantine hydrochloride, Pyrroloquinoline quinone and cis-4-((phosphonomethyl))-2 piperidine carboxylic acid and pharmacologically acceptable salt thereof;

(ix) α-adrenomimetic drug active compound, as quinazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2-(5-methylsulfonyl amido-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl) quinazoline;

(x) tricyclics is as Desipramine, Mi Paming, amytriptiline and go the general woods of first;

(xi) anticonvulsive drug,, pregabalin kind fixed and Sodium Valproate as Carbamzepine, kappa;

(xii) serotonin reuptake inhibitor is as fluoxetine, paroxetine, Citalopram and Sertraline;

(xiii) mix serotonin-NRI, as Midalcipran, venlafaxin and duloxetine;

(xiv) NRI is as Reboxetine;

(xv) tachykinin (NK) antagonist, special Nk-3, NK-2 and NK-1 such as antagonist, (α R, 9R)-7-[3, two (trifluoromethyl) phenmethyls of 5-]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] diazocine [2,1-g] [1,7] 1,5 naphthyridines-6-13-diketone (TAK-637), 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), lanepitant, dapitant and 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl] methylamino]-2-phenyl-piperidines (2S, 3S);

(xvi) Muscainic receptor antagonist is as oxybutin, tolterodine, all woodss of western piperazine, chlorination Spasmo 3 and darifenacin;

(xvii) PDEV inhibitor Virga for example, vardenafil and Cialis (trade mark);

(xviii) cox 2 inhibitor, as celecoxib, Lip river cloth of fragrant former times and valdecoxib;

(xix) non-selective COX inhibitor (preferably having the GI provide protection) is as nitroflurbiprofen (HCT-1026);

(xx) coal-tar pain killer, particularly, Paracetamol;

(xxi) neuroleptic, for example droperidol;

(xxii) Vanilloid receptor stimulant is as resinferatoxin;

(xxiii) β-adrenomimetic drug compound, for example Proprasylyte;

(xxiv) local anesthetic, for example mexiletine;

(XXV) cortical steroid, for example dexamethasone;

(xxvi) 5-hydroxytryptamine receptor agonist and antagonist;

(xxvii) cholinergic (nicotine) pain killer; And

(xxviii) other drug, for example tramadol ^(R)

The combination of compound of the present invention and other drug discriminably, ground or side by side carry out administration successively.Therefore, the present invention also relates to test kit, comprise one or more other treatment medicine of formula (I)-(XXV) compound (for example above-mentioned those that list), and suitable containers.

The compounds of this invention can be individually dosed, but usually with suitable pharmaceutical excipient, the form of mixtures administration of diluent or carrier, select according to the pharmaceutical operation of route of administration and standard.Can add suitable assistant agent.Assistant agent is sanitas, antioxidant, flavouring agent or tinting material.The compounds of this invention quick-release, delay discharge, improvement discharges, continue release, pulse release or control release type.

The compounds of this invention can be with tablet, capsule, many-and little-granule, gelifying agent, film (comprising that mucous membrane attaches), powder, ovule (ovules), elixir, lozenge (comprising liquid filling), the form of masticatory, solution, suspensoid and sprays, by carrying out administration such as but not limited to following route of administration: oral, contain clothes or the hypogloeeis.The compounds of this invention also can permeate agent, or carries out administration with the form of high energy dispersions or coated granule or instant, quickly disintegrated form (as Ashley Publications, 2001 by Liang and Chen put down in writing).The compounds of this invention can crystal or the form of unformed product, frost drying or spraying drying product carry out administration.The appropriate formulation of The compounds of this invention can be in hydrophilic or hydrophobic matrix, ion exchange resin complexes, dressing or the not form and the US6 of dressing, in 106,864 in the other types matrix of record.These pharmaceutical compositions, tablet for example, can comprise vehicle for example Microcrystalline Cellulose, lactose, Trisodium Citrate, lime carbonate, trimagnesium phosphate two generations calcium, Padil and starch (preferred corn, potato or tapioca (flour)), N.F,USP MANNITOL, disintegrating agent, for example Explotab, croscarmellose sodium and complicated silicate, and granulation tamanori for example polyvinylpyrrolidone, HYDROXY PROPYL METHYLCELLULOSE (HPMC), triglyceride level, hydroxy propyl cellulose (HPC), bentonite sucrose, sorbyl alcohol, gelatin and Sudan Gum-arabic.In addition, can be with lubricant, for example Magnesium Stearate, stearic acid, Glyceryl Behenate, PEG and talcum, or wetting agent, for example Sodium Lauryl Sulphate BP/USP joins in the solids composition.In addition, can comprise polymkeric substance for example carbohydrate, phosphatide and protein.

Disperse or dissolve preparation (FDDFs) fast and can comprise following ingredients: aspartyl-phenylalanine methyl ester, acesulfame potassium, citric acid, croscarmellose sodium, cross-linked polyvinylpyrrolidone (crospovidone), diascorbic acid, ethyl propenoate, ethyl cellulose, gelatin, HYDROXY PROPYL METHYLCELLULOSE, Magnesium Stearate, N.F,USP MANNITOL, methyl methacrylate, mint flavouring, polyoxyethylene glycol, (fumed) silicic acid of being fuming, silicon-dioxide, Explotab, sodium stearyl fumarate, sorb (sugar) alcohol or Xylitol.Here be used for describing the solvability that term that FDDFs disperses or dissolves depends on used medicine, that is, when medicine is insoluble, can prepare the fast-dispersing type; When medicinal soluble, can prepare rapid-dissolve dosage form.

Solid dosage, for example tablet is prepared with standard method, and for example, directly compacting or wet method, dry method or melt granulation melt and condense and extrusion method.List or multilayer tablet label can carry out dressing with suitable coating substance well known in the art.

The solids composition of similar type also can be used as for example weighting agent in gelatin, starch or the HPMC capsule of capsule.The preferred vehicle of this purposes comprises lactose, starch, Mierocrystalline cellulose, lactose or high molecular weight polyethylene glycol.Liquid composition also can be used as soft or hard capsule, for example the weighting agent of gelatine capsule.For water-based and oily suspensions, solution, syrup and/or elixir, The compounds of this invention can with many sweet tastes or seasonings, tinting material or dyestuff, with emulsifying agent and/or suspending agent and thinner, for example water, ethanol, propylene glycol, methylcellulose gum, alginic acid or sodiun alginate, glycerine, oil, hydrocolloid and composition forms thereof mix.In addition, the preparation that comprises these compounds and vehicle can be rendered as desciccate, and before using, water or other suitable solvents dissolve again.

Liquid preparation comprises solution, suspensoid and emulsion, for example, and water or water propylene glycol solution.Parenteral injection can be mixed with solution form in the polyoxyethylene glycol aqueous solution with liquid preparation.Being fit to oral aqueous solution can prepare in the following manner: activeconstituents is dissolved in the water, and adds suitable tinting material, seasonings, stablizer and thickening material in needs.Being fit to oral waterborne suspension can prepare in the following manner: the activeconstituents of segmentation is dispersed in the water with viscous substance, viscous substance is for example natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine, and other known suspending agents.

The compounds of this invention also can administrated by injection, promptly, in intravenously, intramuscular, intracutaneous, duodenum or in intraperitoneal, intra-arterial, intrathoracic, the ventricle, in the urethra, in the breastbone, in the encephalic, backbone or subcutaneous administration, or can carry out administration through transfusion, needleless injector or implantable injection technology.Carry out administered parenterally, it is preferably the form of aseptic aqueous solution, suspension or emulsion (or system, can comprise micella), can contain other material well-known in the art, for example, the salt of capacity or carbohydrate, glucose for example is so that solution and blood etc. are opened.In the time of necessary, aqueous solution should carry out suitable buffering (preferred pH is 3～9).For some dosage forms through administered parenterally, it can be used by aseptic non-aqueous system, and fixed oil for example comprises single-or two glyceryl ester, and lipid acid, comprises oleic acid.The preparation of suitable parenteral administration under aseptic condition, for example lyophilize, the pharmaceutical technology of the standard of knowing with those of ordinary skills realizes at an easy rate.Perhaps, activeconstituents can be powder type, dissolves with suitable solvent (as aseptic, apirogen water) before using.

And, but the The compounds of this invention intranasal is interior or inhalation.It can be easily with the form of dry powder (individually, be mixture, for example mix thing with doing of lactose, or blended composition particulate, for example with phosphatide) from Diskus, or with aerosol spray form from pressurized vessel, suction, spraying, atomizer (preferred atomizer produces the segmentation mist with electrofiuid mechanics (electrohydrodynamics)) or sprinker administration, use or do not use suitable propellent, as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, hydro fluoroalkanes for example 1,1,1, the 2-Tetrafluoroethane (the HFA134A[trade mark]) or 1,1,1,2,3,3, the 3-heptafluoro-propane (the HFA227EA[trade mark]), carbonic acid gas, and perfluoroparaffin for example Perflubron (trade mark) or other suitable gas.Under the situation of pressure aerosol, the dose unit of administration can be controlled by the conveying and metering valve that provides.Pressurized vessel, suction, spraying, atomizer or sprinker can comprise the solution or the suspension of active compound, as use alcohol mixture (randomly, aqueous ethanolic solution) or suitable reagent disperses, dissolves or promotes to discharge and propellent as solvent, it can comprise slipping agent in addition, as the sorbitanic trioleate.Capsule, bubble and the film (cartridges) that are used for sucker or insufflator (prepare certainly, for example, gelatin or HPMC), can be prepared into and comprise The compounds of this invention, suitable powder matrix is lactose or starch and the performance improver powdered mixture of 1-leucine, N.F,USP MANNITOL or Magnesium Stearate for example for example.

Before being used for for dry powder formulations that sucks or suspension preparation use, The compounds of this invention will be micronized to suitable size, so that through sucking (it has been generally acknowledged that less than 5 microns) administration.Micronization can realize that for example spiral spray is ground by many methods, and fluidised-bed spray grinds, and uses overcritical liquid phase crystallization or uses spraying drying.

Be used for the appropriate solution preparation that electrofiuid mechanics produces the atomizer of segmentation mist, each stimulation can comprise 1 μ g～10mg The compounds of this invention, and the stimulation volume variation range is 1～100 μ l.Typical formulation can comprise The compounds of this invention, propylene glycol, sterilized water, ethanol and sodium-chlor.Available replace solvents replaces propylene glycol, for example glycerine or polyoxyethylene glycol.

Perhaps, The compounds of this invention can carry out administration to skin, mucous membrane, skin or transdermal partly, for example, with gelinite, hydrogel, lotion, solution, emulsifiable paste, ointment, pulvis, dressing, foam, film, skin patch, wafer, implant, sponge, fibre product, bandage, microemulsion with and array configuration carry out administration.When being used for this purpose, The compounds of this invention can suspend or be dissolved in, for example, with the mixture of one or more following material in: mineral oil, Albolene, white vaseline, propylene glycol, the polyoxyethylene polyoxypropylene compound, emulsifying wax, fixed oil, comprise synthetic list-or two glyceryl ester, and lipid acid (comprising oleic acid), water, sorbitanic but stearate, polyoxyethylene glycol, whiteruss, polysorbate60, the basic ester wax of 16 (alkane), n-Hexadecane (cetearyl) alcohol, 2-octyl group 12 (alkane) alcohol, phenylcarbinol, alcohols (for example ethanol).Perhaps, can use penetration enhancers.Following polymers also can be used, carbohydrate, and protein, phosphatide is with the form of nanoparticle (for example niosomes or liposome) or suspension or lysate.In addition, available iontophoresis, electroporation, phonophoresis and sound saturating (sonophoresis) carry out administration.

Perhaps, but the administration of The compounds of this invention per rectum, for example with the form of suppository or vaginal suppository.But also transvaginal administration.For example, these compositions can be prepared in the following manner: with medicine and suitable nonirritant excipient, for example cocoa butter, synthetic glyceryl ester or polyoxyethylene glycol mix, it is a solid at normal temperature, but liquefaction and/or dissolving in the chamber, thereby discharge medicine.

The compounds of this invention also can carry out administration through the eye approach.When being used for ophthalmic administration, compound is formulated as waiting opens, has regulated the micronization suspension in pH, the Sterile Saline, or, preferably, for waiting, is regulating solution in pH, the Sterile Saline.Can add polymkeric substance, for example cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulosic polymer (as HYDROXY PROPYL METHYLCELLULOSE, hydroxy ethyl cellulose, methylcellulose gum), or mixed polysaccharide polymkeric substance (as gelan gum).Perhaps; can be mixed with ointment for example vaseline or mineral oil; be incorporated into biological degradation (as absorbing the gelinite sponge; collagen) or biology can not absorb (as silicone resin) implant; wafer; drops, lenses, or through particulate or vesicle system for example niosomes or liposome carry out administration.Preparation can be chosen wantonly and sanitas combination, for example chlorination benzalkonium.And available iontophoresis carries out administration.Also can carry out administration, use such as but not limited to drops to ear.

But The compounds of this invention also cyclodextrin is used in combination.Known can formation with drug molecule comprises and the non-mixture that comprises cyclodextrin.The formation of drug-cyclodextrin mixture can change solubleness, dissolution rate, taste, bioavailability and/or the stability of drug molecule.The drug-cyclodextrin mixture is generally used for most of formulations and route of administration.As substituting with the direct compound of medicine, cyclodextrin can be used as supplementary additive, as carrier, and thinner or solubility promoter.α-, β-and γ-Huan Hujing be the most frequently used, and suitable example such as WO-A-91/11172 put down in writing among WO-A-94/02518 and the WO-A-98/55148.

Term ' administration ' comprise is with the administration of virus or non-virus technology.Virus administration mechanism includes but not limited to adenovirus carrier, adeno-associated virus (AAV) carrier, herpesvirus vector, retroviral vector, levivirus (lentivirus) carrier, and baculovirus vector.Non-viral administration mechanism comprises the transfection of lipid mediation, liposome, immunoliposome, lipofectin, the cationic surface amphipathic molecule (cationic facialamphiphiles, CFAs) with and array configuration.The approach that carries out these administration mechanism includes but not limited to per mucous membrane, nose, mouth, parenteral, gi tract, part or hypogloeeis approach.

Medicinal preparations is preferably unit dosage form.In this form, preparation is subdivided into the unitary dose of the activeconstituents that comprises appropriate amount.Unit dosage is the preparation of packing, and this packing comprises discrete preparation, Bao Zhuan tablet for example, capsule, and the powder in bottle or ampoule.And unit dosage can be capsule, tablet, flat jelly or lozenge itself, or it can be any preparation in the proper amt of packaged form.The amount of the activeconstituents in the unitary dose can change or adjusts from 0.1mg～1g, uses and the effect of activeconstituents according to concrete.In medical, medicine can carry out administration three times by every day, for for example, and 100 or the 300mg capsule.When therepic use, be used for the compound of the medicinal method of the present invention, initial dosage is about 0.01mg～about 100mg/kg every day.Preferably every day, dosage range was about 0.01mg～about 100mg/kg.But dosage can change according to the compound of patient's demand, the severity for the treatment of disease and use.The suitable judgement of dosage under the particular case is within those of ordinary skills' ken.Usually, begin to treat with less dosage, this dosage is less than the optimum dosage of compound.After this, dosage progressively increases progressively by less growth, up to being issued to best effect in particular case.For convenience, when needing, total per daily dose can separate and partly administration in a day.

Pharmaceutical composition of the present invention as required, also comprises one or more other compatible medicine.Particularly, said composition can be used for the treatment of the compound of pain with any one or more, for example above-mentioned list those make up.Therefore, the invention provides the compound that comprises the formula of being selected from (I)-(XXV), the pharmaceutical composition of one or more other active medicinal matters and one or more pharmaceutically acceptable carrier.

Integrated approach

Above-claimed cpd can synthesize from following ketone compounds (1)-(12), wherein R ¹And R ²Have above-mentioned given implication:

Above-mentioned formula (1)～(6) intermediate it is believed that it is compounds, and has constituted another aspect of the present invention.According to the present invention, specially suitable intermediate ketone compounds is selected from:

The multiple synthetic method of above-mentioned ketone is described below:

A. ketone 1-12's is synthetic

(1) type (1) ketone compound is synthetic

For example:

(a) known diester compound (13) is reduced into diol compound (14), as using lithium aluminum hydride in organic solvent such as tetrahydrofuran (THF) or ether, carries out to the temperature that refluxes at 0 ℃.

(b) at-60 ℃ to 40 ℃, diol compound (14) is joined in the dichloromethane solution of the pyridine of methylsulfonyl chloride or triethylamine, thus the diformazan sulfonate compound of production (15).

(c) 0 ℃ to the temperature that refluxes, two methanesulfonates (15) are joined lithium aluminum hydride at solvent for example in the solution of tetrahydrofuran (THF) or ether, with the olefin(e) compound of production (16).

(d) above-mentioned olefin(e) compound (16) is joined

● in the mixture of tetracol phenixin or ethyl acetate and acetonitrile, to wherein adding entry, sodium periodate and ruthenium chloride (III), and stir the carboxylic acid cpd of production (17)-40 ℃ to 80 ℃ temperature; Or

● potassium permanganate, produces (17) for example in the presence of the bromination tetrabutylammonium at phase-transfer catalyst in the mixture of water and methylene dichloride.

(e) in room temperature to the temperature that refluxes, carboxylic acid (17) is joined alcohol for example methyl alcohol and concentrated acid for example in the mixture of sulfuric acid or hydrochloric acid, the diester compound of production (18).

(f) at reflux temperature, above-mentioned diester compound (18) is joined for example solution of sodium hydride or potassium tert.-butoxide of highly basic, for example obtain ketone (19) in the tetrahydrofuran (THF)..

(g) 100-180 ℃ of temperature, above-mentioned ketone (19) is joined in the mixture of methyl-sulphoxide and water, obtain the ketone compound of formula (20).

(2) type (4) and (5) ketone compound is synthetic

For example:

(a) known chain ene compound (21), referring to B.D.Kramer, P.D.Bartlett, J.Am.Chem.Soc., 1972,94,3934,0 ℃ to room temperature and organo-borane disiamyl borine for example, thexyl borine or 9-BBN for example mix in ether or the tetrahydrofuran (THF) at solvent.The organo-borane that obtains mixes with the solution of concentrated sodium hydroxide and hydrogen peroxide, obtains the alkylol cpd of formula (22).

(b) alkylol cpd (22) is carried out oxidation, as with oxygenant for example chromium trioxide, dichromic acid pyridine or pyridinium chlorochromate solvent for example in methylene dichloride or the acetone reaction obtain the ketone compound of formula (23).

Similarly method can be used to prepare ketone compound (25), except starting raw material is known alkene (24), and referring to B.D.Kramer, P.D.Bartlett, supra.

(3). synthesizing of type (3) ketone compound

For example:

(a) at-100 ℃ to the temperature between the room temperature, with known ketone (27) compound, referring to patent application U.S.60/160725, join highly basic for example diisopropylamine lithium or hexamethyl dimethyl silyl amine lithium at solvent for example in the solution of tetrahydrofuran (THF) or ether, add methylating reagent then, methyl iodide for example obtains the ketone compound of formula (28).

(b) above-mentioned formula (46) ketone compound further methylates, this reaction is with methylating reagent methyl iodide for example, at highly basic for example in the presence of diisopropylamine lithium or the hexamethyl dimethyl silyl amine lithium, at solvent for example in tetrahydrofuran (THF) or the ether, carry out to the temperature between the room temperature at-100 ℃, obtain the ketone compound product of formula (29).

(4). synthesizing of type (9) and (10) ketone compound

These ketone are compound known, referring to L.Y.Chen, and L.Ghosez, Tetrahedron Letters, 1990,31,4467; C.Houge, A.M.Frisque-Hesbain, A.Mockel, L.Ghosez, J.P.Declereq, G.Germain, M.Van Meerssche, J.Am.Chem.Soc., 1982,104,2920.

These ketone also can be prepared from the known undersaturated ketone of general formula (76),

By with appropriate catalyst for example Pd/C for example carry out hydro-reduction in the ethyl acetate at suitable solvent and be achieved.

(5). synthesizing of type (2) ketone compound

For example:

(a) known carbamate (carbamate) (30) is referring to W.Von der Saal, R.Reinhardt, H.M.Seidenspinner, J.Stawitz, H.Quast, Liebigs Ann.Chem., 1989,703; Z.Cekovic, R.Matovic, J.Serb.Chem.Soc., 1988,53,595, for example in tetrahydrofuran (THF) or the ether, reduce at solvent with lithium aluminum hydride 0 ℃ of temperature to backflow, obtain diol compound (31).

(b)-60 ℃～40 ℃ temperature, diol compound (31) is joined methylsulfonyl chloride in the dichloromethane solution of pyridine or triethylamine, two methanesulfonates of production (32).

(c) 0 ℃ to the temperature that refluxes, two methanesulfonates (32) are joined sodium cyanide or potassium for example in the solution of tetrahydrofuran (THF), ether, methyl-sulphoxide or dimethyl formamide, obtain the dicyanide of structure (33) at solvent.

(d) arrive reflux temperature at 50 ℃, dicyanide (33) is joined in the strong solution of potassium hydroxide or sodium, obtain diprotic acid compound (34).

(e) diprotic acid compound (34) esterification is become diester compound (35), by it is joined

● methyl iodide is being selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene or 1, in the mixture of the solvent of 4-dioxane, to wherein adding alkali for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine or 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), and stir-40 ℃ to 110 ℃ temperature; Or

● methyl alcohol and concentrated acid are for example in the mixture of sulfuric acid or hydrochloric acid, in 0 ℃ to 100 ℃ temperature range; Or

● in trimethyl silyl diazomethane (trimethylsilyldiazomethane) and the mixture of methyl alcohol in benzene or toluene ,-40 ℃ to 100 ℃ temperature; Or

● diazomethane is at solvent for example in the solution in benzene, toluene, the methylene dichloride ,-40 ℃ to 40 ℃ temperature.

(f) for example sodium hydride or potassium tert.-butoxide for example in the solution of tetrahydrofuran (THF), obtain ketone compound (36) at solvent diester compound (35) to be joined highly basic at reflux temperature.

(g) 100-180 ℃ temperature, above-mentioned ketone compound (36) is joined in the mixture of dimethyl sulfoxide (DMSO) and water the ketone compound of production (37).

(6). type 7 and 8 ketone compound synthetic

Such ketone compound can be prepared with ruthenium complex, referring to S-W.Park, and J-H.Son, S-G.Kim, K.H.Ahn, Tetrahedron:Asymmetry, 1999,10,1903.

For example:

With known alkene (38), referring to H.Nishiyama, Y.Itoh, H.Matsumoto, S.B.Park, K.Itoh, J.Am.Chem.Soc., 1994,116,2223, with ruthenium catalyst Cl for example ₂Ru (pybox-ip) (CH ₂=CH ₂), stir to room temperature at 0 ℃ for example in methylene dichloride or the chloroform at solvent, obtain the ketone compound of structure (39).

(a) with known alkylol cpd (40), referring to M.Asami, Bull.Chem.Soc.Jpn., 1990,63,721; T.Sato, Y.Gotoh, Y.Wakabayashi, T.Fujisawa, Tetrahedron Letters, 1983,24,4123, with methylene iodide and zinc alkyl(s) for example zinc methide or zinc ethyl or zinc-copper idol, for example mix to the temperature that reflux at-60 ℃ in toluene or the benzene at solvent, obtain the alkylol cpd of formula (41).

(b) formula (41) alkylol cpd is joined oxygenant, for example chromium trioxide, dichromic acid pyridine or pyridinium chlorochromate for example in the mixture of methylene dichloride or acetone, obtain the ketone compound of formula (42) at solvent.

(7). synthesizing of the ketone compound of type (6)

For example:

With known ketone (43), referring to W.A.Wilczak, D.I.Schuster, Tetrahedron Letters, 1986,27,5331; D.I.Schuster, J.Eriksen, J.Org.Chen, 1979,44,4254, with methylene iodide and zinc alkyl(s) for example zinc methide or zinc ethyl or zinc-copper idol, mix for example in toluene or the benzene at solvent-60 ℃ of temperature to backflow, obtain the ketone compound of structure (44).

(8). synthesizing of the ketone compound of type (11) and (12)

(11) the visible following reference of preparation:

●Ogino，Toshio.Preparation?of?bicyclo[4.2.0]octan-7-ones.NiigataDaigaku?Kyoikugakubu?Kiyo，Shizen?Kagaku?Hen(1973)，15?26-33.

●Marko，Istvan；Ronsmans，Bruno；Hesbain-Frisque，Anne?Marie；Dumas，Stephane；Ghosez，Leon；Ernst，Beat；Greuter，Hans.Intramolecular[2+2]cycloadditions?of?ketenes?and?keteniminium?salts?to?olefins.J.Am.Chem.Soc.(1985)，107(7)，2192-4.

●Chen，Lian?Yong；Ghosez，Leon.Study?of?chiral?auxiliaries?for?theintramolecular[2+2]cycloaddition?of?a?keteniminium?salts?to?an?olefinic?doublebond.A?new?asymmetric?synthesis?of?cyclobutanones.Tetrahedron?Lett.(1990)，31(31)，4467-70.

(12) the visible Marko et of preparation al., supra.

B. the ketone starting raw material is to the conversion of amino-acid compound of the present invention

Can utilize a kind of among following logical method A～E, above-mentioned ketone compound is converted into amino-acid compound, exemplify shown in the explanation with ketone (1) as following, wherein R ¹=R ²=methyl.

Method A:

(a) ketone is breathed out (20) and is changed into unsaturated ester (45a), by with trialkyl phosphine acyl acetic acid ester for example triethyl phosphine acyl acetic acid ester in the presence of alkali, react.Suitable alkali comprises sodium hydride, potassium hydride KH, and hexamethyl dimethyl silanyl amine lithium-or sodium-or potassium, butyllithium or potassium tert.-butoxide.This reaction can for example in tetrahydrofuran (THF), dimethyl formamide, ether or the methyl-sulphoxide, be carried out in-78 ℃ to 100 ℃ temperature range at polar non-proton organic solvent.

(b) Nitromethane 99Min. is added in the unsaturated ester (45a), in the presence of alkali and in polar non-proton organic solvent, carries out the Michael addition reaction at-20 ℃～100 ℃ and obtain nitro ester (45b).Suitable alkali comprises tetrabutylammonium fluoride, tetramethyl guanidine, 1, and in 5-diaza-two ring [4,3,0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene, sodium alkoxide or potassium is potassium tert.-butoxide, salt of wormwood, sodium hydride or Potassium monofluoride for example.Appropriate organic solvent comprises tetrahydrofuran (THF), ether, dimethyl formamide, methyl-sulphoxide, benzene, toluene, methylene dichloride, chloroform or tetracol phenixin.

(c) reduction of nitro ester (45b), and carry out ring-closure reaction by the amino that obtains and ester group and obtain cyclic lactam (45c).Hydrogenation can be in the presence of catalyzer, for example Raney nickel, palladium charcoal or rhodium catalyst or other nickel or palladium-containing catalyst, at solvent for example methyl alcohol, ethanol, Virahol, ethyl acetate, acetate, 1, in 4-dioxane, chloroform or the ether, carry out 20 ℃～80 ℃ temperature.

(d) hydrolysis of cyclic lactam (45c) as using the hydrochloric acid from 0.01M to 12M, and is chosen wantonly at solvent for example 1, and 4-dioxane, acetate or water exist down, produce amino acid (46).

Method B:

(a) with ketone compound (20) and cyanoacetic acid alkane ester, for example ethyl cyanacetate is carried out condensation, this is reflected in the organic solvent that is selected from toluene, benzene, dimethylbenzene or normal heptane and carries out, to wherein adding acetate and β-Beta Alanine or ammonium acetate, or piperidines.This mixture stirs 0 ℃～150 ℃ temperature, by, for example, use Dean-Stark trap or activatory molecular sieve to dewater the cyano group ester of production (47).

(b) cyano group ester (47) is changed into dicyanide (48), by in water and ethanol or methyl alcohol, handling with potassium cyanide or sodium cyanide.Reflux this mixture and passing through for example utilizes the Dean-Stark trap to dewater.

(c) by with saturated toluene of gaseous hydrogen chloride or the ethanol synthesis in the benzene, the cyano methyl of dicyanide (48) is converted into the ethoxy carbonyl methyl.This temperature of reaction is from-30 ℃ to 40 ℃.

(d) cyano group that will obtain cyano group ester (49) is reduced through hydrogenation, and this is reflected at methyl alcohol, in ethanol or the ethyl acetate, for example uses that nickel, palladium, platinum or rhodium catalyst carry out 15 ℃ to 60 ℃ temperature, obtains lactan (50) after the closed loop.

(e) carrying out the hydrolysis of lactan (50), is the hydrochloric acid of 0.01M to 12M as working concentration, and chooses wantonly at solvent for example 1, and 4-dioxane, acetate or water exist down, produce amino acid (51).

Method C:

(a) cyano group ester (47) is joined chlorination, bromination or benzene iodide methyl magnesium at anhydrous solvent such as tetrahydrofuran (THF), 1, in the mixture of 4-dioxane, normal heptane, toluene, ether or t-butyl methyl ether, temperature of reaction obtains the cyano group ester of formula (52) from-100 ℃ to 110 ℃.

(b) cyano group of cyano group ester (52), by with alkali such as potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide are removed in 4-dioxane or the Diethylene Glycol at solvent such as ethylene glycol, 2-methoxy ethyl ether, 1.This mixture stirs 25 ℃～250 ℃ temperature, the carboxylic acid cpd of production (53).

(c) carboxylic acid group of acid compound (53) protects as its methyl esters (54) because of by changing into its 1-6 carbon atom alkyl ester.In order to realize this purpose, acid compound (53) can be added

● methyl iodide is being selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene or 1, in the mixture of the solvent of 4-dioxane, to wherein adding alkali, for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine or 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) also stirs-40 ℃～110 ℃ temperature; Or

● for example in the mixture of sulfuric acid or hydrochloric acid, temperature of reaction is 0 ℃～100 ℃ for methyl alcohol and concentrated acid; Or

● trimethyl silyl diazomethane and methyl alcohol are in the mixture of benzene or toluene, and temperature of reaction is-40 ℃～100 ℃; Or

● for example in the mixture of benzene, toluene, methylene dichloride, temperature of reaction is-40 ℃～40 ℃ to diazomethane at solvent.

(d) phenyl that will obtain ester (54) is oxidized to the carboxylic acid group, handles at the mixture of tetracol phenixin or ethyl acetate and acetonitrile with sodium periodate and ruthenium chloride (III), to wherein adding entry.This mixture obtains carboxylic acid (55)-40 ℃～80 ℃ temperature stirring.

(e) carboxylic acid group with carboxylic acid (55) changes into isocyanic ester, by it is joined

● in the mixture that the alkali that is selected from triethylamine or diisopropyl ethyl amine and the solvent that is selected from toluene, benzene, dimethylbenzene, tetrahydrofuran (THF), ether or normal heptane form, to wherein adding diphenyl phosphoryl azide (DPPA) and stirring the isocyanic ester of production (26) 0 ℃～150 ℃ temperature; Or

● Vinyl chloroformate or isobutyl chlorocarbonate and alkali, for example in the mixture that triethylamine or diisopropyl ethyl amine and tetrahydrofuran (THF) or acetone or ether form, temperature of reaction is-40 ℃～78 ℃, adds water and the tetrahydrofuran (THF) or the acetone soln of sodium azide then, adds toluene or benzo then and refluxes.

(f) isocyanic ester of compound (56) and ester group are hydrolyzed into amino and carboxyl simultaneously, as the hydrochloric acid by 0.01M～12M, choose wantonly at solvent for example 1, and 4-dioxane, acetate or water exist down and reacts generation amino acid (57).

Method D:

(a) fs of the carboxy protective of carboxylic acid (53); be translated into (58) acyl chlorides form; temperature of reaction is-40 ℃～110 ℃; with its with for example react in methylene dichloride, chloroform, ether, toluene or the t-butyl methyl ether at aprotic organic solvent as oxalyl chloride or thionyl chloride; to the N that wherein adds 0.01 molar percentage～10 molar percentages, dinethylformamide (DMF).

(b) muriate (58) is converted into its tert-butyl ester, as by in aprotic organic solvent such as methylene dichloride, chloroform, ether, toluene or t-butyl methyl ether, reacting, to wherein adding N, N-diisopropyl ethyl amine (DIPEA) or triethylamine with the trimethyl carbinol.Reaction mixture stirs the ester cpds of production (59)-40 ℃～110 ℃ temperature.

(c) phenyl with ester cpds (59) is oxidized to carboxyl, itself and sodium periodate and ruthenium chloride (III) is carried out in the mixture of tetracol phenixin or ethyl acetate and acetonitrile, to wherein adding entry.This reaction mixture is at-40 ℃～80 ℃ stirrings, the carboxylic acid cpd of production (60).

(d) acidic group with the carboxylic acid cpd of (60) is converted into ester group, by it is joined

● methyl iodide be selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene or 1, in the mixture that the solvent of 4-dioxane forms, to wherein adding alkali for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine or 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), and at 40 ℃ .～110 ℃. temperature stir the ester cpds of production (61); Or

● trimethyl silyl diazomethane and methyl alcohol are in the solution of benzene or toluene, and temperature of reaction is-40 ℃～100 ℃; Or

● diazomethane is at solvent benzene for example, toluene, and in the solution of methylene dichloride, temperature of reaction is-40 ℃～40 ℃.

(e) remove tert.-butoxy from diester compound (61), by using trifluoroacetic acid and solvent such as methylene dichloride, chloroform, 1, the solution that 4-dioxane, tetrahydrofuran (THF), ether or t-butyl methyl ether form is handled.Reaction mixture stirs-40 ℃～110 ℃ temperature, obtains the carboxylic acid cpd of formula (62).

(f) carboxyl with carboxylic acid (62) changes into isocyanic ester (63), by it is joined

● the alkali that is selected from triethylamine or diisopropyl ethyl amine be selected from toluene, benzene, dimethylbenzene is in the mixture that the solvent of tetrahydrofuran (THF), ether or normal heptane forms, to wherein adding diphenyl phosphoryl azide (DPPA) and stirring 0 ℃～150 ℃ temperature; Or

(g) with the isocyanic ester of compound (63) and ester group hydrolysis simultaneously, as hydrochloric acid, having or solvent-free for example 1 by 0.01M～12M, 4-dioxane, acetate or water exist down and react generation amino acid (64).

Method E:

(a) with cyano group ester (47) and chlorination or bromination allyl group magnesium or chlorination crotyl magnesium and dialkyl group zinc, for example cuprous iodide (I) or cuprous cyanide (I) of zinc methide or copper (I) salt for example, at anhydrous solvent such as tetrahydrofuran (THF), 1, react in 4-dioxane, normal heptane, toluene, ether or the t-butyl methyl ether, temperature of reaction is-100 ℃～110 ℃, obtains the unsaturated adduct of formula (65).

(b) cyano group of adduct (65) by with alkali, as potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide, be selected from ethylene glycol, 2-methoxy ethyl ether, 1, in the organic solvent of 4-dioxane or Diethylene Glycol the reaction and be removed.Reaction mixture stirs 25 ℃～250 ℃ temperature, obtains the carboxylic acid cpd of formula (66).

(c) carboxyl of carboxylic acid cpd (66) changes into ester group, by it is joined

● methyl iodide is being selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene or 1, in the mixture of the solvent of 4-dioxane, to wherein adding alkali, for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine or 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) also stirs the ester cpds of production (67)-40 ℃～110 ℃ temperature; Or

● diazomethane is at solvent benzene for example, toluene, and in the mixture of methylene dichloride,, temperature of reaction is-40 ℃～40 ℃.

(d) unsaturated group in the ester (67) that obtains is carried out oxidation, handle at the mixture of tetracol phenixin or ethyl acetate and acetonitrile with sodium periodate and ruthenium chloride (III), to wherein adding entry.This mixture stirs the carboxylic acid cpd that obtains formula (68)-40 ℃～80 ℃ temperature.

(e), carboxylic acid cpd (68) is converted into amino-acid compound (69) according to method C.

Any among the also available logical method F of above-mentioned ketone compounds～G is translated into amino acid, as following at exemplifying shown in the explanation that type (9) ketone carries out.

Method F

(a), ketone is converted into nitro ester (70) according to above-described method.

(b) with nitro ester (70) with suitable alkali, for example aqueous sodium hydroxide solution is hydrolyzed and obtains nitrocarboxylic acid compound (71), it carries out hydrogenation suitably, and as H ₂In the presence of Pd/carbon catalyst, at suitable solvent, for example reaction obtains amino acid (72) in the ethanol.

Method G

(a) undersaturated ester (73), wherein R is phenmethyl or diphenyl methyl, can prepare from ketone compounds according to above-mentioned any logical method.

(b) nitro ester (74) is carried out the catalytic hydrogenation reduction in suitable solvent and be converted into amino acid (75).

Perhaps, compound of the present invention also can prepare according to following method H and I from the ketone compounds of known undersaturated type (8):

Method H

(a) according to the logical method of foregoing description, ketone (76) is converted into undersaturated nitro ester (78).

(b) nitro ester (78) is with suitable alkali, and for example aqueous sodium hydroxide solution is hydrolyzed and obtains nitrocarboxylic acid compound (79), and the latter is through hydrogenation, as H ₂At suitable solvent, for example reaction obtains amino acid (80) in the ethanol in the presence of Pd/carbon catalyst.

Method I

(a) undersaturated nitro ester (82) can prepare from ketone (76) according to above-described logical method.

(b) nitro ester (82) is carried out the catalytic hydrogenation reduction in suitable solvent and be converted into amino acid (83).

The pharmacologically acceptable salt of The compounds of this invention can prepare easily, and the solution of The compounds of this invention acid or the alkali with needs is suitably mixed.Salt precipitates from solution, filters to collect maybe can obtain by evaporating solvent.

With reference to above-mentioned logical method; the very easy understanding of this area those skilled in the art: when having protecting group, other protecting groups of common available similarity are exchanged, when being described as when carboxyl protecting with ethyl; use any suitable alkyl at an easy rate, suitably C _1-6Alkyl exchanges.

This area those skilled in the art should very easy understanding: concrete steps can anyly never show in the above-mentioned logical method provide the mode of The compounds of this invention to make up suitably.

Therefore, generally speaking, the invention provides:

(i) formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic or prodrug;

The (ii) method of preparation formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic or prodrug;

(iii) pharmaceutical composition comprises formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic or prodrug, and pharmaceutically acceptable vehicle, diluent or carrier;

(iv) formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic, prodrug or composition are as the purposes of medicine;

(v) formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic, prodrug or composition are in the purposes that is used for preparing the medicine for the treatment of above-mentioned any disease of mentioning;

(vi) formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic, prodrug or composition are in the purposes that is used for preparing the medicine for the treatment of above-mentioned any disease of mentioning;

(vii) treat above-mentioned any treatment of diseases method of mentioning in the Mammals, comprise with compound formula I-XXV compound or pharmaceutically acceptable salt thereof, solvate, polymorphic, prodrug or the composition of therapeutic dose described Mammals is treated;

(the viii) novel intermediates of formula (1a), (4a)-(7a), (70), (71), (73), (74), (77)-(79), (81) or (82);

(ix) above-mentioned any treatment of diseases method, it comprises the patient to this treatment of needs, side by side, respectively or successively uses the composition of formula I-XXV compound and other pain therapy medicines.

(x) application of the composition of formula I-XXV compound and other treatment medicine in the medicine of the above-mentioned any disease of preparation treatment; And

(xi) a kind of product comprises formula I-XXV compound and a kind of other medicine, as the combination preparation of side by side, respectively or successively using in above-mentioned any disease treatment.

The present invention exemplifies explanation by following non-limiting examples and intermediate.

Embodiment 1

[(1R, 5R, 6S)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] the acetate hydrochloride

The isocyanic ester (about 9.33mmol) of preparation 9 and 6N hydrochloric acid (30ml) refluxed 18 hours.Mixture is cooled off, dilute with water (60ml), and with methylene dichloride (2 * 50ml) extraction.The water concentrating under reduced pressure obtains yellow solid, obtains the 0.92g title compound with ethyl acetate and acetonitrile washing, is white solid.

¹H-NMR(400MHz，d ₆-DMSO)：δ＝7.94(3H，brs)，3.15(1H，d)，3.07(1H，d)，2.72(1H，quin)，2.46(1H，m)，2.42(1H，d)，2.33(1H，d)，1.98(1H，m)，1.80-1.64(2H，m)，1.59(1H，m)，1.48-1.28(3H，m)，1.23(1H，dd).

LRMS(APCI)：m/z[(MH-HCl) ⁺]184.

LCMS (Prodigy ODS3 (3 μ) 150mm * 4.6mmid post, 20-100% acetonitrile+0.1% formic acid) retention time=4.34 minute, 100% purity.

[α] _D(C=0.127, methyl alcohol)=-12.4 °

Trace analysis: measured value: C, 54.64; H, 8.19; N, 6.42.C ₁₀H ₁₇NO ₂.HCl require C, 54.67; H, 8.26; N, 6.38%.

Fusing point (Perkin Elmer DSC7): 198 ℃.

Perhaps:

Embodiment 1A

Nitrocarboxylic acid compound (the 2.0g of preparation 32; 9.4mmol) (1: 1 IPA: H ₂O or) 1:1MeCN:H ₂O (40ml; 20ml/g) solution is with 10%Pd/C (0.2g; 0.1g/g) 50 ℃ and 60psi hydrogenation 18 hours.Reaction mixture filters Celite, and filter cake is with 1: 1 IPA: H ₂O or 1: 1 MeCN: H ₂O (20ml) washing.The merging filtrate washing, vacuum concentration obtains title compound also further with IPA or MeCN azeotropic drying, is white crystalline solid (1.52g).

Embodiment 1B

Preparation 33 lactan (4.70g, 28.44mmol) and hydrochloric acid (57ml, 6N solution) refluxed together 6 hours.With mixture cooling, and dilute with water (60ml) then.(filter, then reduction vaporization by 2 * 100ml) washings with methylene dichloride for water layer.The pale solid that obtains grinds with ethyl acetate, and uses acetonitrile: 1: 1 recrystallization of water obtains title compound (4.51g).

Embodiment 1C

[(1R, 5R, 6S)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate (zwitter-ion)

The amino acid hydrochloride (2.2g) of embodiment 1 is dissolved in the 7.25ml water (3.3ml/g).This solution is adjusted to pH 7.5, uses the NaOH aqueous solution of about 1.6ml at first, but use the NaOH aqueous solution of several 0.1N at last.Sedimentary zwitter-ion stirred 8 hours at 8 ℃, and filtered soup compound, and residue washs with ice-cold water (6ml).Water-wet cake is soup compound and refluxed 10 minutes in IPA (15ml).After being cooled to envrionment temperature, filter soup compound, residue is with washing IPA (5ml).Filter cake is soup compound again in IPA (15ml), reflux and be cooled to envrionment temperature.Filter soup compound, residue washs with IPA (5ml), and 40 ℃ of vacuum-dryings obtain title compound to constant weight, are crystalline solid (1.4g).

Fusing point (Perkin Elmer DSC7): 208 ℃.

Embodiment 2

[(1S, 5S, 6R)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] the acetate hydrochloride

The isocyanic ester (about 11.0mmol) and the 6N hydrochloric acid (30ml) of preparation 12 were refluxed 16 hours.With mixture cooling, dilute with water (100ml), and with methylene dichloride (2 * 50ml) extract.The water concentrating under reduced pressure obtains yellow solid, and with ethyl acetate and acetonitrile washing, obtains the 0.94g title compound, is white solid.

¹H-NMR(400MHz，d6-DMSO)δ＝7.94(3H，brs)，3.15(1H，d)，3.07(1H，d)，2.72(1H，quin)，2.46(1H，m)，2.42(1H，d)，2.33(1H，d)，1.98(1H，m)，1.80-1.64(2H，m)，1.59(1H，m)，1.48-1.28(3H，m)，1.23(1H，dd).

LRMS(APCI)：m/z[(MH-HCl) ⁺]184。

LCMS (Prodigy ODS3 (3[mu]) 150mm * 4.6mmid post, 20-100% acetonitrile+0.1% formic acid) retention time=4.34 minute, 100% purity.

[α] _D(c=0.35, methyl alcohol)=+ 13.0 °

Embodiment 3

[(1RS, 5RS, 6RS)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] the acetate hydrochloride

The isocyanic ester (about 2.79mmol) and the 6N hydrochloric acid (15ml) of preparation 17 were refluxed 18 hours.With mixture cooling, dilute with water (60ml), and with methylene dichloride (3 * 50ml) extract.The water concentrating under reduced pressure is obtained yellow solid, obtain the 0.45g title compound, be white solid with ethyl acetate and acetonitrile washing.

¹H-NMR(400MHz，d6-DMSO)δ＝7.84(3H，brs)，2.92(1H，d)，2.85(1H，d)，2.75(1H，t)，2.69(1H，d)，2.59(1H，d)，2.39(1H，t)，1.81-1.62(4H，m)，1.41-1.30(4H，m)。

LRMS(APCI)：m/z[(MH-HCl)]184

LCMS (Prodigy ODS3 (3 μ) 150mm * 4.6mmid post, 20-100% acetonitrile+0.1% formic acid) retention time=4.27 minute, 99.8% purity.

Embodiment 4

[(1RS, 6RS, 7SR)-and 7-(amino methyl) two ring [4.2.0] suffering-7-yls] the acetate hydrochloride

With preparation 22 lactan (3.20g, 17.9mmol) 1, the middle reflux of 4-dioxane (15ml) and 6NHCl (50ml).After 4 hours, with the mixture cool to room temperature, and with methylene dichloride (2 * 30ml) washing.Collect water, vacuum desolventizes.Residue grinds with ethyl acetate, and filtration is collected the solid and the vacuum-drying that obtain and obtained the 2.74g title compound, is white solid.

¹H-NMR(400MHz，D ₂O)3.24(2H，m)，2.58(2H，s)，2.39(1H，m)，2.03(1H，m)，1.76(2H，m)，1.59-1.10(7H，m)，0.96(1H，m)。

LRMS(APCI)：m/z[(MH-HCl) ⁺]198。

Embodiment 5

[(1RS, 6RS, 7RS)-and 7-(amino methyl) two ring [4.2.0] suffering-7-yls] the acetate hydrochloride

Under room temperature and nitrogen, with diphenyl phosphoryl azide (0.43ml, 1.98mmol) join stirring triethylamine (0.28ml, 2.03mmol) and preparation 29 carboxylic acid cpd (0.47g, about 1.96mmol) in the solution of toluene (15ml).Mixture was stirred 16 hours, then 35 ℃ warm 1 hour.With mixture cooling, with ethyl acetate (60ml) dilution, with saturated sodium bicarbonate aqueous solution (2 * 100ml), the salt water washing, and dry (MgSO ₄).Remove solvent under reduced pressure, and with the yellow oil reflux in 6NHCl (20ml) that obtains.After 18 hours, mixture is cooled to room temperature, and with methylene dichloride (2 * 60ml) and ether (60ml) washing.Collect water, and vacuum desolventizes.Residue grinds with ethyl acetate, and collects the solid that obtains, and filters and vacuum-drying, obtains the 0.304g title compound, is white solid.

¹H-NMR(400MHz，d6-DMSO)：3.04(1H，d)，2.99(1H，d)，2.68(1H，d)，2.62(1H，d)，1.98(1H，m)，1.83(1H，t)，1.69-1.28(9H，m)，1.00(1H，m)。

LRMS(APCI)：m/z[(MH-HCl) ⁺]198。

Preparation 1

(1RS, 5RS)-two the ring [3.2.0] heptan-6-ketone

With palladium (1g, 10%w/w are adsorbed on the charcoal) join two ring [3.2.0] hept-2-ene"-6-ketone (12ml, in ethyl acetate 111.3mmol) (100ml) solution, with mixture 30 ℃ and 483kPa (70p.s.i.) hydrogenation 6 hours.Filter reaction mixture, solvent evaporated under reduced pressure obtain the 12.1g title compound, are colorless oil.

ν _Max(film)/cm ^-11777.

¹H-NMR(400MHz，CDCl ₃)：δ＝3.54(1H，m)，3.19(1H，ddd)，2.88(1H，m)，2.49(1H，ddd)，2.04(1H，m)，1.91-1.49(5H，m)。

Preparation 1A

(1R, 5R)-two the ring [3.2.0] heptan-6-ketone

(1S, 5R)-two ring [3.2.0] hept-2-ene"-6-ketone ¹(50.0g; EtOAc 462mmol) (375mL) solution, with 50% moistening 5%Pd/C (5.0g) in envrionment temperature 60psi hydrogenation 8 hours.Reaction mixture is filtered Celite, and vacuum concentrated filtrate obtains the 41.3g title compound, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)：δ＝3.55(1H，m)，3.20(1H，m)，2.90(1H，m)，2.50(1H，m)，2.0-1.5(6H，m)。

¹Ref：EP0074856

Preparation 2

(2E/Z)-(1RS, 5RS)-two the ring [3.2.0] heptan-6-subunit (cyano group) ethyl acetate

With preparation 1 ketone compound (22.4g, 204.1mmol), ethyl cyanacetate (21.7ml, 204.1mmol), ammonium acetate (15.7g, 204.1mmol) and glacial acetic acid (11.7ml, 204.1mmol) use Dean-Stark trap refluxes in toluene (220ml).After 8 hours, mixture is cooled off, and with ethyl acetate (300ml) dilution, water (3 * 150ml), the salt water washing, and dry (MgSO ₄).Solvent evaporated under reduced pressure is carried out chromatography (SiO with residue ₂, heptane/ethyl acetate, 95: 5～7: 3) and obtain 6: 4 the title compound isomer mixture of 30g, be yellow solid.

ν _Max(film)/cm ^-12225,1725,1640.

¹H-NMR (400MHz, CDCl ₃): δ (main isomer)=4.26 (2H, m), 3.64 (1H, m), 3.36 (1H, ddd), 2.96 (1H, m), 2.70 (1H, dt), 2.11 (1H, m), (1.92-1.58,5H, m) 1.32 (3H, m); δ (less isomer)=4.26 (2H, m), 3.85 (1H, m), 3.15 (1H, ddd), 2.96 (1H, m), 2.52 (1H, dt, J20.0,4.4), 2.02 (1H, m), (1.92-1.58,5H, m), 1.32 (3H, m).

LRMS(APCI)：m/z[M-H]204。

Preparation 3

[(1RS, 5RS, 6RS)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] (cyano group) ethyl acetate

At-78 ℃, ((the 1M ethereal solution of 78ml is in THF 78mmol) (100ml) solution with the Benzene Chloride methyl magnesium that was added to stirring in 1 hour for 10.0g, THF 48.7mmol) (60ml) solution with preparation 2 cyano group ester cpds under argon gas.After this temperature stirs 2 hours, add saturated ammonium chloride solution (40ml) termination mix.Mixture is warmed to room temperature, and adds dilute hydrochloric acid (150ml).(3 * 100ml) extract water layer with ethyl acetate.Merge organic layer, use the salt water washing, dry (MgSO ₄), and solvent removed under reduced pressure obtained title compound, for diastereomeric mixture and be yellow oil, can be used for next step by crude product.

ν _Max(film)/cm ^-12247,1741.

LRMS(APCI)：m/z[M-H]296。

Preparation 4

[(1RS, 5RS, 6SR)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] acetate

With preparation 3 diastereomeric cyano group ester mixture (20.3g, 68.4mmol) and potassium hydroxide (23.0g, 410.4mmol) in ethylene glycol (350ml) 160 ℃ heated 38 hours.Afterwards, with the mixture cooling, carefully add dilute hydrochloric acid (300ml).(3 * 200ml) extract, and merge organic fraction, use the salt water washing, dry (MgSO with ethyl acetate with mixture ₄), and solvent evaporated under reduced pressure.Residue is carried out chromatography (SiO ₂, heptane/ethyl acetate, 8: 2) and obtain the racemic diastereomeric title compound of 14.6g, be white solid.

ν _Max(film)/cm ^-13344,1704.

¹H-NMR(400MHz，CDCl ₃)：δ＝7.31-7.22(5H，m)，3.02(1H，d)，2.97(1H，d)，2.64(2H，m)，2.34(1H，d)，2.24(1H，d)，2.13(1H，m)，1.84-1.59(3H，m)，1.50-1.32(4H，m)。

LRMS(APCI)：m/z[M-H]243。

Preparation 5

[(1R, 5R, 6S)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] acetate

(6.67g, (24g is in ethyl acetate solution 98.2mmol) 55mmol) to join the racemic acid of the preparation 4 of stirring with (R)-(+)-[α]-methylbenzene methylamine.Acid salt is separated out from solution, is white solid.Obtain the 8.5g acid salt three times with re-crystallizing in ethyl acetate.Further residue is carried out recrystallization, obtain other 8.5g acid salt.First salt is dissolved in the methylene dichloride, with dilute hydrochloric acid, salt water washing and dry (MgSO ₄).Solvent evaporated under reduced pressure obtains the 5.0g title compound, is white solid.

HPLC[Chiralcel OD 250 * 4.6mm post (moving phase: 90% hexane, 10%IPA contains 0.5%TFA)]: retention time=5.1 minute (94%ee).

[α] _D(C=1.13, chloroform)=-20.2 °

Second batch of salt is dissolved in the methylene dichloride, with dilute hydrochloric acid, salt water washing and dry (MgSO ₄), obtain other 5g acid (86%ee).

Similar approach is used for preparation:

Preparation 6

[(1S, 5S, 6R)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] acetate

By the salt that adds (S)-(-)-[α]-methylbenzene methylamine generation is carried out recrystallization.

HPLC[Chiralcel OD 250 * 4.6mm post (moving phase: 90% hexane, 10%IPA contains 0.5%TFA)]: retention time=4.2 minute (95%ee).

[α] _D(c=1.0, chloroform)=+ 17.3 °

Preparation 7

[(1R, 5R, 6S)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] methyl acetate

Under 0 ℃ of argon gas, (the 2M hexane solution of 17.7ml, 35.4mmol), (7.85g is 32.1mmol) in the solution in toluene (90ml) and methyl alcohol (22.5ml) mixture to be added drop-wise to the acid compound of the preparation 5 of stirring with the trimethyl silyl diazomethane.Mixture is warmed to room temperature and stirred 4 hours.Remove solvent under reduced pressure, and residue is dissolved with ethyl acetate (150ml), with saturated sodium bicarbonate (150ml), dilute hydrochloric acid (100ml), salt water washing, and dry (MgSO ₄).Solvent evaporated under reduced pressure, residue carries out chromatography (SiO ₂, heptane/ethyl acetate, 9: 1) and obtain the 7.0g title compound, be colorless oil.

ν _Max(film)/cm ^-11736.

¹H-NMR(400MHz，CDCl ₃)：δ＝7.28-7.21(5H，m)，3.67(3H，s)，2.97(1H，d)，2.92(1H，d)，2.65-2.60(2H，m)，2.26(1H，d)，2.18(1H，d)，2.08(1H，m)，1.82-1.52(3H，m)，1.48-1.22(4H，m)。

LRMS(APCI)：m/z[MH ⁺]259。

[α] _D(c=0.11, methyl alcohol)=-24.1 °.

Preparation 8

[(1R, 5R, 6S)-and 6-(2-methoxyl group-2-oxoethyl) two ring [3.2.0] heptan-6-yl] acetate

Preparation 7 ester cpds (7.0g, 27.1mmol) and sodium periodate (81.1g, 379.3mmol) stirring 5 minutes in ethyl acetate (100ml), acetonitrile (100ml) and water (150ml) together.Mixture is cooled to 0 ℃, and (0.11g is added in the reaction mixture 0.54mmol) with hydration ruthenium chloride (III).Reaction is warmed to room temperature and stirred 24 hours.Add ether (150ml), mixture stirred 40 minutes.(200ml) joins in the mixture with dilute hydrochloric acid, uses ethyl acetate (3 * 100ml) extractions then.Merge organic fraction, with saturated hypo solution, salt water washing, dry (MgSO ₄), and solvent evaporated under reduced pressure obtains title compound, is yellow oil.

ν _Max(film)/cm ^-11733,1715.

¹H-NMR(400MHz，CDCl ₃)：δ＝3.65(3H，s)，2.82-2.76(3H，m)，2.55-2.49(3H，m)，2.05(1H，m)，1.81(1H，m)，1.73-1.69(2H，m)，1.49-1.28(4H，m)。

LRMS(APCI)：m/z[M-H]225。

Preparation 9

[(1R, 5R, 6S)-6-(isocyanato-methyl) two ring [3.2.0 heptan-6-yl] methyl acetate

In room temperature under nitrogen, with diphenyl phosphoryl azide (8.45ml, 39.2mmol) join stirring triethylamine (5.6ml, 40.4mmol) and preparation 8 acid compound (8.78g is 38.8mmol) in toluene (80ml) solution.Mixture was stirred 3 hours, and warm 1.5 hours at 35 ℃ then.Mixture is cooled off, with ethyl acetate (150ml) dilution, with saturated sodium bicarbonate aqueous solution (150ml), salt water washing, and dry (MgSO ₄).Remove solvent under reduced pressure and obtain the 8.7g title compound, be yellow oil.

ν _Max(film)/cm ^-12265,2171,1733.

Preparation 10

[(1S, 5S, 6R)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] methyl acetate

0 ℃ under argon gas, (the 2M hexane solution of 5.7ml, (2.77g is 11.3mmol) in the solution of toluene (30ml) and methyl alcohol (7.5ml) mixture 11.4mmol) to be added drop-wise to the acid compound of the preparation 6 of stirring with the trimethyl silyl diazomethane.Mixture is warmed to room temperature and stirred 4 hours.Remove solvent under reduced pressure, and residue is dissolved in the ethyl acetate (100ml), with saturated sodium carbonate (100ml), dilute hydrochloric acid (100ml), salt water washing and dry (MgSO ₄).Solvent evaporated under reduced pressure is carried out chromatography (SiO with residue ₂, heptane/ethyl acetate, 9: 1) and obtain the 2.84g title compound, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)：δ＝2.28-7.21(5H，m)，3.67(3H，s)，2.97(1H，d)，2.92(1H，d，)，2.65-2.60(2H，m)，2.26(1H，d)，2.18(1H，d)，2.08(1H，m)，1.82-1.52(3H，m)，1.48-1.22(4H，m)；

[α] _D(c=0.11, methyl alcohol)=+ 23.1 °

Preparation 11

[(1S, 5S, 6R)-and 6-(2-methoxyl group-2-oxoethyl) two ring [3.2.0] heptan-6-yl] acetate

(7.0g, 27.1mmol) (81.1g 379.3mmol) stirred 5 minutes in ethyl acetate (100ml), acetonitrile (100ml) and water (150ml) ester cpds of preparation 10 together with sodium periodate.Mixture is cooled to 0 ℃, and (0.11g 0.54mmol) joins in the reaction mixture with hydration ruthenium chloride (III).Reaction is warmed to room temperature and stirred 24 hours.Add ether (150ml) and mixture was stirred 40 minutes.(200ml) joins in the mixture with dilute hydrochloric acid, uses ethyl acetate (3 * 100ml) extractions then.Merge organic fraction, with saturated hypo solution, salt water washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is yellow oil.

¹H-NMR(400MHz；CDCl ₃)：δ＝3.65(3H，s)，2.82-2.76(3H，m)，2.55-2.49(3H，m)，2.05(1H，m)，1.81(1H，m)，1.73-1.69(2H，m)，1.49-1.28(4H，m)。

Preparation 12

[(1S, 5S, 6R)-and 6-(isocyanato-methyl) two ring [3.2.0] heptan-6-yl] methyl acetate

Under room temperature and nitrogen, (2.4ml, (1.6ml is 11.4mmol) and in toluene (30ml) solution of preparation 11 acid compound (about 11.0mmol) 11.1mmol) to join the triethylamine of stirring with diphenyl phosphoryl azide.Mixture was refluxed 2 hours.Mixture is cooled off, with ethyl acetate (150ml) dilution, with saturated sodium bicarbonate aqueous solution (2 * 150ml), the salt water washing, and the drying (MgSO ₄).Remove solvent under reduced pressure and obtain title compound, be yellow oil.

ν _Max(film)/cm ^-12265,2151,1734.

Preparation 13

[(1RS, 5RS, 6SR)-and 6-phenmethyl two ring [3.2.0] heptan-6-yl] tert.-butyl acetate

At 0 ℃, (0.92ml, (2.34g is in methylene dichloride 9.58mmol) (30ml) solution 10.5mmol) to be added drop-wise to the acid compound of the preparation 4 of stirring with oxalyl chloride under argon gas.Carefully add dimethyl formamide (0.3ml), and mixture is warmed to room temperature, and stirred other 4 hours.Vacuum is removed solvent, and residue is diluted with methylene dichloride (20ml).Under argon gas,, join in the reaction mixture carefully with methylene dichloride (20ml) solution of 2-methyl-prop-1-alcohol (10ml), add then diisopropyl ethyl amine (2.5ml, 14.4mmol).Mixture was stirred 17 hours, be dissolved in then in the ethyl acetate, with saturated sodium bicarbonate aqueous solution (2 * 200ml) washings, and dry (MgSO ₄).Remove solvent under reduced pressure, and residue is carried out chromatography (SiO ₂, heptane/ethyl acetate 95: 5) and obtain title compound (2.40g), be yellow oil.

ν _Max(film)/cm ^-11727.

¹H-NMR(400MHz，CDCl ₃)：δ＝7.28-7.21(5H，m，Ph)，2.98(1H，d)，2.92(1H，d)，2.64-2.56(2H，m)，2.16(1H，d)，2.09(1H，d)，2.04(1H，m)，1.80-1.50(3H，m)，1.48(9H，s)，1.47-1.20(4H，m)。

Preparation 14

[(1RS, 5RS, 6SR)-and 6-(2-tert.-butoxy-2-oxoethyl) two ring [3.2.0] heptan-6-yl] acetate

Preparation 13 ester cpds (2.4g, 7.99mmol) and sodium periodate (23.93g, 111.8mmol) stirring 5 minutes in ethyl acetate (24ml), acetonitrile (24ml) and water (36ml) together.Mixture is cooled to 0 ℃, and (0.033g joins in the reaction mixture 0.16mmol) with hydration ruthenium chloride (III).This reaction is warmed to room temperature and stirred 24 hours.Add ether (60ml), and mixture was stirred 40 minutes.(150ml) joins in the mixture with dilute hydrochloric acid, uses ethyl acetate (3 * 100ml) extractions then.Merge organic fraction, use the salt water washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound (1.78g, 83%), is yellow oil.

ν _Max(film)/cm ^-11728,1714.

¹HNMR(400MHz，CDCl ₃)：δ＝2.78(1H，d)，2.71(1H，d)，2.43(1H，d)，2.38(1H，d)，2.01(1H，m)，1.86-1.64(3H，m)，1.52-1.36(6H，m)，1.45(9H，s)。

LRMS(APCI)：m/z[M-H]267。

Preparation 15

[(1RS, 5RS, 6SR)-and 6-(2-tert.-butoxy-2-oxoethyl) two ring [3.2.0] heptan-6-yl] methyl acetate

0 ℃ under argon gas, (the 2M hexane solution of 4.3ml, (1.78g is 6.63mmol) in the stirred solution of toluene (24ml) and methyl alcohol (6ml) mixture 8.6mmol) to be added drop-wise to preparation 14 acid with the trimethyl silyl diazomethane.Mixture is warmed to room temperature and stirred 24 hours.Remove solvent under reduced pressure, and residue is dissolved in the ethyl acetate (100ml), with saturated sodium carbonate (100ml), dilute hydrochloric acid (100ml), salt water washing and dry (MgSO ₄).Solvent evaporated under reduced pressure obtains title compound, is yellow oil.

ν _Max(film)/cm ^-11732.

LRMS(APCI)：m/z[M-O ^tBu]209。

Preparation 16

[(1RS, 5RS, 6RS)-and 6-(2-methoxyl group-2-oxoethyl) two ring [3.2.0] heptan-6-yl] acetate

In methylene dichloride (15ml) solution of 0 ℃ of preparation 15 ester cpds (about 6.63mmol) that trifluoroacetic acid (5ml) are added drop-wise to stirring.Mixture is warmed to room temperature and continues stirring 17 hours.Mixture is reached neutral pH with saturated sodium bicarbonate aqueous solution washing until it, and extract with methylene dichloride (50ml).Again be acidified to pH4 with dilute hydrochloric acid then.Mixture is used methylene dichloride (2 * 50ml) extractions then.Merge organic fraction, use the salt water washing, dry (MgSO ₄), and solvent is removed in decompression.With residue chromatogram purification (SiO ₂, 8: 2～6: 4 heptane/ethyl acetate), obtain the 0.63g title compound, be colorless oil.

ν _Max(film)/cm ^-13200,1738,1705.

¹H-NMR(400MHz，CDCl ₃)δ＝3.68(3H，s)，2.84-2.73(3H，m)，2.61-2.48(3H，m)，2.03(1H，m)，1.80(1H，m)，1.79-1.32(6H，m)。

LRMS(APCI)：m/z[M-H]225。

Preparation 17

[(1RS, 5RS, 6RS)-and 6-(isocyanato-methyl) two ring [3.2.0] heptan-6-yl] methyl acetate

With diphenyl phosphoryl azide (0.61ml, 2.82mmol), triethylamine (0.40ml, 2.90mmol), preparation 16 acid compound (0.63g, 2.79mmol) backflow 6 hours in toluene (15ml) together.Mixture is cooled off, and dilute with ethyl acetate (60ml).The solution that obtains is with saturated sodium bicarbonate aqueous solution (150ml), salt water washing and dry (MgSO ₄).Remove solvent under reduced pressure and obtain title compound, be yellow oil.

Rf (heptane-ethyl acetate, 9: 1) 0.36.

ν _Max(film)/cm ^-12259,2171,1736.

Preparation 18

(1RS, 6SR)-8,8-dichloro two ring [4.2.0] suffering-7-ketone

(2.0g 8.0mmol) is dissolved in the water (75ml), and joins in the zinc bits (30g) with copper sulfate (II).Mixture was stirred 2 hours.Mixture is filtered and collects solid, wash twice and 100 ℃ of vacuum-dryings 24 hours with acetone.Part activatory zinc (8.0g) is joined tetrahydrobenzene, and (10ml is in ether 98.9mmol) (180ml) solution.With trichoroacetic chloride (10.48ml, the speed adding that ether 93.96mmol) (20ml) solution refluxes to keep mixture.After finishing, mixture heating up refluxed 4 hours.With the mixture cool to room temperature,, and carefully be poured in the saturated sodium bicarbonate aqueous solution with ether (50ml) dilution.Mixture carries out acidifying with 2N HCl, and isolates organic layer.Ether extract layer water is then with saturated sodium bicarbonate aqueous solution washing.Collect organic phase, dry (MgSO ₄), decompression desolventizes, with residue flash chromatography (silicic acid, Et0Ac: heptane 1: 9) carry out purifying, obtain the 8.62g title compound, be limpid oily matter.

ν _Max(film)/cm ^-12939,1802.

¹H-NMR(400MHz，CDCl ₃)：δ＝3.94(1H，m)，2.95(1H，m)，2.18-1.82(2H，m)，1.80-1.20(6H，m)。

Preparation 19

(1RS, 6RS)-two ring [4.2.0] suffering-7-ketone

With (1RS, 6SR)-8, (8.60g is 44.6mmol) with zinc bits (29.0g, 446mmol) reflux in acetate (100ml) for 8-dichloro two ring [4.2.0] suffering-7-ketone (preparation 18).After 4 hours,, dilute, and (saturated NaHCO is used in 2 * 100ml) washings then with 2NNaOH with ether (200ml) with the mixture cool to room temperature ₃(4 * 100ml) solution washings.Collect the ether phase, dry (MgSO ₄), remove solvent under reduced pressure and obtain the 4.79g title compound, be bright oily matter.

ν _Max(film)/cm ^-12930,1776.

¹HNMR(400MHz，CDCl ₃)：δ＝3.27(1H，m)，3.12(1H，m)，2.42(2H，m)，2.20-1.02(8H，m)。

Preparation 20

(2Z/E)-(1RS, 6RS)-two ring [4.2.0] suffering-7-subunit ethyl acetate

Sodium hydride (60%, be dispersed in the oil, 1.46g 36.6mmol) is suspended in the anhydrous tetrahydro furan (150ml), and is chilled to 0 ℃.(7.65ml 38.5mmol) adds, and mixture was stirred 15 minutes at 0 ℃ with triethyl phosphine acyl acetic acid ester (triethylphosphonoacetate).Then with (1RS, 6RS)-two (4.78g, THF 38.5mmol) (20ml) solution adds ring [4.2.0] suffering-7-ketone (preparation 19), and mixture is 0 ℃ of stirring.After 1 hour, mixture is warmed to room temperature, dilutes, and (2 * 150ml) wash with 2NHCl with ethyl acetate (200ml).Collect organic phase, dry (MgSO ₄), remove solvent under reduced pressure.With residue carry out flash chromatography (Silica, EtOAc: purifying heptane 3: 20), obtain the 5.49g title compound, be bright oily matter.

ν _Max(film)/cm ^-12929,1715,1186.

¹H-NMR (400MHz, CDCl ₃): δ=5.63 and 5.58 (1H altogether, the E/Z isomer, 2Xm), 4.15 (2H, m), 3.38-2.98 (2H, m), 2.79-2.35 (2H, m), 2.13-1.05 (11H, m).

LRMS(APCI)：m/z[MH ⁺]195。

Preparation 21

[(1RS, 6RS, 7SR)-and 7-(nitro methyl) two ring [4.2.0] suffering-7-yls] ethyl acetate

With (2Z/E)-(1RS, 6RS)-two encircle [4.2.0] suffering-7-subunit acetic ester (preparation 20) (5.47g, 28.2mmol) with tetrahydrofuran (THF) (50ml) in Nitromethane 99Min. (3.05ml, 56.4mmol) and tetrabutylammonium fluoride (the THF solution of 1M, 42ml, mixture heating up to 60 42.0mmol) ℃.After 18 hours, the mixture cool to room temperature dilutes with ethyl acetate (200ml), and (the salt water washing is used in 2 * 100ml) washings then with 2N HCl.Collect organic phase, dry (MgSO ₄) and vacuum desolventize.With residue through flash chromatography (silica gel, EtOAc: purifying heptane 1: 9), obtain the 4.73g title compound, be bright oily matter.

ν _Max(film)/cm ^-11182,1547,1731,2936.

¹HNMR(400MHz，CDCl ₃)：δ＝4.83(2H，m)，4.12(2H，q)，2.66(2H，m)，2.57(1H，m)，2.22(1H，m)，2.05(1H，m)，1.86(1H，m)，1.76-1.31(7H，m)，1.26(3H，t)，1.10(1H，m)。

LRMS(APCI)：m/z[MH ⁺]256。

Preparation 22

(1S, 6S, 7R)-spiral shell [two ring [4.2.0] sufferings-7,3 '-tetramethyleneimine]-5 '-ketone

30 ℃ in the presence of the Raney nickel catalyzator in 483kPa (70p.s.i.) nitrogen atmosphere, with [(1RS, 6RS, 7SR)-7-(nitro methyl) two ring [4.2.0] suffering-7-yls] ethyl acetate (preparation 21) (4.70g, 18.4mmol) vibration in methyl alcohol (150ml).After 4 hours, catalyzer is filtered celite and remove, solvent evaporated under reduced pressure obtains the 3.23g title compound, is bright oily matter, places after fixing.

ν _Max(film)/cm ^-12919,1712,1677.

¹HNMR(400MHz，CDCl ₃)：δ＝5.61(1H，br.s)，3.46(2H，m)，2.42(2H，m)，2.18-1.01(12H，m)。

LRMS(APCI)：m/z[MH ⁺]180。

Preparation 23

(2E/Z)-(1RS, 6RS)-two ring [4.2.0] suffering-7-subunit (cyano group) ethyl acetate

With preparation 19 ketone compound (2.85g, 23.0mmol), ethyl cyanacetate (2.45ml, 23.0mmol), ammonium acetate (1.77g, 23.0mmol) and glacial acetic acid (1.32ml) in toluene (40ml), reflux use Dean-Stark trap.After 6 hours, mixture is cooled off, and dilute, water (50ml), salt water washing and dry (MgSO with ethyl acetate (150ml) ₄).Solvent evaporated under reduced pressure.Residue is carried out chromatography (SiO ₂, heptane/ethyl acetate, 4: 1), obtain cyano group-ester mixture of 2.76g, be yellow solid.

¹H-NMR (400MHz, CDCl ₃): δ (main isomer); 4.26 (2H, q), 3.36 (1H, m), 3.02 (2H, m), 2.58 (1H, m), 1.30-2.18 (8H, m), 1.33 (3H, t).

δ (less important isomer)=4.25 (2H, q), 3.48 (1H, m), 3.23 (2H, m), 2.58 (1H, m), 1.30-2.18 (8H, m), 1.32 (3H, t).

Preparation 24

[(1RS, 6RS, 7RS)-and 7-phenmethyl two ring [4.2.0] suffering-7-yls] (cyano group) ethyl acetate

-78 ℃ under argon gas, ((the 1M ethereal solution of 20ml is in THF 20mmol) (20ml) solution with the Benzene Chloride methyl magnesium that was added to stirring in 1 hour for 2.75g, THF 12.5mmol) (60ml) solution with preparation 23 cyano group ester.After this temperature stirs 2 hours, add saturated ammonium chloride solution (10ml) termination mix.Mixture is warmed to room temperature, and adds dilute hydrochloric acid (30ml).(3 * 40ml) extract water layer with ethyl acetate.Merge organic layer, use the salt water washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains the mixture of diastereomeric cyano group-ester.Residue is carried out chromatography (SiO ₂, heptane/ethyl acetate, 4: 1), obtain the diastereomeric cyano group-ester mixture of 3.53g, be bright oily matter.

Rf (heptane-ethyl acetate, 4: 1)=0.30

ν _Max(film)/cm ^-12247,1740.

Preparation 25

[(1RS, 6RS, 7SR)-and 7-phenmethyl two ring [4.2.0] suffering-7-yls] acetate

With preparation diastereomeric cyano group-ester mixture of 24 (3.52g, 11.3mmol) and potassium hydroxide (3.8g, mixture 67.9mmol) in ethylene glycol (75ml) 160 ℃ heated 72 hours.Afterwards, with mixture cooling, and carefully to add dilute hydrochloric acid be acidity until solution with the pH detection paper.(3 * 100ml) extract, and merge organic fraction, use the salt water washing, dry (MgSO with ethyl acetate with mixture ₄), solvent evaporated under reduced pressure.Residue is carried out chromatography (SiO ₂, ethyl acetate: heptane 1: 4) obtain the racemic diastereomeric acid compound of 2.11g, be yellow oil.

¹H-NMR(400MHz，CDCl ₃)：δ＝7.31-7.22(5H，m)，3.08(1H，d)，3.00(1H，d)，2.56(1H，m)，2.44(1H，d)，2.38(1H，d)，2.25(1H，m)，1.98(1H，m)，1.75(1H，t)，1.71-1.30(7H，m)，1.10(1H，m)。

LRMS(ES)：m/z[M-H]257。

Preparation 26

[(1RS, 6RS, 7SR)-and 7-phenmethyl two ring [4.2.0] suffering-7-yls] tert.-butyl acetate

At 0 ℃, (0.67ml, (1.79g is in methylene dichloride 6.93mmol) (25ml) solution 7.62mmol) to be added drop-wise to the acid compound of the preparation 25 of stirring with oxalyl chloride at nitrogen.Careful add dimethyl formamide (0.25ml), and mixture is warmed to room temperature and stirred other 4 hours.Vacuum desolventizes, and residue is diluted with methylene dichloride (20ml).Under argon gas, methylene dichloride (20ml) solution of 2-methyl-prop-1-alcohol (9ml) is joined in the reaction mixture carefully, add then diisopropyl ethyl amine (1.8ml, 10.4mmol).Mixture was stirred 18 hours, add saturated sodium bicarbonate aqueous solution (30ml) then.(3 * 50ml) extract, and merge organic fraction, with salt water washing and dry (MgSO with ethyl acetate with mixture ₄).Remove solvent under reduced pressure, and residue is carried out chromatography (SiO ₂, heptane/ethyl acetate 98: 2), obtain ester cpds (2.42g).

¹H-NMR(400MHz，CDCl ₃)：δ＝7.33-7.19(5H，m)，3.05(1H，d)，2.96(1H，d)，2.53(1H，m)，2.30-2.18(3H，m)，1.90(1H，m)，1.72(1H，t)，1.65-1.55(2H，m)，1.48(9H，s)，1.47-1.00(6H，m)。

Preparation 27

[(1RS, 6RS, 7SR)-and 7-(2-tert.-butoxy-2-oxoethyl) two ring [4.2.0] suffering-7-yls] acetate

With preparation 26 ester (6.93mmol) and sodium periodate (20.75g, 97.02mmol) stirring 5 minutes in ethyl acetate (20ml), acetonitrile (20ml) and water (30ml) together.Mixture is cooled to 0 ℃, and (0.03g joins in the reaction mixture 0.14mmol) with hydration ruthenium chloride (III).Reaction is warmed to room temperature and stirred 24 hours.Stirred 40 minutes with ether (100ml) adding and with mixture.(150ml) joins in the mixture with dilute hydrochloric acid, uses ethyl acetate (3 * 100ml) extractions then.Merge organic fraction, use the salt water washing, dry (MgSO ₄), and solvent evaporated under reduced pressure obtains acid compound O.64g.

¹H-NMR(400MHz，CDCl ₃)：δ＝2.84(1H，d)，2.75(1H，d)，2.61-2.48(3H，m)，2.17(1H，m)，1.95-1.80(3H，m)，1.78-1.30(7H，m)，1.44(9H，s)。

Preparation 28

[(1RS, 6RS, 7SR)-and 6-(2-tert.-butoxy-2-oxoethyl) two ring [4.2.0] suffering-7-yls] methyl acetate

0 ℃ under argon gas, (the 2M hexane solution of 1.2ml, (0.64g is 2.28mmol) at toluene (10ml) and methyl alcohol (in the solution of 2.5ml mixture 2.4mmol) to be added drop-wise to the acid compound of the preparation 27 of stirring with the trimethyl silyl diazomethane.Mixture is warmed to room temperature, and stirred 16 hours.Remove solvent under reduced pressure, residue is dissolved in the ethyl acetate (150ml), with saturated sodium carbonate (100ml), dilute hydrochloric acid (100ml), salt water washing, and dry (MgSO ₄).Solvent removed under reduced pressure obtains the 0.65g ester cpds, is yellow oil.

¹HNMR(400MHz，CDCl ₃)：δ＝3.66(3H，s)，2.83(1H，d)，2.74(1H，d)，2.57(1H，d)，2.49(1H，d)，2.15(1H，m)，1.94-1.78(3H，m)，1.72-1.06(8H，m)，1.43(9H，s)。

Preparation 29

[(1RS, 6RS, 7SR)-and 7-(2-methoxyl group-2-oxoethyl) two ring [4.2.0] suffering-7-yls] acetate

At 0 ℃, trifluoroacetic acid (3ml) is added drop-wise to ester cpds stirring, preparation 28, and (0.65g is in methylene dichloride 2.19mmol) (9ml) solution.Mixture is warmed to room temperature, and continues to stir 16 hours.Mixture is washed with saturated sodium carbonate solution, use ethyl acetate (50ml) extraction then.Water layer is acidified to pH4 with dilute hydrochloric acid, uses ethyl acetate (2 * 50ml) extractions then.Merge organic fraction, use the salt water washing, dry (MgSO ₄), remove solvent under reduced pressure.Residue is through chromatogram (SiO ₂, 6: 4 heptane/ethyl acetate) and purifying obtains the acid compound of 0.47g, is yellow oil.

¹HNMR(400MHz，CDCl ₃)：δ＝3.67(3H，s)，2.84(1H，d)，2.78(1H，d)，2.74(1H，d)，2.66(1H，d)，2.49(1H，m)，2.14(1H，m)，1.95-1.81(2H，m)，1.70(1H，m)，1.63(1H，m)，1.55-1.30(5H，m)，1.07(1H，m)。

Preparation 30

(2E)-(1R, 5R)-two ring [3.2.0] heptan-6-subunit ethyl acetate/(2Z)-(1R, 5R)-two ring [3.2.0] heptan-6-subunit ethyl acetate

With triethyl phosphine acyl acetic acid ester (53.4g; 238.3mmol) THF (25mL) solution join 60% sodium hydride and disperse (9.53g; 238.3mmol) THF (75mL) suspension in, maintain the temperature between 5-15 ℃.Add (1R, 5R)-two ring [3.2.0] heptan-6-ketone (preparation 1A) (25g, THF 226.9mmol) (150ml) solution,, maintain the temperature between 5-15 ℃.Reaction mixture was stirred 30 minutes in envrionment temperature, add entry (100mL) then.Layering, the organic layer that comprises title compound is directly used in next step.

¹HNMR(400MHz，CDCl ₃)：δ＝5.55(1H，d)，4.15(2H，q)，3.40(1H，m)，3.20(1H，m)，2.90(1H，m)，2.55(1H，m)，1.8-1.5(5H，m)，1.30(3H，t)。

Preparation 31

(1R, 5R, 6S)-[6-(nitro methyl) two ring [3.2.0] heptan-6-yl] ethyl acetate

The THF solution (40.9g compound cumulative volume is 225mL) of preparation 30 compounds is diluted with THF (270ml).Add TBAF.3H ₂O (93.1g; 295.0mmol) and MeNO ₂(453.9mmol), and with vlil 4 hours.With reaction mixture cooling and concentrating under reduced pressure.Toluene (330mL) is added, and with biphase mixture water (165mL), 2M hydrochloric acid (165mL+100mL) washing, and further water (165mL) washing.The toluene layer that will comprise product is at MgSO ₄Last dry, and concentrating under reduced pressure obtains title compound, is red/brown oil (90% (2 step overall yield)).

¹HNMR(400MHz，CDCl ₃)：δ＝4.80(2H，m)，4.15(2H，m)，2.85(1H，m)，2.65(1H，m)，2.55(2H，m)，2.20(1H，m)，1.9-1.4(7H，m)，1.25(3H，t)。

Preparation 32

(1R, 5R, 6S)-[6-(nitro methyl) two ring [3.2.0] heptan-6-yl] acetate

In envrionment temperature, with the nitro ester (200g of preparation 31; 828.9mmol) THF (1.0L) solution and 2M aqueous sodium hydroxide solution (1.04L; 2.08mol) mix and stirred 18 hours.Two-phase mixture dilutes with toluene (500mL), and layering.Water layer is regulated pH to 1-3 with concentrated hydrochloric acid, and uses CH ₂Cl ₂(1.0L+600mL) extraction.Merge the CH that comprises product ₂Cl ₂Layer, concentrating under reduced pressure obtains title compound, is orange, and its placement becomes solid (163.4g).

¹HNMR(400MHz，CDCl ₃)：δ＝4.80(2H，m)，2.85(1H，m)，2.60(3H，m)，2.20(1H，m)，1.85(1H，m)，1.70(2H，m)，1.6-1.4(4H，m)。

Preparation 33

(1RS, 5RS, 6SR)-spiral shell [two ring [3.2.0] heptane-6,3 '-tetramethyleneimine]-5 '-ketone

25 ℃ in the presence of the spongy catalyzer of Nickel, in the nitrogen atmosphere of 345kPa (50p.s.i.), will prepare 31 nitro ester (13.0g, 53.9mmol) vibration in methyl alcohol (125ml).After 24 hours, catalyzer is filtered Arbocel remove, and solvent evaporated under reduced pressure.Residue is carried out chromatography (SiO then ₂, ethyl acetate), obtain lactan (4.76g).

¹H-NMR(400MHz，CDCl ₃)：δ＝5.86(1H，br.s)，3.40(2H，s)，2.79-2.70(1H，m)，2.54-2.47(1H，m)，2.32(1H，d)，2.12(1H，t)，2.03(1H，d)，1.86-1.60(3H，m)，1.57-1.38(4H，m)。

Trace analysis: measured value: C, 72.48; H, 9.15; N, 8.43.C ₁₀H ₁₅NO requires C, 72.69; H, 9.15; N, 8.48%.

[α] _D-28.4°(25℃)

Pharmaceutical composition embodiment

In the following example, active compound can be any compound of formula I-XXV and/or pharmacologically acceptable salt, solvate or its neurological progression derivative.

(i) tablet composition

The solution of following composition A and B available polyethylene pyrrolidone is to composition (a)～(c) and (a)～(d) carry out wet granulation, adds Magnesium Stearate then and suppresses and obtain preparation.

Composition A

The mg/ tablet The mg/ tablet

(a) activeconstituents 250 250

(b) lactose B.P. 210 26

(c) Explotab 20 12

(d) Povidone B.P. 15 9

(e) Magnesium Stearate 5 3

500 300

Composition B

The mg/ tablet The mg/ tablet

(a) activeconstituents 250 250

(b) lactose 150-

(c)Avicel?PH?101 60 26

(d) Explotab 20 12

(e) Povidone B.P. 15 9

(f) Magnesium Stearate 5 3

500 300

Composition C

The mg/ tablet

Activeconstituents 100

Lactose 200

Starch 50

Povidone 5

Magnesium Stearate 4

359

Following composition D and E can be prepared by mixing element is directly suppressed.The lactose that is used for preparation E is direct press type.

Composition D

The mg/ tablet

Activeconstituents 250

Magnesium Stearate 4

Pregelatinized Starch 146

400

Composition E

The mg/ tablet

Activeconstituents 250

Magnesium Stearate 5

Lactose 145

Avicel 100

500

Composition F (controlled release composition)

The mg/ tablet

(a) activeconstituents 500

(b) HYDROXY PROPYL METHYLCELLULOSE 112

(Methocel?K4M?Premium)

(c) lactose B.P. 53

(d) Povidone B.P.C. 28

(e) Magnesium Stearate 7

700

Described preparation method of composition is: the solution with Povidone carries out wet granulation to composition (a)～(c), adds Magnesium Stearate then and suppresses.

Composition G (enteric coated tablet)

The enteric coated tablet of composition C with enteric polymer for example the anionic polymer of Cellacefate, polyvinylacetate phthalic ester, phthalic acid hydroxypropyl methyl-Mierocrystalline cellulose or methacrylic acid and methyl methacrylate (Eudragit L) by the 25mg/ tablet tablet is carried out dressing.Except that Eudragit L, these polymkeric substance also should comprise the softening agent of 10% (weight by used polymkeric substance is calculated), to prevent film rupture in using or storing.Suitable manufacturing methods comprises diethyl phthalate, tributyl citrate and triacetin (triacetin).

Composition H (enteric controlled-release tablet)

The enteric coated tablet of composition F can with enteric polymer for example the anionic polymer of Cellacefate, polyvinylacetate phthalic ester, phthalic acid hydroxypropyl methyl-Mierocrystalline cellulose or methacrylic acid and methyl methacrylate (Eudragit L) by the 50mg/ tablet tablet is carried out dressing.Except that Eudragit L, these polymkeric substance also should comprise the softening agent of 10% (weight by used polymkeric substance is calculated), to prevent film rupture in using or storing.Suitable manufacturing methods comprises diethyl phthalate, tributyl citrate and triacetin.

(ii) capsule composition

Composition A

Be prepared in composition that capsule can be by mixing above-mentioned composition D and the hard gelatin capsule that the mixture that obtains is filled into two joints (two-part).The available similar mode of composition B (hereinafter) is prepared.

Composition B

The mg/ capsule

(a) activeconstituents 250

(b) lactose B.P. 143

(c) Explotab 25

(d) Magnesium Stearate 2

420

Composition C

The mg/ capsule

(a) activeconstituents 250

(b)Macrogol?4000BP 350

600

Fusing Macrogol 4000BP is distributed to activeconstituents in the molten mass, and fills it in the two joint hard gelatin capsules preparation capsule.

Composition D

The mg/ capsule

Activeconstituents 250

Yelkin TTS 100

Peanut oil 100

450

By activeconstituents is disperseed in Yelkin TTS and the peanut oil, and in its filling is soft, the elastic gelatin capsule, thereby the preparation capsule.

Composition E (controlled release capsule)

The mg/ capsule

(a) activeconstituents 250

(b) Microcrystalline Cellulose 125

(c) lactose BP 125

(d) ethyl cellulose 13

513

The controlled release capsule preparation can be prepared by following method: with the mixing element of extrusion machine extruding (a)～(c), and spheroidization and dry extrudate then.The exsiccant bead carries out dressing with discharging controlling diaphragm (d), is filled into two joint hard gelatin capsules then.

Composition F (enteric coated capsule)

The mg/ capsule

(a) activeconstituents 250

(b) Microcrystalline Cellulose 125

(c) lactose BP 125

(d) Cellacefate 50

(e) diethyl phthalate 5

555

The enteric coated capsule composition can be pressed method preparation: with the mixing element of extrusion machine extruding (a)～(c), and spheroidization and dry extrudate then.The exsiccant bead carries out dressing with the enteric film (d) that comprises softening agent (e), and is filled in the two joint hard gelatin capsules.

Composition G (enteric controlled-release capsule)

The enteric coated capsule of composition E can with enteric polymer for example the anionic polymer of Cellacefate, polyvinylacetate phthalic ester, phthalic acid hydroxypropyl methyl-Mierocrystalline cellulose or methacrylic acid and methyl methacrylate (Eudragit L) by the 50mg/ capsule controlled release bead is carried out dressing.Except that Eudragit L, these polymkeric substance also should comprise the softening agent of 10% (weight by used polymkeric substance is calculated), to prevent film rupture in using or storing.Suitable manufacturing methods comprises diethyl phthalate, tributyl citrate and triacetin.

(iii) intravenous injection composition

Activeconstituents 0.200g

Aseptic, pyrogen-free phosphoric acid buffer (pH9.0) is added to 10ml

At 35-40 ℃, activeconstituents is dissolved in most of phosphoric acid buffer, be adjusted to described volume then, and be filled in the aseptic 10ml vial (1 type) by sterile millipore filter, it seals with asepsis plug and seal.

(iv) intramuscularly composition

Activeconstituents 0.20g

Phenylcarbinol 0.10g

Glycofurol?75 1.45g

Water for injection is added to 3.00ml

Activeconstituents is dissolved among the glycofurol.Add phenylcarbinol and dissolving then, add water to 3ml.Then mixture is filled into aseptic 3ml vial (1 type) by sterile millipore filter.

(v) syrup composition

Activeconstituents 0.25g

Sorbitol Solution USP 1.50g

Glycerine 1.00g

Sodium Benzoate 0.005g

Spices 0.0125ml

Pure water is added to 5.0ml

Sodium Benzoate is dissolved in the part pure water, and adds Sorbitol Solution USP solution.Add activeconstituents and dissolving.The solution that obtains mixes with glycerine, is adjusted to the volume that needs with pure water then.

(vi) suppository composition

Mg/ suppository

Activeconstituents 250

Solid fat, BP (Witepsol H15-Dynamit NoBel) 1770

2020

1/5 Witepsol H15 is melted in the dish of the highest 45 ℃ steam overcoat.Activeconstituents is crossed the 200lm sieve, join in the fusing matrix of the Silverson stirring of using assembling crop (cutting head), up to forming level and smooth dispersion.Mixture is remained on 45 ℃, remaining Witepsol H15 is added in the suspension, stir and guarantee to be mixed uniformly.All suspension then by 2501m stainless steel screening and, the stirring that continues makes it to be cooled to 40 ℃.When 38-40 ℃ temperature, the mixture of 2.02g is loaded in the suitable plastic mould, suppository is cooled to room temperature.

(vii) vaginal suppository composition

The mg/ vaginal suppository

Activeconstituents (631m) 250

Anhydrous dextrose 380

Yam starch 363

Magnesium Stearate 7

1000

Mentioned component directly mixes, and the mixture that compacting obtains prepares vaginal suppository (pessaries).

(viii) transdermal composition

Activeconstituents 200mg

Alcohol USP 0.1ml

Hydroxy ethyl cellulose

Activeconstituents and alcohol USP form gel with hydroxy ethyl cellulose, and are seated in surface-area 10cm ²Transdermal device in.

Biological data

Compound in embodiment 1 and 4 is tested with radioligand bind assay described herein, found that its binding affinity is 46.8 and 600nM respectively.

Claims

1. any compound among general formula I-XXV:

R wherein ¹And R ²Be selected from hydrogen atom, straight or branched C independently of one another _1-6Alkyl, C _3-6Cycloalkyl, phenyl and phenmethyl, precondition are when the secocubane of formula (XVII), R ¹And R ²Be not except the situation of hydrogen simultaneously; Or its pharmacologically acceptable salt or solvate; Or its prodrug.

2. the compound of claim 1, wherein R ¹And R ²It all is methyl.

3. claim 1 or 2 compound or its salt, solvate or prodrug are selected from:

((1R, 5R, 6S)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1S, 5S, 6S)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1R, 5R, 6R)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1S, 5S, 6R)-6-amino methyl-two ring [3.2.0] heptan-6-yl)-acetate;

((1R, 2S, 5S)-and 7-amino methyl-3,3-dimethyl-three ring [3.30.0] suffering-7-yl)-acetate:

((1R, 6R, 7S)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1S, 6S, 7S)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1R, 6R, 7R)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1S, 6S, 7R)-7-amino methyl-two ring [4.2.0] suffering-7-yl)-acetate;

((1R, 7R, 8S)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate;

((1S, 7S, 8S)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate;

((1R, 7R, 8R)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate; And

((1S, 7S, 8R)-8-amino methyl-two ring [5.2.0] nonanal-8-group)-acetate.

4. according to any one compound or its salt, solvate or prodrug among the claim 1-3, be selected from:

[(1R, 5R, 6S)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate;

[(1S, 5S, 6R)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate;

[(1RS, 5RS, 6RS)-and 6-(amino methyl) two ring [3.2.0] heptan-6-yl] acetate;

5. according to any one compound or its salt, solvate or prodrug among the claim 1-4, its be [(1R, 5R, 6S)-6-(amino methyl) two rings [3.2.0] heptan-6-yl] acetate.

6. pharmaceutical composition comprises any one compound and pharmaceutically acceptable carrier of 1-5 in the claim for the treatment of significant quantity.

Among the claim 1-5 compound of any one as the purposes of medicine.

8. method for the treatment of disease, described disease is selected from epilepsy, has a syncopal attack, hypokinesia, head disease, nerve degenerative diseases, dysthymia disorders, anxiety disorder, paranoid fears, pain, irritable bowel syndrome, somnopathy, osteoarthritis, rheumatoid arthritis, neuropathic disease, visceral pain, functional bowel disease, inflammatory bowel, pain, pelvic pain, urocystitis and pancreatitis that dysmenorrhoea is relevant, and described method comprises to any one compound among the claim 1-5 of the administration treatment significant quantity of needs treatment.

9. the method for claim 7, wherein disease is a neuropathic pain.

10. the purposes of the compound of any one in preparation treatment disease medicament among the claim 1-5, described disease are selected from epilepsy, have a syncopal attack, hypokinesia, head disease, nerve degenerative diseases, dysthymia disorders, anxiety disorder, terrified, pain, irritable bowel syndrome, somnopathy, osteoarthritis, rheumatoid arthritis, neuropathic disease, visceral pain, functional bowel disease, inflammatory bowel, pain, pelvic pain, urocystitis and pancreatitis that dysmenorrhoea is relevant.

11. the purposes of claim 9, wherein said disease are neuropathic pain.

12. the method for the compound of any one among the preparation claim 1-5 comprises:

(i) with the corresponding 1-6 carbon atom carboxylic acid of acid treatment ester derivative isocyanic ester/alkyl ester;

The (ii) corresponding cyclic lactam of hydrolysis;

(iii) reduce corresponding nitro/acid derivative, it is optional for undersaturated; Or

(iv) reduce corresponding nitro/phenmethyl or diphenyl methyl ester derivative, it is optional for undersaturated.