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CN101027292A - Compounds, compositions containing them, preparation thereof and uses thereof - Google Patents

Compounds, compositions containing them, preparation thereof and uses thereof Download PDF

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Publication number
CN101027292A
CN101027292A CN200580032338.4A CN200580032338A CN101027292A CN 101027292 A CN101027292 A CN 101027292A CN 200580032338 A CN200580032338 A CN 200580032338A CN 101027292 A CN101027292 A CN 101027292A
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Prior art keywords
methyl
alkyl
compound
ylmethyl
benzoglyoxaline
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CN200580032338.4A
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Inventor
丹尼尔·佩奇
刘自平
马克西姆·特伦布莱
克莱尔·米尔本
克里斯托弗·沃波尔
杨华
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AstraZeneca AB
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AstraZeneca AB
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Priority claimed from PCT/GB2004/004112 external-priority patent/WO2005030761A1/en
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Abstract

Compounds of Formula (I) or pharmaceutically acceptable salts thereof; wherein R<1>, R<2>, R<3>, R<4>, n and Ar are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

Compound, the composition that contains them, Its Preparation Method And Use
Technical field
The present invention relates to therapeutic compound, comprise pharmaceutical composition, the Preparation Method And The Use of these compounds.Particularly, the present invention relates to effectively to treat the compound of pain (pain), cancer (cancer), multiple sclerosis (multiple sclerosis), Parkinson's disease (Parkinson ' s disease), Huntington Chorea (Huntington ' s chorea), alzheimer's disease (Alzheimer ' s disease), anxiety disorder (anxietydisorders), gastrointestinal tract disease (gastrointestinal disorder) and/or cardiovascular disorder (cardiovascular disorder).
Background technology
To too much after deliberation year of pain control (pain management).And, know Cannabined receptor (for example, CB 1Acceptor, CB 2Acceptor) part comprises agonist, antagonist and inverse agonist, by with CB 1And/or CB 2Acceptor interaction alleviates the pain in the various animal models.Usually, CB 1Acceptor mastery ground (predominately) is positioned at central nervous system, and CB 2Acceptor mainly is positioned at periphery (periphery), and mainly is subject to and derives from immune cell and tissue.
Although CB 1Receptor stimulant, for example Δ 9-tetrahydrocannabinol (Δ 9-THC) and arachidonic acid (anadamide), can be used for the anti-nociception model of animal, but they often produce undesirable CNS side effect, for example psychoactive side effect, abuse potential, drug dependence and tolerance etc.Known these undesirable side effects are by the CB that is arranged in CNS 1Acceptor mediates.Yet a series of evidences show, act on the periphery position or have the CB that limited CNS exposes 1Agonist can be controlled the pain of the mankind or animal, and overall interior the distribution greatly improved.
Therefore, need new CB 1Receptors ligand, agonist for example, it can be used for pain management or treats other related symptoms or disease, and reduces undesirable CNS side effect or it is minimized.
Summary of the invention
The invention provides CB 1Receptors ligand, it can be used for treating pain and/or other related symptoms or disease.
When using separately or using as prefix, term " C M-n" or " C M-nGroup " be meant the group of any m to n of having carbon atom.
When using separately or using as suffix or prefix, term " alkyl " is meant and comprises the 1 saturated monovalence straight or branched hydrocarbyl group to about 12 carbon atoms.The illustrative examples of alkyl includes, but not limited to C 1-4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, butyl, isobutyl-, the tertiary butyl.
When using separately or using as suffix or prefix, term " cycloalkyl " is meant that the saturated monovalence that comprises at least 3 about at the most 12 carbon atoms contains the hydrocarbyl group of ring.The example of cycloalkyl includes, but not limited to C 3-7Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and saturated cyclic terpene and two cyclic terpenes.Cycloalkyl can be unsubstituted or be replaced by one or more suitable substituents.Preferably, cycloalkyl is monocycle or dicyclo.
When using separately or using as suffix or prefix, term " alkoxyl group " is meant the group of general formula-O-R, and wherein R is an alkyl.Exemplary alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy and isobutoxy.
When using separately or using as suffix or prefix, term " heterocycle (heterocycle) " is meant to have one or more multivalence heteroatomss as the structure that contains ring or the molecule that comprise at least 3 about at the most 20 atoms in the part of ring structure and the ring, and described heteroatoms is independently selected from N, O, P and S.Heterocycle can contain one or more pairs of keys for saturated or undersaturated, and heterocycle can contain a more than ring.When heterocycle contains more than when ring, ring can be condensed or uncondensed.Fused rings (fusion ring) typically refers to shares at least two rings of two atoms therebetween.Heterocycle can have aromaticity or not have aromaticity.
Heterocycle comprises, monocyclic heterocycles for example, for example: ethylene imine (aziridine), oxyethane, thiirane, azetidine (azetidine), trimethylene oxide, Thietane (thietane), tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, tetramethylene sulfone, 2, the 3-dihydrofuran, 2, the 5-dihydrofuran, tetrahydrofuran (THF), tetramethylene sulfide, piperidines, 1,2,3,6-tetrahydrochysene-pyridine, piperazine, morpholine, parathiazan, pyrans, thiapyran, 2, the 3-dihydropyrane, tetrahydropyrans, 1, the 4-dihydropyridine, 1, the 4-dioxane, 1, the 3-dioxane, dioxane (dioxane), high piperidines (homopiperidine), 2,3,4,7-tetrahydrochysene-1H-azepine , high piperazine (homopiperazine), 1,3-Dioxepane (1,3-dioxepane), 4,7-dihydro-1,3-two oxa- (4,7-dihydro-1,3-dioxepin) and oxepane (hexamethylene oxide).
In addition, heterocycle comprises aromatic heterocycle, for example pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furans, furazan, pyrroles, imidazoles, thiazole,  azoles, pyrazoles, isothiazole, different  azoles, 1,2,3-triazole, tetrazolium, 1,2,3-thiadiazoles, 1,2,3- diazole, 1,2,4-triazole, 1,2,4-thiadiazoles, 1,2,4- diazole, 1,3,4-triazole, 1,3,4-thiadiazoles and 1,3,4- diazole.
In addition, heterocycle comprises many ring heterocycles, indoles for example, indoline (indoline), isoindoline (isoindoline), quinoline, tetrahydroquinoline, isoquinoline 99.9, tetrahydroisoquinoline, 1,4-benzo two  alkane, tonka bean camphor, melilotine, cumarone, 2, the 3-Dihydrobenzofuranes, isobenzofuran, chromene, chroman (chroman), heterochromatic full (isochroman), xanthene, fen thiophene  (phenoxathiin), thianthrene, indolizine, isoindole, indazole, purine, phthalazines, naphthyridines, quinoxaline, quinazoline, cinnolines, pteridine, phenanthridines, perimidine (perimidine), phenanthroline (phenanthroline), azophenlyene, thiodiphenylamine, fen  piperazine, 1,2-benzisoxa  azoles, thionaphthene, benzoxazol, benzothiazole, benzoglyoxaline, benzotriazole, Thioxanthine (thioxanthine), carbazole, carboline, acridine, pyrrolizidine (pyrolizidine) and quinoline promise Li Xiding (quinolizidine).
Except above-mentioned many ring heterocycles, heterocycle comprises many ring heterocycles, wherein the fused rings between two or more rings comprise more than one by the public key of two rings and more than two by two atoms that ring is public.The example of this bridged heterocyclic comprises rubane (quinuclidine), diazabicyclo [2.2.1] heptane and 7-oxabicyclo [2.2.1] heptane.
When using separately or using as suffix or prefix, term " Heterocyclylalkyl " is meant and comprises carbon and hydrogen atom and be selected from least one heteroatoms (preferred 1-3 heteroatoms) in nitrogen, oxygen and the sulphur, and do not have the monocycle of unsaturated character or encircle more.The example of Heterocyclylalkyl comprises pyrrolidyl (pyrrolidinyl), pyrrolidino (pyrrolidino), piperidyl (piperidinyl), piperidino-(1-position only) (piperidino), piperazinyl (piperazinyl), Piperazino (piperazino), morpholinyl (morpholinyl), morpholino (morpholino), parathiazan base (thiomorpholinyl), parathiazan generation (thiomorpholino) and pyranyl (pyranyl).Heterocyclylalkyl can be unsubstituted or be replaced by one or two suitable substituents.Preferably, Heterocyclylalkyl is monocycle or dicyclo, monocycle more preferably, and wherein said ring comprises 2-5 carbon atom and 1-3 heteroatoms, is called C in the present invention 2-5Heterocyclylalkyl.
Halogen comprises fluorine, chlorine, bromine and iodine.
" RT " or " rt " is meant room temperature.
On the one hand, embodiments of the present invention provide formula I compound, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture:
Figure A20058003233800101
Wherein
G is selected from-O-,-CHF-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl and C 1-4Alkoxyl group; Perhaps R 1And R 2The N that connects with them can form C 3-6Heterocycle; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
In another embodiment, described compound can be those of formula I, wherein
G is selected from-O-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl and C 1-4Alkoxyl group; Perhaps R 1And R 2The N that connects with them can form C 3-6Heterocycle; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
Another embodiment of the present invention provides formula I compound, wherein
G is selected from-O-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl; Perhaps R 1And R 2The N that connects with them can form C 2-5Heterocyclylalkyl; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
An embodiment more of the present invention provides formula I compound, wherein
G is-O-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl and C 1-4Alkoxy-C 1-4Alkyl, and R 1And R 2It is different groups; Perhaps R 1And R 2The N that connects with their can form and be selected from 2-oxo-pyrrolidine-1-base, tetramethyleneimine-1-base, 1H-1,2, the group of 3-triazol-1-yl and morpholinyl; And
R 3, R 4And R 5Independently be selected from fluorine and methyl, and R 3, R 4And R 5Identical.
Another embodiment of the invention provides formula I compound,
Wherein
G is-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl and C 1-4Alkoxy-C 1-4Alkyl, and R 1And R 2It is different groups; And
R 3, R 4And R 5Be methyl independently of one another.
An embodiment more of the present invention provides compound, is selected from:
The N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(morpholine-4-ylmethyl) benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(1H-1,2,3-triazol-1-yl methyl) benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(methylamino-) methyl] benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-[(ethylamino) methyl]-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-methoxy ethyl) amino] methyl }-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(tetramethyleneimine-1-ylmethyl) benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(2-oxo-pyrrolidine-1-yl) methyl] benzsulfamide;
N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide;
And pharmacologically acceptable salts.
Should be appreciated that when compound of the present invention contained one or more chiral centre, compound of the present invention can exist or is separated into mapping or diastereomeric form formula with mapping or diastereomeric form formula, perhaps exists as racemic mixture.The present invention includes any possible enantiomer, diastereomer, racemoid or its mixture of formula I compound.The optical activity form of The compounds of this invention can prepare in the following way: for example the chiral chromatography of racemoid separates, synthesizes from the optical activity raw material, perhaps based on following described asymmetric synthesis.
Be further appreciated that some compound of the present invention can be used as geometrical isomer, for example the E of alkene and Z isomer and exist.The present invention includes any geometrical isomer of the compound of formula I.It is also understood that the present invention comprises the tautomer of formula I compound.
It is also understood that some compound of the present invention can be with solvation, for example hydrated form exists, and the form of solvation does not exist.It is also understood that the present invention comprises all these solvation forms of formula I compound.
The salt of formula I compound also within the scope of the invention.The pharmacologically acceptable salts of The compounds of this invention can use standard operation known in the art to obtain usually, for example the compound (for example alkylamine) by making enough alkalescence and suitable acid are (for example, HCl or acetate) reaction, obtain the acceptable negatively charged ion of physiology.Also can be by in water-bearing media, handle The compounds of this invention with the oxyhydroxide of monovalent basic metal or alkaline-earth metal or alkoxide (for example b-oxide or methoxide) or suitable alkaline organic amine (for example choline or meglumine), then handle to prepare corresponding alkali metal (for example sodium, potassium or lithium) salt or alkaline-earth metal (for example calcium) salt by conventional purification technique with suitable acid proton (for example carboxylic acid or phenol).
In one embodiment, the compound of above-mentioned formula I can be converted into pharmacologically acceptable salts or its solvate, particularly acid salt for example hydrochloride, hydrobromate, phosphoric acid salt, acetate, formate, maleate, tartrate, Citrate trianion, mesylate or tosilate.
Now, we have found that The compounds of this invention has the activity as medicine, particularly as CB 1The conditioning agent of acceptor or part be agonist, partial agonist, inverse agonist or antagonist for example.More specifically, The compounds of this invention demonstrates as CB 1The selective active of receptor stimulant also is used for the treatment of, particularly alleviate various antalgesics, for example chronic pain (chronic pain), neuropathic pain (neuropathic pain), acute pain (acute pain), cancer pain (cancer pain), the pain that causes by rheumatoid arthritis, migraine (migraine), Encelialgia (visceral pain) etc.Yet this enumerating should not be construed as exhaustive.In addition, The compounds of this invention can be used for wherein existing or involving CB 1Other morbid state of function of receptors disorder.In addition, compound of the present invention can be used for treating cancer, multiple sclerosis, Parkinson's disease, Huntington Chorea, alzheimer's disease, anxiety disorder, gastrointestinal tract disease and cardiovascular disorder.
Compound of the present invention can be used as immunomodulator, and especially for autoimmune disease, for example sacroiliitis is used for dermatoplasty, organ transplantation and similar operation needs, is used for collagen disease, various transformation reactions, is used as antitumour drug and antiviral drug.
Compound of the present invention can be used for following morbid state, wherein has or involve the degeneration or the dysfunction of Cannabined receptor in example.This can be included in the isotopic labeling variant that uses The compounds of this invention in diagnostic techniques and the imaging applications (for example positron emission tomography (PET)).
Compound of the present invention is used for the treatment of diarrhoea; depressed; anxiety and illness (stress-related disorders) that stress be relevant; posttraumatic stress disorder (post-traumatic stress disorder) for example; panic disorder (panic disorder); generalized anxiety disorder; social phobia (social phobia); and obsessive compulsive disorder (obsessive compulsive disorder); the urinary incontinence (urinary incontinence); premature ejaculation; various mental illnesss; cough; pulmonary edema; (for example constipation of various gastrointestinal tract disease; functional gastrointestinal disease is irritable bowel syndrome (Irritable Bowel Syndrome) and functional dyspepsia for example); Parkinson's disease and other dyskinesia; traumatic brain injury; apoplexy; Cardioprotective after the myocardial infarction (cardioprotection); vertebra hurt and dopy; comprise treatment alcohol; Nicotine; opioid and other drug abuse and sympathetic nervous system disorder be hypertension for example.
Compound of the present invention can be used as pain killer, uses in general anesthesia and supervision anesthetic care (monitoredanaesthesia care) process.The different properties combination of agents is generally used for keeping the balance of the required effect of narcosis (for example: forget, analgesia, loosening all muscles and calmness).This combination comprises suction narcotic, soporific, anxiolytic, neuromuscular blocking agent (neuromuscular blockers) and opioid.
Above-mentioned any formula I compound preparation be used for the treatment of in the medicine of above-mentioned any illness purposes also within the scope of the invention.
Another aspect of the present invention is the method that treatment suffers from the patient of above-mentioned any illness, wherein the above-mentioned formula I compound administration of significant quantity is extremely needed the patient of this treatment.
Therefore, the invention provides above-mentioned formula I compound or pharmacologically acceptable salts or its solvate that is used for the treatment of.
On the other hand, the invention provides above-mentioned formula I compound or pharmacologically acceptable salts or the purposes of its solvate in the medicine that preparation is used for the treatment of.
Unless opposite explanation is arranged in addition, in the context of the present specification, term " treatment " also comprises " prevention ".Term " treatment " and " remedially " also should correspondingly be understood.In the context of the present invention, term " treatment " also comprises the The compounds of this invention of effective dosage, to alleviate acute or chronic disease situation or the recurrence illness that is pre-existing in.This definition also comprises the prophylactic treatment and the continued treatment that is used for chronic disease that is used to prevent to recur illness.
Compound of the present invention can be used for treatment, especially for the various antalgesics of treatment, includes but not limited to: acute pain, chronic pain, neuropathic pain, backache, cancer pain and Encelialgia.
Treating for example man-hour of warm-blooded animal, compound of the present invention can be with the form of conventional medicine composition by the administration of various paths, comprise oral, intramuscular, subcutaneous, partly, in the nose, in the intraperitoneal, intrathoracic (intrathoracially), intravenously, epidural, sheath, transdermal, chest indoor (intracerebroventricularly) and injection joint.
In an embodiment of the invention, route of administration can be oral, intravenously or intramuscular.
When determining for optimal each drug regimen of particular patient and dosage level, dosage will depend on the other factors that administration path, severity of disease, patient's age and body weight and attending doctor consider usually.
For from compound pharmaceutical composition of the present invention, inertia, pharmaceutically acceptable carrier can be solid or liquid.But the preparation of solid form comprises pulvis, tablet dispersible granule, capsule, cachet and suppository.
Solid carrier can be one or more materials, and it can be used as thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent or sheet disintegrating agent (table disintegrating agents); It also can be an encapsulating material.
In pulvis, carrier is fine comminuted solids, its can for the compound of the fine pulverizing of the present invention or the mixture of active ingredient.In tablet, active ingredient is compressed with suitable mixed and with required shape and size with the carrier with necessary bond property.
In order to prepare suppository composition, at first melt low melt wax (for example mixture of glycerin fatty acid ester and theobroma oil), then for example by stirring dispersed activity component within it.Pour into the uniform mixture of fusing in the mould of appropriate size then and make it cooling and solidify.
Suitable carriers can be magnesiumcarbonate, Magnesium Stearate, talcum, lactose, sugar, pectin, dextrin, starch, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.
Term " composition " also is intended to comprise active ingredient and the preparation that capsular encapsulating material is provided as carrier, and wherein active ingredient (being with or without other carrier) is by bonded carrier encirclement with it.Similarly, also comprise cachet.
Tablet, pulvis, cachet and capsule can be as being fit to oral solid dosage.
The composition of liquid form comprises solution, suspensoid and emulsion.For example, the sterilized water of active ingredient or water propylene glycol solution can be for being fit to the liquid preparation of administered parenterally.Liquid composition also can be formulated as the form of the polyoxyethylene glycol aqueous solution.
The aqueous solution for oral use can prepare by solubilization of active ingredient is also added suitable tinting material, seasonings, solubilizing agent and thickening material as required in water.Aqueous suspensions for oral use can prepare for example natural synthetical glue of described cohesive material, resin, methylcellulose gum, Xylo-Mucine and known other suspension agent of medicine formulation art by the active ingredient of fine pulverizing and cohesive material are dispersed in the water.
Based on the mode of administration, pharmaceutical composition preferably includes 0.05% to 99w% (weight %), more preferably 0.10 to 50w% The compounds of this invention, and all per-cents all are based on the composition gross weight.
Those of ordinary skills can utilize known standard to determine to put into practice treatment significant quantity of the present invention, and described standard comprises age, body weight and the reaction of single patient, and can explain in the scope of the disease of being treated or preventing.
Scope of the present invention also comprises the purposes of any formula I compound in the preparation medicine of above-mentioned definition.
Any formula I compound that scope of the present invention also comprises above-mentioned definition is used for the treatment of purposes in the medicine of pain in preparation.
In addition, provide any formula I compound to be used for the treatment of purposes in the medicine of various antalgesics in preparation, pain includes but not limited to: acute pain, chronic pain, neuropathic pain, backache, cancer pain and Encelialgia.
Another aspect of the present invention provides the method for the treatment of the patient who suffers from above-mentioned any illness, wherein the above-mentioned formula I compound administration of significant quantity is extremely needed the patient of this treatment.
In addition, provide a kind of pharmaceutical composition, comprise compound or its pharmacologically acceptable salts of formula I, and pharmaceutically acceptable carrier.
Particularly, be provided for treatment, more specifically be used for the treatment of the pharmaceutical composition of pain, it comprises compound or its pharmacologically acceptable salts of formula I, and pharmaceutically acceptable carrier.
In addition, be provided for treating the pharmaceutical composition of above-mentioned any illness, it comprises compound or its pharmacologically acceptable salts of formula I, and pharmaceutically acceptable carrier.
On the other hand, the invention provides the method for preparing The compounds of this invention.
In one embodiment, the invention provides the method for preparation I compound, comprising:
Figure A20058003233800151
I
Make the reaction of formula II compound and formula III compound,
Figure A20058003233800161
Then at reductive agent (for example, Na (CN) BH 3) existence under, use R 1(R 2) NH carries out reductive amination, wherein G, R 1, R 2, R 3, R 4And R 5As defined above.In addition, formula I compound can be prepared as follows: make the reaction of formula II compound and formula III compound, carry out series reaction then, comprise 1) use reductive agent (Na (CN) BH for example 3) reduce; 2) methylsulfonylization; With 3) use R 1(R 2) NH carries out nucleophilic substitution, wherein G, R 1, R 2, R 3, R 4And R 5As defined above.
Compound of the present invention also can prepare according to the synthetic route shown in scheme 1,2 and 3.
Scheme 1
Figure A20058003233800171
Scheme 2
Biological assessment
HCB 1And hCB 2Receptors bind
The human CB of Receptor Biology will be derived from 1Acceptor (hCB 1) or derive from the human CB of BioSignal 2Acceptor (hCB 2) film thaws at 37 ℃, passes 25-number blunt nosed pin 3 times, at cannaboid binding buffer liquid (50mM Tris, 2.5mM EDTA, 5mM MgCl 2With 0.5mg/mL BSA, fatty acids not, pH7.4) in dilution, and will contain an amount of proteinic aliquots containig and be dispensed in the 96-orifice plate.Estimate The compounds of this invention to hCB from 10 dose points-response curve 1And hCB 2IC 50, described dose-response curve is with every hole 20000-25000dpm's in the final volume of 300 μ l 3H-CP55,940 (0.17-0.21nM) and obtain.Total binding and non-specific binding when determining not contain and contain 0.2 μ M HU210 respectively.With the plate vortex and incubated at room temperature 60 minutes, filter by Unifilters GF/B (preimpregnation in 0.1% polymine), collect with Tomtec or Packard collector, and use 3mL lavation buffer solution (50mM Tris, 5mM MgCl 2, 0.5mg BSA, pH7.0) washing.With filter 55 ℃ of dryings 1 hour.Add the MS-20 scintillation solution, every hole 65 μ l calculate radioactivity (cpm) then in TopCount (Packard).
HCB 1And hCB 2GTP γ S combination
The human CB of Receptor Biology will be derived from 1Acceptor (hCB 1) or human CB 2Acceptor (hCB 2) film (BioSignal) thaws at 37 ℃, passes 25-number blunt nosed pin 3 times, at GTP γ S binding buffer liquid (50mM Hepes, 20mM NaOH, 100mM NaCl, 1mM EDTA, 5mM MgCl 2, 0.1%BSA, pH7.4) in the dilution.The EC of The compounds of this invention 50And E MaxEstimated by 10 dose points-response curve, described dose-response curve is to contain an amount of membranin and GTpg with every hole in 300 μ l volumes 35(0.11-0.14nM 100000-130000dpm) obtains S.Determine not contain and contain 1 μ M (hCB respectively 2) or 10 μ M (hCB 1) Win 55, the fundamental sum maximal stimulation combination of 212-2.With film with 56.25 μ M (hCB 2) or 112.5 μ M (hCB 1) GDP cultivated 5 minutes in advance, was dispensed to plate (final 15 μ M (hCB then 2) or 30 μ M (hCB 1) GDP).Cultivated 60 minutes with the plate vortex and in room temperature, filter, collect, and use 3mL lavation buffer solution (50mM Tris, 5mM MgCl with Tomtec or Packard collector by Unifilters GF/B (preimpregnation in water) 2, 50mM NaCl, pH 7.0) washing.With filter 55 ℃ of dryings 1 hour.Add the MS-20 scintillation solution, every hole 65 μ l calculate radioactivity (cpm) then in TopCount (Packard).Carry out antagonist in the same way and reverse (antagonist reversal) research, difference is: (a) obtain the agonist dose-response curve in the presence of the antagonist of constant density, or (b) obtain the antagonist dose-response curve in the presence of the agonist of constant density.
Based on above-mentioned test, particular compound of the present invention can use following formula to measure to the dissociation constant (Ki) of concrete acceptor:
Ki＝IC 50/(1+[rad]/Kd)，
IC wherein 50Be the concentration that The compounds of this invention was observed for 50% when displacement;
[rad] is the standard or the reference concentration of radioligand this moment; With
Kd is the dissociation constant of radioligand to concrete acceptor.
Utilize said determination, record The compounds of this invention human CB 1The Ki value scope of acceptor is at 8-1175nM, the EC of these compounds 50The value scope is 12-49nM, the E of these compounds MaxThe value scope is 109%-143%.
Embodiment
The method of The compounds of this invention preparation, purifying, analysis and bioassay described in the following embodiment describes in further detail the present invention, and it should not be interpreted as limiting the present invention.
Embodiment 1
The N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800201
The steps A .N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800202
In room temperature; with the N-{2-tertiary butyl-1-[(4; 4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-4-formyl radical-N-methyl benzenesulfonamide (1.21g; 2.40mmol) (for synthetic; referring to step B to H), the 2-thanomin (1.45mL, 24.0mmol) and AcOH (2) in MeOH (15mL), stirred 1 hour.Add NaBH 3CN (453mg, 7.22mmol), stirred reaction mixture 3 hours.Remove and desolvate,, obtain title compound, be corresponding tfa salt by preparation type reversed-phase HPLC purifying crude product.Yield: 950mg (73%); MS (ESI) (M+H) +: 515.2; 1H NMR (600MHz, CD 3OD) δ 1.52-1.60 (m, 4H), 1.67 (s, 9H), 1.69-1.79 (m, 4H), 2.04-2.10 (m, 1H), 3.15-3.19 (m, 2H), 3.28 (s, 3H), 3.80-3.84 (m, 2H), 4.34 (s, 2H), 4.53 (d, J=7.42Hz, 2H), 7.29 (dd, J=8.96,2.05Hz, 1H), 7.58 (d, J=1.79Hz, 1H), 7.64-7.69 (m, 4H), 7.84 (d, J=9.22Hz, 1H).
Step B.N-(4-fluoro-3-nitrophenyl) ethanamide
Figure A20058003233800211
In room temperature, (45.0g 0.288mol) adds in the diacetyl oxide (150mL) in batches with 4-fluoro-3-nitro-aniline.Reaction mixture is collected white solid at stirring at room 2h., and vacuum-drying obtains title compound (42.0g, 70%). 1H?NMR(400MHz，CDCl 3)：δ2.23(s，3H)，7.26(m，1H)，7.50(s?br，1H)，7.87(m，1H)，8.23(dd，J＝6.44，2.73Hz，lH).
Step C.N-(4-fluoro-3-nitrophenyl)-N-methylacetamide
Figure A20058003233800212
At 0 ℃, (2.40g, 60mmol) add to N-(4-fluoro-3-nitrophenyl) ethanamide (7.93g is in THF 40mmol) (120mL) solution in batches with sodium hydride.Stirred 20 minutes, and the adding methyl iodide (17.0g, 120mmol).Reaction mixture stirring at room 2 hours, is used saturated NaHCO 3(30mL) quencher is with EtOAc (3 * 100mL) extractions.(2 * 30mL) wash the organic phase that merges with saturated NaCl.After filtering and concentrating, obtain 8.73g (100%) title compound, be brown solid. 1HNMR(400MHz，CDCl 3)：δ1.92(s，3H)，3.30(s，3H)，7.38(s，1H)，7.52(s，1H)，7.95(s，1H).
Step D.N-(4-{[(4,4-difluoro cyclohexyl) methyl] amino }-the 3-nitrophenyl)-the N-methylacetamide
In room temperature, (780mg 2.96mmol) adds to N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (628mg with [(4,4-difluoro cyclohexyl) methyl] amine tfa salt, 2.96mmol) and DIPEA (1.29mL is 7.40mmol) in the mixture of EtOH (15mL).Reaction mixture was heated 18 hours at 70 ℃.Except that after desolvating, use EtOAc/ heptane 70-100%, by MPLC purifying crude product, obtain 855mg (85%) title compound, be orange red solid (84%).MS(ESI)(M+H) +：341.96.
Step e .N-(3-amino-4-{[(4,4-difluoro cyclohexyl) methyl] amino } phenyl)-the N-methylacetamide
Figure A20058003233800221
In the Parr wobbler, in 50psi H 2In room temperature, use 10%Pd/C catalysis, with N-(4-{[(4,4-difluoro cyclohexyl) methyl] amino }-the 3-nitrophenyl)-N-methylacetamide (855mg, 2.50mmol) hydrogenation 18 hours in ethyl acetate (50mL).By diatomite filtration with after concentrating, obtain 716mg (92%) white solid, be not further purified and be directly used in next step.MS(ESI)(M+H) +：311.99
The step F .N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-the N-methylacetamide
Figure A20058003233800222
At 0 ℃, with trimethyl-acetyl chloride (0.29mL 2.41mmol) drops to N-(3-amino-4-{[(4,4-difluoro cyclohexyl) methyl] amino } phenyl)-N-methylacetamide (716mg, 2.30mmol) and Et3N (0.38mL is in methylene dichloride 2.75mmol) (100mL) solution.With the mixture that generates stirring at room 4 hours.Behind evaporating solvent, resistates is dissolved in acetate (16mL), be divided in then in 4 sealing test tubes.In Personal Chemistry SmithSynthesizer microwave device, mixture was heated 3 hours in 150 ℃.The reaction mixture that is combined then evaporates, is dissolved among the EtOAc (200mL), and with saturated sodium bicarbonate solution, salt water washing, and through Na 2SO 4Dry.After filtering and concentrating, the DCM solution that uses MeOH5% and acetone 10% by MPLC purifying resistates, obtains 570mg (65%) title compound as elutriant on silica gel, be white solid.MS(ESI)(M+H) +：378.23.
Step is the tertiary butyl-1-[(4 G.2-, 4-difluoro cyclohexyl) methyl]-N-methyl isophthalic acid H-benzoglyoxaline-5-amine
Figure A20058003233800231
With the N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl-the N-methylacetamide (570mg, 1.51mmol) and concentrated hydrochloric acid (15mL) arise from 80 ℃ of heating 18 hours.When being cooled to room temperature, reaction mixture is poured onto in the frozen water (100mL), and uses dense NaOH that the pH value is adjusted to 13, use EtOAc (3 * 50mL) extraction water solution then.The organic layer salt water washing that merges is through Na 2SO 4Dry.After filtering and concentrating, obtain 459mg (90%) title compound, be white solid.MS(ESI)(M+H) +：336.04.
The step H.N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-4-formyl radical-N-methyl benzenesulfonamide
Figure A20058003233800232
In room temperature; with 4-formyl radical benzene sulfonyl chloride (591mg 2.89mmol) adds to the 2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-N-methyl isophthalic acid H-benzoglyoxaline-5-amine (808mg; 2.40mmol) and DMAP (30mg is in DCE 0.25mmol) (15mL) solution.The reaction mixture stirring is spent the night.Remove and desolvate; In EtOAc (250mL), reclaim crude product, use saturated NaHCO 3Solution (3 * 50mL), the salt water washing, and through anhydrous Na 2SO 4Dry.Obtain title compound, be white solid, be not further purified, be directly used in next step.
Embodiment 2
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800241
The steps A .N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800242
(58mg, 0.192mmol) (for preparation, referring to following step B to E) and the DMAP of catalytic amount are dissolved among the 5mL DCM with the 2-tertiary butyl-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine.Add 4-formyl radical benzene sulfonyl chloride (47mg, 0.230mmol), and with this solution stirring at room 3 hours.The saturated NaHCO of solution 3The aqueous solution, salt water washing, and through anhydrous Na 2SO 4Dry.Evaporating solvent.Then, resistates is dissolved among the 5mL MeOH that contains several Glacial acetic acid.(0.057mL is 0.960mmol) with powdery 3  molecular sieves (500mg) to add thanomin.With solution stirring at room 30 minutes.Add NaCNBH 3(36mg, 0.576mmol), and with this solution stirring at room 3 hours.Filtering solution, evaporating solvent.Resistates is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous Na 2SO 4Dry.Evaporating solvent uses 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 48mg (40%). 1H NMR (400MHz, methyl alcohol-D 4): δ 1.49-1.55 (m, 2H), 1.55-1.61 (m, 2H), 1.67 (s, 9H), and 2.32-2.39 (m, 1H), 3.15-3.18 (m, 2H), 3.27 (s, 3H), 3.34 (m, 2H), 3.81 (dd, J=5.96,4.39Hz, 2H), 3.92 (d, J=3.12Hz, 1H), 3.95 (d, J=3.71Hz, 1H), 4.33 (s, 2H), 4.51 (d, J=7.62Hz, 2H), 7.28 (dd, J=9.08,2.05Hz, 1H), 7.56 (d, J=1.95Hz, 1H), 7.61-7.68 (m, 4H), 7.85 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +515.0; C 27H 38N 4O 4S+2.7TFA+0.9H 2The theoretical value of O: C, 46.40; H, 5.11; N, 6.68. experimental value: C, 46.41; H, 5.05; N, 6.75.
Step B.N-methyl-N-{3-nitro-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl } ethanamide
Figure A20058003233800251
In room temperature, with 4-amino methyl tetrahydropyrans (2.50g, 21.7mmol) add to N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (4.61g, 21.27mmol) (for preparation, referring to embodiment 1, step B and C) and yellow soda ash (5.10g is 47.7mmol) in the mixture in EtOH (120mL).Reaction mixture was heated 3 hours at 60 ℃.After the ethanol evaporation, resistates is dissolved in EtOAc (400mL), uses H 2O (3 * 50mL), (3 * 50mL) washings are and through Na for the saturated NaCl aqueous solution 2SO 4Dry.After filtering and concentrating, obtain 6.62g (100%) title compound, be orange red solid. 1H?NMR(400MHz，CDCl 3)：δ1.38-1.52(m，2H)，1.72-1.81(m，2H)，1.90(s，3H)，1.93-2.02(m，1H)，3.23(s，3H)，3.23-3.27(m，2H)，3.36-3.49(m，2H)，4.01-4.07(m，2H)，6.91(d，J＝9.18Hz，1H)，7.29(dd，J＝9.08，2.64Hz，1H)，8.05(d，J＝2.34Hz，1H)，8.22(t，J＝5.37Hz，1H).MS(ESI)(M+H) +＝309.12.
Step C.N-{3-amino-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl }-the N-methylacetamide
Figure A20058003233800252
In the Parr wobbler, in 30-40psi H 2In room temperature, with 10%Pd/C (0.2g) catalysis, with N-methyl-N-{3-nitro-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl } ethanamide (5.39g, 16.7mmol) hydrogenation 18 hours in ethyl acetate (200mL).By diatomite filtration with after concentrating, obtain 6.0g (100%) purple solid, for HCl salt, be not further purified, be directly used in next step. 1H?NMR(400MHz，CD 3OD)：δ1.32-1.46(m，2H)，1.78-1.84(m，2H)，1.85(s，3H)，1.91-2.06(m，1H)，3.16(d，J＝6.83Hz，2H)，3.20(s，3H)，3.39-3.51(m，2H)，3.94-4.03(m，2H)，7.01(d，J＝8.59Hz，1H)，7.12(d，J＝2.15Hz，1H)，7.17(dd，J＝8.49，4.39Hz，1H).MS(ESI)(M+H) +＝278.7
The step D.N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the N-methylacetamide
Figure A20058003233800261
At 0 ℃, with trimethyl-acetyl chloride (3.27mL, 3.20g, 26.5mmo1) drop to N-{3-amino-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl-N-methylacetamide (7.01g, 25.3mmol) and DIPEA (5.3mL, 3.92g, in methylene dichloride 30.36mmol) (170mL) solution.With the mixture that generates stirring at room 4 hours.Behind evaporating solvent, resistates is dissolved in acetate (75mL), divide then to install in 15 sealing test tubes.In Personal Chemistry SmithSynthesizer microwave device, mixture was heated 2.5 hours in 150 ℃.The reaction mixture that is combined evaporates, be dissolved in then among the EtOAc (200mL), with the 2N NaOH aqueous solution (2 * 10mL), salt solution (2 * 10mL) washings, and through Na 2SO 4Dry.After filtering and concentrating, use EtOAc/MeOH (10: 1), on silica gel,, obtain title compound, be white solid (7.31g, 84%) by MPLC purifying resistates as elutriant.MS(ESI)(M+H) +：344.15.
The step e .2-tertiary butyl-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine
Figure A20058003233800262
With the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-(4.57g 13.3mmol) is dissolved in the concentrated hydrochloric acid (100mL) the N-methylacetamide, then 90-100 ℃ of heated overnight.After concentrating, resistates is dissolved among the EtOAc (200mL), with 2NNaOH (2 * 20mL) and NaCl (2 * 20mL) wash, then through Na 2SO 4Dry.After filtering and concentrating, obtain 4.02g (100%) title compound, be the purple solid. 1H?NMR(400MHz，CDCl 3)：δ1.46-1.54(m，4H)，1.54(s，9H)，2.16-2.37(m，1H)，2.87(s，3H)，3.23-3.38(m，2H)，3.91-4.02(m，2H)，4.13(d，J＝7.42Hz，2H)，6.61(dd，J＝8.59，2.15Hz，1H)，6.99(d，J＝2.15Hz，1H)，7.11(d，J＝8.59Hz，1H).MS(ESI)(M+H) +：302.06.
Embodiment 3
The steps A .N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(morpholine-4-ylmethyl) benzsulfamide
Figure A20058003233800271
According to embodiment 2 steps A identical operations; use the 2-tertiary butyl-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine (50mg; 0.166mmol), DMAP (catalytic amount) and 4-formyl radical benzene sulfonyl chloride (44mg, 5mL DCM solution 0.215mmol).Morpholine (0.045mL, 0.498mmol) and NaCNBH 3(31mg, 5mL MeOH solution 0.498mmol) were used for for second step.Evaporating solvent.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying then obtains title compound, is corresponding tfa salt.Yield: 52mg (48%). 1H NMR (400MHz, methyl alcohol-D 4): δ 1.52-1.57 (m, 2H), 1.57-1.63 (m, 2H), 1.68 (s, 9H), 2.33-2.41 (m, 1H), 3.29 (s, 3H), 3.29-3.32 (m, 4H), 3.35 (m, 2H), 3.79-3.92 (m, 4H), 3.93 (d, J=3.58Hz, 1H), 3.95 (d, J=2.82Hz, 1H), 4.45 (s, 2H), 4.53 (d, J=7.42Hz, 2H), 7.32 (dd, J=8.96,2.05Hz, 1H), 7.60 (d, J=1.79Hz, 1H), 7.65-7.72 (m, 4H), 7.88 (d, J=8.96Hz, 1H); MS (ESI) (M+H) +541.0; C 29H 40N 4O 4The theoretical value of S+2.9 TFA: C, 47.97; H, 4.96; N, 6.43. experimental value: C, 48.08; H, 5.06; N, 6.13.
Embodiment 4
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(1H-1,2,3-triazol-1-yl methyl) benzsulfamide
Figure A20058003233800272
Steps A: the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(1H-1,2,3-triazol-1-yl methyl) benzsulfamide
Figure A20058003233800281
At 0 ℃, with the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-(hydroxymethyl)-N-methyl benzenesulfonamide is (for preparation, referring to following step B) (55mg, 0.117mmol) and TEA (0.025mL 0.176mmol) is dissolved among the 5mL DCM.Drip methylsulfonyl chloride (0.011mL, 0.140mmol), then stirring at room solution 3 hours.The saturated NaHCO of solution 3The aqueous solution, salt water washing, and through anhydrous Na 2SO 4Dry.Evaporating solvent.Then, with resistates be dissolved in 2mL DMF and KI (19mg, 0.117mmol) in, then add 1H-1,2, the 3-triazole (0.135mL, 2.34mmol).Solution was stirred 1 hour at 80 ℃.Evaporating solvent.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying then obtains title compound, is corresponding tfa salt.Yield: 35mg (47%). 1H NMR (400MHz, methyl alcohol-D 4): δ 1.50-1.56 (m, 2H), 1.56-1.65 (m, 2H), 1.68 (s, 9H), 2.32-2.40 (m, 1H), 3.26 (s, 3H), 3.35 (m, 2H), 3.93 (d, J=3.32Hz, 1H), 3.96 (d, J=3.51Hz, 1H), 4.52 (d, J=7.42Hz, 2H), 5.74 (s, 2H), 7.31 (dd, J=8.98,1.95Hz, 1H), 7.41 (d, J=8.59Hz, 2H), 7.54 (s, 1H), 7.55-7.57 (m, 2H), 7.79 (s, 1H), 7.88 (d, J=8.98Hz, 1H), 8.09 (s, 1H); MS (ESI) (M+H) +523.0; C 27H 34N 6O 3The theoretical value of S+2.4 TFA: C, 47.96; H, 4.61; N, 10.55. experimental value: C, 48.02; H, 4.72; N, 10.22.
The step B:N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-(hydroxymethyl)-N-methyl benzenesulfonamide
Figure A20058003233800282
(45mg, 0.149mmol) DMAP with catalytic amount is dissolved among the 3mL DCM with the 2-tertiary butyl-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine.Add 4-formyl radical benzene sulfonyl chloride (37mg, O.179mmol), and with this solution at stirring at room 2h.The saturated NaHCO of solution 3The aqueous solution, salt water washing, and through anhydrous Na 2SO 4Dry.Evaporating solvent.Resistates is dissolved among the 5mLMeOH, adds NaCNBH 3(20mg, 0.298mmol).With solution in stirred overnight at room temperature.Evaporating solvent.Resistates is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous Na 2SO 4Dry.Use EtOAc as elutriant, by flash chromatography on silica gel purifying crude product.Yield: 55mg (78%). 1H NMR (400MHz, methyl alcohol-D 4): δ 1.50-1.56 (m, 2H), 1.57-1.65 (m, 2H), 1.68 (s, 9H), 2.31-2.41 (m, 1H), 3.26 (s, 3H), 3.35 (m, 2H), 3.93 (d, H=3.32Hz, 1H), 3.96 (d, J=3.71Hz, 1H), 4.52 (d, J=7.42Hz, 2H), 4.68 (s, 2H), 7.30 (dd, J=8.98,2.15Hz, 1H), 7.50 (s, 4H), 7.54 (d, J=1.56Hz, 1H), 7.87 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +472.0.
Embodiment 5
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(methylamino-) methyl] benzsulfamide
Figure A20058003233800291
Steps A: the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(methylamino-) methyl] benzsulfamide
With the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide is (for preparation; referring to following step B to G) (50mg 0.106mmol) is dissolved among the 5mL MeOH that contains several Glacial acetic acid and Powdered 3  molecular sieves (400mg).(0.160mL 0.318mmol), and adds Na (CN) BH with this solution at stirring at room 15min. to add methylamine (the THF solution of 2M) 3(20mg, 0.318mmol), and with this solution stirring at room 3 hours.Filtering solution, and evaporating solvent.Product is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 14mg (22%). 1H NMR (400MHz, methyl alcohol-D 4) δ 1.48-1.54 (m, 2H), 1.54-1.62 (m, 2H), 1.65 (s, 9H), 2.29-2.38 (m, 1H), 2.73 (s, 3H), 3.26 (s, 3H) 3.33 (m, 2H), 3.91 (d, J=3.12Hz, 1H), 3.92-3.95 (m, 1H), 4.26 (s, 2H), 4.49 (d, J=7.62Hz, 2H), 7.26 (dd, J=8.98,1.95Hz, 1H), 7.53 (d, J=1.95Hz, 1H), 7.63 (d, J=1.17Hz, 4H), 7.82 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +485.0.
Step B:(4-fluoro-3-nitrophenyl) Urethylane
Figure A20058003233800301
With methyl-chloroformate (13.2mL, 170.2mmol) drop to 4-fluoro-3-N-methyl-p-nitroaniline (24.15g, 154.7mmol) and DIPEA (35mL is in cold (0 ℃) methylene dichloride (200mL) 201mmol).With reaction mixture in stirred overnight at room temperature.Then, solution is with the dilution of 200mL methylene dichloride, and with 2MHCl, salt water washing, and through anhydrous MgSO 4Dry.Concentrated solvent, product is not further purified, and is directly used in next step.Yield: 35.5g (99%). 1H NMR (400MHz, the δ 3.81 of chloroform-D) (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7.72 (d, J=8.59Hz, 1H), 8.17 (dd, J=6.35,2.64Hz, 1H).
Step C:{3-nitro-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl } Urethylane
Figure A20058003233800302
At 75 ℃, (2.0g, 9.32mmol) (1.28g, 11.2mmol) (2.0mL stirred 48 hours among 50mLEtOH 14.0mmol) containing TEA with 4-amino methyl tetrahydropyrans with (4-fluoro-3-nitrophenyl) Urethylane.Evaporating solvent.Resistates is dissolved among the EtOAc, and uses 5%KHSO 4The aqueous solution, saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 1: 1 hexane: EtOAc as elutriant, by flash chromatography on silica gel purifying crude product.Yield: 2.53g (88%). 1H NMR (400MHz, the δ 1.42 of chloroform-D) (m, 2H), 1.73 (d, J=1.76Hz, 1H), 1.76 (d, J=1.95Hz, 1H), 1.88-2.01 (m, 1H), 3.22 (m, 2H), 3.42 (m, 2H), 3.78 (s, 3H), 4.01 (d, J=4.30Hz, 1H), 4.04 (d, J=3.51Hz, 1H), 6.48 (br.s, 1H), 6.85 (d, J=9.37Hz, 1H), 7.65 (br.s, 1H), 8.03-8.09 (m, 2H).
Step D:{3-amino-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl } Urethylane
Figure A20058003233800311
Will 3-nitro-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) and amino] phenyl } (2.53g 8.18mmol) is dissolved among the 50mL EtOAc that contains catalytic amount 10%Pd/C Urethylane.Use the Parr hydrogenation apparatus, at room temperature and H 2Agitation of solutions is spent the night in the atmosphere (40psi).By diatomite filtration solution, and evaporating solvent.Yield: 2.29g (99%). 1H NMR (400MHz, and the δ 1.40 of chloroform-D) (m, 2H), 1.70-1.74 (m, 1H), 1.74-1.77 (m, 1H), 1.81-1.92 (m, 1H), 2.99 (m, 2H), 3.34 (br.s, 2H), 3.41 (m, 2H), 3.74 (s, 3H), 3.99 (d, J=3.51Hz, 1H), 4.02 (d, J=3.51Hz, 1H), 6.38 (br.s, 1H), 6.55-6.60 (m, 1H), 6.62-6.68 (m, 1H), 6.95 (br.s, 1H).
Step e: [the 2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl] Urethylane
Figure A20058003233800312
Will { 3-amino-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl } Urethylane (2.29g, 8.20mmol) and DMAP (0.20g 1.64mmol) is dissolved among the 75mL DCM.Drip trimethyl-acetyl chloride (1.10mL, 9.02mmol), and with this solution stirring at room 2 hours.Solution NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Resistates is dissolved in 25mL AcOH and uses Personal Chemistry microwave device 125 ℃ of heating 1 hour.Evaporating solvent.Resistates is dissolved among the EtOAc, and uses NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 4: 3 hexane: acetone is as elutriant, by flash chromatography on silica gel purifying crude product.Yield: 1.81g (64%). 1H NMR (400MHz, the δ 1.48-1.54 of chloroform-D) (m, 4H), 1.56 (s, 9H), 2.23-2.35 (m, 1H), 3.27-3.35 (m, 2H), 3.78 (s, 3H), 3.96 (t, J=2.93Hz, 1H), 3.99 (t, J=3.03Hz, 1H), 4.18 (d, J=7.42Hz, 2H), 6.63 (br.s, 1H), 7.24-7.28 (m, 1H), 7.41 (br.s, 1H), 7.61 (d, J=1.95Hz, 1H).
Step F: the 2-tertiary butyl-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine
Figure A20058003233800321
At 0 ℃, (1.80g 5.21mmol) is dissolved among the 75mL THF with [the 2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl] Urethylane.(7.3mL 7.29mmol), and stirs solution 15 minutes at 0 ℃ to drip 1M HCl/ ether.Slowly add LiAlH 4(988mg, 26.1mmol), and with this solution in stirred overnight at room temperature.At 0 ℃, add MeOH (5mL), then add water (10mL), thus the quencher reaction, and with solution stirring at room 30 minutes.Add anhydrous Na 2SO 4(10g), and with this solution room temperature restir 30 minutes.Filtering solution, and evaporating solvent.Resistates is dissolved among the EtOAc, and uses NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Evaporating solvent.Yield: 1.54g (98%). 1H NMR (400MHz, and the δ 1.49-1.53 of chloroform-D) (m, 4H), 1.53-1.57 (m, 9H), 2.22-2.32 (m, 1H), 2.87 (s, 3H), 3.26-3.35 (m, 2H), 3.95 (t, J=3.03Hz, 1H), 3.97-4.00 (m, 1H), 4.13 (d, J=7.42Hz, 2H), 6.61 (dd, J=8.59,2.15Hz, 1H), 6.99 (d, J=1.95Hz, 1H), 7.11 (d, J=8.59Hz, 1H).
The step G:N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide
With the 2-tertiary butyl-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine (250mg, 0.829mmol) and DMAP (100mg 0.829mmol) is dissolved among the 10mL DCM.Add 4-formyl radical benzene sulfonyl chloride (205mg, 0.995mmol), and with this solution at stirring at room 2h.Solution NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use EtOAc as elutriant, by flash chromatography on silica gel purifying crude product.Yield: 288mg (74%). 1H NMR (400MHz, and the δ 1.51-1.56 of chloroform-D) (m, 13H), 2.25-2.34 (m, 1H), 3.26 (s, 3H), 3.30-3.38 (m, 2H), 3.99 (t, J=2.93Hz, 1H), 4.02 (t, J=2.93Hz, 1H), 4.20 (d, J=7.42Hz, 2H), 7.19-7.21 (m, 1H), 7.23 (d, J=2.15Hz, 1H), 7.28-7.31 (m, 1H), 7.76 (d, J=8.20Hz, 2H), 7.96 (d, J=8.59Hz, 2H), 10.10 (s, 1H).
Embodiment 6
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-[(ethylamino) methyl]-the N-methyl benzenesulfonamide
Figure A20058003233800331
With the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide (50mg; 0.106mmol; for preparation, referring to embodiment 5 step B to G) be dissolved among the 5mL MeOH that contains several Glacial acetic acid and Powdered 3  molecular sieves (400mg).Add ethamine (2M/THF) (0.160mL, 0.318mmol), and with this solution at stirring at room 15min.Add Na (CN) BH 3(20mg, 0.318mmol), and with this solution stirring at room 3 hours.Filtering solution, and evaporating solvent.Product is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 20mg (31%). 1H NMR (400MHz, methyl alcohol-D 4) δ 1.32 (t, J=7.32Hz, 3H), 1.49-1.54 (m, 2H), 1.54-1.63 (m, 2H), 1.65 (s, 9H), 2.30-2.38 (m, 1H), 3.13 (m, 2H), 3.25 (s, 3H), 3.33 (m, 2H), 3.91 (d, J=2.93Hz, 1H), 3.92-3.95 (m, 1H), 4.26 (s, 2H), 4.49 (d, J=7.42Hz, 2H), 7.27 (dd, J=8.98,2.15Hz, 1H), 7.52 (d, J=2.15Hz, 1H), 7.63 (s, 4H), 7.83 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +499.0.
Embodiment 7
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-methoxy ethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800332
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide (75mg; 0.160mmol; for preparation, referring to embodiment 5 step B to G) be dissolved among the 5mL MeOH that contains several Glacial acetic acid and Powdered 3  molecular sieves (400mg).Add the 2-methoxyethyl amine (0.070mL, 0.800mmol), and with this solution at stirring at room 15min.Add Na (CN) BH 3(50mg, 0.800mmol), and with this solution stirring at room 3 hours.Filtering solution, and evaporating solvent.Product is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 87mg (85%). 1H NMR (400MHz, methyl alcohol-D 4) δ 1.49-1.54 (m, 2H), 1.55-1.63 (m, 2H), 1.66 (s, 9H), 2.31-2.38 (m, 1H), 3.23-3.26 (m, 2H), 3.26 (s, 3H), 3.33m, 2H), 3.39 (s, 3H), 3.63-3.66 (m, 2H), 3.91 (d, J=2.93Hz, 1H), 3.93-3.95 (m, 1H), 4.31 (s, 2H), 4.50 (d, J=7.42Hz, 2H), 7.27 (dd, J=8.98,2.15Hz, 1H), 7.57 (d, J=1.95Hz, 1H), 7.64 (s, 4H), 7.84 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +529.0; Anal.Calcd (%) for C 28H 40N 4O 4S+3.2 TFA+0.1 H 2O:C, 46.15; H, 4.89; N, 6.26. experimental value: C, 46.11; H, 4.66; N, 6.20.
Embodiment 8
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(tetramethyleneimine-1-ylmethyl) benzsulfamide
Figure A20058003233800341
With the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide (75mg; 0.160mmol; for preparation, referring to embodiment 5 step B to G) be dissolved among the 5mL MeOH that contains several Glacial acetic acid and Powdered 3  molecular sieves (400mg).Add tetramethyleneimine (0.068mL, 0.800mmol), and with this solution at stirring at room 15min.Add Na (CN) BH 3(50mg, 0.800mmol), and with this solution stirring at room 3 hours.Filtering solution, and evaporating solvent.Product is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 73mg (71%). 1H NMR (400MHz, methyl alcohol-D 4) δ 1.49-1.54 (m, 2H), 1.55-1.63 (m, 2H), 1.66 (s, 9H), 2.09 (br.s, 4H), 2.29-2.40 (m, 1H), and 3.11-3.25 (m, 2H), 3.27 (s, 3H), 3.33 (m, 2H), 3.40-3.57 (m, 2H), 3.91 (d, J=2.93Hz, 1H), 3.93-3.96 (m, 1H), 4.46 (s, 2H), 4.51 (d, J=7.42Hz, 2H), 7.28 (dd, J=8.98,2.15Hz, 1H), 7.59 (d, J=1.95Hz, 1H), 7.66 (d, J=1.37Hz, 4H), 7.86 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +525.0; Anal.Calcd (%) for C 29H 40N 4O 3S+3.9 TFA+0.1 H 2O:C, 45.51; H, 4.58; N, 5.77. experimental value: C, 45.47; H, 4.55; N, 5.95.
Embodiment 9
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(morpholine-4-ylmethyl) benzsulfamide
Figure A20058003233800351
With the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide (77mg; 0.166mmol; for preparation, referring to embodiment 5 step B to G) be dissolved among the 5mL MeOH that contains several Glacial acetic acid and Powdered 3  molecular sieves (400mg).Add morpholine (0.045mL, 0.498mmol), and with this solution at stirring at room 15min.Add Na (CN) BH 3(31mg, 0.498mmol), and with this solution stirring at room 3 hours.Filtering solution, and evaporating solvent.Product is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 52mg (48%). 1H NMR (600MHz, D 3-MeOD) δ 1.52-1.57 (m, 2H), 1.57-1.63 (m, 2H), 1.68 (s, 9H), 2.33-2.41 (m, 1H), 3.29 (s, 3H), 3.29-3.32 (m, 4H), 3.35 (m, 2H), 3.79-3.92 (m, 4H), 3.93 (d, J=3.58Hz, 1H), 3.95 (d, J=2.82Hz, 1H), 4.45 (s, 2H), 4.53 (d, J=7.42Hz, 2H), 7.32 (dd, J=8.96,2.05Hz, 1H), 7.60 (d, J=1.79Hz, 1H), 7.65-7.72 (m, 4H), 7.88 (d, J=8.96Hz, 1H); MS (ESI) (M+H) +541.0; Anal.Calcd (%) for C 29H 40N 4O 4S+2.9 TFA:C, 47.97; H, 4.96; N, 6.43. experimental value: C, 48.08; H, 5.06; N, 6.13.
Embodiment 10
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(2-oxo-pyrrolidine-1-yl) methyl] benzsulfamide
Figure A20058003233800361
Steps A: the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(2-oxo-pyrrolidine-1-yl) methyl] benzsulfamide
Figure A20058003233800362
With the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-(hydroxymethyl)-N-methyl benzenesulfonamide is (for preparation, referring to following step B) (60mg, 0.127mmol) and TEA (0.021mL 0.152mmol) is dissolved among the 5mL DCM.Add methylsulfonyl chloride (0.011mL, 0.140mmol), and with this solution at stirring at room 1h.The saturated NaHCO of solution 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Evaporating solvent.Resistates is dissolved among the 2mL DMF, and 0 ℃ drop to the 2-Pyrrolidone that stirring (32mg, 0.381mmol) and NaH (15mg is in 3mL DMF solution 0.381mmol).With solution stirring at room 2 hours.Add saturated NaHCO 3Aqueous solution quencher reaction, and evaporating solvent.Product is dissolved among the EtOAc, and uses saturated NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Use 10-70%CH 3CN/H 2O, by the reversed-phase HPLC purified product, freeze-drying obtains title compound, is corresponding tfa salt.Yield: 31mg (37%). 1H NMR (400MHz, methyl alcohol-D 4) δ 1.49-1.54 (m, 2H), 1.55-1.63 (m, 2H), 1.66 (s, 9H), 2.00-2.09 (m, 2H), 2.31-2.38 (m, 1H), 2.43 (m, 2H), 3.24 (s, 3H), 3.30-3.38 (m, 4H), 3.91 (d, J=3.12Hz, 1H), 3.92-3.95 (m, 1H), 4.48-4.52 (m, 4H), 7.29 (dd, J=8.98,2.15Hz, 1H), 7.38 (d, J=8.59Hz, 2H), 7.51 (d, J=8.40Hz, 2H), 7.53 (d, J=1.95Hz, 1H), 7.86 (d, J=8.98Hz, 1H); MS (ESI) (M+H) +538.8; Anal.Calcd (%) for C 29H 38N 4O 4S+1.8 TFA:C, 52.63; H, 5.39; N, 7.53. experimental value: C, 52.78; H, 5.00; N, 7.92.
The step B:N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-(hydroxymethyl)-N-methyl benzenesulfonamide
At 0 ℃; with the N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide (115mg; 0.245mmol, for preparation, referring to embodiment 5 step B to G) and be dissolved in 1: 1 THF of 8mL: among the MeOH.Add NaBH 4(19mg, 0.490mmol), and with this solution at stirring at room 1h.Evaporating solvent.Resistates is dissolved among the EtOAc, and uses NaHCO 3The aqueous solution, salt water washing, and through anhydrous MgSO 4Dry.Evaporating solvent.Yield: 116mg (99%). 1H NMR (400MHz, the δ 1.50-1.57 of chloroform-D) (m, 13H), 2.21 (s, 1H), 2.25-2.35 (m, 1H), 3.21 (s, 3H), 3.30-3.38 (m, 2H), 3.98 (m, 1H), 4.01 (m, 1H), 4.19 (d, J=7.42Hz, 2H), 4.78 (s, 2H), 7.16-7.18 (m, 1H), 7.27-7.29 (m, 2H), 7.44 (d, J=8.59Hz, 2 H), 7.57 (d, J=8.59Hz, 2H).
Embodiment 11
N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800372
Steps A .N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide
Figure A20058003233800373
With thanomin (0.57mL; 9.50mmol) add to N-[2-(1; 1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide (454mg; 0.95mmol) in the mixture of (for preparation, referring to following step B to D) and MeOH (15mL).Stirred reaction mixture 30 minutes, and add AcOH (2).Stirred reaction mixture 1 hour adds NaBH 4Stirred reaction mixture 3 hours, and evaporating solvent.Use the MeCN/ water of 10-90% gradient, by anti-phase preparation HPLC purified product.Obtain the tfa salt of title compound, be white solid.Yield: 420mg (84%); 1H NMR (400MHz, CD 3OD) δ 1.38-1.54 (m, 4H), 2.20 (m, 3H), 2.27-2.34 (m, 1H), 3.14-3.21 (m, 2H), 3.27 (s, 3H), 3.31-3.38 (m, 1H), 3.83 (m, 2H), 3.87-3.96 (m, 2H), and 4.30-4.37 (m, 4H), 7.23-7.32 (m, 2H), 7.59-7.70 (m, 5H); MS (ESI) (M+H) +523.0; C 25H 32F 2N 4O 4S+2.6 TFA+0.1 H 2The theoretical value of O: C, 44.19; H, 4.27; N, 6.83. experimental value: C, 44.27; H, 4.25; N, 6.60.
Step B.N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the N-methylacetamide
Figure A20058003233800381
At 0 ℃, with HATU (3.76g, 9.91mmol) and N-{3-amino-4-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] phenyl-N-methylacetamide (2.50g, 9.01mmol) (for preparation, step B and C referring to embodiment 2) add to 2,2-difluoro propionic acid (0.99g, 9.01mmol) and DIPEA (1.88mL is in DMF 10.8mmol) (100mL) solution.Reaction mixture was stirred 5 hours, and concentrated solvent.Intermediate is heated to 80 ℃ in Glacial acetic acid (100mL), kept 2 hours, and concentrated solvent.In DCM (300mL), reclaim crude product, use saturated NaHCO 3Solution (3 * 100mL), the salt water washing, and through anhydrous MgSO 4Dry.Concentrated solvent, the DCM solution of use MeOH 3% and acetone 5% by positive MPLC purified product, obtains title compound, is the lightpink solid.Yield: 2.40g (76%); MS (ESI) (M+H) +3 52.3.
Step is (1,1-two fluoro ethyls)-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine C.2-
Figure A20058003233800391
With N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the N-methylacetamide (2.40g, 6.82mmol) and the mixture of dense HCl (15mL) 80 ℃ of heated overnight.Reaction mixture is cooled to room temperature, is poured onto in the water (100mL), and use NaOH solution, it is 8 that the mixture that generates is neutralized to the pH value.(4 * 100mL) extract the saturated NaHCO of the organic layer of merging to product with EtOAc 3Solution and salt water washing.Solution is through anhydrous Na 2SO 4Drying, concentrated solvent obtains title compound, is light green oily matter.Yield: 1.96g (92%); MS (ESI) (M+H) +310.1.
Step D.N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-4-formyl radical-N-methyl benzenesulfonamide
Figure A20058003233800392
With 4-formyl radical benzene sulfonyl chloride (238mg; 1.16mmol) add to 2-(1; 1-two fluoro ethyls)-N-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-amine (300mg; 0.96mmol), DIPEA (0.23mL; 1.35mmol) and DMAP (118mg is in solution 0.96mmol).Reaction mixture is heated to 60 ℃ spends the night, and concentrated solvent.In EtOAc, reclaim product, and use saturated NaHCO 3Solution, water and salt water washing.Organic solution is through anhydrous Na 2SO 4Drying, and concentrated solvent.Use the EtOAc/ heptane of 10-90%, purified product on silica gel obtains title compound, is white solid.Yield: 454mg (98%); MS (ESI) (M+H) +478.2.

Claims (14)

1. formula I compound, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture:
Wherein
G is selected from-O-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl and C 1-4Alkoxyl group; Perhaps R 1And R 2The N that connects with them can form C 3-6Heterocycle; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
2. the compound of claim 1, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture, wherein
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl; Perhaps R 1And R 2The N that connects with them can form C 2-5Heterocyclylalkyl; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
3. the compound of claim 1, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture, wherein
G is-O-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl and C 1-4Alkoxy-C 1-4Alkyl, and R 1And R 2It is different groups; Perhaps R 1And R 2The N that connects with their can form and be selected from 2-oxo-pyrrolidine-1-base, tetramethyleneimine-1-base, 1H-1,2, the group of 3-triazol-1-yl and morpholinyl; And
R 3, R 4And R 5Independently be selected from fluorine and methyl, and R 3, R 4And R 5Identical.
4. the compound of claim 1, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture, wherein
G is-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl and C 1-4Alkoxy-C 1-4Alkyl, and R 1And R 2It is different groups; And
R 3, R 4And R 5Be methyl independently of one another.
5. compound is selected from:
The N-{2-tertiary butyl-1-[(4,4-difluoro cyclohexyl) methyl]-1H-benzoglyoxaline-5-yl }-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(morpholine-4-ylmethyl) benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(1H-1,2,3-triazol-1-yl methyl) benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(methylamino-) methyl] benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-[(ethylamino) methyl]-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-methoxy ethyl) amino] methyl }-the N-methyl benzenesulfonamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-(tetramethyleneimine-1-ylmethyl) benzsulfamide;
The N-[2-tertiary butyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-N-methyl-4-[(2-oxo-pyrrolidine-1-yl) methyl] benzsulfamide;
N-[2-(1,1-two fluoro ethyls)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-benzoglyoxaline-5-yl]-the 4-{[(2-hydroxyethyl) amino] methyl }-the N-methyl benzenesulfonamide;
And pharmacologically acceptable salts.
6. formula I compound, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture:
Figure A2005800323380004C1
Wherein
G is selected from-O-,-CHF-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl and C 1-4Alkoxyl group; Perhaps R 1And R 2The N that connects with them can form C 3-6Heterocycle; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
7. each formula I compound, its pharmacologically acceptable salts, diastereomer, enantiomer or their mixture among the claim 1-6, it is as medicine
8. each compound is used for the treatment of purposes in the medicine of pain in preparation among the claim 1-6.
9. each compound is used for the treatment of purposes in the medicine of anxiety disorder in preparation among the claim 1-6.
10. each compound is used for the treatment of purposes in the medicine of cancer, multiple sclerosis, Parkinson's disease, Huntington Chorea, alzheimer's disease, gastrointestinal tract disease and cardiovascular disorder in preparation among the claim 1-6.
11. a pharmaceutical composition, it comprises among the claim 1-6 each compound and pharmaceutically acceptable carrier.
12. the method for pain in the treatment warm-blooded animal comprises each compound among the claim 1-6 of the described animals administer treatment significant quantity of this treatment of needs.
13. the method for preparation I compound comprises:
Figure A2005800323380005C1
Make the reaction of formula II compound and formula III compound,
Figure A2005800323380005C2
Then, in the presence of reductive agent, use R 1(R 2) NH carries out reductive amination,
Wherein
G is selected from-O-,-CHF-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl and C 1-4Alkoxyl group; Perhaps R 1And R 2The N that connects with them can form C 3-6Heterocycle; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
14. the method for preparation I compound comprises:
Figure A2005800323380005C3
Make the reaction of formula II compound and formula III compound,
Figure A2005800323380006C1
Carry out series reaction then, comprise 1) use reductive agent to reduce; 2) methylsulfonylization; With 3) use R 1(R 2) NH carries out nucleophilic substitution,
Wherein
G is selected from-O-,-CHF-and-CF 2-;
R 1And R 2Independently be selected from-H, C 1-4Alkyl, hydroxyl-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl and C 1-4Alkoxyl group; Perhaps R 1And R 2The N that connects with them can form C 3-6Heterocycle; And
R 3, R 4And R 5Independently be selected from fluorine and methyl.
CN200580032338.4A 2004-09-24 2005-09-22 Compounds, compositions containing them, preparation thereof and uses thereof Pending CN101027292A (en)

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