CN103183659A - Chromane derivative used as TRPV3 (transient receptor potential vanillin 3) regulator - Google Patents
Chromane derivative used as TRPV3 (transient receptor potential vanillin 3) regulator Download PDFInfo
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- CN103183659A CN103183659A CN 201110443796 CN201110443796A CN103183659A CN 103183659 A CN103183659 A CN 103183659A CN 201110443796 CN201110443796 CN 201110443796 CN 201110443796 A CN201110443796 A CN 201110443796A CN 103183659 A CN103183659 A CN 103183659A
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- 0 C*(C)(C1)CC1(C[C@]1(C)CC(N**)=O)Oc2c1ccnc2 Chemical compound C*(C)(C1)CC1(C[C@]1(C)CC(N**)=O)Oc2c1ccnc2 0.000 description 1
- KMQOPMDJWBLBJF-UHFFFAOYSA-O CC(c1c(cccc2)c2c(C[NH3+])cc1)=O Chemical compound CC(c1c(cccc2)c2c(C[NH3+])cc1)=O KMQOPMDJWBLBJF-UHFFFAOYSA-O 0.000 description 1
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Abstract
The invention provides a chromane derivative used as a transient receptor potential vanillin (TRPV) regulator. Particularly, the compound provided by the invention can be used for treating or preventing the diseases, symptoms and/or obstacles regulated by TRPV3. Simultaneously, the invention further provides a method for preparing the compound provided by the invention, an intermediate used during synthesis for the compound, a medicine composition of the compound, and a method for treating or preventing the diseases, symptoms and/or obstacles regulated by TRPV3.
Description
Technical field
Present patent application relates to chromanane (chromane) derivative with transient receptor potential vanilla element 3 (TRPV3) activity.
Background technology
Ion moves through cytolemma and realizes by special albumen.The TRP passage is the extended familys of a non-selective cationic channel, plays the effect of assisting regulation and control ionic current and membrane potential.The TRP passage is divided into 6 subfamilies that comprise TRPV family.TRPV3 is the member of the TRPV class of TRP passage.
TRPV3 is the non-selective cationic channel of calcium permeability.Except calcium ion, the TRPV3 passage is permeability for other positively charged ions, as sodium ion.Therefore, the TRPV3 passage is regulated membrane potential by regulating positively charged ion (as calcium ion and sodium ion) stream.The TRPV3 acceptor is different from valtage-gated calcium channel in mechanism.Usually, valtage-gated calcium channel to film depolarize reply, and open passage and flow into from extracellular matrix to allow calcium ion, thereby cause the increase of cellular calcium level or concentration.On the contrary, nonselective L type (long-lasting) TRP passage produces more lasting variation aspect ionic concn, and this passage is part gate (regulating by chemical reagent such as 2-amino ethoxy phenylbenzene boric acid ester [2-APB], vanilla element (vanilloid) and heat).Difference on these mechanism is accompanied by the difference on voltage-gated channel and the TRP channel architecture.Therefore, although replying in various kinds of cell type neutralization has a lot of different passages to play the effect of regulating ionic current and membrane potential aspect numerous stimulations, recognize between different types of ionic channel that the significant difference aspect structural, function and mechanism of is very important.
TRPV3 albumen be skin cells (Peier etc., Science (2002), 296,2046-2049) and dorsal root ganglion, gasserian ganglion, spinal cord and brain (Xu etc., Nature (2002), 418,181-185; Smith etc., Nature (2002), 418,186-188) middle temperature-sensitive passage of expressing.In keratinocyte system, the stimulation of TRPV3 cause inflammation amboceptor, as the release of interleukin 1.Therefore, TRPV3 also can play a significant role in pain that the release of regulating by inflammatory stimulus causes and inflammation.As described herein, especially TRPV3 albumen can be used to the screening analysis, to differentiate the compound that the function of TRPV3 (including but not limited to people TRPV3, mouse TRPV3, rat TRPV3 and fruit bat TRPV3) is regulated.US2004/0009537 (' 537 application) discloses the sequence corresponding to people TRPV3, mouse TRPV3 and fruit bat TRPV3.For example, ' 537 Shen Qing sequence numbering 106 and 107 corresponds respectively to people's nucleotide sequence and aminoacid sequence.The sequence numbering 108 and 109 of ' 537 applications corresponds respectively to nucleotide sequence and the aminoacid sequence of mouse.
The function of TRPV3 involves reception and the transduction of pain basically.Therefore, the compound of one or more functions that can regulate TRPV3 is differentiated and is made in expectation.
WO 2007/056124, WO 2008/140750 and WO 2008/033564 disclose TRPV3 conditioning agent, the especially antagonist of the multiple disease that is used for the treatment of the TRPV3 mediation.
Find in the process of better anodyne being devoted to, still need disease, illness (conditions) and/or the obstacle (disorders) regulated by TRPV3 are carried out therapeutic treatment.
Summary of the invention
Present patent application relates to the compound of formula (I):
Wherein, dotted line (... ..) be optional key; A is for replacing or unsubstituted cycloalkyl, aryl, heteroaryl or heterocyclic group;
Y is-(CHR
1)
r, R wherein
1Be hydrogen, halogen or replacement or unsubstituted alkyl;
X be hydrogen, nitro, cyano group, halogen, replacement or unsubstituted alkyl ,-OR
2,-NR
3R
4,-C (O)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
pNR
3R
4Or-S (O)
pR
3
R
3And R
4Can be identical or different, be independently selected from hydrogen ,-OR
2, replacement or unsubstituted alkyl, thiazolinyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group or heterocyclic radical alkyl;
R
2Be selected from the group of being formed by hydrogen, replacement or unsubstituted alkyl, thiazolinyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclic radical alkyl;
' m ' is the integer of 0-2, comprises endpoints thereof;
' n ' is the integer of 0-2, comprises endpoints thereof;
' p ' is the integer of 0-2, comprises endpoints thereof; And
' r ' is the integer of 0-2, comprises endpoints thereof.
Should be understood that formula (I) has structurally contained all steric isomers and the pharmacy acceptable salt that can be considered by the chemical structure of kind described herein, comprise enantiomer and diastereomer.
According to an embodiment, specifically provide the compound of formula (I), wherein ' A ' is for replacing or unsubstituted aryl.In this embodiment, preferably, ' A ' for replacing or unsubstituted phenyl or naphthyl, wherein said substituting group is independently selected from halogen (for example, fluorine or chlorine), alkoxyl group (for example, methoxyl group) or cycloalkyloxy (for example, cyclopentyloxy).
According to another embodiment, specifically provide the compound of formula (I), wherein ' A ' is for replacing or unsubstituted heteroaryl.In this embodiment, preferably, ' A ' is for replacing or unsubstituted thiazole, benzothiazole, quinoline or dibenzo [b, d] furans, wherein substituting group (for example is independently selected from halogen, alkyl, methyl), alkoxyl group (for example, methoxyl group), cycloalkyloxy or halogenophenyl (for example, bromophenyl).
According to another embodiment, specifically provide the compound of formula (I), wherein ' Y ' is CH
2, CH (CH
3) or key.
According to another embodiment, specifically provide the compound of formula (I), wherein dotted line (... ..) for singly-bound or do not exist.
According to another embodiment, specifically provide the compound of formula (I), wherein X is halogen (for example, fluorine or chlorine) or alkoxyl group (for example, methoxyl group); And ' m ' is 1.
According to another embodiment, specifically provide the compound of formula (I), wherein ' n ' is 1.
Be representative compounds below, these compounds as the explanation of properties, are not to be intended to limit scope of the present invention only.
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(2-p-methoxy-phenyl) ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(2-cyclopentyloxy-3-methoxy-benzyl) ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-1-(4-methoxynaphthalene ylmethyl) ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-[(4-methoxyl group dibenzo [b, d] furans-1-yl) methyl] ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-[(1S)-and the 1-phenylethyl] ethanamide;
(2E)-2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-subunit)-N-[2-(cyclopentyloxy) phenyl] ethanamide;
N-(2-cyclopentyloxy phenyl)-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide;
N-(2,6-difluorobenzyl)-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide;
2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-quinoline-6-yl acetamide;
N-[4-(4-bromophenyl)-1,3-thiazoles-2-yl]-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide;
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the N-1-naphthyl acetamide;
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-1,3-thiazol-2-yl ethanamide; With
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(6-methyl isophthalic acid, 3-benzothiazole-2-yl) ethanamide; Perhaps
The analogue of compound 1-13, tautomer, regional isomer (regiomer), geometrical isomer, steric isomer, enantiomer, diastereomer or pharmacy acceptable salt are also at the row of consideration.
According to another embodiment, specifically provide the compound or its salt of formula (I), this compound or its salt is with the IC less than 10,000nM
50Value suppresses the TRPV3 function.In other embodiments, specifically provide the compound or its salt of formula (I), this compound or its salt is with the IC less than 1000nM
50Value suppresses the TRPV3 function.
This paper also provides the method for preparing compound described herein.
Embodiment
Present patent application provides the chromanane derivative that can be used as the TRPV3 conditioning agent and the method for synthesizing these compounds.The contriver has considered pharmacy acceptable salt, enantiomer and the diastereomer of compound described herein respectively.Also considered respectively to comprise described compound together with the pharmaceutical composition of pharmaceutically acceptable carrier, vehicle or thinner, this pharmaceutical composition can be used for treating disease, illness and/or the obstacle by the TRPV3 mediation.
The present invention is defined by claims, but not is limited by the explanation that hereinafter provides.The term that uses in appending claims glossary part is herein defined, if but the clearly definition of statement is arranged in addition, the term of this claim can use in a different manner.
Term " halogen " or " halo " comprise fluorine, chlorine, bromine or iodine.
Term " alkyl " refer to have 1-8 carbon atom, only form and do not have the hydrocarbon chain group of degree of unsaturation by carbon and hydrogen atom, and be connected with the rest part of molecule by singly-bound, for example: methyl, ethyl, n-propyl, 1-methylethyl (sec.-propyl), normal-butyl, n-pentyl and 1,1-dimethyl ethyl (tertiary butyl).Term " C
1-6Alkyl " refer to have the alkyl chain of 1-6 carbon atom.Unless opposite explanation or narration are arranged, this paper describe or all alkyl of protection can be straight or branched, replacement or unsubstituted.
The hydrocarbon chain that term " thiazolinyl " refers to comprise 2-10 carbon atom and contains at least one carbon-to-carbon double bond.The limiting examples of alkenyl group comprises vinyl, 1-propenyl, 2-propenyl (allyl group), pseudoallyl, 2-methyl isophthalic acid-propenyl, 1-butylene base and crotyl.Unless opposite explanation or narration are arranged, this paper describe or all thiazolinyls of protection can be straight or branched, replacement or unsubstituted.
Term " alkynyl " refers to have 2 to about 12 carbon atoms and has the hydrocarbyl group (group with about 10 carbon atoms of 2-is preferred) of at least one carbon-to-carbon triple bond.The limiting examples of alkynyl group comprises ethynyl, proyl and butynyl.Unless opposite explanation or narration are arranged, this paper describe or all alkynyl groups of protection can be straight or branched, replacement or unsubstituted.
The logical peroxide bridge of term " alkoxyl group " expression is connected to the alkyl group of molecule rest part.The representative example of this class group is-OCH
3With-OC
2H
5Unless opposite explanation or narration are arranged, this paper describe or all alkoxyl groups of protection can be straight or branched, replacement or unsubstituted.
Term " cycloalkyl " expression 3 is to the non-fragrant monocycle of about 12 carbon atoms or encircle ring system more, as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Polycyclic naphthene base examples of groups includes but not limited to perhydro-naphthyl, adamantyl and norcamphyl group, bridged ring group or spiral shell bicyclic radicals (for example, spiral shell (4,4) ninth of the ten Heavenly Stems-2-yl).Unless opposite explanation or narration are arranged, this paper describes or all cycloalkyl of protection can be replacements or unsubstituted.
Term " cycloalkylalkyl " refer to have 3 to about 8 carbon atoms, be directly connected to the group that contains cyclic rings on the alkyl group.The cycloalkylalkyl group can be connected to main structure in any carbon atom place in alkyl, thereby produces stable structure.The limiting examples of this class group comprises cyclopropyl methyl, cyclobutyl ethyl and cyclopentyl ethyl.Unless opposite explanation or narration are arranged, this paper describes or all cycloalkylalkyls of protection can be replacements or unsubstituted.
Term " cycloalkenyl group " refers to have 3 to the group that contains cyclic rings about 8 carbon atoms, that have at least one carbon-to-carbon double bond, as cyclopropenyl radical, cyclobutene base and cyclopentenyl.Unless opposite explanation or narration are arranged, this paper describes or all cycloalkenyl groups of protection can be replacements or unsubstituted.
Term " aryl " refers to have the aromatic group of 6-14 carbon atom, comprises the aroma system of monocycle, dicyclo or three rings, as phenyl, naphthyl, tetralyl, indanyl and xenyl.Unless opposite explanation or narration are arranged, this paper describes or all aryl of protection can be replacements or unsubstituted.
Term " arylalkyl " refers to directly be combined in the aromatic yl group as defined above on the alkyl as defined above, for example-and CH
2C
6H
5Or-C
2H
4C
6H
5
Term " heterocyclic radical " and " heterocyclic ring ", " heterocyclic group " refer to the first cyclic group of the stable 3-15 that is made up of carbon atom and 1-5 the heteroatoms that is selected from nitrogen, phosphorus, oxygen and sulphur.For the purposes of the present invention, the heterocyclic ring group can be monocycle, dicyclo or three ring ring systems, can comprise that the nitrogen, phosphorus, carbon, oxygen or the sulphur atom that condense in ring system, bridge joint ring system or spiro system and the heterocyclic ring group optionally are oxidized to various oxidation state.In addition, nitrogen-atoms is optionally by quaternized; And this cyclic group can be partially or completely saturated (that is, heterocycle or heteroaryl).This class heterocyclic ring examples of groups includes but not limited to: azetidine base, acridyl, benzo dioxolyl, benzo dioxacyclohexyl, benzofuryl, carbazyl, cinnolines base, dioxolanyl, indolizinyl, naphthyridinyl, perhydro-azepine
Base, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridyl, purine radicals, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazyl, imidazolyl, tetrahydro isoquinolyl, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine
Base, azepine
Base, pyrryl, the 4-piperidone base, pyrrolidyl, pyrazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolinyl oxazolidinyl, triazolyl, indanyl isoxazolyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidyl, isothiazolyl, quinuclidinyl, the isothiazole alkyl, indyl, pseudoindoyl, the indoline base, the isoindoline base, the octahydro indyl, the octahydro pseudoindoyl, quinolyl (quinolyl), isoquinolyl (isoquinolyl), the Decahydroisoquinolinpreparation base, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl benzoxazolyl, furyl (furyl), tetrahydrofuran base, THP trtrahydropyranyl, thienyl, benzothienyl, thio-morpholinyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, dioxy phosphorus heterocycle amyl group oxadiazole base, chromanyl and isochroman base.The heterocyclic ring group can be connected to main structure in any heteroatom or carbon atom place, thereby produces stable structure.Unless opposite explanation or narration are arranged, this paper describes or all claimed heterocyclic radical groups can be replacements or unsubstituted, comprises the heterocyclic radical group that contains in the more complicated substructure.
Term " heterocyclic radical alkyl " refers to be directly connected to the heterocyclic ring group on the alkyl group.The heterocyclic radical alkyl can be connected to main structure in any carbon atom place in alkyl group, thereby produces stable structure.
Term " heteroaryl " refers to the heteroaromatic cyclic group.The heteroaryl cyclic group can be connected to main structure in any heteroatom or carbon atom place, thereby produces stable structure.Unless opposite explanation or narration are arranged, this paper describes or all heteroaryls of protection can be replacements or unsubstituted, comprises the heteroaryl that contains in the more complicated substructure.
Term " heteroarylalkyl " refers to be directly connected to the hetero-aromatic ring group on the alkyl group.The heteroarylalkyl group can be connected to main structure in any carbon atom place in alkyl group, thereby produces stable structure.
Unless otherwise prescribed, term used herein " replacement " refers to that group or part have one or more substituting groups that are connected to the structural framework of this group or part, and these substituting groups include but not limited to: hydroxyl, halogen, carboxyl, cyano group, nitro, oxo (=O), sulfo-(=S), replace or unsubstituted alkyl, replace or unsubstituted alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted heterocyclic alkyl ring, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic ring, replace or unsubstituted guanidine,-COOR
x,-C (O) R
x,-C (S) R
x,-C (O) NR
xR
y,-C (O) ONR
xR
y,-NR
xCONR
yR
z,-N (R
x) SOR
y,-N (R
x) SO
2R
y,-(=N-N (R
x) R
y) ,-NR
xC (O) OR
y,-NR
xR
y,-NR
xC (O) R
y,-NR
xC (S) R
y,-NR
xC (S) NR
yR
z,-SONR
xR
y,-SO
2NR
xR
y,-OR
x,-OR
xC (O) NR
yR
z,-OR
xC (O) OR
y,-OC (O) R
x,-OC (O) NR
xR
y,-R
xNR
yC (O) R
z,-R
xOR
y,-R
xC (O) OR
y,-R
xC (O) NR
yR
z,-R
xC (O) R
y,-R
xOC (O) R
y,-SR
x,-SOR
x,-SO
2R
xWith-ONO
2, R wherein
x, R
yAnd R
zBe independently selected from hydrogen, replace or unsubstituted alkyl, replace or unsubstituted alkoxyl group, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, the heterocyclic radical alkyl ring that replaces, replace or unsubstituted heteroarylalkyl, perhaps replace or unsubstituted heterocyclic ring.
Term " treatment " state, obstacle or illness comprise: (a) appearance of the clinical symptom of prevention or suspension status, obstacle or illness, described state, obstacle or illness develop in the experimenter who suffers from or easily suffer from described state, obstacle or illness but do not experience or demonstrate the clinical or inferior clinical symptom of described state, obstacle or illness as yet; (b) suppress described state, obstacle or illness, that is, stop or palliate a disease or the development of its at least a clinical or inferior clinical symptom; Or (c) eliminate a disease, that is, cause at least a clinical or inferior clinical symptom of described state, obstacle or illness or its to disappear.
Term " experimenter " comprises Mammals (especially human) and other animals, as domestic animal (for example household pet comprises cat, dog) and non-domestic animal (as wildlife).
" treatment significant quantity " refer to when giving when needing the experimenter of therapeutic state, obstacle or illness, is enough to the amount of compound that the experimenter as the administration target is told on." treatment significant quantity " is along with compound, disease, its severity and experimenter's to be treated age, body weight, physical appearance and responsiveness (responsiveness) and change.
The compound of describing in the present patent application can form salt.The limiting examples that constitutes the pharmacy acceptable salt of a present patent application part comprises salt, the salt of organic bases, the salt of chiral base, the salt of natural amino acid and the salt of alpha-non-natural amino acid that mineral alkali is derived.With regard to the described whole compounds of formula (I), present patent application is prolonged and stereoisomeric forms in any ratio and its mixture.As long as prior art has been instructed the synthetic of specific steric isomer or has been separated, the various stereoisomer forms of present patent application can be separated from each other by methods known in the art, perhaps can obtain given isomer by stereospecificity or asymmetric synthesis.The tautomeric form of compound described herein and mixture are also at the row of consideration.
Pharmaceutical composition
The pharmaceutical composition of present patent application contains at least a compound as herein described and at least a pharmaceutically acceptable vehicle (as pharmaceutically acceptable carrier or thinner).Preferably, the pharmaceutical composition of considering contains compound as herein described with the amount that is enough to suppress the TRPV3 acceptor in the subject.
The experimenter who considers for example comprises: viable cell and the Mammals that comprises the people.Compound of the present invention can dilute with pharmaceutically acceptable vehicle (as carrier or thinner) combination or by carrier, or is encapsulated in the carrier of capsule, anther sac (sachet), paper or other vessel forms.
The example of suitable carriers includes but not limited to: water, salts solution, alcohol, polyoxyethylene glycol, the Viscotrol C of poly-hydroxy ethoxylation, peanut oil, sweet oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesiumcarbonate, sugar, cyclodextrin, amylose starch, Magnesium Stearate, talcum, gelatin, agar, pectin, gum arabic, stearic acid or Mierocrystalline cellulose hang down alkyl oxide, silicic acid, lipid acid, fatty acid amine, glycerine monofatty ester and two glyceryl ester, the sour ether of tetramethylolmethane fat, polyoxyethylene, Walocel MT 20.000PV and polyvinylpyrrolidone.
Described carrier and thinner can comprise slow-release material, as glyceryl monostearate or distearin (use separately or mix with paraffin).
This pharmaceutical composition also can comprise one or more pharmaceutically acceptable auxiliarys, wetting agent, emulsifying agent, suspension agent, sanitas, the salt that influences osmotic pressure, buffer reagent, sweeting agent, correctives, tinting material or above-mentioned any combination.Also can carry out preparation to pharmaceutical composition of the present invention, thus by program known in the art after experimenter's administration, provide activeconstituents fast, the release that continues or postpone.
Pharmaceutical composition as herein described can be by routine techniques preparation known in the art.For example, active compound can mix with carrier or be diluted by carrier, or is encapsulated in the carrier of ampoule, capsule, anther sac, paper or other vessel forms.When carrier when the thinner, it can be solid, semisolid or the fluent material of auxiliary material, vehicle or the medium effect of playing active compound.Active compound can be adsorbed on the granular solids container, for example in anther sac.
Pharmaceutical composition can be conventional form, for example product of capsule, tablet, aerosol, solution, suspension or topical application.
Route of administration can be transports active compound of the present invention effectively to any approach of action site suitable or expectation.Suitable route of administration includes but not limited to: administration in (subcutaneous) administration under oral administration, nasal administration, pulmonary administration, buccal administration, subcutaneous (subdermal) administration, intradermal administration, percutaneous dosing, parenteral admin, rectal administration, reservoir type administration, the skin, intravenous administration, the urethra, intramuscular administration, intranasal administration, dosing eyes (as using ophthalmic solution) or topical (as using topical ointment).
The solid orally ingestible form includes but are not limited to: tablet, capsule (soft gelatin or glutoid), drageeing (activeconstituents that contains powder or ball shape form), lozenge (troches and lozenges).Tablet, drageeing or capsule with talcum and/or carbohydrate carrier or binding agent etc. are particularly suitable for oral application.Liquid preparation includes but not limited to syrup, emulsion, soft gelatin and aseptic injectable liquids, as water-based or nonaqueous liquid suspension or solution.Use outward for gi tract, injectable solution or suspension preparation are especially suitable.The aqueous solution that preferably has the active compound that is dissolved in polyhydroxylated Viscotrol C.
Those skilled in the relevant art can determine to treat the suitable dose of the used compound of disease as herein described and obstacle.Usually by since the people's that carries out for the basis from the Prima Facie Evidence of animal research dosage range research, make therapeutic dose.Dosage must enough produce the desired therapeutic benefit and not cause undesired side effect.For example, the per daily dose of TRPV3 conditioning agent can be from 0.1mg/kg to about 30.0mg/kg.Those skilled in the art can fine utilizations and are adjusted mode of administration, formulation, suitable pharmaceutical excipient, diluent or carrier.All changes and improvements all are contemplated as falling with in the scope of the present invention.
Methods for the treatment of
The invention provides and be used for the treatment of the disease of being regulated by TRPV3, illness and or compound and its pharmaceutical preparation of obstacle.Present patent application further provides by treat compound of the present invention or the pharmaceutical composition of significant quantity to the experimenter that needs are arranged, to the method for being treated by disease, illness and/or the obstacle of TRPV3 adjusting in the described subject.
It is believed that disease, illness and/or the obstacle regulated by TRPV3 include but not limited to: pain; Nociceptive pain (nociceptive pain); Toothache; It is pained that ischemic myocardium causes; The pain that causes because of migraine; Acute pain; Chronic pain; Neuropathic pain; Post-operative pain; The pain (for example, postherpetic neuralgia or trigeminal neuralgia) that causes because of neurodynia; The pain that causes because of diabetic neuropathy; Toothache and cancer pain; Inflammatory pain illness (for example sacroiliitis and osteoarthritis); Arthrodynia; DPN; Nerve degenerative diseases; Retinopathy; The nervosa skin barrier; Apoplexy; Irritable bladder disease; The urinary incontinence; Vulvodynia (vulvodynia); Gastrointestinal disorders is as irritable bowel syndrome, stomach-esophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel, Crohn disease, celiac disease (celiac disease); Inflammatory diseases is as pancreatitis; Dyspnoea is as supersensitivity and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; The stimulation of skin, eye or mucous membrane; Dermatitis; Pruritus is as uremic pruritus; Heating; Muscle spasm; Vomiting; Dyskinesia; Dysthymia disorders; Huntington's chorea; Hypomnesis; Brain function is limited; Amyotrophic lateral sclerosis (ALS); Dull-witted; Sacroiliitis; Osteoarthritis; Diabetes; Obesity; Urticaria; Actinic keratosis; Keratoacanthoma (keratocanthoma); Alopecia (alopecia); Meniere; Tinnitus; Hyperacusis (hyperacusis); Anxiety disorder; And benign prostatic hyperplasia.Other diseases, illness and/or the obstacle regulated by TRPV3 for example are documented in: WO2007/056124; Wissenbach, U. etc., Biology of the cell (2004), 96,47-54; Nilius, B. etc., Physiol Rev (2007), 87,165-217; Okuhara, D.Y. etc., Expert Opinion on Therapeutic Targets (2007), 11,391-401; Hu, H.Z. etc., Journal of Cellular Physiology, (2006), 208,201-212; In the reference of quoting with this paper; The mode that All Files is quoted by integral body is incorporated this paper into and is used for described purpose.
General preparation method
Compound as herein described (compound and the specific examples that comprise general formula (I)) utilizes the known technology preparation of those of ordinary skills.Reaction sequence (reaction sequences) preparation of compound as herein described by describing in the scheme 1.Can infer, all possible steric isomer is also contained in the scope of the present invention.
The raw material that is used for following reaction scheme is commercially available, or can be according to method known to those skilled in the art or by method preparation disclosed herein.Usually, compound of the present invention can be by the preparation of following reaction scheme, and wherein all symbol is as above-mentioned definition.
The compound of formula (I) can be according to synthetic schemes 1 preparation.Under the situation that alkali (as tetramethyleneimine or piperidines) exists, cyclic ketones condensation in alcoholic solvent of the 2-hydroxy acetophenone of formula (1) and formula (2), the spirocyclic ketone of production (3); Under the Wittig reaction conditions, the reaction of the phosphoryl acetic acid trialkyl ester (wherein R is alkyl) of this spirocyclic ketone and formula (4), the acrylate of production (5) (wherein R is alkyl).With the compound hydrolysis of formula (5), shortening (choosing wantonly) then, the compound of production (6).Under the situation that the coupling agent that is fit to exists, by with the amine coupling with suitable formula (7) of the carboxylic acid of formula (6), prepare the compound of general formula (I).Perhaps, under the situation that the alkali that is fit to exists, the acyl chlorides of intermediate (6) can with the amine coupling of formula (7), generate the compound of general formula (I).
Scheme 1
Experiment
By following example the present invention has been done to further specify, these examples are considered as being limited on scope of the disclosure never in any form, and only are to be intended to describe.Therefore, how those skilled in the art will be appreciated that to come according to disclosed content experiment and embodiment further to be implemented by following example, substituting group, reagent or condition are carried out various changes.
Intermediate
Intermediate 1
(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) acetic acid:
Step 1:6-chlorine spiral shell [chromene-2,1 '-the ring fourth]-4 (3H)-ketone: at room temperature, successively to 5 '-chloro-2 '-hydroxy acetophenone (5.0g, 29.308mmol) add tetramethyleneimine (4.16g in the solution after in methyl alcohol (50ml), stirring, 58.616mmol) and cyclobutanone (4.1g, 58.616mmol).With reaction mixture reflux 14h under nitrogen.Under reduced pressure boil off solvent, the resistates water (100ml) that obtains is diluted, and this mixture is acidified to pH 4.0.(3 * 100ml) extract this mixture with chloroform.Organic extract liquid after water (100ml), salt solution (50ml) washing merge, and use anhydrous sodium sulfate drying.With 15% ethyl acetate that is in the sherwood oil, carry out purifying with boiling off the resistates that obtains behind the solvent by silica gel column chromatography, generate the 6.3g white solid product;
1H NMR (300MHz, CDCl
3) δ 1.69-1.88 (m, 5H), 1.96-2.04 (m, 1H), 2.88 (s, 2H), 6.91 (d, J=9.0Hz, 1H), 7.38 (d, J=6.6Hz, 1H), 7.76 (s, 1H).
Step 2:(2E)-(6-chlorine spiral shell [chromene-2; 1 '-the ring fourth]-4 (3H)-Ji Yaji) ethyl acetate: with the time of 15min; to sodium hydride (431mg; 17.897mmol) in anhydrous tetrahydro furan (25ml) through stir and the mixture of cooling in add the phosphoryl triethyl acetate (4.03g, 17.897mmol).Reaction mixture is stirred 30min, and (2g 8.948mmol) joins in the anhydrous tetrahydro furan-4 (3H)-ketone with 6-chlorine spiral shell [chromene-2,1 '-ring fourth] then.Under nitrogen, in identical temperature reaction mixture is stirred 24h.With first alcohol and water diluting reaction mixed solution, and product extraction entered ethyl acetate (in 3 * 100ml).Water (100ml), salt water washing organic layer, dry (Na
2SO
4) and concentrate the crude product that generates 3.54g, be directly used in next step.
Step 3:(2E)-(6-chlorine spiral shell [chromene-2,1 '-the ring fourth]-4 (3H)-subunits) acetic acid: at room temperature, to (2E)-(6-chlorine spiral shell [chromene-2,1 '-the ring fourth] (3g 10.22mmol) adds 1N sodium hydroxide solution (30ml) to-4 (3H)-Ji Yaji) ethyl acetate in the solution after the stirring in ethanol (30ml).Reaction mixture is at room temperature stirred 2h.The resistates that obtains behind solvent 1NHCl acidifying will under reduced pressure be boiled off.To expect product extraction enter ethyl acetate (in 3 * 50ml), water (100ml), salt water washing, dry (Na
2SO
4) and concentrate generation 2.6g white solid product;
1H NMR (300MHz, CDCl
3) δ 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 3.96 (s, 2H), 6.36 (s, 1H), 6.80 (d, J=8.1Hz, 1H), 7.22 (d, J=9.3Hz, 1H), 7.51 (s, 1H).
Step 4:(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) acetic acid: at room temperature, to (2E)-(6-chlorine spiral shell [chromene-2,1 '-the ring fourth]-4 (3H)-subunits) (2.5g 9.444mmol) adds 10%Pd/C (50mg) in the solution after the stirring to acetic acid in ethyl acetate (25ml).In the Paar hydrogenation equipment, under the 40psi hydrogen pressure, reaction mixture is stirred 12h.By bed of diatomaceous earth filtering reaction mixed solution, with filtrate drying (Na
2SO
4) and concentrate, generate the 2.45g white solid product;
1H NMR (300MHz, CDCl
3) δ 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 2.09-2.21 (m, 2H), 2.29-2.38 (m, 1H), 2.99 (d, J=13.2Hz, 1H), 3.44 (br s, 1H), 6.73 (d, J=8.1Hz, 1H), 7.04 (d, J=9.3Hz, 1H).
Intermediate 2
(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) acetic acid:
By the similar procedure described in intermediate 1, by 5 '-fluoro-2 '-reaction prepares title compound through 4 steps for hydroxy acetophenone and cyclobutanone, generates white solid;
1H NMR (300MHz, CDCl
3) δ 1.66-1.74 (m, 2H), 1.88-1.95 (m, 1H), 2.05-2.14 (m, 3H), 2.26-2.34 (m, 1H), and 2.37-2.44 (m, 1H), 2.48-2.56 (m, 1H), 2.96 (dd, J=4.2,15.6Hz, 1H), 3.35 (br s, 1H), 6.74-6.82 (m, 3H).
Intermediate 3
(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) acetic acid:
Step 1:6-hydroxyl spiral shell [chromene-2,1 '-the ring fourth]-4-(3H)-ketone: by the similar procedure described in the step 1 of intermediate 1, by 2 ', 5 '-resacetophenone (10g, 65.724mmol) and cyclobutanone (13.29ml, 131.44mmol) under the situation that tetramethyleneimine (10.79ml) exists, prepare title compound, generate the 10g product;
1H NMR (300MHz, CDCl
3) δ 1.63-1.73 (m, 2H), 1.84-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.23-2.33 (m, 2H), 6.85 (d, J=8.7Hz, 1H), 7.06 (d, J=9.0Hz, 1H), 7.33 (s, 1H).
Step 2:6-methoxyl group spiral shell [chromene-2,1 '-the ring fourth]-4 (3H)-ketone: to 6-hydroxyl spiral shell [chromene-2,1 '-the ring fourth]-4-(3H)-ketone (8g, 39.215mmol) add salt of wormwood (16.28g in the solution after in dry dimethyl formamide (150ml), stirring, 117.64mmol) and methyl iodide (4.88ml, 78.431mmol), under nitrogen atmosphere with reaction mixture at stirring at room 2h.After reaction was finished, water (100ml) diluted this reaction mixture, with ethyl acetate (3 * 300ml) extractions, water (3 * 100ml), salt solution (60ml) the washing organic layer after merging, dry (Na then
2SO
4), filter and concentrate, generate the 8.13g product;
1H NMR (300MHz, CDCl3) δ 1.67-1.77 (m, 1H), 1.85-1.97 (m, 1H), 2.11-2.18 (m, 2H), 2.23-2.34 (m, 2H), 2.87 (s, 2H), 3.77 (s, 3H), 6.88 (d, J=9.6Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 7.25 (s, 1H).
Step 3: by the similar procedure described in the step 2-4 of intermediate 1, prepare final compound by 6-methoxyl group spiral shell [chromene-2,1 '-ring fourth]-4 (3H)-ketone;
1H NMR (300MHz, DMSO-d6) δ 1.53-1.65 (m, 2H), 1.78 (br s, 1H), and 1.96-2.05 (m, 3H), 2.18-2.23 (m, 2H), and 2.30-2.39 (m, 1H), 2.93 (d, J=15.9Hz, 1H), 3.18 (br s, 1H), 3.64 (s, 3H), 6.64 (s, 2H), 6.75 (s, 1H).
Intermediate 4
1-[2-(cyclopentyloxy)-3-p-methoxy-phenyl] methylamine hydrochloride:
Step 1:2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime: to 2-(cyclopentyloxy)-3-methoxybenzaldehyde (3g, 13.636mmol) add oxammonium hydrochloride (1.758g in the solution after in ethanol, stirring, 27.277mmol) and aqueous sodium hydroxide solution (18ml, 34.091mmol).Under nitrogen atmosphere, with the reaction mixture 6h that refluxes.Under reduced pressure boil off solvent, and with the reaction mixture dilute with water.With chloroform (3 * 200ml) extraction products, with the organic layer water after merging (3 * 100ml), salt solution (50ml) washing, then dry, filter and under vacuum, concentrate, generate the product of 3.12g.
1H?NMR(300MHz，CDCl
3)δ1.58-1.64(m，4H)，1.66-1.72(m，4H)，3.84(s，3H)，4.86(br?s，1H)，6.89(d，J＝8.1Hz，1H)，6.99(t，J＝7.8Hz，1H)，7.31(d，J＝7.8Hz，1H)，8.43(s，1H)。
Step 2:1-[2-(cyclopentyloxy)-3-p-methoxy-phenyl] the methane amine hydrochlorate: at room temperature, (3g 12.448mmol) adds the Raney Ni (0.30g) of catalytic amount in the solution after stirring in methyl alcohol (10ml) to 2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime.In the Paar hydrogenation equipment, under the 50psi hydrogen pressure, reaction mixture is stirred 3h.Reaction mixture is filtered by bed of diatomaceous earth, drier (Na
2SO
4), filter and concentrate, obtain crude product.Then crude product is dissolved in the ethyl acetate, under 10 ℃, in this solution, drips the hydrochloric acid that is in the ethyl acetate, stir 20min, filter then and drying, generate the product of 2.86g, H NMR (300MHz, DMSO-d
6) δ 1.57-1.63 (m, 4H), 1.65-1.72 (m, 4H), 3.81 (s, 3H), 3.94 (s, 2H), 4.90 (br s, 1H), 7.08 (s, 3H), 8.39 (br s, 3H).
Intermediate 5
1-(4-methoxyl group-1-naphthyl) methylamine hydrochloride:
By the similar procedure described in intermediate 4, (1g 5.376mmol) through 2 step prepared in reaction title compounds, generates 1.27g as the product of hydrochloride by 4-methoxyl group-1-naphthaldehyde;
1H NMR (300MHz, CDCl
3) δ 3.85 (s, 3H), 4.26 (s, 2H), 6.68 (d, J=7.2Hz, 1H), 7.40 (br s, 2H), 7.53 (d, J=7.8Hz, 1H), 7.64 (d, J=7.5Hz, 1H), 8.19 (d, J=6.6Hz, 1H).
Intermediate 6
1-(4-methoxyl group dibenzo [b, d] furans-1-yl) methylamine hydrochloride:
By the similar procedure described in intermediate 4, (3g 13.274mmol) through 2 step prepared in reaction title compounds, generates 2.97g as the product of hydrochloride by 4-methoxyl group-dibenzo [b, d] furans-1-formaldehyde;
1H NMR (300MHz, CDCl
3) δ 4.07 (s, 3H), 4.63 (s, 2H), 7.16 (d, J=8.1Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.44 (t, J=6.6Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.66 (d, J=7.5Hz, 1H), 8.22 (d, J=7.8Hz, 1H).
Embodiment
Universal process for the preparation of (3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-yl)-N-(2-p-methoxy-phenyl) acetamide derivative:
Method A
To (3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-yl) acetogenin (1.0mmol) and arylamines hydrochloride (1.0mmol) in methylene dichloride, add in the mixture after being mixed 3-(3-dimethylaminopropyl)-1-ethyl-carbodiimide hydrochloride (EDCIHCl) (1.3mmol), I-hydroxybenzotriazole (HOBt) (1.3mmol) and triethylamine (3.4mmol).At room temperature reaction mixture is stirred 12h.After reaction was finished, the dilute with water reaction mixture was also used chloroform extraction, the organic layer water after the merging, salt water washing, dry (Na
2SO
4), filter and under vacuum, concentrate and generate product.
Method B
Step 1: add the N of oxalyl chloride (1.5mmol) and catalytic amount in (3,4-dihydro spiral shell [chromene-2,1 '-ring fourth]-4-yl) solution after acetogenin (1.0mmol) stirs in methylene dichloride, dinethylformamide.Under nitrogen atmosphere, reaction mixture is at room temperature stirred 2h.Under reduced pressure boil off solvent and excessive oxalyl chloride, generate the acyl chlorides of sticky solid shape, this acyl chlorides is directly used in linked reaction and need not purifying.
Step 2: with the time of 15min, in methylene dichloride, add step 1 intermediate (1.0mmol) that is in the methylene dichloride through stirring also in the cooled mixture to arylamines (1.0mmol) and triethylamine (1.7mmol) in 0 ℃.Make reaction mixture be heated to room temperature, and under nitrogen, stir 2h in identical temperature.The dilute with water reaction mixture is used the chloroform extraction product again.With organic layer water, the salt water washing after merging, dry (Na
2SO
4), filter and under vacuum, concentrate and generate product.
Embodiment 1
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(2-p-methoxy-phenyl) ethanamide:
As described in method B, at triethylamine (225 μ l, 1.624mmol) under the situation about existing, in methylene dichloride (10ml), by (6-chloro-3, the 4-dihydro spiral shell [chromene-2 by intermediate 1 preparation, 1 '-the ring fourth]-the 4-yl) Acetyl Chloride 98Min. (230mg, 0.812mmol) (100mg, coupling 0.812mmol) prepares title compound, generates 159mg pale solid product with the 2-anisidine.IR(KBr)3301，2941，1656，1542，1247，1030，742cm
-1；
1H?NMR(300MHz，CDCl
3)δ1.62-1.75(m，2H)，1.81-1.89(m，1H)，2.02-2.10(m，3H)，2.33-2.48(m，3H)，3.04(dd，J＝4.8，9.6Hz，1H)，3.50(br?s，1H)，3.81(s，3H)，6.72(d，J＝8.7Hz，1H)，6.85(d，J＝8.1Hz，1H)，6.93-7.04(m，3H)，7.14(s，1H)，7.75(br?s，1H)，8.37(d，J＝6.9Hz，1H)；ESI-MS(m/z)372.25(M+H)
+。
Embodiment 2
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(2-cyclopentyloxy-3-methoxy-benzyl) ethanamide:
As described in method A, at EDCIHCl (238mg, 1.248mmol), HOBt (190mg, 1.242mmol) and triethylamine (460 μ l are 3.312mmol) under the situation of Cun Zaiing, in methylene dichloride (5ml), by intermediate 1 (207mg, 0.828mmol) and intermediate 4 (200mg, coupling 0.828mmol) prepares title compound, generates the 157mg white solid product; IR (KBr) 3279,2938,1646,1478,1269,1077cm
-1 1H NMR (300MHz, CDCl
3) δ 1.50-1.67 (m, 5H), 1.81-2.06 (m, 6H), 2.09-2.19 (m, 4H), and 2.28-2.39 (m, 1H), 2.75-2.82 (m, 1H), 3.40 (br s, 1H), 3.83 (s, 3H), 4.47 (d, J=6.0Hz, 2H), 4.95 (br s, 1H), 6.03 (br s, 1H), 6.68 (d, J=8.7Hz, 1H), 6.82-6.90 (m, 2H), 6.95-7.04 (m, 3H); ESI-MS (m/z) 468.46 (M-H)
-
Embodiment 3
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-1-(4-methoxynaphthalene ylmethyl) ethanamide:
As described in method A, at EDCIHCl (192mg, 1.008mmol), HOBt (154mg, 1.008mmol) and triethylamine (375 μ l are 2.686mmol) under the situation of Cun Zaiing, in methylene dichloride (5ml), by intermediate 1 (178mg, 0.671mmol) and intermediate 5 (150mg, coupling 0.671mmol) prepares title compound, generates the 103mg white solid product; IR (KBr) 3289,2933,1632,1480,1092,760cm
-1 1H NMR (300MHz, CDCl
3) δ 1.42-1.68 (m, 5H), 1.80-1.85 (m, 1H), 2.03-2.16 (m, 3H), 2.74-2.81 (m, 1H), 3.44 (br s, 1H), 3.98 (s, 3H), 4.76-4.90 (m, 2H), 5.66 (br s, 1H), 6.65-6.73 (m, 2H), 6.96-7.04 (m, 2H), 7.33 (d, J=8.7Hz, 1H), 7.46-7.55 (m, 2H), 7.92 (d, J=7.8Hz, 1H), 8.28 (d, J=8.1Hz, 1H); ESI-MS (m/z) 434.40 (M-H)
-
Embodiment 4
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-[(4-methoxyl group dibenzo [b, d] furans-1-yl) methyl] ethanamide:
As described in method A, at EDCIHCl (109mg, 0.569mmol), HOBt (87mg, 0.569mmol) and triethylamine (158 μ l are 1.138mmol) under the situation of Cun Zaiing, in methylene dichloride (5ml), by intermediate 1 (121mg, 0.455mmol) and intermediate 6 (100mg, coupling 0.379mmol) prepares title compound, generates the 64mg white solid product; IR (KBr) 3292,2934,1630,1479,1274,747cm
-1 1H NMR (300MHz, CDCl
3) δ 1.50-1.67 (m, 3H), 1.90-2.02 (m, 3H), 2.17-2.29 (m, 3H), 2.79 (dd, J=4.8,9.6Hz, 1H), 3.47 (br s, 1H), 4.05 (s, 3H), 4.83-4.98 (m, 2H), 5.68 (br s, 1H), 6.65 (d, J=8.1Hz, 1H), 6.91-7.04 (m, 3H), 7.16 (d, J=7.8Hz, 1H), 7.35 (t, J=7.2Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 7.96 (d, J=7.8Hz, 1H); ESI-MS (m/z) 475.90 (M)
+
Embodiment 5
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-[(1S)-and the 1-phenylethyl] ethanamide:
As described in method B, at triethylamine (172 μ l, 1.238mmol) under the situation about existing, in methylene dichloride (5ml), acyl chlorides (117mg by intermediate 1,0.412mmol) and (S)-(-)-(50mg, coupling 0.412mmol) prepares title compound to α-Jia Jibianji amine, generates the 98mg white solid product.
1H?NMR(300MHz，CDCl
3)δ1.52-1.61(m，4H)，1.85(br?s，1H)，1.98-2.05(m，4H)，2.27-2.38(m，3H)，2.72(br?s，1H)，3.42(br?s，1H)，5.17(br?s，1H)，5.69(br?s，1H)，6.70(d，J＝8.7Hz，1H)，7.00-7.09(m，2H)，7.31(s，5H)。
Embodiment 6
(2E)-2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-subunit)-N-[2-(cyclopentyloxy) phenyl] ethanamide:
As described in method A, at EDCIHCl (163mg, 0.851mmol), HOBt (130mg, 0.851mmol) and triethylamine (157 μ l are 1.134mmol) under the situation of Cun Zaiing, in methylene dichloride (5ml), by (2E)-(6-chlorine spiral shell [chromene-2,1 '-ring fourth]-4 (3H)-Ji Yaji) ethyl acetate (step 2 of intermediate 1) and 2-(cyclopentyloxy) aniline (120mg, 0.681mmol) (150mg, 0.565mmol) coupling prepare title compound, generate the 95mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.53-1.65 (m, 8H), 1.74-1.90 (m, 4H), 2.22-2.30 (m, 2H), 2.47-2.57 (m, 2H), 3.50 (s, 2H), 4.67 (br s, 1H), 6.75 (d, J=8.1Hz, 2H), 6.85-6.96 (m, 2H), 7.04-7.10 (m, 2H), 8.32 (d, J=7.8Hz, 1H).
Embodiment 7
N-(2-cyclopentyloxy phenyl)-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide:
As described in method B, at triethylamine (188 μ l, 1.353mmol) under the situation about existing, in methylene dichloride (5ml), acyl chlorides (121mg by intermediate 2,0.451mmol) and 2-(cyclopentyloxy) aniline (80mg, coupling 0.451mmol) prepares title compound, generates the 89mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.53-1.60 (m, 1H), 1.64-1.75 (m, 6H), 1.81-1.90 (m, 4H), and 1.92-2.07 (m, 3H), 2.30-2.42 (m, 3H), 3.02 (dd, J=4.8,9.6Hz, 1H), 3.52 (br s, 1H), 4.81 (br s, 1H), 6.74-6.81 (m, 2H), and 6.87-7.04 (m, 4H), 7.76 (br s, 1H), 8.36 (d, J=8.1Hz, 1H).
Embodiment 8
N-(2,6-difluorobenzyl)-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide:
As described in method B, at triethylamine (388 μ l, 2.793mmol) under the situation about existing, in methylene dichloride (5ml), acyl chlorides by intermediate 2 (250mg, 0.931mmol) with 2,6-difluorobenzyl amine (133 μ l, 1.117mmol) coupling prepare title compound, generate the 219mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.58-1.70 (m, 3H), 1.79-1.89 (m, 1H), 2.00-2.07 (m, 2H), 2.16-2.21 (m, 2H), 2.29-2.39 (m, 1H), 2.75 (q, J=5.1Hz, 1H), 3.43 (br s, 1H), 4.51-4.66 (m, 2H), and 6.66-6.77 (m, 3H), 6.89 (t, J=7.8Hz, 2H), 7.19-7.29 (m, 1H).
Embodiment 9
2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-quinoline-6-yl acetamide:
As described in method B, (171 μ l are 1.229mmol) under the situation of Cun Zaiing at triethylamine, in methylene dichloride (5ml), (110mg is 0.409mmol) with 6-quinolylamine (65mg for the acyl chlorides by intermediate 2,0.451mmol) coupling prepare title compound, generate the 99mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.64-1.70 (m, 3H), 1.75-1.88 (m, 1H), 2.06-2.12 (m, 2H), 2.37-2.42 (m, 2H), 2.50-2.55 (m, 1H), 3.04 (dd, J=4.8,10.2Hz, 1H), 3.57 (br s, 1H), 6.77-6.89 (m, 3H), 7.37-7.42 (m, 1H), 7.50 (d, J=8.1Hz, 1H), 7.76 (s, 1H), 8.07 (dd, J=7.8,10.2Hz, 2H), 8.40 (s, 1H), 8.82 (s, 1H).
Embodiment 10
N-[4-(4-bromophenyl)-1,3-thiazoles-2-yl]-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide:
To intermediate 2 (100mg, 0.399mmol) successively add 4-(4-bromophenyl)-1 in the solution after in dimethyl formamide (5ml), stirring, 3-thiazole-2-amine (122mg, 0.679mmol), dicyclohexylcarbodiimide (122mg, 0.598mmol) and N-hydroxy-succinamide (67mg, 0.598mmol).Under nitrogen, reaction mixture is heated to 80 ℃ and keep 24h.Reaction mixture is to room temperature, and by the bed of diatomaceous earth filtration residue.With ethyl acetate (3 * 50ml) extraction products, the organic layer after water, salt water washing merge again, dry (Na then
2SO
4).Use is in 5% ethyl acetate in the sherwood oil, and the crude product that obtains after to reduction vaporization by silica gel column chromatography carries out purifying, generates 79mg pale solid product;
1H NMR (300MHz, CDCl
3) δ 1.45-1.55 (m, 2H), 1.58-1.70 (m, 2H), 1.84-1.90 (m, 1H), 1.98-2.10 (m, 2H), 2.16-2.22 (m, 1H), 2.31-2.38 (m, 1H), 2.77 (dd, J=4.2,10.8Hz, 1H), 3.40 (br s, 1H), 6.56 (d, J=8.7Hz, 1H), 6.72-6.79 (m, 2H), 7.13 (s, 1H), 7.47 (d, J=8.1Hz, 2H), 7.60 (d, J=8.4Hz, 2H), 10.42 (br s, 1H).
Embodiment 11
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the N-1-naphthyl acetamide:
As described in method B, (291 μ l are 2.095mmol) under the situation of Cun Zaiing at triethylamine, in methylene dichloride (5ml), (195mg is 0.698mmol) with 1-amino naphthalenes (100mg for the acyl chlorides by intermediate 3,0.698mmol) coupling prepare title compound, generate the 128mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.63-1.70 (m, 2H), 1.76-1.84 (m, 2H), 2.03-2.10 (m, 3H), and 2.34-2.40 (m, 2H), 2.73-2.80 (m, 1H), 3.09 (q, J=4.8Hz, 1H), 3.60 (br s, 1H), 3.72 (s, 3H), 6.73-6.82 (m, 2H), 7.45-7.52 (m, 5H), 7.66 (d, J=8.1Hz, 1H), 7.82 (d, J=7.5Hz, 1H), 7.96 (d, J=7.2Hz, 1H).
Embodiment 12
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-1,3-thiazol-2-yl ethanamide:
As described in method B, at triethylamine (149 μ l, 1.068mmol) under the situation about existing, in methylene dichloride (5ml), (100mg is 0.356mmol) with 2-amino-1,3-thiazoles (35mg for acyl chlorides by intermediate 3,0.356mmol) coupling prepare title compound, generate the 85mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.62-1.71 (m, 2H), 1.88 (br s, 1H), 2.05-2.12 (m, 3H), 2.30-2.41 (m, 2H), 2.59-2.67 (m, 1H), 3.19 (q, J=4.8Hz, 1H), 3.58 (br s, 1H), 3.69 (s, 3H), and 6.68-6.75 (m, 3H), 6.93-6.70 (m, 1H), and 7.28-7.35 (m, 1H).
Embodiment 13
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(6-methyl isophthalic acid, 3-benzothiazole-2-yl) ethanamide:
As described in method B, at triethylamine (254 μ l, 1.826mmol) under the situation about existing, in methylene dichloride (5ml), acyl chlorides by intermediate 3 (170mg, 0.608mmol) with the 6-methyl isophthalic acid, 3-benzothiazole-2-amine (100mg, 0.608mmol) coupling prepare title compound, generate the 80mg white solid product;
1H NMR (300MHz, CDCl
3) δ 1.60-1.68 (m, 3H), 1.86 (br s, 1H), 1.98-2.05 (m, 3H), 2.28-2.35 (m, 2H), 2.46 (s, 3H), 2.55-2.60 (m, 1H), 3.10 (q, J=4.8Hz, 1H), 3.55 (br s, 1H), 3.66 (s, 3H), 6.61 (br s, 1H), and 6.69-7.77 (m, 2H), 7.17 (d, J=7.8Hz, 1H), 7.53-7.60 (m, 2H).ESI-MS(m/z)409.43(M+H)
+。
Pharmacologically active
According to T ó th, A., Kedei, N., Wang, Y. and Blumberg, P.M., Life Sciences, (2003),
73, the development of 487-498 record is screened the TRPV3 activity of exemplary embodiment of the present invention.Can carry out the screening of compound by additive method well known by persons skilled in the art and step.These screening methods are found in following document: (a) Hu, and J.Biol.Chem. such as H.-Z. (2004),
279, 35741-35747; (b) Smith, Nature such as G.D. (2002),
418, 186-190; (c) Peier, Science such as A.M. (2002),
296, 2046-2049.
Use
45Calcium absorption Analysis and Screening TRPV3 antagonist:
With the inhibition that the cell that the 2-amino ethoxy phenylbenzene boric acid ester (2-APB) of radiocalcium is induced absorbs, investigate the inhibition of TRPV3 receptor activation.Test compounds is dissolved in the methyl-sulphoxide (DMSO), and the stoste (stock solution) of preparation 20mM is used then and is contained 1.8mM CaCl
2DMEM/F-12 ordinary culture medium (plain medium) dilution, obtain desired concn.DMSO final concentration in the reaction is 0.5% (v/v).The people TRPV3 that expresses Chinese hamster ovary celI grows in the DMEM/F-12 substratum that contains 10%FBS, 1% penicillin-Streptomycin sulphate solution and 400 μ g/ml G-418.24h before analyzing in 96 orifice plates, makes cell inoculation in～50,000 cells/well of experiment acquisition on the same day.With test compounds cell was handled 10 minutes, adding final concentration with 4 minutes then is 2-APB and the 5 μ Ci/ml of 500 μ M
45Ca
+ 2Use contains damping fluid washing and the lysing cell of 1%Triton X-100,0.1% deoxycholate salt and 0.1%SDS.After adding liquid scintillator (scintillant), in Packardt Top count, measure the radioactivity in the lysate.Draw the concentration-response curve, as lacking the peak response % that obtains under the test antagonist.Use GraphPad PRISM software, by nonlinear regression analysis, can calculate IC from the concentration-response opisometer
50Value.
Use each compound of above-mentioned analytic process test preparation, acquisition the results are shown in table 1.Concentration is that the inhibition % under 1.0 μ M and the 10.0 μ M is shown in Table 1.
Table 1: the in-vitro screening result of The compounds of this invention
Claims (10)
1. the compound of a formula (I):
Or its pharmacy acceptable salt,
Wherein dotted line (... ..) be optional key; A is for replacing or unsubstituted cycloalkyl, aryl, heteroaryl or heterocyclic group;
Y is-(CHR
1)
r, R wherein
1Be hydrogen, halogen or replacement or unsubstituted alkyl;
X be hydrogen, nitro, cyano group, halogen, replacement or unsubstituted alkyl ,-OR
2,-NR
3R
4,-C (O)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
pNR
3R
4Or-S (O)
pR
3
R
3And R
4Can be identical or different, be independently selected from hydrogen ,-OR
2, replacement or unsubstituted alkyl, thiazolinyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group or heterocyclic radical alkyl;
R
2Be selected from the group of being formed by hydrogen, replacement or unsubstituted alkyl, thiazolinyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclic radical alkyl;
' m ' is the integer of 0-2, comprises endpoints thereof;
' n ' is the integer of 0-2, comprises endpoints thereof;
' p ' is the integer of 0-2, comprises endpoints thereof; And
' r ' is the integer of 0-2, comprises endpoints thereof.
2. compound as claimed in claim 1, described compound is selected from:
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(2-p-methoxy-phenyl) ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(2-cyclopentyloxy-3-methoxy-benzyl) ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-1-(4-methoxynaphthalene ylmethyl) ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-[(4-methoxyl group dibenzo [b, d] furans-1-yl) methyl] ethanamide;
2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-[(1S)-and the 1-phenylethyl] ethanamide;
(2E)-2-(6-chloro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-subunit)-N-[2-(cyclopentyloxy) phenyl] ethanamide;
N-(2-cyclopentyloxy phenyl)-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide;
N-(2,6-difluorobenzyl)-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide;
2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-quinoline-6-yl acetamide;
N-[4-(4-bromophenyl)-1,3-thiazoles-2-yl]-2-(6-fluoro-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl) ethanamide;
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-the N-1-naphthyl acetamide;
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-1,3-thiazol-2-yl ethanamide; With
2-(6-methoxyl group-3,4-dihydro spiral shell [chromene-2,1 '-the ring fourth]-the 4-yl)-N-(6-methyl isophthalic acid, 3-benzothiazole-2-yl) ethanamide; Or
The pharmacy acceptable salt of above-claimed cpd.
3. the pharmaceutical composition that comprises compound as claimed in claim 1 or 2 and pharmaceutically acceptable vehicle, described compound are the form of free alkali or pharmacy acceptable salt.
4. pharmaceutical composition as claimed in claim 3, wherein said pharmaceutically acceptable vehicle is carrier or thinner.
5. prevention in the subject that needs is arranged, improve or disease, obstacle or the syndromic method for the treatment of novel vanilloid receptor mediation, described method comprises and gives the compound as claimed in claim 1 or 2 that described experimenter treats significant quantity.
6. method as claimed in claim 5, wherein the symptom of disease, obstacle, syndrome or the illness relevant with the TRPV3 function is selected from the group of being made up of following symptom: pain; Acute pain; Chronic pain; Nociceptive pain; Neuropathic pain; Post-operative pain; Toothache; Cancer pain; It is pained that ischemic myocardium causes; The pain that causes because of migraine; Arthrodynia; DPN; Neurodynia; Trigeminal neuralgia; Nerve injury; Diabetic neuropathy; Nerve degenerative diseases; Retinopathy; The nervosa skin barrier; Apoplexy; Irritable bladder disease; The urinary incontinence; Vulvodynia; Gastrointestinal disorders is as irritable bowel syndrome, stomach-esophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel, Crohn disease, celiac disease; Inflammatory diseases is as pancreatitis; Dyspnoea is as supersensitivity and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease; The stimulation of skin, eye or mucous membrane; Dermatitis; Pruritus is as uremic pruritus; Heating; Muscle spasm; Vomiting; Dyskinesia; Dysthymia disorders; Huntington's chorea; Hypomnesis; Brain function is limited; Amyotrophic lateral sclerosis (ALS); Dull-witted; Sacroiliitis; Osteoarthritis; Diabetes; Obesity; Urticaria; Actinic keratosis; Keratoacanthoma; Alopecia; Meniere; Tinnitus; Hyperacusis; Anxiety disorder; And benign prostatic hyperplasia.
7. in the method that the subject internal therapy pain that needs is arranged, described method comprises and gives the compound as claimed in claim 1 or 2 that described experimenter treats significant quantity.
8. method as claimed in claim 7, wherein said pain is acute pain, chronic pain or post-operative pain.
9. in the method that the subject internal therapy neuropathic pain that needs is arranged, described method comprises and gives the compound as claimed in claim 1 or 2 that described experimenter treats significant quantity.
10. in the method that the subject internal therapy inflammation that needs is arranged, described method comprises and gives the compound as claimed in claim 1 or 2 that described experimenter treats significant quantity.
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