CN107522668A - TRPV1 antagonists and its production and use - Google Patents
TRPV1 antagonists and its production and use Download PDFInfo
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- CN107522668A CN107522668A CN201710735792.0A CN201710735792A CN107522668A CN 107522668 A CN107522668 A CN 107522668A CN 201710735792 A CN201710735792 A CN 201710735792A CN 107522668 A CN107522668 A CN 107522668A
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- MFOKOKCIFMOUMD-RWEWTDSWSA-N Cc1ccccc1/C(/c1ccccc1)=N\C(CCC(N1CCCCC1)=O)C(N)=O Chemical compound Cc1ccccc1/C(/c1ccccc1)=N\C(CCC(N1CCCCC1)=O)C(N)=O MFOKOKCIFMOUMD-RWEWTDSWSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
Abstract
The invention discloses a kind of TRPV1 antagonists, the compound with formula (I)：Wherein, R is selected from NMe2,
Description
Technical field
The present invention relates to new TRPV1 antagonists and its pharmaceutically acceptable salt, preparation method and use.
Background technology
Pain is clinically one of most common symptom, and due to the complexity of its pathomechanism, pain turns into not to be expired
The major medical demand of foot.Clinically being used for analgesic medicine at present mainly has two classes：Opioid drug and nonsteroidal anti-inflammatory
Medicine (NSAIDs).Opioid drug activates opiate receptor, and then produce analgesic activity by being combined with opiate receptor.Such
Medicine generally works rapidly, and pain can significantly be mitigated or eliminated.But there is side effect in opioid drug：Continuously apply repeatedly,
Drug resistance can be produced and cause habituation, once being discontinued i.e. there is withrawal symptom, and it is very harmful.The effect machine of non-steroidal anti-inflammatory drug
System is to suppress the biosynthesis of prostaglandin by suppressing arachidonic acid cyclooxygenase.The clinic of non-steroidal anti-inflammatory drug
Curative effect is preferable, and be not likely to produce tolerance and it is additive, because its site of action is mainly in periphery, therefore opiates medicine can not be replaced
Thing uses.In addition, the adverse reaction such as the gastrointestinal reaction of non-steroidal anti-inflammatory drug, gastric ulcer, gastrorrhagia and allergy
Still it is bound to arouse fear.
Transient receptor potential vanillic acid hypotype 1 (TRPV1), belong to (TRP family of cationic channel Transient Receptor Channel family
Race) non-selectivity aglucon control cationic channel, in many tissues that are covered with to innervate, including skin, bladder,
The periphery end of the minor diameter sensory neuron of air flue and intestines and stomach is reached by altimeter.TRPV1 acceptors are more clearly located at A δ
Collection and fiber C on, be passed to it is generally relevant with pain (Mezey et al., Proc.Nat1.Acad.Sci.97,3655-3660,
2000).The feature of the passage molecular level makes it as the target for identifying vanillic acid (main pungent constituent of pimiento)
(Caterina etal.Nature 389,816-824,1997).It is intracutaneous to cause calcination exposed to capsaicin in the mankind
As pain feel to be due to irritating for neuron, followed by duration of anesthetic length, it is believed that be feature sensitivity
The result (reviewed in Bley, Exp.Opin Investig Drugs.13,1445-1456,2004) of decline.This causes
Development of the TRPV1 antagonists as potential analgesic compounds.However, these compounds by it is many problem of include pain
With the burning sensation in initial application.TRPV1 antagonists include capsazepine (Walker et al.,
J.Pharm.Exp.Ther._304,56-62,2003) and BCTC (Pomonis et al., J.Phar.Exp.Ther.306,
387-393,2004) prove active to various inflammation and neuralgic preclinical animal model.
The content of the invention
In a first aspect, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt：
R is selected from-NMe2,
The present invention formula (I) compound or its pharmaceutically acceptable salt can also be expressed as following formula (1), (2) or
(3)：
Formula (1) compound name is：N, N- dimethyl -3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzos [1,
4] diazepine -3- bases) propionamide；Formula (2) compound name is：3- (3- oxos -3- (piperidin-1-yl) propyl group) -
5- phenyl -1,3- dihydro -2H- benzos [e] [1,4] diaza -2- ketone；Formula (3) compound name is：3- (3- (benzene first
Acyl piperazine -1- bases) -3- carbonyls propyl group) -5- phenyl -1H- benzos [1,4] diazepine.
According to the embodiment of the present invention, pharmaceutically acceptable salt of the invention is acid with containing orphan in compound (I)
The salt formed to the nitrogen of electronics, such as the salt formed with inorganic acid or organic acid.
According to another embodiment of the present invention, " the pharmaceutically acceptable salt " of the compounds of this invention can be and inorganic acid
The salt of formation, such as the salt formed with following inorganic acid：Hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphorus
Acid or nitric acid；Or the salt formed with organic acid, such as the salt formed with following organic acid：Methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid,
P-methyl benzenesulfonic acid, formic acid, acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, the moon
Cinnamic acid, benzoic acid, salicylic acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose
Acid, 3- hydroxy-2-naphthoic acids, nicotinic acid, flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- hydroxyls
Ethyl sulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, lemon
Lemon acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, butanedioic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-
Gluconic acid, mandelic acid, ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.
In second aspect, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt as TRPV1 antagonisms
Application in agent, particularly preparing the application in being used to provide calmness, hypnosis, analgesia, anaesthetic.One in this method is excellent
Select in embodiment, the compound or its pharmaceutically acceptable salt of intravenous administration formula (I).
Usually, it has therefore proved that favourable amount, to reach required result, formula (1) compound of every kilogram of administration in every 24 hours
Total amount be about 0.01-800mg, preferable total amount is 0.1-80mg/kg.If necessary, it is administered in the form of single dose several times.
However, if necessary, can also deviate above-mentioned dosage, i.e., this depends on the type of subject to be treated and body weight, individual are right
The behavior of medicine, the property of disease and seriousness, preparation and the type of administration and administration time and interval.
In the third aspect, the invention further relates to a kind of pharmaceutical composition, and it includes the compound of formula (I) or it pharmaceutically may be used
The salt and pharmaceutically acceptable carrier of receiving.
In an embodiment of the above-mentioned third aspect, it is used to provide calm method to individual the present invention relates to a kind of,
Methods described includes the compound or its pharmaceutically acceptable salt that formula (I) is administered to the individual.One in this method is preferred
In embodiment, the compound or its pharmaceutically acceptable salt of intravenous administration formula (I).
Present invention additionally comprises pharmaceutical preparation, said preparation include as activating agent logical formula (I) compound or pharmaceutically acceptable salt thereof or
Pharmaceutically acceptable carrier.Above-mentioned pharmaceutically acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field, refers to one kind
Or several inert, atoxic solids or liquid filler material, diluent, auxiliary agent etc., they it is not reverse with reactive compounds or
Patient has an effect.
The formulation of the present composition can be tablet, capsule, pill, suppository, soft capsule, oral liquid, supensoid agent, injection
The formulation commonly used in the pharmacies such as liquid.Tablet and capsule for oral use contain traditional excipient such as filler, diluent, lubrication
Agent, dispersant and adhesive.The various formulations of pharmaceutical composition of the present invention can be entered according to well known method in pharmaceutical field
It is prepared by row.The dosage of above activating agent will be because of formula and different.
Beneficial effects of the present invention
The present invention innovatively organically ties TRPV1 antagonists with benzodiazepine compound using clinical demand to be oriented to
Close in same molecule, while steady patient mood, reduction of patient anxiety, performance calmness, hypnotic activity, moreover it is possible to play
Analgesia, the effect of anesthesia, can be widely applied to clinical treatment.Under 10 μM of concentration, the present invention is to capsicum alkaline activity TRPV1
There is obvious antagonistic activity, lick sufficient time and writhing number has significantly relative to blank group and prior art (compound a)
Reduce；In mouse hot bath contracting tail model, and compared with blank, the compounds of this invention can significantly improve the MPE% of mouse,
Have the function that to weaken thermal induction pain.
Embodiment
In order that the purpose of the present invention, technical scheme are clearer, the preferred embodiments of the present invention are carried out below detailed
Description.It is noted that above example is served only for further explanation of the present invention, it is impossible to is interpreted as to the scope of the present invention
Limitation, those skilled in the art belongs to according to some nonessential modifications and adaptations for making of the above of the present invention
Protection scope of the present invention.Raw materials used and reagent of the invention is commercially available prod.
Preparation example
Embodiment 1：Prepare compound (1)
Syntheti c route：
By 3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzos [1,4] diazepine -3- bases) propionic acid (a) (0.50g,
1.62mmol) it is dissolved in dichloromethane (10ml), sequentially adds the DMAP and diformazan of EDCI (0.34g, 1.78mmol), catalytic amount
Amine (0.072g, 1.62mmol), 2h is reacted, solvent is removed under reduced pressure, column chromatography, obtains faint yellow solid 0.21g, yield
39.6%.1H NMR(300MHz,DMSO-d6)δ:8.34 (d, J=6.5Hz, 2H), 8.27-8.09 (m, 2H), 7.86 (t, J=
7.3Hz, 2H), 7.76-7.46 (m, 3H), 6.15 (s, 1H), 4.07 (t, J=6.6Hz, 1H), 3.70 (s, 6H), 2.47 (d, J
=7.3Hz, 2H), 1.86 (s, 2H)；ESI-MS m/z:336.5([M+H]+).
Embodiment 2：Prepare compound (2)
Syntheti c route：
By 3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzos [1,4] diazepine -3- bases) propionic acid (a) (0.50g,
1.62mmol) it is dissolved in dichloromethane (10ml), sequentially adds the DMAP and piperidines of EDCI (0.34g, 1.78mmol), catalytic amount
(0.138g, 1.62mmol), 2h is reacted, solvent is removed under reduced pressure, column chromatography, obtains faint yellow solid 0.28g, yield 46.8%.1H NMR(300MHz,DMSO-d6)δ:8.34 (d, J=6.5Hz, 2H), 8.27-8.09 (m, 2H), 7.86 (t, J=7.3Hz,
2H), 7.76-7.46 (m, 3H), 6.15 (s, 1H), 4.07 (t, J=6.6Hz, 1H), 3.52 (t, 4H), 2.47 (d, J=
7.3Hz,2H),1.86(s,2H),1.46(t,7H)；ESI-MS m/z:376.5([M+H]+).
Embodiment 3：Prepare compound (3)
Syntheti c route：
Aniline (1g, 10mmol) is dissolved in DMSO (10ml), adds N into solution, N'- carbonyl dimidazoles (2g,
12mmol), after 2h being stirred at room temperature, water (30ml) and ethyl acetate (30ml), extracting and demixing, aqueous layer with ethyl acetate washing are added
(20ml × 3), after merging organic layer 24h, remove solvent under reduced pressure, obtain grease；Products therefrom is dissolved in dichloro under above-mentioned condition
In methane (20ml), 1-Boc- piperazines (1.67g, 9mmol) are added, 2h is stirred at room temperature, removes solvent under reduced pressure, obtains grease,
Column chromatography, proportion of mobile phase are petroleum ether：Ethyl acetate=4:1.Products therefrom is dissolved in into saturation hydrochloric acid, and to be put into ethyl acetate molten
In agent (20ml), 2h is reacted at room temperature, solvent is removed under reduced pressure, obtains compound as white solid.Above white solid is added into saturation
NaHCO3In solution, after stirring 30min, washed (30ml × 3) with ethyl acetate, after merging organic layer 24h, removed under reduced pressure molten
Agent, obtain grease (d) 1.2g；By 3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzos [1,4] diazepine -3- bases) propionic acid
(a) (0.50g, 1.62mmol) is dissolved in dichloromethane (10ml), sequentially adds EDCI (0.34g, 1.78mmol), catalytic amount
DMAP and (d) (0.33g, 1.62mmol), 2h is reacted, solvent is removed under reduced pressure, column chromatography, obtains faint yellow solid 0.339g, produced
Rate 43.7%.1H NMR(300MHz,DMSO-d6)δ:8.59-8.24 (m, 3H), 8.24-8.01 (m, 2H), 7.86 (t, J=
7.6Hz, 2H), 7.76-7.44 (m, 3H), 4.07 (t, J=11.8Hz, 1H), 3.63-3.09 (m, 8H), 2.87 (d, J=
5.5Hz,2H),2.64(s,4H)；ESI-MS m/z:482.3([M+H]+).
Biological examples
Embodiment 4：Antagonistic activity of the compound to TRPV1 acceptors
By TRPV1 expression of receptor in human embryonic kidney cells, after TRPV1 excitements, non-selective cation channel opens, extracellular
Flowed in calcium ion is rapid, concentration of cytoplasm calcium ion rises.Using fura-2 calcium ion fluorescents, add temperature and incubate in liquid by cell
Intake.After cytoplasm calcium ion and fura-2 are combined, its maximum excitation wavelength moves to 340nm from 380nm, and launch wavelength is maintained at
510nm.By the ratio R 340/R380 for the intensity that launch wavelength is scanned during 340nm/380nm two excitation wavelength, can calculate
The concentration of cytoplasm calcium ion.
This experiment is divided into two groups：Blank control group, experimental group, the administration concentration of experimental group is 10 μM.Acceptor compound
TRPV1 antagonistic activity screening experiment ways are：10min adds test-compound before capsaicine acts on acceptor, passes through meter
The value for calculating R340/R380 characterizes intracellular calcium ion relative concentration, antagonism degree with predictive compound to capsaicine, predictionization
Compound the results are shown in Table 1 to the antagonistic activity degree of TRPV1 acceptors.
Screening of the target compound of table 1 to TRPV1 receptor antagonist activities
Under 10 μM of concentration, the compound being related in the present invention shows the antagonism work to capsicum alkaline activity TRPV1
Property, wherein the inhibiting rate of preparing raw material compound a is less than 50%；The inhibiting rate of compound 2 increases compared with compound a,
For 68.56%；The inhibiting rate of compound 3 improves a lot compared with compound a, is 87.68%；-N(CH3)2Substituted chemical combination
The inhibiting rate highest of thing 1, has reached 95.44%.
Embodiment 5：Analgesic experiment inside compound
Mouse licks full test
Mouse is grouped at random by body weight, every group 6.Oral administration gavage administration (30mg/kg, 10ml/kg) in 30 minutes before test,
Blank group gives isometric 0.5%CMC-Na.Hypodermic injection concentration during test on the right instep of mouse is 1.6 μ g/20 μ l's
The μ l of capsicum aqueous slkali 20, record mouse in 5 minutes and lick right sufficient total duration (unit：Second).
Mouse writhing is tested
Mouse is grouped at random by body weight, every group 6.Oral administration gavage administration (30mg/kg, 10ml/kg) in 30 minutes before test,
Blank group gives isometric 0.5%CMC-Na.The acetum of mouse peritoneal injection 0.6% during test, record mouse 15 minutes
Inside there is the number of writhing response (belly indent, stretching, extension hind leg, buttocks are raised).
Mouse contracting tail is tested
Mouse is grouped at random by body weight, every group 6.Mousetail end 1/3rd is immersed in 52 DEG C of hot baths, record
The mouse contracting tail response time, it is spaced measurement in 10 minutes twice, Basic Pain Threshold of the average value as mouse, mousetail immerses hot water
In time do not exceed 15s.30 minutes after measure Basic Pain Threshold, (60mg/kg, 10ml/kg) is administered in every group of oral administration gavage, empty
White group gives isometric 0.5%CMC-Na.The measure that half an hour after refers to Basic Pain Threshold is administered, after test administration half an hour
Contracting tail response time, its average value are the threshold of pain after administration.And calculate the percentmaximal possible effect of each group
(MPE%)=(threshold of pain/(cut-off time- Basic Pain Thresholds) × 100, wherein cut-off time are after Basic Pain Threshold-administration
12s。
Analgesic activities of the compound of table 2 in three kinds of pain model in mice
Note：T is examined, and * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001 are compared with blank group.
The same embodiment of chemical constitution corresponding to compound numbers in table 2.
In the mouse of capsaicine induction licks sufficient model, compound 2 is for blank group and compound a, when licking sufficient
Between and writhing number have a certain degree of reduction；In the mouse writhing model of acetic-acid induced, compound 1,3 can substantially reduce
The writhing number of decimal；In mouse hot bath contracting tail model, and compared with blank, the compound being related in the present invention can show
The MPE% for improving mouse is write, has the function that to weaken thermal induction pain.
Tablet of the embodiment 6 containing activating agent 2：
Supplementary material is mixed according to a conventional method, pelletized, is dried, tabletting.
Unless otherwise indicated, all expression compositions for being used in this specification (including claims), ratio, condition etc.
The numeral of amount should be understood to be modified by term " about " under all conditions.Therefore, unless otherwise opposite explanation, number
Value parameter is approximation, and can be changed according to the desired characteristic by the present invention.It will be appreciated by those skilled in the art that
The many equivalents of the specific embodiment of invention as described herein, and it is covered in the scope of the appended claims
It is interior.Many modifications and variations of the present invention can be carried out without departing from its spirit and scope.
Claims (10)
1. the compound or its pharmaceutically acceptable salt of formula (I)：
R is selected from-NMe2,
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that：Pharmaceutically acceptable salt is acid
The salt formed with the nitrogen containing lone pair electrons in compound (I).
3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that：It is described acid for hydrochloric acid (HCl),
Hydrobromic acid (HBr), hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, first
Acid, acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, laurate, benzoic acid,
Salicylic acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxyl -2- naphthalenes
Formic acid, nicotinic acid, flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid,
It is sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, hard
Resin acid, lactic acid, oxalic acid, malonic acid, butanedioic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D- gluconic acids, mandelic acid,
Ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.
4. the application of the compound or its pharmaceutically acceptable salt of formula (I) in as TRPV1 antagonists.
5. the compound of formula (I) or its pharmaceutically acceptable salt are preparing the application in being used to provide downern；Or making
The application provided in hypnotic drug is provided；Or preparing the application in being used to provide analgesic；Or it is used to provide preparing
Application in anaesthetic.
6. the application as described in claim 4 or 5, it is characterised in that：The compound of intravenous administration formula (I) or its pharmaceutically may be used
The salt of receiving.
7. the application as described in claim any one of 4-6, it is characterised in that：Formula (1) chemical combination of every kilogram of administration in every 24 hours
The total amount of thing is about 0.01-800mg.
8. application as claimed in claim 7, it is characterised in that：The total amount of formula (1) compound of every kilogram of administration in every 24 hours
It is about 0.1-80mg/kg.
9. a kind of pharmaceutical composition, it includes the compound of formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable
Carrier.
10. composition as claimed in claim 9, it is characterised in that：The formulation of the composition is tablet, capsule, pill, bolt
Agent, soft capsule, oral liquid, supensoid agent or parenteral solution.
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