CN107522669B - 1 antagonist of transient receptor potential vanillic acid hypotype and its preparation method and application - Google Patents
1 antagonist of transient receptor potential vanillic acid hypotype and its preparation method and application Download PDFInfo
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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
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- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
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Abstract
The invention discloses a kind of 1 antagonist of transient receptor potential vanillic acid hypotype, the compound with formula (I):R is selected from-NEt2,‑NiPr2With
Description
Technical field
The present invention relates to new 1 antagonist of transient receptor potential vanillic acid hypotype and its pharmaceutically acceptable salt, its preparation
Method and purposes.
Background technique
Pain is clinically one of most common symptom, and due to the complexity of its pathomechanism, pain, which has become, not to be expired
The major medical demand of foot.Clinically for analgesic drug, there are two main classes: opioid drug and nonsteroidal anti-inflammatory at present
Drug (NSAIDs).Opioid drug generates analgesic activity by conjunction with opiate receptor, activating opiate receptor.Such
Drug usually works rapidly, and pain can significantly be mitigated or eliminated.But there are side effects for opioid drug: continuously apply repeatedly,
Drug resistance can be generated 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 inhibit the biosynthesis of prostaglandin by inhibiting 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, since its site of action is mainly in periphery, opiates medicine cannot be replaced
Object uses.In addition, the adverse reactions 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) belongs to (TRP family, 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,
It is highly expressed the periphery end of the minor diameter sensory neuron of air flue and gastrointestinal tract.TRPV1 receptor is more clearly located at A δ
On collection and fiber C, be passed to it is usually related with pain (Mezey et al., Proc.Nat1.Acad.Sci.97,3655-3660,
2000).The feature of the channel molecular level makes it as the target of identification vanillic acid (main pungent constituent of pimiento)
(Caterina etal.Nature 389,816-824,1997).In the mankind, the intradermal capsaicin that is exposed to leads to calcination
As pain feel irritating due to neuron, followed by the lasting period of anesthetic length, it is believed that be functional sensitive
The result (reviewed in Bley, Exp.Opin Investig Drugs.13,1445-1456,2004) of decline.This causes
Development of the TRPV1 antagonist as potential analgesic compounds.However, these compounds include pain by many problems
With the burning sensation in initial application.TRPV1 antagonist 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) it proves active to various inflammation and neuralgic preclinical animal model.
Summary of the invention
In a first aspect, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salts:
R is selected from-NEt2,-NiPr2With
The compound or its pharmaceutically acceptable salt of formula (I) of the invention can also be expressed as following formula (1), formula (2) or
Formula (3):
Formula (1) compound name are as follows: N, N- dimethyl -3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzo [1,
4] diazepine -3- base) propionamide；Formula (2) compound name are as follows: N, N- diisopropyl -3- (2- oxo -5- phenyl -
2,3- dihydro -1H- benzo [e] [1,4] diaza -3- base) propionamide；Formula (3) compound name are as follows: 3- (3- (phenylamino
Base piperazine -1- base) -3- carbonyl propyl) -5- phenyl -1H- benzo [1,4] diazepine.
An embodiment according to the present invention, pharmaceutically acceptable salt of the invention are in acid and compound (I) containing orphan
To the salt that the nitrogen of electronics is formed, such as the salt formed with inorganic acid or organic acid.
" the pharmaceutically acceptable salt " of another embodiment according to the present invention, 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 with organic acid formed salt, such as with following organic acid formed salt: methanesulfonic acid, ethanesulfonic 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 benzoyl) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose
Acid, flutters acid, pectinic acid, persulfuric acid, 3- phenylpropionic acid, picric acid, pivalic acid, 2- hydroxyl at 3- hydroxy-2-naphthoic acid, niacin
Ethanesulfonic 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, succinic 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 compounds of formula (I) or its pharmaceutically acceptable salt as TRPV1 antagonism
Application in agent, especially in preparation for providing calmness, hypnosis, analgesia, the application in anaesthetic.One in this method is excellent
It selects in embodiment, the compound or its pharmaceutically acceptable salt of intravenous administration formula (I).
Generally, it has therefore proved that advantageous amount, it is required as a result, every kilogram of every 24 hours formula (1) compound being administered to reach
Total amount be about 0.01-800mg, preferred 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 weight, individual are right
The behavior of drug, 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, it includes the compound of formula (I) or its pharmaceutically may be used
The salt and pharmaceutically acceptable carrier of receiving.
In an embodiment of the above-mentioned third aspect, the present invention relates to a kind of for providing calm method to individual,
The method includes the compounds or its pharmaceutically acceptable salt to the individual administration formula (I).One in this method is preferred
In embodiment, the compound or its pharmaceutically acceptable salt of intravenous administration formula (I).
The invention also includes 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 pharmaceutical carrier of pharmaceutical field routine, 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 dosage form of the present composition can be tablet, capsule, pill, suppository, soft capsule, oral solution, suspension, injection
Common dosage form in the pharmacies such as liquid.Tablet and capsule for oral use contain traditional excipient such as filler, diluent, lubrication
Agent, dispersing agent and adhesive.The various dosage forms of pharmaceutical composition of the present invention can according to method well known in pharmaceutical field into
Row preparation.The dosage of the above activating agent will be different because of formula.
Beneficial effects of the present invention
The present invention is guiding with clinical demand, innovatively organically ties TRPV1 antagonist with benzodiazepine compound
It closes in the same molecule, in steady patient mood, reduction of patient anxiety, while playing calmness, hypnotic activity, moreover it is possible to play
The effect of analgesia, anesthesia, can be widely applied to clinical treatment.Under 10 μM of concentration, the present invention is to capsicum alkaline activity TRPV1
There is apparent antagonistic activity, lick sufficient time and writhing number has significantly relative to blank group and the prior art (compound a)
It reduces；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 of weakening thermal induction pain.
Specific embodiment
In order to keep the purpose of the present invention, technical solution clearer, the preferred embodiment of the present invention is carried out below detailed
Description.It is noted that above embodiments are served only for further explanation of the present invention, should not be understood as to the scope of the present invention
Limitation, some nonessential modifications and adaptations that those skilled in the art's above content according to the present invention is made belong to
Protection scope of the present invention.The raw materials used in the present invention and reagent are commercial product.
Preparation example
Embodiment 1: prepare compound (1)
Preparation route:
By 3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzo [1,4] diazepine -3- base) propionic acid (a) (0.46g,
It 1.50mmol) is dissolved in methylene chloride (10ml), sequentially adds the DMAP and diethyl of EDCI (0.31g, 1.64mol), catalytic amount
Amine (b) (0.11g, 1.62mmol), reacts 2h, evaporating solvent under reduced pressure, and column chromatography obtains faint yellow solid 0.25g, yield
45.2%.1H NMR (300MHz, DMSO-d6) δ: 8.38 (d, J=6.5Hz, 2H), 8.29-8.03 (m, 2H), 7.82 (t, J=
7.3Hz, 2H), 7.73-7.42 (m, 3H), 6.19 (s, 1H), 4.08 (t, J=6.6Hz, 1H), 3.74 (q, 4H), 2.48 (d, J
=7.3Hz, 2H), 1.84 (s, 3H), 1.00 (t, 6H)；ESI-MS m/z:363.5([M+H]+).
Embodiment 2: prepare compound (2)
Preparation route:
By 3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzo [1,4] diazepine -3- base) propionic acid (a) (0.46g,
It 1.50mmol) is dissolved in methylene chloride (10ml), it is different to sequentially add EDCI (0.31g, 1.64mol), the DMAP and two of catalytic amount
Propylamine (b) (0.16g, 1.62mmol), reacts 2h, evaporating solvent under reduced pressure, and column chromatography obtains faint yellow solid 0.31g, yield
48.9%.1H NMR (300MHz, DMSO-d6) δ: 8.38 (d, J=6.5Hz, 2H), 8.29-8.03 (m, 2H), 7.82 (t, J=
7.3Hz, 2H), 7.73-7.42 (m, 3H), 6.19 (s, 1H), 4.08 (t, J=6.6Hz, 1H), 3.88 (m, 2H), 2.48 (d, J
=7.3Hz, 2H), 1.84 (s, 3H), 1.39 (d, 12H)；ESI-MS m/z:392.5([M+H]+).
Embodiment 3: prepare compound (3)
Preparation route:
By 3- (2- oxygen -5- phenyl -2,3- dihydro -1H- benzo [1,4] diazepine -3- base) propionic acid (a) (0.50g,
It 1.62mmol) is dissolved in methylene chloride (10ml), sequentially adds DMAP the and 1- benzene of EDCI (0.34g, 1.78mmol), catalytic amount
Base piperazine (c) (0.33g, 1.62mmol), reacts 2h, evaporating solvent under reduced pressure, and column chromatography obtains faint yellow solid 0.339g, produces
Rate 43.7%.1H NMR (300MHz, DMSO-d6) δ: 8.52-8.26 (m, 3H), 8.28-8.05 (m, 2H), 7.82 (t, J=
7.6Hz, 2H), 7.77-7.49 (m, 3H), 4.03 (t, J=11.8Hz, 1H), 3.64-3.04 (m, 8H), 2.89 (d, J=
5.5Hz,2H),2.60(s,4H)；ESI-MS m/z:482.3([M+H]+).
Biological examples
Embodiment 4: antagonistic activity of the compound to TRPV1 receptor
By TRPV1 expression of receptor in human embryonic kidney cells, after TRPV1 excitement, non-selective cation channel is open, extracellular
Interior stream, concentration of cytoplasm calcium ion rise calcium ion rapidly.Using fura-2 calcium ion fluorescent, temperature is added and incubates in liquid by cell
Intake.After cytoplasm calcium ion and fura-2 are combined, maximum excitation wavelength moves to 340nm from 380nm, and launch wavelength is maintained at
510nm.By scanning the ratio R 340/R380 of the intensity of launch wavelength when 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 are 10 μM.Acceptor compound
TRPV1 antagonistic activity screening experiment way are as follows: test-compound is added in 10min before capsaicine acts on receptor, passes through meter
The value of R340/R380 is calculated to characterize intracellular calcium ion relative concentration, with predictive compound to the antagonism degree of capsaicine, predictionization
Object is closed to the antagonistic activity degree of TRPV1 receptor, the results are shown in Table 1.
Screening of 1 target compound of table to TRPV1 receptor antagonist activity
Under 10 μM of concentration, compound involved in the present invention shows living to the antagonism of capsicum alkaline activity TRPV1
Property, wherein preparing the inhibiting rate of raw material compound a less than 50%；The inhibiting rate of compound 2 is compared with compound a (prior art)
It increases, is 63.59%；The inhibiting rate of compound 3 improves a lot compared with compound a (prior art), is
75.97%；-NiPr2Substituted 1 inhibiting rate highest of compound, has reached 96.93%.
Embodiment 5: the internal analgesic experiment of compound
Mouse licks full test
Mouse is grouped at random by weight, and every group 6.Preceding 30 minutes oral administration gavages administration (30mg/kg, 10ml/kg) is tested,
Blank group gives isometric 0.5%CMC-Na.Subcutaneous injection concentration when test on the right instep of mouse is 1.6 μ g/20 μ l's
20 μ l of capsicum aqueous slkali records mouse in 5 minutes and licks right sufficient total duration (unit: second).
Mouse writhing experiment
Mouse is grouped at random by weight, and every group 6.Preceding 30 minutes oral administration gavages administration (30mg/kg, 10ml/kg) is tested,
Blank group gives isometric 0.5%CMC-Na.Mouse peritoneal injects 0.6% acetum when test, records mouse 15 minutes
Inside there is the number of writhing response (abdomen indent, stretching, extension hind leg, buttocks are raised).
The experiment of mouse contracting tail
Mouse is grouped at random by weight, and every group 6.Mousetail end one third immerses in 52 DEG C of hot baths, record
The mouse contracting tail response time is spaced measurement in 10 minutes twice, and Basic Pain Threshold of the average value as mouse, mousetail immerses hot water
In time do not exceed 15s.30 minutes after measurement Basic Pain Threshold, (60mg/kg, 10ml/kg) is administered in every group of oral administration gavage, empty
White group is given isometric 0.5%CMC-Na.The measurement that half an hour after refers to Basic Pain Threshold is administered, after test administration half an hour
Contracting tail response time, average value are the threshold of pain after administration.And calculate the percentmaximalpossible effect of each group
(MPE%)=(threshold of pain/(cut-off time- Basic Pain Threshold) × 100 after Basic Pain Threshold-administration, wherein cut-off time be
12s。
Analgesic activities of 2 compound of table in three kinds of pain model in mice
Note: t is examined, and * P < 0.05, * * P < 0.01, * * * P < 0.001 is compared with blank group.
The same embodiment of the corresponding chemical structure of compound numbers in table 2.
It is licked in sufficient model in the mouse of capsaicine induction, compound 2 is for blank group and compound a, when licking sufficient
Between and writhing number have a degree of reduction；In the mouse writhing model of acetic-acid induced, compound 1, compound 3 can be shown
Write the writhing number for reducing decimal；In mouse hot bath contracting tail model, and compared with blank, compound involved in the present invention
Mouse can be significantly improved
MPE% has the function of weakening thermal induction pain.
Tablet of the embodiment 6 containing activating agent 2:
Supplementary material is mixed according to a conventional method, is pelletized, dry, tabletting.
Unless otherwise indicated, all expression compositions, ratio, condition used in this specification (including claims) etc.
The number of amount should be understood as the modification by term " about " under all conditions.Therefore, unless otherwise opposite explanation, number
Value parameter is approximation, and can be changed according to desired characteristic through the 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.Specific embodiment as described herein
It is only provided by way of example, is not meant to limit in any way.True scope and spirit of the invention pass through appended
Claims are shown, and description and embodiments are merely exemplary.
Claims (6)
1. the compound or its pharmaceutically acceptable salt of formula (I):
R is selected from-NEt2,-NiPr2With
2. compound as described 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 described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that: the acid is hydrochloric acid, hydrogen bromine
Acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, formic acid, acetic acid, second
Ethyl acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-
(4- hydroxy benzoyl) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxy-2-naphthoic acid, cigarette
Acid flutters acid, pectinic acid, persulfuric acid, 3- phenylpropionic acid, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acid, itaconic acid, amino sulphur
Acid, trifluoromethanesulfonic acid, dodecyl sulphate, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, cream
Acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D- gluconic acid, mandelic acid, Vitamin C
Acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.
4. the compound or its pharmaceutically acceptable salt of formula (I) are preparing the application in downern；Or preparing somnifacient
Application in object；Or preparing the application in analgesic；Or preparing the application in anaesthetic.
5. a kind of pharmaceutical composition, it includes the compound of formula (I) or its pharmaceutically acceptable salts and pharmaceutically acceptable
Carrier.
6. composition as claimed in claim 5, it is characterised in that: the dosage form of the composition is tablet, capsule, pill, bolt
Agent, oral solution, suspension or injection.
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