CN106243096B - The new application of tricyclic drugs - Google Patents
The new application of tricyclic drugs Download PDFInfo
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- CN106243096B CN106243096B CN201610615308.6A CN201610615308A CN106243096B CN 106243096 B CN106243096 B CN 106243096B CN 201610615308 A CN201610615308 A CN 201610615308A CN 106243096 B CN106243096 B CN 106243096B
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
- C07C211/32—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
- C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D267/20—[b, f]-condensed
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The present invention provides the new applications of tricyclic drugs.Specifically, the present invention provides the purposes of compound shown in formula A or its optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt, they be used to prepare a pharmaceutical composition or preparation, and described pharmaceutical composition or preparation are for (a) inhibition transient receptor potential channel protein TRPA1；(b) relevant to transient receptor potential channel protein disease is treated, in formula, each group definition is as noted in the discussion.
Description
Technical field
The present invention relates to field of medicinal chemistry, relates more specifically to tricyclic drugs and it is inhibiting transient receptor potential logical
Application in terms of road albumen TRPA1.
Background technique
Transient receptor potential channel (Transient receptor potential, TRP) is that one kind is present in cell membrane
On important cationic channel constitute superfamily protein, for the first time by Minke etc. when studying drosophila visual transduction system
It was found that.Subsequent research has found a series of TRP families channel member again.It is logical according to about 30 kinds of TRP found in mammality
The sequence homology in road is divided into altogether 6 subfamilies, i.e. TRPC, TRPV, TRPM, TRPML, TRPA and TRPP.The channel TRP
C-terminal and N-terminal be respectively positioned in cell membrane, and 6 containing S1-S6 transmembrane domains.Wherein ligand knot on structural domain S1-S4
The reaction site of conjunction may be by gate aperture, but lack positive charge amino acid residue as valtage-gated logical in S4 structural domain
Road, most of TRP have very weak voltage sensitivity, lack selection index system (PCa/PNa ratio is less than 10).S5-S6 cross-film
Structural domain hydrophilic area forms duct, and constitutes a low gate in the intracytoplasmic end S6 monocycle, it can be by opening
It closes regulation cation and enters channel.
Letter " A " in TRPA1 refers to ankyrin (Ankyrin), it be able to be distinguished out in TRP family be by
In at least existing ankyrin repeat of the N-terminal of TRPA1 be 14, higher than 3~4 repetitions of other subfamilies.2 spirals
Calcium binding motif structural domain be present in the N-terminal of TRPA1, but the effect of structural domain is unclear.In addition to the critical function of N-terminal,
It is found that the electric current of TRPA1 can be greatly reduced in the mutation of the C-terminal single amino acids of TRPA1.It is newest studies have shown that a position
Acquired function mutation in the transmembrane structure S4 of TRPA1 will lead to the pain syndrome of familial onset, this discovery provides
First case pain relevant TRP ion channel disease.
Activate the channel TRPA1 there are many approach, the channel TPR can generally be activated by phospholipase C, and g protein coupled receptor exists
It is acted in the activation of TRPA1；In ligand activation approach, a series of chemical stimulation can activate TRPA1, be reported
The agonist in road include: cinnaldehydrum (cortex cinnamomi), allicin and diallyl disulfide (garlic), isothiocyanic acid salt (mustard oil, wasabi,
Horseradish), methacrylaldehyde (cigarette), 9- tetrahydrocannabinol (hemp), diallyl disulfide, mustard oil (mustard), icilin, water
Poplar acid methyl esters (wintergreen) etc..There is document to report recently, agonist of the peppermint as TRPM8 has double-hump effect to TRPA1:
Inhibit TRPA1 at high concentrations, when low concentration activates TRPA1.In addition to exogenous agonistic agent, recent studies have shown that TRPA1 can
With the endogenous compound 4- hydroxyl nonenoic acid discharged during tissue damage, inflammation, oxidative stress and deoxidation -12 15-,
14 prostaglandin J2 activation.It is newest the study found that agonist passes through half Guang of N-terminal with TPRA1 in the activation of TRPA1
Histidine residue covalent interaction activates TRPA1.In addition to both the above biochemistry activated pathway, the channel TRPA1 can also be hurt
Evil property low temperature and mechanical stimulus activation.
Research in recent years finds that the diseases such as the channel TRPA1 and pain, neuropathy are related.Currently, studies in China is less,
But external drugmaker has developed a series of hybar X class TRPA1 inhibitor, and the channel TRPA1 also has become novel analgesia
The research hotspot of medicine.Multiple technologies means include that RNA interference, gene knockout etc. have been specified in feeling of pain by present
The effect of TRPA1.The Acute Pain of TRPA1 antagonist and 1 phase of chronic ache and 2 clinical trial phases just in the planning stage, with
The Endorphins antalgesic for replacing tradition to use.Novel targets of the TRPA1 as analgesic, will open up grinding for new type analgesic
Study carefully direction.
Function and effect people to the channel TRPA1 are also constantly carrying out deep understanding, and current research finds its blocking
Agent has antidepression and angst resistance effect.In addition, TRPA1 or one it is verified that treatment inflammation, respiratory disorder (are roared
Asthma, cough, Chronic Obstructive tuberculosis), itch related with oxidative stress, reduction urinary tract infections and inflammatory bowel disease target,
Major drugmaker is very active in this field.
Summary of the invention
The purpose of the present invention is to provide a kind of active compound of inhibition transient receptor potential channel protein TRPA1 and its
Using.
In the first aspect of the present invention, a kind of compound shown in formula A or its optical isomer or its racemic are provided
The purposes of body or its solvate or its pharmaceutically acceptable salt, which is characterized in that be used to prepare pharmaceutical composition or system
Agent, described pharmaceutical composition or preparation inhibit transient receptor potential channel protein TRPA1 for (a)；(b) treatment and transient receptor
The relevant disease of current potential channel protein；
In formula,
RingFor C6-C10Aryl, C4-C9Heteroaryl is selected from the heteroatomic 5-7 circle heterocyclic ring of N, S, O containing 1-2；
X1Indicate without or 1,2 or 3 substituent group selected from the group below: halogen ,-OH, substituted or unsubstituted C1-C8Alkyl,
Substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C1-C8Alkoxy or substituted or unsubstituted C3-C8Cycloalkanes oxygen
Base, wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、C1-C3Alkyl,
C1-C3Halogenated alkyl ,-NH (C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
X2It is expressed as nothing or 1,2 or 3 substituent group selected from the group below: halogen ,-OH, substituted or unsubstituted C1-C8Alkane
Base, substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C1-C8Alkoxy or substituted or unsubstituted C3-C8Ring
Alkoxy, wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、C1-C3
Alkyl, C1-C3Halogenated alkyl ,-NH (C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
R1It is selected from the group: nothing, oxo (=O), halogen ,-OH, substituted or unsubstituted C1-C8It is alkyl, substituted or unsubstituted
C3-C8Naphthenic base, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C3-C8Cycloalkyloxy or replace or not
Substituted 5-8 circle heterocyclic ring, the heterocycle contain the hetero atoms that 1-3 is selected from N, O, S, wherein the substitution refer to one or
Multiple substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、C1-C3Alkyl, C1-C3Halogenated alkyl ,-NH (C1-C3Alkyl) ,-
N(C1-C3Alkyl)2；
R2It is selected from the group: nothing, oxo (=O), halogen ,-OH, substituted or unsubstituted C1-C8It is alkyl, substituted or unsubstituted
C3-C8Naphthenic base, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C3-C8Cycloalkyloxy, or replace or not
Substituted 5-8 circle heterocyclic ring, the heterocycle contain the hetero atoms that 1-3 is selected from N, O, S, wherein the substitution refer to one or
Multiple substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、C1-C3Alkyl, C1-C3Halogenated alkyl ,-NH (C1-C3Alkyl) ,-
N(C1-C3Alkyl)2；
Or R1And R2With adjacent W1And W2Substituted or unsubstituted 5-8 circle heterocyclic ring is collectively formed, the heterocycle contains 1-
3 are selected from the hetero atom of N, O, S；Wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen ,-
OH、-NH2、-CN、C1-C3Alkyl, C1-C3Halogenated alkyl ,-NH (C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
R3It is selected from the group: nothing, H, halogen, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl,
Substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted-(C1-C4Alkyl) Z, substituted or unsubstituted=CH- (C1-C4Alkane
Base) Z or substituted or unsubstituted=CH- (5-8 circle heterocyclic ring), wherein the 5-8 circle heterocyclic ring, which contains 1-3, is selected from the miscellaneous of N, O, S
Atom；Wherein the substitution, which refers to, has one or more substituent groups selected from the group below: halogen ,-OH ,-NH2、-CN、C1-C3Alkane
Base, C1-C3Halogenated alkyl ,-NH (C1-C3Alkyl) ,-N (C1-C3Alkyl)2；
Z isRa and Rb are each independently selected from: H, C1-C6Alkyl or C1-C6Halogenated alkyl or C3-C6Cycloalkanes
Base；
W1Selected from C, N, S, O atom；
W2Selected from C, N, S, O atom；
W3Selected from C, N, S, O atom；
Indicate singly-bound or double bond；
Additional conditions are: working as W1When for S or O, R1For nothing；W1When for N, and W1And W2Between be double bond when, R1For nothing；W1For
When N, and W1And W2Between be singly-bound when, R1It is not oxo；
Work as W2When for S or O, R2For nothing；W2When for N, and W1And W2Between be double bond when, R2For nothing；W2When for N, and W1And W2
Between be singly-bound when, R1It is not oxo；And
Work as W3When for S or O, R3For nothing；W3When for N, R3It is not substituted or unsubstituted=CH- (C1-C4Alkyl) Z.
In another preferred example, ringFor C6Aryl, C4Heteroaryl is miscellaneous selected from the heteroatomic 5-6 member of N, S, O containing 1
Ring.
In another preferred example, R1And R2It is each independently containing 1-2 N be heteroatomic unsubstituted or C1-C3Alkyl replaces
6 circle heterocyclic rings.
In another preferred example, R1And R2It is each independently
In another preferred example, R1、R2、W1And W2It collectively forms containing 1-2 N be heteroatomic unsubstituted or C1-C3Alkyl takes
6 circle heterocyclic rings in generation.
In another preferred example, R1、R2、W1And W2It collectively forms
In another preferred example, R1For oxo (=O).
In another preferred example, R3For substituted or unsubstituted-(C1-C4Alkyl) Z, substituted or unsubstituted=CH- (C1-
C4Alkyl) Z or substituted or unsubstituted=CH- (5-8 circle heterocyclic ring).
In another preferred example, R3For
In another preferred example, Ra and Rb are each independently selected from: C1-C6Alkyl or C1-C6Halogenated alkyl.
In another preferred example, Ra=Rb=methyl.
In another preferred example, Ra is methyl, and Rb is H.
In another preferred example, the formula A compound has structural formula A1:
In formula,
X1、X2、R1、R2、R3、W1、W2And W3As defined above.
In another preferred example, the A formula compound includes following compound or its pharmaceutically acceptable salt:
In another preferred example, the A formula compound is selected from the group:
In another preferred example, the transient receptor potential channel protein TRPA1 is people's transient receptor potential channel egg
White TRPA1.
In another preferred example, the disease relevant to transient receptor potential channel protein includes: pain, inflammation, exhales
Inhale obstacle, itch, urinary-tract disorders, inflammatory bowel disease.
In another preferred example, the respiratory disorder is selected from the group: asthma, cough, Chronic Obstructive tuberculosis.
In another preferred example, 0.001-99wt% is contained in described pharmaceutical composition, preferably 0.1-90wt%, more preferably
The formula A compound or its optical isomer of ground 1-80wt% or its racemic modification or its solvate or its can pharmaceutically connect
The salt received, is based on the total weight of the composition.
In another preferred example, the pharmaceutical composition or preparation can also containing other drugs active constituent or pharmaceutically
Acceptable carrier.
In the second aspect of the present invention, a kind of pharmaceutical composition is provided, which is characterized in that contain (a) active constituent, institute
State active constituent include at least two compounds or its pharmaceutically acceptable salt and its optical isomer selected from the group below or its
Pharmaceutically acceptable salt；
And (b) pharmaceutically acceptable carrier.
In another preferred example, when the active constituent contains there are two types of organizing timesharing, the weight ratios of two kinds of components be 1:20 extremely
20:1, preferably 1:10 to 10:1, more preferably 1:5 to 5:1.
In another preferred example, in the pharmaceutical composition, the total amount of component (a) is 0.001-99wt%, preferably
Ground 0.1-90wt%, more preferably 1-80wt%, are based on the total weight of the composition.
In another preferred example, the pharmaceutical composition or preparation can also containing other drugs active constituent or pharmaceutically
Acceptable carrier.
In the third aspect of the present invention, a kind of medicine box is provided, which is characterized in that the medicine box includes:
(1) the first container, and the first pharmaceutical composition in the container, first pharmaceutical composition contain
There are 1 compound of formula or its pharmaceutically acceptable salt and its optical isomer or its pharmaceutically acceptable salt, and pharmaceutically
Acceptable carrier；
(2) n-th containers, and the n-th pharmaceutical composition in the container, n-th pharmaceutical composition contain
Formula n compound or its pharmaceutically acceptable salt and its optical isomer or its pharmaceutically acceptable salt；And pharmaceutically may be used
The carrier of receiving；Wherein, n is any positive integer in 2-15；
Wherein, the 1st compound and the n-th compound are compound selected from the group below:
And the operation instructions that (3) are optional.
In the fourth aspect of the present invention, a kind of inhibition transient receptor potential channel protein of external non-therapeutic is provided
The active method of TRPA1, which is characterized in that by transient receptor potential channel protein and formula A compound or its optical isomer or
Its racemic modification or its solvate or its pharmaceutically acceptable salt are contacted, to inhibit transient receptor potential channel
The activity of albumen, wherein the formula A compound is as described in first aspect present invention.
In the fifth aspect of the invention, a kind of method for inhibiting transient receptor potential channel protein TRPA1 is provided, it is special
Sign is, comprising steps of formula A compound is applied to the object needed, wherein the formula A compound such as first aspect present invention
Described in.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is that Ketotifen Fumarate (1) inhibits the active amount effect relation curve figure of TRPA1.
Specific embodiment
The present inventor has unexpectedly discovered class formation compound as shown in formula A by depth studying extensively for the first time
It can inhibit the activity of TRPA1 significantly.Experiment shows that the formula A compound has preferable inhibitory effect to TRPA1, this
The formula A compound of invention can be used for treating relevant to TRPA1 target spot pain, inflammation, respiratory disorder, related with oxidative stress
Itch, urinary-tract disorders, inflammatory bowel disease etc..On this basis, the present invention is completed.
Term
Term " C1~C8Alkoxy " refers to the linear or branched alkyl group with 1~8 carbon atom, such as methoxyl group, ethoxy
Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " C1~C8Alkyl " refers to the linear or branched alkyl group with 1~8 carbon atom, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl or similar group.
Term " C3~C8Naphthenic base " refers to the naphthenic base with 3~8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopenta,
Suberyl or similar group.
Term " C2~C6Alkenyl " refers to the alkenyl with 1~6 carbon atom, such as vinyl, acrylic, isopropenyl, fourth
Alkenyl, isobutenyl, secondary cyclobutenyl, tertiary cyclobutenyl or similar group.
Term " 5-7 circle heterocyclic ring ", which refers to, has one or more, and preferably 1-3 heteroatomic cyclic structures, the ring can
To be saturated or unsaturated ring.
Term " halogen " refers to F, Cl, Br and I.
Term " C6-C10Aryl " refers to the cyclic group with aromatic structure, such as phenyl, naphthalene.
Term " C4-C10Heteroaryl " refers to that one or more carbon atoms are formed by cyclic group after being exchanged for heteroatoms in aryl
Group, wherein hetero atom is selected from N, O or S.The example of heteroaryl includes (but being not limited to): pyridyl group, pyridazinyl, pyrimidine radicals, pyrrole
Piperazine base.
Active constituent
As used herein, " the compounds of this invention ", " tricyclic drugs and its derivative of the invention " or " formula A chemical combination
Object " is used interchangeably, and refers to compound shown in formula A or its raceme, corresponding isomers or its pharmaceutically acceptable salt.It answers
Understand, which further includes the mixture of said components.
The compounds of this invention is not only inhibited to TRPA1, also has certain inhibition to other members in TRP family
Effect.
In formula, each group is as defined above.
It in the present invention, further include the pharmaceutically acceptable salt of formula A compound.Term " pharmaceutically acceptable salt " refers to
The compounds of this invention and acid or alkali are formed by the salt for being suitable as drug.Pharmaceutically acceptable salt includes inorganic salts and organic
Salt.A kind of preferred salt is the salt that the compounds of this invention and acid are formed.The acid for suitably forming salt includes but is not limited to: hydrochloric acid,
The inorganic acids such as hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, rich horse
Acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；With
And the acidic amino acids such as aspartic acid, glutamic acid.
Formula A compound of the invention can be used method well known to those skilled in the art in the prior art and be prepared, right
The response parameter of each step is not particularly limited.In addition, typical compound of the invention can also be obtained by commercially available mode.
As used herein, in formula A compound, if there is asymmetric carbon atom, then asymmetric carbon atom can be R configuration,
May be S configuration, or both mixture.
Ketotifen Fumarate, pizotifen malate, anarexol, Desloratadine belong to tricyclic antidepressants antihistamine,
Clinically for treating allergic rhinitis, nettle rash and other anaphylaxis dermatosis etc..Olanzapine belongs to non-classical anti-spirit
A variety of receptors of medicine, Central nervous system all have effect, have extensive curative effect to mental disease, almost without cone outside
It is side effect, is suitable for various schizophrenia.
It up to tens kinds of the kind of antidepressants, is analyzed from action target spot, antidepressants are divided into four classes by mechanism of action: 1.
Monoamine oxidase inhibitors；2. serotonin reuptake inhibitor；3. norepinephrine reuptake inhibitor；④α2Adrenal gland
Plain receptor blocking pharmacon.And the structure of norepinephrine reuptake inhibitor is mainly tricyclic antidepressants, is also the largest one kind, it is main
It to include amoxapine, clomipramine hydrochloride, Amitriptyline Hydrochloride, stangyl, doxepin hydrochloride, third meter of hydrochloric acid
Piperazine, nortriptyline, desipramine etc..
Mianserin hydrochloride is tetracyclic antidepressant class compound, and it is anti-that chemical structure and pharmacological action are different from tricyclic antidepressants
Down (TCA) and monoamine oxidase inhibitors.It was a kind of preferable antidepressant, has angst resistance effect concurrently, in 1967
Start to develop, is initially used as antihistamine.Mirtazapine is currently the only NaSSA (α2Adrenocepter blocking agent) antidepression
Medicine represents the latest developments of antidepressants, is the first-line treatment drug of major depression.
Transient receptor potential channel protein (TRPA1)
Transient receptor potential channel protein (Transient receptor potential, TRPA1) is that one kind is present in
The superfamily protein that important cationic channel on cell membrane is constituted.The study found that the channel TRPA1 and pain, neuropathy etc.
Disease is related.In addition, it is verified that, TRPA1 still treats inflammation, respiratory disorder, itch related with oxidative stress, urinary tract
The target of infection and inflammatory bowel disease.
In general, TRPA1 gene can be obtained with conventional method (such as PCR or fully synthetic), it is then connected into conventional expression vector
(such as pcDNA5, pcDNA3).Then, by the expression vector be transferred to suitable host cell (such as yeast cells, Chinese hamster ovary celI,
293 cells, Escherichia coli etc.), to obtain the cell strain of expression TRPA1.The cell strain of the expression TRPA1 can be used directly
In test, the TRPA1 isolated can also be used to test.
In the present invention, TRPA1 includes people and non-human mammal (such as rodent such as mouse and rat) source
TRPA1。
Purposes
The present invention also provides a kind of method for inhibiting transient receptor potential channel protein TRPA1, and treatment with it is instantaneous
The method of the relevant disease of receptor potential channel protein.
Above-mentioned formula A compound of the invention can be used for inhibiting TRPA1, and then prevention or treatment and transient receptor potential channel
The relevant disease of albumen.
In the present invention, the example of disease relevant to transient receptor potential channel protein includes (but being not limited to): pain
Bitterly, inflammation, respiratory disorder, itch, urinary-tract disorders, inflammatory bowel disease.Preferably, the respiratory disorder is selected from the group: asthma,
Cough, Chronic Obstructive tuberculosis.
In one embodiment, the present invention provides a kind of inhibition transient receptor potential channel proteins of external non-therapeutic
The active method of TRPA1, comprising: for example in vitro in cultivating system, by transient receptor potential channel protein or the expression egg
White cell and formula A compound (or its optical isomer or its racemic modification or its solvate or its is pharmaceutically acceptable
Salt) contacted, to inhibit the activity of transient receptor potential channel protein.
The present invention also provides a kind of methods for inhibiting transient receptor potential channel protein TRPA1, and this method, which can be, to be controlled
It is the property treated or non-therapeutic.In general, the method comprising the steps of: applying formula A compound of the invention to the object of needs.
Preferably, the object includes people and non-human mammal (rodent, rabbit, monkey, domestic animal, dog, cat etc.).
Composition and method of administration
The present invention provides a kind of for inhibiting the composition of transient receptor potential channel protein TRPA1.The combination
Object includes (but being not limited to): pharmaceutical composition, food compositions, dietary supplements, beverage composition for treating dental erosion etc..
In the present invention, the pharmaceutical composition can be directly used for disease treatment, for example, controlling for respiratory disorder
It treats.
The present invention also provides a kind of pharmaceutical composition, it contains the compounds of this invention and pharmaceutically of safe and effective amount
Acceptable carrier or excipient.This kind of carrier includes (but being not limited to): salt water, buffer, glucose, water, glycerol, second
Alcohol, pulvis, and combinations thereof.Pharmaceutical preparation should match with administration mode.
By taking pharmaceutical composition as an example, composition of the invention can be made into injection form, such as with physiological saline or contain
There are glucose and the aqueous solution of other adjuvants to be prepared by conventional method.The pharmaceutical composition of such as tablet and capsule etc
Object can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule preferably aseptically manufacture.
Pharmaceutical composition of the invention can also be made into pulvis for Neulized inhalation.
The dosage of active constituent is therapeutically effective amount, such as about 5 mg/kg body of about 1 microgram/kg body weight-daily
Weight.In addition, transient receptor potential channel protein TRPA1 inhibitor of the invention can be also used together with other therapeutic agents.
For pharmaceutical composition of the invention, required object (such as people and the inhuman food in one's mouth can be applied to by way of conventional
Newborn animal).Representative method of application includes (but being not limited to): oral, injection, Neulized inhalation etc..
It is by the medicament administration of safe and effective amount in mammal when using pharmaceutical composition, the wherein safe and effective amount
Typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg weight, the preferably agent
Amount is about 1 mg/kg weight of about 10 micrograms/kg body weight-.Certainly, specific dosage is also contemplated that administration route, patient health
The factors such as situation, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include:
(a) formula A compound of the invention has preferable inhibitory effect to TRPA1.
(b) typical form A compound of the invention has excellent safety, toxic side effect very little or almost non-toxic secondary work
With.
(c) formula A compound of the invention mediates TRPA1 pain, inflammation have better treatment potential.
(d) formula A compound of the invention has been used for the treatment of human diseases by supervision department's approval, so the new application
Discovery can rapidly enter the clinical II phase and test, be conducive to shorten the research and development time and reduce R & D Cost.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor
Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, no
Then percentage and number are calculated by weight.
Material
Compound 1-15 is commercially available following compound:
Universal method
Test experiments of the compound of the present invention (1-15) to the inhibitory activity of transient receptor potential channel protein TRPA1
The test method of patch-clamp detection is automated by IonWorks Barracuda (IWB): stablizing expression mTRPA1
HEK293 cell, with contain 15g/mL Blasticidin S HCl, 200g/mL Hygromycin B and 10%FBS serum
DMEM culture medium, be placed in the culture bottle of T175, be put into 37 DEG C, 5%CO2Incubator in cultivate, to cell density grow
When to~80%, culture solution is removed, is rinsed one time with the phosphate buffer (PBS) of no calcium and magnesium, the Trypsin digestion 2 of 3mL is added
Minute, 7mL culture solution is added and terminates digestion.Cell is collected into the centrifuge tube of 15mL with 800 rev/min centrifugation 3 minutes,
The extracellular fluid that proper volume is added in cell is resuspended after removing supernatant, makes cell density control in 2-3 × 106/ mL is used in combination
It is tested in IWB.Extracellular fluid formula (in mM): 140 NaCl, 5KCl, 1 MgCl2,10 HEPES,0.5 EGTA,10
Glucose(pH 7.4)；Intracellular fluid formula (in mM): 140 CsCl, 10 HEPES, 5 EGTA, 0.1 CaCl2,1 MgCl2
(pH 7.2).Amphotericin B and experimental day are configured to 0.1mg/ at 28mg/mL, then with intracellular fluid with DMSO Fresh
The final concentration of mL.
IWB experiment uses population patch clamp (PPC) plate, and whole detection process are automatically performed by instrument,
Extracellular fluid is added in 384 holes of PPC plate, and is after intracellular fluid is added in plenum, to be added 6 μ L's under PPC plate
Cell liquid carries out sealing-in test, finally changes the intracellular fluid in plenum into intracellular fluid containing amphotericin B, makes sealing-in
Whole-cell recording technique pattern is formed after cell perforation.The sample frequency for recording TPRA1 electric current is 10kHz, and cell is clamped down in 0mV, electricity
Pressure stimulation order (channel protocol) is slope (ramp) voltage of a 300ms from -100mV to+100mV, every 10s
The stimulation of this voltage is given, mTRPA electric current is induced by 300M AITC.
Data record and current amplitude measurement export are by the completion of IWB software (version 2.5.3, Molecular
Devices Corporation, Union City, CA).Hole of the sealing-in impedance lower than 20M Ω will not record data statistics.It is original
Current data carries out leak subtraction correction by software, and TRPA1 current amplitude is measured in+100mV.Every block of PPC plate of experiment will all have
The dosage effect data of one HC030031 are as positive control, such as the IC of HC03003150Value is more than to obtain on previous every block of plate
IC50At 3 times of average value, repetition measurement will be carried out.Compound dose-effect curve and IC50By GraphPad Prism 5.02
(GraphPad Software, San Diego, CA) is fitted calculating.
Embodiment 1
The compound of the present invention (1-15) inhibits the active IC of transient receptor potential channel protein TRPA150Measurement experiment knot
Fruit
15 kinds of marketed drugs of the invention are automated with the survey of patch-clamp detection by IonWorks Barracuda (IWB)
Method for testing carries out IC50Inhibitory activity test, activity data is as shown in table 1, which has stronger work to suppression TRPA1
Property, half effective inhibition concentration IC50Between 4.76 μM -45.62 μM.
Inhibitory activity data (IC of 1. compound of table (1-15) to TRPA150,μM)
Embodiment 2
Medicine box
A kind of following medicine box is prepared, the medicine box includes:
(1) the first container, and the first pharmaceutical preparation (such as tablet) in the container, said preparation contain following work
Property ingredient；
(2) second container, and the second pharmaceutical preparation (such as tablet) in the container, said preparation contain following work
Property ingredient；
And (3) operation instructions.
The compound of the present invention 1-15 is 15 kinds of typical cases marketed drug, in vitro can potent inhibitions transient receptor potential lead to
The activity of road albumen TRPA1, therefore exploitation is expected into novel therapeutic pain, inflammation, respiratory disorder (asthma, cough, chronic blocking
Property tuberculosis), itch related with oxidative stress, reduce urinary-tract disorders, inflammatory bowel disease drug.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (6)
1. the purposes of a kind of compound shown in formula A or its pharmaceutically acceptable salt, which is characterized in that
It is used to prepare the pharmaceutical composition or preparation of urinary-tract disorders caused by inhibiting transient receptor potential channel protein TRPA1；
Wherein the compound shown in formula A is selected from the group:
2. purposes as described in claim 1, which is characterized in that the compound shown in formula A it is pharmaceutically acceptable
Salt is selected from the group:
3. purposes as described in claim 1, which is characterized in that the formula A in described pharmaceutical composition containing 0.001-99wt%
Compound represented or its pharmaceutically acceptable salt, by the total weight of described pharmaceutical composition.
4. purposes as described in claim 1, which is characterized in that the formula A institute in described pharmaceutical composition containing 0.1-90wt%
The compound shown or its pharmaceutically acceptable salt, by the total weight of described pharmaceutical composition.
5. purposes as described in claim 1, which is characterized in that shown in the formula A in described pharmaceutical composition containing 1-80wt%
Compound or its pharmaceutically acceptable salt, by the total weight of described pharmaceutical composition.
6. a kind of active method of inhibition transient receptor potential channel protein TRPA1 that external non-therapeutic is nondiagnostic, special
Sign is, transient receptor potential channel protein is contacted with compound shown in formula A or its pharmaceutically acceptable salt,
To inhibit the activity of transient receptor potential channel protein, wherein the compound shown in formula A such as institute in claim 1
It states.
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