WO2020228789A1 - 3-芳氧基-3-五元杂芳基-丙胺类化合物及其晶型和用途 - Google Patents
3-芳氧基-3-五元杂芳基-丙胺类化合物及其晶型和用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to the fields of medicinal chemistry and pharmacotherapy, in particular to a 3-aryloxy-3-pentavalent heteroaryl-propylamine compound and its crystal form and application.
- Pain is called the fifth vital sign, and it is a warning sign of damage to body tissues. Pain is one of the most common reasons for patients to seek medical treatment. According to the duration, it is divided into acute pain (rapid onset, short duration, or continuous state) and chronic pain (slow onset or transformed from acute pain, long duration. It can also be intermittent, and many chronic pain can not find obvious damage). Acute pain is mostly nociceptive pain caused by tissue trauma, including postoperative pain, trauma, post-burn pain, childbirth pain, angina, biliary colic, renal colic and other visceral pain, fracture pain, toothache, cancer pain, etc. Surgery and post-traumatic pain are the most common clinical acute pain and the most urgently needed treatment.
- Chronic pain mainly includes neuropathic pain, painful osteoarthritis, chronic low back pain and vascular pain.
- Trigeminal neuralgia, diabetic pain, sciatica or post-zoster neuralgia are the main types of neuropathic pain.
- the global prevalence of neuropathic pain is about 10%, the incidence is high, and the patient population is large. In the United States, 10%-30% of people suffer from chronic pain, causing an annual social expenditure of about 635 billion US dollars, more than the combined amount of cancer and heart disease.
- Chronic pain has complex causes and is a refractory disease. Only less than 50% of patients can achieve effective analgesia through medication. It is estimated that in 2026, the total market size of neuralgia drugs in China will be close to 26 billion yuan, and the market size of ion channel neuralgia drugs will exceed 20 billion yuan.
- Opioids have strong analgesic effects, but long-term use can easily lead to tolerance, dependence and addiction, and have adverse reactions such as respiratory depression and central sedation.
- Non-steroidal anti-inflammatory drugs only exert a moderate analgesic effect, but also have gastrointestinal bleeding and cardiac toxicity.
- the National Security Council recently released a report on preventable deaths, showing that for the first time in American history, deaths caused by opioid overdose exceeded the proportion of deaths caused by car accidents. According to the Commission's analysis of accidental death data in 2017, 1 in 96 Americans died from an opioid overdose, and the number of deaths from a car accident is 1 in 103 Americans. The abuse of opioids has caused a severe social crisis sweeping the United States today, so the market needs a new mechanism of analgesics.
- TRPA1 is a member of the TRP ion channel superfamily and the only member of the TRPA subfamily. It is a non-selective cation channel and is permeable to Na + , K + , Ca 2+ and Mg 2+ .
- TRPA1 is mainly distributed on the primary sensory neurons of the dorsal root nerve (DRG), trigeminal nerve (TG) and vagus nerve (VG). From the distribution of the human system, TRPA1 is highly expressed in the peripheral nervous system, respiratory system, gastrointestinal system and urinary system. When these organs and tissues have abnormal functions, the expression and function of TRPA1 channels are usually abnormal simultaneously.
- TRPA1 can convert cold stimulation, chemical stimulation and mechanical stimulation into inward current, trigger a series of physiological functions, and participate in the formation of various pain sensations. Inflammatory pain is a common problem of certain chronic diseases, and clinically there is still a lack of effective treatment methods. Animal experiments have shown that TRPA1 is involved in inflammatory response and plays an important role in inflammatory pain. The use of TRPA1 specific blockers can significantly reduce the inflammatory pain response in rats. From the current research, TRPA1 plays an important role in the occurrence of asthma and cough. Compounds that induce asthma and cough, whether it is cell endogenous factors or exogenous factors, can activate TRPA1. Antagonists of TRPA1 can reduce asthma symptoms and block airway hyperresponsiveness.
- TRPA1 participates in the regulation of visceral hypersensitivity and plays an important role in visceral pain.
- Neuropathic pain is a pain syndrome caused by central or peripheral nervous system damage or disease. It mainly manifests as hyperalgesia, allodynia, and spontaneous pain.
- TRPA1 channels play an important role in different neurogenic pain, such as diabetic neuropathy and neuropathy caused by chemotherapy drugs.
- TRPA1 also has a mediating role in toothache, migraine and other pains. The administration of TRPA1 antagonists can significantly alleviate the pain symptoms.
- TRPA1 is widely distributed and expressed in the human system. In addition to the physiological functions of TRPA1, the development of TRPA1 inhibitor indications reported so far also involves inflammatory bowel disease, chronic obstructive pulmonary disease, antitussive, antipruritic, Allergic rhinitis, ear disease, anti-diabetic, urinary incontinence, etc. TRPA1 is a proven new target for the treatment of many diseases.
- the purpose of the present invention is to provide a compound with a novel structure and a TRP channel as a target (especially a TRPA1 target), a crystal form and its use.
- a compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof for (a) preparing a transient receptor potential channel protein (TRPA1) inhibitor; (b) preparing Drugs to prevent and/or treat diseases related to transient receptor potential channel protein (TRPA1);
- Ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- X is an oxygen atom, a sulfur atom or a nitrogen atom
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- n 1, 2 or 3;
- any of the "substitution” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five-membered or six-membered heteroaryl (preferably C 5 heteroaryl) ;
- heterocyclic ring, heteroaromatic ring and heteroaryl group each independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
- the compound of formula Z has a structure of formula Z-1:
- ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring and a 5-7 membered heteroaromatic ring.
- X is S or O.
- R 1 and R 2 are each independently hydrogen or substituted or unsubstituted C 1 -C 3 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl.
- the halogen is F, Cl, Br or I.
- each R 3 is the same or different.
- ring A is a substituted or unsubstituted 5-membered carbocyclic ring, a substituted or unsubstituted 6-membered carbocyclic ring, or a substituted or unsubstituted furan ring.
- ring A is not a benzene ring.
- ring A is
- connection structure between ring A and the adjacent benzene ring is:
- the The structure is:
- R 1 and R 2 are each independently hydrogen, methyl or ethyl.
- R 3 is a hydrogen atom, a chlorine atom or a methyl group.
- n 1
- A is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring or a furan ring.
- n 1, 2 or 3.
- X is S.
- ring A is a furan ring.
- the ring containing X is a thiophene ring.
- the structure of the thiophene ring is
- the structure of ring A acene ring is
- the compound of formula Z is selected from the group consisting of
- the disease related to transient receptor potential channel protein is selected from the group consisting of pain, epilepsy, inflammation, respiratory disorder, pruritus, urinary tract disorder, inflammatory bowel disease, or a combination thereof.
- the pain is selected from the group consisting of acute pain, inflammatory pain, visceral pain, neurogenic pain, muscle fiber pain, headache, nerve pain, mixed pain, cancer-induced pain, or a combination thereof.
- the pain is postoperative pain.
- the postoperative pain is postoperative pain after surgery.
- the postoperative pain is postoperative pain of the wound.
- the post-wound pain is selected from the following group: post-operative pain of skin wound, post-operative pain of muscle wound, or a combination thereof.
- the postoperative pain of the wound is postoperative pain of skin and muscle wounds.
- the acute pain is injury pain or postoperative pain.
- the inflammatory pain is chronic inflammatory pain.
- the inflammatory pain is osteoarthritis pain or rheumatoid arthritis pain.
- the headache is migraine or muscle tension pain.
- the neuralgia is trigeminal neuralgia, diabetic pain, sciatica or post-zoster neuralgia.
- the acute pain is injury pain or postoperative pain.
- the second aspect of the present invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for (a) preparing transient receptor potential channel protein (TRP) inhibitors; (b) preparing Drugs to prevent and/or treat diseases related to transient receptor potential channel protein (TRP);
- TRP transient receptor potential channel protein
- Ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- X is an oxygen atom, a sulfur atom or a nitrogen atom
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- n 1, 2 or 3;
- any of the "substitution” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five-membered or six-membered heteroaryl (preferably C 5 heteroaryl) ;
- heterocyclic ring, heteroaromatic ring and heteroaryl group each independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
- the compound of formula I has a structure of formula I-1
- ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring and a 5-7 membered heteroaromatic ring.
- X is S or O.
- R 1 and R 2 are each independently hydrogen or substituted or unsubstituted C 1 -C 3 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl.
- the halogen is F, Cl, Br or I.
- each R 3 is the same or different.
- ring A is a substituted or unsubstituted 5-membered carbocyclic ring, a substituted or unsubstituted 6-membered carbocyclic ring, or a substituted or unsubstituted furan ring.
- ring A is not a benzene ring.
- ring A is
- connection structure between ring A and the adjacent benzene ring is:
- the The structure is:
- R 1 and R 2 are each independently hydrogen, methyl or ethyl.
- R 3 is a hydrogen atom, a chlorine atom or a methyl group.
- n 1
- A is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring or a furan ring.
- n 1, 2 or 3.
- X is S.
- ring A is a furan ring.
- the ring containing X is a thiophene ring.
- the structure of the thiophene ring is
- the structure of ring A acene ring is
- the compound is selected from the following group:
- the transient receptor potential channel protein is TRPA1.
- the disease related to transient receptor potential channel protein is selected from the group consisting of pain, epilepsy, inflammation, respiratory disorder, pruritus, urinary tract disorder, inflammatory bowel disease, or a combination thereof.
- the pain is selected from the following group: acute pain, inflammatory pain, visceral pain, neurogenic pain, muscle fiber pain, headache, nerve pain, mixed pain, cancer-induced pain, or a combination thereof.
- the acute pain is injury pain or postoperative pain.
- the postoperative pain is postoperative pain after surgery.
- the postoperative pain is postoperative pain of the wound.
- the post-wound pain is selected from the following group: post-operative pain of skin wound, post-operative pain of muscle wound, or a combination thereof.
- the postoperative pain of the wound is postoperative pain of skin and muscle wounds.
- the inflammatory pain is chronic inflammatory pain.
- the inflammatory pain is osteoarthritis pain or rheumatoid arthritis pain.
- the headache is migraine or muscle tension pain.
- the neuralgia is trigeminal neuralgia, diabetic pain, sciatica or post-zoster neuralgia.
- the acute pain is injury pain or postoperative pain.
- the third aspect of the present invention provides a compound, or a pharmaceutically acceptable salt or prodrug thereof, the compound having the structure of formula Z:
- Ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- X is an oxygen atom, a sulfur atom or a nitrogen atom
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- n 1, 2 or 3;
- any of the "substitution” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five-membered or six-membered heteroaryl (preferably C 5 heteroaryl) ;
- heterocyclic ring, heteroaromatic ring and heteroaryl group each independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
- the pharmaceutically acceptable salt of the compound of formula Z is a salt formed by the compound of formula Z and an acid selected from the group consisting of hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, and hydrofluoric acid. , Sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzyl Sulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, or a combination thereof.
- the compound of formula Z has a structure of formula Z-1:
- ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring and a 5-7 membered heteroaromatic ring.
- X is S or O.
- R 1 and R 2 are each independently hydrogen or substituted or unsubstituted C 1 -C 3 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl.
- the halogen is F, Cl, Br or I.
- each R 3 is the same or different.
- ring A is a substituted or unsubstituted 5-membered carbocyclic ring, a substituted or unsubstituted 6-membered carbocyclic ring, or a substituted or unsubstituted furan ring.
- ring A is not a benzene ring.
- ring A is
- connection structure between ring A and the adjacent benzene ring is:
- the The structure is:
- R 1 and R 2 are each independently hydrogen, methyl or ethyl.
- R 3 is a hydrogen atom, a chlorine atom or a methyl group.
- n 1
- A is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring or a furan ring.
- n 1, 2 or 3.
- X is S.
- ring A is a furan ring.
- the ring containing X is a thiophene ring.
- the structure of the thiophene ring is
- the structure of ring A acene ring is
- the compound is selected from the following group:
- the fourth aspect of the present invention provides a compound, or a pharmaceutically acceptable salt, or a prodrug thereof, the compound having the structure of Formula I:
- Ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- X is an oxygen atom, a sulfur atom or a nitrogen atom
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- n 1, 2 or 3;
- any of the "substitution” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five-membered or six-membered heteroaryl (preferably C 5 heteroaryl) ;
- heterocyclic ring, heteroaromatic ring and heteroaryl group each independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
- the pharmaceutically acceptable salt of the compound of formula I is a salt formed by the compound of formula I and an acid selected from the group consisting of hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, and hydrofluoric acid. , Sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzyl Sulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, or a combination thereof.
- the compound of formula I has a structure of formula I-1
- A is a substituted or unsubstituted 5-7 membered carbocyclic ring and a 5-7 membered heteroaromatic ring.
- X is S or O.
- R 1 and R 2 are each independently hydrogen or substituted or unsubstituted C 1 -C 3 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl.
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl.
- the halogen is F, Cl, Br or I.
- each R 3 is the same or different.
- A is a substituted or unsubstituted 5-membered carbocyclic ring, a substituted or unsubstituted 6-membered carbocyclic ring, or a substituted or unsubstituted furan ring.
- ring A is not a benzene ring.
- ring A is
- connection structure between ring A and the adjacent benzene ring is:
- the The structure is:
- R 1 and R 2 are each independently hydrogen, methyl or ethyl.
- R 3 is a hydrogen atom, a chlorine atom or a methyl group.
- n 1
- A is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring or a furan ring;
- n 1, 2 or 3.
- X is S.
- ring A is a furan ring.
- the ring containing X is a thiophene ring.
- the structure of the thiophene ring is
- the structure of ring A acene ring is
- the compound is selected from the following group:
- the fifth aspect of the present invention provides a compound of formula A, or a pharmaceutically acceptable salt or prodrug thereof,
- Ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- X is an oxygen atom, a sulfur atom or a nitrogen atom
- W is O or S
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkane base;
- n 1, 2 or 3;
- any of the "substitution” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five-membered or six-membered heteroaryl (preferably C 5 heteroaryl) ;
- heterocyclic ring, heteroaromatic ring and heteroaryl group each independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
- the pharmaceutically acceptable salt of the compound of formula A is a salt formed by the compound of formula A and an acid selected from the group consisting of hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, and hydrofluoric acid. , Sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzyl Sulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, or a combination thereof.
- ring A, R 1 , R 2 , R 3 , X, and n are each independently as described in the third aspect of the present invention.
- W is O.
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl.
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen.
- connection structure between ring A and the adjacent benzene ring is:
- the compound of formula A is a compound of formula Z:
- the compound of formula Z is as described in the third aspect of the present invention.
- the sixth aspect of the present invention provides a compound of formula B, or a pharmaceutically acceptable salt or prodrug thereof,
- Ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- X is an oxygen atom, a sulfur atom or a nitrogen atom
- W is O or S
- R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkane base;
- n 1, 2 or 3;
- any of the "substitution” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five-membered or six-membered heteroaryl (preferably C 5 heteroaryl) ;
- heterocyclic ring, heteroaromatic ring and heteroaryl group each independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
- the pharmaceutically acceptable salt of the compound of formula B is a salt formed by the compound of formula B and an acid selected from the group consisting of hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, and hydrofluoric acid. , Sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzyl Sulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, or a combination thereof.
- ring A, R 1 , R 2 , R 3 , X, and n are each independently as described in the fourth aspect of the present invention.
- W is O.
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl.
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen.
- connection structure between ring A and the adjacent benzene ring is:
- the compound of formula B is a compound of formula I:
- the compound of formula I is as described in the fourth aspect of the present invention.
- a pharmaceutical composition comprises the compound according to the third aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and/or the third aspect of the present invention.
- the eighth aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound according to the fifth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof and/or the first
- the ninth aspect of the present invention provides a compound of formula A according to the fifth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or use of a prodrug thereof, or a compound of formula B according to the sixth aspect of the present invention, Or a pharmaceutically acceptable salt thereof, or the use of a prodrug thereof for (a) preparation of transient receptor potential channel protein (TRPA1) inhibitor; (b) preparation of prevention and/or treatment and transient receptor potential channel protein (TRPA1) Drugs for related diseases.
- TRPA1 transient receptor potential channel protein
- TRP transient receptor potential channel protein
- the disease related to transient receptor potential channel protein is as described in the second aspect of the present invention.
- the tenth aspect of the present invention provides a method for preparing the compound according to the fourth aspect of the present invention, or a pharmaceutically acceptable salt, or a prodrug thereof.
- the method includes the steps of: Intermediate II reacts with R 1 -NH-R 2 compound to form the compound:
- X, A, R 1 , R 2 , R 3 and n are as defined in the fourth aspect of the present invention.
- the method includes the steps:
- X, A, R 1 , R 2 , R 3 and n are as defined in the fourth aspect of the present invention:
- the eleventh aspect of the present invention provides an intermediate, the intermediate having the structure of formula II or formula III:
- X, A, R 3 and n are defined as described in the fourth aspect of the present invention.
- the twelfth aspect of the present invention provides a method for preparing the intermediate according to the seventh aspect of the present invention
- X, A, R 3 and n are defined as described in the fourth aspect of the invention.
- the method includes the steps:
- the intermediate is selected from the following group:
- the thirteenth aspect of the present invention provides a non-therapeutic and non-diagnostic in vitro method for inhibiting the activity of transient receptor potential channel protein.
- the method includes the steps: in an in vitro culture system, combining transient receptor potential channel protein Or the cell expressing the protein is contacted with the compound according to the third, fourth, fifth and/or sixth aspect of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, thereby inhibiting Transient receptor potential channel protein activity.
- the fourteenth aspect of the present invention provides a method for inhibiting transient receptor potential channel protein or preventing and/or treating diseases related to transient receptor potential channel protein (TRP).
- the method includes the steps of: giving a subject in need Administration of the compound described in the third, fourth, fifth and/or sixth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
- the subject includes humans and non-human mammals (rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.).
- the fifteenth aspect of the present invention provides a compound, or a pharmaceutically acceptable salt or prodrug thereof, the compound having the structure of formula G:
- a 1 is Group; where ring B is a substituted or unsubstituted 5-7 membered carbocyclic ring, substituted or unsubstituted 5-7 membered heterocyclic ring, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl group; ring D is a substituted or unsubstituted 5-7 membered heteroaryl group, substituted or unsubstituted C 6 -C 12 aryl group; and when A 1 is a substituted or unsubstituted aromatic structure , A 1 contains 1-3 heteroatoms selected from N, O and S;
- heterocyclic ring or heteroaryl group contains 1-3 heteroatoms selected from N, O and S;
- R 6 and R 7 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 2 -C 4 acyl, substituted Or an unsubstituted C 2 -C 6 ester group, or R 6 , R 7 and the connected N atom form a substituted or unsubstituted C 3 -C 7 heterocycloalkyl group; wherein, the heterocycloalkyl group contains 1 -2 N atoms and 0-1 O or S atoms;
- X 1 is a carbon atom, oxygen atom, sulfur atom or nitrogen atom
- Y 1 is a carbon atom or a nitrogen atom
- At least one of X 1 and Y 1 is a heteroatom
- R 8 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
- n 1, 2, 3, 4 or 5;
- any of the "substituted” means that one to four (preferably 1, 2, 3) hydrogen atoms on the group are replaced by a substituent selected from the following group: C 1 -C 6 alkyl , C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide group , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, five- or six-membered aryl or heteroaryl (preferably C 6 aryl or C 5 heteroaryl).
- a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- a 1 is not a naphthalene ring.
- a 1 is a substituted or unsubstituted C 6 -C 12 bicyclic heteroaryl group, a substituted or unsubstituted 5-6 membered heterocyclic phenyl group, a substituted or unsubstituted 5-6 membered hetero Cyclo 5-6 membered heteroaryl, or substituted or unsubstituted C 6 -C 12 benzoalicyclic group.
- the C 6 -C 12 bicyclic heteroaryl group is quinolinyl, isoquinolinyl, phthalimido, benzofuranyl, benzothienyl, indole Group, benzoxazolyl, benzothiazolyl, quinoxalinyl, imidazopyridyl or benzimidazolone.
- the C 6 -C 12 benzoalicyclic group includes indanyl, tetrahydronaphthyl or dihydronaphthyl.
- a 1 is substituted or unsubstituted benzofuranyl, benzothienyl, or indanyl.
- At least one of X 1 and Y 1 is a heteroatom.
- X 1 is S or O.
- X 1 is S.
- the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S.
- the substitution refers to substitution by one to four substituents (preferably 1, 2, 3) selected from the following group: C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide group, C 1 -C 4 alkoxy group, C 1 -C 6 haloalkoxy, benzyl, five- or six-membered aryl or heteroaryl (preferably C 6 aryl or C 5 heteroaryl).
- substituents preferably 1, 2, 3
- substituents preferably 1, 2, 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, carboxyl, C 2 -C 4 ester group, C 2 -C 4 amide group, C 1 -C 4 al
- a 1 is a substituted or unsubstituted C 6 -C 12 bicyclic heteroaryl group, a substituted or unsubstituted 5-6 membered heterocyclic phenyl group, a substituted or unsubstituted 5-6 membered hetero Cyclo 5-6 membered heteroaryl, or substituted or unsubstituted C 6 -C 12 benzoalicyclic group.
- R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 3 alkyl group, a C 2 -C 4 acyl group; or R 6 , R 7 and the connected N atom form a carboxyl group or C 2- Tetrahydropyrrolyl substituted with C 4 ester group.
- R 8 is a hydrogen atom, halogen, substituted or unsubstituted C 1 -C 3 alkyl.
- a 1 is quinolinyl, isoquinolinyl, phthalimido, benzofuranyl, benzothienyl, indolyl, benzoxazolyl, benzo Thiazolyl, quinoxalinyl, imidazopyridyl, benzimidazolone, indanyl, tetrahydronaphthyl or dihydronaphthyl.
- R 6 and R 7 are each independently a hydrogen atom, a methyl group, or an acetyl group, or R 6 , R 7 and N atoms form a proline group or a proline methyl ester group.
- R 8 is a hydrogen atom, a chlorine atom or a methyl group.
- the compound of formula G is selected from the following group:
- the sixteenth aspect of the present invention provides a use of the compound of formula G as described in the fifteenth aspect of the present invention for (a) preparation of transient receptor potential channel protein (TRP) inhibitors; (b) preparation Drugs for preventing and/or treating diseases related to transient receptor potential channel protein (TRP).
- TRP transient receptor potential channel protein
- the transient receptor potential channel protein is TRPA1.
- the disease associated with transient receptor potential channel protein is selected from the group consisting of pain, epilepsy, inflammation, respiratory disorder, pruritus, urinary tract disorder or inflammatory bowel disease.
- the pain includes acute inflammatory pain, chronic inflammatory pain, visceral pain, neurogenic pain, fibromyalgia, headache, neuralgia or pain caused by cancer.
- the disease related to transient receptor potential channel protein is selected from the group consisting of pain, epilepsy, inflammation, respiratory disorder, pruritus, urinary tract disorder, inflammatory bowel disease, or a combination thereof.
- the pain is selected from the following group: acute pain, inflammatory pain, visceral pain, neurogenic pain, muscle fiber pain, headache, nerve pain, mixed pain, cancer-induced pain, or a combination thereof.
- the acute pain is injury pain or postoperative pain.
- the postoperative pain is postoperative pain after surgery.
- the postoperative pain is postoperative pain of the wound.
- the post-wound pain is selected from the following group: post-operative pain of skin wound, post-operative pain of muscle wound, or a combination thereof.
- the postoperative pain of the wound is postoperative pain of skin and muscle wounds.
- the inflammatory pain is chronic inflammatory pain.
- the inflammatory pain is osteoarthritis pain or rheumatoid arthritis pain.
- the headache is migraine or muscle tension pain.
- the neuralgia is trigeminal neuralgia, diabetic pain, sciatica or post-zoster neuralgia.
- the seventeenth aspect of the present invention provides a method for preparing the compound of formula G, or a pharmaceutically acceptable salt thereof, or a prodrug thereof as described in the fifteenth aspect of the present invention, the method comprising the steps : In an inert solvent, the intermediate G-1 is reacted with the compound R 6 -NH-R 7 to form the compound:
- X 1 , Y 1 , A 1 , R 6 , R 7 , R 8 and "*" are defined as described in the fifteenth aspect of the present invention.
- the eighteenth aspect of the present invention provides a hydrochloride or hydrochloride crystal form A of the compound of formula I-1,
- the molecular molar ratio of the compound of formula I-1 to hydrochloric acid is 4:1, 3:1, 2:1, 1:1 , 1:2, 1:3 or 4:1.
- the hydrochloride crystal form A of the compound of formula I-1 is anhydrous crystal form.
- the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound of formula I-1 has characteristic peaks at 2 ⁇ angles of 18.173 ⁇ 0.2°, 22.084 ⁇ 0.2°, and 22.794 ⁇ 0.2° .
- the hydrochloride crystal form A of the compound of formula I-1 also has characteristic peaks at one or more 2 ⁇ values selected from the following group: 16.734 ⁇ 0.2°, 21.156 ⁇ 0.2°, 23.761 ⁇ 0.2°.
- the hydrochloride crystal form A of the compound of formula I-1 also has characteristic peaks at one or more 2 ⁇ values selected from the following group: 17.092 ⁇ 0.2°, 21.649 ⁇ 0.2°, 25.298 ⁇ 0.2°, 28.099 ⁇ 0.2°.
- the hydrochloride crystal form A of the compound of formula I-1 also has characteristic peaks at one or more 2 ⁇ values selected from the following group: 10.003 ⁇ 0.2°, 26.640 ⁇ 0.2°, 28.615 ⁇ 0.2°, 28.813 ⁇ 0.2°.
- the hydrochloride crystal form A of the compound of formula I-1 also has characteristic peaks at one or more 2 ⁇ values selected from the following group: 10.003 ⁇ 0.2°, 16.734 ⁇ 0.2°, 17.092 ⁇ 0.2°, 18.173 ⁇ 0.2°, 21.156 ⁇ 0.2°, 21.649 ⁇ 0.2°, 22.084 ⁇ 0.2°, 26.640 ⁇ 0.2°.
- the hydrochloride crystal form A of the compound of formula I-1 also has one or more 2 ⁇ values selected from the following group with characteristic peaks: 11.171 ⁇ 0.2°, 15.987 ⁇ 0.2°, 18.849 ⁇ 0.2° ⁇ 20.681 ⁇ 0.2° ⁇ 25.967 ⁇ 0.2° ⁇ 27.273 ⁇ 0.2° ⁇ 29.501 ⁇ 0.2° ⁇ 30.118 ⁇ 0.2° ⁇ 30.513 ⁇ 0.2° ⁇ 32.522 ⁇ 0.2° ⁇ 33.274 ⁇ 0.2° ⁇ 34.081 ⁇ 0.2° ⁇ 35.815 ⁇ 0.2°, 37.553 ⁇ 0.2°, 40.018 ⁇ 0.2°, 42.927 ⁇ 0.2°, 44.129 ⁇ 0.2.
- the hydrochloride crystal form A of the compound of formula I-1 also has characteristic peaks at one or more 2 ⁇ values selected from the following group: 10.003 ⁇ 0.2°, 11.171 ⁇ 0.2°, 15.987 ⁇ 0.2° ⁇ 16.734 ⁇ 0.2° ⁇ 17.092 ⁇ 0.2° ⁇ 18.849 ⁇ 0.2° ⁇ 20.681 ⁇ 0.2° ⁇ 21.156 ⁇ 0.2° ⁇ 21.649 ⁇ 0.2° ⁇ 23.761 ⁇ 0.2° ⁇ 25.298 ⁇ 0.2° ⁇ 25.967 ⁇ 0.2° ⁇ 26.640 ⁇ 0.2°, 27.273 ⁇ 0.2°, 28.099 ⁇ 0.2°, 28.615 ⁇ 0.2°, 28.813 ⁇ 0.2°, 29.501 ⁇ 0.2°, 30.118 ⁇ 0.2°, 30.513 ⁇ 0.2°, 32.522 ⁇ 0.2°, 33.274 ⁇ 0.2°, 34.081 ⁇ 0.2°, 35.815 ⁇ 0.2°, 37.553 ⁇ 0.2°, 40.018 ⁇ 0.2°, 42.927 ⁇ 0.2°, 44.129 ⁇ 0.2.
- the hydrochloride crystal form A of the compound of formula I-1 has characteristic peaks at one or more 2 ⁇ values selected from the following group: 10.003 ⁇ 0.2°, 11.171 ⁇ 0.2°, 15.987 ⁇ 0.2° ⁇ 16.734 ⁇ 0.2° ⁇ 17.092 ⁇ 0.2° ⁇ 18.173 ⁇ 0.2° ⁇ 18.849 ⁇ 0.2° ⁇ 20.681 ⁇ 0.2° ⁇ 21.156 ⁇ 0.2° ⁇ 21.649 ⁇ 0.2° ⁇ 22.084 ⁇ 0.2° ⁇ 22.794 ⁇ 0.2° ⁇ 23.761 ⁇ 0.2° ⁇ 25.298 ⁇ 0.2° ⁇ 25.967 ⁇ 0.2° ⁇ 26.640 ⁇ 0.2° ⁇ 27.273 ⁇ 0.2° ⁇ 28.099 ⁇ 0.2° ⁇ 28.615 ⁇ 0.2° ⁇ 28.813 ⁇ 0.2° ⁇ 29.501 ⁇ 0.2° ⁇ 30.118 ⁇ 0.2° ⁇ 30.513 ⁇ 0.2°, 32.522 ⁇ 0.2°, 33.274 ⁇ 0.2°, 34.081 ⁇ 0.2°, 35.815 ⁇ 0.2°, 37.553 ⁇ 0.2°, 40.018 ⁇ 0.2°, 42.927 ⁇ 0.2°,
- the X-ray powder diffraction pattern of the hydrochloride crystal form A has one or more characteristic peaks and peak intensities at 2 ⁇ values selected from the following group:
- the hydrochloride crystal form A of the compound of formula I-1 has characteristic X-ray powder diffraction peaks as shown in FIG. 7.
- the differential scanning calorimetry (DSC) chart of the hydrochloride crystal form A of the compound of formula I-1 is heated to 142.30°C (preferably ⁇ 4°C, ⁇ 3°C, ⁇ 2°C or ⁇ 1°C) endothermic peaks begin to appear.
- differential scanning calorimetry (DSC) chart of the hydrochloride crystal form A of the compound of formula I-1 is basically shown in FIG. 8.
- thermogravimetric analysis (TGA) chart of the hydrochloride crystal form A of the compound of formula I-1 has about 0.9827% (preferably ⁇ 0.1%, ⁇ 0.2%) when heated to 168.01°C , ⁇ 0.3%, ⁇ 0.4%, or ⁇ 0.5%) weight loss.
- thermogravimetric analysis (TGA) chart of the hydrochloride crystal form A is basically as shown in FIG. 9.
- the nineteenth aspect of the present invention provides a method for preparing the hydrochloride crystal form A of the compound of formula I-1 according to the eighteenth aspect of the present invention, the method comprising the steps:
- the organic solvent includes ethyl acetate.
- the hydrochloric acid is concentrated hydrochloric acid.
- the pH of the system is 6.5-7.5, preferably 7.0.
- the reaction time is 3-8 min, preferably 5 min.
- the reaction is carried out under stirring conditions.
- step (a) the hydrochloric acid is slowly added.
- the weight-to-volume (kg:L) ratio of the compound of formula I-1 to the organic solvent is 0.2-2:2-30, preferably 0.4-1.0:5 -18, more preferably 0.5-0.9: 8-15.
- step (a) after the solid precipitates, it is dried at 40-45° C. to obtain the hydrochloride crystal form A of the compound of formula I-1.
- the twentieth aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the hydrochloride crystal form A of the compound of formula I-1 as described in the eighteenth aspect of the present invention; and a pharmaceutically acceptable Carrier.
- the twenty-first aspect of the present invention provides a use of the hydrochloride crystal form A of the compound of formula I-1 as described in the eighteenth aspect of the present invention for (a) preparing transient receptor potential channel protein (TRP) ) Inhibitors; (b) Preparation of drugs for preventing and/or treating diseases related to transient receptor potential channel protein (TRP).
- TRP transient receptor potential channel protein
- the transient receptor potential channel protein is TRPA1.
- the disease related to transient receptor potential channel protein is selected from the group consisting of pain, epilepsy, inflammation, respiratory disorder, pruritus, urinary tract disorder, inflammatory bowel disease, or a combination thereof.
- the pain is selected from the following group: acute pain, inflammatory pain, visceral pain, neurogenic pain, muscle fiber pain, headache, nerve pain, mixed pain, cancer-induced pain, or a combination thereof.
- the acute pain is injury pain or postoperative pain.
- the postoperative pain is postoperative pain after surgery.
- the postoperative pain is postoperative pain of the wound.
- the post-wound pain is selected from the following group: post-operative pain of skin wound, post-operative pain of muscle wound, or a combination thereof.
- the postoperative pain of the wound is postoperative pain of skin and muscle wounds.
- the inflammatory pain is chronic inflammatory pain.
- the inflammatory pain is osteoarthritis pain or rheumatoid arthritis pain.
- the headache is migraine or muscle tension pain.
- the neuralgia is trigeminal neuralgia, diabetic pain, sciatica or post-zoster neuralgia.
- the acute pain is injury pain or postoperative pain.
- the twenty-second aspect of the present invention provides a non-therapeutic and non-diagnostic in vitro method for inhibiting the activity of transient receptor potential channel proteins, which comprises the steps of: combining transient receptor potential channel proteins or cells expressing the proteins with the The compound according to the third aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, the compound according to the fourth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, the first aspect of the present invention
- the compound of the fifth aspect, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, the compound of the sixth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the tenth aspect of the present invention The hydrochloride crystal form A of the compound of formula I-1 described in the eight aspects is contacted, thereby inhibiting the activity of transient receptor potential channel protein.
- a method for inhibiting transient receptor potential channel protein or preventing and/or treating diseases related to transient receptor potential channel protein (TRP), and administering to a subject in need such as the third method of the present invention
- TRP transient receptor potential channel protein
- the compound described in the aspect, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, the compound described in the fourth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, the fifth aspect of the present invention The compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, the compound described in the sixth aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the eighteenth aspect of the present invention
- Figure 1 is an automatic patch clamp pair of test compounds I-1 TRPA1 inhibitory activity IC 50.
- FIG 2 manual patch clamp pair of test compounds I-1 TRPA1 inhibitory activity IC 50.
- Figure 3 ED 50 calculation results of compound I-1, S-duloxetine of the present invention and comparative compound C1 in a mouse formalin pain model.
- Figure 4 A statistical graph of MPE% of compound I-1, S-duloxetine, comparative compound C1 and gabapentin of the present invention in a rat hot plate pain model at different times.
- Figure 5 Results of analgesic activity of compound I-1, S-duloxetine, indomethacin and anisodamine choline of the present invention in a mouse model of acetic writhing pain.
- Fig. 6 Results of analgesic activity of compound I-1, S-duloxetine and gabapentin of the present invention in a rat SNL model.
- Figure 7 is an X-ray powder diffraction pattern of the hydrochloride crystal form A of compound I-1.
- Figure 8 is a differential scanning calorimetry (DSC) diffractogram of the hydrochloride salt crystal form A of compound I-1.
- FIG. 9 is a thermogravimetric analysis (TGA) chart of the hydrochloride salt form A of compound I-1.
- Figure 10 shows the results of analgesic activity of compound I-1 of the present invention in a rat postoperative pain model.
- the present inventors unexpectedly developed a compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof for the first time.
- the compound has formula I, formula Z, formula G, formula A or formula B structure.
- the compound of the present invention has a significant inhibitory effect on TRP channels.
- the compounds of the present invention can effectively treat pain related to TRP (especially TRPA1) targets.
- the present invention also provides a solid form of the hydrochloride crystal form A of the compound of formula I-1.
- the hydrochloride crystal form A of the compound of formula I-1 is easy to store, transport, and has strong druggability and stability. Strong (especially with excellent thermal stability and high humidity stability). On this basis, the present invention has been completed.
- the terms “comprising”, “including”, and “containing” are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the term includes “consisting of” and “consisting essentially of”.
- R 1 As used herein, “R 1 ", “R 1 “and “R1” have the same meaning and can be substituted for each other, and other similar definitions have the same meaning.
- C 1 -C 6 alkyl refers to having 1-6, 1-3, or 1-4 carbons A straight or branched alkyl group of atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
- C 1 -C 6 alkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy , Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, or similar groups.
- C 6 -C 12 benzoalicyclic group refers to a group having 6-12 carbon atoms, including indanyl, tetrahydronaphthyl, dihydronaphthyl and similar groups.
- C 1 -C 6 haloalkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms.
- One or more hydrogen atoms of a linear or branched alkoxy group are replaced by a halogen group, such as monochloromethoxy Group, monochloroethoxy group, or similar group.
- C 3 -C 7 cycloalkyl and “C 3 -C 6 cycloalkyl” refer to cycloalkyl groups having 3-7 or 3-6 carbon atoms (including monocyclic, bicyclic Or polycyclic ring system), such as cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cycloheptyl, or similar groups.
- C 2 -C 4 ester group refers to a group having a C 1 -C 3 alkyl-OC(O)-structure or a group having a -OC(O)-C 1 -C 5 alkyl structure Groups, where the alkyl group can be linear or branched, such as CH 3 COO-, C 2 H 5 COO-, C 3 H 8 COO-, (CH 3 ) 2CHCOO-, -COOCH 3 , -COOC 2 H 5. -COOC 3 H 8 , or similar groups.
- C 2 -C 4 amido group refers to a group having a C 1 -C 3 alkyl-CO-NH- structure or a group having a -NH-CO-C 1 -C 3 alkyl structure , Where the alkyl group can be straight or branched, such as CH 3 -CO-NH-, C 2 H 5 -CO-NH-, C 3 H 8 -CO-NH-, -COOCH 3 , -CO-NH -C 2 H 5 , -CO-NH-C 3 H 8 , or similar groups.
- C 2 -C 4 acyl group refers to a group having a C 1 -C 3 alkyl-CO- structure where the alkyl group can be linear or branched, such as CH 3 -CO-, C 2 H 5 -CO-, C 3 H 8 -CO-, or similar groups.
- C 3 -C 7 heterocycloalkyl refers to having 3-7 ring carbon atoms and 1-3 heteroatoms (preferably containing 1 nitrogen atom, that is, they are commonly adjacent to R 1 and R 2 The nitrogen atom) of monocyclic and polycyclic heterocycles (preferably monocyclic heterocycles), such as piperidine group, tetrahydropyrrolyl group, or similar groups.
- the term "5-7 membered carbocyclic ring” refers to any stable 5, 6 or 7-membered monocyclic, bicyclic or polycyclic ring.
- the carbocyclic ring may be a saturated, partially unsaturated, or unsaturated ring, but It cannot be an aromatic ring.
- Examples of the carbocyclic ring include, but are not limited to, cyclopropyl ring, cyclobutyl ring, cyclobutene ring, cyclopentene ring, cyclopentene ring, cyclohexene ring, cyclohexene ring, cycloheptene ring, cycloheptene ring, Or similar groups.
- 5-7 membered heterocyclic ring refers to any stable monocyclic, bicyclic or polycyclic ring containing one or more (preferably 1, 2 or 3) selected from N, O and S heteroatom, and the number of ring atoms in the heterocyclic ring is 5-7.
- the heterocyclic ring may be a saturated, partially unsaturated, or unsaturated ring, but cannot be an aromatic ring. It should be understood that when multiple heteroatoms are contained, the heteroatoms may be the same, part of the same, or completely different.
- C 1 -C 3 haloalkyl means that one or more hydrogen atoms of a linear or branched alkyl group having 1-3 carbon atoms are replaced by a halogen group, such as a chloromethyl group , Dichloroethyl, trichloropropyl, or similar groups.
- C 1 -C 4 carboxyl group refers to a group of C 1 -C 3 alkyl-COOH structure, where the alkyl group can be linear or branched, such as CH 3 COOH, C 2 H 5 COOH, C 3 H 8 COOH, (CH 3 ) 2 CHCOOH, or similar groups.
- C 6 -C 12 aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl, or the like Group.
- 5-7 membered heteroaromatic ring refers to an aromatic heterocyclic ring system having one to more (preferably 1, 2, or 3) heteroatoms selected from N, O, and S, and having 5- 7 ring atoms. It should be understood that when multiple heteroatoms are contained, the heteroatoms may be the same, part of the same, or completely different.
- examples of 5-membered heteroaromatic rings include (but are not limited to): pyrrole ring, furan ring, thiophene ring, imidazole ring, oxazole ring, thiazole ring
- examples of 6-membered heteroaromatic ring include (but are not limited to) pyridine ring, Pyrazine ring, pyridazine ring, pyrimidine ring. Or similar groups.
- the term "five- or six-membered heteroaryl” refers to an aromatic group having one to more (preferably 1, 2, or 3) heteroatoms selected from N, O, and S, and having 5 or 6 Ring atoms. It should be understood that when multiple heteroatoms are contained, the heteroatoms may be the same, part of the same, or completely different.
- 5-membered heteroaryl groups include (but are not limited to): pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, or similar groups.
- six-membered aryl group refers to an aromatic group having 6 ring atoms, and the ring atoms are all carbon atoms, such as a phenyl group, or the like.
- halogen refers to F, Cl, Br, and I.
- substitution means that the hydrogen atom on the group is replaced by a non-hydrogen atom group, but the valence requirements must be met and a chemically stable compound is formed by substitution. In this specification, it should be construed that all substituents are unsubstituted, unless expressly described as “substituted” herein.
- any one of the "substituted” means that 1-4 (preferably 1, 2, 3, or 4) hydrogen atoms on the group are each independently replaced by a substituent selected from the following group Substitution: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester Group, C 2 -C 4 amide group, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, six-membered aryl, five- or six-membered heteroaryl (preferably C 5 Heteroaryl).
- substituents can be connected to the parent group or substrate on any atom, unless the connection violates the valence requirement; the same or different substituents can be on the same atom or on different Atomically.
- R-duloxetine and S-duloxetine are as follows:
- the compound of formula I of the present invention refers to a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. It should be understood that the term also includes mixtures of the aforementioned components.
- the compound of formula Z of the present invention refers to a compound having the structure of formula Z, or a pharmaceutically acceptable salt or prodrug thereof. It should be understood that the term also includes mixtures of the aforementioned components.
- the compound of formula G of the present invention refers to a compound having the structure of formula G, or a pharmaceutically acceptable salt or prodrug thereof. It should be understood that the term also includes mixtures of the aforementioned components.
- the compound of the present invention not only has an inhibitory effect on TRPA1, but also has a certain inhibitory effect on other members of the TRP family.
- pharmaceutically acceptable salt refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
- Pharmaceutically acceptable salts include inorganic salts and organic salts.
- a preferred type of salt is the salt formed by the compound of the present invention and an acid.
- Acids suitable for salt formation include (but are not limited to): hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid , Propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid and other organic acids; And acidic amino acids such as aspartic acid and glutamic acid.
- a preferred type of salt is a metal salt formed by the compound of the present invention and a base.
- Suitable bases for salt formation include (but are not limited to): sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and other inorganic bases, Organic bases such as ammonia, triethylamine, diethylamine, etc.
- a preferred example of a pharmaceutically acceptable salt of a compound of formula Z, a compound of formula I, a compound of formula A or a compound of formula B is a compound of formula Z, a compound of formula I, a compound of formula A or a compound of formula B and selected Salts formed from acids of the following group: hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, or combinations thereof.
- the pharmaceutically acceptable salt of a compound of formula Z, a compound of formula I, a compound of formula A or a compound of formula B is formed by a compound of formula Z, a compound of formula I, a compound of formula A or a compound of formula B and an acid selected from the following group Salt: hydrochloride, maleate, oxalate, mucate, fumarate, D-glucuronate, or a combination thereof.
- the preferred compounds of the present invention include any compound selected from Table 1 below:
- the invention also provides a method for preparing the (R)-3-aryloxy-3-pentavalent heteroaryl-propylamine compound represented by the formula I of the invention.
- the present invention also provides methods for preparing intermediates II to III for preparing the above compounds.
- A, X, R 1 , R 2 , R 3 and n are as defined above.
- the compound of formula I, formula Z, formula G, formula A or formula B described in the present invention can be converted to its pharmaceutically acceptable salt by conventional methods.
- a solution of the corresponding acid can be added to the above compound After the salt formation is complete, the solvent is removed under reduced pressure to obtain the corresponding salt of the compound of the present invention.
- TRP Transient Receptor Potential Channel Protein
- Transient receptor potential channel proteins are a kind of protein superfamily composed of important cation channels existing on the cell membrane.
- Transient receptor potential channel proteins include multiple subfamilies, such as TRPA, TRPC, TRPM, TRPV, TRPML, and TRPP subfamilies.
- TRPA1 is a member of TRPA subfamily, TRPA1 is also known as transient receptor potential ankyrin 1. Studies have found that TRPA1 channel protein is related to pain, epilepsy, inflammation, respiratory disorders, itching, urinary tract disorders, inflammatory bowel disease and other diseases. TRPA1 is used to treat pain, epilepsy, inflammation, respiratory disorders, itching, urinary tract disorders, and inflammatory diseases. A target for diseases such as bowel disease.
- the transient receptor potential channel protein (TRP)-related disease is pain.
- the compound of formula I, formula Z, formula G or hydrochloride crystal form A of formula I compound of the present invention has an effective therapeutic effect on pain.
- the pain includes (but is not limited to): acute pain, inflammatory pain, visceral pain, neurogenic pain, muscle fiber pain, headache, nerve pain, mixed pain, pain caused by cancer, inflammatory pain, or combination.
- the acute pain is injury pain or postoperative pain.
- postoperative pain As used herein, the terms “postoperative pain” and “postoperative pain” are used interchangeably.
- the postoperative pain is postoperative pain after surgical operation.
- the postoperative pain is postoperative pain of the wound.
- the post-wound pain is selected from the following group: post-operative pain of skin wound, post-operative pain of muscle wound, or a combination thereof.
- the postoperative pain of the wound is postoperative pain of skin and muscle wounds.
- the inflammatory pain is chronic inflammatory pain.
- the inflammatory pain is osteoarthritis pain or rheumatoid arthritis pain.
- the headache is migraine or muscle tension pain.
- the neuralgia is trigeminal neuralgia, diabetic pain, sciatica or post-zoster neuralgia.
- the acute pain is injury pain or postoperative pain.
- the present invention also provides a method for inhibiting transient receptor potential channel protein (TPR), and a method for treating diseases related to transient receptor potential channel protein.
- TPR transient receptor potential channel protein
- the compound of formula I, formula Z, formula G or the hydrochloride crystal form A of the compound of formula I of the present invention can be used to inhibit transient receptor potential channel protein, thereby preventing or treating diseases related to transient receptor potential channel protein.
- the present invention provides a compound of formula Z, or a pharmaceutically acceptable salt or prodrug thereof, a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, a compound of formula G, Or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the use of the hydrochloride crystal form A of the compound of formula I-1 for (a) preparing a transient receptor potential channel protein (TRPA1) inhibitor; (b) ) Preparation of drugs for preventing and/or treating diseases related to transient receptor potential channel protein (TRPA1).
- TRPA1 transient receptor potential channel protein
- the transient receptor potential channel protein is TPR1.
- examples of diseases related to transient receptor potential channel proteins include (but are not limited to): pain, epilepsy, inflammation, respiratory disorders, pruritus, urinary tract disorders, inflammatory bowel disease, or a combination thereof.
- the pain includes (but is not limited to): acute inflammatory pain, inflammatory pain (such as chronic inflammatory pain, osteoarthritis pain or rheumatoid arthritis pain), visceral pain, neurogenic pain, Muscle fiber pain, headache (for example, migraine, muscle tension pain, etc.), nerve pain (for example, trigeminal neuralgia, diabetic pain, post-zoster neuralgia, etc.), or cancer causes pain.
- the present invention provides a non-therapeutic and non-diagnostic in vitro method for inhibiting the activity of transient receptor potential channel protein, including, for example, in vitro culture system, the transient receptor potential channel protein or expression
- the cells of the protein are contacted with the compound of formula I, formula Z or formula G of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, or the hydrochloride crystal form A of the compound of formula I-1 , Thereby inhibiting the activity of transient receptor potential channel protein.
- in vitro non-therapeutic and non-diagnostic methods for inhibiting the activity of transient receptor potential channel proteins can be used for drug screening, quality control and other purposes.
- the compound of formula I, formula Z or formula G of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, or a hydrochloride crystal of a compound of formula I-1 Type A is in contact with transient receptor potential channel protein or cells expressing the protein, and compounds that can inhibit transient receptor potential channel protein are used as candidate drugs.
- the candidate compound can be further studied through animal experiments and clinical trials on transient receptors. Potential channel protein and the therapeutic effect of related diseases.
- the present invention also provides a method for inhibiting transient receptor potential channel proteins, which method may be therapeutic or non-therapeutic.
- the method includes the steps of: administering the compound of formula I, formula Z, formula G, formula A or formula B of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or formula I to a subject in need -1 Form A of the hydrochloride salt of the compound.
- the subject includes humans and non-human mammals (rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.).
- rodents rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.
- the present invention also provides a hydrochloride crystal form A of the compound of formula I-1,
- the hydrochloride crystal form A of the compound of formula I-1 of the present invention is in a solid form. Compared with the free oily substance of the compound of formula I-1, the salt crystal form of the compound of formula I-1 in solid form is convenient for storage, transportation and Strong medicine.
- the hydrochloride crystal form A of the compound of formula I-1 described in this application also has excellent stability, especially excellent thermal stability and high humidity stability.
- hydrochloride salt form A of the compound of formula I-1 As used herein, the terms "hydrochloride salt form A of the compound of formula I-1", “hydrochloride salt form A” and “crystal form A” can be used interchangeably.
- the hydrochloride crystal form A of the compound of formula I-1 of the present invention has characteristic peaks at one or more 2 ⁇ values selected from the following group: 10.003 ⁇ 0.2°, 11.171 ⁇ 0.2°, 15.987 ⁇ 0.2°, 16.734 ⁇ 0.2° ⁇ 17.092 ⁇ 0.2° ⁇ 18.173 ⁇ 0.2° ⁇ 18.849 ⁇ 0.2° ⁇ 20.681 ⁇ 0.2° ⁇ 21.156 ⁇ 0.2° ⁇ 21.649 ⁇ 0.2° ⁇ 22.084 ⁇ 0.2° ⁇ 22.794 ⁇ 0.2° ⁇ 23.761 ⁇ 0.2° ⁇ 25.298 ⁇ 0.2° ⁇ 25.967 ⁇ 0.2° ⁇ 26.640 ⁇ 0.2° ⁇ 27.273 ⁇ 0.2° ⁇ 28.099 ⁇ 0.2° ⁇ 28.615 ⁇ 0.2° ⁇ 28.813 ⁇ 0.2° ⁇ 29.501 ⁇ 0.2° ⁇ 30.118 ⁇ 0.2° ⁇ 30.513 ⁇ 0.2° ⁇ 32.522 ⁇ 0.2°, 33.274 ⁇ 0.2°, 34.081 ⁇ 0.2°, 35.815 ⁇ 0.2°, 37.553 ⁇ 0.2°, 40.018 ⁇ 0.2°, 42.927 ⁇ 0.2°, 44.129
- the hydrochloride crystal form A of the compound of formula I-1 of the present invention has characteristic X-ray powder diffraction peaks as shown in FIG. 7.
- the differential scanning calorimetry (DSC) chart of the hydrochloride crystal form A of the compound of formula I-1 is heated to 142.30°C (preferably ⁇ 4°C, ⁇ 3°C, ⁇ 2°C or ⁇ 1°C) endothermic peaks begin to appear.
- DSC differential scanning calorimetry
- thermogravimetric analysis (TGA) chart of the hydrochloride crystal form A of the compound of formula I-1 has about 0.9827% (preferably ⁇ 0.1%, ⁇ 0.2% when heated to 168.01°C). %, ⁇ 0.3%, ⁇ 0.4%, or ⁇ 0.5%) weight loss.
- thermogravimetric analysis (TGA) chart of the hydrochloride crystal form A of the compound of formula I-1 is basically shown in FIG. 9
- a method for preparing the hydrochloride crystal form A of the compound of formula I-1 of the present invention preferably includes the steps:
- the reaction time is 3-8 min, preferably 5 min.
- the weight-to-volume (kg: L) ratio of the compound of formula I-1 to the organic solvent is 0.2-2:2-30, preferably 0.4-1.0:5 -18, more preferably 0.5-0.9: 8-15.
- the hydrochloride crystal form A of the compound of formula I-1 of the present invention can inhibit TRPA1.
- the invention provides a composition for inhibiting the activity of transient receptor potential channel proteins.
- the composition includes (but is not limited to): pharmaceutical composition, food composition, dietary supplement, beverage composition and the like.
- the composition is a pharmaceutical composition
- the pharmaceutical composition includes a compound of formula I, formula Z, formula G, formula A or formula B according to the present invention, or a salt of a compound of formula I-1 Salt crystal form A; and a pharmaceutically acceptable carrier.
- the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations.
- Representatives include (but are not limited to): tablets, capsules, injections, infusions, ointments, gels, solutions, microspheres, and films.
- pharmaceutically acceptable carrier refers to: one or more compatible solid, semi-solid, liquid or gel fillers, which are suitable for human or animal use, and must have sufficient purity and low enough toxicity.
- Cosmetic means that the components in the pharmaceutical composition and the active ingredients of the drug and their blending with each other without significantly reducing the drug effect.
- the carrier is not particularly limited, and materials commonly used in the field can be selected, or prepared by conventional methods, or purchased from the market.
- pharmaceutically acceptable carriers include cellulose and its derivatives (such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc.), gelatin, talc, and solid lubricants.
- the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, acetic acid Ethyl esters, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
- the composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, etc.
- the pharmaceutical preparation should match the mode of administration.
- the agent of the present invention can also be used with other co-therapeutic agents (including before, during or after use).
- a safe and effective amount of the drug is administered to the desired object (such as a human or non-human mammal).
- the specific dosage should consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
- the present invention provides a class of compounds of formula I, formula Z, formula G, formula A or formula B with novel structure and excellent TRP channel (especially TRPA1) inhibitory activity.
- the compound of the present invention has less toxicity and higher activity, so the safety window is larger.
- the compound of the present invention has good druggability.
- the compound of the present invention has excellent pharmacokinetic properties.
- the compound of the present invention is suitable for oral administration.
- the present invention also provides a hydrochloride salt crystal form A of the compound of formula I-1.
- the hydrochloride salt crystal form A of the compound of formula I-1 is in solid form and is in oily form with the free compound of formula I-1.
- the salt crystal form of the compound I-1 in solid form is convenient for storage, transportation, and has strong drug-forming properties, and has strong stability (especially excellent thermal stability and high humidity stability).
- Example 1-2 95 mg of compound I-11 was obtained as a colorless oil with a yield of 14.06%.
- the compounds prepared in some examples of the present invention were tested for their inhibitory activity on the transient receptor potential channel protein TRPA1.
- the positive control compound adopts the compound of formula A (WO2010075353):
- Test method by IonWorks Barracuda (IWB) automated patch clamp detection HEK293 cells stably expressing TRPA1, using DMEM medium containing 15 ⁇ g/mL Blasticidin S HCl, 200 ⁇ g/mL Hygromycin B and 10% FBS serum, placed in T175 Put it in a culture flask and place it in a 37°C, 5% CO 2 incubator. When the cell density grows to ⁇ 80%, remove the culture medium, rinse it with calcium and magnesium-free phosphate buffer (PBS), and add 3 mL Trypsin was digested for 2 minutes, and 7 mL of culture medium was added to terminate the digestion.
- IWB IonWorks Barracuda
- Amphotericin B was freshly prepared with DMSO on the day of the experiment to make 28mg/mL, and then with intracellular fluid to make a final concentration of 0.1mg/mL.
- the IWB experiment uses the population patch clamp (PPC) plate, and the entire detection process is automatically completed by the instrument, that is, add extracellular fluid to the 384 wells of the PPC plate, and add the intracellular fluid under the PPC plate, that is, into the plenum, and then add 6L of cells Sealing test is performed on the liquid, and finally the intracellular liquid in plenum is replaced with the intracellular liquid containing amphotericin B, and the sealed cells are perforated to form a whole-cell recording mode.
- the sampling frequency for recording the TPRA1 current is 10kHz
- the cell is clamped at 0mV
- the voltage stimulation command (channel protocol) is a ramp voltage from -100mV to +100mV for 300ms. This voltage stimulation is given every 10s, and the mTRPA1 current is induced by 300M AITC .
- the compounds of the present invention showed potent inhibitory activity against TRPA1.
- 5 compounds had a half effective inhibitory concentration IC 50 for TRPA1 between 1-5 ⁇ M
- 4 compounds had a half effective inhibitory concentration IC 50 for TRPA1.
- the compound I-1 of the present invention has an IC 50 of 2.06 ⁇ M for the TRPA1 inhibitory activity. Therefore, it can be concluded that the compound of formula I-1 of the present invention has a strong inhibitory activity against TRPA1.
- Compound I-1 (a heteroaryl group) and the comparative compound C2 (phenyl containing) the specific activity (IC 50 of Compound C2 / IC I-1 Compound 50) was about 6.3, which indicates that, heteroaryl comprising
- the basic compounds of the present invention (such as I-1) have higher inhibitory activity against TRPA1.
- the inventors measured the TRPA1 inhibitory activity of compound I-1 through the manual patch clamp test method, as shown in Figure 2, which is similar to the test result of the automatic patch clamp test method.
- compound I The IC 50 of -1 is 0.42 ⁇ M, which shows strong inhibitory activity on TRPA1.
- HepG-2 and SH-SY5Y cells culture them in a 10 cmdish at 37°C, 5% CO 2 in a cell incubator; trypsinize and resuspend the cells and count them. According to the 100 ⁇ l/well system, the cells are transferred to 8000cells. In a 96-well plate. 37°C, 5% CO2 cell incubator was cultured for 24 hours; a gradient concentration system of compound I-1 (prepared in Example 2 of the present invention) was prepared, diluted by 2 times, and the system was 100 ⁇ l/well. Remove the supernatant in the 96-well plate cell culture system on the first day, and add the newly configured drug concentration system to the culture plate wells of the cultured cells (set up double multiple wells).
- Cytotoxicity (%) [A (0 medicated) -A (dosing)] / [A (0 medicated) - A(blank)) ⁇ 100
- the determination method is similar to the above-mentioned hepatotoxicity and neurocytotoxicity experiments of the I-1 compound, the difference is that S-duloxetine is used instead of the I-1 compound.
- S-duloxetine has 33.33 ⁇ M and 28.59 ⁇ M for hepatotoxicity and neurotoxicity (IC 50 , ⁇ M), respectively, while the I-1 compound of the present invention has hepatotoxicity and neurotoxicity (IC 50 , ⁇ M) It is about 113.80 ⁇ M and 100.70 ⁇ M, which indicates that the toxic and side effects of the compound of the present invention are significantly lower and have excellent safety.
- mice Take 150 C57BL/6 mice (male, 9 weeks), each group of 10 mice, randomly divided into 15 groups, used for the analgesic activity test of 3 compounds in the mouse formalin pain model: respectively It is the compound I-1 group (the compound I-1 prepared in Example 2, the experiment uses its hydrochloride), the S-duloxetine group (the experiment uses its hydrochloride) and the compound C1 group (the compound prepared in Comparative Example 1 Compound C1, the experiment used its hydrochloride). Before the start of the experiment, the mice were allowed to adapt to the experimental environment for 72 hours, during which there was no need to fast or water. The test drug was given by intraperitoneal injection, and the dosage settings were as follows:
- Compound I-1 group blank Vehicle (blank normal saline control), 0.1mg/kg, 0.5mg/kg, 1mg/kg, 5mg/kg and 10mg/kg;
- S-duloxetine group blank Vehicle (blank normal saline control), 1mg/kg, 5mg/kg, 10mg/kg and 20mg/kg;
- Compound C1 group Blank Vehicle (blank saline control), 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 5 mg/kg and 10 mg/kg.
- ED 50 refers to the dose of the drug that reduces the time to fill up by half compared with the blank control group. The smaller the ED 50 value, the lower the effective analgesic dose of the compound and the better the analgesic effect.
- the test results of the mouse formalin pain model are shown in Table 3 and Figure 3. It can be seen from Table 3 and Figure 3 that the analgesic activities of the three compounds all showed a dose-dependent manner.
- the compounds of the invention I-1 exhibited strong analgesic activity in the mouse formalin pain model, which is stronger than the ED 50 S- duloxetine 30.8 times, while stronger than compound C1 8.5 times.
- the mouse formalin model is a classic model for evaluating the efficacy of drugs for acute pain and inflammatory pain. Therefore, the compound I-1 of the present invention has an excellent therapeutic effect on acute pain and inflammatory pain.
- the 50 selected animals were weighed, and the animals were randomly divided into 5 groups, 10 in each group, which were the normal saline control group (Vehicle, blank control) and the S-duloxetine group (the experiment used them Hydrochloride), gabapentin group, comparative compound C1 group (compound C1 prepared in comparative example 1, the experiment used its hydrochloride) and compound I-1 group (compound I-1 prepared in example 2, the experiment used its hydrochloric acid salt).
- the test compound was prepared fresh on the day of administration.
- a 0.9% NaCl physiological saline solution was prepared as a solvent for later use, and an appropriate amount of the test compound was added to the required volume of physiological saline, fully suspended, and the concentration of the prepared drug was 1 mg/ml.
- the standard administration volume for rats is 10ml/kg, and the rats are administered intraperitoneally. The animals do not need to fast and water before administration.
- the dosage of S-duloxetine, compound C1 and compound I-1 was 30 mg/kg, and the dosage of gabapentin was 100 mg/kg.
- the latency of heat pain was measured for 0.5h, 1h and 2h.
- the maximum incubation time is set to 30s.
- the results of the analgesic activity of the compounds in the rat hot plate pain model are shown in Table 4 and Figure 4. From the results of Table 4 and Figure 4, it can be seen that, compared with the normal saline control group, the compound I-1 of the present invention exhibits a very strong analgesic effect at a dose of 30 mg/kg, with a significant difference. Compared with the positive control group, the analgesic activity of compound I-1 of the present invention is significantly better than 100 mg/kg gabapentin, and better than 30 mg/kg S-duloxetine and comparative compound C1 in 2 hours. effect.
- the rat hot plate pain model is a classic model for evaluating the efficacy of drugs for acute pain. Therefore, the compound I-1 of the present invention has an excellent therapeutic effect on acute pain.
- the negative control group is a normal saline group (Vehicle, blank control)
- the positive control group is set to a dose of 10 mg/kg indomethacin (a non-steroidal anti-inflammatory drug) and a dose of 10 mg/kg anisodamine (An antispasmodic drug with clinical analgesic activity), the administration dose of 10mg/kg S-duloxetine (the experiment uses its hydrochloride) and the administration dose of 20mg/kg S-duloxetine ( The experiment uses its hydrochloride).
- Test Compound I-1 (Compound I-1 prepared in Example 2, and its hydrochloride salt was used in the experiment, and the dosages were set at 5 mg/kg and 10 mg/kg). According to the weight of the mouse, it was administered by gavage. Inject 1.5% acetic acid solution (0.1ml/10g) into the abdominal cavity 1 hour after administration, and observe the number of visceral pains in each group within 30 minutes. The mice have a concave abdomen, the trunk and hind legs are stretched, and the buttocks are high. Once, finally count the number of occurrences of the above phenomenon within 30 minutes. After administration, the fewer visceral pains in mice, the stronger the analgesic effect of the compound.
- the mouse acetic acid writhing pain model test is shown in Figure 5. It can be seen from Figure 5 that a single intragastric administration of compound I-1 (5 mg/kg and 10 mg/kg) of the present invention can significantly reduce the small amount caused by acetic acid. There is a significant difference in the number of writhing reactions in mice compared with the normal saline group (Vehicle, blank control) (49 times). Compound I-1 at a dose of 5 mg/kg, mice had 19 times of visceral pain, which was lower than 50% of the 49 times in the physiological salt control group, suggesting that the half effective dose of compound I-1 in this model (ED 50 ) Less than 5mg/kg.
- the analgesic effect of Compound I-1 at a dose of 10 mg/kg (16 times) was better than the positive drugs indomethacin (28 times), anisodamine (27 times) and S-duloxetine ( 27 times), and the analgesic effect of Compound I-1 at a dose of 5 mg/kg (19 times) was equivalent to that of S-duloxetine at 20 mg/kg (21 times).
- This experiment shows that in the mouse acetic acid writhing pain model, the analgesic activity of the compound I-1 of the present invention is significantly better than the positive control drug.
- the mouse acetic acid writhing pain model is a classic model for evaluating the efficacy of drugs in treating visceral pain and inflammatory pain. Therefore, the compound I-1 of the present invention has an excellent therapeutic effect on visceral pain and inflammatory pain.
- the animals were acclimatized in the experimental environment for 15 minutes/day for 3 days.
- the rats were subjected to a baseline test of mechanical hyperalgesia, and animals that did not exhibit mechanical hyperalgesia (with the withdrawal threshold greater than 5g) were eliminated and randomly divided into 1 control group and 3 experimental groups.
- test fiber is used to test the center of the left hind foot of the rat.
- the test fiber includes 8 test strengths: 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), 4.31 (2g), 4.56 (4g), 4.74 (6g), 4.93 (8g), 5.18 (15g).
- the animal's rapid withdrawal of its feet was recorded as a pain response.
- the withdrawal of the animal's feet when the test fiber leaves the animal's skin is also recorded as a pain response. If the animal moves or walks, the pain response is not remembered and the test should be repeated.
- 4.31 (2g) If the animal has a pain response, use the test fiber with a lower strength in the next test; if the animal has no pain response, use the test fiber with a higher strength in the next test).
- the maximum strength of the tested fiber is 5.18 (15g).
- PWT withdrawal threshold
- the results of analgesic activity in the rat SNL model are shown in Table 5 and Figure 6. It can be seen from the results of Table 5 and Fig. 6 that, compared with the normal saline control group, the compound I-1 of the present invention exhibits a very strong analgesic effect at a dose of 10 mg/kg, with a significant difference. Compared with the positive control group, the analgesic activity of compound I-1 of the present invention is better than that of 100 mg/kg gabapentin and 10 mg/kg S-duloxetine one hour after administration.
- the rat SNL model is a classic model for evaluating the efficacy of drugs in the treatment of nerve pain. Therefore, the compound I-1 of the present invention has an excellent therapeutic effect on nerve pain.
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- DVS dynamic moisture adsorption
- the X-ray powder diffraction analysis method is: PANalytical X-ray powder diffraction analyzer, working voltage: 40kV, working current: 40mA, using Cu target to obtain X-ray powder diffraction pattern.
- DSC Differential scanning calorimetry
- TGA Thermogravimetric analysis
- the X-ray powder diffraction data of the hydrochloride crystal form A of the compound of formula I-1 is shown in Table 6, and the XRPD pattern is shown in Fig. 7, with the following characteristic peaks expressed in angle 2 ⁇ : 10.003, 11.171, 15.987, 16.734, 17.092, 18.173, 18.849, 20.681, 21.156, 21.649, 22.084, 22.794, 23.761, 25.298, 25.967, 26.640, 27.273, 28.099, 28.615, 28.813, 29.501, 30.118, 30.513, 32.522, 33.274, 34.081, 35.815, 37.553, 40.018, 42.927, 37.553, 40.018, 42.927 44.129.
- the differential scanning calorimetry (DSC) chart of the hydrochloride crystal form A is basically as shown in Figure 8, and an endothermic peak begins to appear when heated to 142.30°C.
- thermogravimetric analysis (TGA) chart of the hydrochloride crystal form A is basically shown in FIG. 9, with a weight loss of about 0.9827% when heated to 168.01°C.
- a dynamic moisture adsorption (DVS) instrument was used to test its hygroscopicity.
- the hydrochloride crystal form A of the compound of formula I-1 has a weight change of less than 0.2% under 25°C/80RH, indicating that it has no hygroscopicity and has excellent high humidity. Stability, which eliminates the need for storage and transportation under harsh dry conditions, thereby reducing storage and transportation costs. (Refer to the 2015 edition of Chinese Pharmacopoeia (Guiding Principles for Drug Hygroscopicity Test)).
- Bupivacaine injection purchased from Shanghai Zhaohui Pharmaceutical Co., Ltd.
- the solvent of the test compound I-1 is physiological saline, the administration dose is 10 mg/kg, and the administration mode is intramuscular injection. Weigh 36.13 mg of compound I-1, add 3.140 mL of physiological saline, and vortex until fully mixed.
- the reference compound set up in the experiment was bupivacaine injection, purchased from Shanghai Zhaohui Pharmaceutical Co., Ltd., with a dosage of 10 mg/kg and an intramuscular injection.
- mice Twenty-four hours after the operation, the rats were subjected to a baseline test of mechanical hyperalgesia. Animals that did not exhibit mechanical hyperalgesia (PWT greater than 5g) were eliminated and randomly grouped according to PWT. The experiment was divided into three groups, model control group (physiological saline group, intragastric administration of physiological saline), bupivacaine group (bupivacaine intramuscular injection dose of 10mg/kg) and compound I-1 group (compound The dosage of I-1 intramuscular injection is 10mg/kg). The rats in each group were tested for mechanical hyperalgesia at 1 hour and 2 hours after administration.
- model control group physiological saline group, intragastric administration of physiological saline
- bupivacaine group bupivacaine intramuscular injection dose of 10mg/kg
- compound I-1 group compound The dosage of I-1 intramuscular injection is 10mg/kg.
- the rats in each group were tested for mechanical hyperalgesia at 1 hour
- test fiber Place the rat alone in a plexiglass box with a grid on the bottom of the box to ensure that the rat's feet can be tested.
- the rats will acclimate for 15 minutes before testing.
- the test fiber is used to test the center of the left hind foot of the rat.
- the test fiber includes 8 test strengths: 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), 4.31 (2g), 4.56 (4g), 4.74 (6g), 4.93 (8g), 5.18 (15g).
- the animal's rapid withdrawal of its feet was recorded as a pain response.
- the withdrawal of the animal's feet when the test fiber leaves the animal's skin is also recorded as a pain response. If the animal moves or walks, the pain response is not remembered and the test should be repeated. In the test, first use 4.31 (2g). If the animal has a pain response, use the test fiber with a lower strength in the next test; if the animal has no pain response, use the test fiber with a higher strength in the next test). The maximum strength of the tested fiber is 5.18 (15g). The test results are recorded in the form, with pain response record x and no pain response record o.
- PWT withdrawal threshold
- the results of the analgesic activity of compound I-1 in the postoperative pain model of rats are shown in Table 8 and Figure 10. From the results of Table 8 and Figure 10, it can be seen that, compared with the normal saline control group, the compound I-1 of the present invention at a dose of 10 mg/kg, 1 hour and 2 hours after administration, showed very potent There are significant differences in analgesic effects. Compared with the positive drug bupivacaine, bupivacaine showed a stronger analgesic activity at 1 hour after administration, but no significant analgesic effect at 2 hours after administration, suggesting that compound I-1 is postoperative The pain model has a longer analgesic effect.
- the rat postoperative pain model is a classic model for evaluating the efficacy of drugs in the treatment of postoperative pain. Therefore, the compound I-1 of the present invention has an excellent therapeutic effect on postoperative pain.
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Abstract
Description
2θ值 | d值 | 相对强度% |
10.003 | 8.8355 | 28.3 |
11.171 | 7.9137 | 12.8 |
15.987 | 5.5392 | 15.2 |
16.734 | 5.2936 | 51.9 |
17.092 | 5.1836 | 35.7 |
18.173 | 4.8774 | 100.0 |
18.849 | 4.7041 | 12.7 |
20.681 | 4.2913 | 13.6 |
21.156 | 4.1961 | 65.2 |
21.649 | 4.1017 | 35.3 |
22.084 | 4.0217 | 71.9 |
22.794 | 3.8981 | 91.8 |
23.761 | 3.7416 | 65.0 |
25.298 | 3.5177 | 46.3 |
25.967 | 3.4285 | 11.5 |
26.640 | 3.3433 | 29.2 |
27.273 | 3.2672 | 16.9 |
28.099 | 3.1730 | 35.7 |
28.615 | 3.1170 | 33.1 |
28.813 | 3.0959 | 25.2 |
29.501 | 3.0253 | 10.4 |
30.118 | 2.9647 | 12.1 |
30.513 | 2.9272 | 13.2 |
32.522 | 2.7508 | 18.4 |
33.274 | 2.6904 | 12.4 |
34.081 | 2.6285 | 13.2 |
35.815 | 2.5051 | 13.4 |
37.553 | 2.3931 | 9.6 |
40.018 | 2.2512 | 8.2 |
42.927 | 2.1051 | 10.6 |
44.129 | 2.0505 | 9.0。 |
化合物 | 剂量 | PWT(g), |
对照组 | 3.967±0.775 | |
化合物I-1 | 10mg/kg | 7.869±2.846 |
S-度洛西汀 | 10mg/kg | 6.519±2.226 |
加巴喷丁 | 100mg/kg | 6.352±1.897 |
2θ值 | d值 | 相对强度% |
10.003 | 8.8355 | 28.3 |
11.171 | 7.9137 | 12.8 |
15.987 | 5.5392 | 15.2 |
16.734 | 5.2936 | 51.9 |
17.092 | 5.1836 | 35.7 |
18.173 | 4.8774 | 100.0 |
18.849 | 4.7041 | 12.7 |
20.681 | 4.2913 | 13.6 |
21.156 | 4.1961 | 65.2 |
21.649 | 4.1017 | 35.3 |
22.084 | 4.0217 | 71.9 |
22.794 | 3.8981 | 91.8 |
23.761 | 3.7416 | 65.0 |
25.298 | 3.5177 | 46.3 |
25.967 | 3.4285 | 11.5 |
26.640 | 3.3433 | 29.2 |
27.273 | 3.2672 | 16.9 |
28.099 | 3.1730 | 35.7 |
28.615 | 3.1170 | 33.1 |
28.813 | 3.0959 | 25.2 |
29.501 | 3.0253 | 10.4 |
30.118 | 2.9647 | 12.1 |
30.513 | 2.9272 | 13.2 |
32.522 | 2.7508 | 18.4 |
33.274 | 2.6904 | 12.4 |
34.081 | 2.6285 | 13.2 |
35.815 | 2.5051 | 13.4 |
37.553 | 2.3931 | 9.6 |
40.018 | 2.2512 | 8.2 |
42.927 | 2.1051 | 10.6 |
44.129 | 2.0505 | 9.0 |
3.61 | ||||||
3.84 | ||||||
4.08 | ||||||
4.31 | o | |||||
4.56 | o | o | o | |||
4.74 | x | x | x | |||
4.93 | ||||||
5.18 |
Claims (14)
- 一种化合物,或其药学上可接受的盐、或其前药,其特征在于,所述化合物具有式Z结构:式中:环A为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳环;R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基;X为氧原子、硫原子或氮原子;R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基;n为1、2或3;“*”表示化合物的构型为外消旋体;其中,所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代:C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、六元的芳基、五元或六元的杂芳基(优选C 5杂芳基);其中,所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
- 一种化合物,或其药学上可接受的盐、或其前药,其特征在于,所述化合物具有式I结构:式中:环A为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳环;R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基;X为氧原子、硫原子或氮原子;R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基;n为1、2或3;其中,所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代:C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、六元的芳基、五元或六元的杂芳基(优选C 5杂芳基);其中,所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
- 如权利要求5所述的式I-1化合物的盐酸盐晶型A,其特征在于,所述式I-1化合物的盐酸盐晶型A还在1个或多个选自下组的2θ值处具有特征峰:10.003±0.2°、11.171±0.2°、15.987±0.2°、16.734±0.2°、17.092±0.2°、18.849±0.2°、20.681±0.2°、21.156±0.2°、21.649±0.2°、23.761±0.2°、25.298±0.2°、25.967±0.2°、26.640±0.2°、27.273±0.2°、28.099±0.2°、28.615±0.2°、28.813±0.2°、29.501±0.2°、30.118±0.2°、30.513±0.2°、32.522±0.2°、33.274±0.2°、34.081±0.2°、35.815±0.2°、37.553±0.2°、40.018±0.2°、42.927±0.2°、44.129±0.2。
- 如权利要求5所述的式I-1化合物的盐酸盐晶型A,其特征在于,所述的盐酸盐晶型A的X-射线粉末衍射图谱具有选自下组的2θ值处的特征峰和峰强度:
2θ值 d值 相对强度% 10.003 8.8355 28.3 11.171 7.9137 12.8 15.987 5.5392 15.2 16.734 5.2936 51.9 17.092 5.1836 35.7 18.173 4.8774 100.0 18.849 4.7041 12.7 20.681 4.2913 13.6 21.156 4.1961 65.2 21.649 4.1017 35.3 22.084 4.0217 71.9 22.794 3.8981 91.8 23.761 3.7416 65.0 25.298 3.5177 46.3 25.967 3.4285 11.5 26.640 3.3433 29.2 27.273 3.2672 16.9 28.099 3.1730 35.7 28.615 3.1170 33.1 28.813 3.0959 25.2 29.501 3.0253 10.4 30.118 2.9647 12.1 30.513 2.9272 13.2 32.522 2.7508 18.4 33.274 2.6904 12.4 34.081 2.6285 13.2 35.815 2.5051 13.4 37.553 2.3931 9.6 40.018 2.2512 8.2 42.927 2.1051 10.6 44.129 2.0505 9.0。 - 如权利要求5所述的式I-1化合物的盐酸盐晶型A,其特征在于,所述的式I-1化合物的盐酸盐晶型A包括选自下组的一种或多种特征:(i)所述式I-1化合物的盐酸盐晶型A具有基本如图7所示的X-射线粉末衍射特征峰;(ii)所述式I-1化合物的盐酸盐晶型A的差示扫描量热分析(DSC)图在加热至142.30℃(较佳地±4℃、±3℃、±2℃或±1℃)开始出现吸热峰;(iii)所述式I-1化合物的盐酸盐晶型A的差示扫描量热分析(DSC)图基本如图8所示;(iv)所述式I-1化合物的盐酸盐晶型A的热重分析(TGA)图在加热至168.01℃时具有约0.9827%(较佳地±0.1%、±0.2%、±0.3%、±0.4%、或±0.5%)的重量损失;和/或(v)所述盐酸盐晶型A的热重分析(TGA)图基本如图9所示。
- 一种如权利要求1所述的式Z化合物、或其药学上可接受的盐、或其前药或,如权利要求3所述的式I化合物,或其药学上可接受的盐、或其前药,或如权利要求5所述的式I-1化合物的盐酸盐晶型A的用途,其特征在于,用于(a)制备瞬时受体电位通道蛋白(TRPA1)抑制剂;(b)制备预防和/或治疗与瞬时受体电位通道蛋白(TRPA1)相关的疾病的药物。
- 如权利要求9所述的用途,其特征在于,与瞬时受体电位通道蛋白(TRP)相关的疾病选自下组:疼痛、癫痫、炎症、呼吸障碍、瘙痒、尿路障碍、炎症性肠病,或其组合。
- 如权利要求10所述的用途,其特征在于,所述的疼痛选自下组:急性疼痛、炎性疼痛、内脏疼痛、神经源性疼痛、肌纤维疼痛、头痛、神经疼痛、混合疼痛、癌症引起疼痛,或其组合;
- 如权利要求11所述的用途,其特征在于,所述的急性疼痛为损伤疼痛或术后疼痛;和/或所述的炎性疼痛为骨关节炎痛或风湿性关节炎痛。
- 一种药物组合物,其特征在于,所述的药物组合物包括如权利要求1所述的式Z化合物、或其药学上可接受的盐、或其前药或,如权利要求3所述的式I化合物,或其药学上可接受的盐、或其前药,或如权利要求5所述的式I-1化合物的盐酸盐晶型A;和药学上可接受的载体。
- 一种抑制瞬时受体电位通道蛋白或预防和/或治疗与瞬时受体电位通道蛋白(TRP)相关的疾病的方法,给需要的对象施用如权利要求1所述的式Z化合物、或其药 学上可接受的盐、或其前药或,如权利要求3所述的式I化合物,或其药学上可接受的盐、或其前药,或如权利要求5所述的式I-1化合物的盐酸盐晶型A。
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