WO2024037564A1 - Phenothiazine compound and use thereof - Google Patents
Phenothiazine compound and use thereof Download PDFInfo
- Publication number
- WO2024037564A1 WO2024037564A1 PCT/CN2023/113346 CN2023113346W WO2024037564A1 WO 2024037564 A1 WO2024037564 A1 WO 2024037564A1 CN 2023113346 W CN2023113346 W CN 2023113346W WO 2024037564 A1 WO2024037564 A1 WO 2024037564A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- stereoisomer
- acceptable salt
- solvate
- Prior art date
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- -1 Phenothiazine compound Chemical class 0.000 title description 16
- 229950000688 phenothiazine Drugs 0.000 title description 2
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- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000002207 metabolite Substances 0.000 claims abstract description 41
- 239000012453 solvate Substances 0.000 claims abstract description 41
- 229940002612 prodrug Drugs 0.000 claims abstract description 40
- 239000000651 prodrug Substances 0.000 claims abstract description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 35
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- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 25
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
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- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
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- WCYAALZQFZMMOM-UHFFFAOYSA-N methanol;sulfuric acid Chemical compound OC.OS(O)(=O)=O WCYAALZQFZMMOM-UHFFFAOYSA-N 0.000 description 1
- YICRPERKKBDRSP-UHFFFAOYSA-N methyl 3-amino-4-methylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(C)C=1N YICRPERKKBDRSP-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 210000004357 third molar Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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
- C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
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- 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
- C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention belongs to the field of biomedicine, and specifically relates to a phenothiazine compound and its use.
- Local anesthetics are a type of drugs that can reversibly block the generation and transmission of sensory nerve impulses in the local area where they are administered, referred to as "local anesthetics".
- the effects of local anesthetics are localized to the site of administration and disappear rapidly as the drug spreads from the site of administration.
- Local anesthetics produce local anesthesia by directly inhibiting related ion channels on nerve cells and fiber membranes, blocking the generation of action potentials and the conduction of nerve impulses.
- the currently recognized mechanism of action of local anesthetics is to block voltage-gated Na + channels on the nerve cell membrane, blocking nerve impulse conduction, thereby producing local anesthesia.
- Local anesthetics currently used clinically are hydrophobic compounds without charge, so they can easily enter nerve cells through the cell membrane through diffusion and penetration to reach the blocking site of sodium channels. These anesthetics block sodium channels and thereby block neuronal excitability.
- these local anesthetic molecules easily diffuse into nerve cells to exert their effects, they are also easy to spread rapidly from the administration site through diffusion and free nerve cells, resulting in local anesthetic effects that cannot be sustained for a long time. Even if the dosage is increased, the local anesthesia time can only be prolonged to a certain extent. These local anesthetic drugs cannot achieve the ideal long-term local anesthesia effect.
- Most of the local anesthetics currently commonly used clinically have an action time of no more than 4 hours. Due to the short duration of the effect of traditional local anesthetics, analgesic pumps have to be used to maintain nerve block, and catheters are placed in the spinal canal, nerve roots, subcutaneous and other locations, which greatly increases medical costs and the incidence of infection.
- Oral local anesthetics are generally used for minor outpatient surgeries such as tooth extractions, dental implants, root canal treatments, subgingival scaling and root planing, etc.
- the most common anesthesia methods are infiltration anesthesia and block anesthesia. These characteristics require local anesthetics to have a rapid onset of action, moderate duration, and low toxicity. Therefore, moderately effective local anesthetics such as lidocaine, mepivacaine, prilocaine, and articaine have become reasonable choices.
- articaine is the most widely used local anesthetic in oral treatment and the most powerful amide anesthetic. Its structure is as follows:
- articaine is similar to nitric oxide in that it has a vasodilatory effect and promotes its systemic absorption, but the anesthesia time is limited. Therefore, in order to prolong anesthesia time, reduce anesthetic dosage and reduce To reduce bleeding and improve visualization of the surgical field, epinephrine should be added to local anesthetics in clinical practice. However, the addition of epinephrine limits the application of articaine in special patients such as children, women, patients with cardiovascular and cerebrovascular diseases, diabetes, and hyperthyroidism. At the same time, local vasoconstriction caused by epinephrine may lead to nerve and soft tissue ischemia and functional impairment. Although most literature acknowledges that epinephrine has a safe range, its concentration threshold remains unclear. Therefore, given the increasing number of patients with potential cardiovascular risks in an aging society, traditional local anesthetics cannot meet the needs of all dental procedures.
- the oral cavity and maxillofacial region are the most complex areas of human anatomy. The rich blood vessels and the long-term presence of various flora in the oral cavity and teeth make the oral cavity more complex.
- the maxillofacial region is prone to odontogenic inflammatory reactions, the most common of which is wisdom tooth pericoronitis. These inflammatory reactions can cause great pain to patients. However, clinically, most of them need to control the inflammatory reaction first.
- the inflammation can be eliminated as soon as possible through pericoronal irrigation and the use of antibiotics. After the inflammation is eliminated, the source tooth should be extracted or otherwise treated. This is because local anesthetics cannot function normally in an inflammatory state. When some patients with acute inflammatory conditions require emergency surgical intervention, they will suffer great pain during and after the operation. If the local anesthetic can play a stable role at this time, the pain caused by the treatment operation will be greatly relieved.
- the object of the present invention is to provide a novel compound for local anesthesia.
- R 4 is a C 1 to 8 hydrocarbon group, a C 1 to 8 alkoxy group, a 3 to 8 membered ring hydrocarbon group, a phenyl group or a benzyl group;
- R 1 is a C 1 to 8 hydrocarbon group
- R 2 and R 3 are connected to form ring A:
- R a , R b , R c , R d , R e , R f , R g , and R h are independently selected from H, halogen, substituted or unsubstituted: C 1 to 8 hydrocarbyl, C 1 to 8 alkoxy group or 3 to 8 membered ring hydrocarbon group;
- M is NR 5 , L is a C 3-4 alkane chain and R 5 is H, or L is a C 1-4 alkane chain and R 5 is substituted Or unsubstituted C 1 to 8 hydrocarbon groups, C 1 to 8 alkoxy groups, 3 to 8 membered ring hydrocarbon groups, phenyl or benzyl groups; the number of substituted substituents is 1 to 3, and the substituents are respectively Independently selected from hydroxyl, halogen, amino, C 1 to 8 alkoxy group, 3 to 8 membered ring hydrocarbon group or C 1 to 8 ester group; and Ring A is When, L is not a methylene chain; or, M is O, CH 2 , S, SO or SO 2 , and L is a C 2 to 4 branched alkane chain;
- R 1 is a C 1 to 8 linear alkyl group
- R 2 is a C 1 to 3 linear alkyl group.
- R 3 is hydrogen, unsubstituted or substituted by 1 to 3 hydroxyl groups or C 1 to 4 alkoxy groups C 1 ⁇ 8 alkyl
- L is C 1 ⁇ 4 alkane chain
- R 1 is isobutyl
- R 2 and R 3 are independently selected from hydrogen, substituted or unsubstituted C 1 to 8 hydrocarbon groups, or substituted or unsubstituted C 1 to 8 alkoxy groups, and the substituted The number of groups is 1 to 5, and the substituents are independently selected from hydroxyl or C 1 to 4 alkoxy groups
- L is a C 1 to 4 alkane chain.
- R 4 is methyl
- R 1 is a C 1-8 alkyl group and R 2 and R 3 are connected to form Ring A; preferably, R 1 is methyl, and R 2 and R 3 are connected to form Ring A.
- R a , R b , R c , R d , Re , R f , R g , and Rh are independently selected from H or C 1 to 8 alkyl groups, preferably H or methyl.
- M is NR 5
- L is a C 3-4 alkane chain and R 5 is H, or, L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-8 alkyl group, 3- 8-membered ring alkyl or phenyl; the number of substituted substituents is 1 or 2, and the substituents are independently selected from hydroxyl, C 1 to 4 alkoxy or C 1 to 8 ester groups; and the ring A is When , L is not a methylene chain.
- M is NR 5
- L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-4 alkyl group, cyclopropyl group or phenyl group; the number of substituted substituents is 1 , the substituent is hydroxyl, methoxy or methyl ester; and ring A is When , L is not a methylene chain.
- the compound has the structure shown in Formula IA:
- the compound has the structure shown in formula IA-1 or 1-A-2:
- the compound has the structure shown in formula IA-3:
- R 5 is selected from C 1 to 4 alkyl groups.
- the compound has the structure shown in formula IB:
- the compound has a structure represented by Formula IB-1, Formula IB-2, Formula IB-3 or Formula IB-4:
- the compound has the structure shown in formula IC:
- the compound has the structure shown in formula IC-1:
- the compound has the structure shown in formula ID:
- the compound has the structure shown in formula ID-1:
- the compound has the structure shown in formula IE:
- the compound has the structure shown in formula ID-1:
- the compound has a structure represented by formula IF:
- the compound has the structure shown in formula IF-1:
- R 1 is a C 1-8 linear alkyl group, and R 2 is replaced by 1 hydroxyl, Amino group, C 1 to 4 alkoxy group or C 1 to 4 alkylamino substituted C 1 to 3 alkyl group, R 3 is hydrogen, unsubstituted or C 1 substituted by 1 hydroxyl group or C 1 to 4 alkoxy group ⁇ 3 alkyl; L is a C 1 ⁇ 4 alkane chain.
- R 1 is isobutyl
- R 2 and R 3 are each independently selected from hydrogen or C 1-8 alkyl
- L is a C 1-4 alkane chain.
- the present invention also provides a compound represented by Formula II, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated compound thereof:
- L ⁇ is a C 1 to 4 alkane chain
- R 5 is C 1 ⁇ 8 alkyl
- k is selected from 0, 1, 2 or 3.
- L ⁇ is a first ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
- R 5 is a C 1-4 alkyl group
- R 6 is a C 1-4 alkyl group
- X ⁇ is O, S, CH 2 , NR 7
- R 7 is R i substituted or unsubstituted C 1 to 4 alkyl group or phenyl group
- R i is hydroxyl group, 3 to 6 membered ring hydrocarbon group, C 1 to 4 alkoxy group or C 1 to 4 ester group.
- R 6 is methyl
- X is O, S, NR 7
- R 7 is R i substituted or unsubstituted C 1 to 4 hydrocarbon group or phenyl group
- R i is hydroxyl, cyclopropyl, methoxy or methyl ester group.
- the compound has a structure shown in any one of Formula II-A to Formula II-F:
- the compound has a structure shown in any one of Formula II-G to Formula II-M:
- the compound has a structure shown in any one of Formula II-G to Formula II-M:
- the compound has any of the following structures:
- the pharmaceutically acceptable salt is formed from a compound represented by Formula I and a pharmaceutically acceptable inorganic acid or organic acid;
- the inorganic acid or organic acid is hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid or benzoic acid. .
- the present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated compounds thereof, in the preparation of anesthetic drugs.
- the anesthetic drug is a local anesthetic drug.
- the present invention also provides the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated compounds thereof, in the preparation of anti-inflammatory drugs. use in.
- the present invention also provides a medicine, which is based on the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium
- a medicine which is based on the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium
- the compound of the present invention has a rapid onset of action when used for local anesthesia, and the anesthetic action time is prolonged after a single administration.
- the compound of the present invention has The local anesthetic effect time can be significantly extended to 4 hours; at the same time, the compound of the present invention can still exert a long-lasting local anesthetic effect in an inflammatory state, which is comparable to the local anesthetic effect of articaine of 0.5 hours in an inflammatory state.
- the local anesthetic effect time of the compound of the present invention under inflammatory conditions can be significantly extended to 1 hour.
- the compound of the present invention has a long local anesthetic effect in both infiltration anesthesia and block anesthesia, solves the side effect problem of current local anesthetic drugs used in combination with epinephrine, and has better safety.
- the compound of the present invention can be used to prepare safe drugs with long-term local anesthesia, and has the advantages of long local anesthetic effect, less nerve damage, and high safety.
- alkane chain refers to an alkyl chain formed by removing two hydrogen atoms from a linear or branched alkane.
- Alkyl refers to a straight-chain or branched alkyl group, that is, a group formed by removing one hydrogen atom from a straight-chain or branched alkane.
- C 1-8 ester group refers to RCOO-, where R is C 1-8 alkyl group, and the methyl ester group is CH 3 COO-.
- C 1-4 alkylamino refers to RNH-, where R is C 1-4 alkyl.
- the raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.
- Step 1 Dissolve 3-amino-4-methylthiophene-2-carboxylic acid methyl ester (20.0g, 116.8mmol) in 100mL DCM, add potassium carbonate (32.3g, 233.6mmol), and then incubate at -20°C Add 2-bromopropionyl bromide (32.8g, 151.9mmol) previously dissolved in 20mL DCM and stir at room temperature for 24h. After the reaction was completed, the mixture was washed with water (100 mL ⁇ 3), and the organic phase was collected and dried over anhydrous sodium sulfate.
- Step 2 Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (10.0g, 32.7mmol) in 30mL DMF, and add potassium carbonate (3.86g, 65.3mmol) Propylamine (3.86g, 65.3mmol) was added dropwise. Then stir at room temperature for 5 h. After the reaction is completed, dilute with 200 mL DCM, wash with water (200 mL ⁇ 4), collect the organic phase and dry it over anhydrous sodium sulfate. Filter, dry and concentrate.
- Step 3 Dissolve compound 4-methyl-3-(2-(propylamino)propionamido)thiophene-2-carboxylic acid methyl ester (5.0g, 17.6mmol) in 20mL MeOH, add dropwise and pre-dissolve in 14mL sodium hydroxide (1.4g, 35.2mmol) in water, and then the reaction solution was stirred at 50°C for 2h. After the reaction is completed, concentrate under reduced pressure, and the residue is dissolved in 100 mL of water and washed with 100 mL of DCM. The aqueous phase is then adjusted to pH 7 with hydrochloric acid (2M), and then the aqueous phase is extracted with ethyl acetate.
- 2M hydrochloric acid
- Step 4 Dissolve 4-methyl-3-(2-propylaminopropionamido)thiophene-2-carboxylic acid (500 mg, 1.85 mmol) in 20 mL DMF, add sodium bicarbonate (311 mg, 3.70 mmol), and then cool to room temperature. Isobutyl chloride (340 mg, 3.7 mmol) was added dropwise at 50°C for 5 h. After the reaction was completed, it was diluted with 200 mL DCM and washed four times with 100 mL water. The organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate.
- the reaction steps were the same as in Example 2.
- the product was a white oily substance with a yield of 21.0%.
- Step 1 Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (2.0g, 6.53mmol) in a mixed solvent of 15mL DMF and 15mL ACN, add potassium carbonate ( 1.81g, 13.06mmol), piperazine-1-carboxylic acid tert-butyl ester (1.46g, 7.84mmol), and then stirred at room temperature for 9h. After the reaction was completed, concentrated in vacuo, the residue was dissolved in 100mL DCM, and washed 4 times with 100mL water. . The organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate.
- Step 2 Combine 4-(1-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-1-oxoprop-2-yl)piperazine-1-carboxylic acid Butyl ester (2.68g, 6.51mmol) was dissolved in 10mL dioxane, hydrogen chloride dioxane solution (4M; 4mL, 16mmol) was added dropwise, reacted at room temperature for 5h, and filtered. After washing the filter cake with dioxane, the product 4-methyl-3-(2-(piperazin-1-yl)propionamido)thiophene-2-carboxylic acid methyl ester (2.0g, 79.8%) is white. solid.
- the aqueous phase is washed with DCM, and then washed with 2 M hydrochloric acid.
- the pH of the aqueous phase was adjusted to 10-11 with M sodium hydroxide solution, and the aqueous phase was extracted with DCM.
- the organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate.
- the product 3-(2-(4-isopropylpiperazin-1-yl)propionamido)-4-methylthiophene-2-carboxylic acid methyl ester (5.4 g, 97.8%) was obtained as a colorless oil.
- Step 1 The reaction procedure is the same as step 1 in Example 1, white solid, yield 88.8%.
- Step 2 Same as Example 2, the product is colorless oil, and the yield is 46.3%.
- Step 1 The reaction procedure is the same as step 1 in Example 1, white solid, yield 87.0%.
- Step 2 Same as Example 2, the product is colorless oil, and the yield is 28.7%.
- Example 2 Dissolve 3-(2-(4-ethylpiperazin-1-yl)propionamido)-4-methylthiophene-2-carboxylic acid methyl ester in methanol and drop it at room temperature. Add hydrochloric acid solution, stir at room temperature for 1 hour and then spin to dryness. The residue is dissolved in water and filtered to remove impurities. The filtrate is freeze-dried to obtain the hydrochloride salt of the product.
- reaction conditions in the preparation process of the above compounds are the same as those in Example 1, except that the corresponding raw materials are replaced according to the differences in substituents.
- Dissolve 1a (20.0g, 116.80mmol) in 100mL dichloromethane (DCM), add 23.6g triethylamine, and add dropwise 2-bromopropionyl bromide (27.7g, 128.5mmol) dissolved in 20mL DCM at 0°C.
- the reaction was stirred at room temperature for 12 h, and TLC was used to monitor the reaction.
- extract with DCM dry the organic phase with anhydrous sodium sulfate, filter and spin the solvent to dryness under reduced pressure. 33.2g of off-white solid powder 1c was obtained, with a yield of 93%.
- Dissolve 2c (1.0g, 2.95mmol) in 20mL MeOH, add sodium hydroxide solution, stir at 50°C for 2h, and monitor the reaction to be complete by TLC. After filtration, the solvent was evaporated to dryness under reduced pressure. Dissolve the solid in 50 mL of water, extract with n-butanol (50 mL 5.89mmol), reacted at room temperature for 5 hours, and TLC monitored the reaction to be complete. Add 100 mL DCM, wash 3 times with 200 mL water, dry the organic phase with anhydrous sodium sulfate, and evaporate the solvent to dryness under reduced pressure. Purification by column chromatography yielded 750 mg of colorless oil 2, with a yield of 72%.
- Example 109 Dissolve 1.0 g of the product of Example 109 in 15 mL of methanol, add an equal amount of 0.1 mol/L sulfuric acid-methanol solution dropwise in an ice bath, and concentrate to dryness under reduced pressure. The residue was dissolved in water and filtered, and the filtrate was freeze-dried under vacuum to obtain a white solid (5).
- reaction conditions in the preparation process of the above compounds are the same as those in Example 107, except that the corresponding raw materials are replaced according to the differences in substituents.
- Examples 1 to 168 The compounds prepared in Examples 1 to 168 (compounds 1 to 168) were selected, and the articaine positive control group was administered to 8 groups of test rats that were fully adapted to the experimental environment, with 6 rats in each group.
- the dosage is: the concentration of articaine group is 2% aqueous solution, and the concentration of the drug to be tested is 62mmol/L physiological saline solution.
- each rat for administration or control was 0.5 ml, guided and positioned by a nerve locator, and injected near the sciatic nerve of the rat.
- the von Frey stimulator was used to stimulate the sole of the rat's side of the body where the drug was injected, and the local anesthesia effect was observed.
- the motor function of the rat was evaluated by the Postural Extensor Thrust (PET) test: the rat was lifted vertically and the injected hindlimb was pedaled on the electronic platform. At this time, the muscle strength of the rat's hindlimb was determined by the limb pedaling balance. The numerical value displayed indicates. When the limb is completely paralyzed, the reading is the weight of the limb itself, about 20g. A measurement value exceeding half of the difference between baseline and limb weight is considered recovery of motor function, and a value less than or equal to this value is considered loss of motor function.
- mice ranging from 18.0g to 21.0g were randomly selected for mouse tail vein LD 50 measurement, and the experiment adopted the sequential method. Gently wipe the mouse tail with a 75% alcohol cotton ball to soften the mouse tail cuticle, expand the tail vein, and inject different concentrations of drugs through the tail vein with a syringe. The administration speed is 10-15 seconds, and the total volume of injected liquid does not exceed 1.0 mL. According to the pre-experiment results, another three doses are set according to the geometric sequence between the highest dose (i.e. the minimum value of a certain lethal dose) and the lowest dose (i.e. the maximum value of a non-lethal dose), with a total of five dose groups.
- the highest dose i.e. the minimum value of a certain lethal dose
- the lowest dose i.e. the maximum value of a non-lethal dose
- the dose between groups The ratio is preferably 1:0.6 to 1:0.85.
- Begin administration with an intermediate dose Observe the death of mice. If the mouse does not die, the next mouse will be given a higher dose; if the mouse dies, the next rat will be given a lower dose; and so on until 6 crossovers occur in the same direction and the experiment ends.
- the center group d (group distance) is 0, and as the dose increases, it is 1, 2, and as the dose decreases, it is -1, -2;
- a is the number of positives at the corresponding dose;
- N and A represent the sum of a and ad respectively.
- mice LD 50 value of this type of drug is higher than that of the positive drug articaine, indicating that this type of compound is safer than articaine.
- the drugs of Examples 1 to 168 were selected, and the articaine positive control group was administered to test rats that were fully adapted to the experimental environment, with 8 rats in each group.
- the dosage is: articaine 2% aqueous solution, and the concentration of the drug to be tested is 62mmol/L aqueous solution.
- the injection volume of each rat for administration or control was 0.5 mL, and it was injected near the sciatic nerve of the rat.
- the experimental rats were euthanized by cardiac injection of bupivacaine under isoflurane anesthesia. About 1.5cm of the sciatic nerve at the injection site was taken, stored in 10% formaldehyde solution for 48 hours, HE stained and cut into 5 ⁇ m thick sections.
- Neuropathological damage assessment showed that: compared with the articaine positive control group, the drugs of Examples 1 to 168 had no significant differences in nerve damage, vascular proliferation, degree of demyelination, muscle inflammation, and degree of connective tissue inflammation. Good security.
- the drugs of Examples 1 to 168 were selected, and the articaine positive control group was administered to test rats that were fully adapted to the experimental environment, with 8 rats in each group. After 48 hours of injection of CFA (complete Freund's adjuvant) into the right foot of each rat, significant swelling of the foot was observed and the paw withdrawal threshold of the rat's right hind paw was significantly reduced as measured by the VonFrey stimulator. At this time, subcutaneous administration of CFA can be performed on the foot. medicine.
- the dosage is: articaine 2% aqueous solution, and the concentration of the drug to be tested is 62mmol/L aqueous solution.
- the injection volume of each rat for administration or control was 0.2 mL, which was injected subcutaneously into the swollen part of the rat's sole.
- the von Frey stimulator was used to stimulate the sole of the rat's side of the body where the drug was injected, and the local anesthesia effect was observed. Testing is performed every 10 minutes after the onset of effect. If the measured value exceeds half of the difference between the limb weight and the baseline, it is considered the anesthesia has taken effect. If the value is less than or equal to this value, it is considered the anesthesia has failed.
- Seed 1*10 ⁇ 5 cells (DRG primary cells) in a 6-well plate. After 24 hours of adhesion, the two cells were divided into 3 groups. The first group was treated with complete culture medium for 48 hours, and the second group was treated with 1ug first. /ml LPS for 24 hours, and then replaced with complete medium for 24 hours. The third group was first treated with 1ug/ml LPS for 24 hours, and then replaced with complete medium containing 1mM of the compound of the present invention for 24 hours. RNA was extracted from cells in each group, and after reverse transcription into cDNA, RT-QPCR method was used to detect the expression changes of inflammatory factors (IL1 ⁇ , IL6, TNF ⁇ ) in each group.
- IL1 ⁇ IL1 ⁇ , IL6, TNF ⁇
- the compound of the present invention has a rapid onset of action when used for local anesthesia, prolongs the anesthetic effect after a single administration, and has a long local anesthetic effect in both infiltration anesthesia and block anesthesia, solving the problems of current local anesthetic drugs. There are no side effects when combined with epinephrine during use, and it has better safety.
- the compound of the present invention can be used to prepare safe drugs with long-term local anesthesia, and has the advantages of long local anesthetic effect, less nerve damage, high safety, and can produce anti-inflammatory effects.
Abstract
The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated compound thereof. The compound of the present invention takes effect quickly when being used for local anesthesia, the anesthesia effect lasts longer after single administration, and in infiltration anesthesia and block anesthesia, the compound has a long local anesthesia effect even in an inflammatory state, thereby solving the problem of side effects caused by the current use of local anesthetics combined with adrenaline, and achieving better safety. The compound provided by the present invention can be used for preparing safe and long-lasting local anesthetics, and has the advantages of a long local anesthesia effect, less nerve damage, high safety and an anti-inflammatory effect.
Description
本发明属于生物医药领域，具体涉及一种酚噻嗪类化合物及其用途。The invention belongs to the field of biomedicine, and specifically relates to a phenothiazine compound and its use.
局部麻醉药(Local anesthetics，局麻药)是一类能在用药局部可逆性的阻断感觉神经冲动发生与传递的药品，简称“局麻药”。在动物或人意识清醒的条件下，在局部可逆的阻断感觉神经冲动产生与信号传导，使有关神经支配的部位出现暂时性感觉丧失，从而可逆的引起局部组织痛觉消失的一类药物。一般的，局麻药的作用局限于给药部位并随药物从给药部位扩散而迅速消失。局部麻醉药通过直接抑制神经细胞和纤维膜上的相关离子通道，阻滞动作电位的产生和神经冲动的传导，从而产生局部麻醉作用。目前公认的局麻药作用机制，是阻断神经细胞膜上的电压门控性Na+通道，使神经冲动传导阻滞，从而产生局部麻醉作用。Local anesthetics (local anesthetics) are a type of drugs that can reversibly block the generation and transmission of sensory nerve impulses in the local area where they are administered, referred to as "local anesthetics". A class of drugs that locally and reversibly blocks the generation and signal conduction of sensory nerve impulses when animals or humans are conscious, causing temporary sensory loss in the areas innervated by the nerves, thereby reversibly causing the loss of pain in local tissues. Generally, the effects of local anesthetics are localized to the site of administration and disappear rapidly as the drug spreads from the site of administration. Local anesthetics produce local anesthesia by directly inhibiting related ion channels on nerve cells and fiber membranes, blocking the generation of action potentials and the conduction of nerve impulses. The currently recognized mechanism of action of local anesthetics is to block voltage-gated Na + channels on the nerve cell membrane, blocking nerve impulse conduction, thereby producing local anesthesia.
临床目前所使用的局麻药均为不具备电荷的疏水性化合物，因此容易通过扩散和渗透方式通过细胞膜进入神经细胞达到钠通道的阻断位点。这些麻醉药阻断钠通道从而阻断神经元的兴奋性。实际上，这些局部麻醉药分子虽然容易通过扩散进入神经细胞内发挥作用，但同时也容易通过扩散作用从给药部位迅速扩散，游离出神经细胞，导致局部麻醉作用无法长时间持续。即使加大使用剂量也只能在一定程度内延长局部麻醉时间，这些局部麻醉药物，无法获得理想的长时间局部麻醉作用。目前临床常用的局部麻醉药物作用时间大多不超过4小时。由于传统局部麻醉药的作用维持时间较短，不得不使用镇痛泵来维持神经阻滞，采取椎管内、神经根、皮下等部位的置管，大大增加了医疗成本和感染的发生率。Local anesthetics currently used clinically are hydrophobic compounds without charge, so they can easily enter nerve cells through the cell membrane through diffusion and penetration to reach the blocking site of sodium channels. These anesthetics block sodium channels and thereby block neuronal excitability. In fact, although these local anesthetic molecules easily diffuse into nerve cells to exert their effects, they are also easy to spread rapidly from the administration site through diffusion and free nerve cells, resulting in local anesthetic effects that cannot be sustained for a long time. Even if the dosage is increased, the local anesthesia time can only be prolonged to a certain extent. These local anesthetic drugs cannot achieve the ideal long-term local anesthesia effect. Most of the local anesthetics currently commonly used clinically have an action time of no more than 4 hours. Due to the short duration of the effect of traditional local anesthetics, analgesic pumps have to be used to maintain nerve block, and catheters are placed in the spinal canal, nerve roots, subcutaneous and other locations, which greatly increases medical costs and the incidence of infection.
由于口腔门诊手术的操作特点，局麻药的应用十分广泛。口腔局麻药一般用于门诊的小手术如牙拔除术、牙种植术、根管治疗术及龈下洁治根面平整术等，麻醉方式以浸润麻醉和阻滞麻醉最为多见。这些特点要求局麻药起效快，持续时间适中且毒性小，因此，中效局麻药如利多卡因、甲哌卡因、丙胺卡因和阿替卡因等成为了合理的选择。其中，阿替卡因是目前口腔治疗中最为广泛使用的局麻药，也是效能最强的酰胺类麻醉药，结构如下：
Due to the operational characteristics of oral outpatient surgery, local anesthetics are widely used. Oral local anesthetics are generally used for minor outpatient surgeries such as tooth extractions, dental implants, root canal treatments, subgingival scaling and root planing, etc. The most common anesthesia methods are infiltration anesthesia and block anesthesia. These characteristics require local anesthetics to have a rapid onset of action, moderate duration, and low toxicity. Therefore, moderately effective local anesthetics such as lidocaine, mepivacaine, prilocaine, and articaine have become reasonable choices. Among them, articaine is the most widely used local anesthetic in oral treatment and the most powerful amide anesthetic. Its structure is as follows:
Due to the operational characteristics of oral outpatient surgery, local anesthetics are widely used. Oral local anesthetics are generally used for minor outpatient surgeries such as tooth extractions, dental implants, root canal treatments, subgingival scaling and root planing, etc. The most common anesthesia methods are infiltration anesthesia and block anesthesia. These characteristics require local anesthetics to have a rapid onset of action, moderate duration, and low toxicity. Therefore, moderately effective local anesthetics such as lidocaine, mepivacaine, prilocaine, and articaine have become reasonable choices. Among them, articaine is the most widely used local anesthetic in oral treatment and the most powerful amide anesthetic. Its structure is as follows:
然而阿替卡因也存在在一些亟待解决的问题：However, articaine also has some problems that need to be solved:
一方面，阿替卡因与一氧化氮类似，都具有血管舒张作用，促进了其全身吸收，但麻醉时间有限。因此，为了延长麻醉时间、减少麻醉药用量和减
少出血，提高术野的可视化程度，临床要在局麻药中加入肾上腺素。但肾上腺素的加入限制了阿替卡因在特殊患者如儿童、妇女、心脑血管疾病、糖尿病、甲亢等患者中的应用。同时，肾上腺素引起的局部血管收缩可能导致神经和软组织缺血而使功能受损。尽管大多数文献都承认肾上腺素有一个安全范围，其浓度阈值仍不清楚。因此，鉴于老龄化社会中潜在心血管风险的患者数量不断增加，传统局部麻醉药物并不能满足所有口腔诊疗操作的需求。On the one hand, articaine is similar to nitric oxide in that it has a vasodilatory effect and promotes its systemic absorption, but the anesthesia time is limited. Therefore, in order to prolong anesthesia time, reduce anesthetic dosage and reduce To reduce bleeding and improve visualization of the surgical field, epinephrine should be added to local anesthetics in clinical practice. However, the addition of epinephrine limits the application of articaine in special patients such as children, women, patients with cardiovascular and cerebrovascular diseases, diabetes, and hyperthyroidism. At the same time, local vasoconstriction caused by epinephrine may lead to nerve and soft tissue ischemia and functional impairment. Although most literature acknowledges that epinephrine has a safe range, its concentration threshold remains unclear. Therefore, given the increasing number of patients with potential cardiovascular risks in an aging society, traditional local anesthetics cannot meet the needs of all dental procedures.
另一方面，局部麻醉药在炎症环境下不易起效或不起效，口腔颌面部是人体解剖结构最复杂的区域，丰富的血管加之口腔内及牙齿上长期存在着各种菌群使得口腔颌面部易发生牙源性的炎症反应，最常见的即智齿冠周炎。这些炎症反应会对患者造成极大痛苦，然而临床上大多需要先对炎症反应进行控制，通过冠周冲洗及抗生素的使用使炎症尽快消除，在炎症消除之后对病源牙进行拔除或其他治疗，这是因为在炎症状态下，局麻药无法发挥正常功能。而一些急性炎症状态患者需要紧急手术干预时，术中和术后都会受到极大痛苦，此时如果局部麻醉剂能够发挥稳定的作用，对治疗操作造成的疼痛会是极大缓解。On the other hand, local anesthetics are difficult or ineffective in inflammatory environments. The oral cavity and maxillofacial region are the most complex areas of human anatomy. The rich blood vessels and the long-term presence of various flora in the oral cavity and teeth make the oral cavity more complex. The maxillofacial region is prone to odontogenic inflammatory reactions, the most common of which is wisdom tooth pericoronitis. These inflammatory reactions can cause great pain to patients. However, clinically, most of them need to control the inflammatory reaction first. The inflammation can be eliminated as soon as possible through pericoronal irrigation and the use of antibiotics. After the inflammation is eliminated, the source tooth should be extracted or otherwise treated. This is because local anesthetics cannot function normally in an inflammatory state. When some patients with acute inflammatory conditions require emergency surgical intervention, they will suffer great pain during and after the operation. If the local anesthetic can play a stable role at this time, the pain caused by the treatment operation will be greatly relieved.
因此，进一步研究安全、稳定起效、麻醉起效时间短且麻醉时间长、能产生一定抗炎作用的局部麻醉药，具有重要意义。Therefore, it is of great significance to further study local anesthetics that are safe, have stable onset of action, have short onset of anesthesia and long duration of anesthesia, and can produce certain anti-inflammatory effects.
发明内容Contents of the invention
本发明的目的在于提供一种新型的用于局部麻醉的化合物。The object of the present invention is to provide a novel compound for local anesthesia.
式I所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物：
The compound represented by formula I, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound:
The compound represented by formula I, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound:
其中，R4为C1～8烃基、C1～8烷氧基、3～8元环烃基、苯基或苄基；Among them, R 4 is a C 1 to 8 hydrocarbon group, a C 1 to 8 alkoxy group, a 3 to 8 membered ring hydrocarbon group, a phenyl group or a benzyl group;
其中，R1为C1～8烃基，且R2和R3连接形成环A：
Among them, R 1 is a C 1 to 8 hydrocarbon group, and R 2 and R 3 are connected to form ring A:
Among them, R 1 is a C 1 to 8 hydrocarbon group, and R 2 and R 3 are connected to form ring A:
环A中：Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H、卤素、取代或未取代的：C1～8烃基、C1～8烷氧基或3～8元环烃基；In Ring A: R a , R b , R c , R d , R e , R f , R g , and R h are independently selected from H, halogen, substituted or unsubstituted: C 1 to 8 hydrocarbyl, C 1 to 8 alkoxy group or 3 to 8 membered ring hydrocarbon group;
M为NR5，L为C3～4烷烃链且R5为H，或L为C1～4烷烃链且R5为取代
或未取代的C1～8烃基、C1～8烷氧基、3～8元环烃基、苯基或苄基；所述取代的取代基个数为1～3个，所述取代基分别独立选自羟基、卤素、氨基、C1～8烷氧基、3～8元环烃基或C1～8酯基；且环A为时，L不为亚甲基链；或，M为O、CH2、S、SO或SO2，L为C2～4支链烷烃链；M is NR 5 , L is a C 3-4 alkane chain and R 5 is H, or L is a C 1-4 alkane chain and R 5 is substituted Or unsubstituted C 1 to 8 hydrocarbon groups, C 1 to 8 alkoxy groups, 3 to 8 membered ring hydrocarbon groups, phenyl or benzyl groups; the number of substituted substituents is 1 to 3, and the substituents are respectively Independently selected from hydroxyl, halogen, amino, C 1 to 8 alkoxy group, 3 to 8 membered ring hydrocarbon group or C 1 to 8 ester group; and Ring A is When, L is not a methylene chain; or, M is O, CH 2 , S, SO or SO 2 , and L is a C 2 to 4 branched alkane chain;
或，R1为C1～8直链烷基，且R2为被1～3个羟基、氨基、C1～4烷氧基或C1～4烷基氨基取代的C1～8烷基，R3为氢、未取代或被1～3个羟基或C1～4烷氧基取代的C1～8烷基；L为C1～4烷烃链；Or, R 1 is a C 1 to 8 linear alkyl group, and R 2 is a C 1 to 3 linear alkyl group. hydroxyl, Amino, C 1 to 4 alkoxy or C 1 to 4 alkylamino substituted C 1 to 8 alkyl group, R 3 is hydrogen, unsubstituted or substituted by 1 to 3 hydroxyl groups or C 1 to 4 alkoxy groups C 1～8 alkyl; L is C 1～4 alkane chain;
或，R1为异丁基；R2、R3分别独立选自氢、取代或未取代的C1～8烃基，或取代或未取代的C1～8烷氧基，所述取代的取代基个数为1～5个，所述取代基分别独立选自羟基或C1～4烷氧基；L为C1～4烷烃链。Or, R 1 is isobutyl; R 2 and R 3 are independently selected from hydrogen, substituted or unsubstituted C 1 to 8 hydrocarbon groups, or substituted or unsubstituted C 1 to 8 alkoxy groups, and the substituted The number of groups is 1 to 5, and the substituents are independently selected from hydroxyl or C 1 to 4 alkoxy groups; L is a C 1 to 4 alkane chain.
优选的，R4为甲基。Preferably, R 4 is methyl.
优选的，R1为C1～8烷基且R2和R3连接形成环A；优选地，R1为甲基，且R2和R3连接形成环A。Preferably, R 1 is a C 1-8 alkyl group and R 2 and R 3 are connected to form Ring A; preferably, R 1 is methyl, and R 2 and R 3 are connected to form Ring A.
优选的，环A中：Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H或C1～8烷基，优选为H或甲基。Preferably, in ring A: R a , R b , R c , R d , Re , R f , R g , and Rh are independently selected from H or C 1 to 8 alkyl groups, preferably H or methyl.
优选的，M为NR5，L为C3～4烷烃链且R5为H，或，L为C1～4烷烃链且R5为取代或未取代的C1～8烷基、3～8元环烷基或苯基；所述取代的取代基个数为1或2个，所述取代基分别独立选自羟基、C1～4烷氧基或C1～8酯基；且环A为时，L不为亚甲基链。Preferably, M is NR 5 , L is a C 3-4 alkane chain and R 5 is H, or, L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-8 alkyl group, 3- 8-membered ring alkyl or phenyl; the number of substituted substituents is 1 or 2, and the substituents are independently selected from hydroxyl, C 1 to 4 alkoxy or C 1 to 8 ester groups; and the ring A is When , L is not a methylene chain.
优选的，M为NR5，L为C1～4烷烃链且R5为取代或未取代的C1～4烷基、环丙烷基或苯基；所述取代的取代基个数为1个，所述取代基为羟基、甲氧基或甲酯基；且环A为时，L不为亚甲基链。Preferably, M is NR 5 , L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-4 alkyl group, cyclopropyl group or phenyl group; the number of substituted substituents is 1 , the substituent is hydroxyl, methoxy or methyl ester; and ring A is When , L is not a methylene chain.
优选的，所述化合物具有式I-A所示结构：
Preferably, the compound has the structure shown in Formula IA:
Preferably, the compound has the structure shown in Formula IA:
优选的，所述化合物具有式I-A-1或1-A-2所示结构：
Preferably, the compound has the structure shown in formula IA-1 or 1-A-2:
Preferably, the compound has the structure shown in formula IA-1 or 1-A-2:
优选的，所述化合物具有式I-A-3所示结构：
Preferably, the compound has the structure shown in formula IA-3:
Preferably, the compound has the structure shown in formula IA-3:
其中，R5选自C1～4烷基。Among them, R 5 is selected from C 1 to 4 alkyl groups.
优选的，所述化合物具有式I-B所示结构：
Preferably, the compound has the structure shown in formula IB:
Preferably, the compound has the structure shown in formula IB:
优选的，所述化合物具有式I-B-1、式I-B-2、式I-B-3或式I-B-4所示结构：
Preferably, the compound has a structure represented by Formula IB-1, Formula IB-2, Formula IB-3 or Formula IB-4:
Preferably, the compound has a structure represented by Formula IB-1, Formula IB-2, Formula IB-3 or Formula IB-4:
优选的，所述化合物具有式I-C所示结构：
Preferably, the compound has the structure shown in formula IC:
Preferably, the compound has the structure shown in formula IC:
优选的，所述化合物具有式I-C-1所示结构：
Preferably, the compound has the structure shown in formula IC-1:
Preferably, the compound has the structure shown in formula IC-1:
优选的，所述化合物具有式I-D所示结构：
Preferably, the compound has the structure shown in formula ID:
Preferably, the compound has the structure shown in formula ID:
优选的，所述化合物具有式I-D-1所示结构：
Preferably, the compound has the structure shown in formula ID-1:
Preferably, the compound has the structure shown in formula ID-1:
优选的，所述化合物具有式I-E所示结构：
Preferably, the compound has the structure shown in formula IE:
Preferably, the compound has the structure shown in formula IE:
优选的，所述化合物具有式I-D-1所示结构：
Preferably, the compound has the structure shown in formula ID-1:
Preferably, the compound has the structure shown in formula ID-1:
优选的，所述化合物具有式I-F所示结构：
Preferably, the compound has a structure represented by formula IF:
Preferably, the compound has a structure represented by formula IF:
优选的，所述化合物具有式I-F-1所示结构：
Preferably, the compound has the structure shown in formula IF-1:
Preferably, the compound has the structure shown in formula IF-1:
优选的，R1为C1～8直链烷基，且R2被1个羟基、氨基、C1～4烷氧基或C1～4烷基氨基取代的C1～3烷基，R3为氢、未取代或被1个羟基或C1～4烷氧基取代的C1～3烷基；L为C1～4烷烃链。
Preferably, R 1 is a C 1-8 linear alkyl group, and R 2 is replaced by 1 hydroxyl, Amino group, C 1 to 4 alkoxy group or C 1 to 4 alkylamino substituted C 1 to 3 alkyl group, R 3 is hydrogen, unsubstituted or C 1 substituted by 1 hydroxyl group or C 1 to 4 alkoxy group ~3 alkyl; L is a C 1~4 alkane chain.
优选的，L为
Preferably, L is
优选的，R1为异丁基；R2、R3分别独立选自氢或C1～8烷基；L为C1～4烷烃链。Preferably, R 1 is isobutyl; R 2 and R 3 are each independently selected from hydrogen or C 1-8 alkyl; L is a C 1-4 alkane chain.
优选的，L为
Preferably, L is
本发明还提供式II所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物：
The present invention also provides a compound represented by Formula II, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated compound thereof:
The present invention also provides a compound represented by Formula II, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated compound thereof:
其中，L`为C1～4烷烃链；Among them, L` is a C 1 to 4 alkane chain;
其中，R5为C1～8烷基；Among them, R 5 is C 1～8 alkyl;
其中，X`为O、S、CH2、NR7，R7为Ri取代或未取代的C1～8烷基、苯基或苄基；Ri为羟基、3～8元环烃基、C1～8烷氧基或C1～8酯基；R6为C1～8烷基；m和n为整数，且m+n＝2或4或5；Among them, X` is O, S, CH 2 , NR 7 , R 7 is R i substituted or unsubstituted C 1 to 8 alkyl group, phenyl or benzyl group; R i is hydroxyl, 3 to 8 membered ring hydrocarbon group, C 1 to 8 alkoxy group or C 1 to 8 Ester group; R 6 is C 1 to 8 alkyl group; m and n are integers, and m+n=2 or 4 or 5;
或，X为C时，R6为C1～8烷基；m和n为整数，且m+n＝4或5；Or, when X is C, R 6 is a C 1-8 alkyl group; m and n are integers, and m+n=4 or 5;
k选自0、1、2或3。k is selected from 0, 1, 2 or 3.
优选的，L`为
Preferably, L` is
优选的，R5为C1～4烷基，R6为C1～4烷基，X`为O、S、CH2、NR7，R7为Ri取代或未取代的C1～4烷基或苯基，Ri为羟基、3～6元环烃基、C1～4烷氧基或C1～4酯基。Preferably, R 5 is a C 1-4 alkyl group, R 6 is a C 1-4 alkyl group, and X` is O, S, CH 2 , NR 7 , R 7 is R i substituted or unsubstituted C 1 to 4 alkyl group or phenyl group, R i is hydroxyl group, 3 to 6 membered ring hydrocarbon group, C 1 to 4 alkoxy group or C 1 to 4 ester group.
优选的，R6为甲基，X为O、S、NR7，R7为Ri取代或未取代的C1～4烃基或苯基，Ri为羟基、环丙基、甲氧基或甲酯基。Preferably, R 6 is methyl, X is O, S, NR 7 , R 7 is R i substituted or unsubstituted C 1 to 4 hydrocarbon group or phenyl group, R i is hydroxyl, cyclopropyl, methoxy or methyl ester group.
优选的，所述化合物具有式II-A至式II-F任一项所示结构：
Preferably, the compound has a structure shown in any one of Formula II-A to Formula II-F:
Preferably, the compound has a structure shown in any one of Formula II-A to Formula II-F:
优选的，所述化合物具有式II-G至式II-M任一项所示结构：
Preferably, the compound has a structure shown in any one of Formula II-G to Formula II-M:
Preferably, the compound has a structure shown in any one of Formula II-G to Formula II-M:
优选的，所述化合物具有式II-G至式II-M任一项所示结构：
Preferably, the compound has a structure shown in any one of Formula II-G to Formula II-M:
Preferably, the compound has a structure shown in any one of Formula II-G to Formula II-M:
优选的，所述化合物为如下任一结构：
Preferably, the compound has any of the following structures:
Preferably, the compound has any of the following structures:
优选的，所述药学上可接受的盐是指由式I所示化合物与药学上可接受的无机酸或有机酸形成；Preferably, the pharmaceutically acceptable salt is formed from a compound represented by Formula I and a pharmaceutically acceptable inorganic acid or organic acid;
优选地，所述无机酸或有机酸为盐酸、氢溴酸、乙酸、硫酸、甲磺酸、对甲苯磺酸、琥珀酸、碳酸、酒石酸、月桂酸、马来酸、枸橼酸或苯甲酸。
Preferably, the inorganic acid or organic acid is hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid or benzoic acid. .
本发明还提供上述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备麻醉药物中的用途，优选地，所述麻醉药物为局部麻醉药物。The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated compounds thereof, in the preparation of anesthetic drugs. For use, preferably, the anesthetic drug is a local anesthetic drug.
本发明还提供上述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备抗炎药物中的用途。The present invention also provides the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated compounds thereof, in the preparation of anti-inflammatory drugs. use in.
本发明还提供一种药物，它是以上述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides a medicine, which is based on the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium A preparation prepared by taking a substitute compound as the active ingredient and adding pharmaceutically acceptable excipients.
本发明的有益效果：本发明化合物用于局部麻醉时起效快，单次给药后麻醉作用时间延长，与局麻药物阿替卡因2小时的局麻作用时间相比，本发明化合物的局麻作用时间能显著延长达到4小时；同时，本发明化合物在炎性状态下仍能发挥长效局部麻醉作用，与炎性状态下局麻药物阿替卡因0.5小时的局麻作用时间相比，本发明化合物在炎性状态下的局麻作用时间能显著延长至1小时。Beneficial effects of the present invention: the compound of the present invention has a rapid onset of action when used for local anesthesia, and the anesthetic action time is prolonged after a single administration. Compared with the 2-hour local anesthetic action time of the local anesthetic drug articaine, the compound of the present invention has The local anesthetic effect time can be significantly extended to 4 hours; at the same time, the compound of the present invention can still exert a long-lasting local anesthetic effect in an inflammatory state, which is comparable to the local anesthetic effect of articaine of 0.5 hours in an inflammatory state. Compared with this, the local anesthetic effect time of the compound of the present invention under inflammatory conditions can be significantly extended to 1 hour.
本发明化合物在浸润麻醉与阻滞麻醉中均具有较长的局部麻醉作用，解决了目前局麻药物使用过程中与肾上腺素联用的副作用问题，具有更好的安全性。本发明化合物可用于制备安全的、具有长时间局部麻醉的药物，具有局部麻醉作用时间长、神经损伤更小、安全性高的优点。The compound of the present invention has a long local anesthetic effect in both infiltration anesthesia and block anesthesia, solves the side effect problem of current local anesthetic drugs used in combination with epinephrine, and has better safety. The compound of the present invention can be used to prepare safe drugs with long-term local anesthesia, and has the advantages of long local anesthetic effect, less nerve damage, and high safety.
本发明所述“烷烃链”是指直链或支链的烷烃去掉2个氢原子形成的烷基链。The "alkane chain" mentioned in the present invention refers to an alkyl chain formed by removing two hydrogen atoms from a linear or branched alkane.
“烷基”是指直链或支链烷基，即直链或支链的烷烃去掉1个氢原子形成的基团。"Alkyl" refers to a straight-chain or branched alkyl group, that is, a group formed by removing one hydrogen atom from a straight-chain or branched alkane.
“C1～8酯基”是指RCOO-，其中R为C1～8烷基，甲酯基即CH3COO-。"C 1-8 ester group" refers to RCOO-, where R is C 1-8 alkyl group, and the methyl ester group is CH 3 COO-.
“C1～4烷基氨基”是指RNH-，其中R为C1～4烷基。"C 1-4 alkylamino" refers to RNH-, where R is C 1-4 alkyl.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Obviously, according to the above content of the present invention, according to the common technical knowledge and common means in the field, without departing from the above basic technical idea of the present invention, various other forms of modifications, replacements or changes can also be made.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above contents of the present invention will be further described in detail below through specific implementation methods in the form of examples. However, this should not be understood to mean that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention.
本发明所用原料与设备均为已知产品，通过购买市售产品所得。The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.
实施例1
Example 1
Example 1
步骤1：将3-氨基-4-甲基噻吩-2-羧酸甲酯(20.0g,116.8mmol)溶于100mL DCM中，加入碳酸钾(32.3g,233.6mmol)，随后于-20℃下加入预先溶于20mL DCM的2-溴丙酰溴(32.8g，151.9mmol)，室温搅拌24h。反应完成后用水(100mL×3)洗涤，收集有机相用无水硫酸钠干燥。过滤后浓缩至20mL，加入PE(200mL)搅拌过夜，过滤得到产物3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(35.0g,97.8％)为灰白色固体。Step 1: Dissolve 3-amino-4-methylthiophene-2-carboxylic acid methyl ester (20.0g, 116.8mmol) in 100mL DCM, add potassium carbonate (32.3g, 233.6mmol), and then incubate at -20°C Add 2-bromopropionyl bromide (32.8g, 151.9mmol) previously dissolved in 20mL DCM and stir at room temperature for 24h. After the reaction was completed, the mixture was washed with water (100 mL × 3), and the organic phase was collected and dried over anhydrous sodium sulfate. After filtration, concentrate to 20 mL, add PE (200 mL) and stir overnight, filter to obtain the product 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (35.0 g, 97.8%) as an off-white solid .
1H NMR(400MHz,CDCl3)δ9.30(s,1H),7.16(s,1H),4.57(q,J＝7.0Hz,1H),3.87(s,3H),2.18(s,3H),1.97(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.30 (s, 1H), 7.16 (s, 1H), 4.57 (q, J = 7.0Hz, 1H), 3.87 (s, 3H), 2.18 (s, 3H) ,1.97(d,J＝7.0Hz,3H).
步骤2：将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(10.0g,32.7mmol)溶于30mL DMF中，加入碳酸钾(3.86g,65.3mmol)逐滴滴加丙胺(3.86g,65.3mmol)。随后室温下搅拌5h。反应完成后用200mL DCM稀释，用水(200mL×4)洗涤，收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH＝50:1)得到产物4-甲基-3-(2-(丙氨基)丙酰胺基)噻吩-2-羧酸甲酯(8.66g,93.2％)为淡黄色油，将其溶于80mL甲醇中，滴加盐酸(16mL，2M)，室温搅拌1h，旋干，溶于水中，过滤，滤液冻干得到产物的盐酸盐。Step 2: Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (10.0g, 32.7mmol) in 30mL DMF, and add potassium carbonate (3.86g, 65.3mmol) Propylamine (3.86g, 65.3mmol) was added dropwise. Then stir at room temperature for 5 h. After the reaction is completed, dilute with 200 mL DCM, wash with water (200 mL × 4), collect the organic phase and dry it over anhydrous sodium sulfate. Filter, dry and concentrate. The residue was purified by column chromatography (DCM/MeOH=50:1) to obtain the product 4-methyl-3-(2-(propylamino)propionamido)thiophene-2-carboxylic acid methyl ester (8.66g, 93.2% ) is a light yellow oil, dissolve it in 80 mL of methanol, add hydrochloric acid (16 mL, 2M) dropwise, stir at room temperature for 1 h, spin to dryness, dissolve in water, filter, and freeze-dry the filtrate to obtain the hydrochloride salt of the product.
1H NMR(400MHz,D2O)δ7.36(s,1H),4.19(q,J＝7.0Hz,1H),3.73(s,3H),2.97(ddt,J＝40.5,12.2,7.6Hz,2H),2.05–1.91(m,3H),1.63(dd,J＝12.0,7.2Hz,5H),0.89(t,J＝7.4Hz,3H). 1 H NMR (400MHz, D 2 O) δ7.36 (s, 1H), 4.19 (q, J = 7.0Hz, 1H), 3.73 (s, 3H), 2.97 (ddt, J = 40.5, 12.2, 7.6Hz ,2H),2.05–1.91(m,3H),1.63(dd,J＝12.0,7.2Hz,5H),0.89(t,J＝7.4Hz,3H).
步骤3：将化合物4-甲基-3-(2-(丙氨基)丙酰胺基)噻吩-2-羧酸甲酯(5.0g,17.6mmol)溶于20mL MeOH中，滴加预先溶于14mL水中的氢氧化钠(1.4g,35.2mmol)，随后将反应液于50℃下搅拌2h。反应完成后，减压浓缩，残留物溶于100mL水中，用100mL DCM洗涤，水相随后用盐酸(2M)调整pH至7，随后用乙酸乙酯萃取水相，收集有机相用无水硫酸钠干燥。过滤干燥浓缩。得到粗产品4-甲基-3-(2-丙氨基丙酰胺基)噻吩-2-羧酸(4.59g，96.6％)。Step 3: Dissolve compound 4-methyl-3-(2-(propylamino)propionamido)thiophene-2-carboxylic acid methyl ester (5.0g, 17.6mmol) in 20mL MeOH, add dropwise and pre-dissolve in 14mL sodium hydroxide (1.4g, 35.2mmol) in water, and then the reaction solution was stirred at 50°C for 2h. After the reaction is completed, concentrate under reduced pressure, and the residue is dissolved in 100 mL of water and washed with 100 mL of DCM. The aqueous phase is then adjusted to pH 7 with hydrochloric acid (2M), and then the aqueous phase is extracted with ethyl acetate. The organic phase is collected and washed with anhydrous sodium sulfate. dry. Filter, dry and concentrate. The crude product 4-methyl-3-(2-propylaminopropionamido)thiophene-2-carboxylic acid (4.59 g, 96.6%) was obtained.
1H NMR(400MHz,MeOD)δ7.02(s,1H),3.48(q,J＝6.7Hz,1H),2.73–2.56(m,2H),2.12(s,3H),1.62–1.52(m,2H),1.46–1.39(m,3H),0.94(t,J＝7.4Hz,3H). 1 H NMR (400MHz, MeOD) δ7.02 (s, 1H), 3.48 (q, J = 6.7Hz, 1H), 2.73–2.56 (m, 2H), 2.12 (s, 3H), 1.62–1.52 (m ,2H),1.46–1.39(m,3H),0.94(t,J＝7.4Hz,3H).
HRMS(EI)m/z:calcd for C12H19N2O3S,271.1111；found 271.1114[M+H]+.HRMS(EI)m/z:calcd for C 12 H 19 N 2 O 3 S,271.1111; found 271.1114[M+H] + .
HPLC purity:95.393％,tR＝18.609min.HPLC purity:95.393%, t R =18.609min.
步骤4：将4-甲基-3-(2-丙氨基丙酰胺基)噻吩-2-羧酸(500mg,1.85mmol)溶于20mL DMF中，加入碳酸氢钠(311mg,3.70mmol)后室温下逐滴滴加异丁基氯(340mg,3.7mmol)，随后50℃下反应5h，反应完成后用200mL DCM稀释，100mL水洗四次，收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH＝40:1)得到产物4-甲基-3-(2-(丙氨基)丙酰胺基)噻吩-2-羧酸异丁酯(180mg,29.8％)为无
色油状物。Step 4: Dissolve 4-methyl-3-(2-propylaminopropionamido)thiophene-2-carboxylic acid (500 mg, 1.85 mmol) in 20 mL DMF, add sodium bicarbonate (311 mg, 3.70 mmol), and then cool to room temperature. Isobutyl chloride (340 mg, 3.7 mmol) was added dropwise at 50°C for 5 h. After the reaction was completed, it was diluted with 200 mL DCM and washed four times with 100 mL water. The organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate. The residue was purified by column chromatography (DCM/MeOH=40:1) to obtain the product 4-methyl-3-(2-(propylamino)propionamido)thiophene-2-carboxylic acid isobutyl ester (180 mg, 29.8% ) is none Oily color.
1H NMR(400MHz,D2O)δ7.48–7.34(m,1H),4.27(q,J＝6.9Hz,1H),4.02(dd,J＝6.3,2.2Hz,2H),3.05(ddt,J＝27.5,12.1,7.8Hz,2H),2.71(s,1H),2.06(s,3H),1.97(dt,J＝12.1,6.5Hz,1H),1.81–1.64(m,5H),0.98(t,J＝7.4Hz,3H),0.91(d,J＝6.6Hz,6H). 1 H NMR (400MHz, D 2 O) δ7.48–7.34(m,1H),4.27(q,J＝6.9Hz,1H),4.02(dd,J＝6.3,2.2Hz,2H),3.05(ddt ,J＝27.5,12.1,7.8Hz,2H),2.71(s,1H),2.06(s,3H),1.97(dt,J＝12.1,6.5Hz,1H),1.81–1.64(m,5H), 0.98(t,J＝7.4Hz,3H),0.91(d,J＝6.6Hz,6H).
13C NMR(101MHz,D2O)δ169.00,162.69,136.99,136.64,128.10,124.37,71.63,56.21,48.22,27.37,19.29,18.26,15.98,12.83,10.20. 13 C NMR (101MHz, D 2 O) δ 169.00, 162.69, 136.99, 136.64, 128.10, 124.37, 71.63, 56.21, 48.22, 27.37, 19.29, 18.26, 15.98, 12.83, 10.20.
HRMS(EI)m/z:calcd for C16H17N2O3S,327.1737；found 327.1739[M+H]+.HRMS(EI)m/z:calcd for C 16 H 17 N 2 O 3 S,327.1737; found 327.1739[M+H] + .
HPLC purity:96.722％,tR＝17.558min.HPLC purity:96.722%, t R =17.558min.
实施例2
Example 2
Example 2
将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(1.5g,4.90mmol)溶于20mL DMF中，加入碳酸钾(1.35g,9.80mmol)，滴加乙基哌嗪(671mg,5.88mmol)。随后50℃下反应3h，反应完成后用200mL DCM稀释，200mL水洗四次，收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH＝40:1)得到产物3-(2-(4-乙基哌嗪-1-基)丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(1.47g,88.4％)为淡黄色油。将其溶于20mL甲醇中，滴加盐酸(5mL，2M)，室温搅拌1h，旋干，溶于水中，过滤，滤液冻干得到产物的盐酸盐。Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (1.5g, 4.90mmol) in 20mL DMF, add potassium carbonate (1.35g, 9.80mmol), and add dropwise Ethylpiperazine (671 mg, 5.88 mmol). Then react at 50°C for 3 hours. After the reaction is completed, it is diluted with 200 mL DCM, washed four times with 200 mL water, and the organic phase is collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate. The residue was purified by column chromatography (DCM/MeOH=40:1) to obtain the product 3-(2-(4-ethylpiperazin-1-yl)propionamido)-4-methylthiophene-2-carboxylic acid Methyl ester (1.47g, 88.4%) was a light yellow oil. Dissolve it in 20 mL methanol, add hydrochloric acid (5 mL, 2 M) dropwise, stir at room temperature for 1 h, spin dry, dissolve in water, filter, and freeze-dry the filtrate to obtain the hydrochloride salt of the product.
1H NMR(400MHz,CDCl3)δ9.92(s,1H),7.13(d,J＝0.9Hz,1H),3.84(s,3H),3.22(q,J＝7.0Hz,1H),2.69(d,J＝40.6Hz,8H),2.47(q,J＝7.2Hz,2H),2.16(d,J＝0.9Hz,3H),1.35(d,J＝7.0Hz,3H),1.12(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.92 (s, 1H), 7.13 (d, J = 0.9Hz, 1H), 3.84 (s, 3H), 3.22 (q, J = 7.0Hz, 1H), 2.69 (d,J＝40.6Hz,8H),2.47(q,J＝7.2Hz,2H),2.16(d,J＝0.9Hz,3H),1.35(d,J＝7.0Hz,3H),1.12(t ,J＝7.2Hz,3H).
13C NMR(151MHz,D2O)δ174.13,163.21,137.88,136.70,128.09,123.71,63.16,52.31,51.94,50.87,13.61,12.94,8.52. 13 C NMR (151MHz, D 2 O) δ 174.13, 163.21, 137.88, 136.70, 128.09, 123.71, 63.16, 52.31, 51.94, 50.87, 13.61, 12.94, 8.52.
HRMS(EI)m/z:calcd for C16H26N3O3S,340.1689；found 340.1685[M+H]+.HRMS(EI)m/z:calcd for C 16 H 26 N 3 O 3 S,340.1689; found 340.1685[M+H] + .
HPLC purity:99.316％,tR＝15.207min.HPLC purity:99.316%, t R =15.207min.
实施例3
Example 3
Example 3
反应步骤同实施例2，产物为无色油状物，产率77.1％。The reaction steps were the same as in Example 2. The product was a colorless oil with a yield of 77.1%.
1H NMR(400MHz,D2O)δ7.38(s,1H),4.18(d,J＝6.0Hz,1H),4.05–3.88(m,2H),3.74(s,3H),3.59(d,J＝12.2Hz,1H),3.42(d,J＝12.1Hz,1H),2.93(t,J＝11.6Hz,1H),2.82(t,J＝11.7Hz,1H),1.99(s,3H),1.67(d,J＝6.9Hz,3H),1.18(dd,J＝14.0,6.3Hz,6H). 1 H NMR (400MHz, D 2 O) δ7.38 (s, 1H), 4.18 (d, J = 6.0Hz, 1H), 4.05–3.88 (m, 2H), 3.74 (s, 3H), 3.59 (d ,J＝12.2Hz,1H),3.42(d,J＝12.1Hz,1H),2.93(t,J＝11.6Hz,1H),2.82(t,J＝11.7Hz,1H),1.99(s,3H ),1.67(d,J＝6.9Hz,3H),1.18(dd,J＝14.0,6.3Hz,6H).
13C NMR(151MHz,D2O)δ168.18,163.02,136.54,136.52,128.32,124.49,69.52,64.51,55.06,52.85,52.41,17.40,17.28,13.68,12.68. 13 C NMR (151MHz, D 2 O) δ 168.18, 163.02, 136.54, 136.52, 128.32, 124.49, 69.52, 64.51, 55.06, 52.85, 52.41, 17.40, 17.28, 13.68, 12.68.
HRMS(EI)m/z:calcd for C16H25N2O4S,341.1530；found 341.1523[M+H]+.HRMS(EI)m/z:calcd for C 16 H 25 N 2 O 4 S,341.1530; found 341.1523[M+H] + .
HPLC purity:98.351％,tR＝16.100min.HPLC purity:98.351%, t R =16.100min.
实施例4
Example 4
Example 4
反应步骤同实施例2，产物为无色油状物，产率80.8％。The reaction steps were the same as in Example 2. The product was colorless oil with a yield of 80.8%.
1H NMR(400MHz,D2O)δ7.37(s,1H),4.11(q,J＝6.9Hz,1H),3.74(s,3H),3.52(d,J＝11.5Hz,1H),3.33(d,J＝11.4Hz,1H),2.66(t,J＝12.0Hz,1H),2.52(t,J＝12.0Hz,1H),1.99(s,3H),1.85(ddt,J＝29.5,15.0,10.8Hz,3H),1.65(d,J＝7.0Hz,3H),0.86(dt,J＝15.5,7.8Hz,7H). 1 H NMR (400MHz, D 2 O) δ7.37 (s, 1H), 4.11 (q, J = 6.9Hz, 1H), 3.74 (s, 3H), 3.52 (d, J = 11.5Hz, 1H), 3.33(d,J＝11.4Hz,1H),2.66(t,J＝12.0Hz,1H),2.52(t,J＝12.0Hz,1H),1.99(s,3H),1.85(ddt,J＝29.5 ,15.0,10.8Hz,3H),1.65(d,J＝7.0Hz,3H),0.86(dt,J＝15.5,7.8Hz,7H).
13C NMR(151MHz,D2O)δ168.75,163.06,136.69,136.59,128.34,124.47,64.17,57.70,55.18,52.44,38.27,29.04,28.70,17.65,17.58,13.80,12.74. 13 C NMR (151MHz, D 2 O) δ168.75,163.06,136.69,136.59,128.34,124.47,64.17,57.70,55.18,52.44,38.27,29.04,28.70,17.65,17.58,13.80,12.7 4.
HRMS(EI)m/z:calcd for C17H27N2O3S,339.1737；found 339.1732[M+H]+.HRMS(EI)m/z:calcd for C 17 H 27 N 2 O 3 S,339.1737; found 339.1732[M+H] + .
HPLC purity:96.029％,tR＝19.084min.HPLC purity:96.029%, t R =19.084min.
实施例5
Example 5
Example 5
反应步骤同实施例2，产物为白色油状物，产率21.0％。The reaction steps were the same as in Example 2. The product was a white oily substance with a yield of 21.0%.
1H NMR(400MHz,CDCl3)δ10.20(s,1H),7.12(s,1H),3.93–3.75(m,7H),3.43(dd,J＝10.8,9.1Hz,1H),2.81(ddt,J＝12.2,9.1,4.5Hz,1H),2.63(tdd,J＝11.4,7.9,4.1Hz,2H),2.17(s,3H),1.27(d,J＝7.0Hz,3H),1.08(d,J＝6.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.20 (s, 1H), 7.12 (s, 1H), 3.93–3.75 (m, 7H), 3.43 (dd, J = 10.8, 9.1Hz, 1H), 2.81 ( ddt,J＝12.2,9.1,4.5Hz,1H),2.63(tdd,J＝11.4,7.9,4.1Hz,2H),2.17(s,3H),1.27(d,J＝7.0Hz,3H),1.08 (d,J＝6.3Hz,3H).
13C NMR(101MHz,CDCl3)δ172.50,162.81,142.20,136.06,127.13,117.76,73.36,67.36,58.11,52.22,51.77,46.64,15.75,14.23,8.67. 13 C NMR (101MHz, CDCl 3 ) δ 172.50, 162.81, 142.20, 136.06, 127.13, 117.76, 73.36, 67.36, 58.11, 52.22, 51.77, 46.64, 15.75, 14.23, 8.67.
HRMS(EI)m/z:calcd for C15H23N2O4S,327.1373；found 327.1364[M+H]+.HRMS(EI)m/z:calcd for C 15 H 23 N 2 O 4 S,327.1373; found 327.1364[M+H] + .
HPLC purity:95.906％,tR＝15.160min and 16.403min.HPLC purity:95.906%, t R =15.160min and 16.403min.
实施例6
Example 6
Example 6
反应步骤同实施例2，产物为无色油状物，产率88.9％。The reaction steps were the same as in Example 2. The product was colorless oil with a yield of 88.9%.
1H NMR(400MHz,CDCl3)δ10.07(s,1H),7.20–7.03(m,1H),3.84(s,3H),3.32(q,J＝7.0Hz,1H),2.96(dt,J＝12.7,7.2Hz,2H),2.85(d,J＝6.4Hz,6H),2.17(d,J＝0.9Hz,3H),1.32(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.07 (s, 1H), 7.20–7.03 (m, 1H), 3.84 (s, 3H), 3.32 (q, J = 7.0Hz, 1H), 2.96 (dt, J＝12.7,7.2Hz,2H),2.85(d,J＝6.4Hz,6H),2.17(d,J＝0.9Hz,3H),1.32(d,J＝7.0Hz,3H).
13C NMR(151MHz,D2O)δ168.22,163.00,136.61,136.56,128.32,124.45,64.02,52.42,24.19,13.44,12.71. 13 C NMR (151MHz, D 2 O) δ 168.22, 163.00, 136.61, 136.56, 128.32, 124.45, 64.02, 52.42, 24.19, 13.44, 12.71.
HRMS(EI)m/z:calcd for C14H21N2O3S2,329.0988；found 329.0980[M+H]+.HRMS(EI)m/z:calcd for C 14 H 21 N 2 O 3 S 2 ,329.0988; found 329.0980[M+H] + .
HPLC purity:96.255％,tR＝16.582min.HPLC purity:96.255%, t R =16.582min.
实施例7
Example 7
Example 7
反应步骤同实施例2，产物为淡黄色油状物，产率94.8％。
The reaction steps were the same as in Example 2. The product was a light yellow oil with a yield of 94.8%.
1H NMR(400MHz,CDCl3)δ10.06(s,1H),7.14(s,1H),3.84(s,3H),3.70(t,J＝4.5Hz,4H),3.32(q,J＝6.9Hz,1H),2.92–2.72(m,2H),2.69–2.37(m,6H),2.18(s,3H),1.44(d,J＝6.9Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.06 (s, 1H), 7.14 (s, 1H), 3.84 (s, 3H), 3.70 (t, J＝4.5Hz, 4H), 3.32 (q, J＝ 6.9Hz,1H),2.92–2.72(m,2H),2.69–2.37(m,6H),2.18(s,3H),1.44(d,J＝6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ173.85,162.91,141.94,136.14,127.25,118.39,67.02,59.18,58.09,53.71,53.47,51.83,44.94,20.09,15.53. 13 C NMR (101MHz, CDCl 3 ) δ 173.85, 162.91, 141.94, 136.14, 127.25, 118.39, 67.02, 59.18, 58.09, 53.71, 53.47, 51.83, 44.94, 20.09, 15.53.
HRMS(EI)m/z:calcd for C16H26N3O4S,356.1639；found 356.1630[M+H]+.HRMS(EI)m/z:calcd for C 16 H 26 N 3 O 4 S,356.1639; found 356.1630[M+H] + .
HPLC purity:99.524％,tR＝13.584min.HPLC purity:99.524%, t R =13.584min.
实施例8
Example 8
Example 8
反应步骤同实施例2，产物为无色油状物，产率61.7％。The reaction steps were the same as in Example 2. The product was a colorless oil with a yield of 61.7%.
1H NMR(400MHz,CDCl3)δ10.05(s,1H),7.13(s,1H),4.19(dddd,J＝10.3,8.6,6.2,2.4Hz,1H),3.83(d,J＝1.8Hz,3H),3.27(q,J＝7.0Hz,1H),2.71(dt,J＝10.9,2.0Hz,1H),2.57(dd,J＝10.9,1.6Hz,1H),2.35(d,J＝10.9Hz,1H),2.18(dd,J＝3.0,0.8Hz,3H),1.93(q,J＝11.1Hz,1H),1.46(s,2H),1.44(s,1H),1.36(s,1H),1.34(s,1H),1.30(s,1H),1.29(d,J＝2.6Hz,1H),1.23(d,J＝3.6Hz,3H),1.12(dd,J＝7.3,6.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.05(s,1H),7.13(s,1H),4.19(dddd,J＝10.3,8.6,6.2,2.4Hz,1H),3.83(d,J＝1.8 Hz,3H),3.27(q,J＝7.0Hz,1H),2.71(dt,J＝10.9,2.0Hz,1H),2.57(dd,J＝10.9,1.6Hz,1H),2.35(d,J ＝10.9Hz,1H),2.18(dd,J＝3.0,0.8Hz,3H),1.93(q,J＝11.1Hz,1H),1.46(s,2H),1.44(s,1H),1.36(s ,1H),1.34(s,1H),1.30(s,1H),1.29(d,J＝2.6Hz,1H),1.23(d,J＝3.6Hz,3H),1.12(dd,J＝7.3, 6.4Hz,3H).
13C NMR(101MHz,D2O)δ168.36,167.97,163.07,136.79,136.64,136.52,136.45,128.38,128.34,124.39,71.72,71.62,65.08,64.36,63.70,59.03,55.57,54.70,52.97,52.48,52.40,27.36,27.09,20.65,17.71,13.75,12.73,12.01. 13 C NMR (101MHz, D 2 O) δ168.36,167.97,163.07,136.79,136.64,136.52,136.45,128.38,128.34,124.39,71.72,71.62,65.08,64.36,63.70,59.03, 55.57,54.70,52.97,52.48, 52.40,27.36,27.09,20.65,17.71,13.75,12.73,12.01.
HRMS(EI)m/z:calcd for C17H27N2O4S,355.1686；found 355.1680[M+H]+.HRMS(EI)m/z:calcd for C 17 H 27 N 2 O 4 S,355.1686; found 355.1680[M+H] + .
HPLC purity:96.215％,tR＝19.348min and 19.955min.HPLC purity:96.215%, t R =19.348min and 19.955min.
实施例9
Example 9
Example 9
反应步骤同实施例2，产物为无色固体，产率17.6％。
The reaction steps were the same as in Example 2. The product was a colorless solid with a yield of 17.6%.
1H NMR(400MHz,CDCl3)δ9.99(s,1H),7.18–7.03(m,1H),3.82(s,3H),3.68(q,J＝7.0Hz,1H),3.60–3.49(m,4H),3.31(s,6H),2.91–2.71(m,4H),2.18–2.11(m,3H),1.32(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.99 (s, 1H), 7.18–7.03 (m, 1H), 3.82 (s, 3H), 3.68 (q, J = 7.0Hz, 1H), 3.60–3.49 ( m,4H),3.31(s,6H),2.91–2.71(m,4H),2.18–2.11(m,3H),1.32(d,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.82,162.49,141.58,136.23,126.73,126.64,119.42,71.76,61.58,61.49,58.84,51.80,51.68,50.80,15.35,15.29,10.17,10.11. 13 C NMR (101MHz, CDCl 3 ) δ172.82,162.49,141.58,136.23,126.73,126.64,119.42,71.76,61.58,61.49,58.84,51.80,51.68,50.80,15.35,15.29,10. 17,10.11.
HRMS(EI)m/z:calcd for C16H27N2O5S,359.1635；found 359.1630[M+H]+.HRMS(EI)m/z:calcd for C 16 H 27 N 2 O 5 S,359.1635; found 359.1630[M+H] + .
HPLC purity:95.108％,tR＝14.932min.HPLC purity:95.108%, t R =14.932min.
实施例10
Example 10
Example 10
反应步骤同实施例2，产物为无色油，产率35.3％。The reaction steps were the same as in Example 2. The product was colorless oil with a yield of 35.3%.
1H NMR(400MHz,CDCl3)δ10.42(s,1H),7.07(d,J＝1.1Hz,1H),3.78(s,3H),3.73–3.56(m,2H),3.51(q,J＝7.0Hz,1H),3.47–3.29(m,1H),2.77(ddd,J＝12.9,8.6,3.9Hz,1H),2.66–2.45(m,3H),2.16(d,J＝1.0Hz,3H),1.25(d,J＝7.0Hz,3H),1.07(t,J＝7.1Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.42 (s, 1H), 7.07 (d, J = 1.1Hz, 1H), 3.78 (s, 3H), 3.73–3.56 (m, 2H), 3.51 (q, J＝7.0Hz,1H),3.47–3.29(m,1H),2.77(ddd,J＝12.9,8.6,3.9Hz,1H),2.66–2.45(m,3H),2.16(d,J＝1.0Hz ,3H),1.25(d,J＝7.0Hz,3H),1.07(t,J＝7.1Hz,3H).
13C NMR(101MHz,CDCl3)δ172.70,163.79,143.16,135.91,127.95,116.76,60.60,60.16,53.07,52.13,44.81,16.00,13.39,9.28. 13 C NMR (101MHz, CDCl 3 ) δ172.70,163.79,143.16,135.91,127.95,116.76,60.60,60.16,53.07,52.13,44.81,16.00,13.39,9.28.
HPLC purity:95.438％,tR＝17.154min.HPLC purity:95.438%, t R =17.154min.
实施例11
Example 11
Example 11
反应步骤同实施例2，产物为灰色油，产率19.7％。The reaction steps were the same as in Example 2, the product was gray oil, and the yield was 19.7%.
1H NMR(400MHz,CDCl3)δ10.24(s,1H),7.08(d,J＝1.4Hz,1H),3.76(d,J＝1.6Hz,3H),3.75–3.53(m,6H),3.49(qd,J＝7.1,1.4Hz,1H),2.76(ddt,J＝12.4,10.0,3.1Hz,2H),2.60(dq,J＝13.5,2.4Hz,2H),2.12(t,J＝1.1Hz,3H),1.29(dd,J＝7.1,1.8Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.24 (s, 1H), 7.08 (d, J = 1.4Hz, 1H), 3.76 (d, J = 1.6Hz, 3H), 3.75–3.53 (m, 6H) ,3.49(qd,J＝7.1,1.4Hz,1H),2.76(ddt,J＝12.4,10.0,3.1Hz,2H),2.60(dq,J＝13.5,2.4Hz,2H),2.12(t,J ＝1.1Hz,3H),1.29(dd,J＝7.1,1.8Hz,3H).
13C NMR(101MHz,CDCl3)δ172.21,163.91,142.75,136.47,128.00,118.01,60.95,
60.17,52.54,52.24,15.57,9.40. 13 C NMR (101MHz, CDCl 3 ) δ172.21,163.91,142.75,136.47,128.00,118.01,60.95, 60.17,52.54,52.24,15.57,9.40.
HPLC purity:99.487％,tR＝16.202min.HPLC purity:99.487%, t R =16.202min.
实施例12
Example 12
Example 12
反应步骤同实施例2，产物为淡黄油，产率52.3％。The reaction steps were the same as in Example 2, and the product was light butter with a yield of 52.3%.
1H NMR(400MHz,CDCl3)δ9.82(d,J＝18.2Hz,1H),7.05(d,J＝1.0Hz,1H),3.76(s,3H),3.12(dq,J＝17.8,7.0Hz,1H),2.86–2.68(m,3H),2.60–2.35(m,2H),2.26(s,3H),2.21–1.97(m,5H),1.27(dd,J＝7.0,2.5Hz,3H),1.01(dd,J＝8.7,6.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.82 (d, J = 18.2Hz, 1H), 7.05 (d, J = 1.0Hz, 1H), 3.76 (s, 3H), 3.12 (dq, J = 17.8, 7.0Hz,1H),2.86–2.68(m,3H),2.60–2.35(m,2H),2.26(s,3H),2.21–1.97(m,5H),1.27(dd,J＝7.0,2.5Hz ,3H),1.01(dd,J＝8.7,6.2Hz,3H).
13C NMR(101MHz,CDCl3)δ172.61,172.45,162.74,141.86,141.80,136.25,127.00,118.52,118.43,64.75,64.68,59.98,58.02,57.93,55.85,54.83,52.68,51.74,47.88,42.45,42.41,15.54,15.48,12.72,12.10. 13 C NMR (101MHz, CDCl 3 ) δ172.61,172.45,162.74,141.86,141.80,136.25,127.00,118.52,118.43,64.75,64.68,59.98,58.02,57.93,55.85,54.83,5 2.68,51.74,47.88,42.45,42.41 ,15.54,15.48,12.72,12.10.
HPLC purity:99.293％,tR＝18.441min.HPLC purity:99.293%, t R =18.441min.
实施例13
Example 13
Example 13
反应步骤同实施例2，产物为淡黄油，产率31.9％。The reaction steps were the same as in Example 2, and the product was light butter with a yield of 31.9%.
1H NMR(400MHz,CDCl3)δ10.05(s,1H),7.08(d,J＝1.2Hz,1H),3.76(s,3H),3.46(q,J＝7.0Hz,1H),3.37–2.91(m,8H),2.16–2.07(m,3H),1.57–1.26(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.05 (s, 1H), 7.08 (d, J = 1.2Hz, 1H), 3.76 (s, 3H), 3.46 (q, J = 7.0Hz, 1H), 3.37 –2.91(m,8H),2.16–2.07(m,3H),1.57–1.26(m,3H).
13C NMR(101MHz,CDCl3)δ170.48,163.40,142.22,135.87,127.76,117.27,64.49,52.02,51.67,48.49,15.82,10.85. 13 C NMR (101MHz, CDCl 3 ) δ 170.48, 163.40, 142.22, 135.87, 127.76, 117.27, 64.49, 52.02, 51.67, 48.49, 15.82, 10.85.
HPLC purity:98.852％,tR＝20.326min.HPLC purity:98.852%, t R =20.326min.
实施例14
Example 14
Example 14
步骤1：将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(2.0g,6.53mmol)溶于15mL DMF和15mL ACN的混合溶剂中，加入碳酸钾(1.81g,13.06mmol)、哌嗪-1-羧酸叔丁酯(1.46g,7.84mmol)，随后室温下搅拌9h，反应完成后，真空浓缩，残留物用100mL DCM溶解，用100mL水洗4次。收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH＝50:1)得到产物4-(1-((2-(甲氧羰基)-4-甲基噻吩-3-基)氨基)-1-氧代丙-2-基)哌嗪-1-羧酸叔丁酯(2.68g,99.7％)为无色油。Step 1: Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (2.0g, 6.53mmol) in a mixed solvent of 15mL DMF and 15mL ACN, add potassium carbonate ( 1.81g, 13.06mmol), piperazine-1-carboxylic acid tert-butyl ester (1.46g, 7.84mmol), and then stirred at room temperature for 9h. After the reaction was completed, concentrated in vacuo, the residue was dissolved in 100mL DCM, and washed 4 times with 100mL water. . The organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate. The residue was purified by column chromatography (DCM/MeOH=50:1) to obtain the product 4-(1-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-1-oxo Prop-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.68 g, 99.7%) was a colorless oil.
1H NMR(400MHz,CDCl3)δ9.96(s,1H),7.05(d,J＝1.1Hz,1H),3.76(s,3H),3.52(tt,J＝13.1,7.0Hz,4H),3.17(q,J＝7.0Hz,1H),2.65–2.39(m,4H),2.10(d,J＝1.0Hz,3H),1.41(s,9H),1.27(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.96 (s, 1H), 7.05 (d, J = 1.1Hz, 1H), 3.76 (s, 3H), 3.52 (tt, J = 13.1, 7.0Hz, 4H) ,3.17(q,J＝7.0Hz,1H),2.65–2.39(m,4H),2.10(d,J＝1.0Hz,3H),1.41(s,9H),1.27(d,J＝7.0Hz, 3H).
步骤2：将4-(1-((2-(甲氧羰基)-4-甲基噻吩-3-基)氨基)-1-氧代丙-2-基)哌嗪-1-羧酸叔丁酯(2.68g,6.51mmol)溶于10mL二氧六环中，滴加氯化氢二氧六环溶液(4M；4mL,16mmol)，室温下反应5h，过滤。滤饼用二氧六环清洗后得到产物4-甲基-3-(2-(哌嗪-1-基)丙酰胺基)噻吩-2-羧酸甲酯(2.0g,79.8％)为白色固体。Step 2: Combine 4-(1-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-1-oxoprop-2-yl)piperazine-1-carboxylic acid Butyl ester (2.68g, 6.51mmol) was dissolved in 10mL dioxane, hydrogen chloride dioxane solution (4M; 4mL, 16mmol) was added dropwise, reacted at room temperature for 5h, and filtered. After washing the filter cake with dioxane, the product 4-methyl-3-(2-(piperazin-1-yl)propionamido)thiophene-2-carboxylic acid methyl ester (2.0g, 79.8%) is white. solid.
1H NMR(400MHz,D2O)δ7.39(dd,J＝10.7,4.3Hz,1H),4.35(dq,J＝8.9,6.5Hz,1H),3.83–3.69(m,5H),3.68–3.56(m,6H),2.08–1.93(m,3H),1.71(d,J＝7.0Hz,3H). 1 H NMR (400MHz, D 2 O) δ7.39 (dd, J＝10.7, 4.3Hz, 1H), 4.35 (dq, J＝8.9, 6.5Hz, 1H), 3.83–3.69 (m, 5H), 3.68 –3.56(m,6H),2.08–1.93(m,3H),1.71(d,J＝7.0Hz,3H).
13C NMR(101MHz,D2O)δ168.20,163.08,163.04,136.64,136.61,128.43,124.49,124.44,64.24,52.52,46.97,40.89,40.86,13.95,13.91,12.84,12.80. 13 C NMR (101MHz, D 2 O) δ168.20,163.08,163.04,136.64,136.61,128.43,124.49,124.44,64.24,52.52,46.97,40.89,40.86,13.95,13.91,12.84,12 .80.
HPLC purity:99.543％,tR＝17.497min.HPLC purity:99.543%, t R =17.497min.
实施例15
Example 15
Example 15
将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(4.78g,15.6mmol)溶于30mL DMF中，加入碳酸钾(4.32g,31.2mmol)、1-异丙基哌嗪(2.4g,18.7mmol)，随后将反应液50℃搅拌3h，反应完成后真空浓缩，残留物用100mL DCM溶解，用100mL水洗4次。收集有机相浓缩，溶于水后滴加2M盐酸调整pH至2-3，水相用DCM洗涤，随后再用2
M的氢氧化钠溶液将水相pH调整至10-11，水相用DCM萃取。收集有机相用无水硫酸钠干燥。过滤干燥浓缩。得到产物3-(2-(4-异丙基哌嗪-1-基)丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(5.4g,97.8％)为无色油。将产物溶于50mL甲醇中，滴加15mL 2M盐酸，室温搅拌1h，旋干，溶于水中，过滤，滤液冻干得到产物的盐酸盐。Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (4.78g, 15.6mmol) in 30mL DMF, add potassium carbonate (4.32g, 31.2mmol), 1- Isopropylpiperazine (2.4g, 18.7mmol), and then the reaction solution was stirred at 50°C for 3h. After the reaction was completed, it was concentrated in vacuo. The residue was dissolved in 100mL DCM and washed 4 times with 100mL water. Collect the organic phase and concentrate, dissolve it in water and add 2M hydrochloric acid dropwise to adjust the pH to 2-3. The aqueous phase is washed with DCM, and then washed with 2 M hydrochloric acid. The pH of the aqueous phase was adjusted to 10-11 with M sodium hydroxide solution, and the aqueous phase was extracted with DCM. The organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate. The product 3-(2-(4-isopropylpiperazin-1-yl)propionamido)-4-methylthiophene-2-carboxylic acid methyl ester (5.4 g, 97.8%) was obtained as a colorless oil. Dissolve the product in 50 mL methanol, add 15 mL 2M hydrochloric acid dropwise, stir at room temperature for 1 h, spin dry, dissolve in water, filter, and freeze-dry the filtrate to obtain the hydrochloride salt of the product.
1H NMR(400MHz,CDCl3)δ9.94(s,1H),7.20–7.02(m,1H),3.84(s,3H),3.21(q,J＝7.0Hz,1H),2.70(dq,J＝12.9,6.4Hz,9H),2.17(d,J＝0.9Hz,3H),1.35(d,J＝7.0Hz,3H),1.09(d,J＝6.5Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.94 (s, 1H), 7.20–7.02 (m, 1H), 3.84 (s, 3H), 3.21 (q, J = 7.0Hz, 1H), 2.70 (dq, J＝12.9,6.4Hz,9H),2.17(d,J＝0.9Hz,3H),1.35(d,J＝7.0Hz,3H),1.09(d,J＝6.5Hz,6H).
13C NMR(151MHz,D2O)δ173.85,163.22,137.85,136.69,128.11,123.71,63.16,58.43,52.32,47.62,16.05,13.64,12.94. 13 C NMR (151MHz, D2O) δ173.85,163.22,137.85,136.69,128.11,123.71,63.16,58.43,52.32,47.62,16.05,13.64,12.94.
HRMS(EI)m/z:calcd for C17H28N3O3S,354.1846；found 354.1840[M+H]+.HRMS(EI)m/z:calcd for C 17 H 28 N 3 O 3 S,354.1846; found 354.1840[M+H] + .
HPLC purity:98.948％,tR＝15.932min.HPLC purity:98.948%, t R =15.932min.
实施例16
Example 16
Example 16
反应步骤同实施例15，产物为无色固体，产率61.7％。The reaction steps were the same as in Example 15. The product was a colorless solid with a yield of 61.7%.
1H NMR(400MHz,CDCl3)δ9.91(s,1H),7.21–7.04(m,1H),3.84(s,3H),3.22(q,J＝7.0Hz,1H),2.66(d,J＝51.4Hz,7H),2.40(d,J＝8.6Hz,1H),2.33(s,3H),2.20–2.11(m,3H),1.35(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.91 (s, 1H), 7.21–7.04 (m, 1H), 3.84 (s, 3H), 3.22 (q, J = 7.0Hz, 1H), 2.66 (d, J＝51.4Hz,7H),2.40(d,J＝8.6Hz,1H),2.33(s,3H),2.20–2.11(m,3H),1.35(d,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.54,162.72,141.78,136.20,127.10,127.02,118.45,64.84,55.28,51.86,51.76,46.10,46.02,15.60,15.55,12.59,12.53. 13 C NMR (101MHz, CDCl 3 ) δ172.54,162.72,141.78,136.20,127.10,127.02,118.45,64.84,55.28,51.86,51.76,46.10,46.02,15.60,15.55,12.59,12. 53.
HRMS(EI)m/z:calcd for C15H24N3O3S,326.1533；found 326.1526[M+H]+.HRMS(EI)m/z:calcd for C 15 H 24 N 3 O 3 S,326.1533; found 326.1526[M+H] + .
HPLC purity:98.402％,tR＝14.715min.HPLC purity:98.402%, t R =14.715min.
实施例17
Example 17
Example 17
反应步骤同实施例15，产物为白色油，产率70.8％。The reaction steps were the same as in Example 15. The product was white oil with a yield of 70.8%.
1H NMR(400MHz,CDCl3)δ9.91(s,1H),7.10(s,1H),3.81(s,3H),3.17(q,J＝7.0Hz,1H),2.66(d,J＝26.6Hz,8H),2.14(d,J＝0.9Hz,3H),1.32(d,J＝7.0Hz,3H),1.08(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ9.91 (s, 1H), 7.10 (s, 1H), 3.81 (s, 3H), 3.17 (q, J＝7.0Hz, 1H), 2.66 (d, J＝ 26.6Hz, 8H), 2.14 (d, J = 0.9Hz, 3H), 1.32 (d, J = 7.0Hz, 3H), 1.08 (s, 9H).
13C NMR(101MHz,CDCl3)δ172.76,162.70,141.80,136.19,127.11,127.04,118.49,64.83,53.74,51.83,51.72,45.84,25.92,25.86,15.63,15.58,15.54,12.74,12.67. 13 C NMR (101MHz, CDCl 3 ) δ172.76,162.70,141.80,136.19,127.11,127.04,118.49,64.83,53.74,51.83,51.72,45.84,25.92,25.86,15.63,15.58,15. 54,12.74,12.67.
HRMS(EI)m/z:calcd for C18H30N3O3S,368.2002；found 368.1995[M+H]+.HRMS(EI)m/z:calcd for C 18 H 30 N 3 O 3 S,368.2002; found 368.1995[M+H] + .
HPLC purity:98.050％,tR＝15.109min.HPLC purity:98.050%, t R =15.109min.
实施例18
Example 18
Example 18
反应步骤同实施例15，产物为无色油，产率51.0％。The reaction steps were the same as in Example 15. The product was colorless oil with a yield of 51.0%.
1H NMR(400MHz,CDCl3)δ10.02(s,1H),7.20–7.04(m,1H),3.93–3.79(m,7H),3.18(q,J＝7.0Hz,1H),2.74–2.55(m,4H),2.17(d,J＝0.9Hz,3H),1.36(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.02 (s, 1H), 7.20–7.04 (m, 1H), 3.93–3.79 (m, 7H), 3.18 (q, J = 7.0Hz, 1H), 2.74– 2.55(m,4H),2.17(d,J＝0.9Hz,3H),1.36(d,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.31,162.87,141.96,136.11,127.25,127.21,118.00,67.14,65.39,51.86,51.79,50.71,15.68,15.64,12.74,12.71. 13 C NMR (101MHz, CDCl 3 ) δ172.31,162.87,141.96,136.11,127.25,127.21,118.00,67.14,65.39,51.86,51.79,50.71,15.68,15.64,12.74,12.71.
HRMS(EI)m/z:calcd for C14H21N2O4S,313.1217；found 313.1210[M+H]+.HRMS(EI)m/z:calcd for C 14 H 21 N 2 O 4 S,313.1217; found 313.1210[M+H] + .
HPLC purity:99.358％,tR＝16.611min.HPLC purity:99.358%, t R =16.611min.
实施例19
Example 19
Example 19
反应步骤同实施例15，产物为淡黄色固体，产率74.0％。The reaction steps were the same as in Example 15. The product was a light yellow solid with a yield of 74.0%.
1H NMR(400MHz,CDCl3)δ9.95(s,1H),7.04(d,J＝1.2Hz,1H),3.77(s,3H),3.14(q,J＝7.0Hz,1H),2.70–2.34(m,4H),2.09(d,J＝1.0Hz,3H),1.63(pd,J＝7.8,7.1,3.2Hz,4H),1.41(p,J＝6.0Hz,2H),1.24(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.95 (s, 1H), 7.04 (d, J = 1.2Hz, 1H), 3.77 (s, 3H), 3.14 (q, J = 7.0Hz, 1H), 2.70 –2.34(m,4H),2.09(d,J＝1.0Hz,3H),1.63(pd,J＝7.8,7.1,3.2Hz,4H),1.41(p,J＝6.0Hz,2H),1.24( d,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.95,162.71,141.79,136.20,126.94,118.55,65.39,51.78,51.42,26.24,24.25,15.57,11.71. 13 C NMR (101MHz, CDCl 3 ) δ 172.95, 162.71, 141.79, 136.20, 126.94, 118.55, 65.39, 51.78, 51.42, 26.24, 24.25, 15.57, 11.71.
HPLC purity:95.461％,tR＝17.941min.
HPLC purity:95.461%, t R =17.941min.
实施例20
Example 20
Example 20
反应步骤同实施例15，产物为灰色固体，产率60.2％。The reaction steps were the same as in Example 15. The product was a gray solid with a yield of 60.2%.
1H NMR(400MHz,CDCl3)δ10.01(s,1H),7.33–7.27(m,2H),7.13(d,J＝1.1Hz,1H),7.02–6.94(m,2H),6.88(tt,J＝7.3,1.1Hz,1H),3.82(s,3H),3.44–3.24(m,5H),2.82(dddd,J＝36.3,10.8,6.8,3.8Hz,4H),2.19(d,J＝1.0Hz,3H),1.40(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.01 (s, 1H), 7.33–7.27 (m, 2H), 7.13 (d, J = 1.1Hz, 1H), 7.02–6.94 (m, 2H), 6.88 ( tt,J＝7.3,1.1Hz,1H),3.82(s,3H),3.44–3.24(m,5H),2.82(dddd,J＝36.3,10.8,6.8,3.8Hz,4H),2.19(d, J＝1.0Hz,3H),1.40(d,J＝7.0Hz,3H).
13C NMR(101MHz,Chloroform-d)δ172.39,162.78,151.33,141.89,136.16,129.16,127.14,119.76,118.26,116.16,65.02,51.85,50.25,49.36,15.63,12.67. 13 C NMR (101MHz, Chloroform-d) δ172.39,162.78,151.33,141.89,136.16,129.16,127.14,119.76,118.26,116.16,65.02,51.85,50.25,49.36,15.63,12.6 7.
HPLC purity:98.645％,tR＝20.010min.HPLC purity:98.645%, t R =20.010min.
实施例21
Example 21
Example 21
将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(1.22g,3.98mmol)溶于20mL DMF中，加入碳酸钾(3.30g,23.91mmol)、1-丙基哌嗪(511mg,3.98mmol)，随后将反应液室温搅拌过夜，反应完成后过滤，将滤液真空浓缩，残留物溶于100mL DCM中，用100mL水洗4次。收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH＝40:1)得到产物4-甲基-3-(2-(4-丙基哌嗪-1-基)丙酰胺基)噻吩-2-羧酸甲酯(912mg,74.8％)为无色油。将产物溶于10mL甲醇中，滴加5mL 2M盐酸，室温搅拌1h，旋干，溶于水中，过滤，滤液冻干得到产物的盐酸盐。Dissolve 3-(2-bromopropionamido)-4-methylthiophene-2-carboxylic acid methyl ester (1.22g, 3.98mmol) in 20mL DMF, add potassium carbonate (3.30g, 23.91mmol), 1- Propylpiperazine (511 mg, 3.98 mmol), and then the reaction solution was stirred at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in 100 mL DCM and washed 4 times with 100 mL water. The organic phase was collected and dried over anhydrous sodium sulfate. Filter, dry and concentrate. The residue was purified by column chromatography (DCM/MeOH=40:1) to obtain the product 4-methyl-3-(2-(4-propylpiperazin-1-yl)propionamido)thiophene-2-carboxylic acid. The methyl ester (912 mg, 74.8%) was a colorless oil. Dissolve the product in 10 mL methanol, add 5 mL 2M hydrochloric acid dropwise, stir at room temperature for 1 h, spin dry, dissolve in water, filter, and freeze-dry the filtrate to obtain the hydrochloride salt of the product.
1H NMR(400MHz,CDCl3)δ9.89(s,1H),7.10(d,J＝1.4Hz,1H),3.82(d,J＝1.1Hz,3H),3.27–3.12(m,1H),2.87–2.38(m,8H),2.38–2.28(m,2H),2.14(d,J＝1.1Hz,3H),1.59–1.44(m,2H),1.38–1.28(m,3H),0.96–0.81(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.89 (s, 1H), 7.10 (d, J = 1.4Hz, 1H), 3.82 (d, J = 1.1Hz, 3H), 3.27–3.12 (m, 1H) ,2.87–2.38(m,8H),2.38–2.28(m,2H),2.14(d,J＝1.1Hz,3H),1.59–1.44(m,2H),1.38–1.28(m,3H),0.96 –0.81(m,3H).
13C NMR(101MHz,CDCl3)δ172.58,162.71,141.79,136.21,127.02,118.49,64.87,60.67,53.41,51.78,20.07,15.55,12.53,11.99.
13 C NMR (101MHz, CDCl 3 ) δ172.58,162.71,141.79,136.21,127.02,118.49,64.87,60.67,53.41,51.78,20.07,15.55,12.53,11.99.
HPLC purity:98.935％,tR＝18.446min.HPLC purity:98.935%, t R =18.446min.
实施例22
Example 22
Example 22
反应步骤同实施例21，产物为无色油，产率52.7％。The reaction steps were the same as in Example 21. The product was colorless oil with a yield of 52.7%.
1H NMR(400MHz,CDCl3)δ9.84(s,1H),7.05(d,J＝1.2Hz,1H),3.77(s,3H),3.14(q,J＝7.0Hz,1H),2.90–2.36(m,8H),2.36–2.28(m,2H),2.09(d,J＝1.0Hz,3H),1.50–1.38(m,2H),1.33–1.21(m,5H),0.86(t,J＝7.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.84 (s, 1H), 7.05 (d, J = 1.2Hz, 1H), 3.77 (s, 3H), 3.14 (q, J = 7.0Hz, 1H), 2.90 –2.36(m,8H),2.36–2.28(m,2H),2.09(d,J＝1.0Hz,3H),1.50–1.38(m,2H),1.33–1.21(m,5H),0.86(t ,J＝7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ172.56,162.73,141.80,136.22,127.03,118.49,64.87,58.47,53.43,51.79,29.05,20.81,15.55,14.07,12.53. 13 C NMR (101MHz, CDCl 3 ) δ 172.56, 162.73, 141.80, 136.22, 127.03, 118.49, 64.87, 58.47, 53.43, 51.79, 29.05, 20.81, 15.55, 14.07, 12.53.
HPLC purity:99.409％,tR＝19.173min.HPLC purity:99.409%, t R =19.173min.
实施例23
Example 23
Example 23
反应步骤同实施例21，产物为无色油，产率58.1％。The reaction steps were the same as in Example 21. The product was colorless oil with a yield of 58.1%.
1H NMR(400MHz,CDCl3)δ9.84(s,1H),7.05(s,1H),3.76(s,3H),3.46(t,J＝5.6Hz,2H),3.29(s,3H),3.14(q,J＝7.0Hz,1H),2.78–2.41(m,10H),2.09(s,3H),1.27(d,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.84 (s, 1H), 7.05 (s, 1H), 3.76 (s, 3H), 3.46 (t, J = 5.6Hz, 2H), 3.29 (s, 3H) ,3.14(q,J＝7.0Hz,1H),2.78–2.41(m,10H),2.09(s,3H),1.27(d,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.56,162.71,141.79,136.20,127.02,118.47,70.17,64.85,58.91,57.88,53.78,51.77,15.54,12.50. 13 C NMR (101MHz, CDCl 3 ) δ172.56,162.71,141.79,136.20,127.02,118.47,70.17,64.85,58.91,57.88,53.78,51.77,15.54,12.50.
HPLC purity:99.002％,tR＝18.203min.HPLC purity:99.002%, t R =18.203min.
实施例24
Example 24
Example 24
反应步骤同实施例21，产物为无色油，产率82.0％。The reaction steps were the same as in Example 21. The product was colorless oil with a yield of 82.0%.
1H NMR(400MHz,Chloroform-d)δ9.91(s,1H),7.10(d,J＝1.0Hz,1H),3.82(s,3H),3.21(q,J＝7.0Hz,1H),2.70(dd,J＝26.5,4.6Hz,8H),2.29(d,J＝6.6Hz,2H),2.15(d,J＝1.0Hz,3H),1.34(d,J＝7.0Hz,3H),0.88(ddtd,J＝11.4,7.9,6.5,4.8Hz,1H),0.59–0.44(m,2H),0.17–0.07(m,2H). 1 H NMR (400MHz, Chloroform-d) δ9.91 (s, 1H), 7.10 (d, J = 1.0Hz, 1H), 3.82 (s, 3H), 3.21 (q, J = 7.0Hz, 1H), 2.70(dd,J＝26.5,4.6Hz,8H),2.29(d,J＝6.6Hz,2H),2.15(d,J＝1.0Hz,3H),1.34(d,J＝7.0Hz,3H), 0.88(ddtd,J＝11.4,7.9,6.5,4.8Hz,1H),0.59–0.44(m,2H),0.17–0.07(m,2H).
13C NMR(101MHz,CDCl3)δ172.35,162.50,141.61,135.98,126.82,118.20,64.65,63.51,53.23,51.53,15.35,12.27,8.15,3.70. 13 C NMR (101MHz, CDCl 3 ) δ 172.35, 162.50, 141.61, 135.98, 126.82, 118.20, 64.65, 63.51, 53.23, 51.53, 15.35, 12.27, 8.15, 3.70.
HPLC purity:99.556％,tR＝18.690min.HPLC purity:99.556%, t R =18.690min.
实施例25
Example 25
Example 25
反应步骤同实施例21，产物为无色油，产率40.9％。The reaction steps were the same as in Example 21. The product was colorless oil with a yield of 40.9%.
1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),7.05(d,J＝1.0Hz,1H),3.76(s,3H),3.58(t,J＝5.4Hz,2H),3.15(q,J＝7.0Hz,1H),2.74–2.49(m,10H),2.09(d,J＝1.0Hz,3H),1.28(d,J＝7.0Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.84 (s, 1H), 7.05 (d, J = 1.0Hz, 1H), 3.76 (s, 3H), 3.58 (t, J = 5.4Hz, 2H), 3.15(q,J＝7.0Hz,1H),2.74–2.49(m,10H),2.09(d,J＝1.0Hz,3H),1.28(d,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.54,162.86,141.93,136.27,127.19,118.41,64.96,59.37,57.88,53.13,51.87,15.65,12.72. 13 C NMR (101MHz, CDCl 3 ) δ 172.54, 162.86, 141.93, 136.27, 127.19, 118.41, 64.96, 59.37, 57.88, 53.13, 51.87, 15.65, 12.72.
HPLC purity:99.721％,tR＝17.124min.HPLC purity:99.721%, t R =17.124min.
实施例26
Example 26
Example 26
步骤1：反应步骤同实施例1步骤1，白色固体，产率88.8％。Step 1: The reaction procedure is the same as step 1 in Example 1, white solid, yield 88.8%.
1H NMR(400MHz,CDCl3)δ9.36(s,1H),7.10(s,1H),3.97(s,2H),3.82(s,3H),2.13(d,J＝1.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.36 (s, 1H), 7.10 (s, 1H), 3.97 (s, 2H), 3.82 (s, 3H), 2.13 (d, J = 1.0Hz, 3H) .
步骤2：同实施例2，产物为无色油，产率46.3％。Step 2: Same as Example 2, the product is colorless oil, and the yield is 46.3%.
1H NMR(400MHz,CDCl3)δ9.85(s,1H),7.06(s,1H),3.77(s,3H),3.12(s,2H),2.64(dt,J＝13.6,4.6Hz,9H),2.12(s,3H),1.02(d,J＝6.5Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.85 (s, 1H), 7.06 (s, 1H), 3.77 (s, 3H), 3.12 (s, 2H), 2.64 (dt, J = 13.6, 4.6Hz, 9H), 2.12 (s, 3H), 1.02 (d, J = 6.5Hz, 6H).
13C NMR(101MHz,CDCl3)δ167.83,161.70,140.49,135.23,126.11,117.67,61.03,53.47,52.97,50.77,47.70,17.65,14.59. 13 C NMR (101MHz, CDCl 3 ) δ 167.83, 161.70, 140.49, 135.23, 126.11, 117.67, 61.03, 53.47, 52.97, 50.77, 47.70, 17.65, 14.59.
HPLC purity:97.830％,tR＝17.898min.HPLC purity:97.830%, t R =17.898min.
实施例27
Example 27
Example 27
步骤1：反应步骤同实施例1步骤1，白色固体，产率87.0％。Step 1: The reaction procedure is the same as step 1 in Example 1, white solid, yield 87.0%.
1H NMR(400MHz,CDCl3)δ9.26(s,1H),7.09(d,J＝1.1Hz,1H),4.33(dd,J＝7.8,5.7Hz,1H),3.81(s,3H),2.26–2.01(m,5H),1.06(t,J＝7.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.26 (s, 1H), 7.09 (d, J = 1.1Hz, 1H), 4.33 (dd, J = 7.8, 5.7Hz, 1H), 3.81 (s, 3H) ,2.26–2.01(m,5H),1.06(t,J＝7.3Hz,3H).
步骤2：同实施例2，产物为无色油，产率28.7％。Step 2: Same as Example 2, the product is colorless oil, and the yield is 28.7%.
1H NMR(400MHz,CDCl3)δ9.75(s,1H),7.05(d,J＝1.5Hz,1H),3.77(s,3H),2.89–2.84(m,1H),2.63(ddt,J＝25.6,19.5,8.7Hz,9H),2.13(d,J＝1.4Hz,3H),1.85–1.67(m,2H),1.06–0.92(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ9.75 (s, 1H), 7.05 (d, J = 1.5Hz, 1H), 3.77 (s, 3H), 2.89–2.84 (m, 1H), 2.63 (ddt, J＝25.6,19.5,8.7Hz,9H),2.13(d,J＝1.4Hz,3H),1.85–1.67(m,2H),1.06–0.92(m,9H).
13C NMR(101MHz,CDCl3)δ170.73,161.90,141.18,135.03,126.24,116.70,70.52,53.50,50.74,47.86,20.80,17.63,17.59,15.02,10.19. 13 C NMR (101MHz, CDCl 3 ) δ170.73,161.90,141.18,135.03,126.24,116.70,70.52,53.50,50.74,47.86,20.80,17.63,17.59,15.02,10.19.
HPLC purity:99.081％,tR＝19.175min.HPLC purity:99.081%, t R =19.175min.
实施例28
Example 28
Example 28
反应步骤同实施例1，产物为无色油，产率36.3％。The reaction steps were the same as in Example 1, the product was colorless oil, and the yield was 36.3%.
1H NMR(400MHz,D2O)δ7.43(s,1H),4.27(q,J＝7.0Hz,1H),4.21(t,J＝6.5Hz,2H),3.15–2.97(m,2H),2.83(s,1H),2.07(s,3H),1.80–1.65(m,7H),0.96(dt,J＝22.1,7.4Hz,6H). 1 H NMR (400MHz, D 2 O) δ7.43 (s, 1H), 4.27 (q, J = 7.0Hz, 1H), 4.21 (t, J = 6.5Hz, 2H), 3.15–2.97 (m, 2H ),2.83(s,1H),2.07(s,3H),1.80–1.65(m,7H),0.96(dt,J＝22.1,7.4Hz,6H).
13C NMR(101MHz,D2O)δ169.06,162.85,136.86,136.64,128.20,128.16,124.55,67.53,56.21,48.20,21.52,19.29,15.93,12.81,10.18,9.63. 13 C NMR (101MHz, D 2 O) δ 169.06, 162.85, 136.86, 136.64, 128.20, 128.16, 124.55, 67.53, 56.21, 48.20, 21.52, 19.29, 15.93, 12.81, 10.18, 9.63.
HRMS(EI)m/z:calcd for C15H15N2O3S,313.1580；found 313.1580[M+H]+.HRMS(EI)m/z:calcd for C 15 H 15 N 2 O 3 S,313.1580; found 313.1580[M+H] + .
HPLC purity:97.343％,tR＝19.234min.HPLC purity:97.343%, t R =19.234min.
实施例29
Example 29
Example 29
反应步骤同实施例1，产物为无色油，产率43.1％。The reaction steps were the same as in Example 1, the product was colorless oil, and the yield was 43.1%.
1H NMR(400MHz,D2O)δ7.31(d,J＝7.5Hz,1H),4.17(dt,J＝13.6,6.7Hz,3H),3.06–2.84(m,2H),2.74(s,1H),1.97(d,J＝1.5Hz,3H),1.70–1.52(m,7H),1.28(qt,J＝9.4,4.9Hz,2H),0.88(td,J＝7.4,1.3Hz,3H),0.83–0.75(m,3H). 1 H NMR (400MHz, D 2 O) δ7.31 (d, J＝7.5Hz, 1H), 4.17 (dt, J＝13.6, 6.7Hz, 3H), 3.06–2.84 (m, 2H), 2.74 (s ,1H),1.97(d,J＝1.5Hz,3H),1.70–1.52(m,7H),1.28(qt,J＝9.4,4.9Hz,2H),0.88(td,J＝7.4,1.3Hz, 3H),0.83–0.75(m,3H).
13C NMR(101MHz,D2O)δ168.99,162.78,137.05,136.65,128.07,124.46,65.80,56.21,48.21,30.05,19.30,18.62,15.96,12.99,12.83,10.20. 13 C NMR (101MHz, D 2 O) δ 168.99, 162.78, 137.05, 136.65, 128.07, 124.46, 65.80, 56.21, 48.21, 30.05, 19.30, 18.62, 15.96, 12.99, 12.83, 10.20.
HRMS(EI)m/z:calcd for C16H17N2O3S,327.1737；found 327.1737[M+H]+.HRMS(EI)m/z:calcd for C 16 H 17 N 2 O 3 S,327.1737; found 327.1737[M+H] + .
HPLC purity:98.835％,tR＝19.758min.HPLC purity:98.835%, t R =19.758min.
实施例30
Example 30
Example 30
反应步骤同实施例1，产物为无色油，产率50.7％。The reaction steps were the same as in Example 1, the product was colorless oil, and the yield was 50.7%.
1H NMR(400MHz,D2O)δ7.44(d,J＝0.9Hz,1H),4.29(dq,J＝10.5,7.1Hz,3H),3.15–2.97(m,2H),2.83(s,1H),2.07(s,3H),1.84–1.63(m,5H),1.31(t,J＝7.1Hz,3H),0.98(t,
J＝7.5Hz,3H). 1 H NMR (400MHz, D 2 O) δ7.44 (d, J＝0.9Hz, 1H), 4.29 (dq, J＝10.5, 7.1Hz, 3H), 3.15–2.97 (m, 2H), 2.83 (s ,1H),2.07(s,3H),1.84–1.63(m,5H),1.31(t,J=7.1Hz,3H),0.98(t, J＝7.5Hz,3H).
13C NMR(101MHz,D2O)δ169.10,162.81,136.84,136.64,128.19,124.62,62.23,56.19,48.18,19.28,15.87,13.52,12.80,10.17. 13 C NMR (101MHz, D 2 O) δ169.10,162.81,136.84,136.64,128.19,124.62,62.23,56.19,48.18,19.28,15.87,13.52,12.80,10.17.
HRMS(EI)m/z:calcd for C14H23N2O3S,299.1424；found 299.1427[M+H]+.HRMS(EI)m/z:calcd for C 14 H 23 N 2 O 3 S,299.1424; found 299.1427[M+H] + .
实施例31
Example 31
Example 31
反应步骤同实施例1，产物为无色油，产率31.5％。The reaction steps were the same as in Example 1, the product was colorless oil, and the yield was 31.5%.
1H NMR(400MHz,Chloroform-d)δ6.97(s,1H),4.24(t,J＝6.1Hz,1H),3.84–3.75(m,1H),2.79(qd,J＝5.0,3.1Hz,1H),1.83–1.73(m,1H),1.57–1.46(m,1H),1.44–1.36(m,1H),1.40–1.30(m,1H),1.33–1.24(m,5H),0.90(dt,J＝8.6,6.9Hz,3H).1H NMR(400MHz,Chloroform-d)δ6.97(s,1H),4.24(t,J＝6.1Hz,1H),3.84–3.75(m,1H),2.79(qd,J＝5.0,3.1Hz, 1H),1.83–1.73(m,1H),1.57–1.46(m,1H),1.44–1.36(m,1H),1.40–1.30(m,1H),1.33–1.24(m,5H),0.90( dt,J＝8.6,6.9Hz,3H).
HRMS(EI)m/z:calcd for C20H34N2O3S,299.1424；found 383.2369[M+H]+.HRMS(EI)m/z:calcd for C 20 H 34 N 2 O 3 S,299.1424; found 383.2369[M+H] + .
实施例32
Example 32
Example 32
反应步骤同实施例2，产物为无色油状物，产率71.5％。The reaction steps were the same as in Example 2. The product was colorless oil with a yield of 71.5%.
1H NMR(400MHz,Chloroform-d)δ9.47(s,1H),6.98(s,1H),3.91(s,3H),3.57(q,J＝6.4Hz,1H),2.86–2.69(m,3H),2.25(d,J＝0.7Hz,3H),1.74–1.47(m,4H),1.39–1.26(m,4H),1.11(d,J＝5.9Hz,3H),0.92(d,J＝6.4Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ9.47 (s, 1H), 6.98 (s, 1H), 3.91 (s, 3H), 3.57 (q, J = 6.4Hz, 1H), 2.86–2.69 (m ,3H),2.25(d,J＝0.7Hz,3H),1.74–1.47(m,4H),1.39–1.26(m,4H),1.11(d,J＝5.9Hz,3H),0.92(d, J＝6.4Hz,3H).
HRMS(EI)m/z:calcd for C17H26N2O3S,339.1737；found 339.1670[M+H]+.HRMS(EI)m/z:calcd for C 17 H 26 N 2 O 3 S,339.1737; found 339.1670[M+H] + .
实施例33
Example 33
Example 33
反应步骤同实施例2，将3-(2-(4-乙基哌嗪-1-基)丙酰胺基)-4-甲基噻吩-2-羧酸甲酯溶于甲醇中，室温下滴加盐酸溶液，室温搅拌1h后旋干，残留物溶于水中后过滤除去杂质，滤液冻干后得到产物的盐酸盐。
The reaction steps are the same as in Example 2. Dissolve 3-(2-(4-ethylpiperazin-1-yl)propionamido)-4-methylthiophene-2-carboxylic acid methyl ester in methanol and drop it at room temperature. Add hydrochloric acid solution, stir at room temperature for 1 hour and then spin to dryness. The residue is dissolved in water and filtered to remove impurities. The filtrate is freeze-dried to obtain the hydrochloride salt of the product.
The reaction steps are the same as in Example 2. Dissolve 3-(2-(4-ethylpiperazin-1-yl)propionamido)-4-methylthiophene-2-carboxylic acid methyl ester in methanol and drop it at room temperature. Add hydrochloric acid solution, stir at room temperature for 1 hour and then spin to dryness. The residue is dissolved in water and filtered to remove impurities. The filtrate is freeze-dried to obtain the hydrochloride salt of the product.
以上化合物制备过程中的反应条件与实施例1相同，区别在于根据取代基的差异替换对应的原料。The reaction conditions in the preparation process of the above compounds are the same as those in Example 1, except that the corresponding raw materials are replaced according to the differences in substituents.
实施例106
Example 106
Example 106
将1a(20.0g，116.80mmol)溶于100mL二氯甲烷(DCM)中，加入23.6g三乙胺，0℃滴加溶于20mL DCM的2-溴丙酰溴(27.7g，128.5mmol)，室温搅拌反应12h，利用TLC监测反应情况。待反应基本完全，用DCM萃取，有机相用无水硫酸钠干燥，过滤后减压旋干溶剂。得到33.2g类白色固体粉末1c，产率93％。Dissolve 1a (20.0g, 116.80mmol) in 100mL dichloromethane (DCM), add 23.6g triethylamine, and add dropwise 2-bromopropionyl bromide (27.7g, 128.5mmol) dissolved in 20mL DCM at 0°C. The reaction was stirred at room temperature for 12 h, and TLC was used to monitor the reaction. When the reaction is almost complete, extract with DCM, dry the organic phase with anhydrous sodium sulfate, filter and spin the solvent to dryness under reduced pressure. 33.2g of off-white solid powder 1c was obtained, with a yield of 93%.
1H NMR(500MHz,Chloroform-d)δ9.30(s,1H),7.16(s,1H),4.57(q,J＝7.0Hz,1H),3.87(s,3H),2.18(s,3H),1.97(d,J＝7.0Hz,3H). 1 H NMR (500MHz, Chloroform-d) δ9.30 (s, 1H), 7.16 (s, 1H), 4.57 (q, J = 7.0Hz, 1H), 3.87 (s, 3H), 2.18 (s, 3H ),1.97(d,J＝7.0Hz,3H).
将化合物1c(3.0g，9.80mmol)和碳酸钾(2.7g，19.60mmol)加入到30mL DMF，搅拌下加入1d(1.08g，10.78mmol)，50℃搅拌反应2h，将反应液减压旋干，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝50:1，纯化后得到2.8g无色油状物1。产率88％。Add compound 1c (3.0g, 9.80mmol) and potassium carbonate (2.7g, 19.60mmol) to 30mL DMF, add 1d (1.08g, 10.78mmol) under stirring, stir the reaction at 50°C for 2h, and spin the reaction solution to dryness under reduced pressure. , the crude product was purified by silica gel column chromatography, eluent: DCM:MeOH=50:1, and 2.8g of colorless oil 1 was obtained after purification. Yield 88%.
1H NMR(500MHz,Chloroform-d)δ9.43(s,1H),6.98(s,1H),3.91(s,2H),3.78(d,J＝0.9Hz,1H),3.65(d,J＝0.9Hz,1H),3.45(q,J＝6.8Hz,1H),2.97(ddd,J＝12.3,4.4,1.9Hz,1H),2.66–2.55(m,4H),2.50(ddd,J＝11.4,4.4,1.9Hz,1H),1.32(d,J＝6.6Hz,3H),1.07(t,J＝7.2Hz,3H). 1 H NMR (500MHz, Chloroform-d) δ9.43 (s, 1H), 6.98 (s, 1H), 3.91 (s, 2H), 3.78 (d, J = 0.9Hz, 1H), 3.65 (d, J ＝0.9Hz,1H),3.45(q,J＝6.8Hz,1H),2.97(ddd,J＝12.3,4.4,1.9Hz,1H),2.66–2.55(m,4H),2.50(ddd,J＝ 11.4, 4.4, 1.9Hz, 1H), 1.32 (d, J = 6.6Hz, 3H), 1.07 (t, J = 7.2Hz, 3H).
实施例107
Example 107
Example 107
将化合物1c(2.0g，6.53mmol)和碳酸钾(1.8g，13.06mmol)加入到20mL DMF，搅拌下加入2b(1.08g，10.78mmol)，50℃搅拌反应2h，将反应液减压旋干，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝50:1，纯化后得到1.8g无色油状物2c。产率81％。Add compound 1c (2.0g, 6.53mmol) and potassium carbonate (1.8g, 13.06mmol) to 20mL DMF, add 2b (1.08g, 10.78mmol) under stirring, stir and react at 50°C for 2h, and spin down the reaction solution under reduced pressure. , the crude product was purified by silica gel column chromatography, eluent: DCM:MeOH=50:1, and 1.8g of colorless oil 2c was obtained after purification. Yield 81%.
1H NMR(500MHz,Chloroform-d)δ9.43(s,1H),6.98(s,1H),3.91(s,2H),3.73(t,J＝0.7Hz,1H),3.66(d,J＝0.8Hz,1H),3.46(q,J＝6.7Hz,1H),3.02(ddd,J＝12.3,4.6,2.7Hz,1H),2.99–2.87(m,2H),2.79(dddd,J＝25.4,12.2,4.4,2.6Hz,2H),1.32(d,J＝6.8Hz,3H),1.15(d,J＝6.8Hz,3H),1.10(d,J＝6.6Hz,3H). 1 H NMR (500MHz, Chloroform-d) δ9.43 (s, 1H), 6.98 (s, 1H), 3.91 (s, 2H), 3.73 (t, J = 0.7Hz, 1H), 3.66 (d, J ＝0.8Hz,1H),3.46(q,J＝6.7Hz,1H),3.02(ddd,J＝12.3,4.6,2.7Hz,1H),2.99–2.87(m,2H),2.79(dddd,J＝ 25.4,12.2,4.4,2.6Hz,2H),1.32(d,J＝6.8Hz,3H),1.15(d,J＝6.8Hz,3H),1.10(d,J＝6.6Hz,3H).
将2c(1.0g，2.95mmol)溶于20mL MeOH中，加入氢氧化钠溶液，50℃搅拌2h，TLC监测反应完全。过滤后，减压蒸干溶剂。将固体溶于50mL水中，正丁醇萃取(50mL×5)，有机相用无水硫酸钠干燥，减压浓缩，得800mg白色固体，将固体溶于20mL DMF中，加入溴乙烷(495mg，5.89mmol)，室温反应5h，TLC监测反应完全。加入100mL DCM，200mL水洗3次，有机相用无水硫酸钠干燥后，减压蒸干溶剂。柱层析纯化得到750mg无色油状物2，产率72％。Dissolve 2c (1.0g, 2.95mmol) in 20mL MeOH, add sodium hydroxide solution, stir at 50°C for 2h, and monitor the reaction to be complete by TLC. After filtration, the solvent was evaporated to dryness under reduced pressure. Dissolve the solid in 50 mL of water, extract with n-butanol (50 mL 5.89mmol), reacted at room temperature for 5 hours, and TLC monitored the reaction to be complete. Add 100 mL DCM, wash 3 times with 200 mL water, dry the organic phase with anhydrous sodium sulfate, and evaporate the solvent to dryness under reduced pressure. Purification by column chromatography yielded 750 mg of colorless oil 2, with a yield of 72%.
1H NMR(500MHz,Chloroform-d)δ9.42(s,1H),6.98(s,1H),4.32(q,J＝6.4Hz,2H),3.73(t,J＝0.7Hz,1H),3.66(d,J＝0.7Hz,1H),3.46(q,J＝6.7Hz,1H),3.02(ddd,J＝12.3,4.6,2.7Hz,1H),2.99–2.87(m,2H),2.79(dddd,J＝25.4,12.2,4.3,2.6Hz,2H),1.36(t,J＝6.4Hz,3H),1.32(d,J＝6.8Hz,3H),1.15(d,J＝6.8Hz,3H),1.10(d,J＝6.6Hz,3H). 1 H NMR (500MHz, Chloroform-d) δ9.42 (s, 1H), 6.98 (s, 1H), 4.32 (q, J = 6.4Hz, 2H), 3.73 (t, J = 0.7Hz, 1H), 3.66(d,J＝0.7Hz,1H),3.46(q,J＝6.7Hz,1H),3.02(ddd,J＝12.3,4.6,2.7Hz,1H),2.99–2.87(m,2H),2.79 (dddd,J＝25.4,12.2,4.3,2.6Hz,2H),1.36(t,J＝6.4Hz,3H),1.32(d,J＝6.8Hz,3H),1.15(d,J＝6.8Hz, 3H),1.10(d,J＝6.6Hz,3H).
实施例108
Example 108
Example 108
将实施例70产物600mg溶解于甲醇10mL，冰浴下滴加2倍物质的量的0.1mol/L的盐酸-甲醇溶液，减压浓缩。残留物溶于水后过滤，滤液真空冻干，得到白色固体3。Dissolve 600 mg of the product of Example 70 in 10 mL of methanol, add dropwise a 0.1 mol/L hydrochloric acid-methanol solution that is twice the amount of the substance in an ice bath, and concentrate under reduced pressure. The residue was dissolved in water and filtered, and the filtrate was freeze-dried under vacuum to obtain white solid 3.
实施例109
Example 109
Example 109
将原料4a(3.0g，14.98mmol)溶于30mL ACN中，加入碳酸钾(4.14g，29.96mmol)和1-溴丁烷(2.26g，16.48mmol)，常温下搅拌过夜，TLC监测反应完全。过滤，减压
浓缩ACN，得粗产品。用硅胶柱柱层析纯化(EA:PE＝20％)，得2.0g无色油状物，产率85％。Dissolve raw material 4a (3.0g, 14.98mmol) in 30mL ACN, add potassium carbonate (4.14g, 29.96mmol) and 1-bromobutane (2.26g, 16.48mmol), stir at room temperature overnight, and monitor the reaction to be complete by TLC. filter, reduce pressure Concentrate ACN to obtain crude product. Purified by silica gel column chromatography (EA:PE=20%), 2.0g of colorless oil was obtained with a yield of 85%.
1H NMR(500MHz,Chloroform-d)δ2.84–2.70(m,4H),2.62(dt,J＝6.0,5.2Hz,2H),2.50(dt,J＝11.2,6.3Hz,2H),2.44(t,J＝6.5Hz,2H),2.15–2.08(m,1H),1.76–1.66(m,2H),1.51–1.42(m,2H),1.37–1.27(m,2H),0.93(t,J＝7.4Hz,3H). 1 H NMR(500MHz,Chloroform-d)δ2.84–2.70(m,4H),2.62(dt,J＝6.0,5.2Hz,2H),2.50(dt,J＝11.2,6.3Hz,2H),2.44 (t,J＝6.5Hz,2H),2.15–2.08(m,1H),1.76–1.66(m,2H),1.51–1.42(m,2H),1.37–1.27(m,2H),0.93(t ,J＝7.4Hz,3H).
将其溶于10mL DCM中，加入10mL TFA，常温搅拌反应1h，点板反应完全，旋干溶剂得4c。将化合物1c(3.56g，11.63mmol)和碳酸钾(6.43g，46.54mmol)加入到30mL DMF，搅拌下加入4c(12.80mmol)，室温搅拌反应5h，将反应液减压旋干，粗产品用硅胶柱柱层析纯化，洗脱剂：DCM:MeOH＝50:1，纯化后得到3.6g无色油状物4。产率81％。Dissolve it in 10mL DCM, add 10mL TFA, stir and react at room temperature for 1 hour, spot plate reaction is complete, and spin dry the solvent to obtain 4c. Add compound 1c (3.56g, 11.63mmol) and potassium carbonate (6.43g, 46.54mmol) to 30mL DMF, add 4c (12.80mmol) under stirring, stir and react at room temperature for 5h, spin the reaction solution to dryness under reduced pressure, and use the crude product Purify by silica gel column chromatography, eluent: DCM:MeOH=50:1, and obtain 3.6 g of colorless oil 4 after purification. Yield 81%.
实施例110
Example 110
Example 110
将实施例109产物1.0g溶解于甲醇15mL，冰浴下滴加等物质的量的0.1mol/L的硫酸-甲醇溶液，减压浓缩至干。残留物溶于水后过滤，滤液真空冻干，得到白色固体(5)。Dissolve 1.0 g of the product of Example 109 in 15 mL of methanol, add an equal amount of 0.1 mol/L sulfuric acid-methanol solution dropwise in an ice bath, and concentrate to dryness under reduced pressure. The residue was dissolved in water and filtered, and the filtrate was freeze-dried under vacuum to obtain a white solid (5).
按照上述实施例的方法，得到以下实施例化合物：
According to the method of the above examples, the following example compounds were obtained:
According to the method of the above examples, the following example compounds were obtained:
以上化合物制备过程中的反应条件与实施例107相同，区别在于根据取代基的差异替换对应的原料。The reaction conditions in the preparation process of the above compounds are the same as those in Example 107, except that the corresponding raw materials are replaced according to the differences in substituents.
以下通过实验例证明本发明的有益效果。以下实验中，各实施例制备得到的化合物以实施例的序号命名，例如，实施例1制备得化合物命名为化合物1。The beneficial effects of the present invention are demonstrated below through experimental examples. In the following experiments, the compounds prepared in each example are named with the serial number of the example. For example, the compound prepared in Example 1 is named compound 1.
实验例1、本发明化合物的局部麻醉作用Experimental Example 1. Local anesthetic effect of the compound of the present invention
1、坐骨神经阻滞模型1. Sciatic nerve block model
选取实施例1～168制备的化合物(化合物1-168)，阿替卡因阳性对照组给予8组完全适应实验环境的受试大鼠，每组6只。
The compounds prepared in Examples 1 to 168 (compounds 1 to 168) were selected, and the articaine positive control group was administered to 8 groups of test rats that were fully adapted to the experimental environment, with 6 rats in each group.
给药剂量为：阿替卡因组浓度为2％水溶液，待测药物浓度均为62mmol/L的生理盐水溶液。The dosage is: the concentration of articaine group is 2% aqueous solution, and the concentration of the drug to be tested is 62mmol/L physiological saline solution.
每只大鼠给药或对照的注射体积为0.5ml，通过神经定位器导向定位，注射于大鼠坐骨神经附近。通过von Frey刺激仪，刺激大鼠注射药物体侧足底，观测局部麻醉效果。同时，由后肢蹬踏试验(Postural Extensor Thrust,PET)评价大鼠运动功能情况：垂直提起大鼠并使注射侧后肢蹬在电子天平台面上，此时大鼠后肢肌力由肢体蹬踏天平而显示出的数值表示。肢体完全麻痹时，读数为肢体自身重量，约20g。测量值超过基线与肢体重量差值的一半视为运动功能恢复，小于或等于该值视为运动功能消失。The injection volume of each rat for administration or control was 0.5 ml, guided and positioned by a nerve locator, and injected near the sciatic nerve of the rat. The von Frey stimulator was used to stimulate the sole of the rat's side of the body where the drug was injected, and the local anesthesia effect was observed. At the same time, the motor function of the rat was evaluated by the Postural Extensor Thrust (PET) test: the rat was lifted vertically and the injected hindlimb was pedaled on the electronic platform. At this time, the muscle strength of the rat's hindlimb was determined by the limb pedaling balance. The numerical value displayed indicates. When the limb is completely paralyzed, the reading is the weight of the limb itself, about 20g. A measurement value exceeding half of the difference between baseline and limb weight is considered recovery of motor function, and a value less than or equal to this value is considered loss of motor function.
表1本发明化合物的坐骨神经局部麻醉效果
Table 1 The local anesthetic effect of the sciatic nerve of the compounds of the present invention
Table 1 The local anesthetic effect of the sciatic nerve of the compounds of the present invention
实验结果表明，该类药物能够产生较阿替卡因更强的麻醉作用，相同给药剂量下该类药物在坐骨神经阻滞模型中能够产生大于2小时的局部麻醉感觉阻滞时间。Experimental results show that this type of drug can produce a stronger anesthetic effect than articaine. At the same dose, this type of drug can produce a local anesthetic sensory block time of more than 2 hours in the sciatic nerve block model.
2、大鼠皮下浸润模型2. Rat subcutaneous infiltration model
250～300克体重的大鼠背部剃毛消毒后，在裸露的背部一侧画出直径约1.5厘米圆形，并将圆形进行6等分。在中心的皮肤处皮下注射含有药物的溶液0.5mL(以生理盐水为溶剂，2％阿替卡因(62mmol/L)，本发明专利所述化合物浓度范围62mmol/L)。将Von Frey纤维丝中100克力度的纤维丝与针头绑定进行皮肤局部刺激。药物注射1min后，使用上述方法在6个划分范围内进行刺激，若在同一等分范围内的连续3次刺激均未出现背部皮肤收缩行为，视为药效效应阳性，若出现背部皮肤收缩则视为局部麻醉效应消失。6个等分范围中有4个或4个以上区域显示局部麻醉阳性，则视为药物的局部麻醉有效，6个等分范围中少于4个区域显示阳性，视为局部麻醉失效。每种化合物使用6只大鼠进行实验。After shaving and disinfecting the back of a rat weighing 250 to 300 grams, draw a circle with a diameter of about 1.5 cm on one side of the exposed back, and divide the circle into 6 equal parts. Subcutaneously inject 0.5 mL of a drug-containing solution (using physiological saline as solvent, 2% articaine (62 mmol/L), the concentration range of the compound described in the patent of the invention is 62 mmol/L) in the central skin. Bind the 100-gram strength fiber of Von Frey fiber to the needle for local stimulation of the skin. 1 minute after drug injection, use the above method to stimulate within 6 divided ranges. If there is no contraction of the back skin in three consecutive stimulations within the same divided range, it is considered as a positive drug effect. If there is contraction of the back skin, it is considered as positive. The local anesthetic effect is deemed to have disappeared. If 4 or more areas among the 6 equal parts of the range show positive local anesthesia, the local anesthesia of the drug is deemed to be effective. If less than 4 areas among the 6 equal parts of the range show positive, the local anesthesia is deemed to be invalid. Experiments were performed using 6 rats per compound.
表2本发明化合物的皮下浸润局部麻醉效果
Table 2 Subcutaneous infiltration local anesthetic effect of the compounds of the present invention
Table 2 Subcutaneous infiltration local anesthetic effect of the compounds of the present invention
实验结果表明，相同给药剂量下，该类药物较阿替卡因相比，在大鼠皮下浸润模型中能够产生大于3小时的局部麻醉作用时间。Experimental results show that at the same dosage, compared with articaine, this type of drug can produce local anesthesia for more than 3 hours in the rat subcutaneous infiltration model.
实验例2、本发明化合物的安全性Experimental Example 2, Safety of Compounds of the Invention
1、小鼠LD50值1. Mouse LD 50 value
随机选取18.0g-21.0g小鼠进行小鼠尾静脉LD50测量，实验采用序贯法。用75％酒精棉球轻轻擦拭鼠尾，软化小鼠尾巴角质层，扩张尾静脉，用注射器经尾静脉注射不同浓度药物。给药速度10-15秒，注射液体总体积不超过1.0mL。根据预实验结果，在最高剂量(即一定致死剂量的最小值)和最低剂量(即不致死剂量的最大值)之间按照等比数列设置另外三个剂量，共五个剂量组，组间剂量比值以1︰0.6至1︰0.85为佳。从中间剂量开始给药，
观察小鼠死亡情况。若小鼠未死亡，则下一只小鼠给予高一个剂量；若小鼠死亡，则下一只大鼠给予低一个剂量；以此类推进行实验，直到同向出现6个交叉则实验结束。Mice ranging from 18.0g to 21.0g were randomly selected for mouse tail vein LD 50 measurement, and the experiment adopted the sequential method. Gently wipe the mouse tail with a 75% alcohol cotton ball to soften the mouse tail cuticle, expand the tail vein, and inject different concentrations of drugs through the tail vein with a syringe. The administration speed is 10-15 seconds, and the total volume of injected liquid does not exceed 1.0 mL. According to the pre-experiment results, another three doses are set according to the geometric sequence between the highest dose (i.e. the minimum value of a certain lethal dose) and the lowest dose (i.e. the maximum value of a non-lethal dose), with a total of five dose groups. The dose between groups The ratio is preferably 1:0.6 to 1:0.85. Begin administration with an intermediate dose, Observe the death of mice. If the mouse does not die, the next mouse will be given a higher dose; if the mouse dies, the next rat will be given a lower dose; and so on until 6 crossovers occur in the same direction and the experiment ends.
采用序贯法计算公式LD50＝lg-1[X0+i(A/N)±0.5]计算药物的LD50。Use the sequential method to calculate the formula LD 50 =lg -1 [X 0 +i(A/N)±0.5] to calculate the LD 50 of the drug.
其中取中心组d(组距)为0，随剂量增大依次为1、2，剂量减小依次为-1、-2；X0表示d＝0时的对数剂量；i(对数剂量组距)表示公比倒数的对数值；a为相应剂量下阳性的个数；分别用N和A代表a和ad的总和。Among them, the center group d (group distance) is 0, and as the dose increases, it is 1, 2, and as the dose decreases, it is -1, -2; X 0 represents the logarithmic dose when d=0; i (logarithmic dose Group distance) represents the logarithm of the reciprocal of the common ratio; a is the number of positives at the corresponding dose; N and A represent the sum of a and ad respectively.
表3本发明化合物的小鼠尾静脉LD50值测量结果
Table 3 Measurement results of mouse tail vein LD 50 value of the compounds of the present invention
Table 3 Measurement results of mouse tail vein LD 50 value of the compounds of the present invention
实验结果表明，该类药物的小鼠LD50值较阳性药物阿替卡因高，说明该类化合物较阿替卡因具有更高的安全性高。Experimental results show that the mouse LD 50 value of this type of drug is higher than that of the positive drug articaine, indicating that this type of compound is safer than articaine.
2、神经病理损伤评估2. Neuropathological damage assessment
选取实施例1～168的药物，阿替卡因阳性对照组分别给予完全适应实验环境的受试大鼠，每组8只。The drugs of Examples 1 to 168 were selected, and the articaine positive control group was administered to test rats that were fully adapted to the experimental environment, with 8 rats in each group.
给药剂量为：阿替卡因2％水溶液，待测药物浓度均为62mmol/L的水溶液。每只大鼠给药或对照的注射体积为0.5mL，注射于大鼠坐骨神经附近。在坐骨神经注射后第7天和第14天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位坐骨神经约1.5cm，存于10％甲醛溶液中48h，HE染色并切成5μm厚度的切片。The dosage is: articaine 2% aqueous solution, and the concentration of the drug to be tested is 62mmol/L aqueous solution. The injection volume of each rat for administration or control was 0.5 mL, and it was injected near the sciatic nerve of the rat. On days 7 and 14 after sciatic nerve injection, the experimental rats were euthanized by cardiac injection of bupivacaine under isoflurane anesthesia. About 1.5cm of the sciatic nerve at the injection site was taken, stored in 10% formaldehyde solution for 48 hours, HE stained and cut into 5 μm thick sections.
神经病理损伤评估显示：实施例1～168的药物与阿替卡因阳性对照组相比，在神经损伤、血管增生、脱髓鞘程度、肌肉炎症、结缔组织炎症程度方面都没有显著差异，具有良好的安全性。Neuropathological damage assessment showed that: compared with the articaine positive control group, the drugs of Examples 1 to 168 had no significant differences in nerve damage, vascular proliferation, degree of demyelination, muscle inflammation, and degree of connective tissue inflammation. Good security.
实验例3、本发明化合物在炎症环境下仍能发挥作用且具有抗炎作用Experimental Example 3. The compound of the present invention can still function in an inflammatory environment and has anti-inflammatory effects
1、CFA诱导的足底炎症模型1. CFA-induced plantar inflammation model
选取实施例1～168的药物，阿替卡因阳性对照组分别给予完全适应实验环境的受试大鼠，每组8只。每只大鼠右侧足底注射CFA(完全弗式佐剂)48h后可观察到足底明显肿胀且VonFrey刺激仪测量大鼠右后爪缩爪阈值明显降低，此时可进行足底皮下给药。The drugs of Examples 1 to 168 were selected, and the articaine positive control group was administered to test rats that were fully adapted to the experimental environment, with 8 rats in each group. After 48 hours of injection of CFA (complete Freund's adjuvant) into the right foot of each rat, significant swelling of the foot was observed and the paw withdrawal threshold of the rat's right hind paw was significantly reduced as measured by the VonFrey stimulator. At this time, subcutaneous administration of CFA can be performed on the foot. medicine.
给药剂量为：阿替卡因2％水溶液，待测药物浓度均为62mmol/L的水溶液。每只大鼠给药或对照的注射体积为0.2mL，注射于大鼠足底肿胀部位皮下。通过von Frey刺激仪，刺激大鼠注射药物体侧足底，观测局部麻醉效果。起效后每10min测试一次，测量值超过肢体重量与基线差值的一半视为麻醉起效，小于或等于该值视为麻醉失效。
The dosage is: articaine 2% aqueous solution, and the concentration of the drug to be tested is 62mmol/L aqueous solution. The injection volume of each rat for administration or control was 0.2 mL, which was injected subcutaneously into the swollen part of the rat's sole. The von Frey stimulator was used to stimulate the sole of the rat's side of the body where the drug was injected, and the local anesthesia effect was observed. Testing is performed every 10 minutes after the onset of effect. If the measured value exceeds half of the difference between the limb weight and the baseline, it is considered the anesthesia has taken effect. If the value is less than or equal to this value, it is considered the anesthesia has failed.
表4本发明化合物在CFA诱导的足底炎症模型发挥作用
Table 4 Compounds of the present invention play a role in CFA-induced plantar inflammation model
Table 4 Compounds of the present invention play a role in CFA-induced plantar inflammation model
实验结果表明，相同给药剂量下，该类药物较阿替卡因相比，在CFA诱导的足底炎症模型中能够产生至少大于1小时的局部麻醉作用时间。Experimental results show that at the same dosage, compared with articaine, this type of drug can produce local anesthesia for at least more than 1 hour in the CFA-induced plantar inflammation model.
2、细胞分子水平LPS炎症模型2. LPS inflammation model at cellular and molecular levels
将1*10^5细胞(DRG原代细胞)种于6孔板中，24h待贴壁后将两种细胞分为3组，第一组使用完全培养基处理48h，第二组先使用1ug/ml LPS处理24h，后更换完全培养基处理24h，第三组先使用1ug/ml LPS处理24h，后更换含1mM本发明化合物的完全培养基处理24h。提取各组细胞RNA，逆转录为cDNA后，使用RT-QPCR方法检测各组中炎症因子(IL1β，IL6，TNFα)表达改变Seed 1*10^5 cells (DRG primary cells) in a 6-well plate. After 24 hours of adhesion, the two cells were divided into 3 groups. The first group was treated with complete culture medium for 48 hours, and the second group was treated with 1ug first. /ml LPS for 24 hours, and then replaced with complete medium for 24 hours. The third group was first treated with 1ug/ml LPS for 24 hours, and then replaced with complete medium containing 1mM of the compound of the present invention for 24 hours. RNA was extracted from cells in each group, and after reverse transcription into cDNA, RT-QPCR method was used to detect the expression changes of inflammatory factors (IL1β, IL6, TNFα) in each group.
实施例15制备的化合物(化合物15)：
Compound prepared in Example 15 (Compound 15):
Compound prepared in Example 15 (Compound 15):
实施例16制备的化合物(化合物16)：
Compound prepared in Example 16 (Compound 16):
Compound prepared in Example 16 (Compound 16):
实施例22制备的化合物(化合物22)：
Compound prepared in Example 22 (Compound 22):
Compound prepared in Example 22 (Compound 22):
实验结果表明，该类药物能够明显降低LPS诱导下的细胞炎症因子(IL1β，IL6，TNFα)水平，差异有统计学意义(P<0.05)Experimental results show that this type of drug can significantly reduce the levels of cellular inflammatory factors (IL1β, IL6, TNFα) induced by LPS, and the difference is statistically significant (P<0.05)
综上所述，本发明化合物用于局部麻醉时起效快，单次给药后麻醉作用时间延长，在浸润麻醉与阻滞麻醉中均具有较长的局部麻醉作用，解决了目前局麻药物使用过程中与肾上腺素联用的副作用问题，具有更好的安全性。本发明化合物可用于制备安全的、具有长时间局部麻醉的药物，具有局部麻醉作用时间长、神经损伤更小、安全性高、能产生抗炎作用的优点。
In summary, the compound of the present invention has a rapid onset of action when used for local anesthesia, prolongs the anesthetic effect after a single administration, and has a long local anesthetic effect in both infiltration anesthesia and block anesthesia, solving the problems of current local anesthetic drugs. There are no side effects when combined with epinephrine during use, and it has better safety. The compound of the present invention can be used to prepare safe drugs with long-term local anesthesia, and has the advantages of long local anesthetic effect, less nerve damage, high safety, and can produce anti-inflammatory effects.
Claims (35)
- 式I所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物：
The compound represented by formula I, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound:
其中，R4为C1～8烃基、C1～8烷氧基、3～8元环烃基、苯基或苄基；Among them, R 4 is a C 1 to 8 hydrocarbon group, a C 1 to 8 alkoxy group, a 3 to 8 membered ring hydrocarbon group, a phenyl group or a benzyl group;其中，R1为C1～8烃基，且R2和R3连接形成环A：
Among them, R 1 is a C 1 to 8 hydrocarbon group, and R 2 and R 3 are connected to form ring A:
环A中：Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H、卤素、取代或未取代的：C1～8烃基、C1～8烷氧基或3～8元环烃基；In Ring A: R a , R b , R c , R d , R e , R f , R g , and R h are independently selected from H, halogen, substituted or unsubstituted: C 1 to 8 hydrocarbyl, C 1 to 8 alkoxy group or 3 to 8 membered ring hydrocarbon group;M为NR5，L为C3～4烷烃链且R5为H，或L为C1～4烷烃链且R5为取代或未取代的C1～8烃基、C1～8烷氧基、3～8元环烃基、苯基或苄基；所述取代的取代基个数为1～3个，所述取代基分别独立选自羟基、卤素、氨基、C1～8烷氧基、3～8元环烃基或C1～8酯基；且环A为时，L不为亚甲基链；或，M为O、CH2、S、SO或SO2，L为C2～4支链烷烃链；M is NR 5 , L is a C 3-4 alkane chain and R 5 is H, or L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-8 alkyl group or C 1-8 alkoxy group , 3 to 8-membered ring hydrocarbon group, phenyl or benzyl; the number of substituted substituents is 1 to 3, and the substituents are independently selected from hydroxyl, halogen, amino, C 1 to 8 alkoxy, 3-8 membered ring hydrocarbon group or C 1-8 ester group; and ring A is When, L is not a methylene chain; or, M is O, CH 2 , S, SO or SO 2 , and L is a C 2 to 4 branched alkane chain;或，R1为C1～8直链烷基，且R2为被1～3个羟基、氨基、C1～4烷氧基或C1～4烷基氨基取代的C1～8烷基，R3为氢、未取代或被1～3个羟基或C1～4烷氧基取代的C1～8烷基；L为C1～4烷烃链；Or, R 1 is a C 1 to 8 linear alkyl group, and R 2 is a C 1 to 3 linear alkyl group. hydroxyl, Amino, C 1 to 4 alkoxy or C 1 to 4 alkylamino substituted C 1 to 8 alkyl group, R 3 is hydrogen, unsubstituted or substituted by 1 to 3 hydroxyl groups or C 1 to 4 alkoxy groups C 1～8 alkyl; L is C 1～4 alkane chain;或，R1为异丁基；R2、R3分别独立选自氢、取代或未取代的C1～8烃基，或取代或未取代的C1～8烷氧基，所述取代的取代基个数为1～5个，所述取代基分别独立选自羟基或C1～4烷氧基；L为C1～4烷烃链。Or, R 1 is isobutyl; R 2 and R 3 are independently selected from hydrogen, substituted or unsubstituted C 1 to 8 hydrocarbon groups, or substituted or unsubstituted C 1 to 8 alkoxy groups, and the substituted The number of groups is 1 to 5, and the substituents are independently selected from hydroxyl or C 1 to 4 alkoxy groups; L is a C 1 to 4 alkane chain. - 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，R4为甲基。The compound of claim 1, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by That is, R 4 is methyl.
- 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特 征在于，R1为C1～8烷基且R2和R3连接形成环A；优选地，R1为甲基，且R2和R3连接形成环A。The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated compound thereof, particularly The characteristic is that R 1 is a C 1-8 alkyl group and R 2 and R 3 are connected to form Ring A; preferably, R 1 is methyl, and R 2 and R 3 are connected to form Ring A.
- 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，环A中：Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H或C1～8烷基，优选为H或甲基。The compound of claim 1, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by That is, in ring A: R a , R b , R c , R d , Re , R f , R g , and Rh are independently selected from H or C 1 to 8 alkyl groups, preferably H or methyl.
- 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，M为NR5，L为C3～4烷烃链且R5为H，或，L为C1～4烷烃链且R5为取代或未取代的C1～8烷基、3～8元环烷基或苯基；所述取代的取代基个数为1或2个，所述取代基分别独立选自羟基、C1～4烷氧基或C1～8酯基；且环A为时，L不为亚甲基链。The compound of claim 1, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by M is NR 5 , L is a C 3-4 alkane chain and R 5 is H, or L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-8 alkyl group, 3-8 Ring alkyl or phenyl; the number of substituted substituents is 1 or 2, and the substituents are independently selected from hydroxyl, C 1 to 4 alkoxy or C 1 to 8 ester groups; and Ring A for When , L is not a methylene chain.
- 如权利要求5所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，M为NR5，L为C1～4烷烃链且R5为取代或未取代的C1～4烷基、环丙烷基或苯基；所述取代的取代基个数为1个，所述取代基为羟基、甲氧基或甲酯基；且环A为时，L不为亚甲基链。The compound of claim 5, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by M is NR 5 , L is a C 1-4 alkane chain and R 5 is a substituted or unsubstituted C 1-4 alkyl group, cyclopropyl group or phenyl group; the number of substituted substituents is 1, The substituent is hydroxyl, methoxy or methyl ester; and Ring A is When , L is not a methylene chain.
- 如权利要求1～6任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-A所示结构：
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has a structure shown in formula IA:
- 如权利要求7所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-A-1或1-A-2所示结构：
The compound according to claim 7, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has the structure shown in formula IA-1 or 1-A-2:
- 如权利要求8所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-A-3所示结构：
The compound according to claim 8, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has the structure shown in formula IA-3:
其中，R5选自C1～4烷基。Among them, R 5 is selected from C 1 to 4 alkyl groups. - 如权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-B所示结构：
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has a structure shown in formula IB:
- 如权利要求10所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-B-1、式I-B-2、式I-B-3或式I-B-4所示结构：
The compound according to claim 10, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has a structure represented by formula IB-1, formula IB-2, formula IB-3 or formula IB-4:
- 如权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-C所示结构：
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has a structure shown in formula IC:
- 如权利要求12所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-C-1所示结构：
The compound according to claim 12, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has the structure shown in formula IC-1:
- 如权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-D所示结构：
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has the structure shown in formula ID:
- 如权利要求14所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-D-1所示结构：
The compound according to claim 14, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has the structure shown in formula ID-1:
- 如权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-E所示结构：
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has a structure represented by formula IE:
- 如权利要求16所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-D-1所示结构：
The compound of claim 16, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has the structure shown in formula ID-1:
- 如权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-F所示结构：
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has a structure represented by formula IF:
- 如权利要求18所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式I-F-1所示结构：
The compound according to claim 18, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has the structure shown in formula IF-1:
- 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，R1为C1～8直链烷基，且R2被1个羟基、氨基、C1～4烷氧基或C1～4烷基氨基取代的C1～3烷基，R3为氢、未取代或被1个羟基或C1～4烷氧基取代的C1～3烷基；L为C1～4烷烃链。The compound of claim 1, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by That is, R 1 is a C 1 to 8 linear alkyl group, and R 2 is replaced by 1 hydroxyl, Amino group, C 1 to 4 alkoxy group or C 1 to 4 alkylamino substituted C 1 to 3 alkyl group, R 3 is hydrogen, unsubstituted or C 1 substituted by 1 hydroxyl group or C 1 to 4 alkoxy group ~3 alkyl; L is a C 1~4 alkane chain.
- 如权利要求20所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，L为 The compound of claim 20, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by That is, L is
- 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，R1为异丁基；R2、R3分别独立选自氢或C1～8烷基；L为C1～4烷烃链。The compound of claim 1, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by R 1 is an isobutyl group; R 2 and R 3 are each independently selected from hydrogen or a C 1-8 alkyl group; L is a C 1-4 alkane chain.
- 权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，L为 The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated compound thereof, characterized in that , L is
- 式II所示化合物、或其药学上可接受的盐、或其立体异构体、或其 溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物：
The compound represented by formula II, or its pharmaceutically acceptable salt, or its stereoisomer, or its Solvates, or prodrugs thereof, or metabolites thereof, or deuterated compounds thereof:
其中，L`为C1～4烷烃链；Among them, L` is a C 1 to 4 alkane chain;其中，R5为C1～8烷基；Among them, R 5 is C 1～8 alkyl;其中，X`为O、S、CH2、NR7，R7为Ri取代或未取代的C1～8烷基、苯基或苄基；Ri为羟基、3～8元环烃基、C1～8烷氧基或C1～8酯基；R6为C1～8烷基；m和n为整数，且m+n＝2或4或5；Among them, X` is O, S, CH 2 , NR 7 , R 7 is R i substituted or unsubstituted C 1 to 8 alkyl group, phenyl or benzyl group; R i is hydroxyl, 3 to 8 membered ring hydrocarbon group, C 1 to 8 alkoxy group or C 1 to 8 Ester group; R 6 is C 1 to 8 alkyl group; m and n are integers, and m+n=2 or 4 or 5;或，X为C时，R6为C1～8烷基；m和n为整数，且m+n＝4或5；Or, when X is C, R 6 is a C 1-8 alkyl group; m and n are integers, and m+n=4 or 5;k选自0、1、2或3。k is selected from 0, 1, 2 or 3. - 如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，L`为 The compound of claim 24, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by That is, L` is
- 如权利要求25所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，R5为C1～4烷基，R6为C1～4烷基，X`为O、S、CH2、NR7，R7为Ri取代或未取代的C1～4烷基或苯基，Ri为羟基、3～6元环烃基、C1～4烷氧基或C1～4酯基。The compound according to claim 25, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by R 5 is a C 1 to 4 alkyl group, R 6 is a C 1 to 4 alkyl group, and X` is O, S, CH 2 , NR 7 , R 7 is R i substituted or unsubstituted C 1 to 4 alkyl group or phenyl group, R i is hydroxyl group, 3 to 6 membered ring hydrocarbon group, C 1 to 4 alkoxy group or C 1 to 4 ester group.
- 如权利要求26所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，R6为甲基，X为O、S、NR7，R7为Ri取代或未取代的C1～4烃基或苯基，Ri为羟基、环丙基、甲氧基或甲酯基。The compound of claim 26, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by That is, R 6 is methyl, X is O, S, NR 7 , R 7 is R i substituted or unsubstituted C 1 to 4 hydrocarbon group or phenyl group, R i is hydroxyl, cyclopropyl, methoxy or methyl ester group.
- 如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式II-A至式II-F任一项所示结构：
The compound of claim 24, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has a structure shown in any one of Formula II-A to Formula II-F:
- 如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式II-G至式II-M任一项所示结构：
The compound of claim 24, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has a structure represented by any one of formula II-G to formula II-M:
- 如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物具有式II-G至式II-M任一项所示结构：
The compound of claim 24, or its pharmaceutically acceptable salt, or its stereoisomer, or its solvate, or its prodrug, or its metabolite, or its deuterated compound, characterized by The compound has a structure represented by any one of formula II-G to formula II-M:
- 如权利要求1～30任一项所述的化合物，或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述化合物为如下任一结构：
The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the compound has any of the following structures:
- 根据权利要求1～30任一项所述的化合物，或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物，其特征在于，所述药学上可接受的盐是指由式I所示化合物与药学上可接受的无机酸或有机酸形成；The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or its deuterium generation compound, characterized in that the pharmaceutically acceptable salt refers to a compound represented by formula I and a pharmaceutically acceptable inorganic acid or organic acid formed;优选地，所述无机酸或有机酸为盐酸、氢溴酸、乙酸、硫酸、甲磺酸、对甲苯磺酸、琥珀酸、碳酸、酒石酸、月桂酸、马来酸、枸橼酸或苯甲酸。Preferably, the inorganic acid or organic acid is hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid or benzoic acid. .
- 权利要求1～32任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备麻醉药物中的用途，优选地，所述麻醉药物为局部麻醉药物。The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated product thereof The use of the compound in preparing an anesthetic drug. Preferably, the anesthetic drug is a local anesthetic drug.
- 权利要求1～32任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备抗炎药物中的用途。The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated product thereof Use of compounds in the preparation of anti-inflammatory drugs.
- 一种药物，其特征在于，它是以权利要求1～32任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物为活性成分，加上药学上可接受的辅料制备而成的制剂。 A medicine, characterized in that it is a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a precursor thereof Preparations prepared by taking drugs, their metabolites, or their deuterated compounds as active ingredients and adding pharmaceutically acceptable excipients.
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| CN202210983240.2 | 2022-08-16 | ||
| CN202210983240 | 2022-08-16 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3855243A (en) * | 1967-07-07 | 1974-12-17 | Hoechst Ag | 3-aminoacylamino thiophenes |
| WO1999031096A1 (en) * | 1997-12-18 | 1999-06-24 | Shaman Pharmaceuticals, Inc. | Piperazine derivatives useful as hypoglycemic agents |
| CN114828845A (en) * | 2019-11-06 | 2022-07-29 | 诺西恩医疗公司 | Charged ion channel blockers and methods of use thereof |
-
2023
- 2023-08-16 WO PCT/CN2023/113346 patent/WO2024037564A1/en unknown
- 2023-08-16 CN CN202311033423.9A patent/CN117586223A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3855243A (en) * | 1967-07-07 | 1974-12-17 | Hoechst Ag | 3-aminoacylamino thiophenes |
| WO1999031096A1 (en) * | 1997-12-18 | 1999-06-24 | Shaman Pharmaceuticals, Inc. | Piperazine derivatives useful as hypoglycemic agents |
| CN114828845A (en) * | 2019-11-06 | 2022-07-29 | 诺西恩医疗公司 | Charged ion channel blockers and methods of use thereof |
Non-Patent Citations (3)
| Title |
|---|
| DATABASE Registry 4 June 2015 (2015-06-04), ANONYMOUS: "2-Thiophenecarboxylic acid, 3-[[2-[(2-methoxyethyl)amino]acetyl]amino]-4- methyl-, methyl ester (CA INDEX NAME)", XP093141235, retrieved from STNext Database accession no. 1773471-39-8 * |
| DATABASE Registry 5 June 2019 (2019-06-05), ANONYMOUS: "2-Thiophenecarboxylic acid, 3-[[3-(4-methyl-1-piperazinyl)-1- oxopropyl]amino]-4-phenyl-, ethyl ester (CA INDEX NAME)", XP093141237, retrieved from STNext Database accession no. 2324639-25-8 * |
| DATABASE Registry 5 June 2019 (2019-06-05), ANONYMOUS: "2-Thiophenecarboxylic acid, 3-[[3-(4-methyl-1-piperazinyl)-1- oxopropyl]amino]-4-phenyl-, methyl ester (CA INDEX NAME)", XP093141236, retrieved from STNext Database accession no. 2324639-13-4 * |
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