WO2024037564A1 - Composé de phénothiazine et son utilisation - Google Patents

Composé de phénothiazine et son utilisation Download PDF

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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
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compound
pharmaceutically acceptable
stereoisomer
acceptable salt
solvate
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PCT/CN2023/113346
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Chinese (zh)
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柯博文
梁新华
刘进
叶玲
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四川大学
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A—HUMAN NECESSITIES
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    • 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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    • A61K31/395—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
    • 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
    • A61K31/435—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
    • 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
    • A61K31/495—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
    • 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
    • A61K31/535—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
    • 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
    • A61K31/54—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
    • 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
    • A61K31/55—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
    • 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
    • A61K31/55—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
    • 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
    • C07D333/38—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
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    • 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

La présente invention concerne un composé représenté par la formule I ou un sel pharmaceutiquement acceptable ou un stéréoisomère ou un solvate ou un promédicament ou un métabolite ou un composé deutéré de celui-ci. Le composé selon la présente invention a un effet rapide lorsqu'il est utilisé pour une anesthésie locale, l'effet d'anesthésie dure plus longtemps après une administration unique, et dans une anesthésie par infiltration et une anesthésie par blocs, le composé a un effet d'anesthésie locale long même dans un état inflammatoire, ce qui permet de résoudre le problème d'effets secondaires provoqués par l'utilisation actuelle d'anesthésiques locaux combinés à l'adrénaline, et d'obtenir une meilleure sécurité. Le composé selon la présente invention peut être utilisé pour préparer des anesthésiques locaux sans danger et de longue durée, et présente les avantages d'un long effet d'anesthésie locale, d'une moindre lésion nerveuse, d'une sécurité élevée et d'un effet anti-inflammatoire.
PCT/CN2023/113346 2022-08-16 2023-08-16 Composé de phénothiazine et son utilisation WO2024037564A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3855243A (en) * 1967-07-07 1974-12-17 Hoechst Ag 3-aminoacylamino thiophenes
WO1999031096A1 (fr) * 1997-12-18 1999-06-24 Shaman Pharmaceuticals, Inc. Derives de piperazine pouvant etre utilises comme agents hypoglycemiques
CN114828845A (zh) * 2019-11-06 2022-07-29 诺西恩医疗公司 带电的离子通道阻滞剂及其使用方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3855243A (en) * 1967-07-07 1974-12-17 Hoechst Ag 3-aminoacylamino thiophenes
WO1999031096A1 (fr) * 1997-12-18 1999-06-24 Shaman Pharmaceuticals, Inc. Derives de piperazine pouvant etre utilises comme agents hypoglycemiques
CN114828845A (zh) * 2019-11-06 2022-07-29 诺西恩医疗公司 带电的离子通道阻滞剂及其使用方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
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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