CN115969991A - Combination of anesthetic, preparation method and application thereof - Google Patents
Combination of anesthetic, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a combination of anesthetic, a preparation method and application thereof, in particular to application in the field of medicine. In the conjugate, P and D are connected through a non-degradable connecting group, D is not degraded, and the part B-D has anesthetic effectAnd due to the existence of the P part, the medicine stays for a longer time at the focus part, thereby achieving the purposes of slow release and controlled release.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a combination of anesthetics, a preparation method and application thereof, and especially relates to application in the field of medicines.
Background
Local anesthesia is a commonly used anesthesia method in clinic, which is beneficial to keeping patients awake, enables anesthesia to return smoothly and facilitates postoperative analgesia. The local anesthetic can be classified into para-aminobenzoates, amides, aminoketones, aminoethers, and carbamates according to the structural type. The local anesthetic includes lidocaine, prilocaine, bupivacaine, ropivacaine, etc. Generally, local anesthetic drugs are active enough to relieve certain pain, but not long enough, and patients more hope to continuously input lower concentration of local anesthetic drugs to block pain nerves and not affect motor nerves, so as to achieve the purpose of analgesia only and not affecting movement. Therefore, a local anesthetic capable of slowly releasing and long-acting is an ideal choice. The method for prolonging the action time of the local anesthetic is to structurally modify the original local anesthetic. For example, bupivacaine is structurally similar to lidocaine, but the local anesthetic effect is stronger and longer lasting than lidocaine; levobupivacaine is a novel long-acting local anesthetic, and has relatively low toxicity as an isomer of bupivacaine. Ropivacaine is structurally similar to bupivacaine in that it has a strong pain blocking effect and a weak exercise effect. In recent years, the development of peripheral nerve blocking technology and local anesthetics has provided patients with more ideal perioperative analgesic methods, and they are usually combined with opioids to reduce the dosage of opioids. Amide local anesthetics such as bupivacaine, levobupivacaine and ropivacaine are most widely used in regional analgesia, and especially ropivacaine has the characteristic of separation of sensation and motor retardation, so that the amide local anesthetics become the first choice for regional analgesia. However, the action time of these drugs is still low for postoperative analgesia or chronic pain treatment, the action time of lidocaine is 1-2 hours, the action time of ropivacaine is 4.4 hours, and the action time of even the long-acting local anesthetic drug levobupivacaine is only 5-7 hours.
Several sustained release formulations of local anesthetic drugs have been developed and reported in the literature, such as polymeric microspheres of polylactic acid in combination with glycolic acid containing bupivacaine and dexamethasone to produce a prolonged local anesthetic effect. Crystals of local anesthetics have also been shown to have a longer duration of action. Lipophilic bupivacaine radicals are incorporated into multilamellar liposomal cell membranes, and large, proton-loaded unilamellar liposomes have shown efficacy, lasting 6-11 hours. Multivesicular liposomes are being developed as a lipid-based sustained release drug with local or systemic effect. In 11 months 2011, the us FDA approved bupivacaine (bupivacaine) 1.3% liposomal injection suspension Exparel developed by Pacira pharmaceuticals, inc, for direct injection to the surgical site to help control post-operative pain. Bupivacaine is a non-opioid anesthetic, and the conventional injection (0.5%) can only provide the analgesic effect for less than 7 hours, while the postoperative pain can usually last for 48 to 72 hours and is most difficult to control in the time, so an internally-arranged catheter or an infusion pump is frequently used for continuously administering the opioid, the management is inconvenient, and various harmful side effects can be caused.
In order to meet clinical needs, there is a need to develop new long-acting, sensory and motor retardant isolated local anesthetic active ingredients.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a conjugate and a preparation method and application thereof.
In a first aspect of the invention, there is provided a conjugate having the structure:
wherein, the first and the second end of the pipe are connected with each other,
p contains one or more
Structure;
a is selected from: a single bond, an alkylene group,
b has the following structure:
wherein R is 1 Selected from: a single bond, alkylene, R 2 Selected from: single bond (-), -O-, -S-, -NR a -、-C(O)-、-C(S)-、-S(O)-、-S(O) 2 -；R a Selected from: H. alkyl, cycloalkyl, hydroxy, alkoxy;
d is an anesthetic residue;
m is an integer from 1 to 10 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10).
Specifically, moiety D has the following structure:
wherein the content of the first and second substances,
R 3 is alkyl, R 5 Selected from: H. an alkyl group; or, R 3 、R 5 Together with the atoms to which they are attached form a cyclic group;
R 4 is an alkyl group;
R 6 and R 7 Independently selected from: H. an alkyl group;
X - is an anion.
Specifically, X is selected from: F. cl, br, I, methanesulfonate, ethylsulfonate, benzenesulfonate, citrate, lactate, succinate, fumarate, glutamate, citrate, salicylate, maleate, in particular F, cl, br or I.
Specifically, R 3 Is C1-6 alkyl, such as methyl, ethyl, n-propyl, n-butyl.
Specifically, R 5 Selected from: H. c1-6 alkyl, for example, methyl, ethyl, n-propyl, n-butyl.
In one embodiment of the invention, R 3 、R 5 Together with the atoms to which they are attached form a 5-8 membered heteroalicyclic, particularly a 6 membered heteroalicyclic, preferably a piperidinyl group.
Specifically, R 4 Is C1-6 alkyl, such as methyl, ethyl, n-propyl, n-butyl.
Specifically, R 6 Selected from H, C1-6 alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, especially R 6 Is H or methyl.
Specifically, R 7 Selected from H, C1-6 alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, especially R 7 Is H or methyl.
More specifically, the moiety D is selected from the following structures:
in some embodiments of the invention, moiety D is
Specifically, R a May be selected from: H. c1-6 alkyl, hydroxy, C1-6 alkoxy, especially H.
Specifically, R 1 Selected from: a single bond, C1-6 alkylene (e.g., methylene, ethylene).
Specifically, R 2 Selected from: single bond (-), -O-, -S-; in one embodiment of the invention, R 2 is-O-.
In some embodiments of the invention, B has the structure:
specifically, a is selected from: a single bond, C1-6 alkylene (e.g., methylene, ethylene).
Specifically, the P moiety is a polyethylene glycol residue (e.g., a linear, double-ended, Y-type or multi-branched polyethylene glycol residue (including 2-arm PEG, 4-arm PEG, 6-arm PEG, or 8-arm PEG residue, etc.)) or a poly-ethylene glycol residue (which has a single molecular weight) which may have a molecular weight of 100 to 100000Da, e.g., 100, 200, 400, 500, 600, 800, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 50000, 100000Da, e.g., 100 to 00500da, 100 to 10000da,500 to 5000Da, e.g., 500, 1000, 2000, 3000, 4000, 5000Da.
In one embodiment of the invention, the moiety P has the following structure:
wherein n is an integer of 1 to 5000 (e.g., 1, 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000), particularly, an integer of 10 to 1000, an integer of 10 to 100, an integer of 10 to 50.
In another embodiment of the invention, the moiety P has the structure:
wherein n is an integer of 1 to 5000 (e.g.1.5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000), in particular, an integer of 10 to 1000, an integer of 10 to 100, an integer of 10 to 50.
In another embodiment of the invention, the moiety P has the structure:
wherein n is an integer of 1 to 5000 (e.g., 1, 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000), particularly, an integer of 10 to 1000, an integer of 10 to 100, an integer of 10 to 50.
In another embodiment of the present invention, the moiety P has the following structure:
wherein R is c Is a core group selected from: residues of pentaerythritol, oligomeric pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerol and polyglycerol, j is an integer from 3 to 8 (e.g. 3, 4, 5, 6, 7, 8), n is an integer from 1 to 5000 (e.g. 1, 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000), in particular an integer from 10 to 1000, an integer from 10 to 100, an integer from 10 to 50.
Specifically, R c Has the following structure:
wherein k is an integer of 1 to 3 (e.g., 1,2, 3), and i is an integer of 1 to 5 (e.g., 1,2, 3, 4, 5).
In one embodiment of the invention, the P moiety has the following structure:
wherein n is an integer of 1 to 5000 (e.g., 1, 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000), particularly, an integer of 10 to 1000, an integer of 10 to 100, an integer of 10 to 50.
In particular, m is between 1,2, 3, 4, 5, 6, 7 or 8, in particular 1,2, 3 or 4; in some embodiments of the invention, m is 2; in other embodiments of the present invention, m is 4.
In one embodiment of the present invention, the above conjugate has the following structure:
in another embodiment of the present invention, the above conjugate has the following structure:
in some embodiments of the invention, the above-described conjugate is selected from the following specific structures:
in the formulae V and VI, n is an integer of 1 to 5000 (e.g., 1, 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000); more specifically, n is an integer of 10 to 1000, an integer of 10 to 100, an integer of 10 to 50.
In a second aspect of the invention, there is provided a stereoisomer of a conjugate according to the first aspect, wherein the moiety D has the structure:
wherein R is 3 、R 4 、R 5 、R 6 、R 7 X, P, A, B have the respective definitions as described in the first aspect of the invention.
In some embodiments of the invention, the stereoisomers are selected from the following specific structures:
in a third aspect of the invention there is provided a prodrug, solvate of a conjugate of the first aspect.
In a fourth aspect of the invention, there is provided a process for the preparation of a conjugate according to the first aspect, comprising the step of reacting a compound of formula VII with a compound of formula VIII:
specifically, the above reaction is carried out in the presence of a catalyst; more specifically, the catalyst includes a copper catalyst and ascorbic acid, such as copper sulfate pentahydrate and ascorbic acid.
Specifically, the above reaction is carried out in a solvent; more specifically, the reaction solvent is selected from: n, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and N, N-dimethylacetamide, in particular dimethyl sulfoxide.
Specifically, the temperature of the above reaction may be 20 to 60 ℃ (e.g., 20, 25, 30, 35, 40, 45, 50, 55, 60 ℃), e.g., room temperature.
Specifically, the time of the above reaction may be 6 to 24 hours (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours), for example, 12 hours.
Specifically, the above preparation method further comprises a purification step.
In particular, moiety D is
The compound of formula VIII can be prepared by the following reaction:
in some embodiments of the invention, the compound of formula IX is ropivacaine, mepivacaine, bupivacaine, lidocaine or etidocaine, particularly ropivacaine.
Specifically, the above reaction is carried out in a solvent; more specifically, the reaction solvent is a polar aprotic solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, and the like, particularly acetonitrile.
Specifically, the temperature of the above reaction is 40 to 75 ℃ (e.g., 40, 45, 50, 55, 60, 65, 70 ℃).
Specifically, the reaction time is 6 to 18 hours (e.g., 6, 8, 10, 12, 14, 16, 18 hours).
In a fifth aspect of the invention, there is provided a pharmaceutical composition comprising a conjugate of the first aspect, a stereoisomer of the second aspect or a prodrug, solvate of the third aspect, and one or more pharmaceutically acceptable excipients.
In particular, the pharmaceutically acceptable excipients may be selected from: one or more of excipients, disintegrants, binders, lubricants, wetting agents, suspending agents, stabilizers, fillers, pH buffering agents, antioxidants, preservatives, flavoring agents, and the like.
In particular, the pharmaceutical composition may be administered by any suitable route of administration, such as gastrointestinal or parenteral (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, etc.) routes of administration.
In particular, the pharmaceutical composition may be in any suitable form, such as a form for parenteral administration, for example, including, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, and the like; parenteral administration, for example, injection administration: such as injections (e.g., for subcutaneous, intravenous, intramuscular, intraperitoneal), respiratory administration: such as sprays, aerosols, powders, etc., dermal administration forms, such as topical solutions, lotions, ointments, plasters, pastes, patches, etc., mucosal administration forms: such as eye drops, eye ointment, nose drops, gargle, sublingual tablet, etc., and the dosage form of the oral administration: such as suppository, aerosol, effervescent tablet, drop, dripping pill, etc., and can be used for rectum, vagina, urethra, nasal cavity, auditory canal, etc.
In particular, the pharmaceutical composition will comprise from about 1 to about 99% by weight of the compound or stereoisomer, prodrug, solvate thereof, and from 99 to 1% by weight of a suitable pharmaceutically acceptable excipient, e.g., the pharmaceutical composition may comprise from about 5 to 75% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%) by weight of the compound or stereoisomer, prodrug, solvate thereof, with the remainder being suitable pharmaceutically acceptable excipients.
In a sixth aspect of the invention, there is provided the use of a conjugate according to the first aspect, a stereoisomer according to the second aspect, a prodrug, solvate according to the third aspect and a pharmaceutical composition according to the fifth aspect of the invention for the manufacture of an anaesthetic.
In particular, the anesthetic is a local anesthetic, in particular a long-acting local anesthetic (e.g. can have an effective anesthetic effect within 16 hours).
Specifically, the medicine can be used for human medicine or veterinary medicine.
In a seventh aspect of the invention, there is provided the use of a conjugate according to the first aspect, a stereoisomer according to the second aspect, a prodrug, solvate according to the third aspect, or a pharmaceutical composition according to the fifth aspect of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of pain.
In particular, the pain may be acute pain or chronic pain.
In particular, the pain may be neuropathic pain or inflammatory pain.
In particular, the pain may be caused by a condition or disease selected from: congenital or genetic diseases; trauma, surgery or burn; infection and/or parasitic diseases; metabolic diseases; inflammation; autoimmune diseases; poisoning; metabolic diseases; neurodegenerative and degenerative symptoms; a dysfunctional condition; psychological disorders; a tumor.
More specifically, the pain may be one or more selected from the group consisting of: bone joint, muscle, root or medullary lesions; mechanical damage caused by radiation, surgery, and thermal, chemical, or electrical burns; osteoarthritis, rheumatoid arthritis; musculoskeletal pain, particularly after trauma; toothache; headache, migraine; abdominal pain; cancer pain; post-operative pain; multiple sclerosis, amyotrophic lateral sclerosis; rupture of the intervertebral disc; diabetes, hypothyroidism or hyperthyroidism; pain from repetitive strain injury; pain from congenital or genetic diseases; pain from leprosy, herpes zoster, acquired immunodeficiency syndrome (AIDS), pain from heavy metal poisoning; afferent nerve block pain, central pain, phantom limb pain, causalgia, myelopathic pain, complex regional pain syndrome, myofascial pain syndrome, fibromyalgia, residual limb pain, reflex sympathetic dystrophy, post-herpetic neuralgia, diabetic mononeuropathy, ischemic neuropathy, polyarteritis nodosa, pain after radiation therapy, polyneuropathy, multiple mononeuritis, infectious and neurodegenerative myelopathy, toxic neuropathy, vasculitis, and syringomyelia.
Specifically, the medicine can be used for human or veterinary medicine.
In an eighth aspect of the present invention, there is provided a method of anesthesia comprising the step of administering to a subject in need thereof an effective amount of the conjugate of the first aspect, the stereoisomer of the second aspect, the prodrug, solvate of the third aspect or the pharmaceutical composition of the fifth aspect.
In particular, the anesthesia is local anesthesia, in particular long-acting local anesthesia (which may, for example, have an effective anesthetic effect within 16 hours).
In particular, the subject is a mammal, in particular a human.
In a ninth aspect of the present invention, there is provided a method for the prevention and/or treatment of pain, comprising the step of administering to a subject in need thereof an effective amount of the conjugate of the first aspect, the stereoisomer of the second aspect, the prodrug, solvate of the third aspect or the pharmaceutical composition of the fifth aspect.
In particular, pain has the corresponding definition as set forth in the seventh aspect of the invention.
In particular, the subject is a mammal, in particular a human.
The invention provides a conjugate with a novel structure, which can be used as an anesthetic, particularly a long-acting local anesthetic, wherein P and D are connected through a non-degradable connecting group, D is not degraded, B-D part has an anesthetic effect, and the drug stays for a longer time at a focus part due to the existence of the P part, so that the aims of slow release and controlled release are fulfilled.
Drawings
FIG. 1 shows the nuclear magnetic spectrum of 4 AR-5K.
FIG. 2 shows the nuclear magnetic spectrum of 2 AR-2K.
FIG. 3 shows the nuclear magnetic spectrum of 2AR-PEG 24.
Detailed Description
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
The term "alkyl" refers to a hydrocarbon group of an alkane molecule lacking one hydrogen atom, which may be straight or branched chain, and which is attached to the rest of the molecule by a single bond. Alkyl groups as used herein typically contain 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms (i.e., C) 1 -C 6 Alkyl groups). Examples of such alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neoPentyl, tert-pentyl, n-hexyl, isohexyl, and the like.
The term "alkylene" refers to a hydrocarbon group (divalent alkyl group) of an alkane molecule lacking two hydrogen atoms, which may be straight or branched chain and which is attached to the rest of the molecule by a single bond. Alkylene groups as used herein generally contain from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably from 1 to 6 carbon atoms. Examples of the alkylene group include, but are not limited to, methylene (-CH) 2 -) ethylene (-CH 2 CH 2 -), propylene, butylene, and the like.
The term "alkoxy" refers to a substituent formed by substituting a hydrogen in a hydroxyl group with an alkyl group, and as used herein, an alkoxy group generally has 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms. Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and/or fused rings, 3 to 18 carbon atoms, preferably 1 monocyclic, 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
The term "solvate" is understood to mean any form of the compound of the invention in which the compound is attached to another molecule by non-covalent bonds (usually a polar solvent), including in particular hydrates and alcoholates, such as methanolate. Preferred solvates are hydrates.
The term "prodrug" is used in its broadest sense and encompasses derivatives that are convertible in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (I), including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Prodrugs can generally be prepared by known methods, such as those described in Burger "Medicinal Chemistry and Drug Discovery sixth edition (Donald J. Abrahamed.,2001, wiley) and" Design and Applications of drugs "(H.Bundgaard, 1985, harwood Academic Publishers).
The term "treating pain" includes eradicating, removing, reversing, relieving, altering, or controlling pain after the onset of pain.
The term "preventing pain" refers to the ability to avoid, minimize or make difficult the onset or progression of pain by treatment prior to the onset of pain.
The term "subject" refers to any animal or cell thereof, whether in vitro or in situ, treated according to the methods described herein. Specifically, the aforementioned animals include mammals, for example, wild animals, zoo animals, economic animals (e.g., pigs, cows, sheep, horses, donkeys, foxes, racoon dogs, minks, camels, etc.), pets (e.g., dogs, cats, rabbits, mice (e.g., guinea pigs, hamsters, gerbils, dragon cats, squirrels, etc.), laboratory animals (e.g., monkeys, dogs, rabbits, cats, mice (e.g., rats, mice), etc.), humans, and particularly humans.
The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entirety.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: synthesis of 4AR-5K
4AR-PEG5K-N 3 (7.5g, 1.5mmol), compound 1 (3.8g, 18mmol) and ascorbic acid (63.2g, 18mmol) were added to dimethyl sulfoxide (100 mL), and the mixture was stirred uniformly, an aqueous solution (100 mL) of copper sulfate pentahydrate (3.9g, 15.6 mmol) was added dropwise, and the mixture was stirred at room temperatureAnd (4) at night. Adding 1M ammonium chloride aqueous solution and ethyl acetate into the reaction solution, separating the solution, washing the aqueous phase with ethyl acetate once, extracting with dichloromethane three times, combining the organic phases, drying with anhydrous sodium sulfate, filtering and concentrating. Recrystallizing with isopropanol, vacuum filtering, and vacuum drying the filter cake to obtain off-white solid 4AR-5K 7.2g with yield 80%, and its nuclear magnetic spectrum is shown in FIG. 1. 1 H NMR(300MHz,DMSO-d 6 ):δ10.60(s,4H),8.23(s,4H),7.53-7.50(m,8H),7.19-7.14(m,20H),5.20-5.16(m,10H),4.99-4.90(m,4H),4.75-4.68(m,4H),4.66-4.54(m,8H),3.84-3.82(m,8H),3.81-3.73(m,4H),3.57-3.42(m,450H),3.40-3.18(m,16H),2.52-2.51(m,8H),2.26-2.22(m,24H),2.12-1.85(m,12H),1.80-1.62(m,8H),0.89(t,12H,J＝6.9Hz)。
Example 2: synthesis of 2AR-2K
2AR-PEG2K-N 3 (3.0g, 1.5 mmol), compound 1 (1.9g, 4.5 mmol) and ascorbic acid (31.6g, 9 mmol) were added to dimethyl sulfoxide (30 mL), and stirred uniformly, an aqueous solution (30 mL) of copper sulfate pentahydrate (3.9g, 15.6 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. Adding 1M ammonium chloride aqueous solution and ethyl acetate into the reaction solution, separating the solution, washing the aqueous phase with ethyl acetate once, extracting with dichloromethane three times, combining the organic phases, drying with anhydrous sodium sulfate, filtering and concentrating. Recrystallizing with isopropanol, filtering, and vacuum drying the filter cake to obtain off-white solid 2AR-2K 2.6g with yield of 82%, and its nuclear magnetic spectrum is shown in FIG. 2. 1 H NMR(300MHz,DMSO-d 6 ):δ10.60(s,2H),8.23(s,2H),7.53-7.45(s,4H),7.27-7.14(m,10H),5.25-5.18(m,5H),4.99-4.90(m,2H),4.75-4.68(m,2H),4.66-4.54(m,4H),3.84-3.82(m,4H),3.81-3.73(m,2H),3.57-3.42(m,180H),3.40-3.18(m,8H),2.52-2.51(m,4H),2.26-2.22(m,12H),2.12-1.85(m,6H),1.80-1.62(m,4H),0.90(t,6H,J＝7.2Hz)。
Example 3: synthesis of 2AR-PEG24
2AR-PEG24-N 3 (3.0g, 1.5 mmol), compound 1 (1.9g, 4.5 mmol) and ascorbic acid (31.6g, 9 mmol) were added to dimethyl sulfoxide (30 mL), stirred well, an aqueous solution (30 mL) of copper sulfate pentahydrate (3.9g, 15.6 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. Adding 1M ammonium chloride aqueous solution and ethyl acetate into the reaction solution, separating, extracting and washing the water phase with ethyl acetate once, extracting with dichloromethane three times, combining organic phases, drying with anhydrous sodium sulfate, filtering and concentrating. Recrystallizing with isopropanol, filtering, and vacuum drying the filter cake to obtain 2AR-PEG 24.4 g with yield of 78%, and its nuclear magnetic spectrum is shown in FIG. 3. 1 H NMR(300MHz,DMSO-d 6 ):δ10.40(s,2H),8.23(s,2H),7.53-7.45(s,4H),7.27-7.14(m,10H),5.25-5.18(m,5H),4.99-4.90(m,2H),4.75-4.68(m,2H),4.66-4.54(m,4H),3.84-3.82(m,4H),3.57-3.42(m,96H),3.40-3.18(m,6H),2.52-2.51(m,4H),2.26-2.22(m,14H),2.12-1.85(m,6H),1.80-1.62(m,4H),0.89(t,6H,J＝7.2Hz)。
Example 4: study of drug efficacy
1. Material
32 SD rats, male, with a body weight of 260-280 g; physiological saline; ropivacaine hydrochloride injection; 2AR-2K injection; 2AR-PEG24 injection.
2. Method of producing a composite material
2.1 grouping and administration
24 qualified rats (animals without dyskinesia) were randomly and averagely divided into 4 groups, each group had 6 animals, group 1 was a control group, the experimental animals were given physiological saline, and the other groups were given 4mg/kg bupivacaine hydrochloride injection, 2AR-2K injection and 2AR-PEG24 injection, respectively. The administration was performed by direct injection of the sciatic nerve, with the rat back facing up, around the right sciatic nerve trunk between the right hip and the right thigh.
2.2 motor block (four-point score):
the exercise condition of each group of rats was evaluated by a four-stage assessment method of exercise retardation, with the assessment criteria: the paw can carry out normal movements such as dorsiflexion, extension, eversion and the like for 1 minute; the paw can do dorsiflexion movement, can be bent or adducted, but can be stretched again, but the stretching ability is weakened to 2 minutes; the paw can do dorsiflexion movement, but does not have the stretching ability for 3 minutes after being curled; the paw completely lost the ability to move in dorsiflexion, curl and stretch, and the rat developed a gait deficit of 4 points. Time points for determining the motor block score were 0.5h, 1h, 2h, 4h, 8h, 12h, 16h, 24h of dosing.
3. Experimental results and discussion
3.1 results of the experiment
The results of the experiment are shown in table 1.
TABLE 1 results of the experiment
2.3 discussion of results
The anesthetic effect of ropivacaine hydrochloride after 2 hours with an anesthesia score of 1,2ar-2K that is still greater than 2,2ar-PEG24 at 4 hours may last up to 24 hours. Therefore, compared with ropivacaine, the anesthetic prepared by the invention has the advantage that the action time is obviously prolonged.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and the like that are within the spirit and principle of the present invention are included in the present invention.
The foregoing embodiments and methods described in this disclosure may vary based on the abilities, experience, and preferences of those skilled in the art.
The mere order in which the steps of a method are listed in the present invention does not constitute any limitation on the order of the steps of the method.
Claims (17)
1. A conjugate, or a stereoisomer, prodrug, solvate thereof, the conjugate having the structure:
wherein, the first and the second end of the pipe are connected with each other,
p contains one or more
Structure;
a is selected from: a single bond, an alkylene group,
b has the following structure:
wherein R is 1 Selected from the group consisting of: a single bond, alkylene, R 2 Selected from: single bond (-), -O-, -S-, -NR a -、-C(O)-、-C(S)-、-S(O)-、-S(O) 2 -；R a Selected from: H. alkyl, cycloalkyl, hydroxy, alkoxy;
d is an anesthetic residue;
m is an integer of 1 to 10.
2. The conjugate of claim 1, wherein moiety D has the structure:
wherein the content of the first and second substances,
R 3 is alkyl, R 5 Selected from the group consisting of: H. an alkyl group; or, R 3 、R 5 Together with the atoms to which they are attached form a cyclic group;
R 4 is an alkyl group;
R 6 and R 7 Independently selected from: H. an alkyl group;
X - is an anion.
3. The conjugate of claim 2, wherein X is selected from the group consisting of: F. cl, br, I, methanesulfonate, ethylsulfonate, benzenesulfonate, citrate, lactate, succinate, fumarate, glutamate, citrate, salicylate, maleate, in particular F, cl, br or I.
4. The conjugate of claim 2, wherein R is 3 Is C1-6 alkyl, R 5 Selected from: H. a C1-6 alkyl group; or, R 3 、R 5 Together with the atoms to which they are attached form a 5-8 membered heteroalicyclic, particularly a 6 membered heteroalicyclic;
R 4 is C1-6 alkyl;
R 6 selected from H, C1-6 alkyl;
R 7 selected from H, C1-6 alkyl.
5. The conjugate of claim 2, wherein the moiety D is selected from the structures:
6. the conjugate according to any one of claims 1 to 5, wherein R is 1 Selected from the group consisting of: a single bond, C1-6 alkylene; and/or, R 2 Selected from: single bond (-), -O-, -S-;
preferably, B has the structure:
7. the conjugate of any one of claims 1 to 6, wherein A is selected from: a single bond, C1-6 alkylene.
8. The conjugate of any of claims 1-7, wherein the moiety P has the structure:
wherein n is an integer of 1 to 5000; or the like, or a combination thereof,
p moietyHas the following structure:
wherein n is an integer of 1 to 5000; or the like, or, alternatively,
the P moiety has the following structure:
wherein n is an integer of 1 to 5000; or the like, or, alternatively,
the P moiety has the following structure:
wherein R is c Is a core group selected from: residues of pentaerythritol, oligomeric pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerol and polyglycerol, j is an integer from 3 to 8, and n is an integer from 1 to 5000;
preferably, R c Has the following structure:
wherein k is an integer of 1 to 3, and i is an integer of 1 to 5;
more preferably, the moiety P has the following structure:
wherein n is an integer of 1 to 5000. />
9. The conjugate of claim 1, wherein the conjugate is selected from the specific structures:
wherein n is an integer of 1 to 5000.
10. The conjugate of claim 1, wherein the stereoisomer is selected from the following specific structures:
wherein n is an integer of 1 to 5000.
11. The conjugate according to any of claims 8 to 10, wherein n is an integer from 10 to 1000, preferably from 10 to 100, more preferably from 10 to 50.
12. The conjugate according to any one of claims 1 to 10, wherein the moiety P has a molecular weight of from 100 to 100000Da, preferably from 100 to 50000Da, more preferably from 100 to 10000Da, further preferably from 500 to 5000Da.
13. A process for the preparation of a conjugate as claimed in any one of claims 1 to 12, which comprises the step of reacting a compound of formula vii with a compound of formula viii, wherein:
14. the method of claim 13, wherein moiety D is
Wherein R is 3 Is alkyl, R 5 Selected from: H. an alkyl group; or, R 3 、R 5 Together with the atoms to which they are attached form a cyclic group;
R 4 is an alkyl group;
R 6 and R 7 Independently selected from: H. an alkyl group;
X - is an anion;
the compound shown in the formula VIII is prepared by the following reaction:
15. a process according to claim 14, wherein the compound of formula ix is ropivacaine, mepivacaine, bupivacaine, lidocaine or etidocaine.
16. A pharmaceutical composition comprising a conjugate of any one of claims 1 to 12, or a stereoisomer, prodrug or solvate thereof, and one or more pharmaceutically acceptable excipients.
17. Use of a conjugate according to any one of claims 1 to 12, or a stereoisomer, prodrug or solvate thereof, for the manufacture of an anaesthetic or a medicament for the prevention and/or treatment of pain;
preferably, the anesthetic is a local anesthetic;
preferably, the pain is acute pain or chronic pain.
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| CN202210008444 | 2022-01-05 | ||
| CN2022100084444 | 2022-01-05 |
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