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CN110563601A - Compound with analgesic and sedative effects and application thereof - Google Patents

Compound with analgesic and sedative effects and application thereof Download PDF

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Publication number
CN110563601A
CN110563601A CN201910939157.3A CN201910939157A CN110563601A CN 110563601 A CN110563601 A CN 110563601A CN 201910939157 A CN201910939157 A CN 201910939157A CN 110563601 A CN110563601 A CN 110563601A
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China
Prior art keywords
compound
analgesic
pain
morphine
sedative
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CN201910939157.3A
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Chinese (zh)
Inventor
赵洁
吕冰洁
杨阳
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a compound for easing pain and calming, a preparation method and application thereof. The compound has excellent analgesic and sedative activities, has stronger inhibiting effect on common pains, such as tumor pain, postoperative pain and various repeated severe acute and chronic pains, and has wide clinical application prospect.

Description

Compound with analgesic and sedative effects and application thereof
Technical Field
The invention relates to a substituted naphthalene compound, in particular to an analgesic and sedative compound, and also relates to a preparation method and application of the compound.
Background
pain is a protective response to the body after being subjected to noxious stimuli, often accompanied by emotional activities such as fear, tension, uneasiness, etc. Pain is a symptom of some diseases and can cause pain. Severe pain is reflected in both sensory distress and emotional distress, and can lead to physiological dysfunction, cause insomnia, and even induce shock and endanger life. Therefore, it is necessary to use analgesics appropriately in clinical practice to relieve severe pain and prevent shock, and it is of great importance in the treatment of diseases and wound care.
Narcotic analgesics are drugs that act on the central nervous system to relieve or reduce pain and alter the emotional response to pain. Since early on these drugs were natural opioid alkaloids or their semisynthetic derivatives, narcotic analgesics were also called opioid analgesics. Wherein, fentanyl, morphine and codeine are all opioid receptor agonists, and pethidine is an artificial synthesized opioid receptor agonist.
Morphine is the first analgesic recommended by WHO, is the third-step medication in the three-step analgesic treatment principle of cancer, and is the first choice for severe cancer pain. The WHO experts considered morphine consumption in a country to be an important marker for evaluating the improvement of cancer pain in that country. The injection is mainly used for postoperative self-control analgesia (PCA); the oral morphine controlled release tablet has convenient administration, stable blood concentration level, less adverse reaction and weak addiction. However, morphine has some adverse reactions such as nausea, vomiting, constipation, etc., and can also cause respiratory depression.
Codeine (codeine), acts similarly to morphine but is less potent. The analgesic effect is about 1/10 of that of morphine. The antitussive effect is about 1/4 of that of morphine. Used for moderate pain and severe dry cough. Has no obvious side effects of constipation, urinary retention, orthostatic hypotension and the like, and has euphoria and addiction lower than morphine.
The analgesic strength of the pethidine (pethidine) is 1/10-1/7 of that of morphine, and the effects of sedation, respiratory depression, euphoria and blood vessel expansion are equivalent to those of morphine; constipation and urinary retention are not caused; the labor process is not prolonged; large doses can cause bronchial smooth muscle contraction.
Fentanyl (fentanyl) and its homologues, short-acting analgesics (100 times stronger than morphine), used for narcotic adjuvant and intravenous compound anaesthesia, or used in combination with haloperidol to produce nerve-block analgesia. Sufentanil (supentinil) and alfentanil (alfentinil) are both analogs of fentanyl. Sufentanil is 1000 times more analgesic than fentanyl, whereas alfentanil is weaker than fentanyl. The two drugs have little influence on cardiovascular system, and are commonly used for anesthesia in cardiovascular surgery.
Dihydroetorphine (dihydroetorphine) is a strong analgesic produced in China, and the analgesic effect of dihydroetorphine is 500-1000 times that of morphine. The compound is clinically used for chronic intractable pain and advanced cancer pain which are not effective by meperidine, morphine and the like.
Tramadol, a weak agonist of the mu receptor, NA, 5-HT reuptake inhibitors. Analgesic potency is similar to pentazocine. The cough relieving effect is half of that of codeine. Respiratory depression, smooth muscle spasm and dependence were weak. Has no obvious cardiovascular effect. It is indicated for moderate and severe acute and chronic pain.
Rotundine (rotundine), the effective part is L-form of tetrahydropalmatine. Has tranquilizing, analgesic, and central muscle relaxing effects. May be related to the promotion of synthesis and release of enkephalins and endorphins, and the blocking of DA receptors in the brain. Has good effect on chronic persistent dull pain. Can be used for treating dull pain of gastrointestinal system, headache after concussion, and traumatic and cancerous pain.
In addition, the antipyretic analgesic and anti-inflammatory drug is a drug with antipyretic and analgesic effects. The analgesic action parts of the medicines are mainly at the periphery, and when tissues are damaged or inflamed, pain is caused by locally generating and releasing PG, bradykinin, histamine, 5-HT and other pain-causing substances, PG not only has the pain-causing effect, but also can obviously improve the sensitivity of pain nerve endings to the pain-causing substances such as bradykinin and the like, and generate persistent dull pain. NSAIDs inhibit PG synthesis during inflammation and thus have good analgesic effects on chronic dull pain. Including salicylic acids (aspirin), anilines (acetaminophen), pyrazolones, indoleacetic acids, fenamic acids, propionic acids, and oxicams.
At present, clinical analgesic drugs are easy to have the defects of dependence, more side effects and the like in application, so that more novel analgesic and sedative drugs capable of solving the defects are needed.
Disclosure of Invention
In view of the disadvantages of the prior art, the technical problem to be solved by the present invention is to provide a novel analgesic and sedative compound, further provide a pharmaceutical composition containing the above compound as an active ingredient, and application in preparing analgesic and sedative drugs
The invention provides a compound with analgesic and sedative effects and a stereoisomer and a tautomer thereof, wherein the structure of the compound is as shown in formula (I):Wherein R1, R2 and R3 are halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl, X is (CH)2)nWherein n is 1 to 5, preferably n is 1 to 3.
preferably, R1 and R2 are halogen, hydroxyl, cyano, amino and nitro, and R3 is C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl.
Further, R1 is different from R2, R3 is C1-C3 alkyl, and n is 1-3.
The most preferred compounds are
Also included in the invention are compositions of the above compounds comprising a therapeutically effective amount of a compound of formula (I) above, together with one or more pharmaceutically acceptable carriers. The acceptable carriers described above are non-toxic, can be adjunctive to administration, and do not adversely affect the therapeutic benefits of the compounds of formula (I). Such carriers can be any solid excipient, liquid excipient, semi-solid excipient, or in aerosol compositions, gaseous excipient, commonly available to those skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl stearyl ester, sodium chloride, anhydrous skim milk, and the like. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil and the like, preferably liquid carriers, particularly for injectable solutions, including water, saline, aqueous dextrose and glycols.
The compounds of the invention are administered in pharmaceutical compositions by the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred method of administration is oral using a convenient daily dosage regimen which may be adjusted depending on the extent of the disease.
The pharmaceutical composition can be prepared into common clinical dosage forms such as tablets, capsules, emulsions, infusion solutions, injections, sprays and the like. The various dosage forms can be prepared according to conventional methods in the pharmaceutical field. For example, the compound (active ingredient) can be combined with one or more carriers and then formulated into a desired dosage form, e.g., tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, formulations, aerosols, and the like.
The amount of the compound in the dosage form may vary within the full range used by those skilled in the art. Typically, the dosage form contains about 1-99 wt% of the compound of formula (I) based on the total dosage form, in weight percent (wt%), and one or more suitable pharmaceutical excipients as a balance. Preferably, the compound is present in a proportion of about 20 to 70 wt%.
The invention also provides application of the compound in preparation of analgesic and sedative drugs.
Detailed Description
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.
EXAMPLE 1 preparation of N- (2- (4-fluoro-6-chloro-1-yl) ethyl) propionamide
Step 1 Synthesis of (E) -4-fluoro-6-chloro-4- (2-nitrovinyl) naphthalene
4-fluoro-6-chloro-1-naphthaldehyde (3.0g) and NH4OAc (828mg) were added to nitromethane (20mL), and the mixture was reacted at 140 ℃ in an oil bath for 8 hours, followed by stopping the reaction, diluting with ethyl acetate (80mL), washing with saturated brine (40 mL. times.3), and separating the liquid, the organic phase was dried over anhydrous sodium sulfate. Filtration and spin-drying of the filtrate under reduced pressure gave the title compound as a red solid (1.8 g).
MS(ESI,pos.ion)m/z:264.1[M+1]+；
Step 2) Synthesis of 2- (4-fluoro-6-chloro-naphthyl) ethylamine
(E) -4-fluoro-6-chloro-4- (2-nitrovinyl) naphthalene (1.8g) was added to tetrahydrofuran (30mL) at 0 deg.C, followed by LiAlH4(2.5 g). After reacting for 30min, the temperature is raised to 70 ℃, and the reaction is stirred for 24 h. Quenching with 15% KOH solution, adding 30mL of chloroform for extraction, suction-filtering, washing the filtrate with saturated sodium chloride solution (40mL), adding triethylamine (250. mu.L) to the washed residue, adding to dichloromethane (25mL), slowly adding propionyl chloride (150. mu.L) dropwise in a low-temperature bath at 0 ℃, transferring to 30 ℃ for reaction for 5 hours after dropwise addition, adding 30mL of dichloromethane, washing with saturated sodium chloride solution (40mL), separating, and drying the organic phase with anhydrous sodium sulfate. Filtration, spin-drying of the filtrate under reduced pressure and purification by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave the title compound as a white solid (100 mg).
MS(ESI,pos.ion)m/z:281.6[M+1]+；
1H NMR(600MHz,CDCl3)7.33,7.66,7.73,6.91,7.06(s，1H，CH)，3.24,3.54，2.23,1.15 (s，2H，CH2)，8.0(1H，NH)
13CNMR(150MHz,CDCl3)127.5,131.6,119.7,124.7,132.8,125.6,156.7,111.6,126.8,130.1,35.6
in addition, the compounds Are synthesized and prepared according to the reaction flow.
Example 2 biological assay
In vivo analgesic effect of compound mouse acetic acid writhing method
the compound the serial numbers of the compounds are compounds a, b, c and d.
1. Experimental animals:
Kunming mice, clean-grade KM mice were purchased from Shanghai Slek laboratory animals, Inc., and were bred in the general environment.
2. Experimental administration mode:
The compounds a, b, c and d are prepared into 4mg/ml and 2mg/ml solutions by using water for injection, and the control group and the administration group are administrated by adopting animals through neck subcutaneous injection.
3. Experimental dosing:
Two different doses were used, respectively: 10mg/kg, 20 mg/kg.
4. The experimental method comprises the following steps:
aspirin was used as a positive control drug and the acetic acid writhing method was used for the experiments.
5. Specific experimental operations:
30 mice were selected, half male and half female, and the body weight was 18-23 g. It is divided into four groups, which are respectively: the negative control group, the positive control group, the sample group 1 and the sample group 2 are as follows:
Mice are firstly subjected to gastric lavage to administer a test sample (10mg/kg, 20mg/kg), a negative control group is orally administered with normal saline (20ml/kg), a positive control group is orally administered with aspirin (200mg/kg), after 1 hour, each group of mice are respectively ip with 0.7% acid 10ml/kg, the times of writhing reaction of each group of mice within 15min are recorded at intervals of 5min, and the writhing reaction inhibition rate of each administration group is calculated according to the following formula.
The inhibition rate is (average number of wriggles in negative control group-average number of wriggles in treated group)/(average number of wriggles in negative control group) × 100%
6. Results of the experiment
Positive control group 85.3%
Sample set 1 Sample set 2
Compound a 92.4％ 96.7％
compound b 91.2％ 93.5％
Compound c 92.2％ 94.1％
Compound d 89.2％ 93.4％
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims (7)

1. Compound with analgesic and sedative effects and stereoisomerism thereofA compound, tautomer, characterized in that said compound has the structure of formula (I):Wherein R1, R2 and R3 are halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl, X is (CH)2)nWherein n is 1 to 5, preferably n is 1 to 3.
2. the compound of claim 1, wherein: r1 and R2 are halogen, hydroxyl, cyano, amino and nitro, and R3 is C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl.
3. The compound of claim 1 or 2, wherein: r1 is different from R2, R3 is C1-C3 alkyl, and n is 1-3.
4. The compound of claim 1, wherein: the compound is
5. Use of a compound according to claim 1, wherein: the compound is used for preparing analgesic and sedative drugs.
6. A composition comprising the compound of claim 1, wherein: the composition comprises auxiliary materials such as a filling agent, a lubricating agent, an excipient and the like.
7. The composition of claim 6, wherein: the composition can be made into tablet, capsule, lotion, infusion solution, injection, spray, etc.
CN201910939157.3A 2019-09-30 2019-09-30 Compound with analgesic and sedative effects and application thereof Pending CN110563601A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3467710A (en) * 1968-05-27 1969-09-16 Parke Davis & Co Beta-(4- or 5-phenyl-1-naphthalene) ethylamines
DE3828566A1 (en) * 1988-08-23 1990-03-15 Thomae Gmbh Dr K NEW BENZOLSULFONAMIDO COMPOUNDS, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US20110159048A1 (en) * 2009-12-22 2011-06-30 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
CN104230742A (en) * 2014-08-14 2014-12-24 广东东阳光药业有限公司 Naphthalene derivatives and their application in medicine
CN104292125A (en) * 2014-08-14 2015-01-21 广东东阳光药业有限公司 Naphthalene derivatives and their application in medicine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3467710A (en) * 1968-05-27 1969-09-16 Parke Davis & Co Beta-(4- or 5-phenyl-1-naphthalene) ethylamines
DE3828566A1 (en) * 1988-08-23 1990-03-15 Thomae Gmbh Dr K NEW BENZOLSULFONAMIDO COMPOUNDS, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US20110159048A1 (en) * 2009-12-22 2011-06-30 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
CN104230742A (en) * 2014-08-14 2014-12-24 广东东阳光药业有限公司 Naphthalene derivatives and their application in medicine
CN104292125A (en) * 2014-08-14 2015-01-21 广东东阳光药业有限公司 Naphthalene derivatives and their application in medicine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MERVE KASAP等: ""Opioid system mediated anti-nociceptive effect of agomelatine in mice"", 《LIFE SCIENCES》 *

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