阅读说明：本技术 局部镇痛用药物组合物、其制备方法及其应用 (Pharmaceutical composition for local analgesia, preparation method and application thereof ) 是由 陈明英 于 2019-08-23 设计创作，主要内容包括：本发明关于镇痛用药物组合物,特别是关于一种局部镇痛用药物组合物及其应用,所述局部镇痛用药物组合物包括(i)有效含量的木犀草素；(ii)有效含量的至少一种具有结构式(1)的杂吲哚衍生物或其非毒性药理学上可允许的盐；<Image he="441" wi="700" file="DDA0002176828330000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本申请还分别提供了包含所述局部镇痛用药物组合物的镇痛剂和镇痛用纳米脂质体制剂。所述局部镇痛用药物组合物对疼痛、特别是神经性疼痛和/或纤维肌痛症具有强的镇痛作用,其镇痛效果优于度洛西汀,但其毒性小于度洛西汀,以本发明所述局部镇痛用药物组合物作为效用成分制备镇痛用纳米脂质体,可以获得较好的粒径控制和质量控制,在疼痛的预防和治疗方面具有良好的应用潜力。(The invention relates to a pharmaceutical composition for relieving pain, in particular to a pharmaceutical composition for local pain relieving and application thereof, wherein the pharmaceutical composition for local pain relieving comprises (i) luteolin with effective content; (ii) an effective amount of at least one heteroindole derivative of formula (1) or a non-toxic pharmacologically acceptable salt thereof; the application also provides an analgesic and an analgesic nanoliposome preparation containing the pharmaceutical composition for local analgesia respectively. The local analgesic drug composition has strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, the analgesic effect is better than that of duloxetine, but the toxicity is less than that of duloxetine.)

1. A pharmaceutical composition for topical analgesia, said pharmaceutical composition comprising:

(i) an effective amount of luteolin;

(ii) an effective amount of at least one heteroindole derivative of formula (1) or a non-toxic pharmacologically acceptable salt thereof;

wherein R is₁Is benzyl selected from unsubstituted or substituted by one, two or three groups selected from hydroxy, halogen, C_1-4Alkyl and C_1-4Substituted with an alkoxyalkyl group;

R₂is NR₅R₆Wherein

R₅Is selected from C_1-4Alkyl and or C_1-4An alkoxyalkyl group;

R₆selected from C optionally substituted by at least one halogen atom_1-4Alkyl radical, C_1-4Alkoxyalkyl group, C (O) OC_1-4Alkyl, C (O) NHC_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_1-4Carbonylalkyl or C_1-4A mercaptoalkyl group; or

R₅、R₆Together with the nitrogen atom to which they are attached form a heterocyclic group;

R₃selected from 4-6 membered cycloalkyl or 5-6 membered heterocyclic non-aromatic ring, wherein said 4-6 membered cycloalkyl is optionally substituted or unsubstituted by hydroxy, halogen, C_1-3Alkyl or C_1-3Alkoxyalkyl, said 5-to 6-membered heterocyclic non-aromatic ring comprising at least one heteroatom selected from N, O or S and optionally substituted or unsubstituted by hydroxy, C_1-3Alkyl radical, C_1-3Alkoxyalkyl substitution;

R₄is selected from C_1-6Alkyl radical, C_1-6Alkoxyalkyl group, C_1-6Hydroxyalkyl radical, C_1-6Carbonylalkyl, C_1-6Mercaptoalkyl radical, C_1-6Aralkyl, C (O) OC_1-4Alkyl or C (O) NHC_1-4An alkyl group.

2. The composition of claim 1, wherein:

the R is₁Is benzyl selected from the group consisting of mono-and di-substituted hydroxy, halogen, C_1-2Alkyl and C_1-2Substituted with an alkoxyalkyl group;

R₂is NR₅R₆Wherein

R₅Is selected from C_1-4Alkyl and or C_1-4An alkoxyalkyl group;

R₆is selected from C_1-2Alkoxyalkyl group, C (O) OC_1-2Alkyl or C (O) NHC_1-2An alkyl group;

R₃selected from 5-6 membered heterocyclic non-aromatic rings, said 5-6 membered heterocyclic non-aromatic rings comprising at least one heteroatom selected from N, O or S and optionally substituted by hydroxyl, C_1-2Alkyl radical, C_1-2Alkoxyalkyl substitution;

R₄is selected from C_1-2Alkyl radical, C_1-2Alkoxyalkyl group, C_1-2Hydroxyalkyl radical, C_1-2Carbonylalkyl, C_1-2Mercaptoalkyl radical, C_1-2Aralkyl, C (O) OC_1-2Alkyl or C (O) NHC_1-2An alkyl group.

3. The composition of claim 1, wherein: the non-toxic pharmacologically permissible salts may be selected from inorganic acid salts or organic acid salts.

4. The composition of claims 1-3, wherein: the weight ratio of the luteolin to at least one heteroindole derivative with a structural formula (1) or a non-toxic pharmacologically allowable salt thereof is 1: 1-5.

5. Analgesic, characterized in that it comprises any one of the pharmaceutical compositions according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier.

6. The nano liposome preparation for relieving pain is characterized by comprising the following components in percentage by weight:

-0.1 to 30.0 wt% of a pharmaceutical composition for topical analgesia according to any one of claims 1 to 4;

-60.0-99.0 wt.% of lipids;

-0.05 to 0.1 wt% of a germacular plant acid;

-0.5 to 10.0 wt% of water-soluble vitamin E.

7. The nanoliposome formulation for analgesia as claimed in claim 7 wherein: the lipid is at least one selected from triglyceride, soybean lecithin, C12-20 even number carbon linear chain saturated or unsaturated fatty acid, cholesterol, ergosterol, beta-sitosterol, menthol, cholesterin, myrcene, andrographolide and beta-carotene.

8. A method for preparing the nanoliposome preparation for analgesia as claimed in claim 6 or 7, which comprises:

1) dissolving the local analgesic medicinal composition, lipid and water-soluble vitamin E in methanol according to the formula amount, and removing the methanol by rotary evaporation to form a film;

2) adding ammonium sulfate, and then carrying out ultrasonic treatment;

3) passing through 200nm polycarbonate membrane with liposome extruder, and replacing liposome external phase liquid with PBS solution;

4) adding fel Ursi plant acid, heating, and shaking.

9. The method according to claim 8, wherein at least 75% of the particles of the nanoliposome formulation for pain relief have a particle size distribution ranging from 100 to 130 nm.

10. Use of a composition according to claims 1 to 6 for the preparation of a medicament for the treatment and/or prevention and/or co-treatment of neurological disorders such as neuralgia, addiction, Parkinson's disease, epilepsy, ischaemia, excitatory neuronal cell death, dementia, breast cancer, lung cancer, encephalomyelitis, or for the treatment of wound healing or analgesia.

Technical Field

The invention relates to a pharmaceutical composition for analgesia, in particular to a pharmaceutical composition for local analgesia and application thereof.

Background

Neuropathic pain (Neuropathicpain) is a chronic pain caused by damage or disease of the central or peripheral somatosensory nervous system, mainly manifested as spontaneous pain (persistent pain and paroxysmal pain) and induced pain (hyperalgesia and allodynia), characterized in that after the nervous system injury heals, the pain sense persists, and seriously affects the quality of daily life of the patient.

The neurogenic pain has wide causes, high morbidity, complex pathological mechanism and the lack of specific treatment drugs in clinic at present, which always troubles the medical field. It is estimated that only 1/4 patients have a greater than 50% relief of post-drug neuralgia and significant central system side effects. Traditional analgesic drugs mainly include opioids and non-steroidal anti-inflammatory drugs. Opioid analgesics have strong analgesic effect, but are easy to cause tolerance, dependence and addiction after long-term use, have adverse reactions such as respiratory depression, central tranquilization and the like, and are currently used for acute pain, cancer severe pain and the like. The nonsteroidal anti-inflammatory drug only exerts moderate analgesic effect, is suitable for mild and moderate chronic dull pain, but is ineffective for sharp pain caused by direct stimulation of sensory endings, and has adverse reactions such as gastrointestinal bleeding and cardiotoxicity. There is therefore still a need in the art to develop new analgesic drugs.

The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and does not necessarily belong to the prior art of the present patent application, and should not be used for evaluating the novelty and inventive step of the present application in the case that there is no clear evidence that the above content is disclosed at the filing date of the present patent application.

Disclosure of Invention

The invention aims to provide a pharmaceutical composition for local analgesia and application thereof, wherein the pharmaceutical composition for local analgesia has strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, the analgesic effect is better than duloxetine, but the toxicity is lower than that of duloxetine.

To achieve the above object, the present invention adopts the technical means including the following items [1] to [4 ].

[1] A pharmaceutical composition for topical analgesia, said pharmaceutical composition comprising:

(i) an effective amount of luteolin;

(ii) an effective amount of at least one heteroindole derivative of formula (1) or a non-toxic pharmacologically acceptable salt thereof.

Wherein R is₁Is benzyl selected from unsubstituted or substituted by one, two or three groups selected from hydroxy, halogen, C_1-4Alkyl and C_1-4Substituted with an alkoxyalkyl group; the benzyl group is preferably substituted by one or two groups selected from hydroxy, halogen, C_1-2Alkyl and C_1-2Substituted with an alkoxyalkyl group;

R₂is NR₅R₆Wherein

R₅Is selected from C_1-4Alkyl and or C_1-4An alkoxyalkyl group;

R₆selected from C optionally substituted by at least one halogen atom_1-4Alkyl radical, C_1-4Alkoxyalkyl group, C (O) OC_1-4Alkyl, C (O) NHC_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_1-4Carbonylalkyl or C_1-4A mercaptoalkyl group; r6 is preferably selected from C_1-2Alkoxyalkyl group, C (O) OC_1-2Alkyl or C (O) NHC_1-2An alkyl group; or

R₅、R₆Together with the nitrogen atom to which they are attached form a heterocyclic group;

preferably, R₅、R₆Together with the nitrogen atom to which they are attached form a heterocyclic group;

R₃selected from 4-6 membered cycloalkyl or 5-6 membered heterocyclic non-aromatic ring, wherein said 4-6 membered cycloalkyl is optionally substituted or unsubstituted by hydroxy, halogen, C_1-3Alkyl or C_1-3Alkoxyalkyl, said 5-to 6-membered heterocyclic non-aromatic ring comprising at least one heteroatom selected from N, O or S and optionally substituted or unsubstituted by hydroxy, C_1-3Alkyl radical, C_1-3Alkoxyalkyl substitution; r₃Preferably selected from 5-6 membered heterocyclic non-aromatic rings, said 5-6 membered heterocyclic non-aromatic rings comprising at least one heteroatom selected from N, O or S and optionally substituted by hydroxyl, C_1-2Alkyl radical, C_1-2Alkoxyalkyl substitution;

R₄is selected from C_1-6Alkyl radical, C_1-6Alkoxyalkyl group, C_1-6Hydroxyalkyl radical, C_1-6Carbonylalkyl, C_1-6Mercaptoalkyl radical, C_1-6Aralkyl, C (O) OC_1-4Alkyl or C (O) NHC_1-4An alkyl group; r₄Preferably selected from C_1-2Alkyl radical, C_1-2Alkoxyalkyl group, C_1-2Hydroxyalkyl radical, C_1-2Carbonylalkyl, C_1-2Mercaptoalkyl radical, C_1-2Aralkyl, C (O) OC_1-2Alkyl or C (O) NHC_1-2An alkyl group.

In the summary of the invention and the preferred embodiment, the luteolin has a structural formula shown as a formula (2).

In the summary and preferred embodiment of the present invention, in the pharmaceutical composition for local analgesia, the weight ratio of luteolin to at least one heteroindole derivative having a structural formula (1) or a non-toxic pharmacologically acceptable salt thereof is 1: 1-5; the preferable weight ratio is 1: 2-3; more preferably, the weight ratio is 1: 2.3-2.7. The weight ratio of the luteolin to the at least one heteroindole derivative of the formula (1) or the non-toxic pharmacologically acceptable salt thereof may be selected from, but is not limited to, any ratio within the following ratio ranges: 1: 1-1.5, 1: 1-2, 1: 1-2.5, 1: 1-3, 1: 1-3.5, 1: 1-4, 1: 1-4.5, 1: 1-5, and optionally any ratio between any two ratio ranges: 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, 1:2.3, 1:2.4, 1:1.5, 1:2.6, 1:1.7, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1: 5.0.

The local analgesic pharmaceutical composition containing the effective content of luteolin and at least one heteroauxin derivative with a structural formula (1) or a non-toxic pharmacologically allowable salt thereof has a strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, and the analgesic effect of the local analgesic pharmaceutical composition is evaluated by a formalin method, a writhing acetate method and a rat sciatic nerve branch selective injury model, so that the analgesic effect is proved to be superior to that of duloxetine, the composition has an excellent analgesic effect, and the toxicity of the composition is lower than that of duloxetine, so that a novel effective medicament is provided for preventing and/or treating pain, particularly neuropathic pain and/or fibromyalgia.

[2] An analgesic comprising any one of the pharmaceutical compositions described in item [1] and at least one pharmaceutically acceptable carrier.

In the present summary and preferred embodiments, the substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.

[3] The nano liposome preparation for relieving pain comprises the following components in percentage by weight:

-0.1 to 30.0 wt% of the pharmaceutical composition for topical analgesia described in item [1 ];

-60.0-99.0 wt.% of lipids;

-0.05 to 0.1 wt% of a germacular plant acid;

-0.5 to 10.0 wt% of water-soluble vitamin E.

In summary and preferred embodiments of the invention, the lipid is selected from at least one of triglycerides, soy lecithin, C12-20 even-numbered carbon linear saturated or unsaturated fatty acids, cholesterol, ergosterol, beta-sitosterol, menthol, cholesterol, myrcene, andrographolide, and beta-carotene.

In the summary of the invention and preferred embodiments, the method of preparing the nanoliposome formulation for analgesia comprises:

1) dissolving the local analgesic pharmaceutical composition of item [1], lipids and water-soluble vitamin E in methanol according to the formula amount, and removing the methanol by rotary evaporation to form a film;

2) adding ammonium sulfate, and then carrying out ultrasonic treatment;

3) passing through 200nm polycarbonate membrane with liposome extruder, and replacing liposome external phase liquid with PBS solution;

4) adding fel Ursi plant acid, heating, and shaking.

In the summary and preferred embodiment of the present invention, at least 75% of the particles of the nanoliposome preparation for relieving pain have a particle size distribution range of 100 to 130 nm.

Based on the consideration that the local analgesic pharmaceutical composition comprising effective content of luteolin and at least one heteroauxin derivative having the structural formula (1) or a non-toxic pharmacologically acceptable salt thereof according to the present invention has strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, the preparation of the analgesic nanoliposome preparation using the local analgesic pharmaceutical composition according to the present invention as an effective ingredient is an practicable scheme, however, the existing liposome preparation technology is more difficult to obtain nanoliposomes with narrow particle size distribution, which may be influenced by some drug characteristics, and the inventors found that, when the nanoliposome is prepared according to the method of the present invention, the addition of cryptophygmic acid and water-soluble vitamin E during the preparation process is easier to obtain a nanoliposome preparation with narrow particle size distribution, and the combined use of cryptophygmic acid and water-soluble vitamin E can produce excellent particle size control effect, the nano liposome preparation has narrow particle size distribution, is beneficial to the quality control of the preparation, and has good application potential in the aspects of preventing and treating pain.

[4] Use of a composition according to item [1] for the preparation of a medicament for the treatment and/or prevention and/or co-treatment of neurological disorders such as neuralgia, addiction, Parkinson's disease, epilepsy, ischaemia, excitatory neuronal cell death, dementia, breast cancer, lung cancer, encephalomyelitis, or for the treatment of wound healing or analgesia; in particular, the neuropathic pain is caused by one or more of the following factors: cancer and cancer chemotherapy, alcoholism, sciatica, diabetes, trigeminal neuralgia, sclerosis, shingles, mechanical and surgical wounds, aids, cranial nerve paralysis, drug intoxication, industrial pollution intoxication, lymphatics neuralgia, myeloma, multi-site motor neuralgia, chronic congenital sensory neuropathy, acute severe idiopathic neuralgia, crush neuralgia, vasculitis, ischemia, uremia, childhood biliary liver disease, chronic respiratory disorder, compound neuralgia, multiple organ failure, sepsis/sepsis, hepatitis, porphyria, vitamin deficiency, chronic liver disease, primary biliary cirrhosis, hyperlipidemia, leprosy, lyme arthritis, sensory neurofasciitis, or allergy.

The invention has the beneficial effects that:

the local analgesic pharmaceutical composition containing the effective content of luteolin and at least one heteroauxin derivative with a structural formula (1) or a non-toxic pharmacologically allowable salt thereof has strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, the analgesic effect of the local analgesic pharmaceutical composition is evaluated by a formalin method, a writhing acetate method and a rat sciatic nerve branch selective injury model, and the analgesic effect is proved to be superior to duloxetine, so that the composition has excellent analgesic effect and has toxicity lower than that of duloxetine, and a new effective medicament is provided for preventing and/or treating pain, particularly neuropathic pain and/or fibromyalgia; when the nano liposome is prepared according to the method, the nano liposome preparation with narrow particle size distribution can be easily obtained by adding the cryptocryo-fel catus phytoacid and the water-soluble vitamin E in the preparation process, the combined use of the cryptocryo-fel catus phytoacid and the water-soluble vitamin E can generate good particle size control effect, the particle size distribution of the nano liposome preparation is narrow, the quality control of the preparation is facilitated, and the nano liposome preparation has good application potential in the aspects of pain prevention and treatment.

The invention adopts the technical scheme to provide the model essay, makes up the defects of the prior art, and has reasonable design and convenient operation.

Drawings

In order to make the aforementioned and other objects, features, and advantages of the invention, as well as others which will become apparent, reference is made to the following description taken in conjunction with the accompanying drawings in which:

FIG. 1 is a schematic structural diagram of a heteroindole derivative of the present invention;

FIG. 2 is a schematic diagram of the structural formula of luteolin in the present invention;

FIG. 3 is a schematic diagram of the analgesic effect of the pharmaceutical composition for local analgesia on formalin-induced inflammatory pain in mice, wherein the pain in stage I is an acute pain stage caused by formalin directly stimulating a nerve ending pain receptor and occurs 0-10 min after injection; phase II pain is a strong and straight phase, caused by central sensitization due to progressive attenuation of peripheral pain receptor afferent stimulation, continuous local tissue activation and release of inflammatory mediators, secondary inflammatory pain, mainly transmitted by C-fiber mediated stimulation, occurs 10-40 min after injection.

Detailed Description

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present invention uses the methods and materials described herein; other suitable methods and materials known in the art may be used. The materials, methods, and examples described herein are illustrative only and are not intended to be limiting. All publications, patent applications, patents, provisional applications, database entries, and other references mentioned herein, and the like, are incorporated by reference herein in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description, the accompanying drawings, and the claims.

The various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art and, to the extent that the terms and phrases are not inconsistent with their known meaning, the meaning of the present invention as expressed herein applies.

The term "treatment" as used herein has its ordinary meaning and refers herein, in particular, to the treatment of a mammal already suffering from pain with a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof in an attempt to produce a therapeutic, curative, palliative, etc., effect on said pain.

Similarly, the term "prevention" as used herein has its ordinary meaning and refers herein in particular to the treatment of a mammal which may suffer from pain or is at risk of suffering from said pain with a compound of the invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in order to produce a preventing, arresting, abrogating, etc. effect on said pain.

The term "pharmaceutically acceptable" as used herein generally refers to those compounds that are useful in the pharmaceutical arts, are not deleterious to the product or mammal, or have a reasonable or acceptable benefit/risk ratio.

The term "pharmaceutical adjuvant" as used herein refers to all the pharmaceutical materials except the main drug added to solve the problems of moldability, effectiveness, stability and safety of the preparation during the formulation design. The particular choice will depend upon the mode of administration or the type and state of the disease used to treat a particular patient. The preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical art. For example, solvents, propellants, solubilizers, solubilizing agents, emulsifying agents, colorants, binders, disintegrating agents, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickening agents, encapsulation agents, humectants, absorbents, flocculating and deflocculating agents, filter aids, release retardants, and the like, which are conventional in the pharmaceutical art, may be included as pharmaceutically acceptable adjuvants.

The term "pain" as used herein can be classified into somatic pain, visceral pain and neuropathic pain according to the site where the pain impulse occurs. Somatic pain is caused by various nociceptors of tissues on the surface and in the deep layer of the body (for example, a mouse foot sole formalin injection model), namely surface somatic pain (or skin pain) and deep somatic pain (for example, fibromyalgia, lumbocrural pain, cervical spondylosis, lumbar intervertebral disc protrusion, gonarthritis, talalgia, temporomandibular joint dysfunction syndrome, degenerative osteoarthritis, supraspinatus ligamentitis, lumbar dorsal myofascitis, piriformis syndrome, tenosynovitis, scapulohumeral periarthritis, tennis elbow and the like), and can be divided into acute pain (also called acute pain) and chronic pain (also called dull pain). The former is sharp and clearly positioned stabbing pain, the nociceptive stimulation occurs immediately after reaching a threshold value, and the stimulation disappears quickly after being removed; the latter is a strong and poorly localized "burning pain" that occurs slowly and lasts longer. Visceral pain is caused by inflammation, pressure, friction or traction on pain receptors in the internal organs, serosa of body cavity walls and tissues of pelvic organs (e.g., mouse writhing model of acetoplasts). Neuropathic pain is due to damage to the nervous system or compression or infiltration by tumors (e.g., selective injury to the sciatic nerve branch (SNL) model in rats and chronic compressive injury to the sciatic nerve (CCI) model in rats), including trigeminal neuralgia, intercostal neuralgia, sciatica, acute herpes zoster, postherpetic neuralgia, and the like. According to the cause of pain, there are divided into inflammatory pain and cancer pain. Also included are headaches (e.g., migraine, cervicogenic headache, muscular tension headache, post-traumatic headache), and the like. Pain as described herein includes the various types of pain described above.

The term "non-toxic pharmacologically acceptable salt" may be any salt or ester which is physiologically acceptable and suitable for administration. For example, pharmaceutically acceptable salts include salts of inorganic or organic acids, wherein the inorganic acid salt can be a hydrochloride, hydrobromide, hydrofluoride, hydroiodide, perchlorate, chlorate, hypochlorite, hypobromite, bromate, hypoiodate, iodate, periodate, carbonate, bicarbonate, nitrate, nitrite, hyponitrate, borate, metaborate, hypoborate, metasilicate, silicate, sulfate, bisulfate, sulfite, bisulfite, pyrosulfate, persulfate, hemisulfate, bisulfate, thiocyanate, peroxodisulfate, dithionate, thiosulfate, metaphosphate, phosphite, pyrophosphite, hypophosphite, monohydrogen phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, phosphate, dihydrogenphosphate, periodate, nitrate, nitrite, borate, metaborate, borate, bromide, hyposulfite, metabisulfite, persulfate, and/or a mixture thereof, A manganate, permanganate, molybdate, tungstate, or any combination thereof; the organic acid salt can be formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, L-malate, methanesulfonate, propiolate, 2-butynoate, vinylacetate, L-tartrate, fumarate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, 1, 2-ethyldisulfonate, naphthalenesulfonate, beta-naphthalenesulfonate, oxalate, maleate, tartrate, trifluoroacetate, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1, 4-dioate, hexyne-1, 6-dioate, glycolate, alginate, ascorbate, isoascorbate, aspartate, glutamate, 2-phenoxybenzoate, 2- (4-hydroxybenzoyl) benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, levocamphorsulfonate, methylbenzoate, dinitrobenzoate, sulfamate, lactobionate, galacturonate, cyclopentylpropionate, dodecylsulfate, acrylate, cyclopentanepropionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, pivalate, glucuronate, laurate, phthalate, lauryl sulfate, 2-acetoxybenzoate, isoascorbate, aspartate, glutamate, 2-phenoxybenzoate, and mixtures thereof, Nicotinate, cinnamate, oleate, palmitate, embonate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2-dichloroacetate, aminoacylate, alginate, 4-acetamidobenzenesulfonate, decanoate, cholate, octanoate, nonanoate, cyclamate, phthalate, cysteine hydrochloride, sorbate, pamoate, mucate, glycinate hydrochloride, napadisylate, xylenesulfonate, cystine dihydrochloride, undecanoate, polyvinyl sulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyvinyl sulfate, pentanedionate, heptanedionate, pentanedionate, Naphthalene-1-sulfonate, naphthalene-2-sulfonate, valerate, or any combination thereof.

In the summary of the invention and in a preferred embodiment, the heteroindole derivative of formula (1) may be selected from compounds of formulae (1a) to (1 p).