WO2021013086A1 - Deuterated peptide amide compound, and preparation method therefor and application thereof in medicine - Google Patents

Abstract

A compound as represented by general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, or a co-crystal thereof, a composition thereof, a preparation method therefor, and an application thereof in medicine. The general formula (I) is as shown below, and the definitions of the substituents are the same as those in the description.

Description

Deuterated peptide amide compounds, preparation method thereof and use in medicine Technical field

The present invention relates to a peptide amide compound with analgesic effect, a preparation method and medical use thereof.

Background technique

Opioids have been used in the treatment of pain for thousands of years, and they play a physiological role mainly by binding to the three known classic opioid receptors μ, δ and κ. These three receptors are all members of the G protein-coupled receptor family, mainly distributed in the central nervous system, but also in many peripheral tissues. The most classic drug is morphine, which mainly exerts analgesic effects through the action of mu opioid receptors.

In addition, commonly used clinical analgesics also include other mu opioid receptor drugs, such as traditional opioids represented by dihydromorphone and fentanyl.

However, after long-term use of mu opioid receptor drugs, there will be a variety of side effects, such as tolerance, dependence, respiratory depression, and impact on gastrointestinal motility. This not only increases the cost of treatment, but also affects the patient's recovery cycle. Some non-opioid injections, such as acetaminophen and NSAIDs (non-steroidal anti-inflammatory drugs), have poor analgesic effects, which limit their scope and dosage. In addition, they also have certain side effects, such as increased acetaminophen. Liver toxicity, NSAIDs (non-steroidal anti-inflammatory drugs) cause various gastrointestinal diseases.

With the increasing pressure of life and work in modern society and the advent of the elderly society, and the opioid receptors play a vital role in the treatment of different types of pain, it is important to find new opioids with high analgesic activity and low toxic side effects. Scientific and social significance.

Studies have found that by using κ opioid receptor agonists, κ opioid receptors can be used as targets for intervention to treat pain and prevent a wide variety of diseases and conditions. For example, in 1993, Woold et al. in Anesthesia and Analgesia (1993, 77, 362-379) described the use of kappa opioid receptor agonists for the treatment of pain including hyperalgesia; in 1999, Wu et al. in Circulation Res (1999, 84, 1388- 1395) proposed to use κ opioid receptor agonists as a target for the prevention and treatment of cardiovascular diseases; Kaushik et al. in 2003 described the effects of κ opioid receptor agonists in J. Postgraduate Medicine (2003, 49(1), 90-95) Neuroprotection; In 2004, Potter et al. in Pharmacol. Exp. Ther (2004, 209, 548-553) described the application of κ opioid receptor agonists in ocular disorders and eye pain; in 2005, Wikstrom et al. in J. Am .Soc.Nephrol (2005, 16, 3742-3747) described the application of κ agonists in the treatment of uremia and opioid-induced itching; in 2006 Bileviciute-Ljungar et al. evaluated the effects of κ opioid in Rheumatology (2006, 45, 295-302). The nature of agonists used in osteoarthritis, rheumatoid arthritis and other inflammatory diseases; in 2006, Lembo evaluated the κ opioid receptor agonist gastrointestinal tract in Diges.Dis. (2006, 24, 91-98) Application in disease; in 2006, Jolevalt et al. in Diabetologia (2006, 49(11), 2775-2785) described the role of the kappa opioid receptor agonist Asimadoline in rodent diabetic neuropathy; in 2008, Kara treatment Schteingart, Claudio, D, etc. of Science Co., Ltd. evaluated the effects of κ opioid receptor agonists in visceral pain, pH-sensitive nociceptor activation-related pain, and capsaicin-induced eye pain in WO2008057608A2.

Summary of the invention

The present invention relates to a deuterated peptide amide compound represented by general formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals, and their compositions and preparations Methods and medical applications in kappa opioid receptor-related conditions such as pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma.

The present invention relates to a compound of general formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals, wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , and R ⁵⁵ are each independently selected from H or D, provided that they are not H at the same time.

Some specific embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein

At least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ is D.

In some specific embodiments of the present invention, at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is D.

In some specific embodiments of the present invention, at least one of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is D.

In some specific embodiments of the present invention, at least two of R ⁴ , R ⁵ , R ⁶ , and R ⁷ are D. Some specific embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein

R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each independently selected from D.

In some specific embodiments of the present invention, R ⁴ , R ⁵ , R ⁶ , and R ⁷ are D.

Some specific embodiments of the present invention relate to a compound of general formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from From one of the following structures:

The present invention relates to a compound of general formula (II) and general formula (III) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals, wherein

Some specific embodiments of the present invention relate to a compound of general formula (II) and general formula (III) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co- Crystal, wherein the salt is selected from hydrochloride and the like.

The present invention provides a pharmaceutical composition comprising a compound of general formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals , And one or more pharmaceutically acceptable carriers and/or excipients.

The present invention provides a compound of general formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals or compounds comprising general formula (I) or Stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystal pharmaceutical compositions for the manufacture of drugs for the treatment or prevention of diseases or conditions related to the kappa opioid receptor in mammals application.

In the preferred embodiment of the present invention, the condition related to the κ opioid receptor is selected from the group consisting of pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma.

In a preferred embodiment of the present invention, the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain and skin pain.

In the preferred embodiment of the present invention, the pain is selected from the group consisting of: arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, pain after surgery, and after medical treatment Pain, eye pain, otitis pain, explosive cancer pain, and pain associated with GI disorders.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon and oxygen involved in the groups and compounds of the present invention , Sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, and sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the free base is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refer to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.

"Carrier" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives Agent and disintegrant.

"Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl groups.

"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multiple eutectic formed between a neutral solid and a salt or solvate.

"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.

"Stereoisomers" refer to isomers arising from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Optional" or "optionally" or "selective" or "selectively" means that the event or condition described later can but does not necessarily occur, and the description includes the event or condition in which the event or condition occurs and the What happened. For example, "heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but does not necessarily exist. The description includes the case where the heterocyclic group is substituted by an alkyl group, and the heterocyclic group is not substituted by an alkyl group Happening.

Detailed ways

The following specific examples illustrate the implementation process and beneficial effects of the present invention in detail, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present case.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and the solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) ), the internal standard is tetramethylsilane (TMS).

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC measurement uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm～0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology Waiting for the company.

Example 1

The first step: tert-butyl N-[(1R)-2-[[(1R)-2-[[(1R)-1-[[(1R)-1-(2-acetyl-1,1, 3,3-Tetradeuterium-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-(tert-butoxycarbonyl)pentyl]carbamoyl]-3-methyl-butan Yl]amino]-1-benzyl-2-oxo-ethyl]amino)-1-benzyl-2-oxo-ethyl]carbamic acid tert-butyl ester (1B)

tert-butyl N-[(1R)-2-[[(1R)-2-[[(1R)-1-[[(1R)-1-(2-acetyl-1,1,3,3-tetradeuterio -2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-(tert-butoxycarbonylamino)pentyl]carbamoyl]-3-methyl-butyl]amino]-1-benzyl-2-oxo-ethyl]amino]- 1-benzyl-2-oxo-ethyl]carbamate

Under nitrogen protection, 1-(2,7-diazaspiro[3.5]non-2-yl-1,1,3,3-tetradeuterium)ethanone hydrochloride (purchased from Nanjing Yaoshi Technology Co., Ltd. , 7.0 g, 33.68 mmol) was added to ethyl acetate (200 mL). Cool down to 0℃ in an ice bath, add (2R)-6-(tert-butoxycarbonylamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-( Tert-Butoxycarbonylamino)-3-phenylpropionyl]amino]-3-phenylpropionyl]amino]-4-methylpentanoyl]amino]hexanoic acid (see WO2019015644, 25.4g, 33.68mmol) , Triethylamine (5.2mL, 40.42mol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.91g, 67.36mol), 1-hydroxybenzotriazole (5.46g, 67.36mmol), after the addition, the reaction was stirred at room temperature for 1.5h. Subsequently, 1N aqueous hydrochloric acid (300 mL) was added to the reaction solution, stirred and then separated. A saturated aqueous sodium carbonate solution (300 mL) was added to the organic phase, stirred for 30 minutes, and then separated. The organic phase was washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound N-[(1R)-2-[[(1R)-2-[[(1R )-1-[[(1R)-1-(2-Acetyl-1,1,3,3-tetradeuterium)tert-butyl-2,7-diazaspiro[3.5]nonane-7-carbonyl )-5-(tert-Butoxycarbonyl)pentyl]carbamoyl)-3-methyl-butyl]amino]-1-benzyl-2-oxo-ethyl]amino)-1-benzyl Tert-Butyl-2-oxo-ethyl]carbamate, a white foamy solid (30 g, yield: 99%), used directly in the next reaction.

The second step: (2R)-N-[(1R)-1-(2-acetyl-1,1,3,3-tetradeuterium-2,7-diazaspiro[3.5]nonane-7- Carbonyl)-5-amino-pentyl]-2-[[(2R)-2-[[(2R)-2-amino-3-phenylpropionyl]amino]-3-phenylpropionyl]amino] -4-Methyl-pentanoamide (Compound 1)

(2R)-N-[(1R)-1-(2-acetyl-1,1,3,3-tetradeuterio-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-amino-pentyl]- 2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanamide

N-[(1R)-2-[[(1R)-2-[[(1R)-1-[[(1R)-1-(2-acetyl-1,1,3,3-tetradeuterium )Tert-Butyl-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-(tert-butoxycarbonyl)pentyl]carbamoyl]-3-methyl-butyl]amino ]-1-Benzyl-2-oxo-ethyl]amino]-1-benzyl-2-oxo-ethyl]carbamic acid tert-butyl ester (30g, 0.033mol) was dissolved in dichloromethane (150mL ), the temperature was lowered to 0°C, and trifluoroacetic acid (75mL) was added dropwise. After the addition, the temperature was naturally raised to room temperature for reaction. After the completion of the reaction monitored by LC-MS, the reaction solution was concentrated under reduced pressure at no higher than 30°C. The residue was separated and purified by preparative liquid phase (preparation conditions: instrument: Gilson GX-281; column: Xbridge C18, 150×30mm ID, 5μm.; mobile phase: A for ACN and B for H ₂ O; isocratic: A 65%; Flow rate: 30mL/min; Back pressure: 1000PSI; Column temperature: 30°C; Wavelength: 210nm; Period: 18min; Sample preparation: The compound was dissolved in 12mL methanol; Injection: 0.9mL/needle), freeze-dried, The lyophilized product is passed through an ion exchange resin (water ~ 3.3% ammonia water elution), the received elution solution is concentrated under reduced pressure (the water temperature is 60°C under reduced pressure to 300 mL), and further lyophilized to obtain (2R)-N-[ (1R)-1-(2-Acetyl-1,1,3,3-tetradeuterium-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-amino-pentyl)- 2-[[(2R)-2-[[(2R)-2-amino-3-phenylpropionyl]amino]-3-phenylpropionyl]amino]-4-methyl-pentanamide (6.5g , The yield is 27.9%).

LCMS m/z=354.9 [M+2H] ⁺ /2.

¹ H NMR(400MHz, D ₂ O) δ7.45--7.16(m,10H), 4.85-4.75(m,1H), 4.64(t,1H), 4.35(t,1H), 3.74-3.63(m, 3H), 3.62--3.50 (m, 1H), 3.50 - 3.39 (m, 1H), 3.17 - 2.65 (m, 6H), 2.01 - 1.66 (m, 9H), 1.65 - 1.30 (m, 7H), 0.96 ( dd,6H).

Test 1: Mouse writhing test

After intraperitoneal injection of acetic acid in mice, it can cause writhing behavior in mice. Writhing response refers to the characteristic behavioral response of the mice showing typical abdominal muscle contraction or extension. The analgesic activity of the compound can be reflected by detecting the inhibitory effect of the compound on the writhing behavior of mice caused by acetic acid. The specific method is as follows:

ICR mice aged 6-8 weeks (purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number: SCXK (京)-2016-0006). Randomly group, 10 animals in each group, half male and half female. On the day of the experiment, different doses of test compound were given intravenously, and the control group was given blank reagent. 15min or 24h after administration, 0.6% (v/v) acetic acid solution was injected intraperitoneally at a dose of 0.4 mL/head. Record the number of writhing times of mice within 15 minutes after the injection of acetic acid, and calculate the percentage of inhibition of the writhing behavior of the mice caused by acetic acid by the test compound ((number of writhing times of blank reagent-number of writhing times of the administration group) / writhing of the blank reagent group Times*100), and use Origin9.5 software to fit the ED50 value of the test compound with the DoseResp function. The analysis results are shown in Table 1.

Table 1 Pharmacodynamic ED50 value of test compound

Compound number	15min ED50 (mg/kg)	24h ED50 (mg/kg)
Compound 1	0.14	0.74
WO2019015644 Compound 8-1	N/A	1.48
CR845	N/A	24.62

CR845 structure is

HPLC purity: 98.6%.

Conclusion: The compound of the present invention has obvious analgesic effect and has the advantage of long-term effect.

Claims (13)

1. A compound of general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal, wherein

   

   R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R1 ² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , and R ⁵⁵ are each independently selected from H or D, provided that they are not H at the same time.
2. The compound or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals thereof according to claim 1, wherein

   At least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ is D.
3. The compound according to claim 2 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein

   R ⁴ , R ⁵ , R6 and R7 are each independently selected from D.
4. The compound of claim 1 or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals thereof, wherein the compound is selected from one of the following structures:

   

   

   

   

   

   

   

   

   

   

   
5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals thereof , And one or more pharmaceutically acceptable carriers and/or excipients.
6. The compound of any one of claims 1 to 4 or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals, or the pharmaceutical composition of claim 5 for use Use of drugs for the treatment or prevention of diseases or conditions related to the kappa opioid receptor in mammals.
7. The use according to claim 6, wherein the condition related to the kappa opioid receptor is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction , Cough and glaucoma.
8. The use according to claim 7, wherein the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain and skin pain.
9. The application according to claim 7, wherein the pain is selected from the group consisting of: arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, pain after surgery, Pain after medical treatment, eye pain, otitis pain, explosive cancer pain, and pain related to GI disorders.
10. A method for treating or preventing diseases or conditions associated with κ opioid receptors in mammals, said method comprising administering the compound of any one of claims 1 to 4 or its stereoisomers, hydrates, Metabolites, solvates, pharmaceutically acceptable salts or co-crystals, or the pharmaceutical composition of claim 5.
11. The method of claim 10, wherein the condition related to the kappa opioid receptor is selected from the group consisting of pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, Cough and glaucoma.
12. The method according to claim 11, wherein the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain and skin pain.
13. The method according to claim 12, wherein the pain is selected from the group consisting of: arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, pain after surgery, medical treatment Pain after treatment, eye pain, otitis pain, explosive cancer pain, and pain related to GI disorders.