TWI769493B - Deuterated peptidamide compound and its preparation method and use in medicine - Google Patents

Abstract

The present invention relates to a compound represented by the general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal and its composition, preparation method and medicinal use thereof. For use, the general formula (I) is shown below, and the definitions of the respective substituents are the same as those in the specification.

Description

Deuterated peptidamide compound and its preparation method and use in medicine

The present invention relates to a peptidamide compound with analgesic effect, its preparation method and its use in medicine.

Opioids have been used for the treatment of pain for thousands of years, and they exert their physiological effects mainly by interacting with the three known classical opioid receptors μ, δ and κ. All three receptors are members of the G protein-coupled receptor family, mainly distributed in the central nervous system, but also in many peripheral tissues. One of the most classic drugs is morphine, which mainly exerts analgesic effect through the action of mu opioid receptors.

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

However, after long-term use of μ-opioid receptor drugs, there will be a variety of side effects, such as tolerance, dependence and respiratory depression, as well as the impact on gastrointestinal motility, which not only increases the cost of treatment, but also affects the recovery period of patients. Some non-opioid injections, such as acetaminophen and NSAIDs (non-steroidal anti-inflammatory drugs), limit their scope of use and dosage due to their poor analgesic effect; in addition, they also have certain side effects, such as acetamide. Base phenols increase liver toxicity, and NSAIDs (non-steroidal anti-inflammatory drugs) cause various gastrointestinal disorders.

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

Studies have found that through the use of kappa opioid receptor agonists, kappa opioid receptors can be targeted for intervention to treat pain and prevent a wide variety of diseases and conditions. For example, Woold et al. in Anesthesia and Analgesia ( 1993, 77, 362-379) in 1993 described the use of kappa opioid receptor agonists for the treatment of pain including hyperalgesia; Wu et al. in Circulation Res ( 1999, 84, 1388-1999) 1395) proposed κ opioid receptor agonists as targets for the prevention and treatment of cardiovascular diseases; in 2003, Kaushik et al in J.Postgraduate Medicine (2003, 49(1), 90-95) described the effect of κ opioid receptor agonists. Neuroprotection; 2004 Potter et al in. Pharmacol . Exp. Ther (2004, 209, 548-553 ) describe the use of kappa opioid agonists in ocular disorders and ocular pain; 2005 Wikstrom et al in J.Am .Soc.Nephrol (2005, 16, 3742-3747) described the use of kappa agonists in the treatment of uremia and opiate-induced pruritus; Bileviciute-Ljungar et al. in Rheumatology ( 2006, 45, 295-302) assessed the effect of kappa opium Properties of agonists for inflammatory diseases such as osteoarthritis, rheumatoid arthritis; 2006 Lembo in Diges. Dis. (2006, 24, 91-98) evaluated kappa opioid agonists for gastrointestinal diseases 2006 Jolivalt et al. in Diabetologia (2006, 49(11), 2775-2785) described the effect of the kappa opioid agonist asimadoline in rodent diabetic neuropathy; 2008 Cara Therapeutics In WO2008057608A2 , Schteingart, Claudio, D et al., Inc. evaluated the role of kappa opioid agonists in visceral pain, pain associated with pH-sensitive nociceptor activation, and capsaicin-induced ocular pain.

The present invention relates to a deuterated peptidamide compound represented by the general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal and its composition, preparation Methods and medicinal uses in kappa opioid receptor related conditions such as pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma.

The present invention relates to a compound of general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, 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 R ¹ , R At least one of 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 a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from One of the following structures:

The present invention relates to a compound of general formula (II), general formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein

Some specific embodiments of the present invention relate to a compound of general formula (II), general formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof , wherein the salt is selected from hydrochloride and the like.

The present invention provides a pharmaceutical composition comprising the compound of general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal, and one or more of the above pharmaceutically acceptable carriers and/or excipients.

The present invention provides compounds of general formula (I) or stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals thereof or compounds comprising general formula (I) or Pharmaceutical compositions of stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals for the manufacture of a medicament for the treatment or prevention of a kappa opioid receptor-related disease or condition in a mammal application.

A preferred embodiment of the present invention, wherein the kappa opioid receptor-related condition is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough cough and glaucoma.

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

A preferred version of the present invention, 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 Post pain, ocular pain, otitis pain, cancer flare-up pain and pain associated with GI disorders.

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

Carbon, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention all include their isotopic conditions, as well as carbon, oxygen, and carbon involved in the groups and compounds of the present invention. , sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon ^include12C , ^{13C and14C} , isotopes of oxygen ^include16O , ^{17O and18O} , and isotopes of sulfur 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 salts" or "pharmaceutically acceptable salts thereof" means that the compounds of the present invention retain the biological effectiveness and properties of free acids or free bases that are treated with nontoxic inorganic bases or organic Base, said free base salt obtained by reaction with non-toxic inorganic or organic acid.

"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" means pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.

"Carrier" refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.

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

A "prodrug" refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amine groups in the compounds of the present invention, which can be removed by conventional manipulations or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amine or carboxyl groups.

"Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature is a solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.

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

"Optional" or "optionally" or "selective" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Happening.

The implementation process and beneficial effects of the present invention are described in detail below through specific examples, 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 structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were 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)).

For the HPLC measurement, an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm) was used.

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 for thin layer chromatography (TLC) is 0.15mm~0.20mm, and the specification used for TLC 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 using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.

Example 1

The first step: tertiary butyl N-[(1R)-2-[[(1R)-2-[[(1R)-1-[[(1R)-1-(2-acetyl-1, 1,3,3-Tetradeutero-2,7-diazaspiro[3.5]nonane-7-carbonyl)--5-(tert-butoxycarbonylamino)pentyl]aminocarboxyl] -3-Methyl-butyl]amino]-1-benzyl-2-oxy-ethyl]amino]-1-benzyl-2-oxy-ethyl]carbamic acid 3rd 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). Cooled in an ice bath to 0°C, added (2R)-6-(3-butoxycarbonylamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2 -(Third-butoxycarbonylamino)-3-phenylpropionyl]amino]-3-phenylpropionyl]amino]-4-methylpentanoyl]amino]hexanoic acid (synthesized For the method, see WO2019015644, 25.4 g, 33.68 mmol), triethylamine (5.2 mL, 40.42 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.91 g, 67.36 mol), 1-hydroxybenzotriazole (5.46 g, 67.36 mmol), after the addition, the reaction was stirred at room temperature for 1.5 h. Subsequently, 1N aqueous hydrochloric acid (300 mL) was added to the reaction solution, and the mixture was stirred and separated. Saturated aqueous sodium carbonate solution (300 mL) was added to the organic phase, and the mixture was 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]aminocarboxy]-3-methyl-butyl]amino]-1-benzyl-2-pendoxyl-ethyl]amine 3-butyl]-1-benzyl-2-oxy-ethyl]carbamate, white foamy solid (30 g, yield: 99%), which was directly used 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-phenyl Propionyl]amino]-4-methyl-pentamylamine (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

Convert N-[(1R)-2-[[(1R)-2-[[(1R)-1-[[(1R)-1-(2-acetyl-1,1,3,3-tetra Deuterium) tert-butyl-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-(tert-butoxycarbonyl)pentyl]aminocarbamoyl]-3-methyl -butyl]amino]-1-benzyl-2-oxy-ethyl]amino]-1-benzyl-2-oxy-ethyl]carbamic acid tert-butyl ester (30 g, 0.033mol) was dissolved in dichloromethane (150mL), cooled to 0°C, added dropwise trifluoroacetic acid (75mL), and the reaction was naturally heated to room temperature after the addition. After the reaction was monitored by LC-MS, the temperature was not higher than 30°C The reaction solution was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (preparation conditions: instrument: Gilson GX-281; column: Xbridge C18, 150×30 mm ID, 5 μm.; mobile phase: A for ACN and B for H ₂ O; isocratic: A 65%; flow rate: 30mL/min; back pressure: 1000 PSI; column temperature: 30°C; wavelength: 210nm; cycle: 18min; sample preparation: compound dissolved in 12mL methanol; injection: 0.9mL/needle), lyophilized, The lyophilized product was passed through ion-exchange resin (water ~ 3.3% ammonia water elution), the received elution solution was concentrated under reduced pressure (at a water temperature of 60 ° C, the elution solution was concentrated to 300 mL under reduced pressure), and further lyophilized to obtain (2R)-N -[(1R)-1-(2-Acetyl-1,1,3,3-tetradeutero-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-amino- Amyl]-2-[[(2R)-2-[[(2R)-2-amino-3-phenylpropionyl]amino]-3-phenylpropionyl]amino]-4 - Methyl-pentamamide (6.5 g, 27.9% yield).

LCMS m/z=354.9[M+2H] ⁺ /2.

¹ H NMR (400MHz, D ₂ O) δ 7.45-7.16 (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 experiment

Intraperitoneal injection of acetic acid in mice can induce writhing behavior in mice. The writhing response refers to the characteristic behavioral response of 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 induced by acetic acid. The specific method is as follows: 6-8 week old ICR mice (purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number: SCXK (Jing)-2016-0006). Random grouping, 10 animals in each group, half male and half female. On the day of the experiment, different doses of the test compounds were administered intravenously, and the control group was given a blank reagent. 15min or 24h after administration, 0.6% (v/v) acetic acid solution was injected intraperitoneally at a dose of 0.4mL/mouse. The number of writhing in mice within 15 minutes after the injection of acetic acid was recorded, and the percentage of inhibition of the writhing behavior of mice induced by acetic acid by the test compound was calculated ((the number of writhing in the blank reagent-the number of writhing in the administration group)/the writhing in the blank reagent group times * 100), and use Origin9.5 software to fit the pharmacodynamic ED50 value of the test compound with the DoseResp function. The analysis results are shown in Table 1.

，HPLC純度：98.6%。 The structure of CR845 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 (8)

A compound of general formula (I) or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof, wherein

R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^{1 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 , R ⁵⁵ is each independently selected from H or D, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are D. The compound according to claim 1 or a stereoisomer, hydrate, or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ At least one of , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ is D. The compound according to claim 1 or a stereoisomer, hydrate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

A pharmaceutical composition, the pharmaceutical composition comprising the compound described in any one of claims 1 to 3 or a stereoisomer thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carrier and/or excipient. A compound as described in any one of claims 1 to 3 or a stereoisomer, hydrate, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 4 for the manufacture of treatment or prevention of breastfeeding Use of a medicament for a kappa opioid receptor-related disease or condition in an animal. Use according to claim 5, wherein the kappa opioid receptor-related condition is selected from the group consisting of pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction , cough and glaucoma. The use according to claim 6, wherein the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain and skin pain. Use according to claim 6, wherein the pain is selected from the group consisting of arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, Post-medical treatment pain, eye pain, otitis pain, cancer flare-up pain, and pain associated with GI disorders.