CN114127085A - Peptide amide salt, preparation method and medical application thereof - Google Patents
Peptide amide salt, preparation method and medical application thereof Download PDFInfo
- Publication number
- CN114127085A CN114127085A CN202080030211.3A CN202080030211A CN114127085A CN 114127085 A CN114127085 A CN 114127085A CN 202080030211 A CN202080030211 A CN 202080030211A CN 114127085 A CN114127085 A CN 114127085A
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- Prior art keywords
- acid
- pain
- amino
- compound
- phenyl
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- -1 amide salt Chemical class 0.000 title description 81
- 108090000765 processed proteins & peptides Proteins 0.000 title description 4
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- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
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- 238000003756 stirring Methods 0.000 claims description 32
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- 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
Abstract
The invention relates to a compound shown in a general formula (I) or a stereoisomer thereof, a preparation method and application thereof in medicine, wherein the general formula (I) is shown as follows, and the definition of each substituent is consistent with that in the specification.
Description
The invention relates to a peptide amide salt with analgesic effect, a preparation method and medical application thereof.
Opioids have been used for thousands of years in the treatment of pain, which exerts physiological effects primarily through binding to the three known classical opioid receptors, μ, δ and κ. These three receptors are members of the G protein-coupled receptor family, are distributed primarily in the central nervous system, and are also present in many peripheral tissues. The most classical of these drugs is morphine, which exerts its analgesic effect primarily through the action of the mu opioid receptor.
In addition, the commonly used clinical analgesic drugs also comprise other mu opioid receptor drugs, such as traditional opioid drugs represented by hydromorphone and fentanyl.
However, mu opioid receptor drugs can cause a variety of side effects after long-term use, such as tolerance, dependence, and respiratory depression, as well as gastrointestinal motility, which 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 limited application range and dosage due to their poor analgesic effect; in addition, there are certain side effects, such as acetaminophen increases liver toxicity, and NSAIDs (non-steroidal anti-inflammatory drugs) cause various gastrointestinal diseases.
With the continuous increase of the working pressure of modern society and the arrival of the elderly society and the vital function of opioid receptors on treating different types of pain, the search for novel opioid drugs with high analgesic activity and low toxic and side effects has important scientific and social significance.
Studies have found that by using kappa opioid receptor agonists, kappa opioid receptors can be targeted for intervention to treat pain and prevent a wide variety of diseases and conditions. The use of kappa opioid receptor agonists for the treatment of pain, including hyperalgesia, was described by Woold et al, Anesthesia and Analgesia (1993, 77, 362-379); wu et al 1999 Circulation Res (1999,84,1388-1395) proposed kappa opioid agonists as targets for the prevention and treatment of cardiovascular disease; the neuroprotective effects of kappa opioid receptor agonists were described by Kaushik et al in j.postgradate Medicine (2003,49(1),90-95) in 2003; potter et al, Pharmacol. exp. Ther (2004, 209,548-553) described the use of kappa opioid agonists in ocular disorders and pain; in 2005 Wikstrom et al, j.am.soc.nephrol (2005,16, 3742-; Bileviciute-Ljungar et al in 2006 assessed the properties of kappa opioid receptor agonists for inflammatory diseases such as osteoarthritis, rheumatoid arthritis, etc., in Rheumatology (2006,45, 295-; lembo evaluated the use of kappa opioid receptor agonists in gastrointestinal tract disease in diges.dis. (2006,24,91-98) in 2006; in 2006 Jolivalt et al in Diabetologia (2006,49(11), 2775-; schteingart, Claudio, D et al, 2008 Calla therapeutics, Inc. in WO2008057608A2 evaluated the effects of kappa opioid agonists on visceral pain, pain associated with activation of pH sensitive nociceptors, and capsaicin-induced ocular pain.
WO2019015644 discloses a kappa opioid receptor agonist having a novel structure, good biological activity and good analgesic effect, represented by formula (I), which is represented by the following structure:
disclosure of Invention
The invention relates to a peptide amide salt shown in a general formula (I) or a stereoisomer thereof, a composition thereof, a preparation method and medical application in kappa opioid receptor-related conditions such as pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough, glaucoma and the like.
The invention relates to a compound of general formula (I) or a stereoisomer thereof, wherein
A is selected from propionic acid, methanesulfonic acid, acetic acid, citric acid, D-tartaric acid, benzenesulfonic acid, phosphoric acid, aspartic acid, L-tartaric acid, maleic acid, fumaric acid, benzoic acid, lactic acid, hydrochloric acid, formic acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, succinic acid, mandelic acid, malonic acid, malic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, salicylic acid, citric acid, glutamic acid, cinnamic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid; n is selected from 0.20-2.00.
Some embodiments of the invention relate to a compound of formula (I) wherein a is selected from propionic acid, methanesulfonic acid, acetic acid, citric acid, D-tartaric acid, benzenesulfonic acid, phosphoric acid, aspartic acid, L-tartaric acid, maleic acid, fumaric acid, benzoic acid, lactic acid, or hydrochloric acid; dipropionic acid, propionic acid, diacetic acid, acetic acid, D-tartaric acid, phosphoric acid, aspartic acid, L-tartaric acid, benzoic acid and lactic acid are preferred.
It is understood that the specific implementation of dipropionic acid and diacetic acid means that a is propionic acid and n is 2, and a is acetic acid and n is 2, respectively.
Some embodiments of the invention relate to a compound of formula (I), wherein
n is selected from 0.50, 0.73, 0.67, 1.0, 1.5 or 2.0.
Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer thereof, wherein the compound is selected from one of the following structures
The invention relates to a method for producing compounds of general formula (I) or stereoisomers thereof, wherein
Dissolving a compound shown as a formula (II) in a first solvent at room temperature, adding a second solvent dissolved with A, stirring, precipitating a solid, and collecting the solid to obtain a compound shown as a formula (I);
or at room temperature, dissolving the compound shown in the formula (II) in a first solvent, adding A, stirring, and freeze-drying to obtain a solid to obtain the compound shown in the formula (I);
or dissolving the compound shown in the formula (I) in a first solvent at room temperature, adding a second solvent, stirring, precipitating a solid, and collecting the solid to obtain the compound shown in the formula (I);
the definition of A is identical to that described for formula (I).
Some embodiments of the present invention relate to a process for the preparation of a compound of formula (I) or a stereoisomer thereof, wherein
The first solvent is selected from one or more of water, methanol, ethanol, acetonitrile and tetrahydrofuran;
the second solvent is one or more selected from methyl tert-butyl ether, acetonitrile, tetrahydrofuran and methanol.
The invention provides a pharmaceutical composition, which comprises a compound shown in a general formula (I) or a stereoisomer thereof, and one or more than one pharmaceutically acceptable carriers and/or excipients.
Use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof of the invention for the manufacture of a medicament for the treatment or prevention of a kappa opioid receptor associated disease or condition in a mammal.
A preferred embodiment of the invention, wherein said kappa opioid receptor associated condition is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma.
A preferred embodiment of the present invention, wherein said pain is selected from the group consisting of: neuropathic pain, somatic pain, visceral pain, and skin pain.
A preferred embodiment of the present invention, wherein said pain is selected from the group consisting of: arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, post-medical treatment pain, ocular pain, otitis pain, breakthrough 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.
Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include12C、 13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、 17O and18isotopes of O, sulfur including32S、 33S、 34S and36isotopes of S, NIncluded14N and15isotopes of N, F include17F and19isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
by "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to an organism and 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.
By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" or "selective" or "selectively" 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 where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
Example 1: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide dipropionate (Compound 1)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；di-propionic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.281g, 0.4mmol) and distilled water (30mL) were added to a reaction flask and stirred at room temperature to a clear solution; propionic acid (0.089g, 1.2mmol) was added dropwise to give a clear solution; stirring for 2 hours at room temperature; the reaction was lyophilized overnight (lyophilizer cavity temperature-70 ℃, sample was left hanging) to give (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide dipropionate (compound 1) as a white solid in 0.315g, yield: 92 percent.
1H NMR(400MHz,D 2O)δ7.45–7.29(m,6H),7.24(d,4H),5.00-4.76(m,1H),4.66(t,1H),4.26(dt,2H),4.02(d,2H),3.78(d,2H),3.72–3.59(m,2H),3.55-3.42(m,1H),3.42–3.29(m,1H),3.18(d,2H),3.12-2.94(m,4H),2.22(q,4H),1.95–1.63(m,11H),1.61-1.48(m,3H),1.48–1.31(m,2H),1.06(t,6H),0.96(d,3H),0.90(d,3H)。
Example 2: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide propionate (Compound 2)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；propionic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide dipropionate (Compound 1) (0.261g, 0.31mmol) was dissolved in ethanol (4mL), methyl tert-butyl ether (50mL) was added dropwise slowly with stirring at room temperature, gradually precipitating a large amount of white solid, and stirring was continued for 1 h; subsequently, filtration was carried out under reduced pressure, and the cake was dried under reduced pressure at 40 ℃ for 30min to give (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide propionate (Compound 2) as a white solid in an amount of 0.19g, yield: 81.5 percent.
1H NMR(400MHz,D 2O)δ7.39–7.26(m,6H),7.19(dd,4H),4.80-4.75(m，1H),4.60(t,1H),4.29(t,1H),4.02(d,2H),3.78(d,2H),3.72-3.60(m,3H),3.53-3.44(m,1H),3.42–3.32(m,1H),3.06(dd,1H),3.02–2.90(m,3H),2.87(d,2H),2.18(q,2H),1.90(d,3H),1.88–1.78(m,3H),1.77-1.64(m,5H),1.5 8-1.49(m,3H),1.48–1.30(m,2H),1.06(t,3H),0.94(d,3H),0.89(d,3H)。
Example 3: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide disulfonate (Compound 3)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；methanesulfonic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.24g, 0.34mmol) and acetonitrile (4mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping solution of methanesulfonic acid (0.066g, 0.68mmol) in acetonitrile (2mL), gradually precipitating a large amount of white solid at room temperature under stirring, and crystallizing at room temperature for 0.5h under stirring; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide disulfonate (compound 3) as a white solid in an amount of 0.126g, yield: 41 percent.
1H NMR(400MHz,D 2O)δ7.46–7.20(m,10H),4.79-4.76(m,1H),4.66(t,1H),4.32-4.21(m,2H),4.02(d,2H),3.77(d,2H),3.72–3.58(m,2H),3.54-3.42(m,1H),3.42–3.30(m,1H),3.18(d,2H),3.10-2.93(m,4H),2.81(s,6H),1.90(d,3H),1.88–1.77(m,3H),1.77-1.63(m,5H),1.60–1.49(m,3H),1.49–1.30(m,2H),0.95(d,3H),0.90(d,3H)。
Example 4: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -3-phenylpropionyl ] amino ] -4-methyl-pentanamide diacetate (Compound 4)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；di-acetic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (2.0g, 2.84mmol) was dissolved in water (30mL), acetic acid (0.49mL, 8.53mmol) was added with stirring at room temperature, stirring was continued for 1h and then lyophilized to give (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ ("2 (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -3-phenylpropionyl ] amino ] -4-methyl-pentanamide diacetate (compound 4) as a white solid in 2.3g, yield: 98 percent.
1H NMR(400MHz,D 2O)δ7.55–7.16(m,10H),4.80-4.74(m,1H),4.66(t,1H),4.30(t,1H),4.20(t,1H),4.02(d,2H),3.78(d,2H),3.72-3.60(m,2H),3.55–3.43(m,1H),3.43–3.31(m,1H),3.16(d,2H),3.09-2.95(m,4H),1.93(s,6H),1.91–1.64(m,11H),1.60–1.27(m,5H),0.96(d,3H),0.90(d,3H).
Example 5: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide acetate (Compound 5)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；acetic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide diacetate (Compound 4) (0.315g, 0.38mmol) was dissolved in ethanol (5mL), methyl tert-butyl ether (50mL) was added dropwise slowly with stirring at room temperature, gradually precipitating a large amount of white solid, and stirring was continued for 1 h; subsequently, filtration was carried out under reduced pressure, and the cake was dried under reduced pressure at 40 ℃ for 30min to give (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide acetate (Compound 5) as a white solid in an amount of 0.26g, yield: 85 percent.
1H NMR(400MHz,D 2O)δ7.48–7.27(m,6H),7.5-7.14(m,4H),4.89-4.78(m,1H),4.60(t,1H),4.29(t,1H),4.02(d,2H),3.78(d,2H),3.73-3.60(m,3H),3.55–3.43(m,1H),3.43–3.30(m,1H),3.15–2.83(m,6H),1.97–1.88(m,6H),1.88–1.78(m,3H),1.78–1.62(m,5H),1.60–1.49(m,3H),1.48–1.30(m,2H),1.00–0.84(m,6H)。
Example 6: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide citrate (Compound 6)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；2-hydroxypropane-1,2,3-tricarboxylic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.281g, 0.4mmol) and tetrahydrofuran (5mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping citric acid (0.051g, 0.27mmol) tetrahydrofuran (1.2mL) solution, gradually precipitating a large amount of white solid under stirring at room temperature, and stirring at room temperature for crystallization for 0.5 h; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide citrate (compound 6) as a white solid in 0.234g, yield: 54 percent.
1H NMR(400MHz,D 2O)δ7.45–7.14(m,10H),4.85-4.76(m,1H),4.65(t,1H),4.29(t,1H),4.19(t,1H),4.02(d,2H),3.78(d,2H),3.72-3.59(m,2H),3.56-3.42(m,1H),3.42–3.31(m,1H),3.15(d,2H),3.10-2.93(m,4H),2.65(dd,3H),1.90(d,3H),1.88-1.62(m,8H),1.61-1.49(m,3H),1.48-1.34(m,2H),0.96(d,3H),0.90(d,3H)。
Example 7: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide D-tartrate (Compound 7)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；D-tartaric acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.281g, 0.4mmol) and tetrahydrofuran (5mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping D-tartaric acid (0.060g, 0.4mmol) solution in tetrahydrofuran (1.2mL), gradually precipitating a large amount of white solid at room temperature under stirring, and crystallizing at room temperature for 0.5h under stirring; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide D-tartrate (compound 7) as a white solid in 0.243g, yield: 71 percent.
1H NMR(400MHz,D 2O)δ7.48–7.16(m,10H),4.82-4.77(m,1H),4.66(t,1H),4.36– 4.20(m,4H),4.02(d,2H),3.78(d,2H),3.71-3.61(m,2H),3.54–3.42(m,1H),3.42–3.28(m,1H),3.18(d,2H),3.12-2.92(m,4H),1.90(d,3H),1.88–1.62(m,8H),1.61–1.48(m,3H),1.48–1.31(m,2H),0.96(d,3H),0.90(d,3H)。
Example 8: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide benzenesulfonate (Compound 8)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；benzenesulfonic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.211g, 0.3mmol) and tetrahydrofuran (5mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping solution of benzenesulfonic acid monohydrate (0.112g, 0.606mmol) in tetrahydrofuran (1.5mL), gradually precipitating a large amount of white solid at room temperature under stirring, and crystallizing at room temperature for 0.5h under stirring; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide benzenesulfonate (compound 8) as a white solid in an amount of 0.292g, yield: 95 percent.
1H NMR(400MHz,D 2O)δ7.81(d,4H),7.63-7.50(m,6H),7.44–7.28(m,6H),7.23(d,4H),4.66(t,1H),4.32-4.20(m,2H),3.99(d,2H),3.80-3.71(m,3H),3.69-3.58(m,2H),3.54-3.42(m,1H),3.40–3.28(m,1H),3.17(d,2H),3.11-2.93(m,4H),1.92-1.48(m,14H),1.47–1.31(m,2H),0.95(d,3H),0.89(d,3H)。
Example 9: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide phosphate (Compound 9)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；phosphoric acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.211g, 0.3mmol) and tetrahydrofuran (3mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping solution of phosphoric acid (0.0594g, 0.606mmol) in tetrahydrofuran (1.5mL), gradually precipitating a large amount of white solid at room temperature under stirring, and crystallizing for 2h at room temperature under stirring; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide phosphate (compound 9) as a white solid in 0.24g, yield: 90 percent.
1H NMR(400MHz,D 2O)δ7.49–7.20(m,10H),4.70(t,1H),4.35(t,1H),4.21(t,1H),4.07(d,2H),3.88-3.78(m,3H),3.77-3.64(m,2H),3.60-3.49(m,1H),3.48–3.34(m,1H),3.19(d,2H),3.16–2.99(m,4H),2.03–1.68(m,11H),1.66-1.54(m,3H),1.53-1.37(m,2H),1.01(d,3H),0.95(d,3H)。
Example 10: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide aspartate (Compound 10)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；L-aspartic acid
To a 50mL reaction flask were added (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.211g, 0.3mmol), distilled water (15mL) and acetonitrile (5mL), and stirred at room temperature to a clear solution; adding aspartic acid particles (0.08g, 0.6mmol) to obtain a suspension; stirring for 3h at room temperature to obtain a clear solution; the reaction solution was filtered through a 0.2 μ M pore size filter, and the filtrate was lyophilized overnight to give (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide aspartate (compound 10) as a white solid in 0.233g, yield: 80 percent.
1H NMR(400MHz,D 2O)δ7.45-7.15(m,10H),4.85-4.80(m,1H),4.66(t,1H),4.30(t,1H),4.19(t,1H),4.02(d,2H),3.90(dd,2H),3.78(d,2H),3.72–3.59(m,2H),3.54–3.43(m,1H),3.43–3.30(m,1H),3.16(d,2H),3.11–2.93(m,4H),2.82(dd,2H),2.67(dd,2H),1.94–1.62(m,11H),1.60–1.30(m,5H),0.96(d,3H),0.91(d,3H)。
Example 11: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide L-tartrate (Compound 11)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；L-tartaric acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (5.0g, 7.1mmol) and tetrahydrofuran (150mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping L-tartaric acid (1.07g, 7.1mmol) solution in tetrahydrofuran (25mL), gradually precipitating a large amount of white solid at room temperature under stirring, and crystallizing at room temperature for 0.5h under stirring; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide L-tartrate (compound 11) as a white solid in 5.27g, yield: 87 percent.
1H NMR(400MHz,D 2O)δ7.57–7.21(m,10H),4.82-4.77(m,1H),4.72(t,1H),4.42(s,2H),4.38-4.26(m,2H),4.07(d,2H),3.82(d,2H),3.76-3.66(m,2H),3.60–3.48(m,1H),3.46–3.33(m,1H),3.24(d,2H),3.19-2.95(m,4H),1.99–1.68(m,11H),1.66–1.36(m,5H),1.01(d,3H),0.96(d,3H)。
Example 12: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide maleate (Compound 12)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；maleic acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.211g, 0.3mmol) and tetrahydrofuran (5mL) were added to a reaction flask and stirred at room temperature to a clear solution; dripping solution of maleic acid (34.8mg, 0.3mmol) in tetrahydrofuran (1.2mL), gradually precipitating a large amount of white solid at room temperature under stirring, and crystallizing at room temperature for 0.5h under stirring; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide maleate (Compound 12) as a white solid in 198mg yield: 80.5 percent.
1H NMR(400MHz,D 2O)δ7.39–7.13(m,10H),6.08(s,2H),4.70-4.66(m,1H),4.61(t, 1H),4.25(t,1H),4.12(t,1H),3.98(d,2H),3.72(d,2H),3.67-3.56(m,2H),3.50-3.40(m,1H),3.37–3.27(m,1H),3.10(d,2H),3.05–2.90(m,4H),1.88–1.58(m,11H),1.56–1.45(m,3H),1.43–1.27(m,2H),0.91(d,3H),0.86(d,3H)。
Example 13: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide fumarate (Compound 13)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；fumaric acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.211g, 0.3mmol) and tetrahydrofuran (5mL) were added to a reaction flask and stirred at room temperature to a clear solution; dropwise adding a methanol (1.5mL) solution of fumaric acid (34.8mg, 0.3mmol), stirring at room temperature to precipitate no white solid, slowly adding tetrahydrofuran (30mL) into the reaction solution to gradually precipitate a large amount of white solid, and stirring at room temperature to crystallize for 0.5 h; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide fumarate (Compound 13) as a white solid in 157mg, yield: and (3.8).
1H NMR(400MHz,D 2O)δ7.52–7.25(m,10H),6.58(s,2H),4.89-4.83(m,1H),4.71(t,1H),4.38-4.26(m,2H),4.08(d,2H),3.83(d,2H),3.77-3.65(m,2H),3.60-3.50(m,1H),3.46-3.36(m,1H),3.24(d,2H),3.16-3.00(m,4H),1.98-1.70(m,11H),1.67-1.36(m,5H),1.01(d,3H),0.96(d,3H)。
Example 14: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide benzoate (Compound 14)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；benzoic acid
To a 50mL reaction flask was added (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.28g, 0.4mmol), acetonitrile (3mL) and stirred at room temperature to a clear solution; dropwise adding a solution of benzoic acid (0.098g, 0.8mmol) in acetonitrile (2ml), gradually precipitating a solid, stirring for crystallization for 2h, filtering under reduced pressure, and drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide benzoate (compound 14) as a white solid in 0.29g, yield: 76.8 percent.
1H NMR(400MHz,D 2O)δ7.99–7.76(m,4H),7.59–7.52(m,2H),7.51–7.44(m,4H),7.41–7.31(m,6H),7.27–7.20(m,4H),4.72-4.69(m,1H),4.65(t,1H),4.30(t,,1H),4.19(t,,1H),4.00(d,2H),3.76(d,2H),3.69–3.58(m,2H),3.52–3.41(m,1H),3.41–3.29(m,1H),3.19–3.12(m,2H),3.09–2.93(m,4H),1.92–1.30(m,16H),0.98–0.87(m,6H)。
Example 15: (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide lactate (Compound 15)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；lactic acid
To a 50mL reaction flask was added (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.28g, 0.4mmol), acetonitrile (3mL) and stirred at room temperature to a clear solution; dropwise adding a solution of lactic acid (0.072g, 0.8mmol) in acetonitrile (2ml), gradually precipitating a solid, stirring for crystallization for 2h, filtering under reduced pressure, and drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide lactate (compound 15) as a white solid in 0.26g, yield: 73.8 percent.
1H NMR(400MHz,D 2O)δ7.58–7.06(m,10H),4.80-4.76(m,1H),4.66(t,1H),4.30(t,1H),4.23–3.94(m,5H),3.78(d,2H),3.72–3.60(m,2H),3.55–3.44(m,1H),3.43–3.30(m,1H),3.18–3.1(m,2H),3.10–2.95(m,4H),1.93–1.30(m,22H),1.04–0.84(m,6H)。
Example 16: synthesis of (2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide hydrochloride (Compound 16)
(2R)-N-[(1R)-1-(2-acetyl-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-pentana mide；hydrochloric acid
(2R) -N- [ (1R) -1- (2-acetyl-2, 7-diazaspiro [3.5] nonane-7-carbonyl) -5-amino-pentyl ] -2- [ [ (2R) -2- [ [ (2R) -2-amino-3-phenyl-propionyl ] amino ] -4-methyl-pentanamide (0.38g, 0.54mmol) was added to a 2N solution of ethyl acetate hydrochloride (2.5mL), stirred at room temperature for 2 hours, after filtration the solid was dissolved in 5mL of water and lyophilized to give a white solid (Compound 16), 340mg, 81% yield.
1H NMR(400MHz,D 2O)δ7.41–7.15(m,10H),4.69–4.66(m,1H),4.63(t,1H),4.31–4.15(m,2H),3.98(d,2H),3.74(d,2H),3.67–3.56(m,2H),3.51-3.39(m,1H),3.38-3.26(m,1H),3.22–3.09(m,2H),3.07–2.89(m,4H),1.86(s,3H),1.85-1.60(m,8H),1.55–1.28(m,5H),0.92(d,3H),0.86(d,3H)。
And (3) data testing:
1. stability data
Stability of different kinds of pharmaceutically acceptable salts under different conditions
(determination of content by HPLC)
And (4) conclusion: the compound dipropionate, propionate, diacetate, acetate, D-tartrate, phosphate, aspartate, L-tartrate, benzoate and lactate have good stability.
Claims (14)
- A compound of the general formula (I) or a stereoisomer thereof, wherein
A is selected from propionic acid, methanesulfonic acid, acetic acid, citric acid, D-tartaric acid, benzenesulfonic acid, phosphoric acid, aspartic acid, L-tartaric acid, maleic acid, fumaric acid, benzoic acid, lactic acid, hydrochloric acid, formic acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, succinic acid, mandelic acid, malonic acid, malic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, salicylic acid, citric acid, glutamic acid, cinnamic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid;n is selected from 0.20-2.00. - A compound according to claim 1 or a stereoisomer thereof, whereinn is selected from 0.50, 0.73, 0.67, 1.0, 1.5 or 2.0.
- A compound according to claim 1 or 2, or a stereoisomer thereof, wherein the compound is selected from one of the following structures
- A process for the preparation of a compound of formula (I) as claimed in claim 1 or a stereoisomer thereof, wherein
Dissolving a compound shown as a formula (II) in a first solvent at room temperature, adding a second solvent dissolved with A, stirring, precipitating a solid, and collecting the solid to obtain a compound shown as a formula (I); or at room temperature, dissolving the compound shown in the formula (II) in a first solvent, adding A, stirring, and freeze-drying to obtain a solid to obtain the compound shown in the formula (I);or dissolving the compound shown in the formula (I) in a first solvent at room temperature, adding a second solvent, stirring, precipitating a solid, and collecting the solid to obtain the compound shown in the formula (I);the definition of a is in accordance with claim 1. - The method according to claim 4, whereinThe first solvent is selected from one or more of water, methanol, ethanol, acetonitrile and tetrahydrofuran;the second solvent is one or more selected from methyl tert-butyl ether, acetonitrile, tetrahydrofuran and methanol.
- A pharmaceutical composition comprising a compound of claim 1, 2 or 3, or a stereoisomer, solvate, pharmaceutically acceptable salt or co-crystal thereof, and one or more of the above pharmaceutically acceptable carriers and/or excipients.
- Use of a compound of claim 1, 2 or 3, or a stereoisomer thereof, or a pharmaceutical composition of claim 6, for the manufacture of a medicament for treating or preventing a kappa opioid receptor-associated disease or condition in a mammal.
- The use of claim 7, wherein the kappa opioid receptor associated condition is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma.
- The use of claim 8, wherein the pain is selected from the group consisting of: neuropathic pain, somatic pain, visceral pain, and skin pain.
- The use of claim 9, wherein the pain is selected from the group consisting of: arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, post-medical treatment pain, ocular pain, otitis pain, breakthrough cancer pain and pain associated with GI disorders.
- A method of treating or preventing a kappa opioid receptor associated disease or condition in a mammal, comprising administering a compound of claim 1, 2, or 3, or a stereoisomer thereof, or a pharmaceutical composition of claim 6.
- The method of claim 11, wherein the kappa opioid receptor associated condition is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma.
- The method of claim 12, wherein the pain is selected from the group consisting of: neuropathic pain, somatic pain, visceral pain, and skin pain.
- The method of claim 13, wherein the pain is selected from the group consisting of: arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, post-medical treatment pain, ocular pain, otitis pain, breakthrough cancer pain and pain associated with GI disorders.
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