CN108610313B - Enzyme inhibitor and application thereof - Google Patents
Enzyme inhibitor and application thereof Download PDFInfo
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- CN108610313B CN108610313B CN201810589260.5A CN201810589260A CN108610313B CN 108610313 B CN108610313 B CN 108610313B CN 201810589260 A CN201810589260 A CN 201810589260A CN 108610313 B CN108610313 B CN 108610313B
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- hydrazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The invention relates to application of hydrazone compounds such aS (3R,3aR,6S, 7aS) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol, (2Z,3R,3aR, 6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol and the like aS urease inhibitors. The compound has high-efficiency inhibitory action on urease, and can be used as a novel medicament for treating gastric ulcer, duodenal ulcer and gastritis.
Description
Technical Field
The invention relates to (3R,3aR,6S,7aS, E) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol (1) or (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol (2) or a mixture of both, (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) or (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4) or two Hydrazone compounds such as the mixture of the above compounds have urease inhibiting activity and can be used for treating gastric ulcer, duodenal ulcer and gastritis.
Background
At present, with the social development and the change of life style of people, the incidence rate of peptic ulcer caused by factors such as smoking, drinking, emotional stress, drug stimulation, helicobacter pylori infection and the like is gradually increased, so that the peptic ulcer becomes a common disease and frequently encountered disease, and brings great pain to patients.
Proton Pump Inhibitors (PPIs) are the most advanced class of drugs currently used for treating peptic ulcers (Li H, Meng L, Liu F, et al.H.)+/K+-ATPase inhibitors: a patent review. expert Opin Ther Patents,2013,23: 99-111). Gastric acid is one of the important factors causing peptic ulcer and other digestive diseases, and is rapidly and strongly expressedEffective inhibition of gastric acid secretion is currently an important means of treating peptic ulcers. The final step in gastric acid secretion is the intracellular proton pump (H) in the gastric parietal cell+,K+ATPase) drives intracellular H+And in the tubule K+And (4) exchanging. Action of PPIs on Key target H+,K+ATP enzyme, which blocks the last channel of gastric acid secretion, can inhibit acid secretion caused by various factors such as histamine, acetylcholine, gastrin and food irritation, and has strong acid-inhibiting effect, high specificity and long duration (Shanghai: Shanghai science and technology education Press, 2004).
However, after the acid-suppressing treatment with the proton pump inhibitor, peptic ulcer easily comes with heavy earth and is repeatedly attacked. Australian scientists bali Marshall (Barry J Marshall) and robin Warren (J. robin Warren) in 1984 suggested that Helicobacter pylori (Hp) is involved in the etiology of gastritis and peptic ulcers and received a 2005 nobel physiological or medical prize. Helicobacter pylori is a gram-negative bacterium inhabited in the stomach of a human body, is a main disease treatment factor for gastritis, gastric ulcer and duodenal ulcer, and is listed as a main factor causing gastric cancer by the world health organization. Helicobacter pylori is very easy to infect, the detection rate of Hp in common people in China is quite high, and the Hp infection rate reaches 55% (Hufulian, epidemiology of helicobacter pylori infection, Chinese medical journal, 2007,42 (2): 17-18). More than 90% of duodenal ulcers and around 80% of gastric ulcers are caused by Hp. Currently, triple therapy (1 proton pump inhibitor or colloidal bismuth agent +2 antibiotics) or quadruple therapy (1 proton pump inhibitor + colloidal bismuth agent +2 antibiotics) is generally used for treating helicobacter pylori infection. However, the therapy takes longer time, is easy to generate side effects such as epigastric distending pain, antibiotic resistance and the like, and has higher medication cost.
Urease in helicobacter pylori is a hydrolase that catalyzes urea decomposition into ammonia and carbon dioxide, increasing the ammonia concentration in gastric acid, neutralizing part of gastric acid and forming a nearly neutral liquid film on the surface of bacteria, providing a suitable microenvironment for helicobacter pylori, which in turn enables helicobacter pylori to survive in the strongly acidic environment of the stomach (Krajewska B. ureas i.functional, catalytic and kinetic properties: a review. j Mol cat c enzyme B, 2009,59(1): 9-21). Therefore, urease has become an important target for designing anti-helicobacter pylori medicines in recent years. If the proton pump inhibitor and the urease inhibitor are combined into a whole, the novel urease and proton pump dual inhibitor is invented and is a new treatment way.
In 2018 She et al reported that (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol compounds have a mechanism of action on proton pumps and a better inhibitory activity (She XX, Dong Q, Luo HJ, et al. molecular locking, binding from energy analysis, and biological evaluation of biochemical reactions of biochemical hydrocarbon amides H +, K + -ATPase reversible inhibitors. Med. Chem Res,2018,27(1): 332-340).
The invention takes computer-aided drug design aS guidance to screen out urease inhibitor (3R,3aR,6S,7aS, E) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol (1) or (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol (2) or a mixture of the two, (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) or (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, hydrazone compounds such as 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4) or a mixture of both were measured for inhibitory activity against urease.
Disclosure of Invention
The invention aims to provide a novel high-activity urease inhibitor (3R,3aR,6S,7aS, E) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol (1) or (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isoamyl-3, 6-dimethyl octahydrobenzofuran-3-ol (2) or a mixture of the two, (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) or (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4) or a mixture of the two, wherein the structural formula of the compound is as follows:
1. structural characterization of a mixture of (3R,3aR,6S,7aS, E) -4-hydrazine-2-isopentyl-3, 6-dimethyloctahydrobenzofuran-3-ol (1) and (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isopentyl-3, 6-dimethyloctahydrobenzofuran-3-ol (2) (50% each)
A white solid; m.p.114-116 ℃; MS (ESI) M/z 291.19(M + Na)+；IR:νmax/cm-1(KBr)3456,2955,2868,1639,1462,1385,1165,1098,1038,985；1H NMR(CDCl3,400MHz)δ:5.08(s,1H),4.23–4.10(m,1H),3.44(dd,J＝6.9,5.3Hz,1H),2.89(d,J＝9.1Hz,1H),2.71(d,J＝9.2Hz,1H),2.59–2.45(m,1H),2.16–1.94(m,2H),1.69(dd,J＝22.3,8.7Hz,1H),1.62–1.44(m,7H),1.38(s,1H),1.32(s,3H),1.29–1.21(m,3H),1.02(d,J＝6.3Hz,3H),0.90(dd,J＝6.4,2.4Hz,7H)；13C NMR(CDCl3,100MHz)δ:152.89,86.75,80.13,76.42,52.84,39.52,36.13,36.02,33.24,28.28,26.72,26.35,24.40,22.57,22.47,21.99.
2. Structure identification of a mixture of (50% each) of (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) and (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4)
A white solid; m.p.99-101 ℃; MS (ESI) M/z 289.17(M + Na)+；IR:νmax/cm-1(KBr)3456,2955,2868,1639,1462,1385,1165,1098,1038,985；1H NMR(CDCl3,400MHz)δ:5.12(s,2H),4.47(ddd,J＝14.9,9.9,5.1Hz,2H),3.01(s,1H),2.68(d,J＝7.6Hz,1H),2.59–2.46(m,1H),2.06–2.01(m,1H),1.94(t,J＝7.1Hz,2H),1.76–1.48(m,6H),1.43(s,3H),1.26(d,J＝11.0Hz,2H),1.04(d,J＝6.0Hz,4H),0.88(dd,J＝4.2,2.5Hz,6H)；13C NMR(CDCl3,100MHz)δ:160.52,152.00,94.72,78.45,78.29,51.62,37.47,33.72,32.49,28.78,26.73,26.62,22.36,22.19,21.73.
3. Urease inhibiting activity assay
(1) Culture of helicobacter pylori strains
Helicobacter pylori was inoculated in Brookfield broth containing horse serum (10%) under microaerobic conditions (85% N)2，10％CO2And 5% of O2) Culturing at 37 deg.C for 24 h.
(2) Preparation of helicobacter pylori urease
Taking cultured helicobacter pylori liquid, centrifuging for 15min at 5000G and 4 ℃, collecting helicobacter pylori, washing for 3 times by using phosphate buffer with pH 7.4, placing the helicobacter pylori at-80 ℃ for storing for 24h, taking out and recovering to room temperature, adding 3mL of distilled water and protease inhibitor, performing ultrasonic treatment for 1min, centrifuging for 10min at 12000G and 4 ℃, removing salt from supernatant by using a Sephadex G-25 chromatographic column, adding glycerol with the same volume to crude enzyme, storing at 4 ℃ and using for activity determination.
(3) Urease half-inhibitory concentration determination
Urease activity was tested according to the method reported by Weatherburn. The method comprises the following specific steps: mu.L of urease solution (10U/mL), 25. mu.L of test compound (concentration set according to the experiment, in DMSO-phosphate buffer), was added to a 96-well plate, co-incubated at 37 ℃ for 30min, 50. mu.L of phosphate buffer containing 25mmol of urea was added, co-incubated at 37 ℃ for 30min, 50. mu. L A reagent (127mM phenol and 0.168mM sodium nitroprusside) and 50. mu. L B reagent (125mM NaOH and 11.3mM NaOCl) were added, co-incubated at 37 ℃ for 30min, and absorbance values were measured at 620 nm. Separately setting blank group, normal control group, and positive control group (acetohydroxamic acid), and calculating the inhibition rate and half inhibition concentration IC of the inhibitor50。
A mixture of (3R,3aR,6S,7aS, E) -4-hydrazine-2-isopentyl-3, 6-dimethyloctahydrobenzofuran-3-ol (1) and (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isopentyl-3, 6-dimethyloctahydrobenzofuran-3-ol (2) (50% each) has an IC for urease50A mixture of (50% each) of (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) and (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4) with a value of 0.79. mu.M IC for urease50The value was 0.78. mu.M.
And (4) conclusion: (3R,3aR,6S,7aS, E) -4-hydrazine-2-isoamyl-3, 6-dimethyloctahydrobenzofuran-3-ol (1) or (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isoamyl-3, 6-dimethyloctahydrobenzofuran-3-ol (2) or a mixture of both, (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) or (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4) or a mixture of both Is a novel high-efficiency urease inhibitor, and can be applied to the treatment of gastric ulcer and gastritis.
Detailed Description
Example 1:
mu.L of urease solution (10U/mL), 25. mu.L of a mixture of (3R,3aR,6S,7aS, E) -4-hydrazine-2-isoamyl-3, 6-dimethyloctahydrobenzofuran-3-ol (1) and (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isoamyl-3, 6-dimethyloctahydrobenzofuran-3-ol (2) (50% each) were added to a 96-well plate (0.25. mu.M, 0.50. mu.M, 1.00. mu.M, 2.00. mu.M, 4.00. mu.M, prepared with DMSO-phosphate buffer solution), co-incubated at 37 ℃ for 30min, 50. mu.L of phosphate buffer solution containing 25mmol of urea was added, co-incubated at 37 ℃ for 30min, then 50. mu. L A reagent (127mM phenol and 0.168mM sodium nitroprusside) and 50 mM NaOH and 50. mu. L B reagent (125mM NaOH and 11.3mM NaOCL) were added, co-incubation was performed at 37 ℃ for 30min and absorbance values were determined at 620 nm. Setting blank group, normal control group and positive control group (acetohydroxamic acid), calculating half inhibition concentration IC of inhibitor on urease500.79 μ M, positive control acetoxyhydroxamic acid IC5018.2. mu.M.
Example 2:
mu.L of urease solution (10U/mL), 25. mu.L of a mixture (50% each) of (2Z,3R,3aR,4E,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (3) and (2Z,3R,3aR,4Z,6S,7aS) -4-hydrazine-3, 6-dimethyl-2- (3-methylbutenyl) octahydrobenzofuran-3-ol (4) were added to a 96-well plate (0.25. mu.M, 0.50. mu.M, 1.00. mu.M, 2.00. mu.M, 4.00. mu.M in DMSO-phosphate buffer solution), incubated at 37 ℃ for 30min, 50. mu.L of phosphate buffer solution containing 25mmol of urea was added, and incubated at 37 ℃ for 30min, then 50. mu. L A reagent (127mM phenol and 0.168mM sodium nitroprusside) and 50. mu. L B reagent (125mM NaOH and 0.168mM sodium nitroprusside) were added11.3mM NaOCl), incubated at 37 ℃ for 30min and the absorbance value was determined at 620 nm. Setting blank group, normal control group and positive control group (acetohydroxamic acid), calculating half inhibition concentration IC of inhibitor on urease500.78 μ M, positive control acetoxyhydroxamic acid IC5018.2. mu.M.
Claims (2)
1. Use of an enzyme inhibitor which is a mixture of (3R,3aR,6S,7aS, E) -4-hydrazine-2-isoamyl-3, 6-dimethyloctahydrobenzofuran-3-ol (1) and (3R,3aR,6S,7aS, Z) -4-hydrazine-2-isoamyl-3, 6-dimethyloctahydrobenzofuran-3-ol (2) for the preparation of a medicament for inhibiting urease; the structural formula of the compound is:
2. use of an enzyme inhibitor for inhibiting urease for the manufacture of a medicament for the treatment of gastric ulcer, duodenal ulcer, gastritis, according to claim 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1046515C (en) * | 1993-12-29 | 1999-11-17 | 辉瑞大药厂 | Diazabicyclic neurokinin antagonists |
| WO2008036445A2 (en) * | 2006-06-12 | 2008-03-27 | Viamet Pharmaceuticals, Inc. | Metallo-hydrolase inhibitors using metal binding moieties in combination with targeting moieties |
| CN102993152A (en) * | 2012-12-29 | 2013-03-27 | 吉首大学 | Urease inhibitor genistein hydroxamic acid compound and synthesis and application thereof |
| CN102993153A (en) * | 2012-12-29 | 2013-03-27 | 吉首大学 | Isoflavone-N-methyl hydroxamic acid urease inhibitor and synthesis method and use thereof |
-
2018
- 2018-06-08 CN CN201810589260.5A patent/CN108610313B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1046515C (en) * | 1993-12-29 | 1999-11-17 | 辉瑞大药厂 | Diazabicyclic neurokinin antagonists |
| WO2008036445A2 (en) * | 2006-06-12 | 2008-03-27 | Viamet Pharmaceuticals, Inc. | Metallo-hydrolase inhibitors using metal binding moieties in combination with targeting moieties |
| CN102993152A (en) * | 2012-12-29 | 2013-03-27 | 吉首大学 | Urease inhibitor genistein hydroxamic acid compound and synthesis and application thereof |
| CN102993153A (en) * | 2012-12-29 | 2013-03-27 | 吉首大学 | Isoflavone-N-methyl hydroxamic acid urease inhibitor and synthesis method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| ynthesis, Structure and Gastric H+/K+-ATPase Inhibitory Activities of Bisabolonalone Hydrazone Carboxamides;Jin, L et al.;《Advanced Materials Research》;20131231;第781-784卷;第1098-1101页 * |
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