CN1736381A - Use of morpholine methyltetralone in preparation of smooth muscles spasmolytic - Google Patents
Use of morpholine methyltetralone in preparation of smooth muscles spasmolytic Download PDFInfo
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Abstract
The invention relates to the use of CY in preparing smooth muscle spasmolysis agent, and in preparing medicaments for treating stomach and intestinal spasm colicky pain, intestine excitable syndrome, ulcerative colitis, stomach and intestine dysfunction, and functional diarrhea.
Description
Technical field:
The present invention relates to medical technical field, exactly is that morpholine methyltetralone (CY) is used to prepare the purposes of smooth muscle spasmolysis agent.
Background technology
The chemical name of CY is a morpholine methyltetralone
(3,4-dihydro-2-(4-morpholinylmethyl)-1 (2H)-naphthalenone), this chemical compound in 1977 by Welch, Willard M.; Harbert, Charles A.; Sarges, Reinhard; Stratten, Wilford P.; Weissman waits the people successfully to synthesize, and its analgesic activities is investigated.The result shows that this chemical compound has more weak analgesic activities, but does not see the report of relevant CY diastole smooth muscle effect so far, and the inventor finds first that through many-sided experiment screening this chemical compound has the smooth muscle spasmolysis effect.
The chemical system title of morpholine methyltetralone is 2-(4-morpholine methyl)-1-tetralone, and its synthetic method is as follows
With 4.20g (0.028mol) 1-tetralone, 2.50g (0.029mol) morpholine mixes with the 10mL absolute methanol, regulate pH=2 with the saturated methanol solution of hydrogen chloride, add 2.25g (0.075mol) paraformaldehyde again, reflux 6h, separate out solid after the cooling, sucking filtration, use methanol wash, get white solid, use the absolute methanol recrystallization, obtain 3-(4-morpholine methyl)-1-tetralone hydrochlorate white solid, productive rate 77.1%.CY is soluble in water, is insoluble to ether, ethyl acetate, cyclohexane extraction, chloroform, is slightly soluble in methanol, ethanol, acetone.
Summary of the invention:
The present invention provides the purposes of treatment smooth muscle spasm to morpholine methyltetralone (CY).
Studies show that: the strong contraction of smooth muscle causes spasm and can cause multiple disease, can cause asthma as bronchial muscular spasm, the gastrointestinal smooth muscular spasm can cause stomachache, the biliary tract smooth muscle contraction can cause biliary colic, the strong contraction of bladder can cause urine urgency-frequency, and uterine smooth muscle shrinks may cause premature labor, influences the fetus normal development, so research smooth muscle spasmolysis medicine has very big realistic meaning, and diseases such as treatment asthma, frequent micturition, urgent micturition, the various angor of alleviation are all had directive significance and reference value.
We studies show that: CY can reduce the tension force and the amplitude of isolated small intestines of rabbits spontaneous activity, isolated small intestines of rabbits, colon, gallbladder that diastole acetylcholine, barium chloride, potassium chloride shrink; The stripped bladder of the rabbit that diastole acetylcholine, potassium chloride shrink, trachea.The CY gastric infusion can obviously suppress the diarrhea of mouse due to Oleum Ricini, magnesium sulfate, the liquid paraffin, and the intestinal propulsion and the large intestine that also can obviously suppress normal mouse advance.Therefore, CY can be used to prepare the spasmolytic for the treatment of smooth muscle spasm.
Description of drawings:
Fig. 1 is the amount effect curve of CY to the isolated small intestines of rabbits diastole effect that causes the convulsion agent and shrink, meansigma methods ± standard error
Fig. 2 for CY to the exsomatize amount effect curve of colon diastole effect of the rabbit that causes the convulsion agent and shrink, meansigma methods ± standard error
Fig. 3 for CY to the exsomatize amount effect curve of gallbladder diastole effect of the rabbit that causes the convulsion agent and shrink, meansigma methods ± standard error
Fig. 4 for CY to the exsomatize amount effect curve of bladder diastole effect of the rabbit that causes the convulsion agent and shrink, meansigma methods ± standard error.
Fig. 5 is the amount effect curve of CY to the rabbit isolated tracheal diastole effect that causes the convulsion agent and shrink, meansigma methods ± standard error
The specific embodiment:
One, isolated experiment
1, animal: new zealand rabbit, the male and female dual-purpose, body weight 2.0～2.5kg, Shenyang Pharmaceutical University's Experimental Animal Center provides, the quality certification number: SCXK (the Liao Dynasty) 2003-008
1, instrument:
(1) HSS-1 (B) type thermostatic bath: Chengdu Instruement Factory
(2) RM6240B type multi-path physiology signal acquiring processing system: Chengdu Instruement Factory
(3) JZJ01 type muscle tone transducer: Chengdu Instruement Factory
(4) TG-328A photoelectric analytical balance: Shanghai balance equipment factory
(5) T-500 type electronic balance: the two outstanding test instrunment in Changshu factory
(6) medical oxygen supply device: Jizhou City, Hebei province welfare medical apparatus and instruments factory
(7) micropipettor: Shanghai Rong Tai biochemical engineering company limited
2, reagent
(1) sodium chloride (NaCl): Tianjin Da Mao chemical reagent factory product, lot number: 20041121
(2) potassium chloride (KCl): Shenyang chemical reagent factory product, lot number: 9908011
(3) magnesium sulfate (MgSO
47H
2O): Kaiyuan chemical reagent factory product, lot number: 990201
(4) sodium dihydrogen phosphate (NaH
2PO
4): Shenyang chemical reagent factory product, lot number: 9804012
(5) anhydrous calcium chloride (CaCl
2): rich Dihua, Tianjin worker's company limited product, lot number: 20020910
(6) sodium bicarbonate (NaHCO
3): rich Dihua, Tianjin worker's company limited product, lot number: 20040406
(7) glucose (Glucose): Shenyang chemical reagent factory product, lot number: 2001030811
(8) barium chloride (BaCl
2): the Xing Dong of Shenyang City chemical reagent work product, lot number: 2000928
(9) dipotassium hydrogen phosphate (KH
2PO
4): rich Dihua, Tianjin worker's company limited product, lot number: 20021231
(10) acetylcholine (ACh): east, Beijing ring amalgamation factory products, lot number: 20041125
4, experimental technique
4.1 effect: after treating the specimen tension stability, in bathing pipe, add the CY (10 of variable concentrations respectively to the isolated small intestines of rabbits spontaneous activity
-4Mol/L, 0.3 * 10
-4Mol/L, 10
-3Mol/L) 0.1ml and aqueous solvent, the variation of observing and writing down small intestinal shrinkage curve under every kind of concentration is before the record administration, the variation of tension force, amplitude and frequency after the administration 0,5,10,15,20 minute the time.Experimental data is represented with means standard deviation, and is made paired t-test, the significance of judgement difference.
4.2 to causing the effect that isolated small intestines of rabbits, colon, gallbladder, bladder, trachea that the convulsion agent causes shrink: after treating the specimen tension stability, in bathing pipe, add and cause convulsion agent (acecoline 1mg/ml, barium chloride 10%, potassium chloride 60mmol/L), after obtaining maximum collapse, fully the flushing tissue adds with the convulsion agent that causes of concentration and induces contrast to shrink once more, when with preceding once shrink basically identical after, totally add CY (10 respectively
-5Mol/L～10
-3Mol/L), record amount effect curve.So that the maximum shrinkage amplitude of convulsion agent is 100%, draws amount effect curve, and data are represented with meansigma methods ± standard error, and obtained EC
50
5, experimental result: (table 1～table 8, Fig. 1～Fig. 5), by harmony in the exterior figure as can be known CY can reduce the tension force and the amplitude of isolated small intestines of rabbits spontaneous activity, isolated small intestines of rabbits, colon, gallbladder that diastole acetylcholine, barium chloride, potassium chloride shrink; The stripped bladder of the rabbit that diastole acetylcholine, potassium chloride shrink, trachea.
6、
7, table 1.CY is to the influence of isolated small intestines of rabbits spontaneous activity amplitude (g) (x ± S)
| Group | Dosage (mol/L) | Before the administration | After the administration | ||||
| 0min | 5min | 10mi n | 15mi n | 20mi n | |||
| Solvent (n=5) CY (n=5) CY (n=5) CY (n=5) | ---- 10 -3 0.3× 10 -4 10 -4 | 0.82 ± 0.55 1.33 ± 0.44 0.78 ± 0.61 0.73 ± 0.55 | 0.79 ± 0.55 0.40 ± 0.07 ** 0.39 ± 0.25 0.51 ± 0.40 | 0.80 ± 0.60 0.44 ± 0.11 ** 0.47 ± 0.38 0.66 ± 0.51 | 0.85 ± 0.65 0.43 ± 0.12 ** 0.54 ± 0.46 * 0.71 ± 0.57 | 0.84 ± 0.61 0.39 ± 0.12 ** 0.54 ± 0.47 * 0.69 ± 0.54 | 0.82 ± 0.62 0.35 ± 0.11 ** 0.56 ± 0.50 * 0.73 ± 0.58 |
* p＜0.05**p＜0.01 is with comparing Student ' s t-test before the administration
Table 2.CY is to the influence of isolated small intestines of rabbits spontaneous activity tension force (g) (x ± S)
| Group | Dosage | Administration | After the administration |
| (mol/L) | Before | 0min | 5min | 10mi n | 15mi n | 20mi n |
* p＜0.05**p＜0.01 is with comparing Student ' s t-test before the administration
Table 3.CY is to the influence of isolated small intestines of rabbits spontaneous activity frequency (inferior/minute) (x ± S)
| Group | Dosage (mol/L) | Before the administration | After the administration | ||||
| 0min | 5min | 10mi n | 15mi n | 20mi n | |||
| Solvent (n=5) CY (n=5) CY (n=5) CY (n=5) | ---- 10 -3 0.3× 10 -4 10 -4 | 0.26 ± 0.23 0.73 ± 0.10 0.20 ± 0.24 0.23 ± 0.18 | 0.26 ± 0.25 0.20 ± 0.21 ** -0.0 1± 0.08 0.13 ± 0.11 | 0.25 ± 0.23 0.22 ± 0.22 ** 0.02 ± 0.11 0.19 ± 0.16 | 0.27 ± 0.24 0.22 ± 0.21 ** 0.06 ± 0.16 * 0.18 ± 0.15 | 0.30 ± 0.28 0.22 ± 0.21 ** 0.07 ± 0.17 * 0.21 ± 0.17 * | 0.30 ± 0.31 0.20 ± 0.22 ** 0.08 ± 0.18 * 0.19 ± 0.15 * |
| Solvent, (n=5) CY, (n=5) CY, (n=5) CY, (n=5) | ---- 10 -3 0.3× 10 -4 10 -4 | 11.4 ± 1.65 11.7 ± 1.14 11.7 ± 1.61 12.3 ± 0.36 | 11.9 ± 1.88 10.9 ± 1.24 12.9 ± 1.14 12.7 ± 1.23 | 12.9 ± 3.53 9.6 ± 0.63 * 11.0 0± 0.92 12.4 ± 1.94 | 11.5 ± 1.14 11.2 ± 2.47 10.6 4± 1.67 11.8 ± 1.77 | 11.7 ± 1.33 10.5 ± 2.46 10.9 ± 0.40 11.3 ± 0.79 | 10.7 ± 1.60 11.5 ± 0.74 10.7 ± 2.00 11.5 ± 0.81 |
* p＜0.05 is with comparing Student ' s t-test before the administration
Table 4.CY is to causing the EC that the convulsion agent causes the diastole effect of intestinal smooth muscle spasm
50Value (x ± S)
| Cause the convulsion agent | -logEC 50(mol/L) |
| ACh(n＝5) KCl(n＝5) BaCl 2(n＝5) | 3.77±0.17 3.65±0.04 3.71±0.05 |
Table 5.CY is to causing the EC that the convulsion agent causes the diastole effect of colonic smooth muscle spasm
50Value (x ± S)
| Cause the convulsion agent | -logEC 50(mol/L) |
| ACh(n＝5) KCl(n＝5) BaCl 2(n＝5) | 3.44±0.17 3.84±0.08 3.55±0.20 |
Table 6.CY is to causing the EC that the convulsion agent causes the diastole effect of smooth muscle of bile vesica spasm
50Value (x ± S)
| Cause the convulsion agent | -logEC 50(mol/L) |
| ACh(n＝5) KCl(n＝5) BaCl 2(n＝5) | 3.61±0.11 3.69±0.21 3.02±1.52 |
Table 7.CY is to causing the EC that the convulsion agent causes the diastole effect of smooth muscle of bladder spasm
50Value (x ± S)
| Cause the convulsion agent | -logEC 50(mol/L) |
| ACh(n＝5) KCl(n＝5) | 3.35±0.19 3.47±0.08 |
Table 8.CY is to causing the EC that the convulsion agent causes the diastole effect of tracheal smooth muscle spasm
50Value (x ± S)
| Cause the convulsion agent | -logEC 50(mol/L) |
| ACh(n＝5) KCl(n＝5) | 3.23±0.13 3.62±0.17 |
Two, integral experiment
1, animal: Kunming mouse, male, body weight 18～22g, Shenyang Pharmaceutical University's Experimental Animal Center provides, the quality certification number: SCXK (the Liao Dynasty) 2003-008
2, instrument: TG328A analytical balance (Shanghai balance equipment factory); T-500 type electronic balance (Changshu two outstanding test instrunment factory)
3, reagent
(1) morphine hydrochloride injection: every specification 10mg/ml, Shenyang No. 1 Pharmaceutical Factory, lot number: 002747
(2) Oleum Ricini: Shenyang City tiger Shitai County chemical reagent factory, lot number: 940805
(3) magnesium sulfate: Kaiyuan chemical reagent factory, lot number: 890201
(4) liquid paraffin: peace chemical plant, Shenyang City, lot number: 911109
(5) activated carbon powder: Tianjin Da Mao chemical reagent factory, lot number: 20040305
(6) sodium chloride injection: Zhiying Pharmaceutical Factory, Shenyang, lot number: 04090702
4, experimental technique
4.1 to diarrheal effect due to Oleum Ricini, magnesium sulfate, the liquid paraffin: get 50 of body weight 18～22g healthy male mices, be divided into 5 groups at random, every group 10, weigh behind the labelling, each group is irritated stomach Oleum Ricini (sodium sulfate, liquid paraffin) 0.2ml/10g respectively, behind the 30min, first group of normal saline 0.2ml/10g irritates stomach as negative control; Second group of morphine 0.2ml/10g irritates stomach as positive control; Third and fourth, five groups irritate stomach respectively and give CY 27.72mg/kg, 13.86mg/kg, 6.93mg/kg, the administration capacity is 0.2ml/10g.With in the single respectively plastics mouse cage that places the white filter paper that is covered with 12.5 * 23.0cm of mice, changing packing paper one time every 1h after the administration, just is 0 minute with normal mice, soft stool is 0.5 minute, and loose stool or watery stool are 1.0 minutes, calculates the diarrhea of mouse number of times, observe 4～5h, statistical data continuously.
4.2 to the propulsive influence of small intestine movement of mice: get 50 of body weight 18～22g healthy male mices, be divided into 5 groups at random, 10 every group, water 20-24h is can't help in fasting before the experiment, weighs behind the labelling, and first group of normal saline 0.2ml/10g irritates stomach as negative control; Second group of morphine 0.2ml/10g irritates stomach as positive control; Third and fourth, five groups irritate stomach respectively and give CY 27.72mg/kg, 13.86mg/kg, 6.93mg/kg, the administration capacity is 0.2ml/10g, behind the 15min, each group is irritated the suspension 0.2ml/10g of stomach 10% active carbon respectively, behind 30min, the mice dislocation is put to death, open the abdominal cavity, separate mesentery, the clip pylorus is tiled in small intestinal on the glass plate to the ileocecus intestinal tube, measuring intestinal tube length is the small intestinal total length, length from pylorus to the powdered carbon forward position is the displacement at powdered carbon peak, calculates powdered carbon according to following formula and advances percentage rate, statistical data.Powdered carbon moves percentage rate=(powdered carbon displacement/small intestinal total length) * 100%.
4.3 to the propulsive influence of normal mouse large intestine: get 50 of body weight 18～22g healthy male mices, be divided into 5 groups at random, 10 every group, water 20-24h is can't help in fasting before the experiment, weighs behind the labelling, and first group of normal saline 0.2ml/10g irritates stomach as negative control; Second group of morphine 0.2ml/10g irritates stomach as positive control; Third and fourth, five groups irritate stomach respectively and give CY 27.72mg/kg, 13.86mg/kg, 6.93mg/kg, the administration capacity is 0.2ml/10g, behind the 15min, each group is irritated the suspension 0.2ml/10g of stomach 10% active carbon respectively, and with in the single respectively plastics mouse cage that places the white filter paper that is covered with 12.5 * 23.0cm of mice, observe and write down the time that mice is discharged melena for the first time, statistical data.
5, experimental result: (table 1～table 5), by table 1～table 5 as can be known, the CY gastric infusion can obviously suppress the diarrhea of mouse due to Oleum Ricini, magnesium sulfate, the liquid paraffin, and the intestinal propulsion and the large intestine that also can obviously suppress normal mouse advance.
Table 1.CY causes the diarrhea mice exponential influence of suffering from diarrhoea to Oleum Ricini
| The diarrhoea index (x ± S) |
| Group | Dosage (mg/k g) | 0-1h | 1-2h | 2-3h | 3-4h | 4-5h |
| NS morphine CY | - 10 27.72 13.86 6.93 | 2.45± 2.44 0.50± 0.83* 4.25± 3.49 3.50± 2.32 2.70± 3.12 | 3.30± 2.05 1.00± 1.22 3.50± 2.27 2.70± 1.08 2.70± 1.72 | 2.80± 1.06 1.80± 0.98 1.20± 1.40** 1.20± 1.23** 1.65± 1.20* | 2.20± 1.20 1.00± 1.50 0.70± 1.06** 1.20± 0.79 0.95± 1.06* | 0.95± 0.96 0.90± 0.81 0.40± 0.52 0.50± 0.85 1.35± 1.45 |
* * P＜0.001, * * P＜0.01, compare with the NS group * P＜0.05
Table 2.CY causes the diarrhea mice exponential influence of suffering from diarrhoea to magnesium sulfate
| Group | Dosage (mg/kg) | The diarrhoea index (x ± S) | |||
| 0-1h | 1-2h | 2-3h | 3-4h | ||
| NS morphine CY | - 10 27.72 13.86 6.93 | 4.15± 2.68 0.30± 0.67*** 1.00± 1.39** 1.50± 1.49* 2.90± 2.61 | 4.70± 3.60 0.40± 0.66** 1.70± 2.04* 1.40± 1.49* 2.85± 1.16 | 3.20± 1.69 1.75± 1.78 2.55± 2.22 1.55± 1.61* 2.20± 1.48 | 1.50± 1.72 2.30± 1.81 1.90± 1.60 1.80± 1.49 1.20± 1.40 |
* * P＜0.001, * * P＜0.01, compare with the NS group * P＜0.05
Table 3.CY causes the diarrhea mice exponential influence of suffering from diarrhoea to liquid paraffin
| Group | Dosage (mg/kg) | The diarrhoea index (x ± S) | |||
| 0-1h | 1-2h | 2-3h | 3-4h | ||
| NS morphine CY | - 10 27.72 | 2.15±0.94 0.00± 0.00*** 1.15± 0.78* | 0.60± 0.77 0.20± 0.35 0.95± 0.83 | 0.65± 0.82 0.30± 0.48 0.95± 0.76 | 0.00± 0.00 0.15± 0.24 0.45± 0.50 |
| 13.86 6.93 | 1.30± 0.54* 1.55±0.50 | 1.05± 0.76 1.05± 0.50 | 0.95± 0.86 0.75± 0.42 | 0.05± 0.16 0.80± 0.71 |
* * P＜0.001, * * P＜0.01, compare with the NS group * P＜0.05
Table 4.CY is to the propulsive inhibitory action of small intestine movement of mice
| Group | Dosage (mg/kg) | Propelling rate (%) |
| NS morphine CY | - 10 27.72 13.86 6.93 | 0.65±0.14 0.20±0.12*** 0.46±0.16* 0.55±0.13* 0.63±0.18 |
* * P＜0.001, * * P＜0.01, compare with the NS group * P＜0.05
Table 5.CY is to the propulsive inhibitory action of normal mouse large intestine intestinal
| Group | Dosage (mg/kg) | Arrange the melena time (min) for the first time |
| NS morphine CY | - 10 27.72 13.86 6.93 | 60.3±21.9 97.7±30.9* 87.6±11.3* 86.2±5.0* 84.4±14.1 |
* * P＜0.001, * * P＜0.01, compare with the NS group * P＜0.05
Above experimental result explanation CY can reduce the tension force and the amplitude of isolated small intestines of rabbits spontaneous activity, isolated small intestines of rabbits, colon, gallbladder that diastole acetylcholine, barium chloride, potassium chloride shrink; The stripped bladder of the rabbit that diastole acetylcholine, potassium chloride shrink, trachea.The CY gastric infusion can obviously suppress the diarrhea of mouse due to Oleum Ricini, magnesium sulfate, the liquid paraffin, and the intestinal propulsion and the large intestine that also can obviously suppress normal mouse advance.Therefore, CY can be used to prepare the spasmolytic for the treatment of smooth muscle spasm.CY can be used for preparing the application of the gastrointestinal dysfunction disease medicament that gastrointestinal convulsion angor medicine, irritable bowel syndrome medicine, ulcerative colitis that treatment causes a variety of causes cause; Be used for preparing the application of the functional diarrhea medicine that the treatment a variety of causes causes; Application in the spasmic pain medicine of the gallbladder biliary tract that preparation treatment cholecystitis, cholelithiasis, gallbladder ascariasis cause; Also can be in the application in irritation sign of bladder such as the urine urgency-frequency that causes at preparation treatment cystitis, vesical calculus, prostatitis and the bed-wetting disease drug; In the renal colic medicine that preparation treatment ureteritis, lithangiuria, renal calculus cause, use; Application in the asthma disease medicine that the bronchospasm that preparation treatment a variety of causes causes causes.
Claims (1)
1, the application of morpholine methyltetralone in the spasmolytic medicine of the various smooth muscle spasms of preparation treatment is characterized in that: the application in the gastrointestinal dysfunction disease medicament that gastrointestinal convulsion angor medicine, irritable bowel syndrome medicine, the ulcerative colitis that CY causes a variety of causes in the preparation treatment causes; Application in the functional diarrhea medicine that preparation treatment a variety of causes causes; Application in the spasmic pain medicine of the gallbladder biliary tract that preparation treatment cholecystitis, cholelithiasis, gallbladder ascariasis cause; Also can be in the application in irritation sign of bladder such as the urine urgency-frequency that causes at preparation treatment cystitis, vesical calculus, prostatitis and the bed-wetting disease drug; In the renal colic medicine that preparation treatment ureteritis, lithangiuria, renal calculus cause, use; Application in the asthma disease medicine that the bronchospasm that preparation treatment a variety of causes causes causes.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510047044 CN1736381B (en) | 2005-08-11 | 2005-08-11 | Use of morpholine methyltetralone in preparation of smooth muscles spasmolytic |
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|---|---|---|---|
| CN 200510047044 CN1736381B (en) | 2005-08-11 | 2005-08-11 | Use of morpholine methyltetralone in preparation of smooth muscles spasmolytic |
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| CN1736381A true CN1736381A (en) | 2006-02-22 |
| CN1736381B CN1736381B (en) | 2010-09-08 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4900743A (en) * | 1987-01-27 | 1990-02-13 | Merrell Dow Pharmaceuticals Inc. | 3-aryl-5-alkylthio-4H-1,2,4-triazoles |
| US5500442A (en) * | 1994-06-10 | 1996-03-19 | American Home Products Corporation | Cyclobut-3-ene-1,2-dione derivatives as smooth muscle relaxants |
| US5482942A (en) * | 1994-06-28 | 1996-01-09 | American Home Products Corporation | (3,4-dioxocyclobuten-1-yl)chromene, indene, and dihydronaphthalenone derivatives as smooth muscle relaxants |
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