CN1301715C - Pregnenolone in steroid species and isomeric compound in application of preparing medicaton for treating high blood pressure - Google Patents
Pregnenolone in steroid species and isomeric compound in application of preparing medicaton for treating high blood pressure Download PDFInfo
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- CN1301715C CN1301715C CN 200310109965 CN200310109965A CN1301715C CN 1301715 C CN1301715 C CN 1301715C CN 200310109965 CN200310109965 CN 200310109965 CN 200310109965 A CN200310109965 A CN 200310109965A CN 1301715 C CN1301715 C CN 1301715C
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Abstract
The present invention relates to pregnenolone in steroid species and an isomeric compound thereof in the application of preparing medicines for treating high blood pressure, which belongs to the field of medicine preparation. The present invention has the advantages of safety, no toxicity, high pharmacological action, wide medicinal prospect, low price, little toxicity, simple preparing progress and easy use and can be made into peroral agents, injection agents, tablets, etc., wherein the injection agents need to be injected in muscles and acupoints.
Description
Technical field:
The present invention relates to the purposes of a kind of pregnanolone (the English Pregnanolone of being) and optical isomer thereof, particularly relate to a kind of pregnanolone (Pregnanolone) and the application of optical isomer in preparation treatment hypertension drug thereof of steroid, belong to pharmaceutical field.
Background technology:
Psychology-spiritual irritability hypertension and central nervous system have substantial connection, domestic and international research is verified to have multiple material to participate in the hypertensive formation of irritability, comprise catecholamine hormones, adrenocortical hormone, Angiotensin II, glucagon etc., especially the effect of Angiotensin II in the irritability hypertension incidence extremely paid attention to.At present, the antihypertensive of using clinically mainly is to reach hypotensive activity by diuresis, vasodilator symptomatic treatment approach.Abroad, angiotensin ii receptor antagonist is applied to hypertensive treatment more and more as a kind of novel antihypertensive drugs.The nineties, China begins from external introduction antihypertensive agent Lu Shatan, its mechanism is to play hypotensive activity by the stress that the nervous plain II of antagonizing vessel causes, but because its medicine high price is expensive, limited its application at home, therefore at present symptomatic therapy is mainly adopted in hypertensive treatment, be difficult to the fundamentally thoroughly hypertensive generation of control.Pregnanolone of steroid (Pregnanolone) and optical isomer thereof at home and abroad do not appear in the newspapers on the document as the control hypertension drug.
Summary of the invention:
The object of the present invention is to provide a kind of new purposes of pregnanolone and optical isomer thereof of steroid, i.e. new application in pharmacy.
In fact the pregnanolone (Pregnanolone) that the present invention relates to steroid is as the application in preparation treatment and the prophylaxis of hypertension medicine.
The optical isomer of pregnanolone (Pregnanolone) that the invention still further relates to steroid is as the application in preparation treatment and the prophylaxis of hypertension medicine.
In order to understand essence of the present invention better, with the pregnanolone (Pregnanolone) of steroid and the pharmacological tests of optical isomer thereof its new purposes in pharmaceutical field is described below.Composition: 5 β-Pregnan-3 α-OL-20-ONE (Pregnanolone).Molecular formula: C
21H
34O
2, molecular weight: 318.5.Its structural formula is:
The structural formula of the optical isomer that it comprises is:
PGN's is synthetic: application Progosterone is a raw material, obtains key intermediate I by selective hydrogenation, then with the synthetic end-product PGN of Stereoselective reduction method.
One, PGN and optical isomer are to the influence of Hypertensive Rats cardiovascular activity
1, the foundation of model:
72 of Wistar male rats, body weight 250-280g, the vola of shocking by electricity every day stimulates in conjunction with noise, every day 2 times, each 2-2.5 hour.Animal is placed on electric shock gives the randomness foot sole stimulation in the cage, intensity is 2-4mA, and the persistent period is 50ms, gives noise 80-100ds simultaneously, the stimulation of time-histories 50ms, and blood pressure all reaches more than the 20kpa behind the continued stimulus 15d.
2, animal grouping: (1) hypertensive rat model: divide PGN dose-effect curve group (n=30), PGN group (n=14), Bic group (n=11), PGN+Bic to organize (n=11), saline control group (n=6); (2) normal rat group: PGN group (n=12), Bic group (n=8), PGN+Bic organize (n=11), saline control group (n=6); Wherein n is a number of elements.
3, administering mode: will expose skull behind the rat anesthesia, 1mm behind bregma, sleeve pipe is vertically inserted in the other 1.5mm of center line place's boring, dark 3.5-4.0mm, conduit is fixed on the skull, injects normal saline or dissolve in wherein medicine to tricorn through sleeve pipe, its solution pH value is 7.2-7.4, injection capacity is 0.7 μ l, the 1-2min constant speed is annotated and is finished, every rat injection 1 time or 2 medicines, midfeather at least 2 hours.
4, experimental result: (1) is with 6 Hypertensive Rats injection various dose PGN 9 * 10
-7, 9 * 10
-6, 9 * 10
-5, 9 * 10
-4, 9 * 10
-3Mol.L
-1, blood pressure is reduced to (1.2 ± 0.1), (3.0 ± 0.4), (4.7 ± 1.3), (1.8 ± 0.3), (0.5 ± 0.1) kPa (n=6) successively.Relatively PGN is to the influence of normal rat and irritability hypertensive rat blood pressure, and 14 Hypertensive Rats inject 9 * 10
-4Mol.L
-1PGN, blood pressure by administration before (20.2 ± 2.0) kPa be reduced to (16.7 ± 1.3) kPa, difference is (4.7 ± 1.6) kPa (P＜0.001).12 normal arterial pressure rats, behind the injection same dose PGN, blood pressure by administration before (12.3 ± 1.6) kPa, be reduced to (9.6 ± 1.3) kPa, difference is (2.9 ± 0.1) kPa.Hypertensive Rats and normal rat blood pressure reduce difference relatively significant difference.As shown in Figure 1.
(2) cardiovascular effect that causes behind the rat icv Bic: 11 Hypertensive Rats icv8.2 * 10
-5Mol.L
-1Bic0.7 μ l, 5 seconds blood pressures raise rapidly after the injection, peaking in the time of 10 seconds, (20.2 ± 1.6) kPa by before the injection rises to (23.2 ± 1.2) kPa, and difference is (2.8 ± 0.8), descends gradually then, returns near level before the injection after 55 seconds.And 8 normal rat icv equivalent Bic, blood pressure raises rapidly after 5 seconds, and 12 seconds left and right sides peakings, rise to (12.9 ± 1.3) kPa by (11.1 ± 1.5) kPa before the injection, and difference is (1.8 ± 0.6) kPa.Hypertensive Rats and normal rat hypertension difference relatively have significance.As shown in Figure 1.
(3) Icv Bic is to the influence of PGN pressure reduction effect: 11 rat tricorns inject Bic (8.2 * 10 in advance
-5Mol.L
-1/ 0.7 μ l), the back 5 seconds PGN (9.4 * 10 that reinject
-5Mol.L
-1Bic0.7 μ l), though injecting Bic in the variation of each time point merely with 11 Hypertensive Rats, blood pressure compares decline to some extent, but with inject PGN before compare difference and do not have significance (P＞0.05), compared utmost point significant difference (P＜0.001) with 14 simple PGN groups of injecting.7 rat tricorns inject 5 seconds PGN that reinject behind the Bic in advance, compare and decrease though blood pressure injects Bic merely at the variation of each time point and 8 normal rats, but with inject PGN before compare, difference does not have significance (P＞0.05), has compared significance (P＜0.001) with 12 normal rats of simple injection PGN and 11 Hypertensive Rats of injection Bic and PGN.As shown in Figure 1.
Two, PGN and the optical isomer effect in stress in rats hypertension forms
1, animal grouping:
38 of Wistar male rats, body weight 250-280g is divided into normal group at random, stress organizes, stress organize, stress organize, stress organize by 15d+PGN by 15d by 1h+PGN by 1h.7 stress 1h group give 1h electric shock vola and stimulate 1h in conjunction with noise stress, animal is placed in the special electric shock cage during stimulation, give the vola electricity irritation of computer-controlled randomness, intensity is 2-4ma, persistent period is 50ms, give noise 80-100ds simultaneously, intraperitoneal injection of saline 2ml is carried out in the stimulation of time-histories 50ms before stimulation; Stress organize before giving above-mentioned stress stimulation lumbar injection PGN0.24mg/kg by 1h+PGN; Stress give stress stimulation 2 times every day by 15d group rat, each 2h, continuous 15d is during the stress stimulation, through intraperitoneal injection of saline 2ml.d; Stress 15d+PGN the rat of group during giving stress stimulation, through lumbar injection PGN0.24mg/kg.d.Control animals does not give any stimulation.
2, rat arteria caudalis systolic pressure is measured:
Under animal is in waking state, survey the systolic pressure of rat arteria caudalis with tail cover method, survey once every day, averages after surveying three times at every turn.
3, experimental result:
Stress 15d+PGN the normal control rats of group rat arteria caudalis systolic pressure remarkable rising (P＜0.05) be arranged, stress 15d group (P＜0.001) but significantly be lower than, stress the 1h group and stress not have significant change by 1h+PGN group rat arteria caudalis systolic pressure.Simultaneously, detect and respectively organize nervous plain II (AII) content of rat serum medium vessels, found that stress 1h+PGN in group and the 15d+PGN group blood AII level than matched group remarkable rising (P＜0.001) is arranged, stress the 1h group and stress organize (P＜0.05) by 15d but significantly be lower than merely; Stress 15d AII content stress the 1h group raise (P＜0.05) in the group blood; The normal control group, stress 15d group, stress 15d+PGN group rat brain in rarely seen minority Fos albumen sample immunoreation (FLI) neuron.Compare with matched group, stress 1h in the group rat brain visible outer side habenular nucleus (LHb), HM (MHb), paraventricular nucleus test (PVN), NAC (CeA) and lateral hypothalamic region position FLI neurons such as (LH) significantly increase, and again stress 1h behind the lumbar injection PGN, can suppress above-mentioned effect, can reduce the content of the nervous plain II of stress rats blood medium vessels, Angiotensin II is a kind of irritability mediator, show that PGN can pass through anti-stress, the concentration that reduces Angiotensin II reaches hypotensive activity.
Above result can draw good effect of the present invention and be: the present invention has excavated new medical application to known pregnanolone Pregnanolone and optical isomer thereof; Its safety non-toxic, pharmacological action is strong, and good prospect in medicine is arranged; Have low price, toxicity is little.Preparation technology is simple, and can make peroral dosage form, injection type, tablet etc., and easy to use, wherein injection is wanted intramuscular injection and acupoint injection therapy.
Description of drawings:
Fig. 1 is response curve figure of the present invention.
The specific embodiment:
The present invention will be further described below in conjunction with embodiment:
Embodiment 1
Hypertensive Rats anesthesia back is exposed skull, 1mm behind bregma, sleeve pipe is vertically inserted in the other 1.5mm of center line place's boring, dark 3.5-4.0mm, conduit is fixed on the skull, injects normal saline or dissolve in wherein medicine to tricorn through sleeve pipe, its solution pH value is 7.2, injection capacity is 0.7 μ l, the 1-2min constant speed is annotated and is finished, every rat injection 1 time or 2 medicines, midfeather at least 2 hours.Injection 9 * 10
-4Mol.L
-1PGN, blood pressure by administration before (20.2 ± 2.0) kPa be reduced to (16.7 ± 1.3) kPa, difference is (4.7 ± 1.6) kPa (P＜0.001).
Embodiment 2:
Giving the Hypertensive Rats injected dose with said method is PGN9 * 10
-7Mol.L
-1, blood pressure reduces (1.2 ± 0.1) kPa.
Embodiment 3:
Giving the Hypertensive Rats injected dose with said method is PGN9 * 10
-6Mol.L
-1, blood pressure reduces (3.0 ± 0.4) kPa.
Embodiment 4:
Giving the Hypertensive Rats injected dose with said method is PGN9 * 10
-5Mol.L
-1, blood pressure reduces (4.7 ± 1.3) kPa.
Embodiment 5:
Giving the Hypertensive Rats injected dose with said method is PGN9 * 10
-3Mol.L
-1, blood pressure reduces (1.8 ± 0.3) kPa.
Claims (3)
1, the application of the pregnanolone of steroid in preparation treatment hypertension drug.
2, the application of the pregnanolone of steroid according to claim 1 in preparation treatment hypertension drug, the optical isomer of pregnanolone that it is characterized in that described steroid is as the application in preparation treatment and the prophylaxis of hypertension medicine.
3, the pregnanolone of steroid according to claim 1 and 2 and optical isomer thereof the application in preparation treatment hypertension drug is characterized in that described preparation treatment and prophylaxis of hypertension medicine comprise peroral dosage form, injection type, tablet.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310109965 CN1301715C (en) | 2003-11-03 | 2003-11-03 | Pregnenolone in steroid species and isomeric compound in application of preparing medicaton for treating high blood pressure |
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|---|---|---|---|
| CN 200310109965 CN1301715C (en) | 2003-11-03 | 2003-11-03 | Pregnenolone in steroid species and isomeric compound in application of preparing medicaton for treating high blood pressure |
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|---|---|
| CN1539423A CN1539423A (en) | 2004-10-27 |
| CN1301715C true CN1301715C (en) | 2007-02-28 |
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| US20110201579A1 (en) * | 2010-02-18 | 2011-08-18 | Woodward John R | Method of Improving the Overall Health of a Patient by Application of Pregnenolone |
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