CN105732612B - A kind of preparation of pril jamaicin conjugates and medical usage - Google Patents
A kind of preparation of pril jamaicin conjugates and medical usage Download PDFInfo
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- CN105732612B CN105732612B CN201610150124.7A CN201610150124A CN105732612B CN 105732612 B CN105732612 B CN 105732612B CN 201610150124 A CN201610150124 A CN 201610150124A CN 105732612 B CN105732612 B CN 105732612B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
Abstract
The conjugates preparation method of offer formula (I) of the present invention is used as in treatment hypertension, regulation blood pressure medication with it and applied.Found by experiment in terms of pharmacology, such conjugates has the pharmaceutical activity of various value, particularly its performance easily absorbed is not available for pril medicine, and specifically such conjugates shows excellent adjusting hypertension rat blood pressure effect in zoopery.Its main function, which is embodied in, can block all angiotensinⅡs caused by various approach to be combined with its specific receptor, so as to weaken or block its boosting.
Description
Technical field
The present invention relates to food pharmaceutical technical field, and in particular to a kind of pril jamaicin conjugates are treating high blood
Application in pressure, regulation blood pressure product.
Background technology
According to survey data in 2002, more than the 18 years old adult hypertension illness rate in China was 18.8%, estimates current China
200,000,000 hyperpietics are there are about, just there are 2 people to suffer from hypertension in every 10 adults, accounts for the 1/5 of global hypertension total number of persons.
In China's Hypertensive Population, the overwhelming majority is light, moderate hypertension (accounting for 90%), and mild hypertension accounts for more than 60%.However,
Population of China normal arterial pressure (<120/80mmHg) proportion is less than 1/2.The horizontal crowd of In Prehypertensive accounts for total Adult Groups
Ratio constantly increase, it is especially young and middle-aged, increase to 34% in 2002 from 29% in 1991, be China's hypertension
Illness rate persistently raises the main source to increase severely with number of patients.Estimate that China increases the people of hyperpietic 10,000,000 newly every year.
The sales volume of global pril medicine in 2007 has reached 19,400,000,000 dollars, occupies the 2.72% of global drug market.Pril
Medicine main function, which is embodied in, can block all angiotensinⅡs caused by various approach to be combined with its specific receptor, so as to subtract
It is weak or block its boosting, can long-term use of regulation blood pressure.
Jamaicin BBR (Berberine, BBR) is the main active of the coptis, BBR content highests in the coptis, accounts for 5.2-
7.69%.Coptis bitter, the effect of there is heat-clearing, removing toxic substances, purging intense heat and control diabetes.It is not easy to absorb after thinking oral in the past more,
It is effective to enteric infection, eye conjunctivitis, otitis media suppurative etc. caused by shigella dysenteriae, Escherichia coli, staphylococcus aureus,
Clinic is mainly used in the treatment of enteric infection.With going deep into for research, find that it has anti-arrhythmia, diastole successively in recent years
The pharmacological action such as blood vessel, protection cardiac muscle, platelet aggregation-against, hypoglycemic, reducing blood lipid, anti-inflammatory, antiviral, antitumor.
Yet with the water-soluble poor of pril, oral administration biaavailability is low, limits giving full play to for its drug effect.And
Berberine hydrochloride water solubility very little, fat-soluble smaller, intestines and stomach malabsorption, cause its oral administration biaavailability low, have impact on
Its whole body therapeutic effect.Although pril medicine, jamaicin has many similar pharmacological activity, all because of biological utilisation
The low use limited to a certain extent clinically is spent, therefore finds a kind of biology profit for improving pril medicine and jamaicin
The method of both synergies of expenditure and performance will clinically have very important meaning.
The content of the invention：
The conjugates preparation method of offer formula (I) of the present invention and its as treatment hypertension, adjust blood pressure medicine in answer
With.Find that such conjugates has the pharmaceutical activity of various value by experiment in terms of pharmacology, particularly it easily absorbs
Performance is not available for pril medicine, and specifically such conjugates shows that excellent adjusting hypertension is big in zoopery
Mouse blood pressure acts on.Its main function, which is embodied in, can block all angiotensinⅡs caused by various approach and its specific receptor knot
Close, so as to weaken or block its boosting.
The conjugates of offer formula (I) of the present invention, structure are as follows：
In, R is
R1=H or C1~C18 straight or branched alkane.
1. the conjugates preparation method of formula (I), comprises the following steps：
(1) Berberine hydrochloride is dissolved in 0.01~5mol/L inorganic alkali solutions；
(2) formula (I) described respective acids compound solution, 60-70 DEG C of heating stirring are added into the solution obtained by step (1)
1-8h；
(3) by reaction product cooling crystallization, filter, be drying to obtain formula (I) described compound.
2. the inorganic alkali solution in step (1)：It is characterized in that Berberine hydrochloride is 1 with inorganic base molar ratio:1~1:3,
It is preferred that 1:1.0~1.05；Wherein inorganic base is more than one or both of sodium hydroxide, potassium hydroxide, calcium hydroxide；Solution
For 0-100% (volume ratio) methanol, ethanol, isopropanol, methanol/water, ethanol/water, preferably isopropanol/water solution, 70% ethanol
Solution.
3. respective acids compound solution refers in step (2), refer to that corresponding acid compound is dissolved in 0-100% (volume ratio) first
Alcohol, ethanol, isopropanol, methanol/water, ethanol/water, isopropanol/water solution, preferably 70% ethanol solution.
4. formula (I) compound described in claim 1 adds by common process or indirectly pharmaceutically acceptable excipient
Clinically acceptable formulation, including injection, oral agents, preferably oral formulations is made.
The conjugates of offer formula (I) of the present invention pass through common process or add pharmaceutically acceptable excipient indirectly and be made and face
Formulation is subjected on bed, is clinically used to treat hypertension, regulation blood pressure.
Specific embodiment
By following examples to better illustrate the present invention.But the present invention is not limited by following embodiments.
Embodiment 1
The synthesis of enalapril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 100ml ethanol is added, with 3mol/l sodium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 3.5g enalaprils, keeps this temperature to stir 1-5h, cooling
To room temperature, crystallization, filtering, drying, enalapril jamaicin conjugates 5.7g, yield 84% are produced.
Embodiment 2
The synthesis of enalapril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 100ml ethanol is added, with 3mol/l potassium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 3.7g enalaprils, keeps this temperature to stir 1-5h, cooling
To room temperature, crystallization, filtering, drying, enalapril jamaicin conjugates 6.1g, yield 90% are produced.ESI-MS(M++H)m/z
calcd for C20H18NO4 +337.12found 337.21；ESI-MS(M++H)m/z calcd for C18H23N2O5
348.16found 348.34。
Embodiment 3
The synthesis of Imidapril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 100ml ethanol is added, with 3mol/l sodium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 4.3g Imidaprils, keeps this temperature to stir 1-3h, cooling
To room temperature, crystallization, filtering, drying, Imidapril jamaicin conjugates 6.5g, yield 88% are produced.ESI-MS(M++H)m/z
calcd for C20H18NO4 +337.12found 337.16；ESI-MS(M++H)m/z calcd for C20H26N3O6
405.19found 405.27。
Embodiment 4
The synthesis of captopril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 150ml ethanol is added, with 3mol/l sodium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 2.3g captoprils, keeps this temperature to stir 1-4h, cooling
To room temperature, crystallization, filtering, drying, captopril jamaicin conjugates 4.9g, yield 89% are produced.ESI-MS(M++H)m/z
calcd for C20H18NO4 +337.12found 337.26；ESI-MS(M++H)m/z calcd for C9H14NO3S
217.07found 217.08。
Embodiment 5
The synthesis of zofenopril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 150ml ethanol is added, with 3mol/l sodium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 4.5g zofenoprils, keeps this temperature to stir 1-5h, cooling
To room temperature, crystallization, filtering, drying, zofenopril jamaicin conjugates 6.7g, yield 87% are produced.ESI-MS(M++H)m/z
calcd for C20H18NO4 +337.12found 337.15；ESI-MS(M++H)m/z calcd for C22H22NO4S2
429.10found 427.09。
Embodiment 6
The synthesis of Ramipril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 150ml ethanol is added, with 3mol/l sodium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 4.1g Ramiprils, keeps this temperature to stir 1-5h, cooling
To room temperature, crystallization, filtering, drying, Ramipril jamaicin conjugates 6.4g, yield 88% are produced.ESI-MS(M++H)m/z
calcd for C20H18NO4 +337.12found 337.14；ESI-MS(M++H)m/z calcd for C21H27N2O5
388.20found 388.23。
Embodiment 7
The synthesis of Perindopril jamaicin conjugates
Berberine hydrochloride 3.7g is taken, is added in 500ml three-necked flasks, 150ml ethanol is added, with 3mol/l sodium hydroxide
PH to 7-8 is adjusted, 60-70 DEG C is warming up to, stirring and dissolving, adds 4.2g Perindoprils, keeps this temperature to stir 1-5h, cooling
To room temperature, crystallization, filtering, drying, Perindopril jamaicin conjugates 5.9g, yield 87% are produced.ESI-MS(M++H)m/z
calcd for C20H18NO4 +337.12found 337.16；ESI-MS(M++H)m/z calcd for C17H27N2O5
340.20found 340.27。
The hypoglycemic effect of the pril jamaicin conjugates of embodiment 8
Hypotensive is tested：Spontaneous hypertensive rat 300 is chosen, adaptability is supported 1 week, single oral gavage administration, is used
Softron intelligence non-invasive blood pressure measuring detects rat blood pressure and heart rate.Choose rat that pressure value is 125-190mmHg be modeling into
Work(rat, the successful rat of modeling is then divided into totally 14 groups of three major types (every group 10).One kind is hypertension model (control
Group)；Two classes are respectively enalapril, Imidapril, captopril, zofenopril, Ramipril, Perindopril, jamaicin group,
Feed trial drug (1mg/Kg)；Three classes are enalapril jamaicin conjugates, Imidapril jamaicin conjugates, captopril
Jamaicin conjugates, zofenopril jamaicin conjugates, Ramipril jamaicin conjugates, Perindopril jamaicin conjugates,
Feed trial drug (8mg/Kg)；After continuously feeding 15 days, blood pressure content in blood is determined.
Hypotensive experimental result
Experimental result shows that pril jamaicin conjugates blood pressure lowering effect is substantially better than pril and jamaicin monomer
Group.
Claims (4)
- It is 1. a kind of as the pril jamaicin conjugates of formula (I), structure are as follows：It is characterized in that：In formula (I), R isR1=CH3。
- 2. pril jamaicin conjugates according to claim 1, it is characterised in that its preparation method includes following step Suddenly：(1) Berberine hydrochloride is dissolved in 0.01~5mol/L inorganic alkali solutions；(2) formula (I) described respective acids compound solution is added into the solution obtained by step (1), in 60-70 DEG C of heating stirring 1- 5h；(3) by reaction product cooling crystallization, filtering, dry, produce formula (I) described conjugates.
- 3. pril jamaicin conjugates according to claim 2, it is characterised in that：The Berberine hydrochloride and inorganic base Mol ratio is 1:1~1.05, wherein inorganic base is one in sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate Kind is two or more, and solution is 70% volume ratio ethanol solution.
- 4. pril jamaicin conjugates according to claim 2, it is characterised in that：The corresponding acid compound is dissolved in 70% volume ratio ethanol solution.
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