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WO2000071115A1 - Compose anthypertensif produit a partir de caesalpinia brasiliensis - Google Patents

Compose anthypertensif produit a partir de caesalpinia brasiliensis Download PDF

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Publication number
WO2000071115A1
WO2000071115A1 PCT/US2000/013880 US0013880W WO0071115A1 WO 2000071115 A1 WO2000071115 A1 WO 2000071115A1 US 0013880 W US0013880 W US 0013880W WO 0071115 A1 WO0071115 A1 WO 0071115A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
blood pressure
hypertension
leachate
haematoxylin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2000/013880
Other languages
English (en)
Inventor
Noel L. Owen
Steven Glen Wood
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Brigham Young University
Original Assignee
Brigham Young University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Brigham Young University filed Critical Brigham Young University
Priority to US09/979,376 priority Critical patent/US6569891B1/en
Priority to AU52771/00A priority patent/AU5277100A/en
Publication of WO2000071115A1 publication Critical patent/WO2000071115A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • This invention relates to a composition and methods for treating hypertension. More particularly, the invention relates to a compound purified from a water extract of Palo de Brazil ⁇ Caesalpinia brasiliensis) , methods of making, and methods of using for treating hypertension.
  • Blood pressure is measured as systolic (pressure of the blood in the arteries when the heart beats) and diastolic (pressure between heartbeats) .
  • High blood pressure, or hypertension is generally considered to be a pressure greater than or equal to 140 systolic and 90 diastolic (measured in millimeters of mercury) .
  • High blood pressure is a serious but modifiable risk factor for heart disease and stroke.
  • High blood pressure occurs when the body's smaller blood vessels (known as the arterioles) narrow, which causes the blood to exert excessive pressure against the vessel walls.
  • the heart must therefore work harder to maintain this higher pressure.
  • the body can tolerate increased blood pressure for months and even years, eventually the heart can enlarge and be damaged (a condition called hypertrophy) , and injury to blood vessels in the kidneys, the brain, and the eyes can occur.
  • Hypertension has been aptly called a silent killer, because it usually produces no symptoms.
  • Hypertension is referred to as essential, or primary, when the physician is unable to identify a specific cause. This is by far the most common type of high blood pressure, occurring in up to 95% of patients. Genetic factors appear to play a major role in essential hypertension. Several genetic factors, however, are probably involved that regulate important physiologic processes and interact with environmental influences to produce essential high blood pressure. Experts appear to have located the chromosomes (13 and 18) that house the genes responsible for blood pressure regulation, although pinning down the range of specific genes involved in hypertension is more difficult. Secondary hypertension has recognizable causes, which are usually treatable or reversible. Causes of secondary hypertension include certain medical conditions, medications, alcohol, caffeine, and smoking.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Such drugs include aspirin, ibuprofen (Advil, Motrin, Rufen) , indomethacin (Indocin) , naproxen (Anaprox, Naprosyn, Aleve) , and many others. Of these drugs, aspirin appears to have the least detrimental effect on blood pressure.
  • Temporary high blood pressure can also result from stress, exercise, and long-term consumption of large amounts of licorice. Exposure to even low lead levels also appears to cause hypertension in adults.
  • mobile phone use triggers a temporary rise in blood pressure, which may be harmful in people with existing hypertension. Only 27% of American adults with high blood pressure have it under control; about the same percentage is on medications but not controlling their blood pressure, and nearly 15% of those with hypertension are not on medication at all. Aggressive drug treatment of long-term high blood pressure can significantly reduce the incidence of death from heart disease and other causes in both men and women. In people with diabetes, controlling both blood pressure and blood glucose levels prevents serious complications of that disease.
  • beta-blockers which block the effects of adrenaline, thus easing the heart's pumping action and widening blood vessels
  • vasodilators which expand blood vessels
  • calcium channel blockers which help decrease the contractions of the heart and widen blood vessels.
  • beta-blockers or diuretics which are inexpensive, safe, and effective, for most people with hypertension who have no complicating problems. Certain individuals, however, may have special requirements that call for specific drugs or combinations. All drugs used for hypertension have side effects, some distressing, and on-going compliance is difficult.
  • Plants have provided mankind with a valuable resource of unique and novel chemical compounds that have shown a wide variety of biological activities and have been used to treat a myriad of ailments. Ethnobotanical sources, such as modern and ancient herbals or carefully conducted - A - interviews with indigenous healers and native shaman, have proven to be very effective means of identifying those plants of greatest medicinal importance. Some representative compounds discovered using documented ethnobotanical methodology include digitoxin (cardiac anti- arrhythmetic) , turbocurarine (muscle relaxant) , quinine (anti-malarial), and morphine (analgesic).
  • digitoxin cardiac anti- arrhythmetic
  • turbocurarine muscle relaxant
  • quinine anti-malarial
  • morphine analgesic
  • the aqueous leachate is from heartwood of Caesalpinia brasiliensis .
  • FIG. 1 shows an HPLC chromatogram of a water extract of Caesalpinia brasiliensis
  • FIG. 2 shows the antihypertensive activities of fractions identified in the HPLC trace of FIG. 1 as compared to controls.
  • FIG. 3 shows a 13 C spectrum of the composition of the present invention.
  • FIG. 4 shows a DEPT spectrum of the composition of the present invention.
  • FIG. 5 shows a HETCOR spectrum of the composition of the present invention.
  • FIG. 6 shows a 1 H spectrum of the composition of the present invention.
  • FIG. 7 shows a COSY spectrum of the composition of the present invention.
  • FIG. 8 shows an HMBC spectrum of the composition of the present invention.
  • FIG. 9 shows the chemical structure of the composition of the present invention.
  • FIG. 10 shows the chemical structure of haematoxylin, a primary component of fraction B of FIG. 1.
  • an effective amount means an amount of a drug or pharmacologically active agent that is nontoxic but sufficient to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
  • An effective amount of the compound of the present invention is an amount sufficient to reduce the systolic blood pressure of an individual to a selected level.
  • purified means separated from other molecules to the extent that the compound of the present invention appears as a single peak when analyzed by HPLC on a C-8 reverse phase Rainin Microsorb-mv (5 ⁇ m particle size, 100 A pore size) analytical column (4.6 x 250 mm), using HPLC grade water and acetonitrile, both acidified with 0.1% trifluoroacetic acid, as a sample solvent system, and at a 10% acetonitrile isocratic gradient for elution.
  • substantially free of haematoxylin means that no peak corresponding to haematoxylin is present when analyzed by HPLC on a C-8 reverse phase Rainin Microsorb-mv (5 ⁇ m particle size, 100 A pore size) analytical column (4.6 x 250 mm), using HPLC grade water and acetonitrile, both acidified with 0.1% trifluoroacetic acid, as a sample solvent system, and at a 10% acetonitrile isocratic gradient for elution.
  • administering means delivering the composition to the individual being treated such that the composition exerts its pharmacological effect of reducing blood pressure.
  • the composition is preferably administered to the individual by systemic administration, typically by oral administration, for example, as a powder, capsule, tablet, or liquid.
  • Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like. If desired, minor amounts of auxiliary substances such as buffers and the like can be added.
  • such a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers. Those skilled in the art will be able to select the best method of administration, for example as a powder, capsule, tablet, or liquid, using the information set forth herein.
  • COSY means correlation spectroscopy. COSY is used for determining proton-proton scalar coupling. This technique produces a two-dimensional spectrum with both the axis and ordinate labeled by the chemical shift of the observed nucleus (most often a proton) . Cross peaks, or off-diagonal peaks, indicate the presence of scalar coupling between the nuclei whose chemical shifts determine the location of the cross peak. The peaks along the diagonal reproduce the one-dimensional spectrum.
  • DEPT means distortionless enhancement by polarization transfer. DEPT allows for the identification of the degree of saturation of each carbon.
  • HETCOR means heteronuclear correlation spectroscopy. HETCOR detects proton-carbon scalar coupling and identifies individual proton carbon attachments.
  • HMBC multiple bond heteronuclear multiple quantum coherence
  • Example 1 About 300 g of the heartwood of C. brasiliensis, purchased from Pharmacia Gonzalez (Ponce, Puerto Rico) was ground to a find powder in a Wiley mill and exhaustively extracted with water. Removal of the water yielded about 10 g of solid residue.
  • Analytical HPLC separation of this heartwood water extract was performed using a Rainin HPLC system with Dynamax pumps (63.5 cm (25 in.) head size) and Dynamax UV/VIS detector.
  • a C-8 reverse phase Rainin Microsorb-mv (5 ⁇ m particle size, 100 A pore size) analytical column (4.6 x 250 mm) with guard was used.
  • Samples were prepared by dissolving 100 mg of powdered extract in 3 ml of solvent, allowing the solution to stand for 2.5 hours, drying a 200 ⁇ l aliquot of the solution, and then dissolving the dried aliquot in 1 ml of water and immediately injecting 20 ⁇ l of the resulting solution into the analytical HPLC system at a 10% acetonitrile isocratic gradient.
  • This analytical HPLC separation revealed several major peaks and many minor peaks (FIG. 1) . The major peaks were labeled A, B, C, D, and E.
  • Example 2 The crude extract and HPLC fractions prepared according to the procedure of Example 1 (with a preparative-scale (21.4 x 250 mm) column), were tested for antihypertensive activity by adding the sample to be tested at a concentration of 100 ⁇ g/ml to the drinking water of hypertensive Sprague-Dawley rats. After 36 hours, systolic blood pressures were measured with a Harvard tail cuff apparatus attached to a Beckman R511A recorder.
  • FIG. 2 shows the results of these tests, wherein “Normal” represents the blood pressure of non-hypertensive rats, “Water” represents the blood pressure of hypertensive rats given water without extract, “Crude” represents the blood pressure of hypertensive rats given the crude (unfractionated) extract, and "A,” “B,” and “Back Peaks” represent the respective blood pressure measurements obtained from rats given HPLC fraction A, B, or combined peaks C, D, and E.
  • Peak A reduced systolic blood pressure about 35%, thus bringing it into the normal range of 110-120 mm Hg.
  • Peak B showed moderate activity, yielding about a 12% reduction in systolic blood pressure.
  • the combined peaks C, D, and E (“Back Peaks") exhibited little activity. Peaks B and D were identified as haematoxylin and brazilin, respectively.
  • Example 3 mass spectral analysis of Palo A, purified according to the procedure of Examples 1 and 2, was performed. Mass spectral data were obtained on a Jeol SX 102A double focusing reverse geometry high resolution mass spectrometer using FAB-Xenon methodology in a standard sodiated thioglycerol matrix and standard software. Mass spectral analysis of Palo A showed the molecular ion [M+l] + to be at 601 mass units. Under high resolution conditions, this mass of 600 corresponds to a molecular formula of C 32 H 24 0 12 (-1.1/-0.7). This formula yields an index of unsaturation of 21. A second peak of 583 mass units, corresponding to a possible loss of a hydroxyl group, was also observed. Several other large peaks were also visible, indicating the presence of many degradation fragments .
  • NMR spectral data were obtained at ambient temperature in DMSO-d 6 on a Varian VXR-500S spectrometer using a standard 5 mm NMR tube. Standard Varian pulse sequences, software, and parameters were used. Computer estimations of 13 C shift data were obtained using ACD/CNMR datatables software, version 2.51.
  • a 1 H spectrum in DMSO-d 6 showed 6 aromatic protons, 1 vinylic proton, and 9 aliphatic protons (FIG. 6) .
  • 6 phenolic hydroxyl groups resonating at 9.01, 8.71, 8.58, 8.44, 8.29, and 8.24 ppm and two hydroxyl groups at 6.93 and 5.38 ppm were also identified.
  • a summary of non-exchangeable resonances and their respective couplings is shown in Table 2. Cross peaks as seen in the COSY spectrum confirmed all observed 1 H couplings (FIG. 7) .
  • This carbon is at 115.0 ppm.
  • Palo A The structure of Palo A is shown in FIG. 9. It appears to be a dimer-like compound formed from haematoxylin and a closely related compound. It has a unique acetal linkage between the two structural units.
  • the structure of haematoxylin is shown in FIG. 10.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne un composé isolé à partir d'un produit de lixiviation aqueux provenant du bois de coeur du « Palo de Brazil » Caesalpinia Brasiliensis, ce composé possédant une activité antihypertensive. On a isolé le composé par chromatographie en phase liquide à haute pression et en phase inverse pour le séparer de l'hématoxyline qui est co-extraite avec le nouveau composé. Le composé s'est révélé efficace pour faire baisser la pression sanguine de rats de Sprague-Dawley hypertendus.
PCT/US2000/013880 1999-05-21 2000-05-19 Compose anthypertensif produit a partir de caesalpinia brasiliensis Ceased WO2000071115A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/979,376 US6569891B1 (en) 2000-05-19 2000-05-19 Antihypertensive compound from Caesalpinia brasiliensis
AU52771/00A AU5277100A (en) 1999-05-21 2000-05-19 Antihypertensive compound from caesalpinia brasiliensis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13541699P 1999-05-21 1999-05-21
US60/135,416 1999-05-21

Publications (1)

Publication Number Publication Date
WO2000071115A1 true WO2000071115A1 (fr) 2000-11-30

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Application Number Title Priority Date Filing Date
PCT/US2000/013880 Ceased WO2000071115A1 (fr) 1999-05-21 2000-05-19 Compose anthypertensif produit a partir de caesalpinia brasiliensis

Country Status (2)

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AU (1) AU5277100A (fr)
WO (1) WO2000071115A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TOKES A.L. ET AL.: "Absolute configuration and total synthesis of (-)-cabenegrin A-1", TETRAHEDRON,, vol. 55, July 1999 (1999-07-01), pages 9283 - 9296, XP002930315 *

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AU5277100A (en) 2000-12-12

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