WO2007051314A1 - Composés curcuminoïdes dans l'inhibition de l'inhibiteur-1 de l'activateur du plasminogène - Google Patents
Composés curcuminoïdes dans l'inhibition de l'inhibiteur-1 de l'activateur du plasminogène Download PDFInfo
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- 0 CC(C1*)C(C=CC(CC(C=Cc(cc2*)cc(OC)c2O)=O)=O)=CC(OC)=C1O Chemical compound CC(C1*)C(C=CC(CC(C=Cc(cc2*)cc(OC)c2O)=O)=O)=CC(OC)=C1O 0.000 description 2
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- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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Definitions
- the invention relates generally to pharmaceutical compounds.
- the invention relates to pharmaceutical compounds derived from curcumin, which act as inhibitors of plasminogen activator inhibitor-1 (PAI-I).
- PAI-I plasminogen activator inhibitor-1
- PAI-I is a serine protease inhibitor which acts on its targets, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), thereby regulating the conversion of plasminogen to plasmin in the fibrinolytic cascade.
- uPA urokinase plasminogen activator
- tPA tissue plasminogen activator
- PAI-I has also been shown to be elevated in disease conditions such as polycystic ovary syndrome 8 , bone loss due to estrogen deficiency 9 , and thus inhibition of PAI-I may have therapeutic and prophylactic benefits for these conditions. It appears that PAI-I is normally present at low levels in circulating plasma.
- Inhibition of plasma PAI-I thus has promise as a treatment or prophylactic measure in mammals, in particular humans, for various thrombotic- related disease conditions including deep vein thrombosis, coronary artery disease, pulmonary fibrosis and polycystic ovary syndrome.
- curcumin (diferuloylmethane) is a polyphenol derived from the plant species Curcuma longa, commonly known as the spice, turmeric. Turmeric has been found to reduce plasma levels of PAI-I. 10 ' 11 Traditionally, turmeric has been used for wound healing and other medicinal purposes. [0005] Aspects of the biochemistries of uPA, tPA, and PAI-I are reasonably well known. uPA acts by cleaving a single peptide bond in plasminogen, converting it into plasmin, which proceeds to degrade a broad spectrum of proteins including fibrin, fibronectin, and laminin. Plasmin also has other effects including affecting various growth factor systems.
- uPA has been identified in extracts from human lung, colon, breast, and other tissues, including tumor tissues of various types.
- One of the natural controls for uPA activity is PAI-I, which inactivates into a latent form. This inactivation may be prevented by binding to vitronectin. PAI-I seems to inhibit receptor-bound uPA, as well as uPA in solution.
- Studies conducted on patients have shown that a high PAI- 1 level is associated with a poor prognosis in cancer patients, including high risk breast cancer patients and those with lung adenocarcinoma, suggesting that PAI-I promotes tumor growth, invasion, or metastasis.
- the present invention therefore relates to curcuminoid compounds which inhibit PAI-I.
- the compounds of the invention inhibit the inhibitory activity of PAI-I towards uPA, thereby up-regulating uPA. It is believed that these compounds also inhibit the interaction of PAI-I with tPA and with vitronectin.
- the invention thus provides according to a first aspect, for a compound of formula IA or IB:
- Q x and Q 2 can each be independently selected from optionally substituted phenyl, optionally substituted thio- phene and optionally substituted fused aryl group which optionally contains a hetero atom.
- Qi may be selected from optionally substituted phenyl, optionally substituted thiophene and optionally substituted fused aryl group which optionally contains a hetero atom
- Q 2 is selected from Ci to C 6 linear, branched, saturated, unsaturated or cyclic alkyl group.
- the invention provides for a compound of formula II:
- R 5 to R i4 are each independently selected from H, OH, SH, NO 2 , SO 2 , halogen and Ci to C 6 linear, branched, saturated, unsaturated, cyclic, bicyclic, fused, substituted, or unsubstituted alkyl or aryl group optionally containing at least one halogen and/or hetero atom; or at least two consecutive groups R 5 to Ri 4 form a substituted or un-substituted aromatic or aliphatic cycle which optionally contains at least one halogen and/or hetero atom; Xi and X 2 are each independently selected from OH, O and S; and denotes a chemical bond that is present or absent, and a pharmaceutically acceptable salt thereof.
- the invention provides for a compound of formula III:
- R 5 to R 9 are each independently selected from H, OH, SH, NO 2 , SO 2 , halogen and Ci to C 6 linear, branched, saturated, unsaturated, cyclic, bicyclic, fused, substituted, or unsubstituted alkyl or aryl group optionally containing at least one halogen and/or hetero atom; or at least two consecutive groups R 5 to Ri 4 form a substituted or un-substituted aromatic or aliphatic cycle which optionally contains at least one halogen and/or hetero atom; Xi and X 2 are each independently selected from OH, O and S; and denotes a chemical bond that is present or absent, and a pharmaceutically acceptable salt thereof.
- R i5 and Ri 6 are each independently a Ci to C 6 linear, branched, saturated, unsaturated, cyclic, fused, substituted or unsubstituted aromatic or alkyl group optionally containing at least one halogen and/or hetero atom, and a pharmaceutically acceptable salt thereof.
- the invention provides for a compound of formula VI:
- R i7 and Ri 8 are each independently selected from halogen, OH, SH and Ci to C 6 linear, branched, saturated, unsaturated, cyclic, bicyclic, fused substituted or unsubstituted alkyl or aryl group optionally containing at least one halogen and/or hetero atom, and a pharmaceutically acceptable salt thereof.
- the invention provides for a compound of formula VII:
- R 5 to R 9 are each independently selected from H, OH, SH, NO 2 , SO 2 , halogen and Ci to C 6 linear, branched, saturated, unsaturated, cyclic, bicyclic, fused, substituted, or unsubstituted alkyl or aryl group optionally containing at least one halogen and/or hetero atom; or at least two consecutive groups R 5 to R 9 form a substituted or un-substituted aromatic or aliphatic cycle which optionally contains at least one halogen and/or hetero atom.
- R 6 and Ru can be each independently selected from H and ORi 9 , wherein Ri 9 is a Ci to C 6 alkyl, alkenyl or aryl group; R 7 and R 12 can be each independently selected from OH and OR 2O , R 20 being a Ci to C 6 alkyl, alkenyl or aryl group or CR21COOR2 1 , R21 being H, an alkyl or an alkenyl group, or each independently R 6 and R 7 or Ru and Ri 2 form a cycle containing a heteroatom; and R 8 and Ri 3 can be each independently selected from H; halogen; NO 2 ; COOH; ArS; ArSO 2 ; CH 2 OR 22 , R 22 being H or an alkyl, alkenyl or arylalkyl group; CH 2 R 23 , R 23 being 1-pyrrolidinyl or 1-morpholinyl; and CH 2 N(CH 2 CH 2 ) 2 NR 24 , R 24
- the hetero atom can be O, S or N, and the halogen atom can be Cl, Br or I.
- the invention relates to any one of the compounds listed below.
- the invention also relates to pharmaceutically acceptable salts of the above compounds, as well as pharmaceutical compositions and preparations which comprise one or more of these compounds.
- the invention relates to enol forms of the compounds according to the invention.
- Salt forms of the compounds include but are not limited to sodium, potassium, calcium, magnesium salts as well as hydrochlorides, hydrobromides and sulfates. Salt forms of the compounds may also be salts of organic acids including acetic, fumaric, maleic, citric, tartaric salts, or the like. Other useful salt forms of these compounds may comprise pharmaceutically acceptable inorganic and organic bases including hydroxides, carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals, such as sodium potassium, magnesium, calcium and the like.
- Acceptable organic bases include amines, such as benzylamine, mono-, di- and trialkylamines, preferably those having alkyl groups of form 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethyl- amine, diethylamine, triethylamine, mono-, di-, and triethanolamine.
- amines such as benzylamine, mono-, di- and trialkylamines, preferably those having alkyl groups of form 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethyl- amine, diethylamine, triethylamine, mono-, di-, and triethanolamine.
- alkylene diamines containing up to 6 carbon atoms such as hexameth- ylenediamine; cyclic saturated or unsaturated bases containing up to 6 carbon atoms, including pyrrolidine, piperidine, morpholine, piperazine and their N- alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine and N-(2- hydroxyethyl)-piperidine, or pyridine.
- Quaternary salts may also be formed, such as tetralkyl forms, such as tetramethyl forms, alkyl-alkanol forms, such as methyl-triethanol or trimethyl-monoethanol forms, and cyclic ammonium salt forms, such as N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpho- linium, N,N-dimethylnnorpholinium, N-methyl-N-(2-hydroxyethyl)-morpho- linium, or N,N-dimethyl-piperidinium salt forms.
- tetralkyl forms such as tetramethyl forms
- alkyl-alkanol forms such as methyl-triethanol or trimethyl-monoethanol forms
- cyclic ammonium salt forms such as N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpho- linium, N,N-dimethylnnorpholinium, N-methyl-N
- the compounds of the present invention are useful in the treatment, inhibition, prevention or prophylaxis in a mammal, preferably in a human, of processes which involve the production and/or action of PAI-I.
- the compounds are useful in the treatment or prevention of at least some of the following: noninsulin dependent diabetes mellitus and cardiovascular disease caused by such conditions; prevention of thrombotic events associated with coronary artery and cerebrovascular disease; inhibiting the disease process involving the thrombotic and prothrombotic states which include atherosclerotic plaques, venous and arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, blood clotting disorders, pulmonary fibrosis, cerebral thrombosis, thromboembolic complications of surgery (eg.
- diseases associated with extracellular matrix accumulation including, but not limited to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovary syndrome, restenosis, renovascular disease and organ transplant rejection; malignancies and diseases associated with neoangiogenesis (such as diabetic retinopathy); cancer, including, but not limited to, breast, ovary, colon, central nervous system, kidney and prostate cancers, and as imaging agents for the identification of metastatic cancers; myelofibrosis with myeloid metaplasia by regulating stromal cell hyperplasia and increases in extracellular matrix proteins; diabetic nephropathy and renal dialysis associated with nephropathy; septicemia, obesity, insulin resistance, proliferative diseases such as psoriasis, improving coagulation homeostasis, cerebrovascular disease, microvascular disease, hypertension, dementia, osteoporosis, asthma, and
- the disease when it is cancer, it can be leukemia, non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma, kidney cancer, ovarian cancer, renal cancer, prostate cancer or breast cancer.
- the invention furthermore relates to the use of the compounds according to the invention for the preparation of medicaments which are used in the treatment or prevention of the above mentioned diseases.
- the compounds of the invention may be used in conjunction with procedures involving blood vessels, including vascular surgery, vascular graft and stent patency, organ, tissue and cell implantation and transplantation.
- the compounds in the invention may also be useful in the treatment of inflammatory diseases, septic shock and the vascular damage associated with infections.
- the compounds of the invention are useful for the treatment of blood and blood products used in dialysis, blood storage in the fluid phase, especially ex vivo platelet aggregation.
- the present compounds may also be added to human plasma during the analysis of blood chemistry in hospital settings to determine the fibrinolytic capacity thereof.
- the compounds in the present invention may also be used in combination with prothrombolytic, fibrinolytic and anti-coagulant agents.
- the compounds of the invention may also be used in conjunction with protease inhibitor-containing highly active antiretroviral therapy (HAART) for the treatment of diseases which originate from fibrinolytic impairment and hypercoagulability of HIV-I infected patients receiving such therapy.
- HAART highly active antiretroviral therapy
- a pharmaceutically effective amount of a compound herein refers to an amount of the compound which will inhibit the serine protease inhibitor PAI-I in the mammal in need thereof to a sufficient extent to provide a desirable improvement in the condition in question or provide sufficient inhibition of the serine protease inhibitor PAI-I to prevent, inhibit or limit the onset of the physiological basis for the malady or condition in question.
- Compounds of the present invention may be used to treat diseases associated with elevated levels of PAI-I as well as reduced levels of targets of PAI-I.
- diseases include but are not limited to pulmonary and cardiovascular diseases; cancers, including breast, lung, and ovarian cancers; Alzheimer's disease; and prophylaxis for prevention of the above conditions and others associated with increased PAI-I activity or levels in vivo.
- Compounds of the invention may be administered to mammalian patients in need of treatment or prophylaxis, in a therapeutically effective amount, consisting of an amount sufficient to provide prophylaxis or treatment of the disease condition in question.
- Compounds of the invention may be administered alone or in combination with one or more pharmaceutically acceptable carriers, excipients, other medicinally active components, and other pharmaceutically acceptable substances.
- Compounds of the invention may be administered orally or by injection, either intramuscular or intravenous.
- Figures 1 through 8 are graphs of PAI-I bound to vitronectin versus concentration in log ⁇ M of compounds according to the invention, as well as control compounds.
- Figures 9A-9I present dose response curves for anticancer activities of Q012095H.
- Figures 10A-10I represent dose response curves for anticancer activities of Q011030.
- Figures 11A-11I represent dose response curves for anticancer activities of Q012098C.
- the reaction mixture was cooled to r.t. and poured into a cold 5.5 N HCI (500 ml).
- the product was extracted with diethyl ether (3 x 300 ml), the extract was washed with 5.5 N HCI (2 x 100 ml) and water (3 x 150 ml) and dried over MgSO 4 .
- Vanillin (30.4 g, 200 mM) was dissolved in ethanol (200 ml). Potassium carbonate (27.2 g, 200 mM) was added and the suspension was stirred at 7O 0 C until it turned to a clear solution. Ethyl ⁇ -bromoisobutyrate (50 g, 250 mM) was added and the mixture was refluxed for 9 hrs. After cooling to r.t. the KBr was filtered off and washed with ethanol. The filtrate was rotavaped down to dryness, diethyl ether (300 ml) was added and the organic layer was washed with NaHCO 3 (5 g) and Na 2 CO 3 (5 g) dissolved in 400 ml of water.
- the crude product was subjected to chromatographic filtration through silica gel with hexane:ethyl acetate (15% to 35% gradient ethyl acetate) to give pure l,7-bis-[4-(l-ethoxycarbonyl-l- methyl-ethyloxy)-3-methoxyphenyl]-l,6-heptadiene-3,5-dione as a red oil (500 mg, 25%).
- the assay is based on using a fluorescent substrate (SpectroFluor) to measure residual uPA following inhibition of uPA by PAI-I.
- PAI-I used in the assay is pre-treated in the presence of increasing concentrations of the lead compounds to screen for any inhibitory effects on PAI-I.
- Method This assay was performed in 96 well microtiter plates. The concentrations of uPA (8 nM) and PAI-I (6 nM) used in this assay were carefully optimized when using the fluorescent substrate, SpectroFluor. Stock solutions (10 mM) of all lead compounds were prepared fresh in DMSO.
- the lead compounds do not appear to follow this pharmacological dose-response model with respect to their inhibition of PAI-I, leading to the following two issues: a) it becomes impossible to obtain IC 50 values in the absence of a sigmoidal dose response; b) it is possible that the mechanism by which these compounds interact with PAI-I may not be a typical pharmacological phenomena and/or may involve multiple mechanisms.
- uPA inhibition serves as a functional index of structural/conform- ational alterations in PAI-I produced by these small molecule inhibitors.
- Table 1 The data presented in Table 1 provide both the maximum PAI-I inhibition achieved by each compound as well as the concentration of the compound required for the inhibition.
- This assay was to screen compounds for their inhibitory effects on PAI-I, preventing the interaction of PAI-I with vitronectin. Vitronectin can stabilize PAI-I in active form, enhancing and prolonging its activity.
- This ELISA assay is based on the interaction of wildtype human PAI-I (aa 110-145) with the N-terminal somatomedin B-like (SMB) domain (aa 1-40) on vitronectin.
- PAI-I was allowed to bind to vitronectin coated plates.
- the bound PAI-I was detected with a HRP-conjugated polyclonal goat anti-human PAI-I antibody using a standard ELISA method.
- PAI-I was pre-incubated with various concentrations of the lead compounds before being allowed to bind to vitronectin.
- Vitronectin consists of several domains of which the N-terminal amino acids 1-40 portion comprises of a somatomedin B like (SMB) domain which has been proposed to encompass a high-affinity PAI-I binding site. 13 In addition, there are reports regarding additional low-affinity PAI-I binding sites on the C-terminal of vitronectin (aa K348-370). 14 ' 15 It may be reasonably expected that PAI-I binding to these secondary low-affinity sites will not be measured in ELISA method due to extensive washing after the PAI-1/vitronectin incubation.
- SMB somatomedin B like
- the mAb was able to significantly block the interaction of the pretreated PAI-I with uPA (functional assay) as well as vitronectin.
- Table 1 below provides a summary of data obtained in the assays described above.
- PAI-I Inhibition by Curcuminoid Compounds according to the invention Data from Bioactivity Assays of PAI-I Interaction with u PA, tPA or Vitronectin
- NCI National Cancer Institute
- cell suspensions of the human cancer cell lines are diluted according to the particular cell type and their expected target cell density (5000-40,000 cells per well). 100 ⁇ L of the cell suspension is added to each well in a 96-well microtiter plate. Inoculates are allowed a preincubation period of 24h at 37°C for attachment and stabilization. Dilutions of the test compound at twice the intended concentration (in DMSO) are added at time zero (TO) in 100 ⁇ L aliquots to the microtiter plate wells. Usually, the test compounds are evaluated in five dilutions ranging from 10 nM to 100 ⁇ M. Incubations are carried out for 48h in 5% CO 2 and 100% humidity. Cell proliferation is then measured by a protein stain assay using sulforhodamine B. An ELISA plate reader is used to obtain optical densities and the following special concentration parameters are calculated:
- the GI50 value is a measure of the compound's ability to inhibit growth of cancer cells by 50% as compared to a "control" in the absence of the test compound.
- the NCI renamed the pharmacokinetic term IC50, the concentration that causes 50% growth inhibition, as the GI50 value since it incorporates a correction for the cell count at time zero when the cells are first added to the microtiter plate wells.
- the optical density of the test well of cancer cells after a 48 hour period of exposure to the compound is "T", which is a factor in the parameter TGI (total growth inhibition) which measures a compound's cytostatic ability.
- the LC50 half lethal concentration
- the control optical density is not factored into the calculation of the LC50.
- results Compounds according to the invention including Q012095H, Q011030 and Q012098C inhibited growth and proliferation of human primary cell-lines representing various cancers as can be seen in Table 2 below.
- Dose response curves obtained for Q012095, Q011030 and Q012098C are outlined in Figures 9A-9I, 10A-10I and 11A-11I, respectively.
- Q012095H had cytotoxic effects on cancer cell-lines representing leukemia, melanoma and cancers of the CNS, colon, kidney, ovary and breast.
- Other compounds had mainly cytostatic effects with a preferred biological response pattern toward leukemias, melanomas, central nervous system (CNS) and breast cancers.
- GI50 range for all cell-lines in a disease subpanel is provided.
- GI50, TGI and LC50 data of the most sensitive cell-line in each disease subpanel is provided.
- the precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition being treated, the mode of administration and the particular active substance employed.
- the compounds may be administered by any conventional route, in particular enterally, preferably orally in the form of tablets or capsules.
- Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of atherosclerosis and sequelae (angina pectoris, myocardial infarction, arrhythmias, heart failure, kidney failure, stroke, peripheral arterial occlusion, and related disease states). These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
- atherosclerosis and sequelae angina pectoris, myocardial infarction, arrhythmias, heart failure, kidney failure, stroke, peripheral arterial occlusion, and related disease states.
- any suitable carrier known to the art can be used to prepare the pharmaceutical compositions.
- the carrier may be a solid, liquid or mixture of a solid and a liquid.
- Solid compositions include powders, tablets and capsules.
- a solid carrier can be one or more substances which may also act as a flavoring agent, lubricant, solubilizer, suspending agent, binder, or tablet disintegrant.
- the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
- Encapsulating materials may also be employed with the compounds of this invention, and the term "composition" is intended to include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers. Cachets may also be used in the delivery of the anti-atherosclerotic medicament of this invention.
- Sterile liquid compositions include solutions, suspension, emulsions, syrups and elixirs.
- the compounds of this invention may be dissolved or suspended in the pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
- the liquid carrier is one suitable for parental injection.
- suitable organic solvents such as propylene glycol or polyethylene glycol.
- dispersions of the finely divided compounds can be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, such as arachis oil.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by intramuscular, intraperitoneal or subcutaneous injection. In many instances a liquid composition form may be used instead of the preferred solid oral method of administration.
- unit dosage forms of the compounds for standard administration regimes.
- the composition can be subdivided readily into smaller doses at the physician's direction.
- unit dosages may be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.
- the active compound present in these unit dosage forms of the composition may be present in an amount of from about one gram to about fifteen grams or more, for single or multiple daily administration, according to the particular need of the patient.
- the daily dose of active compound will vary depending upon the route of administration, the size, age and sex of the patient, the severity of the disease state, and the response to the therapy as traced by blood analysis and the patient's recovery rate.
- the blood levels of PAI-I and the patient's symptomatic relief analysis may be used to determine whether a larger dose is indicated.
- the projected daily dose for both human and veterinary use will be from about 25 to about 200 milligrams/kilogram per day, and more usually, from about 50 to 100 milligrams/kilogram per day.
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Abstract
La présente invention porte sur des composés pharmaceutiques analogues de la curcumine [bis-l,7-(4-hydroxy-3-méthoxyphényl)-hepta-l,6-diène-3,5-dione] qui agissent en tant qu'inhibiteurs de l'inhibiteur-1 de l'activateur du plasminogène (PAI-1) et peuvent donc être employés dans le traitement prophylactique et thérapeutique de divers états pathologiques liés à la thrombose, incluant la thrombose veineuse profonde, la maladie coronarienne, la fibrose pulmonaire et le syndrome des ovaires polykystiques.
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