Classifications

• • 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
  • A61K31/275—Nitriles; Isonitriles
  • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to a therapeutic method for treating or preventing a disease or condition of platelet aggregation in a subject wherein the method includes administering a pharmaceutically effective amount of a compound that inhibits platelet aggregation and specifically, collagen-induced platelet aggregation.
• Heart disease a common cause of death in today's society, is often a result of ischemic syndromes that are produced by atherosclerosis and arteriosclerosis including myocardial infarction, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and other cardiovascular devices.
• ischemic syndromes that are produced by atherosclerosis and arteriosclerosis including myocardial infarction, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and other cardiovascular devices.
• These syndromes represent a variety of
• BTK Bruton's tyrosine kinase
• PTKs protein tyrosine kinases
• BTK participates in signal transduction pathways initiated by the binding of a variety of extracellular ligands to their cell surface receptors. Following ligand binding of B cell antigen receptors (BCR), BTK activation by the concerted actions of the PTKs Lyn and Syk (Kurosaki, T. (1997) Curr Opin. Immunol. 9, 309-318) is required for induction of phospholipase C- ⁇ 2 mediated calcium mobilization (Kurosaki, T. (1997) Curr Opin. Immunol. 9, 309-318).
• BCR B cell antigen receptors
• BTK participates in the collagen receptor glycoprotein VI (GP NI)-Fc receptor gamma (FcR ⁇ ) chain coupled signaling.
• Tyrosine phosphorylation of the immune-receptor tyrosine based activation motif (IT AM) of the FcR ⁇ chain leads to phosphorylation and activation of phosphoslipase C gamma 2 (PLC ⁇ 2).
• Activated PLC ⁇ 2 converts PI-4,5-bisphospate (PIP2) to inositol triphosphate (IP3), leading to intracellular calcium mobilization.
• throombin induced platelet aggregation describes platelet aggregation in response to the enzyme thrombin, which is formed in blood from prothrombin.
• Collagen induced platelet aggregation describes platelet aggregation in response to the protein collagen.
• this invention in one aspect, relates to a method for inhibiting platelet aggregation by administering an effective amount of a compound of the formula:
• the invention in a second aspect, relates to a method of preventing or treating a disease or condition of platelet aggregation in a subject comprising administering to a subject an effective amount of a compound of the formula:
• Figures la- If are graphs showing experimental results for Example 1, including the platelet aggregation effects of collagen at 5 micrograms per milliliter for 20 minutes (Fig. la) and 24 hours (Fig. Id) and collagen at 2 micrograms per milliliter for 20 minutes (Fig. lb) and 24 hours (Fig. le) and thrombin for 20 minutes (Fig. lc) and 24 hours (Fig. If).
• Figure 2 is a graph showing experimental results for Example 2, including the selective, dose-dependent inhibition of collagen-induced platelet aggregation by LFM- A 13.
• platelet aggregation is meant the clumping together of platelets or red blood cells.
• inhibiting platelet aggregation includes slowing platelet aggregation, as well as completely eliminating and/or preventing platelet aggregation.
• inhibiting platelet function includes decreasing platelet function, as well as completely eliminating and/or preventing the platelet function.
• Conditions of platelet aggregation include, but are not limited to, embolus formation, thrombolytic complications, disseminated intravascular comgelopathy, thrombosis, coronary heart disease, thromboernbolic complications, myocardial infarction, restenosis, and atrial thrombosis formation in atrial fibrillation, chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and chronic exposure to cardiovascular devices.
• thromboembolism and reocclsion include platelet aggregation in response to the enzyme thrombin, which is formed in blood from prothrombin.
• Collagen induced platelet aggregation includes platelet aggregation in response to the protein collagen.
• contacting is meant an instance of exposure of at least one cell (e.g., a neural cell, a stem cell, a cardiac cell) to an agent (e.g., a compound that inhibits platelet aggregation and specifically, collagen induced platelet aggregation).
• an agent e.g., a compound that inhibits platelet aggregation and specifically, collagen induced platelet aggregation.
• the term “subject” is meant an individual.
• the subject is a mammal such as a primate, and more preferably, a human.
• the "subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.).
• terapéuticaally effective amount means the amount needed to achieve the desired result or results (treating or preventing platelet aggregation).
• an "effective amount” can vary for the various compounds that inhibit platelet aggregation and specifically, collagen induced platelet aggregation used in the invention.
• One skilled in the art can readily assess the potency of the compounds.
• pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected bicyclic compound without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
• a preferred compound for use in the present invention is ⁇ -Cyano- ⁇ - hydroxy- ⁇ -methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13), and is structurally shown below (formula I):
• salts of ⁇ -Cyano- ⁇ -hydroxy- ⁇ -methyl- N-(2,5-dibromophenyl)-propenamide may be used in the present invention.
• acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, including, but not limited to, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ - glycerophosphate.
• Suitable inorganic salts may also be formed, including, but not limited to, hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
• Acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
• the compound of the present invention is readily synthesized using techniques generally known to synthetic organic chemists. Suitable experimental methods for making and derivatizing the compound is described in PCT Published Application No. WO99/54286 to Uckun et al., the disclosure of which is hereby incorporated by reference.
• the therapeutic method included herewith is useful for treating or preventing a condition of platelet aggregation, in a subject comprising administering a pharmaceutically effective amount of a compound or composition that inhibits BTK and that inhibits platelet aggregation, specifically, collagen induced platelet aggregation.
• the condition of platelet aggregation includes cardiovascular, hematopoietic and cerbrovascular diseases such as, but not limited to, embolus formation, thrombolytic complications, disseminated intravascular comgelopathy, thrombosis, coronary heart disease, thromboembolic complications, myocardial infarction, restenosis, or atrial thrombosis formation in atrial fibrillation.
• cardiovascular, hematopoietic and cerbrovascular diseases such as, but not limited to, embolus formation, thrombolytic complications, disseminated intravascular comgelopathy, thrombosis, coronary heart disease, thromboembolic complications, myocardial infarction, restenosis, or atrial thrombosis formation in atrial fibrillation.
• embolus formation such as embolus formation, embolus formation, thrombolytic complications, disseminated intravascular comgelopathy, thrombosis, coronary heart disease, thromboembolic complications, my
• the methods include contacting the cells with such compound or compositions, or administering to the subject a therapeutically effective amount of these compound or compositions.
• the cells are part of the blood and immune system including: red blood cell, megakaryocytes, macrophages (e.g. monocytes, connective tissue macrophages, Langerhans cells, osteoclasts, dendritic cells, microglial cells), neutrophils, eosinophils, basophils, mast cells, T lymphocytes (e.g. helper T cells, suppressor T cells, killer T cells), B lymphocytes (e.g. IgM, IgG, IgA, IgE), killer cell, and stem cells and committed progenitors for the blood and immune system.
• macrophages e.g. monocytes, connective tissue macrophages, Langerhans cells, osteoclasts, dendritic cells, microglial cells
• neutrophils eosinophils, basophils, mast cells
• the cells are contractile cells such as skeletal muscle cells (e.g. red, white, intermediate, muscle spindle, satellite cells), heart muscle cells (e.g. ordinary, nodal, Purkinje fiber), smooth muscle cells, and myoepithelial cells.
• skeletal muscle cells e.g. red, white, intermediate, muscle spindle, satellite cells
• heart muscle cells e.g. ordinary, nodal, Purkinje fiber
• smooth muscle cells e.g. ordinary, nodal, Purkinje fiber
• myoepithelial cells e.g. skeletal muscle cells (e.g. red, white, intermediate, muscle spindle, satellite cells), heart muscle cells (e.g. ordinary, nodal, Purkinje fiber), smooth muscle cells, and myoepithelial cells.
• the method would result in at least a 10% reduction in collagen-induced platelet aggregation, including, for example, 15%, 20%, 25%, 30%, 40%, 50%,
• the method would result in at least a 10% reduction in collagen-induced intracellular calcium mobilization including, for example, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%.
• the method would result in at least a 10% reduction in the level of phosphorylated PLCg 2 including, for example, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%.
• the reduction can be measured, for example, by comparing the optical impedence in a chronology platelet aggregometer. Any other known measurement method may also be used. For example, (1) upon collagen stimulation, the level of collagen-induced intracellular calcium mobilization increases over time and so the measurement may include measuring the level of collagen- induced intracellular calcium or (2) upon collagen stimulation, the level of phosphorylated PLCg 2 increases over time and so the measurement may include measuring the level of phosphorylated PLCg 2.
• the cells can be contacted in vitro, for example, by adding the compound to the culture medium (by continuous infusion, by bolus delivery, or by changing the medium to a medium that contains the agent) or by adding the agent to the extracellular fluid in vivo (by local delivery, systemic delivery, inhalation, intravenous injection, bolus delivery, or continuous infusion).
• contact with a cell or population of cells is determined by the time the compound is present at physiologically effective levels or at presumed physiologically effective levels in the medium or extracellular fluid bathing the cell or cells.
• the duration of contact is 1 -96 hours, and more preferably, for 24 hours, but such time would vary based on the half life of the compound and could be optimized by one skilled in the art using routine experimentation.
• the compound useful in the present invention can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient or a domestic animal in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intranassalyy by inhalation, intravenous, intramuscular, topical or subcutaneous routes.
• the compound of the present invention can also be administered using gene therapy methods of delivery. See, e.g., U.S. Patent No. 5,399,346, which is incorporated by reference in its entirety.
• gene therapy methods of delivery See, e.g., U.S. Patent No. 5,399,346, which is incorporated by reference in its entirety.
• primary cells transfected with the gene for the compound of the present invention can additionally be transfected with tissue specific promoters to target specific organs, tissue, grafts, tumors, or cells.
• the present compound may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
• a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
• the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1 % of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
• the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be
• the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
• a liquid carrier such as a vegetable oil or a polyethylene glycol.
• any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
• the active compound may be incorporated into sustained-release preparations and devices.
• the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
• Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
• the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
• the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
• the present compound may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
• a dermatologically acceptable carrier which may be a solid or a liquid.
• Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
• Useful liquid carriers include water, hydroxyalkyls or glycols or water-alcohol/glycol blends, in which the present compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
• Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
• the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
• Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
• useful dermatological compositions which can be used to deliver the compound of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
• Useful dosages of the compound can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
• the concentration of the compound(s) of formula I in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
• concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%>, preferably about 0.5-2.5 wt-%.
• the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
• the dosage of the compound varies depending on the target cell, tumor, tissue, graft, or organ. In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
• the compound may conveniently be administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
• the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.0005 to about 300 ⁇ M, preferably, about .001 to 100 ⁇ M, more preferably, about 1 to about 100 ⁇ M. This may be achieved, for example, by the intravenous injection of a concentration of the active ingredient, optionally in saline, or orally administered as a bolus. Desirable blood levels may be maintained by continuous infusion to provide about 0.0005-50.0 mg/kg/hr or by intermittent infusions containing about 0.004-150 mg/kg of the active ingredient(s).
• the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
• the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
• An administration regimen could include long-term, daily treatment.
• long-term is meant at least two weeks and preferably, several weeks, months, or years of duration. Necessary modifications in this dosage range may be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. See Remington's Pharmaceutical Sciences (Martin, E.W., ed. 4), Mack Publishing Co., Easton, PA. The dosage can also be adjusted by the individual physician in the event of any complication.
• Example 1 Platelets treated with lOO ⁇ M LFM-A13 for 20 minutes or 24 hours and were stimulated with 0.1 U/ml thrombin or lO ⁇ g/ml collagen. Platelet aggregation with respect to control was monitored in a Chronolog Model 560 Dual Chamber Platelet Aggregometer. LFM-A13 significantly reduced the platelet response to high and low doses of collagen (as shown in Fig. la, Id and Fig. lb, le). No significant effect with LFM-A13 was noted on the thrombin- induced platelet aggregation (shown in Fig. lc, If). Platelets treated with LFM-A13 for 24 hours responded in the same manner as those treated with the compound for 20 minutes. The results are shown on Fig. 1.
• Platelets treated with varying concentration s of LFM-A13 were stimulated with 2 and ⁇ g/ml collagen and 0.1 U/ml thrombin. Platelet aggregation with respect to control was monitored in a Chronolog Model 560 Dual Chamber Platelet Aggregometer. LFM-A13 significantly reduced the platelet response to 2 ⁇ g/ml collagen with an IC 50 value of 2.78 ⁇ M and the platelet response to 5 ⁇ g/ml collagen with an IC 50 value of 66.1 ⁇ M. No significant effect was noted on the thrombin-induced platelet aggregatory response. The results are charted on Fig. 2.
• Example 3 Platelets were incubated with 100 ⁇ M LFM-A13 or DMSO for 30 minutes at 37 degrees C and then stimulated with 2 ⁇ g/ml collagen. The samples were subjected to immunoprecipiation utilizing antibodies raised against BTK. The BTK immune complexes were subjected to immune kinase assays. Additional BTK immune complexes were collected, boiled in 2x SDS reducing sample buffer, fractionated on 8% polyacrylamide gels, transferred to PNDF membranes and examined for the presence of BTK by western blotting analysis. The enzymatic activity (activity index) of BTK was estimated by comparing the autophosphorylation (PIU) to the relative density of the protein bands in densitometric scanning units (DSU). The results are shown in Table 1 and indicate that LFM-A13 significantly inhibited BTK kinase activity.
• POU autophosphorylation
• Platelets were incubated with 100 ⁇ M LFM-A13 or DMSO for 30 minutes at 37 degrees C and then stimulated with 2 ⁇ g/ml collagen.
• the samples were subjected to immunoprecipiation utilizing antibodies raised against PLCg2 and immunoblotted against antibodies against phosphotyrosine.
• the membrane was stripped and reprobed with antibodies raised against PLCg2.
• An increase in the level of phosphorylated PLCg2 was seen between 30 and 45 seconds following collagen stimulation. No phosphorylation of PLCg2 was noted with LFM-A13 treatment.
• LFM-A13 inhibited collagen induced PLCg2 tyrosine phosphorylation.
• Platelets were loaded with 3 mM fura-3 (Molecular Probes, Eugene Oregon) for 15 minutes at 37 degrees C. Following a short wash (10 minutes, 3000 rpm), the platelets were resuspended in Hepes buffer (lxlO 8 cells/ml) and stimulated with collagen (20 ⁇ g/ml) in the presence or absence of 100 ⁇ M LFM-A13. The changes in fluorescence were monitered on a spectrofluorimeter. LFM-A13 significantly reduced (inhibited) collagen-induced calcium mobilization.
• Platelets (lxlO 9 ) were incubated with and without 100 ⁇ M LFM-A13 for 30 minutes at 37 degrees C. Platelets were stimulated at 37 degrees C with 2 ⁇ g/ml collagen for various times. Activation was stopped by the addition of ice cold 20%) perchloric acid. The amount of inositol 1,4,5-triphosphate production was measured using a detection kit from Amersham. The results show that LFM-A13 inhibited collagen-stimulated PI-PLC activity. The results are shown in Table 2 below.

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  • 2000-11-29 EP EP00992536A patent/EP1235567A2/de not_active Withdrawn
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  • 2000-11-29 CA CA002390857A patent/CA2390857A1/en not_active Abandoned
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