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WO2000066577A2 - Ligands de thromboxane sans effets secondaires de coagulation du sang - Google Patents

Ligands de thromboxane sans effets secondaires de coagulation du sang Download PDF

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Publication number
WO2000066577A2
WO2000066577A2 PCT/US2000/011760 US0011760W WO0066577A2 WO 2000066577 A2 WO2000066577 A2 WO 2000066577A2 US 0011760 W US0011760 W US 0011760W WO 0066577 A2 WO0066577 A2 WO 0066577A2
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group
radical
compound
hydroxy
radicals
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WO2000066577A3 (fr
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Robert M. Burk
Achim H. Krauss
David F. Woodward
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Allergan Sales LLC
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Allergan Sales LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • 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
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • Patent No. 5,516,791 which is a divisional of U.S. Patent Application Serial No.
  • the present invention relates to thromboxane receptor ligands including a carboxylic acid group derivative, which do not cause blood clotting.
  • the thromboxane receptor ligands are bicyclic carboxylic acid derivatives wherein said bicyclic rings may be hydrocarbyl or oxohydrocarbyl, e.g. 7-[carboxyalkyl or alkenyl]-6-[alkyl or alkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octanes and derivatives thereof.
  • hydroxyl, nitro, amino, amido, azido, oxime, thiol, ether and thiol ether derivatives of said carboxylic acid group are contemplated.
  • 7-[6-carboxy-2-hexenyl]-6-[3-hydroxy-l-octenyl] 3-oxo-2,4-dioxobicyclo-[3.2.1] octane derivatives are disclosed. These compounds are useful as thromboxane agonists and antagonists. These compounds are also useful as ocular hypotensives.
  • Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
  • Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
  • the underlying causes of primary glaucoma are not yet known.
  • the increased intraocular tension is due to the obstruction of aqueous humor outflow.
  • chronic open-angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
  • acute or chronic angle-closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
  • Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
  • Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates.
  • Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
  • glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
  • topical ⁇ -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
  • U.S. Patents have recently issued which relate to thromboxane ligands and/or treating hemorrhaging.
  • U.S. Patents 5,128,322; 5,128,354; 5,149,540; 5,389,630; 5,415,863; 5,436,260; 5,447,712; 5,482,960;
  • 5,478,844 and 5,504,090 relate to methods of treating hemorrhaging.
  • U.S. Patents 5,248,507; 5,264,220; 5,382,569; 5,409,956; 5,443,848; 5,476,846; 5,480,645; 5,482,960 and 5,504,090 relate to thromboxane ligands. It is thus clear that a great deal of research is currently involved in thromboxane ligands, especially for treating hemorrhaging and related conditions.
  • bicyclic carboxylic acid derivatives wherein said bicyclic rings may be hydrocarbyl or oxy hydrocarbyl, e.g. 7-[carboxylalkyl or alkenyl] -6- [alkyl or alkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octane derivatives thereof, e.g. hydroxyl, nitro, amino, amido, azido, oxime, thiol, ether and thiol ether derivatives of said carboxy group are potent ocular hypotensive agents.
  • these compounds are thromboxane ligands and may have the unique ability, described herein, to mimic the vasoconstrictor properties of thromboxane A2 and its endoperoxide precursors, without causing concomitant platelet aggregation, i.e. blood clotting, and therefore said compounds provide a diverse variety of medical uses.
  • Their potent vasoconstrictor properties may be safely used in therapy as they do not cause the platelet aggregation and resultant thrombosis that would arise from using known thromboxane mimetics.
  • the vasoconstrictor properties would substantially reduce blood flow in blood vessels and could be used to prevent hemorrhaging associated with external or internal injuries without the risk of thrombosis.
  • These compounds may also be used as surgical adjuncts to reduce the bleeding from incisions at any anatomical location. Similarly, these compounds would be useful in limiting the bleeding associated with tooth extraction.
  • the ability of these compounds to prevent hemorrhage, without causing platelet aggregation and resultant thrombosis allows their safe application in systemic diseases where hemorrhage occurs. For example, bleeding from the gastrointestinal tract associated with hemorrhoids, inflammatory bowel diseases, or gastric and peptic ulcer may be prevented. Bleeding associated with stroke may be prevented.
  • Bleeding associated with stroke may be reduced without causing thrombosis and a potentially fatal complication. Bleeding is also a frequent complication in retinal diseases and surgeries resulting in impaired vision. This would also be amenable to safe treatment by the vascular-selective thromboxane mimetics described herein. Excessive bleeding associated with menstruation, childbirth, and uterine dysfunction may also be safely treated.
  • the selective vasoconstrictor properties of these compounds may be used to treat systemic hypotension. They may also be employed to restore normal blood pressure in haemorragic, anaphylactic, or septic shock episodes, without the serious risks associated with typical thromboxane mimetics which would result from their pro-aggregatory effects on platelets.
  • the selective vasoconstrictor properties may also be used to provide local anti-inflammatory effects in tissues such as the eye, skin, and nose. They may also be used to limit plasma exudation in burns and scalds.
  • a thromboxane-like vasoconstrictor that does not cause platelet aggregation may also be useful in optimizing blood born delivery of drugs and diagnostics in encapsulating vehicles.
  • delivery of drugs or diagnostic substances encapsulated in heat-sensitive or light-sensitive liposomes to the retina may be safely enhanced by agents described herein which selectively produce vasoconstriction.
  • bicyclic carboxylic acid derivatives of the present invention are useful as thromboxane antagonists for treating systemic or pulmonary hypertension, myocardial ischemia, angina pectoris, coronary contraction, cerebrovascular contraction after subarachnoidal hemorrhage, cerebral hemorrhage and asthma.
  • Y is (CH 2 ) X
  • Z is selected from the group consisting of O
  • R is hydrogen or an alkyl radical of from 1 to 4 carbons, e.g. methyl, or ethyl;
  • A is an alkylene or alkenylene radical having from two to seven carbon atoms, e.g.
  • radical may be substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups or said alkylene or alkenylene may have one or more enchained oxo or imino radicals;
  • B is a methyl radical or a cycloalkyl radical having from three to seven carbon atoms, e.g.
  • aryl radical selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms; and
  • R is Ci to C10 alkyl, phenyl or benzyl and Ri is R or hydrogen; or a pharmaceutically acceptable salt thereof.
  • A may be a straight chain alkylene radical, e.g. heptylene, or alkenylene radical, e.g. 3 -hydroxy- 1-heptylenyl, or an ethylenyloxyethylenyl radical or amino carbonyl hydrazino methyl radical and B may be selected from the group consisting of methyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyridyl, etc.
  • B may also be substituted by radicals selected from the group consisting of halo, e.g. fluoro, chloro, iodo etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, etc.
  • halo e.g. fluoro, chloro, iodo etc.
  • B is methyl, cyclohexyl or phenyl.
  • the present invention preferably provides thromboxane agonists having the formula 1(a)
  • the present invention relates to the use of the compounds of Formula I, above, as ocular hypotensives or a thromboxane ligands.
  • the present invention relates to the use of a 7-[carboxylalkyl or alkenyl] -6- [alkyl or alkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octane derivative, e.g. a hydroxyl, nitro, amino, amido, azido, oxime, thiol, ether or thiol ether derivative as thromboxane ligands.
  • octane derivative e.g. a hydroxyl, nitro, amino, amido, azido, oxime, thiol, ether or thiol ether derivative as thromboxane ligands.
  • These preferred therapeutic agents are represented by compounds having the formula ⁇ ,
  • aliphatic means linear and branched alkylene and alkenylene radicals
  • alkylene alkylene
  • alkenylene mean divalent radicals derived from alkanes and alkenes, respectively.
  • alkyl refers to alkyl groups having from one to ten carbon atoms
  • cycloalkyl refers to cycloalkyl groups having from three to seven carbon atoms
  • aryl refers to aryl groups having from four to ten carbon atoms.
  • saturated or unsaturated acyclic hydrocarbon group is used to refer to straight or branched chain, saturated or unsaturated hydrocarbon groups having from one to about six, preferably one to about four carbon atoms.
  • Such groups include alkyl, alkenyl and alkynyl groups of appropriate lengths, and preferably are alkyl, e.g. methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric form thereof. More preferably the method of the present invention comprises administering a 7-[carboxyalkyl or alkenyl] -6- [alkyl or alkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octane derivative represented by the formula IH,
  • the derivative used in the above method of treatment is a compound of formula IN,
  • hatched lines indicate the ⁇ configuration and a solid triangle is used to indicate the ⁇ configuration.
  • R7 preferably is phenyl, and the heteroaromatic rings have oxygen, nitrogen or sulfur as a heteroatom, i.e., R7 may be thienyl, furanyl, pyridyl, etc.
  • the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formulae (I), (II), (III) or IV wherein the symbols have the above meanings, or a pharmaceutically acceptable salt thereof in admixture with a non-toxic, pharmaceutically acceptable carrier or liquid vehicle.
  • a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered.
  • Such salts are those formed with pharmaceutically acceptable cations, e.g., alkali metals, alkali earth metals, amines, etc.
  • the compounds utilized in the method of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally.
  • the following dosage forms may comprise as the active component, either a compound of Formula I through IV or a corresponding pharmaceutically acceptable salt of a compound of Formula 1 through IV.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active compounds is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizmg agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit: doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the method of this invention are administered at the initial dosage of about 0.01 mg to about 10 mg/kg daily.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • compositions for treating glaucoma or lowering intraocular pressure may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use.
  • the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
  • solutions are prepared using a physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • a preferred surfactant is, for example, Tween 80.
  • various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations are chelating agents.
  • the preferred chelating agent is edentate disodium, (sodium EDTA) although other chelating agents may also be used in place of or in conjunction with it.
  • the ingredients are usually used in the following amounts:
  • Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make
  • the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye.
  • Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
  • One package may contain one or more unit doses.
  • Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops.
  • the volume of one drop usually is about 20-35 ⁇ l.
  • PGF2a (542 mg, 1.53 mmol) was dissolved in ethylether (Et2 ⁇ ) (20 mL) and cooled to O°C. A solution of CH2N2 in Et2 ⁇ was added dropwise to the above suspension until a yellow color persisted. The solution was warmed to 25° C for 0.5 h and then concentrated in vacuo to yield PGF 2 ⁇ methyl ester as an oil. The crude ester was heated at reflux with n-butyl boronic acid (0.188 g, 1.84 mmol) in CH2Cl2(3.1 mL) for 2h.
  • Example 7 60 mg (0.1037 mmol) of the compound of Example 5 in 1.0 mL of THF was treated with 0.20 mL a 1.0 M solution of B114NF and stirred at 23°C for 16 hours. The reaction mixture was diluted with EtOAc, and then washed, consecutively, with H2O and brine and dried over anhydrous MgSO4. The dried organic phase was filtered and the filtrate concentrated under vacuum. Elution on silica gel with a 1 : 1 mixture of hexane and EtOAc yielded 29.7 mg (62% yield) of the named compound.
  • Example 7 60 mg (0.1037 mmol) of the compound of Example 5 in 1.0 mL of THF was treated with 0.20 mL a 1.0 M solution of B114NF and stirred at 23°C for 16 hours. The reaction mixture was diluted with EtOAc, and then washed, consecutively, with H2O and brine and dried over anhydrous MgSO4. The dried organic phase was filtered and the filtr
  • CYCLOPENTANE HEPTENOIC ACID 5-CIS-2-(3 ⁇ -PIVALOYLOXY-l- TRANS-OCTENYL)-3-HYDROXY, 5-IMIDAZOLYLOXY [l ⁇ , 2 ⁇ , 3a, 5a]
  • 1,1-carbonyldiimidazole were dissolved in 1.0 mL of CH2CI2 and stirred for 24 hours at 23°C to yield the named compound.
  • Example 13 The compound of Example 11 was treated according to the procedure of Example 7 to yield the named compound.
  • Example 13 The compound of Example 11 was treated according to the procedure of Example 7 to yield the named compound.
  • Example 16 The compound of Example 14 was converted into the named compound at 95% yield by the procedure of Example 6.
  • PGF2a methyl ester (prepared as described in Example 1) was treated according to the procedure of Example 9 to yield the named compound.
  • FP-activity was measured as contraction of the isolated feline iris sphincter.
  • EPi was measured as contraction of the longitudinal smooth muscle of the isolated guinea pig ileum.
  • EP3-activity was measured as inhibition of the twitch response induced by electrical field stimulation in the isolated guinea pig was deferens and as contraction of the longitudinal smooth muscle of the isolated chick ileum.
  • TP- vasoconstrictor activity was measured as contraction of rings of the isolated rat thoracic aorta. Effects on platelets from healthy human donors were measured by incubating platelet-rich plasma with the compounds described herein. Inhibition of aggregation was determined by the ability of the compounds described herein to inhibit platelet aggregation in platelet-rich plasma induced by 20 ⁇ M ADP. The activity profile of various compounds is reported in
  • thromboxane A2 -receptor antagonist SQ29,548 [lS-[l ⁇ , 2 ⁇ (5Z), 3 ⁇ , 4 ⁇ ]]-7-[3-[[2-[phenylamino)carbonyl]-hydrazino]methyl]-7- oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid) of vasoconstrictor activity was investigated.
  • Tables 1 and 7 reveals an unexpected and unique trend in biological activity associated with certain examples of formula IV.
  • thromboxane (TP-) receptor agonists indiscriminately cause both platelet aggregation and smooth muscle contraction. It has, therefore, been concluded that there is no convincing evidence that subtypes of the TP-receptor exist (Jones, R.L., Wilson, N.H., Armstrong, R.A., Tymkewycz, P.M. Colloque INSERM 152:335-344, 1987).
  • Examples 4, 15 and 16 and 19 through 21 exhibit pronounced activity in contracting vascular smooth muscle but have no or minimal ability to cause platelet aggregation. Further evidence is provided below to demonstrate that the ability of examples 4, 15 and 16 and 19 through 21 to cause contraction of vascular smooth without causing platelet aggregation involves selective stimulation of a subtype of TP-receptor present on vascular smooth muscle.
  • a TP-receptor antagonist blocks the effect of agonists which are selective for the vascular TP-receptor (Example 4) and non-selective with respect to vascular and platelet TP-receptors (Example 7, U-46619), see Table 2. This shows that Example 4 and its congeners, which show selectivity for contracting vascular smooth muscle, produce their effect by interacting with a subtype of TP-receptor as opposed to some other type of eicosanoid receptor.
  • Example 4 neither causes platelet aggregation nor inhibits the ability of U-46619 or Example 7 to cause platelet aggregation, see Table 3. Moreover, Example 4 did not inhibit ADP or arachidonic acid induced platelet aggregation (Table 4) and, therefore, its activity cannot be ascribed to a mechanism which opposes the aggregatory response, e.g., behaving as a prostacyclin or prostaglandin D2 mimetic, inhibition of cyclooxygenase.
  • formula IV selectively constrict smooth muscle by stimulating a TP-receptor subtype which exists on smooth muscle but not on platelets.
  • Such antagonists may be useful in treating systemic and local vasoconstriction and other indications without concommitant inhibition of normal platelet function and blood clotting.
  • the effects of four examples of Formula IV and the thromboxane mimetic U- 46619 on intraocular pressure are provided in the following tables.
  • the compounds were prepared at the said concentrations in a vehicle comprising 0.1% polysorbate 80 and 10 mM TRIS base. Dogs and monkeys were treated by administering 25 ul to the ocular surface, the contralateral eye received vehicle as a control. Intraocular pressure was measured by applanation pneumatonometry. Experiments were performed with dogs and monkeys. Dog intraocular pressure was measured immediately before drug administration and at 2, 4 and 6 hour thereafter. Additional studies in monkeys were performed over a 5 day period and drug was administered at times 0, 6, 24, 30, 48, 54, 72, 78, and 96 hours.
  • thromboxane ligands comprising a carboxylic acid derivative may be prepared from the parent carboxylic acid to obtain thromboxane receptor agonists which are useful in treating hemorrhage by constricting the cardiovascular network without the side effect of causing blood clotting or thromboxane antagonists, which are useful in treating hypertension without the side effect of causing blood clotting.
  • TRL-COOH wherein TRL represents a thromboxane receptor ligand residue having thromboxane agonist activity may be converted by methods known in the art to TRL-W, wherein W is C(O)(NR ⁇ ) 2 , CH 2 OR !
  • E-P E£l EZ-3.(c) EJi3.(d) XEvnsc Platelets (Human) Inhibition (Cat Iris) (Guinea (Guinea Pig (Chick (Rat A p g r ep n 1 ion of Apprcpntion Pi R lcum) vas dcfercns) Ileum) Aorla) to
  • EC50 (nM) nM concentration required to produce a 50% oF maximal response
  • TAIJLE 6 The effect of compounds of Formula iv and U-46619 (9,11-dideoxy - 9 ⁇ , ll ⁇ , methanoepoxy prostaglandin F2 ⁇ ) on monkey intraocular pressure.

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Abstract

L'invention concerne un procédé de traitement des affections suivantes: hypotension oculaire, hypertension, hémorragie, ischémie myocardique, angine de poitrine, contraction coronarienne, contraction cérébrovasculaire survenant après une hémorragie sous-arachnoïdienne, hémorragie cérébrale et asthme. On administre au mammifère à traiter une quantité thérapeutiquement efficace de ligand de thromboxane qui est un composé de formule (I(a)), les hachures indiquant la configuration α et le triangle en trait plein indiquant la configuration β; Y est (CH2)x; Z peut être (1), O, OCH2, O-C-O et(Cr2)x, x étant un entier valant 1 ou 2; R2 est hydrogène ou un radical alkyle ayant de 1 à 4 atomes de carbone; A est un radical alkylène ou alcénylène ayant de 2 à 7 atomes de carbone, pouvant être substitué par un ou plusieurs groupes hydroxy, oxo, alkyloxy ou alkylcarboxy, et ce radical alkylène ou alcénylène peut comporter un ou plusieurs radicaux oxo ou imino en chaîne; B est un radical méthyle ou cycloalkyle ayant de 3 à 7 atomes de carbone, ou un radical aryle, pouvant être un radical hydrocarbyle aryle et hétéroaryle, sachant que l'hétéroatome peut être azote, oxygène et soufre, ou des dérivés substitués des radicaux considérés, sachant que le substituant peut être halo, nitro, amino, thiol, hydroxy, alkyloxy et alkylcarboxy; et X peut être un radical cyano, -COOR, -CH2OR1, -C(O)N(R1)2, -CH2N(R1)2 -CH=N-OH et -CH2SR1, sachant que R est alkyle C1-10, phényle ou benzyle et que R1 est R ou hydrogène. Il peut aussi s'agir d'un sel pharmaceutiquement acceptable correspondant.
PCT/US2000/011760 1999-04-29 2000-04-27 Ligands de thromboxane sans effets secondaires de coagulation du sang Ceased WO2000066577A2 (fr)

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AU46875/00A AU4687500A (en) 1999-04-29 2000-04-27 Thromboxane ligands without blood clotting side effects

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AU2003241260B2 (en) * 2002-06-14 2007-04-26 Astrazeneca Ab 2,5-disubstituted 3-mercaptopentanoic acid
US9688689B2 (en) 2014-05-13 2017-06-27 Novartis Ag Compounds and compositions for inducing chondrogenesis

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US4654364A (en) * 1984-11-30 1987-03-31 E. R. Squibb & Sons, Inc. Hydroxamic acids of 7-oxabicycloheptane substituted ethers
JP2561466B2 (ja) * 1987-05-18 1996-12-11 塩野義製薬株式会社 フェニルスルホニルアミノアルキルビシクロヘプチルヘプテン酸誘導体
US4973604A (en) * 1988-12-13 1990-11-27 National Research Development Corporation Thromboxane A2 antagonists and pharmaceutical compositions thereof
US4942256A (en) * 1988-12-13 1990-07-17 National Research Development Corporation Novel intermediates in the manufacture of novel thromboxane A2 antagonists
CA2012852A1 (fr) * 1989-05-01 1990-11-01 Miguel A. Ondetti Methode d'inhibition des spasmes des vaisseaux et de l'aggregation des plaquettes resultant d'une angioplastie a l'aide d'antagonistes des recepteurs de la thromboxane a
US4977174A (en) * 1989-06-12 1990-12-11 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane imidazole prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease
JPH0377862A (ja) * 1989-08-18 1991-04-03 Ono Pharmaceut Co Ltd ビシクロ［２．２．１］ヘプタン誘導体、その精製方法および製造方法
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US6017953A (en) * 1993-12-28 2000-01-25 Allergan Sales, Inc. Thromboxane ligands
US5741812A (en) * 1993-12-28 1998-04-21 Allergan Thromboxane ligands without blood clotting side effects
US5650431A (en) * 1993-12-28 1997-07-22 Allergan Thromboxane ligands without blood clotting side effects

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003241260B2 (en) * 2002-06-14 2007-04-26 Astrazeneca Ab 2,5-disubstituted 3-mercaptopentanoic acid
US9688689B2 (en) 2014-05-13 2017-06-27 Novartis Ag Compounds and compositions for inducing chondrogenesis
US10188638B2 (en) 2014-05-13 2019-01-29 Novartis Ag Compounds and compositions for inducing chondrogenesis
US10383863B2 (en) 2014-05-13 2019-08-20 Novartis Ag Compounds and compositions for inducing chondrogenesis
US10660881B2 (en) 2014-05-13 2020-05-26 Novartis Ag Compounds and compositions for inducing chondrogenesis
US11510912B2 (en) 2014-05-13 2022-11-29 Novartis Ag Compounds and compositions for inducing chondrogenesis
US12280041B2 (en) 2014-05-13 2025-04-22 Novartis Ag Compounds and compositions for inducing chondrogenesis

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WO2000066577A3 (fr) 2001-03-01

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