WO2000057701A1 - Composes de prostaglandine, compositions et methodes de traitement de maladies vasculaires peripheriques et de l'hypertension pulmonaire - Google Patents

Composes de prostaglandine, compositions et methodes de traitement de maladies vasculaires peripheriques et de l'hypertension pulmonaire Download PDF

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Publication number
WO2000057701A1
WO2000057701A1 PCT/US2000/008240 US0008240W WO0057701A1 WO 2000057701 A1 WO2000057701 A1 WO 2000057701A1 US 0008240 W US0008240 W US 0008240W WO 0057701 A1 WO0057701 A1 WO 0057701A1
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compound
compounds
group
pharmaceutically acceptable
molecular weight
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English (en)
Inventor
Robert Shorr
Martine Rothblatt
Michael D. Bentley
Xuan Zhao
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United Therapeutics Corp
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United Therapeutics Corp
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Priority to AU43273/00A priority Critical patent/AU4327300A/en
Priority to JP2000607467A priority patent/JP2003523935A/ja
Priority to KR1020017012628A priority patent/KR20020012169A/ko
Priority to CA002359652A priority patent/CA2359652A1/fr
Priority to EP00923092A priority patent/EP1164846A1/fr
Publication of WO2000057701A1 publication Critical patent/WO2000057701A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to modified prostaglandins, specifically long-
  • Prostaglandins including prostacyclin, a prostaglandin analog produced by
  • prostacyclin is inherently unstable, with an effective life of less than about six
  • Prostaglandins including prostacyclins appear to act in three ways to keep
  • vascular diseases are characterized by the degradation of lining of the
  • Pulmonary hypertension is a progressive, life-threatening vascular disease
  • Elevated pulmonary blood pressure typically causes a strain on the right side
  • pulmonary hypertension Primary pulmonary hypertension is defined as pulmonary
  • pulmonary hypertension with a known cause such as heart lung or
  • liver dysfunction or schleroderma a disease of the connective tissue
  • pulmonary hypertension is used herein to include both primary and secondary pulmonary hypertension
  • peripheral vascular disease the condition is generally referred to as peripheral vascular disease
  • ischemic cerebrovascular disease includes, but is not limited to ischemic cerebrovascular disease
  • arteriovenous fistulas arteriovenous fistulas, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, non-patent ductus arte ⁇ osus, non-obstructive
  • Peripheral vascular disease affects approximately six million people in the
  • peripheral vascular disease confirmed annually in the United States Peripheral vascular disease.
  • vascular disease is also responsive to the presence of prostaglandins including
  • Prostaglandins are useful for treating peripheral vascular diseases and
  • prostaglandins The short effective life of prostaglandins is due to a) rapid deactivation of the active groups of the molecules by enzymes, and b) their low molecular weight which
  • Prostaglandins have active sites typically in the form of hydroxyl and carboxyl groups. Enzymes can rapidly deactivate the active groups thereby rendering the
  • effects include nausea, swelling, gastrointestinal upset, jaw pain, rash, and
  • PAO polyalkylene oxides
  • Conjugates are generally formed by reacting
  • a therapeutic agent with, for example, a several fold molar excess of a polymer which has been modified to contain a terminal linking group
  • the linking group
  • the activated polymers are reacted with a therapeutic agent having nucleophihc functional groups that serve as attachment sites
  • a therapeutic agent having nucleophihc functional groups that serve as attachment sites One nucleophilic
  • Biologically active polymer conjugates can be formed having hydrolyzable
  • Prodrugs are advantageous because they enable modification of the onset and/or duration of action of a biologically-active compound in vivo Prodrugs are often biologically
  • the active drug is influenced by several factors including the rate of hydrolysis of the
  • the present invention is generally directed to novel prostaglandin
  • the present invention provides compounds, compositions and methods of
  • composition Improved stability, effective life and more acceptable modes of
  • administration and dosage regimens are achieved by modifying one or more of the
  • one or more active sites of the present invention one or more active sites of the present invention
  • active group of P is a pharmaceutically acceptable group which is bound to T and which slows the metabolic rate of said compound
  • n is an integer of at least 1 ,
  • Figure 1 is a graph showing the effects on pulmonary arterial pressure of a
  • Figure 2 is a graph depicting the effects of a dose of mPEG20kDa-ester-
  • Compound X given as an intravenous bolus, on the pulmonary arterial pressure of a sheep intravenously-induced with a pulmonary hypertensive agent,
  • Figure 3 is a graph depicting the effects of a dose of mPEG20kDa-ester-
  • Compound X given as an aerosol, on the pulmonary arterial pressure of a sheep intravenously-induced with a pulmonary hypertensive agent,
  • Figure 4 is a graph depicting the effects of a dose of mPEG20kDa-ester-
  • Figure 5 is a graph showing the effects of mPEG5kDa-ester-Compound X
  • the present invention is directed to novel prostaglandins and analogs thereof in which at least one active site has attached thereto an inert, non-antigenic, non-
  • immunogenic group having a structure which protects the active site when
  • the target area e g afflicted tissue and vasculature regions, such as the pulmonary artery
  • prostaglandin compounds shall mean all
  • prostaglandin compounds and variations thereof which have at least one active
  • prostaglandin compounds shall refer to prostaglandin compounds as defined, which
  • active group shall mean a site on the prostaglandin compound, which is capable of binding to or otherwise engaging a targeted tissue such as vascular
  • the present invention includes present prostaglandin (PG) compounds of all types.
  • PG prostaglandin
  • the present prostaglandin compounds employed in the present invention include present prostaglandin compounds of all types.
  • the present prostaglandin compounds employed in the present invention include present prostaglandin compounds of all types.
  • the present prostaglandin compounds employed in the present invention include present prostaglandin compounds of all types.
  • modified PGA PGB, PGC, PGD, PGE, PGF, and PGI type
  • prostaglandin compounds as well as all subtypes of the foregoing
  • the prostaglandin compounds can be isolated or extracted from a warm-blooded animal source or prepared synthetically by techniques known to those of ordinary skill in the art
  • Preferred present prostaglandin compounds are represented by Formula II
  • Z, and Z 2 are independently selected from hydrogen and the groups
  • X is selected from O or NH
  • More highly preferred compounds of Formula II are compounds of Groups 1 ,
  • Z 1 is a pharmaceutically acceptable polymer which binds to X and slows the metabolic rate of the compound
  • X is selected from O and NH
  • Z 2 is selected from H and an acetyl group
  • X is O
  • Z 2 is a pharmaceutically acceptable polymer which slows the
  • Z 1 is a pharmaceutically acceptable polymer as defined in Group 1 ,
  • X is 0 or NH
  • Z 2 is a pharmaceutically acceptable polymer as defined in
  • Z and Z 2 include the same groups as previously defined in Formula II; f is an integer of from 1 to 3; X is selected from O and NH; and
  • R is selected from hydrogen and an alkyl group preferably having 1 -6 carbon atoms
  • More highly preferred compounds of Formula III are compounds of Groups 4.
  • Z. is a pharmaceutically acceptable polymer which binds to X and slows the
  • X is selected from O and NH
  • Z 2 is selected from hydrogen and an acetyl
  • Z- is hydrogen, X is O, and Z 2 is an acetyl group, or a pharmaceutically
  • Z is a pharmaceutically acceptable polymer as defined in Group 4, X is
  • Z 2 is a pharmaceutically acceptable polymer as
  • Z 1 and/or Z 2 groups are polyethylene glycols having the formula CH 3 OCH 2 CH 2 (OCH 2 CH 2 ) a , wherein a is from
  • a particularly preferred group of present prostaglandin compounds are those
  • a and X are as defined above.
  • a is from about 6 to 600 most
  • the present invention also provides a method of treating a warm-blooded
  • vascular disease including peripheral vascular disease and/or
  • pulmonary hypertension comprising administering to the warm-blooded animal an
  • compositions containing said compounds which are suitable for administration to warm-blooded animals for said purposes are part of the present invention
  • Peripheral vascular disease is characterized by decrease in blood flow to the legs and feet with accompanying ischemia Deposition of plaque on the inner
  • Organic peripheral vascular disease is characteristic of this disorder.
  • anti-platelet aggregatory and cytoprotective activities of the present prostaglandin compounds is believed to promote healing by inhibiting inflammatory response in
  • vasodilation is
  • peripheral vascular disease the inherent anti-platelet aggregation
  • the present prostaglandin compounds e g , COOH and OH are attached to linear,
  • the polymers must be capable of separating
  • the activated polymers are reacted with the prostaglandin compound so that
  • attachment preferably occurs at the free carboxyhc acid groups and/or hydroxyl
  • amide or ester linkages are formed
  • PAO's polyalkylene oxides
  • PEG polyethylene glycols
  • mPEG's Bis-activated polyethylene oxides are also contemplated for purposes of cross-linking the prostaglandin compound or providing a means for
  • Suitable polymers especially PEG or mPEG will vary substantially by weight Polymers having molecular weights ranging from about 200 to about 80,000 daltons are typically employed in the present invention Molecular weights from about 2,000
  • the polymers preferably employed in the present invention as protective groups are water-soluble at room temperature A non-limiting list of such polymers
  • polyalkylene oxide homopolymers such as PEG and mPEG or polypropylene
  • glycols polyoxyethylenated polyols, copolymers thereof and block copolymers
  • .4 alkyl-terminated polymers are also useful
  • prostaglandin compounds may further include, but are not limited to, acetylation,
  • prostaglandin compounds are coupled to the protective groups as
  • prostaglandin compounds are therefore particularly suited for the treatment of peripheral vascular disease and pulmonary hypertension.
  • peripheral vascular disease and pulmonary hypertension therapy have a very short effective life in a warm blooded animal, typically less than one hour In
  • present prostaglandin compounds are N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • prostaglandin compound may be administered and may therefore enable the
  • prostaglandin compounds to be delivered in lower dosage unit amounts and
  • the active groups of the present prostaglandin compounds include COOH and OH groups One or more of these active groups are protected by a protective
  • the protective groups are any groups which serve to protect the active
  • alkylene groups all of which may be substituted with substituents selected from, for example, alkyl, aryl, and
  • polyglycols polyvinyl polymers, polyesters, polyamides, polysaccha ⁇ des, and
  • polymeric acids polymeric acids, lipids, ammo acids, nucleic acids, carbohydrates, and combinations
  • the preferred polyglycols include polyethylene glycol and polypropylene
  • the preferred polysaccha ⁇ des are those selected from polysaccha ⁇ de B Among the polyacids which may preferably be used in accordance with the
  • present invention are polyami ⁇ o acids and polyactic acid
  • PEG polyethylene glycols
  • cellulosic polymers and starches may be also used in accordance with the present
  • the polymers may be attached to the active COOH or OH group through a
  • the compounds of Formula I are typically employed as part of a pharmaceutical composition including a pharmaceutically acceptable carrier for the
  • vascular disease including peripheral vascular disease and pulmonary vascular disease
  • composition comprising at least one compound of
  • Formula I may be formulated, for example by employing conventional solid or liquid
  • vehicles or diluents as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives,
  • the compounds of Formula I may be administered by any suitable means, for example
  • orally such as in the form of tablets, capsules, granules or powders,
  • intramuscular, or intrasternal injection or infusion techniques e g , as sterile
  • injectable aqueous or non-aqueous solution or suspensions nasally such as by inhalation spray; topically, such as in the form of a cream or ointment, or rectally such as in the form of suppositories; in dosage unit formulations containing non-
  • compositions for oral administration include suspensions which
  • microcrystallme cellulose for imparting bulk algmic acid or sodium algmate as a suspending agent, methylcellulose as a viscosity enhancer,
  • sweeteners or flavoring agents such as those known in the art, and immediate
  • release tablets which may contain, for example, microcrystallme cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients,
  • binders such as those known in the art
  • present compounds may also be delivered through the oral cavity by
  • Molded tablets, compressed tablets or freeze-d ⁇ ed tablets are exemplary forms which may be used Exemplary
  • compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodext ⁇ ns Also included in
  • Such formulations may be high molecular weight excipients such as celluloses (avicel) Such formulations may also include an excipient to aid mucosal adhesion
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • maleic anhydride copolymer e g Gantrez
  • agents to control release such as polyacry c copolymer (e g
  • compositions for nasal aerosol or inhalation administration include
  • solutions in saline which may contain, for example, benzyl alcohol or other suitable
  • solubilizing or dispersing agents such as those known in the art
  • compositions for parenteral administration include mjectable solutions or suspensions which may contain, for example, suitable non-toxic,
  • parenterally acceptable diluents or solvents such as mannitol, 1 ,3-butaned ⁇ ol, water, Ringer's solution, an isotonic sodium chloride solution or other suitable
  • dispersing or wetting and suspending agents including synthetic mono- or
  • compositions for rectal administration include suppositories which
  • a suitable non-ir ⁇ tating excipient such as cocoa butter or synthetic glyce ⁇ de esters, which are solid at ordinary temperatures but liquify and/or dissolve in the rectal cavity to release the drug
  • compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene)
  • prostaglandin compound per day which may be administered in a single dose or in
  • Preferred subjects for treatment include animals most preferably mammalian species such as humans and domestic animals such as dogs, cats and the like subject to vascular diseases
  • the present prostaglandin compounds of the present invention may be any one of the present prostaglandin compounds of the present invention.
  • the prostaglandin compounds are reconstituted with a medium normally utilized for intravenous injection, e g , preservative-free sterile water Administration may be accomplished by continuous intravenous or subcutaneous infusion or by
  • Platelet aggregation was measured using a dual channel Payton
  • the aggregating agent collagen (1 ⁇ g/ml) was added to the PRP and the platelet aggregation was monitored as the increase in light transmission observed over a 4
  • aqueous vehicle acetate buffer
  • the concentration of Compound X inhibiting aggregation by 50% was determined to be 20 ng/ml Referring to Table 3, the incubation of Compound X (3 and 300 ng/ml) with
  • the trachea was cannulated to facilitate breathing
  • the right carotid artery was cannulated and connected to a pressure transducer (Spectramed
  • the left femoral vein or the right jugular vein was cannulated for the administration of drugs
  • the body temperature of the test animal was maintained at 37 ⁇ 1 °C by means of a rectal probe thermometer attached to a
  • Compound 1 was about 15 minutes and about 30 minutes, respectively
  • a compound of Group 5 wherein Z, is hydrogen X is O and each Z 2 is an acetyl group was prepared in the following manner In a round-bottom flask, Compound X (400 mg) and py ⁇ dine (200 ⁇ l) were
  • Compounds 6 and 7 are respectively, mPEG 20kDa-am ⁇ de-Compound X and
  • Each of Compounds 6 and 7 are compounds of Group 4 wherein Z., is a mPEG having a molecular weight of about 20,000 daltons and X is NH.
  • Z. is a mPEG having a molecular weight of about 20,000 daltons and X is NH.
  • Z 2 is hydrogen
  • Z 2 is an acetyl group
  • Compound X Compound 4 was some 3 x 10 3 times less active in inhibiting platelet
  • Compound 6 was the most active of the three PEG conjugated derivatives (Compounds 5-7), after incubation with the
  • the anti-platelet activity of Compounds 5-7 were variably affected by incubation with platelet-poor plasma (PPP) for periods up to four (4) hours Time
  • MAP mean arterial pressure
  • the right carotid artery was cannulated and connected to a
  • MAP mean arterial pressure
  • HR heart rate
  • Compound 7 ( 3, 10 and 30 mg/kg i v ) caused a gradual fall in MAP which reached its plateau levels only after 135-165 minutes The gradual fall
  • the cardiovascular profile of the present compounds permits some definition of the structure-activity relationship, and hence design of Compound X derivatives
  • Compound 2 was evaluated following subcutaneous administration Male
  • Wistar rats 250-330 g were anesthetized with thiopentone sodium (INTRAVAL®,
  • the trachea was cannulated to facilitate respiration
  • the right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL), for the measurement of mean arterial pressure (MAP) and heart rate (HR)
  • MAP mean arterial pressure
  • HR heart rate
  • Body temperature was maintained at 37 ⁇ 1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard
  • Compound X Compound 4
  • Compound 7 and mPEG5kDa-am ⁇ de-Compound X Diacetate hereinafter referred to as Compound 8 were evaluated following
  • thiopentone sodium 120 mg/kg i p
  • the trachea was cannulated to facilitate respiration
  • the right carotid artery was cannulated and connected to a
  • MAP heart pressure
  • HR heart rate
  • Compound is a compound of Group 4 wherein Z, is a mPEG having a molecular
  • Compound 4 were >300, >330 and >300 minutes respectively (See Table 5)
  • the compound used in the present study was the acetylated mPEG 350 Da
  • the Compound 9 ( 10 and 30 mg/kg) was administered as an intravenous bolus
  • a rubber catheter was positioned in the stomach (via the esophagus) to
  • the ethanohc vehicle also caused a progressive fall in heart rate (see Table
  • the lower molecular weight PEG may be less
  • Compound X if this is the active species that elicits the hypotensive responses
  • the compound tested was the acetylated mPEG 350 Da-ester-Compound X, hereinafter referred to as "Compound 10", in which the mPEG of 350 daltons
  • the right carotid artery was cannulated and connected to a pressure transducer
  • polygraph recorder (Grass, Mass., U.S A ) The left femoral vein or the right jugular vein was cannulated for the administration of drugs Body temperature was
  • Compound 10 (0 3, 3, 10 and 30 mg/kg) was administered as an intravenous bolus.
  • Compound 10 was dissolved in ethanol for storage at -20°C Aliquots of the stock solution were removed for dilution in the aqueous vehicle prior to use

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne la prostaglandine et des analogues de cette dernière contenant des groupes protecteurs fixés à au moins un site, et étant pharmaceutiquement acceptables et capables de ralentir le rythme métabolique des groupes actifs en vue d'une administration à des animaux à sang chaud pour le traitement de maladies vasculaires périphériques et de l'hypertension pulmonaire. La figure illustre les effets d'une dose de mPEG20kDa-amide-Composé X sur la pression artérielle pulmonaire, administré sous forme d'infusion intraveineuse à un mouton ayant reçu, par voie intraveineuse, un agent d'hypertension pulmonaire.
PCT/US2000/008240 1999-03-31 2000-03-29 Composes de prostaglandine, compositions et methodes de traitement de maladies vasculaires peripheriques et de l'hypertension pulmonaire Ceased WO2000057701A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU43273/00A AU4327300A (en) 1999-03-31 2000-03-29 Prostaglandin compounds, compositions and methods of treating peripheral vascular disease and pulmonary hypertension
JP2000607467A JP2003523935A (ja) 1999-03-31 2000-03-29 末梢血管疾患と肺高血圧症を治療するためのプロスタグランジン化合物、組成物および方法
KR1020017012628A KR20020012169A (ko) 1999-03-31 2000-03-29 프로스타글란딘 화합물, 조성물 및 말초혈관질병 및폐고혈압증의 치료방법
CA002359652A CA2359652A1 (fr) 1999-03-31 2000-03-29 Composes de prostaglandine, compositions et methodes de traitement de maladies vasculaires peripheriques et de l'hypertension pulmonaire
EP00923092A EP1164846A1 (fr) 1999-03-31 2000-03-29 Composes de prostaglandine, compositions et methodes de traitement de maladies vasculaires peripheriques et de l'hypertension pulmonaire

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US12725599P 1999-03-31 1999-03-31
US12725499P 1999-03-31 1999-03-31
US60/127,255 1999-03-31
US60/127,254 1999-03-31

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EP (1) EP1164846A1 (fr)
JP (1) JP2003523935A (fr)
KR (1) KR20020012169A (fr)
CN (1) CN1354622A (fr)
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CA (1) CA2359652A1 (fr)
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