WO1994011021A1 - Antagoniste de bradykinine - Google Patents

Antagoniste de bradykinine Download PDF

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Publication number
WO1994011021A1
WO1994011021A1 PCT/US1993/010222 US9310222W WO9411021A1 WO 1994011021 A1 WO1994011021 A1 WO 1994011021A1 US 9310222 W US9310222 W US 9310222W WO 9411021 A1 WO9411021 A1 WO 9411021A1
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WO
WIPO (PCT)
Prior art keywords
bkan
pharmacophore
heterodimer
peptide
heterodimer according
Prior art date
Application number
PCT/US1993/010222
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English (en)
Inventor
John C. Chronis
James K. Blodgett
Val Smith Goodfellow
Manoj V. Marathe
Lyle W. Spruce
Eric T. Whalley
Original Assignee
Cortech, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cortech, Inc. filed Critical Cortech, Inc.
Priority to JP6512112A priority Critical patent/JPH08503460A/ja
Priority to EP93924412A priority patent/EP0671941A4/fr
Priority to AU54109/94A priority patent/AU5410994A/en
Publication of WO1994011021A1 publication Critical patent/WO1994011021A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/18—Kallidins; Bradykinins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to
  • bradykinin antagonist BKAn
  • bradykinin antagonist dimers of the type:
  • BKAn represents a bradykinin antagonist peptide
  • X is a linking group which joins the two BKAn components at points intermediate to their ends.
  • the BKAn substituents may be the same or different.
  • certain heterodimers involving the linkage of a BKAn peptide and another peptide of different receptor activity through the linking group X, e.g. an NK 2 or NK 2 antagonist peptide or a mu-opioid receptor agonist peptide.
  • Such heterodimers are particularly useful where there is a close relationship between the activities of concern.
  • tissue and plasma derived mediators such as kinins acting at BK 2 receptors
  • neuronally derived factors such as substance P (NK 1 receptors) and neurokinin A (NK 2 receptors).
  • NK 1 receptors neurokinin A
  • NK 2 receptors neurokinin A
  • NK 1 receptors neurokinin A
  • NK 2 receptors neurokinin A
  • neuronal receptors of the mu-opiate class that when stimulated can inhibit the release of the neurogenic peptides regardless of type (substance P, neurokinin A, neurokinin B, cholecystokinin, CGRP, etc.).
  • the present invention in its broadest aspect, is. concerned with heterodimers obtained by linking a BKAn peptide to another pharmacophore which is not a bradykinin antagonist, i.e. which may be either a peptide as described in WO 92/17201, or a non- peptide, effective against a different, non- bradykinin component responsible, for example, for pain and/or the inflammatory process, or other problems related to or occurring in concert with the activity of the kinins.
  • the resulting compounds are "dual action" compounds that are capable of
  • the overall pharmacological effect of administering such a compound in an appropriate dose is at least the summation of the two types of activities.
  • the compounds can be designed to remain intact or they can be designed to be dissociated into two separate molecules each retaining its own identifiable activity.
  • heterodimers of the invention can be structurally represented as follows:
  • BKAn is a bradykinin antagonist peptide
  • X is a linking group
  • Y is a peptide or non-peptide pharmacophore which is not a bradykinin antagonist and demonstrates activity towards a different receptor or enzyme than the BKAn component
  • the present heterodimers offer the possibility of providing a wider spectrum of treatment for pain and inflammation. It is a generally held opinion that in inflammatory states, regardless of severity, the likelihood that a single agent or mediator is completely responsible for all of the clinical manifestations of the syndrome being addressed is extraordinarily small. A corollary to this is that, given the role of bradykinin in inflammatory
  • any combination therapy used in the treatment of inflammatory disorders should include bradykinin antagonism as part of its overall profile of action.
  • Broad spectrum and potent non-specific therapies (such as the use of steroids in asthma) while perhaps efficacious, carry with them the burdens of undesired and potentially serious side effects and toxicities.
  • Atrial natriuretic peptide (Chino, N., et al, BBRC, 141, 665-672, 1986). Dimerization of antagonists has been shown for parathyroid hormone (Caproale, L.H., et al, Proc. 10th Amer. Pept.
  • heterodimers comprised of a bradykinin antagonist and a different pharmacophore as
  • bradykinin antagonist peptides are known in the art and any of these may be used for present purposes to provide the BKAn substituent of the present dimers.
  • One of the more potent bradykinin antagonist peptides are known in the art and any of these may be used for present purposes to provide the BKAn substituent of the present dimers.
  • bradykinin antagonists in vi tro is the peptide having the formula: D-ARG 0 -Arg 1 -Pro 2 -Hyp 3 -Gly 4 -Phe 5 -Ser 6 -D-Phe 7 -Leu 8 - Arg 9
  • bradykinin antagonist peptides can also be used for present purposes.
  • a wide variety of such bradykinin antagonist peptides have been disclosed in the recent patent literature and any of these can be used for present purposes. See, for example, EP-A-0334244 (Procter and Gamble) whichdiscloses nona- and larger bradykinin antagonist peptides in which certain amino acid residues are modified.
  • EP-A-0370453 Hoechst
  • WO 89/01780 and WO 89/01781 Stewart et al
  • None of these patent publications appears to show dimers as contemplated herein. However, as noted, the
  • Any linking group X may be used for present purposes to chemically or covalently link together the BKAn and Y components provided this does not interfere with the activity of the components BKAn and Y.
  • the linking group may be inorganic (e.g. -S- ) or organic and may be selected so as to hydrolyze or otherwise dissociate in order to liberate the two active components BKAn and Y in vivo .
  • the linking group may be such that the heterodimer remains intact when used.
  • the linking group X can include an -S- atom derived by reacting a sulfhydryl group on the BKAn peptide chain with the other pharmacophore component. This can be accomplished by reaction involving a cysteine (Cys) sulfhydryl group within the peptide chain, i.e. intermediate the ends of the peptide. This may require initially modifying the starting BKAn peptide so that it includes a Cys group in the appropriate position in the peptide chain.
  • Cys cysteine
  • CP-0088 may be modified by replacing the Ser in the 6-position with Cys (such modified CP-0088 being called CP-0126 hereinafter) to provide for convenient linking to the other pharmacophore through the Cys sulfhydryl.
  • CP-0126 can be structurally illustrated as follows:
  • the linking group X then includes the -S- of the cysteine sulfhydryl. This may be the entire linking group X (as in a disulfide based dimer) or only a part thereof.
  • the linking group may comprise a bissuccinimidoalkane such as
  • linking groups X can be derived from the six families of compounds listed below which can be generically categorized as amino acid analog linkers or maleimide-based linkers. These linkers are included as examples only and are not intended to be totally inclusive of all potential linking moieties:
  • ammo acid analog linkers (Class I) can be directly incorporated into the peptide chain of the BKAn and then used to form esterase stable or labile heterodimers with the geminal pharmacophore
  • linker (component Y).
  • the maleimide based linker can be reacted with the desired pharmacophore and then conjugated to a sulfhydryl containing peptide.
  • R 1 and R 2 can be varied so as to provide for completely unhindered or significantly hindered access to the carbonyl carbon of an ester based linking element so that the rate of in vivo hydrolysis of said ester can be controlled as desired.
  • pharmacophores used herein to prepare the dimers of the invention are themselves novel and constitute a further aspect of the invention.
  • the component Y of the present heterodimers may be any peptide or non-peptide pharmacophore, other than a bradykinin antagonist, which demonstrates activity towards a different (non-bradykinin)
  • the component Y may be a non-peptide mu-opioid receptor agonist, e.g.
  • morphine or one of its derivatives such as oxycodone or oxymorphone.
  • Indomethacin is a useful choice for the Y component when cyclooxygenase inhibition (COI) is desired.
  • COI cyclooxygenase inhibition
  • any of the other conventional non-steroidal anti-inflammatory agents such as aspirin, ibuprofen, napr ⁇ xyn or the like can be. used.
  • the BKAn/COI heterodimer may need to be hydrolyzed in order to obtain in vivo COI activity as cyclooxygenase is generally considered to be an intra-cellular enzyme.
  • this may be an active ester, e.g. 2- phenyl-alkanoate ester. There may also be used a heteroaryl alkanoate esterase inhibitor.
  • component Y preferred neutrophil elastase inhibitor for use herein as component Y is identified below as CE- 1218. This is believed to be a new compound and constitutes a further feature of the present
  • elastase inhibitors which may also be used as component Y, include fluoromethyl ketones, phosphonates, benzoxazoles, beta-lactams, etc.
  • component Y may comprise a peptide or non-peptide inhibitor having a desired activity other than bradykinin antagonist activity.
  • the Y component is preferably selected to provide activity against receptors or enzymes which have a common or close relationship to the activity of bradykinin, e.g. the treatment of pain or
  • neutrophil elastase inhibitor neutrophil elastase inhibitor, cyclooxygenase
  • C-Fiber afferents are known to mediate both the sensation of pain as well as the neurogenic
  • neuropeptides include: substance-P, neurokinin A, neurokinin B, calcitonin gene related peptide
  • CRP cholecystokinin
  • VIP vasoactive intestinal polypeptide
  • neuropeptide Y neuropeptide Y
  • small molecular weight compounds such as morphine, oxymorphone, fentanyl and their
  • neuropeptides from peripheral C-fibers by acting as mu-opioid receptor agonists locally (at terminal muopioid receptors in the periphery) and in the CNS. This inhibition is independent of both the constellation of peptides contained in the specific C-fiber as well as the stimulus causing their release.
  • BKAn/mu-opioid receptor agonist heterodimers BKAn/mu-opioid receptor agonist heterodimers. These compounds would be expected to attenuate or block both the humoral component of the inflammatory process as represented by the kinins as well as the neurogenic aspects of inflammation produced by the release of the neuropeptides.
  • one of the limiting aspects of the use of existing mu opioid agonists is their propensity to produce sedation, confusion, and a depressed
  • mu-opioid receptor agonists due to their ability to easily penetrate the CNS.
  • BKAn/mu-opoid receptor agonist heterodimers should not penetrate the CNS due to the highly cationic nature of the BKAn. Consequently, mu-opoid receptor agonist activity should be limited to the periphery and should result in a
  • the ability to block the activity of a primary mediator responsible for the initiation and maintenance of the inflammatory process may be a key to "single drug therapy" of sepsis or other severe inflammatory conditions requiring parenteral therapy or for the treatment of
  • a primary mediator responsible for the initiation and maintenance of the inflammatory process such as bradykinin
  • a primary final pathway effector responsible for actual tissue degradation and injury such as neutrophil elastase
  • Heterodimers containing combined BKAn/NEI activities can be designed to remain intact or to be dissociable as both targets (bradykinin receptors and neutrophil elastase) are extracellular in nature. However, should dissociation of the two active pharmacophores be desired, linking moieties tethering the two active components of the
  • heterodimer can be designed to be hydrolyzed by, for example, plasma hydrolases.
  • bradykinin A large proportion of the biological activity of bradykinin is interwoven with the generation of prostaglandins. For example, much of the
  • hyperalgesia associated with inflammatory pain appears to be dependent on the generation of certain prostaglandins both by the injured tissues and by the C-fibers themselves.
  • bradykinin and substance-P appear to be the primary stimuli for these "second messengers".
  • the local generation of prostaglandins by the injured tissues is bradykinin independent. This interaction of peptide pro-inflammatory mediators and
  • prostaglandins occurs in other settings as well and can also be considered a target for dual action compounds.
  • BKAn/COI activities may need to undergo in vivo dissociation of the respective pharmacophores as cyclooxygenase is an intracellular enzyme and functional bradykinin receptors are limited to the external plasma membrane.
  • Bradykinin and substance-P are known to act synergistically in the initiation and maintenance of the inflammatory and neurogenic components of both asthma and a variety of painful conditions.
  • bradykinin is one of the more potent, if not the most potent, agents capable of stimulating C-fiber sensory afferents that mediate peripheral pain and/or the sensation of cough and dyspnea in asthma.
  • These neurons regardless of the primary stimulus, will release substance-P which amplifies and augments the activity of bradykinin and other stimuli at the sensory nerve endings where these stimuli are acting.
  • This "one/two punch" of initial stimulus followed by local amplification is well documented and has significant implications for the success or failure of any single intervention.
  • Bradykinin's ability to produce acute bronchial smooth muscle constriction is at least partially dependent on the release of neurokinin A by the same C-fibers that release substance-P.
  • Neurokinin A exerts its effect via NK 2 receptors on the bronchial smooth muscle.
  • more than just bradykinin can release neurokinin A from these neurons and, as a result, a dually-specific antagonist with combined BK 2 /NK 2 antagonist activity should provide better overall amelioration of bronchoconstriction in the asthmatic patient than any other single agent.
  • heterodimers of the invention may be prepared in generally the same manner as described in WO 92/17201. Normally this involves adding the linking group X to the BKAn component at an
  • the linking group may be added to the non-peptide pharmacophore and the BKAn thereafter joined to the linker-modified pharmacophore. Representative procedures are described below although it will be recognized that various modifications may be used.
  • Oxycodone hydrochloride (0.182g, 0.52 mmol), acetic acid (0.475 ml, 8.3 mmol), S-benzyl
  • cysteamine (0.174g, 1.04 mmol) and methanol (5 ml) were combined and stirred at room temperature for an hour.
  • Sodium cyanoborohydride (95%, 0.033g, 0.52 mmol) was added, and the reaction stirred at room temperature for 24 h.
  • the mixture was concentrated in vacuo.
  • the resulting oil was dissolved in ethyl acetate and the ethyl acetate fraction was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo.
  • the thiol isolated was dissolved in a minimum quantity of DMF (N,N-dimethyl formamide, 2 ml).
  • Compound X (approximately 0.3 equiv) was dissolved in tris buffer (0.5 M, 4.0 ml) and added to the DMF solution and then stirred for 17h.
  • the crude mixture was purified on a reverse phase Vydac C-18 HPLC column using the gradient 15 - 40% CH 3 CN in water, 0.1% constant TFA, over 20 minutes. Retention time was 16.0 minutes. 26.4 mg of II was isolated as a white powder on lyophillization.
  • the BOC protecting group was removed off the compound IV with TFA (5.0 ml) in methylene chloride (5.0 ml). Methylene chloride was removed in vacuo and the residue was stripped with methylene chloride (20 ml x 3) and then with triethyl amine (3 ml x 3). 3-S-benzyl mercapto propionic acid (0.15g, 0.75 mmol), EDC (0.15g, 0.75 mmol), HOBt (0.103g, 0.75 mmol) and Et3N (0.35 ml, 2.48 mmol) were dissolved in DMF (5.0 ml) and stirred at 0°C for an hour.
  • Oxymorphone hydrochloride (0.56g, 1.66 mmol) , S-benzyl cysteamine (0.69g, 4.15 mmol), acetic acid (1.52 ml, 26.5 mmol) and sodium cyanoborohydride (0.11g, 1.66 mmol) were used according to the procedure for I.
  • the composition of the third eluant, EtOAc-MeOH-Et 3 N, used in the purification of the crude mixture was 9:1:0.3, v/v/v. On
  • VII (0.063g, 0.14 mmol) was deprotected following the procedure for II. The thiol was then treated with X (0.335g, 0.152 mmol) in tris buffer. The crude mixture was purified on a reverse phase Vydac C-18 HPLC column using the gradient 15 - 70% CH 3 CN in water, 0.1% constant TFA over 35 minutes. VIII had a retention time of 15.0 minutes. 119.0 mg (45.0%) of VII was isolated as a white powder on lyophillization.
  • heterodimers were evaluated in vi tro using the rat uterus (BK 2 -receptor activity) and the electrically stimulated guinea pig ileum (mu-opiate receptor activity) assays. These assays are well known in the art. The results obtained are shown in Table I :
  • mice (open circles) show a characteristic bi-phasic response to the injected formalin wherein there is a short lasting initial response followed by a quiescent period which is then followed by a sustained period of hind limb licking.
  • the licking behavior is interpreted to mean that the limb is irritated and painful. The greater the time spent licking, the more painful the stimulus.
  • Oxymorphone (Fig. 2 A and B) reduces both phases of the licking behavior but with significant behavioral obtundation resulting in catalepsy and frank respiratory depression at the highest doses (0.9 and 3.0 umoles/kg).
  • the bradykinin antagonist CP-0127 (a potent BK 2 selective antagonist--Fig. 3 A and B) will reduce the time spent licking in both phases of the formalin test but at doses that are substantially greater than would be practical in a clinical setting.
  • CP-0494 (Fig.
  • the linking element used in this heterodimer was chosen so as to allow for unhindered' hydrolysis of the joining ester bond by serum esterases.
  • the linker can be modified so as to provide different rates of hydrolysis varying from rapid to practically zero by altering the steric accessibility of the ester carbonyl carbon or by changing the chemistry to an amide linkage.
  • Completely stable linker moieties can also be used which are free from potential hydrolytic degradation.
  • Trifluoroacetic acid 25 mL was added to a stirred solution of 4-(3'-carbo-tert-butoxy- propylmercapto) phenyl 4-tert-butylphenylisobutrate
  • BKAn activity (pA 2 ) was assessed using the rat uterus preparation and NEI (K i ss ) activity was evaluated using purified human neutrophil elastase (HNE) and a synthetic soluble chromogenic substrate,
  • MOS-AAPV-pNA methoxysuccinyl-alanyl-alanyl-prolyl-valyl- paranitroaniline
  • succinimidohexanol derivative of CP-0126 wherein the intact compound is almost a full log less potent than the monomeric BKAn.
  • CP-0502 was added to freshly obtained normal human plasma and allowed to incubate at 37°C for varying amounts of time. At the designated time the samples were treated with acidified (0.1 N HCl) acetonitrile in order to precipitate the plasma proteins. Aliquots (75 ul) of the supernatents were then analyzed on a Vydac C-18 reverse phase HPLC column using 24% to 80% acetonitrile gradient in 0.1% TFA. The eluent was monitored at 214 nm.
  • Figures 5 a and b are representative reverse phase HPLC chromatograms illustrative of this type of analysis. As can be seen from these
  • the dissociation of the heterodimer into its two component parts will have less of an effect on its activity than that for the BKAn component.
  • reaction mixture was purified in 1 injection on a Vydac 1" C-18 reverse phase column at 10ml/min, using a gradient running from 15% acetonitrile/0.1% TFA to 40% acetonitrile/0.1% TFA in 20 minutes. Appropriate fractions were lyophilized to yield 64 mg (45%) of a colorless powder (CP-0460).
  • Laser desorption mass
  • CP-0460 was exposed to rat lung parenchymal strips which were then challenged with arachidonic acid.
  • This tissue is known to contain both non-specific esterase activity as well as to convert arachidonic acid to thromboxane (via a cyclooxygenase dependent pathway) which is then ultimately responsible for the smooth muscle contraction observed in this assay.
  • CP-0460 (similarly to CP-0502) did not behave as a classical competitive antagonist of bradykinin induced uterine contraction but rather as a type of "pseudo-non-competitive" antagonist, particularly at higher concentrations. This atypical behavior cannot be attributed to COI activity per se as free indomethacin has no effect on this assay at any concentration.
  • heterodimers can be made using a variety of
  • linking moieties to provide a free hydroxyl and the carboxyl group (a common feature of many COIs) of the COI monomer to form a hydrolyzable ester based heterodimer.
  • Compounds such as these may be used in the treatment of a variety of
  • this component may equally comprise in whole or part a peptide as exemplified in the afore-mentioned WO 92/17201, including the heterodimers therein
  • dimers of the invention may be used in the form of conventional pharmaceutical compositions comprising the active component and a
  • compositions may be adapted for topical, oral, aerosolized, intramuscular, subcutaneous or
  • the amount of active component present in such compositions will range from, for example, about 0.001 to 90.0% by weight depending on the application and mode of
  • an effective dose is in the order of 0.1 to 1000 micrograms per kg body weight.

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Abstract

Antagoniste de bradykinine de la formule (BKAn) (X) (Y) dans laquelle BKAn est un peptide antagoniste de la bradykinine, Y est un pharmacophore et X une liaison en pont liant chimiquement les composants BKAn et Y.
PCT/US1993/010222 1992-11-10 1993-10-29 Antagoniste de bradykinine WO1994011021A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6512112A JPH08503460A (ja) 1992-11-10 1993-10-29 ブラジキニンアンタゴニスト
EP93924412A EP0671941A4 (fr) 1992-11-10 1993-10-29 Antagoniste de bradykinine.
AU54109/94A AU5410994A (en) 1992-11-10 1993-10-29 Bradykinin antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US97400092A 1992-11-10 1992-11-10
US07/974,000 1992-11-10

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WO1994011021A1 true WO1994011021A1 (fr) 1994-05-26

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JP (1) JPH08503460A (fr)
CN (1) CN1094058A (fr)
AU (1) AU5410994A (fr)
CA (1) CA2147869A1 (fr)
IL (1) IL107400A0 (fr)
MX (1) MX9306988A (fr)
NZ (1) NZ257477A (fr)
PL (1) PL304654A1 (fr)
WO (1) WO1994011021A1 (fr)
ZA (1) ZA938014B (fr)

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EP0663401A1 (fr) * 1993-07-23 1995-07-19 Toray Industries, Inc. Derive de morphinane et application medicale
WO1996039425A2 (fr) * 1995-06-05 1996-12-12 Cortech, Inc. Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde
FR2739553A1 (fr) * 1995-10-06 1997-04-11 Oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
US5863901A (en) * 1996-03-27 1999-01-26 Hoechst Aktiengesellschaft Use of bradykinin antagonists for the production of pharmaceuticals for the treatment of chronic fibrogenetic liver disorders and acute liver disorders
US6143719A (en) * 1995-06-09 2000-11-07 The Regents Of The University Of Michigan Bradykinin analogs as selective thrombin inhibitors
US6245736B1 (en) 1996-10-14 2001-06-12 Aventis Pharma Deutschland Gmbh Use of peptidic bradykinin antagonists for the treatment and prevention of Alzheimer's disease
US6359111B1 (en) * 1998-05-28 2002-03-19 Neorx Corporation Opioid receptor targeting
WO2003020200A2 (fr) 2000-11-16 2003-03-13 New River Pharmaceuticals Inc. Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose
EP1357928A2 (fr) * 2000-11-16 2003-11-05 New River Pharmaceuticals Inc. Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose
WO2004012735A2 (fr) * 2002-07-31 2004-02-12 Schering Ag Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci
US6982249B1 (en) 1997-04-23 2006-01-03 The Regents Of The University Of Michigan Bradykinin analogs as selective inhibitors of cell activation
US7060708B2 (en) 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US7129254B2 (en) 2002-07-31 2006-10-31 Schering Aktiengesellschaft Effector conjugates, process for their production and their pharmaceutical use
US7169752B2 (en) 2003-09-30 2007-01-30 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
US7338939B2 (en) 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
US7375083B2 (en) 2003-09-30 2008-05-20 Shire Llc Pharmaceutical compositions for prevention of overdose or abuse
US7375082B2 (en) 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
AU2001297565B2 (en) * 2000-11-16 2008-06-05 Takeda Pharmaceutical Company Limited A novel pharmaceutical compound and methods of making and using same
US7427600B2 (en) 2000-08-22 2008-09-23 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
EP2080511A2 (fr) * 2000-08-22 2009-07-22 Shire LLC Systèmes d'administration de principe actif et procédé pour la protection et l'administration de principes actifs
US7622441B2 (en) 2002-02-22 2009-11-24 Shire Llc Sustained release pharmaceutical compounds to prevent abuse of controlled substances
US7700561B2 (en) 2002-02-22 2010-04-20 Shire Llc Abuse-resistant amphetamine prodrugs

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GB0624880D0 (en) * 2006-12-14 2007-01-24 Johnson Matthey Plc Improved method for making analgesics

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EP0663401A1 (fr) * 1993-07-23 1995-07-19 Toray Industries, Inc. Derive de morphinane et application medicale
WO1996039425A2 (fr) * 1995-06-05 1996-12-12 Cortech, Inc. Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde
WO1996039425A3 (fr) * 1995-06-05 1997-01-30 Cortech Inc Composes ayant une activite antagoniste de la bradykinine et une activite agoniste mu-opioïde
US6143719A (en) * 1995-06-09 2000-11-07 The Regents Of The University Of Michigan Bradykinin analogs as selective thrombin inhibitors
US6468972B1 (en) 1995-10-06 2002-10-22 Societe L'oreal S.A. Method to promote, stimulate and/or delay hair loss by a brady kinin antagonist
WO1997013493A1 (fr) * 1995-10-06 1997-04-17 L'oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
FR2739553A1 (fr) * 1995-10-06 1997-04-11 Oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
US5863901A (en) * 1996-03-27 1999-01-26 Hoechst Aktiengesellschaft Use of bradykinin antagonists for the production of pharmaceuticals for the treatment of chronic fibrogenetic liver disorders and acute liver disorders
US6245736B1 (en) 1996-10-14 2001-06-12 Aventis Pharma Deutschland Gmbh Use of peptidic bradykinin antagonists for the treatment and prevention of Alzheimer's disease
US6982249B1 (en) 1997-04-23 2006-01-03 The Regents Of The University Of Michigan Bradykinin analogs as selective inhibitors of cell activation
US6359111B1 (en) * 1998-05-28 2002-03-19 Neorx Corporation Opioid receptor targeting
US7060708B2 (en) 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
EP2080511A3 (fr) * 2000-08-22 2009-09-30 Shire LLC Systèmes d'administration de principe actif et procédé pour la protection et l'administration de principes actifs
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US7427600B2 (en) 2000-08-22 2008-09-23 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
EP1357928A2 (fr) * 2000-11-16 2003-11-05 New River Pharmaceuticals Inc. Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose
EP1357928A4 (fr) * 2000-11-16 2004-12-29 New River Pharmaceuticals Inc Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose
AU2001297565B2 (en) * 2000-11-16 2008-06-05 Takeda Pharmaceutical Company Limited A novel pharmaceutical compound and methods of making and using same
WO2003020200A2 (fr) 2000-11-16 2003-03-13 New River Pharmaceuticals Inc. Nouveau compose pharmaceutique et procedes de fabrication et d'utilisation de ce compose
US7375082B2 (en) 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
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US7700561B2 (en) 2002-02-22 2010-04-20 Shire Llc Abuse-resistant amphetamine prodrugs
WO2004012735A3 (fr) * 2002-07-31 2004-05-27 Schering Ag Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci
US7335775B2 (en) 2002-07-31 2008-02-26 Schering Aktiengesellschaft Effector conjugates, process for their production and their pharmaceutical use
US7129254B2 (en) 2002-07-31 2006-10-31 Schering Aktiengesellschaft Effector conjugates, process for their production and their pharmaceutical use
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US7375083B2 (en) 2003-09-30 2008-05-20 Shire Llc Pharmaceutical compositions for prevention of overdose or abuse
US7338939B2 (en) 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
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CA2147869A1 (fr) 1994-05-26
PL304654A1 (en) 1995-01-09
ZA938014B (en) 1994-07-11
NZ257477A (en) 1996-07-26
IL107400A0 (en) 1994-01-25
AU5410994A (en) 1994-06-08
CN1094058A (zh) 1994-10-26
EP0671941A1 (fr) 1995-09-20
JPH08503460A (ja) 1996-04-16
EP0671941A4 (fr) 1996-05-29
MX9306988A (es) 1995-01-31

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