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WO1995003798A2 - UTILISATION D'AGONISTES D'α-2 A EFFICACITE CENTRALE POUR INHIBER LE METABOLISME DE POSTAGRESSION - Google Patents

UTILISATION D'AGONISTES D'α-2 A EFFICACITE CENTRALE POUR INHIBER LE METABOLISME DE POSTAGRESSION Download PDF

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Publication number
WO1995003798A2
WO1995003798A2 PCT/EP1994/002475 EP9402475W WO9503798A2 WO 1995003798 A2 WO1995003798 A2 WO 1995003798A2 EP 9402475 W EP9402475 W EP 9402475W WO 9503798 A2 WO9503798 A2 WO 9503798A2
Authority
WO
WIPO (PCT)
Prior art keywords
imidazoline
amino
tetrahydro
manufacture
radical
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1994/002475
Other languages
German (de)
English (en)
Other versions
WO1995003798A3 (fr
Inventor
Norbert Mertes
Christiane Goeters
Joseph Zander
Martin Kuhmann
Hans-Michael Brecht
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to AU75331/94A priority Critical patent/AU7533194A/en
Priority to EP94925399A priority patent/EP0719139A1/fr
Publication of WO1995003798A2 publication Critical patent/WO1995003798A2/fr
Anticipated expiration legal-status Critical
Publication of WO1995003798A3 publication Critical patent/WO1995003798A3/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to the use of ⁇ -2 agonists for
  • the hormonal changes serve to restore circulation and organ perfusion.
  • the metabolism rate is reduced.
  • the catabolic flow phase is characterized by an increased metabolism rate and negative nitrogen balances.
  • the hormonal changes result in a large number of metabolic changes in the intermediate metabolism.
  • Antiinsulinary factors primarily catecholamines, glucagon and cortisol - lead to an increase in hepatic gluconeogenesis with simultaneous inhibition of insulin secretion. Lactate, glycerin, alanine and glutamine are used as substrates.
  • the increased supply of glucose is metabolized well by the brain, erythocytes and the wound areas, while the glucose sterilization in the remaining tissues is largely disturbed. Lipolysis and fat oxidation are increased. Fat serves as a source of energy for most organs in the stress metabolism, this applies in particular to the liver, muscles and myocardium.
  • the protein breakdown is increased.
  • the increasingly mobilized amino acids serve to build up acute phase proteins, intestinal proteins (intestinal mucosa) and various immune factors, as well as a substrate for increased gluconeogenesis.
  • Alanine and glutamine play a key role here. These changes normalize as the patient enters the anabolic flow phase. Glucose sterilization increases and fat oxidation decreases, nitrogen balances become positive.
  • the postaggressive metabolism is characterized by a characteristic hormonal constellation, the result of which is an increase in the resting energy requirement and an increased nitrogen excretion (protein breakdown rate exceeds the protein synthesis rate). Since there are no protein deposits that can be broken down without loss of function, the immune system and wound healing can be significantly impaired in the postoperative phase. For this reason, an adequate supply of energy substrates and an adequate supply of amino acids to improve the nitrogen balance perioperatively is of the utmost importance.
  • the centrally active ⁇ -2 receptor agonist clonidine appears to be suitable for the treatment of the post-aggression syndrome, in particular for the inhibition of the post-aggression metabolism.
  • imidazolines of the general formula are of interest
  • X, Y, Z may be the same or different, a hydrogen or halogen atom, e.g. F, Cl, Br, an alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitrile, hydroxyl, alkylthio or halothio group, a cyclopropyl radical, Rl a hydrogen atom, an alkyl or tetrahydropyran radical, and the like Acid addition salts.
  • halogen atom e.g. F, Cl, Br
  • Rl a hydrogen atom, an alkyl or tetrahydropyran radical, and the like Acid addition salts.
  • alkyl in the sense of the present definition, branched or unbranched alkyl groups with 1 to 4 are also - insofar as they are part of other radicals Understand carbon atoms, for example the following are mentioned: methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl, sec-butyl and tert-buty.
  • Azepines and tetrazines of the general formulas below likewise have a centrally active ⁇ -2-receptor active component and are claimed for the use according to the invention.
  • R ⁇ is a hydrogen atom, a straight-chain or branched alkyl radical which may be substituted by a hydroxyl group and has 1-4 carbon atoms, an allyl, cycloalkyl, hexahydrobenzyl, phenyl, phenylethyl or benzyl radical, where the benzyl radical in the nucleus can be substituted by one or two halogen atoms, by one to three methoxy groups, by a trifluoromethyl or alkyl group having 1-3 carbon atoms and if X represents a sulfur atom,
  • R represents a hydrogen atom, a straight-chain or branched alkyl radical having 1-5 carbon atoms, an allyl, cycloalkyl, phenyl, benzyl or phenylethyl radical or, if X represents an oxygen atom, a hydrogen atom.
  • Preferred compounds are 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4-d] azepine (BHT 933) and 6-allyl-2-amino-4,5,7 , 8-tetrahydro-6H-thiazolo [5,4-d] aze ⁇ in (BHT 920) and, if appropriate, their acid addition salts.
  • R 1 is an unsubstituted or halogen atom, preferably fluorine, chlorine or bromine atom, methyl, methoxy or trifluoromethyl group, the same or different mono- to trisubstituted phenyl radical and R2 is a hydrogen atom or an unsubstituted or one to more than one halogen atom, preferably chlorine atom , substituted phenyl radical;
  • 6-Quinoxalinamine 5-bromo-N- (4,5-dihydro-lH-imidazol-2-yl) - (brimonidine tartrate), (5-bromo-N- (4,5-dmydro-lH-imidazol-2 -yl) -6-quinoxalinamine); 2H- [l] benzopyrano [3,4] pyridin-7-ol, 1,3,4, 4a, 5, 10b-hexahydro-4-propyl hydrochloride (CGS 15873), (1,3,4, 4a, 5, 10b-hexahydro-4-propyl-2H- [1] benzopyrano [3,4] pyridin-7-ol); lH-imidazole, 4- [l- (2,3-dimethylphenyl) ethyl] -, (4- [l- (2,3-dimethylphenyl) ethyl] - lH-imidazole), (dexmedeto
  • Guanidines (4,7-dichloro-l, 3-dihydro-2H-isoindol-2-yl) -; ((4,7-dichloro-l, 3-dihydro-2H-isoindol-2-yl) guanidine), (Aganodine); lH-Imidazole-2-carboxylic acid, l - [[8.beta.) - 6-methylergolin-8-yl] methyl] -, ethyl ester; (l-
  • Benzenemethanol 4-hydroxy-.alpha .- [[[3- (2-methoxyphenyl) -l, l-dimethylpropyl] amino] methyl], (4-hydroxy-.alpha .- [[[3- (2-methoxyphenyl ) -l, l-dimethylpropy ⁇ amino] methyl] -benzenemethanol),
  • R C] tCH 3 - (4-t-butyl-2,6-dimethyl-3-hydroxy-benzyl) -2-imidazoline. - (4-t-Butyl-2,6-dimethyl-benzyl) -2-imidazoline.
  • a dose in the order of 2-5 ⁇ / kg / h can be given continuously intravenously, the hemodynamic behavior of the patient being important for controlling the dose in individual cases.
  • the therapy should be terminated gradually (e.g. reduction of the dose by 50% every 12 hours), but at the earliest after 4-5 days.
  • the compounds mentioned according to the invention can be used in conventional pharmaceutical preparations. Injection solutions are preferred according to the invention.
  • the dosage is of course dependent on the potency of the ⁇ -2 receptor agonist.
  • clonidine for example, in an i.V.
  • a dosage of 1 - 10 ⁇ g / kg / h can be used.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'agonistes des récepteurs α-2 dans le traitement du syndrome de postagression.
PCT/EP1994/002475 1993-07-29 1994-07-27 UTILISATION D'AGONISTES D'α-2 A EFFICACITE CENTRALE POUR INHIBER LE METABOLISME DE POSTAGRESSION Ceased WO1995003798A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU75331/94A AU7533194A (en) 1993-07-29 1994-07-27 Use of centrally effective alpha-2 agonists for inhibiting postaggression metabolism
EP94925399A EP0719139A1 (fr) 1993-07-29 1994-07-27 UTILISATION D'AGONISTES D'$g(a)-2 A EFFICACITE CENTRALE POUR INHIBER LE METABOLISME DE POSTAGRESSION

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4325491.8 1993-07-29
DE19934325491 DE4325491A1 (de) 1993-07-29 1993-07-29 Verwendung von zentral wirksamen alpha-2-Agonisten zur Hemmung des Postaggressionsstoffwechsels

Publications (2)

Publication Number Publication Date
WO1995003798A2 true WO1995003798A2 (fr) 1995-02-09
WO1995003798A3 WO1995003798A3 (fr) 2001-05-03

Family

ID=6494011

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002475 Ceased WO1995003798A2 (fr) 1993-07-29 1994-07-27 UTILISATION D'AGONISTES D'α-2 A EFFICACITE CENTRALE POUR INHIBER LE METABOLISME DE POSTAGRESSION

Country Status (4)

Country Link
EP (1) EP0719139A1 (fr)
AU (1) AU7533194A (fr)
DE (1) DE4325491A1 (fr)
WO (1) WO1995003798A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977121A (en) * 1995-02-28 1999-11-02 Eli Lilly And Company Use of moxonidine for the treatment of atherosclerosis

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2196792A1 (fr) 1994-08-04 1996-02-15 Yoon T. Jeon Nouveaux derives de benzimidazole
EP0914128A1 (fr) * 1996-06-06 1999-05-12 Eli Lilly And Company Formulation et methode pour traiter l'insuffisance cardiaque congestive
US6495583B1 (en) 1997-03-25 2002-12-17 Synaptic Pharmaceutical Corporation Benzimidazole derivatives
AUPP020297A0 (en) * 1997-11-05 1997-11-27 University Of Melbourne, The A novel receptor, and compounds which bind thereto
DE19938825A1 (de) * 1999-08-19 2001-04-26 Boehringer Ingelheim Pharma Wirkstoffkombination mit Clonidin
GB0119435D0 (en) * 2001-02-15 2001-10-03 Aventis Pharm Prod Inc Method of treating of demyelinating diseases or conditions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5120713A (en) * 1990-09-10 1992-06-09 Applied Research Systems Ars Holding N.V. Treatment of obesity with an alpha-2-adrenergic agonist and a growth hormone releasing peptide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977121A (en) * 1995-02-28 1999-11-02 Eli Lilly And Company Use of moxonidine for the treatment of atherosclerosis

Also Published As

Publication number Publication date
EP0719139A1 (fr) 1996-07-03
WO1995003798A3 (fr) 2001-05-03
DE4325491A1 (de) 1995-02-02
AU7533194A (en) 1995-02-28

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