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 PDFInfo
- 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
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- 125000003287 1H-imidazol-4-ylmethyl group Chemical group [H]N1C([H])=NC(C([H])([H])[*])=C1[H] 0.000 description 1
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- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
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- 102000008934 Muscle Proteins Human genes 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- BIWSVIWRBAFQDU-UHFFFAOYSA-N N-(2,6-dichlorophenyl)-N-(oxan-2-yl)-4,5-dihydroimidazol-1-amine Chemical compound ClC1=C(N(C2OCCCC2)N2C=NCC2)C(=CC=C1)Cl BIWSVIWRBAFQDU-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- UHUZBXCDYJGKIY-QDBJXHRASA-N OC[C@H](O)[C@@H](O)[C@H](O)CO.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O UHUZBXCDYJGKIY-QDBJXHRASA-N 0.000 description 1
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000005800 cardiovascular problem Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
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- 239000000122 growth hormone Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
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- 229960000890 hydrocortisone Drugs 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 231100001039 immunological change Toxicity 0.000 description 1
- VUSYGSNEEYEGGX-UHFFFAOYSA-N indol-1-amine Chemical compound C1=CC=C2N(N)C=CC2=C1 VUSYGSNEEYEGGX-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
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- 210000005027 intestinal barrier Anatomy 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- MGFHWOWUPGRINA-UHFFFAOYSA-N n-(dicyclopropylmethyl)-1,3-oxazol-2-amine Chemical compound C1CC1C(C1CC1)NC1=NC=CO1 MGFHWOWUPGRINA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SACAEVOKRBNXPN-UHFFFAOYSA-N n-phenyl-4,5-dihydroimidazol-1-amine Chemical class C1=NCCN1NC1=CC=CC=C1 SACAEVOKRBNXPN-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000022001 negative regulation of insulin secretion Effects 0.000 description 1
- 230000010503 organ complication Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- MSGRFBKVMUKEGZ-UHFFFAOYSA-N quinoxalin-6-amine Chemical compound N1=CC=NC2=CC(N)=CC=C21 MSGRFBKVMUKEGZ-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 210000003019 respiratory muscle Anatomy 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 230000000638 stimulation Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
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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
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 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)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0775134A4 (fr) * | 1994-08-04 | 1997-08-13 | Synaptic Pharma Corp | Nouveaux derives de benzimidazole |
CZ397698A3 (cs) * | 1996-06-06 | 1999-05-12 | Eli Lilly And Company | Prostředky a způsob léčení městnatého srdečního selhání |
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)
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 |
-
1993
- 1993-07-29 DE DE19934325491 patent/DE4325491A1/de not_active Withdrawn
-
1994
- 1994-07-27 AU AU75331/94A patent/AU7533194A/en not_active Abandoned
- 1994-07-27 WO PCT/EP1994/002475 patent/WO1995003798A2/fr not_active Application Discontinuation
- 1994-07-27 EP EP94925399A patent/EP0719139A1/fr not_active Ceased
Cited By (1)
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 |
DE4325491A1 (de) | 1995-02-02 |
AU7533194A (en) | 1995-02-28 |
WO1995003798A3 (fr) | 2001-05-03 |
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