DE19548812A1 - Use of inhibitors of the cellular Na · + · / H · + · exchanger (NHE) for the manufacture of a medicament for respiratory stimulation - Google Patents

Use of inhibitors of the cellular Na · + · / H · + · exchanger (NHE) for the manufacture of a medicament for respiratory stimulation

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Publication number
DE19548812A1
DE19548812A1 DE19548812A DE19548812A DE19548812A1 DE 19548812 A1 DE19548812 A1 DE 19548812A1 DE 19548812 A DE19548812 A DE 19548812A DE 19548812 A DE19548812 A DE 19548812A DE 19548812 A1 DE19548812 A1 DE 19548812A1
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Germany
Prior art keywords
hoe
medicament
manufacture
exchange inhibitor
inhibitors
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.)
Withdrawn
Application number
DE19548812A
Other languages
German (de)
Inventor
Klaus Dr Wirth
Wolfgang Dr Scholz
Hans-Willi Dr Jansen
Hans Jochen Dr Lang
Joachim Dr Brendel
Heinz-Werner Dr Kleemann
Jan-Robert Dr Schwark
Andreas Dr Weichert
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Hoechst AG
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Hoechst AG
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Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Priority to DE19548812A priority Critical patent/DE19548812A1/en
Priority to BR9612287-0A priority patent/BR9612287A/en
Priority to IL12511496A priority patent/IL125114A0/en
Priority to HU9900807A priority patent/HUP9900807A3/en
Priority to CN96199403A priority patent/CN1207676A/en
Priority to TR1998/01235T priority patent/TR199801235T2/en
Priority to SK883-98A priority patent/SK88398A3/en
Priority to PCT/EP1996/005614 priority patent/WO1997024113A1/en
Priority to PL96327693A priority patent/PL327693A1/en
Priority to KR1019980704927A priority patent/KR19990076802A/en
Priority to AU13720/97A priority patent/AU717247B2/en
Priority to EP96943956A priority patent/EP0869779A1/en
Priority to CA002241531A priority patent/CA2241531A1/en
Publication of DE19548812A1 publication Critical patent/DE19548812A1/en
Priority to MX9805141A priority patent/MX9805141A/en
Priority to NO982989A priority patent/NO982989L/en
Priority to CZ982021A priority patent/CZ202198DA3/en
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/425—Thiazoles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60L—PROPULSION OF ELECTRICALLY-PROPELLED VEHICLES; SUPPLYING ELECTRIC POWER FOR AUXILIARY EQUIPMENT OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRODYNAMIC BRAKE SYSTEMS FOR VEHICLES IN GENERAL; MAGNETIC SUSPENSION OR LEVITATION FOR VEHICLES; MONITORING OPERATING VARIABLES OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRIC SAFETY DEVICES FOR ELECTRICALLY-PROPELLED VEHICLES
    • B60L50/00—Electric propulsion with power supplied within the vehicle
    • B60L50/50—Electric propulsion with power supplied within the vehicle using propulsion power supplied by batteries or fuel cells
    • B60L50/60—Electric propulsion with power supplied within the vehicle using propulsion power supplied by batteries or fuel cells using power supplied by batteries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60L—PROPULSION OF ELECTRICALLY-PROPELLED VEHICLES; SUPPLYING ELECTRIC POWER FOR AUXILIARY EQUIPMENT OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRODYNAMIC BRAKE SYSTEMS FOR VEHICLES IN GENERAL; MAGNETIC SUSPENSION OR LEVITATION FOR VEHICLES; MONITORING OPERATING VARIABLES OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRIC SAFETY DEVICES FOR ELECTRICALLY-PROPELLED VEHICLES
    • B60L7/00—Electrodynamic brake systems for vehicles in general
    • B60L7/10—Dynamic electric regenerative braking
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60L—PROPULSION OF ELECTRICALLY-PROPELLED VEHICLES; SUPPLYING ELECTRIC POWER FOR AUXILIARY EQUIPMENT OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRODYNAMIC BRAKE SYSTEMS FOR VEHICLES IN GENERAL; MAGNETIC SUSPENSION OR LEVITATION FOR VEHICLES; MONITORING OPERATING VARIABLES OF ELECTRICALLY-PROPELLED VEHICLES; ELECTRIC SAFETY DEVICES FOR ELECTRICALLY-PROPELLED VEHICLES
    • B60L7/00—Electrodynamic brake systems for vehicles in general
    • B60L7/10—Dynamic electric regenerative braking
    • B60L7/16—Dynamic electric regenerative braking for vehicles comprising converters between the power source and the motor
    • E—FIXED CONSTRUCTIONS
    • E01—CONSTRUCTION OF ROADS, RAILWAYS, OR BRIDGES
    • E01C—CONSTRUCTION OF, OR SURFACES FOR, ROADS, SPORTS GROUNDS, OR THE LIKE; MACHINES OR AUXILIARY TOOLS FOR CONSTRUCTION OR REPAIR
    • E01C19/00—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving
    • E01C19/22—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving for consolidating or finishing laid-down unset materials
    • E01C19/23—Rollers therefor; Such rollers usable also for compacting soil
    • E01C19/26—Rollers therefor; Such rollers usable also for compacting soil self-propelled or fitted to road vehicles
    • E—FIXED CONSTRUCTIONS
    • E01—CONSTRUCTION OF ROADS, RAILWAYS, OR BRIDGES
    • E01C—CONSTRUCTION OF, OR SURFACES FOR, ROADS, SPORTS GROUNDS, OR THE LIKE; MACHINES OR AUXILIARY TOOLS FOR CONSTRUCTION OR REPAIR
    • E01C19/00—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving
    • E01C19/22—Machines, tools or auxiliary devices for preparing or distributing paving materials, for working the placed materials, or for forming, consolidating, or finishing the paving for consolidating or finishing laid-down unset materials
    • E01C19/23—Rollers therefor; Such rollers usable also for compacting soil
    • E01C19/28—Vibrated rollers or rollers subjected to impacts, e.g. hammering blows

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Mechanical Engineering (AREA)
  • Transportation (AREA)
  • Power Engineering (AREA)
  • Civil Engineering (AREA)
  • Architecture (AREA)
  • Structural Engineering (AREA)
  • Sustainable Energy (AREA)
  • Sustainable Development (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The active ingredients identified as NHE inhibitors are particularly suitable for the preparation of a drug for respiratory stimulation. They are particularly good for treating sleep apnea or other respiratory disorders.

Description

Verwendung von Inhibitoren des zellulären Na⁺/H⁺-Exchangers (NHE) zur Herstellung eines Medikament zur Atemstimulation.Use of inhibitors of the cellular Na⁺ / H⁺ exchanger (NHE) for Manufacture of a medication for breathing stimulation.

Die Erfindung betrifft die Verwendung NHE-Inhibitoren zur Herstellung eines Medikaments zur Atemstimulation.The invention relates to the use of NHE inhibitors for the production of a Medication for breathing stimulation.

Bei den bekannten und als NHE-Inhibitoren identifizierten Wirkstoffen handelt es sich um Guanidin-Derivate der Formel I, vorzugsweise um Acylguanidine der Formel II:The known active substances identified as NHE inhibitors are are guanidine derivatives of the formula I, preferably acylguanidines Formula II:

worin R die Bedeutung eines Resteswhere R is the meaning of a radical

hat, worin R1 bis R5, X und Cy die in der WO 95 95 04 052 A1 angegebenen Bedeutungen haben, bzw. worin R′ ein substituierter aromatischer oder heterocyclischer Rest ist, wie in folgenden Publikationen und Patentveröffentlichungen beschrieben: Edward J. Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine", J. WILEY & Sons (1983), 303-341, und in folgenden Patent- bzw. Offenlegungsschriften:
DE 43 37 611; DE 43 37 609; EP-OS 667 341 A1; EP-OS 622 356 A1; WO 9426709; WO 95 04052-A1; EP-OS 416 499, US 5 091 394, US 5 292 755 (HOE 89/F 288); EP-OS 556 674, US 5 373 024 (HOE 92/F 034); EP-OS 556 673 (HOE 92/F 035); DE-OS 42 04 577.0, US 5 364 868, EP-OS 556 672 (HOE 92/F 036), EP 612 723 (HOE 92/F 054); NZ 248 013 (HOE 92/F 197 K); NZ 264 130, DE-OS 43 26 005 A1 (HOE 92/F 223 K); NZ 248 703, EP-OS 589 336 (HOE 92/F 303 K); US 5 416 094, NZ 248 761 (HOE 92/F 304); EP 602 522, NZ 250 438 (HOE 92/F 404); EP 602 523, NZ 250 437 (HOE 92/F 405); NZ 250 450, EP 603 650 (HOE 92/F 411); DE-OS 43 05 250.9, NZ 250 919 (HOE 93/F 054); EP-OS 627 413, NZ 260 660 (HOE 93/F 153); DE-OS 43 18 756, EP 628 543, NZ 260 681 (HOE 93/F 154); EP-OS 640 593, DE-OS 43 25 822, NZ 264 117 (HOE 93/F 220); EP-OS 638 548; NZ 264 216 (HOE 93/F 236); DE-OS 43 28 352, EP-OS 640 587, NZ 264 282 (93/F 249); DE-OS 43 28 869, EP-OS 640 588, NZ 264 307 (HOE 93/F 254); EP-OS 638 548, NZ 264 216 (HOE 93/F 236); DE-OS 43 44 550, EP-OS 659 748, NZ 270 264 (HOE 93/F 436); NZ 270 370, EP-OS 666 252 (HOE 94/F 014); NZ 270 894, EP-OS 676 395, DE-OS 44 12 334 (HOE 94/F 094); EP-OS 682 017, NZ 272 058, DE-OS 44 15 873 (HOE 94/F 123); NZ 272 103, DE-OS 44 17 004, EP-OS 686 627 (HOE 94/F 134); DE-OS 44 21 536, EP-OS 690 048, NZ 272 373 (HOE 94/F 168); P 44 22 685.3 (HOE 94/F 182); P 44 28 480.2 (HOE 94/F 227); P 44 32 106.6 (HOE 94/F 265); P 44 32 105.8 (HOE 94/F 266); P 44 32 101.5 (HOE 94/F 267); P 44 41 880.9 (HOE 94/F 352); P 195 04 805.9 (HOE 95/F 021); EP 95 105 724.9 (HOE 95/F 072); 195 18 073.9 (HOE 95/F 109); P 195 18 796.2 (HOE 95/F 115); 195 26 381.2 (HOE 95/F 167); 195 27 305.2 (HOE 95/F 173); EP 95 115 240.4 (HOE 95/F 220); 195 40 995.7 (HOE 95/F 253); 195 42 306.2 (HOE 95/F 265); 195 43 194 (HOE 95/F 269).in which R1 to R5, X and Cy have the meanings given in WO 95 95 04 052 A1, or in which R 'is a substituted aromatic or heterocyclic radical, as described in the following publications and patent publications: Edward J. Cragoe, Jr ., "DIURETICS, Chemistry, Pharmacology and Medicine", J. WILEY & Sons (1983), 303-341, and in the following patent and published documents:
DE 43 37 611; DE 43 37 609; EP-OS 667 341 A1; EP-OS 622 356 A1; WO 9426709; WO 95 04052-A1; EP-OS 416 499, US 5,091,394, US 5,292,755 (HOE 89 / F 288); EP-OS 556 674, US 5 373 024 (HOE 92 / F 034); EP-OS 556 673 (HOE 92 / F 035); DE-OS 42 04 577.0, US 5 364 868, EP-OS 556 672 (HOE 92 / F 036), EP 612 723 (HOE 92 / F 054); NZ 248 013 (HOE 92 / F 197 K); NZ 264 130, DE-OS 43 26 005 A1 (HOE 92 / F 223 K); NZ 248 703, EP-OS 589 336 (HOE 92 / F 303 K); US 5 416 094, NZ 248 761 (HOE 92 / F 304); EP 602 522, NZ 250 438 (HOE 92 / F 404); EP 602 523, NZ 250 437 (HOE 92 / F 405); NZ 250 450, EP 603 650 (HOE 92 / F 411); DE-OS 43 05 250.9, NZ 250 919 (HOE 93 / F 054); EP-OS 627 413, NZ 260 660 (HOE 93 / F 153); DE-OS 43 18 756, EP 628 543, NZ 260 681 (HOE 93 / F 154); EP-OS 640 593, DE-OS 43 25 822, NZ 264 117 (HOE 93 / F 220); EP-OS 638 548; NZ 264 216 (HOE 93 / F 236); DE-OS 43 28 352, EP-OS 640 587, NZ 264 282 (93 / F 249); DE-OS 43 28 869, EP-OS 640 588, NZ 264 307 (HOE 93 / F 254); EP-OS 638 548, NZ 264 216 (HOE 93 / F 236); DE-OS 43 44 550, EP-OS 659 748, NZ 270 264 (HOE 93 / F 436); NZ 270 370, EP-OS 666 252 (HOE 94 / F 014); NZ 270 894, EP-OS 676 395, DE-OS 44 12 334 (HOE 94 / F 094); EP-OS 682 017, NZ 272 058, DE-OS 44 15 873 (HOE 94 / F 123); NZ 272 103, DE-OS 44 17 004, EP-OS 686 627 (HOE 94 / F 134); DE-OS 44 21 536, EP-OS 690 048, NZ 272 373 (HOE 94 / F 168); P 44 22 685.3 (HOE 94 / F 182); P 44 28 480.2 (HOE 94 / F 227); P 44 32 106.6 (HOE 94 / F 265); P 44 32 105.8 (HOE 94 / F 266); P 44 32 101.5 (HOE 94 / F 267); P 44 41 880.9 (HOE 94 / F 352); P 195 04 805.9 (HOE 95 / F 021); EP 95 105 724.9 (HOE 95 / F 072); 195 18 073.9 (HOE 95 / F 109); P 195 18 796.2 (HOE 95 / F 115); 195 26 381.2 (HOE 95 / F 167); 195 27 305.2 (HOE 95 / F 173); EP 95 115 240.4 (HOE 95 / F 220); 195 40 995.7 (HOE 95 / F 253); 195 42 306.2 (HOE 95 / F 265); 195 43 194 (HOE 95 / F 269).

Bevorzugt sind die NHE-Inhibitoren, in denen R′ einen substituierten Phenylrest oder Phenylalkylen-Rest bedeutet, wie sie beispielsweise in den Patent- und Offenlegungsschriften sowie in den Patentanmeldungen:
DE 43 37 611; DE 43 37 609; EP-OS 667 341 A1; EP-OS 622 356 A1; WO 9426709; WO 95 04052-A1; EP-OS 416 499, US 5 091 394, US 5 292 755 (HOE 89/F 288); EP-OS 556 674, US 5 373 024 (HOE 92/F 034); EP-OS 556 673 (HOE 92/F 035); DE-OS 42 04 577.0, US 5 364 868, EP-OS 556 672 (HOE 92/F 036), EP 612 723 (HOE 92/F 054); NZ 248 013 (HOE 92/F 197 K); NZ 264 130, DE-OS 43 26 005 A1 (HOE 92/F 223 K); NZ 248 703, EP-OS 589 336 (HOE 92/F 303 K); US 5 416 094, NZ 248 761 (HOE 92/F 304); EP 602 522, NZ 250 438 (HOE 92/F 404); EP 602 523, NZ 250 437 (HOE 92/F 405); NZ 250 450, EP 603 650 (HOE 92/F 411); DE-OS 43 05 250.9, NZ 250 919 (HOE 93/F 054); EP-OS 627 413, NZ 260 660 (HOE 93/F 153); DE-OS 43 18 756, EP 628 543, NZ 260 681 (HOE 93/F 154); EP-OS 640 593, DE-OS 43 25 822, NZ 264 117 (HOE 93/F 220); EP-OS 638 548; NZ 264 216 (HOE 93/F 236); DE-OS 43 28 352, EP-OS 640 587, NZ 264 282 (93/F 249); DE-OS 43 28 869, EP-OS 640 588, NZ 264 307 (HOE 93/F 254); EP-OS 638 548, NZ 264 216 (HOE 93/F 236); DE-OS 43 44 550, EP-OS 659 748, NZ 270 264 (HOE 93/F 436); NZ 270 370, EP-OS 666 252 (HOE 94/F 014); NZ 270 894, EP-OS 676 395, DE-OS 44 12 334 (HOE 94/F 094); EP-OS 682 017, NZ 272 058, DE-OS 44 15 873 (HOE 94/F 123); NZ 272 103, DE-OS 44 17 004, EP-OS 686 627 (HOE 94/F 134); DE-OS 44 21 536, EP-OS 690 048, NZ 272 373 (HOE 94/F 168); P 44 22 685.3 (HOE 94/F 182); P 44 28 480.2 (HOE 94/F 227); P 44 32 106.6 (HOE 94/F 265); P 44 32 105.8 (HOE 94/F 266); P 44 32 101.5 (HOE 94/F 267); P 44 41 880.9 (HOE 94/F 352); P 195 04 805.9 (HOE 95/F 021); EP 95 105 724.9 (HOE 95/F 072); 195 18 073.9 (HOE 95/F 109); P 195 18 796.2 (HOE 95/F 115); 195 26 381.2 (HOE 95/F 167); 195 27 305.2 (HOE 95/F 173); EP 95 115 240.4 (HOE 95/F 220); 195 40 995.7 (HOE 95/F 253); 195 42 306.2 (HOE 95/F 265); 195 43 194 (HOE 95/F 269) beschrieben sind.Preferred are the NHE inhibitors in which R 'is a substituted phenyl radical or phenylalkylene radical, as described, for example, in the patent and laid-open publications and in the patent applications:
DE 43 37 611; DE 43 37 609; EP-OS 667 341 A1; EP-OS 622 356 A1; WO 9426709; WO 95 04052-A1; EP-OS 416 499, US 5,091,394, US 5,292,755 (HOE 89 / F 288); EP-OS 556 674, US 5 373 024 (HOE 92 / F 034); EP-OS 556 673 (HOE 92 / F 035); DE-OS 42 04 577.0, US 5 364 868, EP-OS 556 672 (HOE 92 / F 036), EP 612 723 (HOE 92 / F 054); NZ 248 013 (HOE 92 / F 197 K); NZ 264 130, DE-OS 43 26 005 A1 (HOE 92 / F 223 K); NZ 248 703, EP-OS 589 336 (HOE 92 / F 303 K); US 5 416 094, NZ 248 761 (HOE 92 / F 304); EP 602 522, NZ 250 438 (HOE 92 / F 404); EP 602 523, NZ 250 437 (HOE 92 / F 405); NZ 250 450, EP 603 650 (HOE 92 / F 411); DE-OS 43 05 250.9, NZ 250 919 (HOE 93 / F 054); EP-OS 627 413, NZ 260 660 (HOE 93 / F 153); DE-OS 43 18 756, EP 628 543, NZ 260 681 (HOE 93 / F 154); EP-OS 640 593, DE-OS 43 25 822, NZ 264 117 (HOE 93 / F 220); EP-OS 638 548; NZ 264 216 (HOE 93 / F 236); DE-OS 43 28 352, EP-OS 640 587, NZ 264 282 (93 / F 249); DE-OS 43 28 869, EP-OS 640 588, NZ 264 307 (HOE 93 / F 254); EP-OS 638 548, NZ 264 216 (HOE 93 / F 236); DE-OS 43 44 550, EP-OS 659 748, NZ 270 264 (HOE 93 / F 436); NZ 270 370, EP-OS 666 252 (HOE 94 / F 014); NZ 270 894, EP-OS 676 395, DE-OS 44 12 334 (HOE 94 / F 094); EP-OS 682 017, NZ 272 058, DE-OS 44 15 873 (HOE 94 / F 123); NZ 272 103, DE-OS 44 17 004, EP-OS 686 627 (HOE 94 / F 134); DE-OS 44 21 536, EP-OS 690 048, NZ 272 373 (HOE 94 / F 168); P 44 22 685.3 (HOE 94 / F 182); P 44 28 480.2 (HOE 94 / F 227); P 44 32 106.6 (HOE 94 / F 265); P 44 32 105.8 (HOE 94 / F 266); P 44 32 101.5 (HOE 94 / F 267); P 44 41 880.9 (HOE 94 / F 352); P 195 04 805.9 (HOE 95 / F 021); EP 95 105 724.9 (HOE 95 / F 072); 195 18 073.9 (HOE 95 / F 109); P 195 18 796.2 (HOE 95 / F 115); 195 26 381.2 (HOE 95 / F 167); 195 27 305.2 (HOE 95 / F 173); EP 95 115 240.4 (HOE 95 / F 220); 195 40 995.7 (HOE 95 / F 253); 195 42 306.2 (HOE 95 / F 265); 195 43 194 (HOE 95 / F 269).

Besonders bevorzugt sind die NHE-Inhibitoren, die in den Patentschriften, den Offenlegungsschriften sowie in den Patentanmeldungen:
EP-OS 416 499, US 5 091 394, US 5 292 755 (HOE 89/F 288); EP-OS 556 674, US 5 373 024 (HOE 92/F 034); EP-OS 556 673 (HOE 92/F 035); DE-OS 42 04 577.0, US 5 364 868, EP-OS 556 672 (HOE 92/F 036), EP 612 723 (HOE 92/F 054); NZ 248 013 (HOE 92/F 197 K); NZ 264 130, DE-OS 43 26 005 A1 (HOE 92/F 223 K); NZ 248 703, EP-OS 589 336 (HOE 92/F 303 K); US 5 416 094, NZ 248 761 (HOE 92/F 304); EP 602 522, NZ 250 438 (HOE 92/F 404); EP 602 523, NZ 250 437 (HOE 92/F 405); NZ 250 450, EP 603 650 (HOE 92/F 411); DE-OS 43 05 250.9, NZ 250 919 (HOE 93/F 054); EP-OS 627 413, NZ 260 660 (HOE 93/F 153); DE-OS 43 18 756, EP 628 543, NZ 260 681 (HOE 93/F 154); EP-OS 640 593, DE-OS 43 25 822, NZ 264 117 (HOE 93/F 220); EP-OS 638 548; NZ 264 216 (HOE 93/F 236); DE-OS 43 28 352, EP-OS 640 587, NZ 264 282 (93/F 249); DE-OS 43 28 869, EP-OS 640 588, NZ 264 307 (HOE 93/F 254); EP-OS 638 548, NZ 264 216 (HOE 93/F 236); DE-OS 43 44 550, EP-OS 659 748, NZ 270 264 (HOE 93/F 436); NZ 270 370, EP-OS 666 252 (HOE 94/F 014); NZ 270 894, EP-OS 676 395, DE-OS 44 12 334 (HOE 94/F 094); EP-OS 682 017, NZ 272 058, DE-OS 44 15 873 (HOE 94/F 123); NZ 272 103, DE-OS 44 17 004, EP-OS 686 627 (HOE 94/F 134); DE-OS 44 21 536, EP-OS 690 048, NZ 272 373 (HOE 94/F 168); P 44 22 685.3 (HOE 94/F 182); P 44 28 480.2 (HOE 94/F 227); P 44 32 106.6 (HOE 94/F 265); P 4 432 105.8 (HOE 94/F 266); P 44 32 101.5 (HOE 94/F 267); P 44 41 880.9 (HOE 94/F 352); P 195 04 805.9 (HOE 95/F 021); EP 95 105 724.9 (HOE 95/F 072); 195 18 073.9 (HOE 95/F 109); P 195 18 796.2 (HOE 95/F 115); 195 26 381.2 (HOE 95/F 167); 195 27 305.2 (HOE 95/F 173); EP 95 115 240.4 (HOE 95/F 220); 195 40 995.7 (HOE 95/F 253); 195 42 306.2 (HOE 95/F 265); 195 43 194 (HOE 95/F 269) beschrieben sind.Particularly preferred are the NHE inhibitors, which in the patent specifications, the published specifications and in the patent applications:
EP-OS 416 499, US 5,091,394, US 5,292,755 (HOE 89 / F 288); EP-OS 556 674, US 5 373 024 (HOE 92 / F 034); EP-OS 556 673 (HOE 92 / F 035); DE-OS 42 04 577.0, US 5 364 868, EP-OS 556 672 (HOE 92 / F 036), EP 612 723 (HOE 92 / F 054); NZ 248 013 (HOE 92 / F 197 K); NZ 264 130, DE-OS 43 26 005 A1 (HOE 92 / F 223 K); NZ 248 703, EP-OS 589 336 (HOE 92 / F 303 K); US 5 416 094, NZ 248 761 (HOE 92 / F 304); EP 602 522, NZ 250 438 (HOE 92 / F 404); EP 602 523, NZ 250 437 (HOE 92 / F 405); NZ 250 450, EP 603 650 (HOE 92 / F 411); DE-OS 43 05 250.9, NZ 250 919 (HOE 93 / F 054); EP-OS 627 413, NZ 260 660 (HOE 93 / F 153); DE-OS 43 18 756, EP 628 543, NZ 260 681 (HOE 93 / F 154); EP-OS 640 593, DE-OS 43 25 822, NZ 264 117 (HOE 93 / F 220); EP-OS 638 548; NZ 264 216 (HOE 93 / F 236); DE-OS 43 28 352, EP-OS 640 587, NZ 264 282 (93 / F 249); DE-OS 43 28 869, EP-OS 640 588, NZ 264 307 (HOE 93 / F 254); EP-OS 638 548, NZ 264 216 (HOE 93 / F 236); DE-OS 43 44 550, EP-OS 659 748, NZ 270 264 (HOE 93 / F 436); NZ 270 370, EP-OS 666 252 (HOE 94 / F 014); NZ 270 894, EP-OS 676 395, DE-OS 44 12 334 (HOE 94 / F 094); EP-OS 682 017, NZ 272 058, DE-OS 44 15 873 (HOE 94 / F 123); NZ 272 103, DE-OS 44 17 004, EP-OS 686 627 (HOE 94 / F 134); DE-OS 44 21 536, EP-OS 690 048, NZ 272 373 (HOE 94 / F 168); P 44 22 685.3 (HOE 94 / F 182); P 44 28 480.2 (HOE 94 / F 227); P 44 32 106.6 (HOE 94 / F 265); P 4 432 105.8 (HOE 94 / F 266); P 44 32 101.5 (HOE 94 / F 267); P 44 41 880.9 (HOE 94 / F 352); P 195 04 805.9 (HOE 95 / F 021); EP 95 105 724.9 (HOE 95 / F 072); 195 18 073.9 (HOE 95 / F 109); P 195 18 796.2 (HOE 95 / F 115); 195 26 381.2 (HOE 95 / F 167); 195 27 305.2 (HOE 95 / F 173); EP 95 115 240.4 (HOE 95 / F 220); 195 40 995.7 (HOE 95 / F 253); 195 42 306.2 (HOE 95 / F 265); 195 43 194 (HOE 95 / F 269).

Für derartige Inhibitoren des Na⁺/H⁺ Austauschs werden bereits zahlreiche medizinische Verwendungen beschrieben, wie beispielsweise Krankheitsformen, die durch chronische oder akute Blutunterversorgung eines Organs (Ischämie), insbesondere des Herzens, entstehen. Sie sind deshalb geeignet beispielsweise zur Behandlung ischämisch induzierter Arrhythmien, unterschiedlicher Formen der Angina Pectoris, bei Herztransplantationen, in der Herzchirurgie und bei angioplastischen chirurgischen Eingriffen. Weitere beschriebene Indikationen für NHE-Inhibitoren sind Schlaganfall und Hirnödem, Schock und proliferationsbedingte Krankheiten, wie Atherosklerose, diabetische Spätschäden, fibrotische Erkrankungen und Organhypertrophien.Such inhibitors of Na⁺ / H⁺ exchange are already numerous described medical uses, such as forms of disease, caused by chronic or acute shortage of blood in an organ (ischemia), especially of the heart. They are therefore suitable, for example for the treatment of ischemically induced arrhythmias, various forms the angina pectoris, in heart transplants, in cardiac surgery and in  angioplasty surgery. Further described indications for NHE inhibitors are stroke and cerebral edema, shock and proliferation-related diseases, such as atherosclerosis, diabetic Late damage, fibrotic diseases and organ hypertrophy.

Es wurde nun überraschend gefunden, daß NHE-Inhibitoren die Atmung durch eine Zunahme der Chemosensibiliät der Atmungs-Chemorezeptoren stimulieren können. Diese Chemorezeptoren sind in beträchtlichem Umfang für die Aufrechterhaltung einer geordneten Atemtätigkeit verantwortlich. Sie werden durch Hypoxie, pH-Abfall und Anstieg von CO₂ (Hyperkapnie) im Körper aktiviert und führen zu einer Anpassung des Atemminutenvolumens. Im Schlaf ist die Atmung besonders störanfällig und in hohem Maße abhängig von der Aktivität der Chemorezeptoren.It has now surprisingly been found that NHE inhibitors cause respiration stimulate an increase in chemosensitivity of the respiratory chemoreceptors can. These chemoreceptors are significant for that Responsible for maintaining orderly breathing. you will be due to hypoxia, a drop in pH and an increase in CO₂ (hypercapnia) in the body activated and lead to an adjustment of the minute ventilation. While sleeping breathing is particularly susceptible to interference and highly dependent on the Chemoreceptor activity.

Eine Verbesserung des Atemantriebes durch Stimulation der Chemorezeptoren mit Substanzen, die den Natrium-Protonen-Austausch hemmen, führt zu einer Verbesserung der Atmung bei folgenden klinischen Zuständen und Krankheiten: Gestörter zentraler Atemantrieb (z. B. zentrale Schlaf-Apnoen, plötzlicher Kindstod, postoperative Hypoxie), muskulär-bedingte Atemstörungen, Atemstörungen nach Langzeitbeatmung, Atemstörungen bei Adaptation im Hochgebirge, obstruktive und gemischte Form der Schlaf-Apnoen, akute und chronische Lungenkrankheiten mit Hypoxie und Hyperkapnie.An improvement in respiratory drive through stimulation of the chemoreceptors with substances that inhibit sodium-proton exchange leads to one Improved breathing in the following clinical conditions and diseases: Impaired central respiratory drive (e.g. central sleep apneas, sudden Child death, postoperative hypoxia), muscular breathing disorders, Breathing disorders after long-term ventilation, breathing disorders with adaptation in High mountains, obstructive and mixed form of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.

Die genannten Verbindungen finden deshalb vorteilhaft Verwendung zur Herstellung eines Medikaments zur Behandlung von gestörtem Atemantrieb; zur Herstellung eines Medikaments zur Behandlung von muskulär-bedingten Atemstörungen; zur Herstellung eines Medikaments zur Behandlung von Atemstörungen nach Langzeitbeatmung; zur Herstellung eines Medikaments zur Behandlung von Atemstörungen bei Adaptation im Hochgebirge; zur Herstellung eines Medikaments zur Behandlung von obstruktiven und gemischten Formen der Schlaf-Apnoen; zur Herstellung eines Medikaments zur Behandlung von akuten und chronischen Lungenkrankheiten mit Hypoxie und Hyperkapnie; besonders zur Herstellung eines Medikaments zur Behandlung der genannten Leiden in Kombinationen mit einem Inhibitor der Carboanhydratase, bevorzugt mit Acetazolamid.The compounds mentioned are therefore advantageously used for Manufacture of a medicament for the treatment of disrupted respiratory drive; to Manufacture of a medication for the treatment of muscular-related Breathing disorders; for the manufacture of a medicament for the treatment of Breathing disorders after long-term ventilation; for the manufacture of a medication for Treatment of respiratory disorders when adapting to high mountains; for the production a drug used to treat obstructive and mixed forms the sleep apnea; for the manufacture of a medicament for the treatment of  acute and chronic lung diseases with hypoxia and hypercapnia; especially for the manufacture of a medicament for the treatment of the named Suffering in combination with an inhibitor of carbonic anhydratase is preferred with acetazolamide.

Eine Kombination eines NHE-Inhibitors mit einem Carboanhydrase-Hemmer (z. B. Acetazolamid), wobei letzterer eine metabolische Azidose herbeiführt und dadurch bereits die Atmungstätigkeit steigert, erweist sich als günstige Kombination mit verstärkter Wirkung und vermindertem Wirkstoffeinsatz.A combination of an NHE inhibitor and a carbonic anhydrase inhibitor (e.g. Acetazolamide), the latter causing metabolic acidosis and already increasing breathing activity proves to be beneficial Combination with increased effectiveness and reduced use of active ingredients.

Beansprucht wird die Gabe von Natrium-Protonen-Austausch-Hemmern als neuartige Arzneimittel zur Verbesserung der Atmung, Atemstimulantien, sowie die Kombination von Natrium-Protonen-Austausch-Hemmern mit Carboanhydrase-Hemmern.The use of sodium proton exchange inhibitors is claimed as novel drugs to improve breathing, respiratory stimulants, as well the combination of sodium proton exchange inhibitors with Carbonic anhydrase inhibitors.

Claims (8)

1. Verwendung eines Na⁺/H⁺-Exchange Inhibitors zur Herstellung eines Medikaments zur Behandlung von gestörtem Atemantrieb.1. Use of a Na⁺ / H⁺ exchange inhibitor to produce a Medicament for the treatment of disturbed respiratory drive. 2. Verwendung eines Na⁺/H⁺-Exchange Inhibitors nach Anspruch 1 zur Herstellung eines Medikaments zur Behandlung von muskulär-bedingten Atemstörungen.2. Use of a Na⁺ / H⁺ exchange inhibitor according to claim 1 for Manufacture of a medication for the treatment of muscular-related Breathing disorders. 3. Verwendung eines Na⁺/H⁺-Exchange Inhibitors nach Anspruch 1 zur Herstellung eines Medikaments zur Behandlung von Atemstörungen nach Langzeitbeatmung.3. Use of a Na⁺ / H⁺ exchange inhibitor according to claim 1 for Manufacture of a medication to treat breathing disorders after Long-term ventilation. 4. Verwendung eines Na⁺/H⁺-Exchange Inhibitors nach Anspruch 1 zur Herstellung eines Medikaments zur Behandlung von Atemstörungen bei Adaptation im Hochgebirge.4. Use of a Na⁺ / H⁺ exchange inhibitor according to claim 1 for Manufacture of a medication to treat respiratory disorders Adaptation in the high mountains. 5. Verwendung eines Na⁺/H⁺-Exchange Inhibitors zur Herstellung eines Medikaments zur Behandlung von obstruktiven und gemischten Formen der Schlaf-Apnoen.5. Use of a Na⁺ / H⁺ exchange inhibitor to produce a Medicament to treat obstructive and mixed forms of Sleep apneas. 6. Verwendung eines Na⁺/H⁺-Exchange Inhibitors zur Herstellung eines Medikaments zur Behandlung von akuten und chronischen Lungenkrankheiten mit Hypoxie und Hyperkapnie.6. Use of a Na⁺ / H⁺ exchange inhibitor to produce a Medicament for the treatment of acute and chronic lung diseases with hypoxia and hypercapnia. 7. Verwendung eines Na⁺/H⁺-Exchange Inhibitors zur Herstellung eines Medikaments nach Ansprüchen 1 bis 6 in Kombinationen mit einem Inhibitor der Carboanhydratase.7. Use a Na⁺ / H⁺ exchange inhibitor to produce a Medicament according to claims 1 to 6 in combinations with an inhibitor of Carbonic anhydratase. 8. Verwendung eines Na⁺/H⁺-Exchange Inhibitors zur Herstellung eines Medikaments nach Ansprüchen 1 bis 6 in Kombinationen mit Acetazolamid.8. Use of a Na⁺ / H⁺ exchange inhibitor to produce a Medicament according to Claims 1 to 6 in combinations with acetazolamide.
DE19548812A 1995-12-27 1995-12-27 Use of inhibitors of the cellular Na · + · / H · + · exchanger (NHE) for the manufacture of a medicament for respiratory stimulation Withdrawn DE19548812A1 (en)

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DE19548812A DE19548812A1 (en) 1995-12-27 1995-12-27 Use of inhibitors of the cellular Na · + · / H · + · exchanger (NHE) for the manufacture of a medicament for respiratory stimulation
PCT/EP1996/005614 WO1997024113A1 (en) 1995-12-27 1996-12-13 USE OF INHIBITORS OF THE CELLULAR Na+/H+ EXCHANGER (NHE) FOR THE PREPARATION OF A DRUG FOR RESPIRATORY STIMULATION
AU13720/97A AU717247B2 (en) 1995-12-27 1996-12-13 Use of inhibitors of the cellular Na+/H+ exchanger (NHE) for the production of a medicament for respiratory stimulation
HU9900807A HUP9900807A3 (en) 1995-12-27 1996-12-13 Use of inhibitors of the cellular na+/h+exchanger (nhe) for the preparation of a drug for respiratory stimulation
CN96199403A CN1207676A (en) 1995-12-27 1996-12-13 Use of inhibitors of cellular Na+/H+ exchanger (NHE) for preparation of drug for respiratory stimulation
TR1998/01235T TR199801235T2 (en) 1995-12-27 1996-12-13 Use of inhibitors in the manufacture of drugs for respiratory stimulation.
SK883-98A SK88398A3 (en) 1995-12-27 1996-12-13 Use of inhibitors of the cellular na+/h+ exchanger (nhe) for the preparation of a drug for respiratory stimulation
BR9612287-0A BR9612287A (en) 1995-12-27 1996-12-13 Use of cellular na + / h + (nhe) exchange inhibitors for the preparation of a breath-stimulating drug
PL96327693A PL327693A1 (en) 1995-12-27 1996-12-13 Application of cellular na+/h+(nhe) ions exchanger inhibitors in production of a respiration stimulating drug
KR1019980704927A KR19990076802A (en) 1995-12-27 1996-12-13 Use of cellular NA + / H + exchanger (NHE) inhibitors for the manufacture of medicaments for respiratory stimulation
IL12511496A IL125114A0 (en) 1995-12-27 1996-12-13 Use of inhibitor of the cellular na+/h+ exchanger (nhe) for the production of a medicament for respiratory stimulation
EP96943956A EP0869779A1 (en) 1995-12-27 1996-12-13 USE OF INHIBITORS OF THE CELLULAR Na?+ /H?+ EXCHANGER (NHE) FOR THE PREPARATION OF A DRUG FOR RESPIRATORY STIMULATION
CA002241531A CA2241531A1 (en) 1995-12-27 1996-12-13 Use of inhibitors of the cellular na+/h+ exchanger (nhe) for the preparation of a drug for respiratory stimulation
MX9805141A MX9805141A (en) 1995-12-27 1998-06-24 USE OF INHIBITORS OF THE CELLULAR Na+/H+ EXCHANGER (NHE) FOR THE PREPARATION OF A DRUG FOR RESPIRATORY STIMULATION.
NO982989A NO982989L (en) 1995-12-27 1998-06-26 Use of inhibitors of the cellular Na + / H + exchanger (NHE) for the manufacture of a medicament for respiratory stimulation
CZ982021A CZ202198DA3 (en) 1995-12-27 2021-03-03 USE OF Na+/H+ EXCHANGE INHIBITORS FOR PREPARING A MEDICAMENT INTENDED FOR TREATING IMPAIRED STIMULATION OF BREATHING

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