WO2014053533A1 - Utilisation de dérivés substitués de l'acide 3-hétéroaroylamino-propionique en tant que produits pharmaceutiques destinés à la prévention/au traitement de la fibrillation auriculaire - Google Patents

Utilisation de dérivés substitués de l'acide 3-hétéroaroylamino-propionique en tant que produits pharmaceutiques destinés à la prévention/au traitement de la fibrillation auriculaire Download PDF

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WO2014053533A1
WO2014053533A1 PCT/EP2013/070524 EP2013070524W WO2014053533A1 WO 2014053533 A1 WO2014053533 A1 WO 2014053533A1 EP 2013070524 W EP2013070524 W EP 2013070524W WO 2014053533 A1 WO2014053533 A1 WO 2014053533A1
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alkyl
chosen
series consisting
phenyl
het
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Sven Ruf
Thorsten Sadowski
Klaus Wirth
Herman Schreuder
Christian Buning
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Sanofi
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • Atrial fibrillation is the most common type of sustained tachyarrhythmia and is associated with significant morbidity and mortality.
  • 1 Diabetes is a strong independent risk factor for atrial fibrillation (AF) and stroke 2,3,4 and has been shown to produce an arrhythmogenic substrate in the atrium with an increase in AF susceptibility due to increased atrial fibrosis amount in a diabetic rat model.
  • 5,6 Additionally, an abnormal response to exercise is frequently observed in asymptomatic diabetic patients who do not have clinical evidence of cardiovascular disease. 7,8,9 Atrial and/or ventricular dysfunction limit exercise capacity and increase risk for stroke in diabetic patients. 10
  • Cathepsin A is an extracellular enzyme which has been suggested to play an important role in degradation of extracellular peptides.
  • 11 ,12 Several peptide hormones have been described as substrates for CathA in vitro like angiotensin I and bradykinin.
  • Evidence of upregulation of alternative angiotensin-generating enzymes like chymase or cathepsins has been described in many pathologies e.g. in myocardial infarction, CHF or diabetes. 13,14,15
  • Pharmacological inhibition of CathA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt- induced hypertension. 16 Similar effects were observed by antisense oligonucleotides suppressing the expression of CathA.
  • 17 CathA also has been suggested to play a role in inflammation. 11
  • a subject of the present invention is the use compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a
  • A is chosen from the series consisting of C(R 1 ) and N;
  • D is chosen from the series consisting of N(R 2 ), O and S;
  • E is chosen from the series consisting of C(R 3 ) and N;
  • G is chosen from the series consisting of R 71 -O-C(O)-, R 72 -N(R 73 )-C(O)-, NC- and tetrazol-5-yl;
  • R 1 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, Ar, HO-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(O) m - and NC-;
  • R 2 is chosen from the series consisting of (Ci-C 7 )-alkyl, (C3-C 7 )-cycloalkyl-C 3 H 2s - and Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 3 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, (d-Ce)- alkyl-O-, (Ci-C 6 )-alkyl-S(O) m - and NC-;
  • R 10 is chosen from the series consisting of R 1 1 -O-, R 12 -N(R 13 )-C(O)-O- and Het 2 -C(O)- O-;
  • R 1 1 is chosen from the series consisting of hydrogen, R 14 , (C3-C 7 )-cycloalkyl, Ar and Het 3 ;
  • R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen, R 15 and Ar;
  • R 14 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, R 16 -O-, oxo, (C3-C7)- cycloalkyl, Ar, Het 1 , Het 3 , NC-, H 2 N-C(O)-, (Ci-C 4 )-alkyl-NH-C(O)-, di((Ci-C 4 )-alkyl)N- C(O)-, Het 1 -C(O)-, (Ci-C 4 )-alkyl-C(O)-NH- and (Ci-C 4 )-alkyl-S(0) m -;
  • R 15 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series
  • R 16 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO-, (Ci-C 4 )-alkyl-O- and NC-;
  • R 30 is chosen from the series consisting of R 31 , (C3-C 7 )-cycloalkyl, R 32 -C u H 2u - and Het 3 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 31 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C3-C 7 )-cycloalkyl, HO-, (Ci- C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, R 33 , HO-, (C1-C-6)- alkyl-O-, R 33 -O-, R 33 -(Ci-C 4 )-alkyl-O-, -O-CH2-O-, -O-CF2-O-, (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, (Ci-C 4 )-alkyl-NH-S(
  • R 33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C-6)-alkyl-0- , (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, (Ci-C 4 )-alkyl-NH-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(O) 2 - and NC-;
  • R 40 is chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl; or R 30 and R 40 together are (CH 2 ) X which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein x is an integer chosen from the series consisting of 2, 3, 4 and 5;
  • R 50 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, HO- and (C1-C6)- alkyl-O-;
  • R 60 is chosen from the series consisting of hydrogen and (Ci-C6)-alkyl; or R and R together are (CH 2 ) y which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein y is an integer chosen from the series consisting of 2, 3, 4 and 5;
  • R is chosen from the series consisting of hydrogen and (Ci-CsJ-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (Ci-C6)-alkyl-O- and (Ci-C6)-alkyl-C(O)-O-;
  • R 72 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, (C3-C6)-cycloalkyl, -CH 2 -(CH 2
  • R 73 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Ar independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-Ce)- alkyl, (Ci-C 6 )-alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 - and NC-;
  • Het 1 is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-;
  • Het 2 is a saturated 4-mennbered to 7-mennbered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Het 3 independently of each other group Het 3 , is a saturated 4-mennbered to 7- membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (Ci-C 4 )- alkyl and oxo;
  • Het 4 is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-; m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2; wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl, C s H 2s , C u H 2u , (CH 2 ) X and (CH 2 ) y groups, independently of each other, and
  • Another embodiment is the use of a compound of the formula I, in any of its
  • Another embodiment is the use of a compound of the formula I, in any of its
  • Another embodiment is the use of a compound of the formula I, in any of its
  • A is chosen from the series consisting of C(R 1 ) and N;
  • D is N(R 2 );
  • R 1 is chosen from the series consisting of hydrogen, halogen and (Ci-C 4 )-alkyl;
  • R 2 is Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0, 1 and 2.
  • Another embodiment is the use of a compound of the formula I, in any of its
  • Another embodiment is the use of a compound of the formula I, in any of its
  • G is chosen from the series consisting of R 71 -O-C(O)- and R 72 -N(R 73 )-C(O)-;
  • R 30 is R 32 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0 and 1 ; R 32 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring
  • heteroatoms wherein the phenyl and the heterocycle all are optionally substituted by one, two or three identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , (Ci-C 6 )-alkyl-O-, R 33 -O-, R 33 -(d-C 4 )- alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, (Ci-C 6 )-alkyl-NH-, di((Ci-C 6 )- alkyl)N-, Het 1 and NC-;
  • R 33 is chosen from the series consisting of phenyl and pyridinyl which all are optionally substituted by one, two or three identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, (Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-S(O) m - and NC-;
  • R 40 is hydrogen
  • R 50 is hydrogen
  • R 60 is hydrogen
  • a further embodiment is the use of a compound of the formula I, in any of its
  • A is chosen from the series consisting of C(R 1 ) and N;
  • D is N(R 2 );
  • E is chosen from the series consisting of C(R 3 ) and N;
  • G is chosen from the series consisting of R -O-C(O)- and R -N(R )-C(O)-;
  • R 1 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, HO- and (Ci-C 6 )-alkyl-O-;
  • R 2 is chosen from the series consisting of (Ci-C 7 )-alkyl, (C3-C 7 )-cycloalkyl-C 3 H 2s - and Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 3 is chosen from the series consisting of hydrogen, halogen, (Ci-Ce)-alkyl and (Ci- C 6 )-alkyl-O-;
  • R 10 is chosen from the series consisting of R 11 -O-, R 12 -N(R 13 )-C(O)-O- and Het 2 -C(O)- O-;
  • R 11 is chosen from the series consisting of hydrogen, R 14 , (C3-C 7 )-cycloalkyl and Het 3 ;
  • R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen, R 15 and Ar;
  • R 14 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, R 16 -O-, oxo, (C3-C 7 )- cycloalkyl, Ar, Het 1 , Het 3 , NC-, H 2 N-C(O)-, (Ci-C 4 )-alkyl-NH-C(O)-, di((Ci-C 4 )-alkyl)N- C(O)- and Het 1 -C(O)-;
  • R 15 is (Ci-C 6 )-alkyl;
  • R 16 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO- and (Ci-C 4 )-alkyl-O-;
  • R 30 is chosen from the series consisting of (C3-C 7 )-cycloalkyl, R 32 -C u H 2u - and Het 3 - C u H 2u -, wherein u is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring
  • heteroatoms wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , HO-, (Ci-C 6 )-alkyl-O-, R 33 -O-, R 33 -(d- C 4 )-alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, di((Ci-C 4 )-alkyl)N-S(O) 2 -, H 2 N-, di((Ci-C 6 )-alkyl)N-, Het 1 , (Ci-C 4 )-alkyl-C(O)-NH-, Ar-C(O)-NH- and NC-;
  • R 33 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring
  • heteroatoms wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(O) 2 - and NC-;
  • R 40 is hydrogen
  • R is chosen from the series consisting of hydrogen and HO-; R bU is hydrogen;
  • R is chosen from the series consisting of hydrogen and (Ci-Cs)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (Ci-C6)-alkyl-O- and (Ci-C6)-alkyl-C(O)-O-;
  • R 72 and R 73 are independently of each other chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • Ar independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C-6)- alkyl, (Ci-C 6 )-alkyl-0-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(0) m - and NC-; Het 1 , independently of each other group Het 1 , is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two identical or different further ring
  • Het 2 is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Het 3 is a saturated 4-membered to 7- membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (Ci-C 4 )- alkyl and oxo; m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2; wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl, C s H 2s , C u H 2u , (CH 2 ) X and (CH 2 ) y groups, independently of each other, and independently of any other substituents, are optionally
  • a further embodiment is the use of a compound of the formula I, in any of its
  • A is C(R 1 ); D is N(R 2 ); E is N;
  • G is chosen from the series consisting of R 71 -O-C(O)- and R 72 -N(R 73 )-C(O)-;
  • R 1 is chosen from the series consisting of hydrogen, halogen and (Ci-C 4 )-alkyl;
  • R 2 is Ar-C 3 H 2s -, wherein s is 0; R 10 is R 11 -O-; R 11 is chosen from the series consisting of hydrogen and R 14 ;
  • R 14 is (Ci-Cio)-alkyl which is optionally substituted by one, two or three identical or different substituents chosen from the series consisting of HO-, R 16 -O-, oxo, (C3-C7)- cycloalkyl, Ar, Het 1 , di((Ci-C 4 )-alkyl)N- and Het 1 -C(O)-;
  • R 16 is (Ci-C6)-alkyl which is optionally substituted by one or two identical or different substituents chosen from the series consisting of HO- and (Ci-C 4 )-alkyl-O-;
  • R is R -C u H 2u -, wherein u is an integer chosen from the series consisting of 0 and 1 ;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring
  • heteroatoms wherein the phenyl and the heterocycle all are optionally substituted by one, two or three identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , (Ci-C 6 )-alkyl-O-, R 33 -O-, R 33 -(d-C 4 )- alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, di((Ci-C 6 )-alkyl)N-, Het 1 and NC- ;
  • R 33 is chosen from the series consisting of phenyl and pyridinyl which all are optionally substituted by one, two or three identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, (Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-S(O) m - and NC-;
  • R 40 is hydrogen
  • R 50 is hydrogen
  • R 60 is hydrogen
  • R 71 is chosen from the series consisting of hydrogen and (Ci-Cs)-alkyl which is optionally substituted by one substituent chosen from the series consisting (Ci-Ce)- alkyl-O- and (Ci-C 6 )-alkyl-C(O)-O-;
  • R 72 and R 73 are independently of each other chosen from the series consisting of hydrogen and (Ci-C2)-alkyl;
  • Ar is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle are all optionally substituted by one, two or three identical or different substituents chosen from the series consisting of halogen, (C1-C-6)- alkyl, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-;
  • Het 1 is a saturated or unsaturated 4- membered to 6-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one, two or three identical or different substituents chosen from the series consisting of fluorine, (Ci-C 4 )-alkyl, HO- and oxo; m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2; wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl, C s H 2s and C u H 2u groups, independently of each other, and
  • Another embodiment is the use of a compound of the formula I, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, chosen from
  • a subject of the invention is the use of a compound of the formula I or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, which is chosen from
  • the invention relates also to the use of a compound of the formula II, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a
  • A is chosen from the series consisting of C(R 1 ) and N;
  • D is chosen from the series consisting of C(R 2 ) and N;
  • E is chosen from the series consisting of C(R 3 ) and N;
  • L is chosen from the series consisting of C(R 4 ) and N;
  • G is chosen from the series consisting of R 71 -O-C(O)-, R 72 -N(R 73 )-C(O)- and tetrazol-5- yi;
  • R 1 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, HO-, (Ci- C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-;
  • R 2 is chosen from the series consisting of hydrogen, halogen, (Ci-C 7 )-alkyl, (C1-C-6)- alkyl-O-, (Ci-C 6 )-alkyl-CO-, (Ci-C 6 )-alkyl-CO-HN-, -NR 12 R 13 , Het 2 ' (C 3 -C 7 )-cycloalkyl- C s H 2s - and Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 3 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, (C1-C-6)- alkyl-S(O) m -, Het 4 -(O) r , -NR 12 R 13 , Het 2 , R 11 -O-, R 12 -N(R 13 )-C(O)-O- and Het 2 -C(O)-O- and NC-, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1 ;
  • R 4 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, (C1-C-6)- alkyl-O-, HO-, NR 12 R 13 , Het 2 ;
  • R 10 is chosen from the series consisting hydrogen, halogen, (Ci-C6)-alkyl, (C1-C-6)- alkyl-O-, (Ci-C 6 )-alkyl-S(O) m -, HO-, -NR 12 R 13 , Het 2 , phenyl-C 3 H 2 s-(O)t-, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1 ; or R 1 and R 2 or R 2 and R 3 or form pyridyl;
  • R 11 is chosen from the series consisting of hydrogen, R 14 , (C3-C 7 )-cycloalkyl, Ar and Het 3 ;
  • R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen and R 15 ;
  • R 14 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, R 16 -O-, oxo, (C3-C7)- cycloalkyl, Ar, Het 1 , Het 3 , NC-, H 2 N-C(O)-, (Ci-C 4 )-alkyl-NH-C(O)-, di((Ci-C 4 )-alkyl)N- C(O)-, Het 1 -C(O)-, (Ci-C 4 )-alkyl-C(O)-NH- and (Ci-C 4 )-alkyl-S(0) m -;
  • R 15 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting halogen, HO- and (Ci-C6)-alkyl-O-;
  • R 30 is chosen from the series consisting of R 31 , (C3-C 7 )-cycloalkyl, R 32 -C u H 2u - and Het 3 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 31 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C3-C 7 )-cycloalkyl, HO-, (Ci- C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , HO-, (Ci-C 6
  • R 33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C6)-alkyl-O- , (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, (Ci-C 4 )-alkyl-NH-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(O) 2 - and NC-;
  • R 40 is chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl; or R 30 and R 40 together are (CH 2 ) X which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein x is an integer chosen from the series consisting of 2, 3, 4 and 5; R 50 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, HO- and (d-Ce)- alkyl-O-;
  • R 60 is chosen from the series consisting of hydrogen and (Ci-C6)-alkyl; or R 50 and R 60 together are (CH 2 ) y which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein y is an integer chosen from the series consisting of 2, 3, 4 and 5;
  • R 71 is chosen from the series consisting of hydrogen and (Ci-Cs)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (Ci-C6)-alkyl-O- and (Ci-C6)-alkyl-C(O)-O-;
  • R 72 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, (C3-C6)-cycloalkyl, -CH 2 -(CH 2 ) b -(C 3 -C 6 )-cycloalkyl, Het 4 and -(CH 2 ) b -Het 4 , where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, HOOC-, (Ci-C 6 )-alkyl-O- and (Ci-C 6 )-alkyl-C(O)-O-, NC-, N((Ci-C 4 )-alkyl) 2 and b is 0, 1 or 2;
  • R 73 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (CrC 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Ar independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C-6)- alkyl, HO-(Ci-C 6 )-alkyl, Het 4 , -(CH 2 ) X -Phenyl, (Ci-C 6 )-alkyl-O-, (C 3 -C 7 )-cycloalkyl- (CH 2 )x-O-, -CF 3 , -CO-(Ci-C 6 )-alkyl, -NR 12 R 13 , Het 2 , -CO-NR 12 R 13 , CO-
  • Het 1 is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-
  • Het 2 is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Het 3 is a saturated 4-membered to 7- membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (Ci-C 4 )- alkyl and oxo;
  • Het 4 independently of each other group Het 4 , is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-;
  • m independently of each other number m
  • Another embodiment is the use of a compound of the formula II, in any of its
  • G is chosen from the series consisting of R 71 -O-C(O)- and R 72 -N(R 73 )-C(O)-;
  • R 30 is R 32 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0 and 1 ; R 32 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring
  • heteroatoms wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R M , HO-, (Ci-C 6 )-alkyl-0-, R -O-, R M -(C C 4 )-alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, di((Ci-C 4 )-alkyl)N-S(O) 2 -, H 2 N-, di((Ci-C 6 )-alkyl)N-, Het 1 , (Ci-C 4 )-alkyl-C(O)-NH-, Ar-C(O)-NH- and NC-; R 33 is chosen from the
  • heteroatoms wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(O) 2 - and NC-;
  • R 40 is hydrogen
  • Another embodiment is the use of a compound of the formula II, in any of its
  • G is R 71 -O-C(O)-;
  • R 30 is R 32 -C u H 2u -, wherein u is 0;
  • R 32 is chosen from the series consisting of phenyl, wherein the phenyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , HO-, (Ci-C 6 )-alkyl-O-, R 33 - O-, R 33 -(Ci-C 4 )-alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, di((d-C 4 )- alkyl)N-S(O) 2 -, H 2 N-, di((Ci-C 6 )-alkyl)N-, Het 1 , (Ci-C 4 )-alkyl-C(O)-NH-, Ar-C(O)-NH-
  • R 33 is chosen from the series consisting of phenyl, wherein the phenyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )- alkyl-S(O) m -, H 2 N-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(O) 2 - and NC-;
  • R 40 is hydrogen. Another embodiment is the use of a compound of the formula II, in any of its
  • R 50 is hydrogen
  • R 60 is hydrogen
  • Another embodiment is the use of a compound of the formula II, in any of its
  • a further embodiment is the use of a compound of the formula 11-1 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a
  • R 2 is Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0;
  • R 3 is chosen from the series consisting of hydrogen, halogen, R 11 -O-, HO-, (C1-C-6)- alkyl and (Ci-C 6 )-alkyl-0-; preferred HO- and(Ci-C 6 )-alkyl
  • R 4 is hydrogen
  • R 10 is hydrogen
  • a further embodiment is the use of a compound of the formula II, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a
  • R 3 is R 11 -O-, wherein R1 1 is hydrogen or (Ci-Cio)-alkyl.
  • a further embodiment is the use of a compound of the formula II, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a
  • Another embodiment is the use of a compound of the formula II, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, chosen from
  • Another embodiment is the use of a compound of the formula II, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, chosen from
  • the present invention relates to the use of compounds of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a
  • A is chosen from the series consisting of C(R ) and N
  • D is chosen from the series consisting of N(R 2 ), O and S;
  • E is chosen from the series consisting of C(R 3 ) and N;
  • G is chosen from the series consisting of R -O-C(O)-, R -N(R )-C(O)-, NC- and tetrazol-5-yl;
  • R 1 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, Ar, HO-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(O) m - and NC-;
  • R 3 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, (d-Ce)- alkyl-O-, (Ci-C 6 )-alkyl-S(O) m - and NC-;
  • R 10 is chosen from the series consisting of R 11 , R 12 -N(R 13 )-C(O)- and Het 2 -C(O)-, R 14 - C(O)- and (Ci-C 4 )-alkyl-S(O) m -;
  • R 11 is chosen from the series consisting of hydrogen, R 14 , (C3-C 7 )-cycloalkyl, Ar and Het 3 ;
  • R 10 and R 11 form Het 2 ;
  • R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen, R 15 and Ar;
  • R 14 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, R 16 -O-, R 17 -O-, oxo, (C 3 -C 7 )-cycloalkyl, Ar, Het 1 , Het 3 , NC-, H 2 N-C(O)-, (Ci-C 4 )-alkyl-NH-C(O)-, di((d-C 4 )- alkyl)N-C(O)-, Het 1 -C(O)-, (Ci-C 4 )-alkyl-C(O)-NH- and (Ci-C 4 )-alkyl-S(O) m -;
  • R 15 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting halogen, HO- and (Ci-C6)-alkyl-O-;
  • R 16 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO-, (Ci-C 4 )-alkyl-O- and NC-;
  • R 17 is (C3-C 7 )-cycloalkyl-C u H2u- which is optionally substituted by one or more identical or different substituents chosen from the series consisting halogen, (Ci-C6)-alkyl, HO- and (Ci-C6)-alkyl-O-, wherein u is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 18 is chosen from the series of hydrogen, halogen, (Ci-C6)-alkyl, HO- and (C1-C-6)- alkyl-O-;
  • R 19 is chosen from the series of hydrogen, halogen, (Ci-C6)-alkyl, HO- and (C1-C-6)- alkyl-O-;
  • R 30 is chosen from the series consisting of R 31 , (C3-C 7 )-cycloalkyl, R 32 -C u H 2u - and Het 3 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 31 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C3-C 7 )-cycloalkyl, HO-, (Ci- C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(O) m - and NC-;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, R 33 , HO-, (C1-C6)- alkyl-O-, R 33 -O-, R 33 -(Ci-C 4 )-alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -,
  • R 33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C-6)-alkyl-0- , (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, (Ci-C 4 )-alkyl-NH-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(0) 2 - and NC-;
  • R 40 is chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl; or R 30 and R 40 together are (CH 2 ) X which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein x is an integer chosen from the series consisting of 2, 3, 4 and 5;
  • R 50 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, HO- and (C1-C-6)- alkyl-O-;
  • R 60 is chosen from the series consisting of hydrogen and (Ci-C6)-alkyl; or R 50 and R 60 together are (CH 2 ) y which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein y is an integer chosen from the series consisting of 2, 3, 4 and 5; or R 30 and R 50 together are (CH 2 ) Z which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein z is an integer chosen from the series consisting of 2, 3, 4 and 5; R is chosen from the series consisting of hydrogen and (Ci-CsJ-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (Ci-C6)-alkyl-O- and (Ci-C6)-alkyl-C(O)-O-; R 72 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, (C3-
  • R 73 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Ar independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-Ce)- alkyl, (Ci-C 6 )-alkyl-O-, -O-CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 - and NC-;
  • Het 1 is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-
  • Het 2 is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, oxo and (Ci-C 4 )-alkyl-O-;
  • Het 3 independently of each other group Het 3 , is a saturated 4-membered to 7- membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (Ci-C 4 )- alkyl and oxo;
  • Het 4 is a saturated or unsaturated 4- membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-; m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2; wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl, C s H 2s , C u H 2u , (CH 2 ) X and (CH 2 ) y groups, independently of each other, and
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein E is N.
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein D is N(R 2 ).
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • G is R 71 -O-C(O)- and R 72 -N(R 73 )-C(O)-;
  • R 71 is chosen from the series consisting of hydrogen and (Ci-CsJ-alkyl;
  • R 72 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 73 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl.
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • R 50 is hydrogen
  • R 60 is hydrogen.
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • A is chosen from the series consisting of C(R 1 );
  • D is N(R 2 );
  • R 1 is chosen from the series consisting of hydrogen, halogen and (Ci-C 4 )-alkyl;
  • R 2 is Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0 and 1 .
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • R 30 is R 32 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0 and 1 ;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, R 33 , HO-, (C1-C-6)- alkyl-O-, R 33 -O-, R 33 -(Ci-C 4 )-alkyl-O-, -O-CH2-O-, -O-CF2-O-, (Ci-C 6 )-alkyl-
  • R 33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C-6)-alkyl-0- , (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, (Ci-C 4 )-alkyl-NH-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(0) 2 - and NC-;
  • R 40 is hydrogen
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • R 2 is Ar-C 3 H 2s -, wherein s is an integer 0;
  • R 30 is R 32 -C u H 2u - wherein u is an integer 0;
  • R 40 is hydrogen
  • a further preferred embodiment is the use of a compound of the formula III, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • A is chosen from the series consisting of C(R 1 );
  • D is N(R 2 );
  • R 1 is chosen from the series consisting of hydrogen, halogen and (Ci-C 4 )-alkyl;
  • a further preferred embodiment is the use of a compound of the formula III, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, chosen from
  • a subject of the present invention is ther use a compound of the formula III-36, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them,
  • the group G is chosen from the series consisting of R 71 -O-C(O)-, R 72 -N(R 73 )-C(O)- and tetrazol-5-yl, in another embodiment from the series consisting of R 71 -O-C(O)- and R 72 -N(R 73 )-C(O)-, in another embodiment G is R 71 -O-C(O)-, and in another embodiment G is R 72 -N(R 73 )-C(O)-.
  • a subject of the invention also is the use of a compound of the formula III which is chosen from any of the specific compounds of the formula III which are disclosed herein, or is any one of the specific compounds of the formula III which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a specific salt, or a physiologically acceptable salt thereof, or a physiologically
  • a subject of the invention is the use of a compound of the formula III which is chosen from
  • the present invention relates also to the use compounds of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them,
  • Ht is chosen from the series consisting of
  • G is chosen from the series consisting of R -O-C(O)-, R -N(R )-C(O)-, NC- and tetrazol-5-yl;
  • R 1 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, CF 3 , (C3- C 7 )-cycloalkyl-C 3 H 2 s-, Ar-C 3 H 2s -, Ar-O, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-; wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3; R 2 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, CF 3 , (Cr C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-;
  • R 3 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 4 is chosen from the series consisting of (Ci-C 7 )-alkyl, (C3-C 7 )-cycloalkyl-C 3 H 2s - and Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 5 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, (C1-C-6)- alkyl-O-, (Ci-C 6 )-alkyl-S(0) m - and NC-;
  • R 10 is chosen from the series consisting of R 1 1 , Het 2 -C(O)-, R 14 -C(O)- and (C1-C4)- alkyl-S(O) m -;
  • R 1 1 is chosen from the series consisting of hydrogen, R 14 , (C3-C 7 )-cycloalkyl, Ar and Het 3 ;
  • R 14 is (Ci-Cio)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, R 16 -O-, oxo, (C3-C7)- cycloalkyl, Ar, Het 1 , Het 3 , NC-, H 2 N-C(O)-, (Ci-C 4 )-alkyl-NH-C(O)-, di((Ci-C 4 )-alkyl)N- C(O)-, Het 1 -C(O)-, (Ci-C 4 )-alkyl-C(O)-NH- and (Ci-C 4 )-alkyl-S(0) m -;
  • R 16 is (Ci-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO-, (Ci-C 4 )-alkyl-O- and NC-;
  • R 30 is chosen from the series consisting of R 31 , (C3-C 7 )-cycloalkyl, R 32 -C u H 2u - and Het 3 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R is (Ci-Cio)-alkyl which is substituted by one or more identical or different
  • R is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C-6)-alkyl-0- , R 33 -O-, R 33 -(Ci-C 4 )-alkyl-O-, -O
  • R 33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C-6)-alkyl-0- , (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, (Ci-C 4 )-alkyl-NH-S(O) 2 -, di((Ci-C 4 )-alkyl)N-S(O) 2 - and NC-; R 40 is chosen from the series consisting of hydrogen and (Ci
  • R 50 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, HO- and (d-Ce)- alkyl-O-;
  • R 60 is chosen from the series consisting of hydrogen and (Ci-C6)-alkyl; or R and R together are (CH 2 ) y which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein y is an integer chosen from the series consisting of 2, 3, 4 and 5; or R 30 and R 50 together are (CH 2 ) Z which is optionally substituted by one or more identical or different (Ci-C 4 )-alkyl substituents, wherein z is an integer chosen from the series consisting of 2, 3, 4 and 5;
  • R 71 is chosen from the series consisting of hydrogen and (Ci-CsJ-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (Ci-C6)-alkyl-O- and (Ci-C6)-alkyl-C(O)-O-;
  • R 72 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl, (C3-C6)-cycloalkyl, -CH2-(CH 2 ) b -(C3-C 6 )-cycloalkyl, Het 4 and -(CH 2 ) b -Het 4 , where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO-, HOOC-, (Ci-C 6 )-alkyl-O- and (Ci-C 6 )-alkyl-C(O)-O-, NC-, N((Ci-C 4 )-alkyl) 2 and b is 0, 1 or 2;
  • R 73 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO- and (Ci-C 4 )-alkyl-O-;
  • Ar independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-Ce)- alkyl, (Ci-C 6 )-alkyl-0-, -O-CH 2 -O-, O-CH 2 -CH 2 -O-, -O-CF 2 -O-, (Ci-C 6 )-alkyl-S(O) m -, H 2 N-S(O) 2 -, CF 3 and NC-;
  • Het 1 is a saturated or unsaturated 4- membered to 8-mennbered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-;
  • Het 2 is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, oxo and (Ci-C 4 )-alkyl-O-;
  • Het 3 is a saturated 4-membered to 7- membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (Ci-C 4 )- alkyl and oxo;
  • Het 4 independently of each other group Het 4 , is a saturated or unsaturated 4- membered to 8-mennbered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl, HO-, (Ci-C 4 )-alkyl-O-, oxo and NC-; m, independently of each other number
  • a further preferred embodiment is the use of a compound of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • Ht is chosen from the series consisting of
  • R 1 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, CF 3 , (C3- C 7 )-cycloalkyl-C 3 H 2s -, Ar-C 3 H 2s -, Ar-O, (Ci-C6)-alkyl-O-; wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 2 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, CF 3 , (Cr C 6 )-alkyl-O- and NC-;
  • R 3 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl;
  • R 4 is chosen from the series consisting of (Ci-C 7 )-alkyl, (C3-C 7 )-cycloalkyl-C 3 H 2s - and Ar-C 3 H 2s -, wherein s is an integer chosen from the series consisting of 0, 1 , 2 and 3;
  • R 5 is chosen from the series consisting of hydrogen, halogen, (Ci-C6)-alkyl, (C1-C-6)- alkyl-O-, and NC-.
  • a further preferred embodiment is the use of a compound of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • R 30 is R 32 -C u H 2u -, wherein u is an integer chosen from the series consisting of 0 and 1 ;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6- membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl, HO-, (Ci-C-6)-alkyl-0- , R 33 -O-, R 33 -(Ci-C 4 )-alkyl-O-, -O-CH2-O-, -O-CF2-O-, (Ci-C 6 )-alkyl-S(O)
  • R 40 is hydrogen.
  • a further preferred embodiment is the use of a compound of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • G is R 71 -O-C(O)- and R 72 -N(R 73 )-C(O)-;
  • R 71 is chosen from the series consisting of hydrogen and (Ci-CsJ-alkyl;
  • R 72 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl
  • R 73 is chosen from the series consisting of hydrogen, (Ci-C6)-alkyl.
  • a further preferred embodiment is the use of a compound of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • R 50 is hydrogen
  • R 60 is hydrogen
  • a further preferred embodiment is the use of a compound of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein
  • R 30 is R 32 -C u H 2u - wherein u is an integer 0;
  • R 40 is hydrogen
  • a further preferred embodiment is the use of a compound of the formula IV, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein the compound is chosen from (S)-3-[(2-Phenyl-1 H-imidazole-4-carbonyl)-annino]-3-o-tolyl-propionic acid (S)-3-[(5-Phenyl-isoxazole-3-carbonyl)-amino]-3-o-tolyl-propionic acid
  • a subject of the invention also is the use of a compound of the formula IV which is chosen from any of the specific compounds of the formula IV which are disclosed herein, or is any one of the specific compounds of the formula IV which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a specific salt, or a physiologically acceptable salt thereof, or a physiologically
  • a subject of the invention is the use of a compound of the formula IV which is chosen from (S)-3-[(2-Phenyl-1 H-imidazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid

Abstract

La présente invention concerne l'utilisation de composés de formule (I) pour le traitement/la prévention de la fibrillation auriculaire, dans laquelle A, D, E, G, R10, R30, R40, R50 et R60 ont les mêmes significations que celles proposées dans les revendications. Ils sont des inhibiteurs de la protéase cathépsine A.
PCT/EP2013/070524 2012-10-05 2013-10-02 Utilisation de dérivés substitués de l'acide 3-hétéroaroylamino-propionique en tant que produits pharmaceutiques destinés à la prévention/au traitement de la fibrillation auriculaire WO2014053533A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2018123918A1 (fr) * 2016-12-26 2018-07-05 科研製薬株式会社 Dérivé de pyrazole et médicament le contenant
JP2019534848A (ja) * 2016-10-12 2019-12-05 アールティーアイ インターナショナル 複素環式アペリン受容体（ａｐｊ）アゴニスト及びそれらの使用
US11401244B2 (en) 2014-06-06 2022-08-02 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
CN115093400A (zh) * 2021-09-18 2022-09-23 重庆华森制药股份有限公司 AhR抑制剂及其用途和制备方法
US11535630B2 (en) 2015-12-09 2022-12-27 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
JP2023512579A (ja) * 2020-08-05 2023-03-27 杭州維坦医薬科技有限公司 Ｐ２ｘ３受容体のアンタゴニストとしてのｎ－カルボキサミドピラゾリン系誘導体及びその使用

Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017679A1 (fr) 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, notamment de ns3 protease du virus de l'hepatite c
WO1999050230A1 (fr) 1998-03-31 1999-10-07 Vertex Pharmaceuticals Incorporated Inhibiteurs de serine protease, particulierement de la protease ns3 du virus de l'hepatite c
WO2001074768A2 (fr) 2000-04-03 2001-10-11 Vertex Pharmaceuticals Incorporated Inhibiteurs de serine proteases, notamment de la protease ns3 du virus de l'hepatite c
WO2002008244A2 (fr) 2000-07-21 2002-01-31 Schering Corporation Nouveau peptide sous forme d'inhibiteurs de protease a serine ns3 d'hepatite virale c
WO2003006490A1 (fr) 2001-07-11 2003-01-23 Vertex Pharmaceuticals Incorporated Inhibiteurs bicycliques pontes de la serine protease
WO2003035060A1 (fr) 2001-10-24 2003-05-01 Vertex Pharmaceuticals Incorporated Inhibiteurs de la serine protease, en particulier de la protease ns3-ns4a du virus de l'hepatite c, integrant un systeme de cycles accoles
WO2003062265A2 (fr) 2002-01-18 2003-07-31 Schering Corporation Nouveaux peptides utiles comme inhibiteurs de serine protease ns3 du virus de l'hepatite c
WO2003087092A2 (fr) 2002-04-11 2003-10-23 Vertex Pharmaceuticals Incorporated Inhibiteurs de la serine protease, notamment de la protease ns3-ns4a du virus de l'hepatite c
WO2004092161A1 (fr) 2003-04-11 2004-10-28 Vertex Pharmaceuticals Incorporated Inhibiteurs des serine proteases, en particulier de la protease ns3-ns4a du vhc
WO2004092162A1 (fr) 2003-04-11 2004-10-28 Vertex Pharmaceuticals, Incorporated Inhibiteurs des serine proteases, en particulier de la protease ns3-ns4a du vhc
WO2005007681A2 (fr) 2003-07-18 2005-01-27 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, en particulier de la protease ns3-ns4a du vhc
WO2005028502A1 (fr) 2003-09-18 2005-03-31 Vertex Pharmaceuticals, Incorporated Inhibiteurs de serines proteases, en particulier de la protease ns3-ns4a du vhc
WO2005035525A2 (fr) 2003-09-05 2005-04-21 Vertex Pharmaceuticals Incorporated Inhibiteurs des serines proteases, en particulier de la protease ns3-ns4a du virus de l'hepatite c (vhc)
WO2006113942A2 (fr) 2005-04-20 2006-10-26 Schering Corporation Procede d'inhibition de l'activite de cathepsine
WO2007016589A2 (fr) 2005-08-02 2007-02-08 Vertex Pharmaceuticals Incorporated Inhibiteurs des serines proteases
WO2007022459A2 (fr) 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Procedes et intermediaires
US20070237818A1 (en) * 2005-06-02 2007-10-11 Malcolm Bruce A Controlled-release formulation of HCV protease inhibitor and methods using the same
US7772178B2 (en) 2005-06-02 2010-08-10 Schering Corporation Pharmaceutical formulations and methods of treatment using the same
WO2010136493A1 (fr) * 2009-05-28 2010-12-02 Novartis Ag Dérivés aminopropioniques substitués comme inhibiteurs de néprilysine
WO2011092187A1 (fr) 2010-01-26 2011-08-04 Sanofi Dérivés d'acide 3-hétéroaroylamino-propionique à substitution oxygène et leur utilisation comme produits pharmaceutiques
WO2012101199A1 (fr) 2011-01-26 2012-08-02 Sanofi Dérivés de l'acide 3-hétéroaroylamino-propionique amino substitués et leur utilisation en tant que produits pharmaceutiques
WO2012101197A1 (fr) 2011-01-26 2012-08-02 Sanofi Dérivés substitués de l'acide 3-hétéroaroylamino-propionique et leur utilisation comme composés pharmaceutiques
WO2013014204A2 (fr) 2011-07-26 2013-01-31 Sanofi Dérivés d'acide 3-hétéroaroylaminopropionique et leur utilisation comme produits pharmaceutiques
WO2013014205A1 (fr) 2011-07-26 2013-01-31 Sanofi Dérivés d'acide 3-(thiazole-4-carbonyl)aminopropionique ou 3-(thiazole-2-carbonyl)aminopropionique substitué et leur utilisation comme produits pharmaceutiques
WO2013072327A1 (fr) 2011-11-14 2013-05-23 Sanofi Utilisation de boceprevir et de composés associés pour le traitement de l'athérosclérose, d'une insuffisance cardiaque, de néphropathies, de maladies hépatiques ou de maladies inflammatoires
WO2013072328A1 (fr) 2011-11-14 2013-05-23 Sanofi Utilisation de telaprevir et de composés associés pour le traitement de l'athérosclérose, d'une insuffisance cardiaque, de néphropathies, de maladies hépatiques ou de maladies inflammatoires

Patent Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017679A1 (fr) 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, notamment de ns3 protease du virus de l'hepatite c
WO1999050230A1 (fr) 1998-03-31 1999-10-07 Vertex Pharmaceuticals Incorporated Inhibiteurs de serine protease, particulierement de la protease ns3 du virus de l'hepatite c
WO2001074768A2 (fr) 2000-04-03 2001-10-11 Vertex Pharmaceuticals Incorporated Inhibiteurs de serine proteases, notamment de la protease ns3 du virus de l'hepatite c
WO2002008244A2 (fr) 2000-07-21 2002-01-31 Schering Corporation Nouveau peptide sous forme d'inhibiteurs de protease a serine ns3 d'hepatite virale c
US7012066B2 (en) 2000-07-21 2006-03-14 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
WO2003006490A1 (fr) 2001-07-11 2003-01-23 Vertex Pharmaceuticals Incorporated Inhibiteurs bicycliques pontes de la serine protease
WO2003035060A1 (fr) 2001-10-24 2003-05-01 Vertex Pharmaceuticals Incorporated Inhibiteurs de la serine protease, en particulier de la protease ns3-ns4a du virus de l'hepatite c, integrant un systeme de cycles accoles
WO2003062265A2 (fr) 2002-01-18 2003-07-31 Schering Corporation Nouveaux peptides utiles comme inhibiteurs de serine protease ns3 du virus de l'hepatite c
WO2003087092A2 (fr) 2002-04-11 2003-10-23 Vertex Pharmaceuticals Incorporated Inhibiteurs de la serine protease, notamment de la protease ns3-ns4a du virus de l'hepatite c
WO2004092161A1 (fr) 2003-04-11 2004-10-28 Vertex Pharmaceuticals Incorporated Inhibiteurs des serine proteases, en particulier de la protease ns3-ns4a du vhc
WO2004092162A1 (fr) 2003-04-11 2004-10-28 Vertex Pharmaceuticals, Incorporated Inhibiteurs des serine proteases, en particulier de la protease ns3-ns4a du vhc
WO2005007681A2 (fr) 2003-07-18 2005-01-27 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, en particulier de la protease ns3-ns4a du vhc
WO2005035525A2 (fr) 2003-09-05 2005-04-21 Vertex Pharmaceuticals Incorporated Inhibiteurs des serines proteases, en particulier de la protease ns3-ns4a du virus de l'hepatite c (vhc)
WO2005028502A1 (fr) 2003-09-18 2005-03-31 Vertex Pharmaceuticals, Incorporated Inhibiteurs de serines proteases, en particulier de la protease ns3-ns4a du vhc
WO2006113942A2 (fr) 2005-04-20 2006-10-26 Schering Corporation Procede d'inhibition de l'activite de cathepsine
US20070237818A1 (en) * 2005-06-02 2007-10-11 Malcolm Bruce A Controlled-release formulation of HCV protease inhibitor and methods using the same
US7772178B2 (en) 2005-06-02 2010-08-10 Schering Corporation Pharmaceutical formulations and methods of treatment using the same
WO2007016589A2 (fr) 2005-08-02 2007-02-08 Vertex Pharmaceuticals Incorporated Inhibiteurs des serines proteases
WO2007022459A2 (fr) 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Procedes et intermediaires
WO2010136493A1 (fr) * 2009-05-28 2010-12-02 Novartis Ag Dérivés aminopropioniques substitués comme inhibiteurs de néprilysine
WO2011092187A1 (fr) 2010-01-26 2011-08-04 Sanofi Dérivés d'acide 3-hétéroaroylamino-propionique à substitution oxygène et leur utilisation comme produits pharmaceutiques
WO2012101199A1 (fr) 2011-01-26 2012-08-02 Sanofi Dérivés de l'acide 3-hétéroaroylamino-propionique amino substitués et leur utilisation en tant que produits pharmaceutiques
WO2012101197A1 (fr) 2011-01-26 2012-08-02 Sanofi Dérivés substitués de l'acide 3-hétéroaroylamino-propionique et leur utilisation comme composés pharmaceutiques
WO2013014204A2 (fr) 2011-07-26 2013-01-31 Sanofi Dérivés d'acide 3-hétéroaroylaminopropionique et leur utilisation comme produits pharmaceutiques
WO2013014205A1 (fr) 2011-07-26 2013-01-31 Sanofi Dérivés d'acide 3-(thiazole-4-carbonyl)aminopropionique ou 3-(thiazole-2-carbonyl)aminopropionique substitué et leur utilisation comme produits pharmaceutiques
WO2013072327A1 (fr) 2011-11-14 2013-05-23 Sanofi Utilisation de boceprevir et de composés associés pour le traitement de l'athérosclérose, d'une insuffisance cardiaque, de néphropathies, de maladies hépatiques ou de maladies inflammatoires
WO2013072328A1 (fr) 2011-11-14 2013-05-23 Sanofi Utilisation de telaprevir et de composés associés pour le traitement de l'athérosclérose, d'une insuffisance cardiaque, de néphropathies, de maladies hépatiques ou de maladies inflammatoires

Non-Patent Citations (47)

* Cited by examiner, † Cited by third party
Title
ACAR G; AKCAY A; SOKMEN A; OZKAYA M; GULER E; SOKMEN G; KAYA H; NACAR AB; TUNCER C: "Assessment of atrial electromechanical delay, diastolic functions, and left atrial mechanical functions in patients with type 1 diabetes mellitus", J AM SOC ECHOCARDIOGR., vol. 22, 2009, pages 732 - 738
ASHIZAWA N; GRAF K; DO YS; NUNOHIRO T; GIACHELLI CM; MEEHAN WP; TUAN TL; HSUEH WA: "Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction", J CLIN INVEST., vol. 98, 1996, pages 2218 - 2227
BRAND FN; ABBOTT RD; KANNEL WB; WOLF PA: "Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study", JAMA, vol. 254, 1985, pages 3449 - 3453
BURSTEIN B; COMTOIS P; MICHAEL G; NISHIDA K; VILLENEUVE L; YEH YH; NATTEL S: "Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure", CIRC RES., vol. 4, no. 105, 2009, pages 1213 - 1222
COSSON S; KEVORKIAN JP: "Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy?", DIABETES METAB., vol. 29, 2003, pages 455 - 466
DANIELS A; LINZ D; VAN BILSEN M; RUTTEN H; SADOWSKI T; RUF S; JURETSCHKE HP; NEUMANN-HAEFELIN C; MUNTS C; VAN DER VUSSE GJ: "Long-term severe diabetes only leads to mild cardiac diastolic dysfunction in Zucker diabetic fatty rats", EUR J HEART FAIL., vol. 14, 2012, pages 193 - 201
ERDOS EG; JACKMAN HL; BROVKOVYCH V; TAN F; DEDDISH PA: "Products of angiotensin I hydrolysis by human cardiac enzymes potentiate bradykinin", J MOL CELL CARDIOL, vol. 34, 2002, pages 1569 - 1576
GREISER M; NEUBERGER HR; HARKS E; EL-ARMOUCHE A; BOKNIK P; HAAN S; VERHEYEN F; VERHEULE S; SCHMITZ W; RAVENS U: "Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation", J MOL CELL CARDIOL., vol. 46, 2009, pages 385 - 394
HANNA N; CARDIN S; LEUNG TK; NATTEL S: "Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure", CARDIOVASC RES., vol. 63, 2004, pages 236 - 244
HAYASHI I; MAJIMA M; FUJITA T; OKUMURA T; KUMAGAI Y; TOMITA N; MORISHITA R; HIGAKI J; OGIWARA T: "In vivo transfer of antisense oligonucleotide against urinary kininase blunts deoxycorticosterone acetate-salt hypertension in rats", BR J PHARMACOL ., vol. 131, 2000, pages 820 - 826
HIRAIWA M: "Cathepsin A/protective protein: an unusual lysosomal multifunctional protein", CELL MOL LIFE SCI., vol. 56, 1999, pages 894 - 907
ITO H; MAJIMA M; NAKAJIMA S; HAYASHI I; KATORI M; IZUMI T: "Effect of prolonged administration of a urinary kinase inhibitor, ebelactone B on the development of deoxycorticosterone acetate-salt hypertension in rats", BR J PHARMACOL., vol. 126, 1999, pages 613 - 620
JACKMAN HL; MASSAD MG; SEKOSAN M; TAN F; BROVKOVYCH V; MARCIC BM; ERDOS EG: "Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A", HYPERTENSION, vol. 39, 2002, pages 976 - 981
JARVINEN V; KUPARI M; HEKALI P; POUTANEN VP: "Assessment of left atrial volumes and phasic function using cine magnetic resonance imaging in normal subjects", AM J CARDIOL., vol. 73, 1994, pages 1135 - 1138
KANNEL WB; WOLF PA; BENJAMIN EJ; LEVY D: "Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates", AM J CARDIOL., vol. 82, 1998, pages 2N - 9N
KATO T; YAMASHITA T; SEKIGUCHI A; SAGARA K; TAKAMURA M; TAKATA S; KANEKO S; AIZAWA T; FU LT: "What are arrhythmogenic substrates in diabetic rat atria?", J CARDIOVASC ELECTROPHYSIOL., vol. 17, 2006, pages 890 - 894
LI D; FAREH S; LEUNG TK; NATTEL S: "Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort", CIRCULATION, vol. 100, 1999, pages 87 - 95
LINZ ET AL.: "Cathepsin A -inhibition reduces susceptibility to atrial tachyarrhythmia and prevents impairment of atrial emptying function in old zucker diabetic fatty rats.", 27 August 2012 (2012-08-27), XP002689581, Retrieved from the Internet <URL:http://spo.escardio.org/sessiondetails.aspx?eevtid=54&fp=2280&doc=slides#.UNG7JBqwXP8> [retrieved on 20121219] *
LINZ ET AL.: "CathepsinA-Inhibition Reduces Susceptibility to Atrial Tachyarrhythmia and Prevents Impairment of Atrial Emptying Function in old Zucker Diabetic Fatty Rats", 11 May 2012 (2012-05-11), XP002689582, Retrieved from the Internet <URL:http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2863&sKey=1842e375-2180-47e7-b757-4f258e424dad&cKey=1ae5e6b4-91e5-4138-913e-15e1b31d74e9&mKey={BAEF2DB4-7615-4F2C-851A-E5D7461EBD4E}> [retrieved on 20121219] *
LINZ W; WIEMER G; GOHLKE P; UNGER T; SCH6LKENS BA: "Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors", PHARMACOL REV., vol. 47, 1995, pages 25 - 49
MIHM MJ; YU F; CARNES CA; REISER PJ; MCCARTHY PM; VAN WAGONER DR; BAUER JA: "Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation", CIRCULATION, vol. 104, 2001, pages 174 - 180
MOVAHED MR; HASHEMZADEH M; JAMAL MM: "Diabetes mellitus is a strong, independent risk for atrial fibrillation and flutter in addition to other cardiovascular disease", INT J CARDIOL., vol. 105, 2005, pages 315 - 318
NEUBERGER HR; SCHOTTEN U; VERHEULE S; EIJSBOUTS S; BLAAUW Y; VAN HUNNIK A; ALLESSIE M: "Development of a substrate of atrial fibrillation during chronic atrioventricular block in the goat", CIRCULATION, vol. 111, 2005, pages 30 - 37
NORI D; RAFF G; GUPTA V; GENTRY R; BOURA J; HAINES DE: "Cardiac magnetic resonance imaging assessment of regional and global left atrial function before and after catheter ablation for atrial fibrillation", J INTERV CARD ELECTROPHYSIOL., vol. 26, 2009, pages 109 - 117
OKAMOTO H.: "Osteopontin and cardiovascular system", MOL CELL BIOCHEM., vol. 300, 2007, pages 1 - 7
OSTGREN CJ; MERLO J; RASTAM L; LINDBLAD U: "Atrial fibrillation and its association with type 2 diabetes and hypertension in a Swedish community", DIABETES OBES METAB., vol. 6, 2004, pages 367 - 374
POLONTCHOUK L; HAEFLIGER JA; EBELT B; SCHAEFER T; STUHLMANN D; MEHLHORN U; KUHN-REGNIER F; VIVIE ER; DHEIN S: "Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria", J AM COLL CARDIOL., vol. 38, 2001, pages 883 - 891
REGENSTEINER JG; BAUER TA; REUSCH JE; BRANDENBURG SL; SIPPEL JM; VOGELSONG AM; SMITH S; WOLFEL EE; ECKEL RH; HIATT WR: "Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus", J APPL PHYSIOL., vol. 85, 1998, pages 310 - 317
REGENSTEINER JG; SIPPEL J; MCFARLING ET; WOLFEL EE; HIATT WR: "Effects of non-insulin-dependent diabetes on oxygen consumption during treadmill exercise", MED SCI SPORTS EXERC., vol. 27, 1995, pages 875 - 881
ROCKEN C; PETERS B; JUENEMANN G; SAEGER W; KLEIN HU; HUTH C; ROESSNER A; GOETTE A: "Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation", CIRCULATION, vol. 106, 2002, pages 2091 - 2097
RUCKER-MARTIN C; MILLIEZ P; TAN S; DECROUY X; RECOUVREUR M; VRANCKX R; DELCAYRE C; RENAUD JF; DUNIA I; SEGRETAIN D: "Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts", CARDIOVASC RES., vol. 72, 2006, pages 69 - 79
RUF SVEN ET AL: "Novel beta-Amino Acid Derivatives as Inhibitors of Cathepsin A", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 17, September 2012 (2012-09-01), pages 7636 - 7649, XP002689580, ISSN: 0022-2623 *
RUSKOAHO H: "Atrial natriuretic peptide: synthesis, release, and metabolism", PHARMACOL REV., vol. 44, 1992, pages 479 - 602
SATOH T; ZIPES DP: "Cesium-induced atrial tachycardia degenerating into atrial fibrillation in dogs: atrial torsades de pointes?", J CARDIOVASC ELECTROPHYSIOL., vol. 9, 1998, pages 970 - 975
SCHAFER S; HUBER J; WIHLER C; RUTTEN H; BUSCH AE; LINZ W: "Impaired left ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of N(epsilon)-(carboxymethyl) lysine", EUR J HEART FAIL., vol. 8, 2006, pages 2 - 6
SCHOTTEN U; VERHEULE S; KIRCHHOF P; GOETTE A: "Pathophysiological mechanisms of atrial fibrillation: a translational appraisal", PHYSIOL REV., vol. 91, 2011, pages 265 - 325
STECKELINGS UM; ROMPE F; KASCHINA E; UNGER T: "The evolving story of the RAAS in hypertension, diabetes and CV disease: moving from macrovascular to microvascular targets", FUNDAM CLIN PHARMACOL., vol. 23, 2009, pages 693 - 703
SUBRAMANIAN V; KRISHNAMURTHY P; SINGH K; SINGH M: "Lack of osteopontin improves cardiac function in streptozotocin-induced diabetic mice", AM J PHYSIOL HEART CIRC PHYSIOL., vol. 292, 2007, pages H673 - 83
TAKAHASHI M; HOSHII Y; KAWANO H; GONDO T; YOKOTA T; OKABAYASHI H; SHIMADA I; LSHIHARA T: "Ultrastructural evidence for the formation of amyloid fibrils within cardiomyocytes in isolated atrial amyloid", AMYLOID, vol. 5, 1998, pages 35 - 42
TRUEBLOOD NA; XIE Z; COMMUNAL C; SAM F; NGOY S; LIAW L; JENKINS AW; WANG J; SAWYER DB; BING OH: "Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin", CIRC RES., vol. 88, 2001, pages 1080 - 1087
URATA H; GANTEN D: "Cardiac angiotensin II formation: the angiotensin-I converting enzyme and human chymase", EUR HEART J., vol. 14, no. I, 1993, pages 177 - 182
URATA H; HOFFMANN S; GANTEN D: "Tissue angiotensin II system in the human heart", EUR HEART J., vol. 15, no. D, 1994, pages 68 - 78
W. LINZ ET AL., JRAAS, vol. 7, 2006, pages 155 - 161
WAKILI R; YEH YH; YAN QI X; GREISER M; CHARTIER D; NISHIDA K; MAGUY A; VILLENEUVE LR; BOKNIK P; VOIGT N: "Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs", CIRC ARRHYTHM ELECTROPHYSIOL., vol. 3, no. 5, 2010, pages 530 - 41
WEI M; GIBBONS LW; MITCHELL TL; KAMPERT JB; LEE CD; BLAIR SN: "The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men", ANN INTERN MED., vol. 130, 1999, pages 89 - 96
WOLF PA; ABBOTT RD; KANNEL WB: "Atrial fibrillation as an independent risk factor for stroke: the Framingham Study", STROKE, vol. 22, 1991, pages 983 - 988
XIE Z; SINGH M; SINGH K: "Osteopontin modulates myocardial hypertrophy in response to chronic pressure overload in mice", HYPERTENSION, vol. 44, 2004, pages 826 - 831

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