US2022363675A1PendingUtilityA1
Novel Ferroportin Inhibitors
Est. expiryOct 23, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Franz DürrenbergerMichael BurgertSusanna BurckhardtWilm BuhrAris KalogerakisStefan ReimVania ManolovaSusan BoyceChristopher John YarnoldPaula PenaJon ShepherdCristina LecciRichard Jarjes-PikeJohn Scott
C07D 417/14C07D 495/04C07D 235/14C07D 487/04A61K 31/4184A61P 7/06C07D 401/12Y02A50/30C07D 401/14A61K 31/55A61P 25/00A61K 31/437C07D 471/04A61K 31/4439C07D 413/14A61K 31/4725A61P 3/12A61K 31/506A61K 2300/00A61K 31/497A61P 25/16A61K 31/4709A61K 31/501A61P 7/00C07D 403/14A61K 31/5377A61K 31/4375A61K 31/16A61K 31/427A61K 31/4355A61K 31/4985C07D 413/04A61K 31/4422A61K 31/426A61K 45/06C07D 277/56A61K 31/435C07D 417/12A61K 31/444A61P 25/28A61K 36/9066
71
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Claims
Abstract
The invention relates to novel compounds of the general formula (I),with Het-2 being an optionally substituted bicyclic heteroaryl of the formulapharmaceutical compositions comprising them and the use thereof as medicaments, in particular for the use as ferroportin inhibitors, more particularly for the use in the prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload states such as in particular thalassemia and hemochromatosis.
Claims
exact text as granted — not AI-modified1 . Compounds according to formula (A-I)
wherein
Het-2 is an optionally substituted bicyclic heteroaryl of the formula
wherein * indicates the binding site to A 2 and
R 4 indicates 1, 2 or 3 optional substituents, which may independently be selected from the group consisting of
halogen,
cyano,
optionally substituted alkyl,
optionally substituted alkoxy, and
a carboxyl group;
X 1 is C, N, S or O;
X 2 is C or N;
X 3 is C, N, S or O; and
X 4 is C, N, or S
with the proviso that 1 to 3 heteroatoms X are present,
and wherein X 1 , X 3 and X 4 , when having the meaning of C or N, may carry a further substituent;
R 1 is selected from the group consisting of
hydrogen and
optionally substituted alkyl;
Cycl is selected from the group consisting of
substituted aryl and
substituted or unsubstituted heteroaryl;
Q is
hydrogen or
C 1 -C 4 -alkyl, which may form a fused 5- or 6-membered ring with Cycl;
n is 0 or an integer of 1 to 8, preferably n is 0 or 1 to 4, preferably n is 0, 1, 2 or 3;
A 1 is
optionally substituted alkanediyl;
A 2 is
optionally substituted alkanediyl or
a direct bond;
R 3 is
hydrogen, or
optionally substituted alkyl; or
A 1 and R 3 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 6-membered mono- or bicyclic ring; or
R 3 and A 2 together with the nitrogen atom to which they are bonded form an optionally substituted 4- to 7-membered ring; and
Y 2 is C or N, wherein
both Y 2 may be C or
one Y 2 may be N and one Y 2 may be C;
or pharmaceutically acceptable salts thereof.
2 . Compounds according to claim 1 , having the formula (A-II)
or pharmaceutically acceptable salts thereof.
3 . Compounds according to claim 1 or 2 , wherein Cycl is substituted or unsubstituted heteroaryl, or pharmaceutically acceptable salts thereof.
4 . Compounds according to any one of the preceding claims, wherein Cycl is a substituted or unsubstituted heteroaryl, which is selected from a substituted or unsubstituted pyridinyl, forming compounds according to formula (A-IIIa) or (A-IIIb)
wherein
R 5 indicates 1 to 4 optional substituents, which may independently be selected from the group consisting of
halogen, preferably F and Cl,
optionally substituted alkyl, preferably methyl, trifluoromethyl, hydroxymethyl,
hydroxy,
alkoxy, preferably methoxy,
an oxo group (═O), forming a substituted pyridinyl-group of the formula
an amino group, such as —NH 2 , mono- or dialkylamino, preferably dialkylamino
an aminocarbonyl group, preferably NH 2 —(C═O)—,
cyano, and
a heterocyclyl group, preferably a morpholinyl-group,
or pharmaceutically acceptable salts thereof.
5 . Compounds according to claim 4 , having the formula (A-IVa) or (A-IVb)
or pharmaceutically acceptable salts thereof.
6 . Compounds according to claim 4 or 5 , wherein R 5 indicates 1 to 3 substituents, which may independently be selected from the group consisting of
halogen
optionally substituted alkyl,
hydroxy, and
alkoxy,
or pharmaceutically acceptable salts thereof.
7 . Compounds according to claim 6 , wherein R 5 indicates 1 substituent, which is selected from the group consisting of
halogen optionally substituted alkyl, hydroxy, and alkoxy,
or pharmaceutically acceptable salts thereof.
8 . Compounds according to any one of claims 5 to 7 , having the formula (A-IVc) or (A-IVd)
or pharmaceutically acceptable salts thereof.
9 . Compounds according to any one of claims 5 to 8 , wherein R 5 is selected from the group consisting of
halogen and
optionally substituted alkyl,
or pharmaceutically acceptable salts thereof.
10 . Compounds according to any one of claims 5 to 9 , wherein R 5 is selected from a halogen, or pharmaceutically acceptable salts thereof.
11 . Compounds according to claim 10 , wherein R 5 is selected from Cl and F, preferably R 5 is F, or pharmaceutically acceptable salts thereof.
12 . Compounds according to claim 1 or 2 , wherein Cycl is an aryl group, which is substituted with 1 to 3 substituents selected from the group consisting of
hydroxy,
halogen,
cyano,
optionally substituted alkyl,
optionally substituted amino,
optionally substituted acyl,
optionally substituted alkoxy,
optionally substituted aryloxy,
optionally substituted heterocyclyloxy,
optionally substituted aryl, and
optionally substituted heterocyclylyl;
or pharmaceutically acceptable salts thereof.
13 . Compounds according to claim 12 , wherein Cycl is a substituted phenyl group, forming compounds according to formula (A-Va) or (A-Vb)
wherein R 6 indicates 1, 2 or 3 substitutens which are independently selected from the group consisting of
hydroxy,
halogen,
cyano,
optionally substituted alkyl,
optionally substituted amino,
optionally substituted acyl,
optionally substituted alkoxy,
optionally substituted aryloxy,
optionally substituted heterocyclyloxy,
optionally substituted aryl, and
optionally substituted heterocyclylyl;
or pharmaceutically acceptable salts thereof.
14 . Compounds according to claim 12 or 13 , wherein R 6 indicates 1 or 2 substituents as defined in claim 12 ,
or pharmaceutically acceptable salts thereof.
15 . Compounds according to claim 13 or 14 , wherein R 6 indicates 1 substituent selected from the group as defined in claim 12 ,
or pharmaceutically acceptable salts thereof.
16 . Compounds according to any one of claims 13 to 15 , wherein R 6 is selected from the group consisting of
hydroxy,
halogen, preferably F and Cl,
cyano,
optionally substituted alkyl,
optionally substituted amino, such as (—NH 2 ) or mono- or dialkylamino, preferably dimethylamino,
optionally substituted alkoxy, preferably methoxy, di-fluoromethoxy and trifluoromethoxy,
optionally substituted heterocyclylyl, preferably optionally substituted pyrrolininyl, morpholinyl, and piperazinyl, and
an optionally substituted sulfonyl-group, such as preferably heterocyclyl-substituted sulfonyl, preferably of the formula
or pharmaceutically acceptable salts thereof.
17 . Compounds according to any one of claims 13 to 16 , wherein R 6 is selected from the group consisting of
halogen, preferably F,
cyano,
dimethylamino,
methoxy, di-fluoromethoxy and trifluoromethoxy,
optionally substituted heterocyclylyl, preferably optionally substituted pyrrolininyl, morpholinyl, and piperazinyl, and
an optionally substituted sulfonyl-group, such as preferably heterocyclyl-substituted sulfonyl, preferably of the formula
or pharmaceutically acceptable salts thereof.
18 . Compounds according to any one of the preceding claims, wherein
X 1 is N and wherein one or two further heteroatoms X (X 2 , X 3 , X 4 ) are present, and wherein X 2 is C or N; X 3 is C, N, S or 0; and X 4 is C or N, forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
with the proviso that in case of two further heteroatoms both are selected to be N or one is N and one (except X 2 ) is O;
and wherein X 3 and X 4 , when having the meaning of C or N, may carry a further substituent,
or pharmaceutically acceptable salts thereof.
19 . Compounds according to any one of the preceding claims, wherein
X 1 is N, X 2 is C and X 3 is O; and X 4 is N or C, preferably C, forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
and wherein
X 4 may carry a further substituent,
or pharmaceutically acceptable salts thereof.
20 . Compounds according to any one of the preceding claims, wherein
X 1 is N, X 2 is C and X 3 is S; and X 4 is N or C, preferably C, forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
and wherein
X 4 may carry a further substituent,
or pharmaceutically acceptable salts thereof.
21 . Compounds according to any one of the preceding claims, wherein
X 2 and X 3 are both N, forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
and wherein
X 1 and X 4 are C;
and wherein X 1 and/or X 4 may carry a further substituent,
or pharmaceutically acceptable salts thereof.
22 . Compounds according to any one of the preceding claims, wherein
X 1 is C, and X 2 , X 3 and X 4 are N, forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
and wherein
X 1 may carry a further substituent,
or pharmaceutically acceptable salts thereof.
23 . Compounds according to any one of the preceding claims, wherein
X 1 , X 2 and X 4 are N, and X 3 is C, forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
and wherein
X 3 may carry a further substituent,
or pharmaceutically acceptable salts thereof.
24 . Compounds according to any one of the preceding claims, wherein
X 1 is O, X 2 is C, X 3 is N, and X 4 is C, and wherein Y 1 indicates
hydrogen or
an optional subsitutent to X 4 ;
forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
or pharmaceutically acceptable salts thereof.
25 . Compounds according to any one of the preceding claims, wherein
X 1 is S, X 2 is C, X 3 is N, and X 4 is C, and wherein Y 1 indicates
hydrogen or
an optional subsitutent to X 4 ;
forming a group
wherein * indicates the binding site to the aminocarbonyl-group and ** indicates the binding site to the A 1 -group;
or pharmaceutically acceptable salts thereof.
26 . Compounds according to any one of the preceding claims, wherein the further substituents of X 1 , X 3 and X 4 are selected from the group consisting of
halogen, and optionally substituted alkyl,
or pharmaceutically acceptable salts thereof.
27 . Compounds according to claims 26 , wherein the further substituents of X 1 , X 3 and X 4 are selected from the group consisting of
Cl, and linear or branched C 1 -C 3 -alkyl, which may be substituted with 1 to 3 halogens or with a methylene-group; such as preferably a methyl-group, an iso-propyl-group, a CF3-group or a methylene-substituted ethyl-group
or pharmaceutically acceptable salts thereof.
28 . Compounds according to any one of the preceding claims, wherein n is 1,
or pharmaceutically acceptable salts thereof.
29 . Compounds according to any one of the preceding claims, wherein Q is H,
or pharmaceutically acceptable salts thereof.
30 . Compounds according to any one of the preceding claims, wherein R 1 is H,
or pharmaceutically acceptable salts thereof.
31 . Compounds according to any one of the preceding claims, wherein Cycl is a group of the formula
wherein * indicates the binding site,
or pharmaceutically acceptable salts thereof.
32 . Compounds according to any one of the preceding claims, wherein
A 1 and A 2 are optionally substituted alkanediyl and are the same or different and are independently selected from optionally substituted
methylene and
ethane-1,2-diyl, or wherein
A 1 and R 3 together with the nitrogen atom to which they are bonded form an optionally substituted 4-membered aliphatic monocyclic ring; or pharmaceutically acceptable salts thereof.
33 . Compounds according to any one of the preceding claims, which are selected from
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or pharmaceutically acceptable salts thereof.
34 . Compounds according to any one of the preceding claims for the use as a medicament.
35 . Compounds according to any one of the preceding claims for the use as ferroportin inhibitor.
36 . Compounds as defined in any one of the preceding claims for the use in the inhibition of iron transport mediated by ferroportin.
37 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of iron metabolism disorders leading to increased iron levels or increased iron absorption.
38 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of iron overload.
39 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of diseases related to or caused by increased iron levels, increased iron absorption or iron overload.
40 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of diseases associated with ineffective erythropoiesis, such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera and congenital dyserythropoietic anemia.
41 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of diseases caused by reduced levels of hepcidin.
42 . Compounds as defined in any one of the preceding claims for the use in an adjunctive therapy by limiting the amount of iron available to pathogenic microorganisms, such as the bacterium Vibrio vulnificus, thereby treating infections caused by said pathogenic microorganisms.
43 . Compounds as defined in any one of the preceding claims for the use according to claim 39 , wherein the diseases, which are related to or caused by increased iron levels, increases iron absorption or iron overload are selected from thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, haemochromatosis, hemolytic anemia.
44 . Compounds as defined in any one of the preceding claims for the use according to claim 43 , wherein the thalassemia includes alpha-thalassemia, beta-thalassemia and delta-thalassemia.
45 . Compounds as defined in any one of the preceding claims for the use according to claim 43 , wherein the hemolytic anemia is sickle cell anemia or congenital dyserythropoietic anemia.
46 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by limiting the deposition or increase of iron in tissue or cells.
47 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of formation of radicals, reactive oxygen species (ROS) and oxidative stress.
48 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of cardiac, liver and endocrine damage caused by iron overload.
49 . Compounds as defined in any one of the preceding claims for the use in the prophylaxis and/or treatment of inflammation triggered by excess iron.
50 . A medicament containing one or more of the compounds as defined in any one of the preceding claims.
51 . The medicament according to claim 50 for the use as defined in any one of claims 35 to 49 .
52 . The medicament according to claims 50 and 51 , which further contains one or more pharmaceutical carriers and/or auxiliaries and/or solvents.
53 . The medicament according to any one of claims 50 to 52 , which further contains at least one additional pharmaceutically active compound.
54 . The medicament according to claim 53 , wherein the at least one additional pharmaceutically active compound is selected from active compounds for the prophylaxis and treatment of iron overload, thalassemia, or haemochromatosis.
55 . The medicament according to claim 53 , wherein the at least one additional pharmaceutically active compound is selected from active compounds for the prophylaxis and treatment of neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, and the associated symptoms.
56 . The medicament according to any one of claims 50 to 55 , which contains at least one additional pharmaceutically active compound, which is an iron-chelating compound.
57 . The medicament according to any one of claims 50 to 56 , which is in the form of a formulation for oral or parenteral administration.
58 . Compounds as defined in any one of the preceding claims for the use in a combination therapy, comprising co-administration of the compounds as defined in any of the preceding claims with at least one additional pharmaceutically active compound.
59 . Compounds for the use according to claim 58 , wherein the co-administration of the combination therapy is carried out in a fixed dose combination therapy by co-administration of the compounds as defined in any of the preceding claims with at least one additional pharmaceutically active compound in a fixed-dose formulation.
60 . Compounds for the use according to claim 58 , wherein the co-administration of the combination therapy is carried out in a free dose combination therapy by co-administration of the compounds as defined in any of the preceding claims and the at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a time period.
61 . Compounds for the use according to any one of claims 58 to 60 , wherein the combination therapy comprises co-administration of the compounds as defined in any of the preceding claims with one or more other pharmaceutically active compounds for reducing iron overload, which are selected from Tmprss6-ASO, iron chelators, curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and/or deferiprone.
62 . Compounds for the use according to any one of claims 58 to 61 , wherein the combination therapy comprises co-administration of the compounds as defined in any of the preceding claims with one or more other pharmaceutically active compounds which are selected from antioxidants, such as n-acetyl cysteine; anti-diabetics, such as GLP-1 receptor agonists; antibiotics, such as vancomycin (Van) or tobramycin; drugs for the treatment of malaria; anticancer agents; antifungal drugs; drugs for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, comprising dopamine agonists such as Levodopa; anti-viral drugs, such as interferon-α or ribavirin; immunosuppressents, such as cyclosporine A or cyclosporine A derivatives; iron supplements; vitamin supplements; red cell production stimulators; anti-inflammatory biologies; anti-thrombolytics; statins; vasopressors; and inotropic compounds.Cited by (0)
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