Affinity small molecules for the EPO receptor
AssigneeReceptron
InventorsLennart Olsson, Tatjana Naranda
Life of this patent
Estimating the term…
Abstract
Compounds are provided that complex with the modulating domain of erythropoietin receptor (EPO-R) for use with EPO-R to determine the presence of EPO-R, the ability of other molecules to bind to the modulating domain in competitive assays and to induce a signal by EPO-R into a cell when bound by the subject compounds in a physiological environment. The compounds are characterized by having a six-membered heterocyclic ring comprising at least one nitrogen atom and include substituted triazolopyrimidine, pyridazinone, pyridine and piperidine.
Claims32
A combination comprising a polypeptide comprising the modulating sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 41
- wherein:
- X is of from 1 to 7 atoms other than hydrogen and is oxygen, sulfur bonded to 0 to 2 oxygen atoms, amino and alkyl substituted amino;
- n is 0 or 1;
- R1 is hydrogen or an organic group of from 1 to 12 carbon atoms and from 0 to 6 heteroatoms, which are chalcogen, nitrogen, and halogen consisting of an aliphatic group of from 1 to 6 carbon atoms having from 0 to 2 sites of unsaturation, non-oxo-carbonyl and the nitrogen and sulfur derivatives thereof, alicyclic having from 0 to 2 sites of unsaturation, aryl, heterocyclic and combinations thereof, where the cyclic structures may have from 1 to 2 rings;
- R2 is hydrogen, a heterofunctionality having nitrogen and/or chalcogen bonded to annular carbon, a heterofunctionality having nitrogen and/or chalcogen bonded to annular carbon to which is substituted with an organic group of from 1 to 10 carbon atoms, aryl, alkaryl, aralkyl and aralkenyl of from 5 to 10 carbon atoms, aroyl of from 6 to 10 carbon atoms, or an organic group bonded through a carbon atom of from 1 to 12 carbon atoms having from 1 to 4, as described above for R1;
- R3 is hydrogen or an organic group of from 1 to 10 carbon atoms and from 0 to 4 chalcogen and nitrogen heteroatoms;
- R4 is hydrogen or alkyl and substituted alkyl of from 1 to 6 carbon atoms, where the substituents are oxy, amino and halo;
- with the proviso that R3 and R4 can be taken together to form a ring with the annular atoms to which they are attached of from 4 to 10 annular atoms and forming from 1 to 2 rings, where the annular atoms are unsubstituted or substituted with halo, alkyl of from 1 to 3 carbon atoms, oxy of from 0 to 3 carbon atoms, thio of from 0 to 3 carbon atoms and amino of from 0 to 4 carbon atoms;
- 42
- wherein:
- p is 0, 1 or 2;
- and
- R5 is a group having from 1 to 3 atoms other than hydrogen and is oxy, thio, amino, nitro, cyano, and alkyl;
- 43
- wherein:
- Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
- R6 is H or alkyl of from 1-3 carbon atoms;
- R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
- V is an aryl group having 6 annular members comprising 0 to 2 nitrogen atoms and the remainder carbon atoms
- U is a substituent group of from 0 to 5 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, halo, and alkyl;
- and
- u is 0 to 3;
- and
- 44
- wherein:
- Y is oxygen, sulfur, NH, (alkyl of from 1 to 3 carbon atoms, H) or H2
- R7 is hydrogen or an organic group of from 1 to 12 carbon atoms and 0 to 4 heteroatoms;
- R8 is hydrogen, an aliphatic group of from 1 to 6 carbon atoms or a heterocycle of from 5 to 6 annular members and from 1 to 2 heteroannular members that are oxygen, nitrogen or sulfur;
- and
- R9, R10, R13, R14, R15 and R16 are the same or different and are hydrogen or an organic radical of from 1 to 12 carbon atoms or a heterosusbtituent of from 1 to 3 heteroatoms;
- R11 and R12 are the same or different and are hydrogen or an organic group of from 1 to 12 carbon atoms.
A combination comprising a polypeptide comprising the modulating domain sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 45
- wherein:
- X is of from 1 to 3 atoms other than hydrogen and is oxygen, sulfur bonded to 0 to 2 oxygen atoms, amino and alkyl substituted amino;
- n is 0 or 1;
- R1 is a lower alkyl group of 1 to 3 carbon atoms or an organic group having a six annular membered aromatic group having from 0 to 3 substituents, where the substituents are halo, lower alkyl of from 1 to 3 carbon atoms, nitro, trihalomethyl, and is either directly bonded to X or bonded through a linking group of from 1 to 4 carbon, nitrogen, or chalcogen atoms in the chain, being particularly carbon and nitrogen, and there being from 0 to 2 heteroatoms in the chain, where heteroatoms are bonded solely to carbon and hydrogen, or_-acetamidinyl having from 0 to 1 N—OH;
- R2 is hydrogen, amino of 0 to 3 carbon atoms, oxy of from 0 to 3 carbon atoms, a heterofunctionality having nitrogen or chalcogen bonded to annular carbon to which is substituted an organic group of from 1 to 10 carbon atoms and from 0 to 3 heteroatoms;
- R3 is hydrogen or an organic group of from 1 to 10 carbon atoms and from 0 to 4 chalcogen and nitrogen heteroatoms;
- R4 is hydrogen, alkyl or substituted alkyl of from 1 to 6 carbon atoms, where the substituents are oxy, amino and halo;
- with the proviso that R3 and R4 can be taken together to form a ring with the annular atoms to which they are attached of from 4 to 10 annular atoms and forming from 1 to 2 rings, where the annular atoms are unsubstituted or substituted with halo, alkyl of from 1 to 3 carbon atoms, oxy of from 0 to 3 carbon atoms, thio of from 0 to 3 carbon atoms and amino of from 0 to 4 carbon atoms.
A combination
A combination comprising a polypeptide comprising the modulating sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 46
- wherein:
- Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
- R6 is H or alkyl of from 1-3 carbon atoms;
- R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
- V is a phenyl group;
- U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen;
- and u is 0 to 3.
A combination comprising a polypeptide comprising the modulating sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 48
- wherein:
- Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
- R6 is H or alkyl of from 1-3 carbon atoms;
- R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
- V is a phenyl group;
- U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen;
- and
- u is 0 to 3.
A combination comprising a polypeptide comprising the modulating domain sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 47
- wherein:
- R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain or N-hydroxyamidinyl;
- R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
- R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
- R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
- with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo, _—CH3-halobenzene, where halo is F or Cl. A method for modulating the activity of EPO-R present as a cell membrane component comprising:
- forming a complex by bringing together the members of the combination of claim 13 under complex forming conditions, where said polypeptide is EPO-R.
A combination comprising a polypeptide comprising the modulating domain sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 49
- wherein:
- R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain or N-hydroxyamidinyl;
- R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
- R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
- R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
- with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo, _—CH3-halobenzene, where halo is F or Cl.
A method of inducing a physiological response of EPO-R in a host, said method comprising:
- administering to said host a physiologically effective amount of a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 50
- wherein:
- R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain, N-hydroxyamidinyl;
- R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
- R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
- R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
- with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo,_-CH3-halobenzene, where halo is F or Cl;
- or
- 51
- wherein:
- Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
- R6 is H or alkyl of from 1-3 carbon atoms;
- R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
- V is a phenyl group;
- U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen;
- and
- u is 0 to 3.
A method of modulating the response to a stimulus of hematopoietic or neuronal cells influenced by the binding of EPO to EPO-R, said method comprising:
- contacting said cells with an effective amount to modulate said response of a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
- 52
- wherein:
- R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain, N-hydroxyamidinyl;
- R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
- R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
- R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
- with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo,_-CH3-halobenzene, where halo is F or Cl;
- or
- 53
- wherein:
- Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
- R6 is H or alkyl of from 1-3 carbon atoms;
- R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
- V is a phenyl group;
- U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen;
- and
- u is 0 to 3.
Dependencies are inferred from the claim text.