Substituted amino acids as erythropoietin mimetics

Details Substituted amino acids as erythropoietin mimetics Substituted amino acids as erythropoietin mimetics

2001-08-10

2004-06-15

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C514S567000

Reexamination Certificate

active

06750369

ABSTRACT:

This invention relates to a series of small molecules which bind to the erythropoietin receptor and compete with the natural ligand for binding to said receptor. The invention includes pharmaceutical compositions containing these mimetics, their methods of production as well as intermediates used in their synthesis.
Erythropoietin (EPO) is a 34,000 dalton glycoprotein hormone which is produced in the mammalian kidney. Its primary role is stimulation of mitotic cell division and differentiation of erythrocyte precursor cells. As a result this hormone regulates the production of erythrocytes, the hemoglobin contained therein and the blood's ability to carry oxygen. The commercial product Epogen® is used in the treatment of anemia. This drug is produced by recombinant techniques and is formulated in aqueous isotonic sodium chloride/sodium citrate. Even though it has been used successfully in the treatment of anemia, it is a costly drug that is administered intravenously. This method of administration is both costly and inconvenient for the patient; therefore it would be desirable to find a EPO mimetic which has the potential for oral activity.
A small molecule EPO mimetic has advantages over the natural protein. The immune response associated with large peptides is unlikely to occur with small molecules. In addition, the variety of pharmaceutical formulations that may be used with small molecules are technically unfeasible for proteins. Thus the use of relatively inert formulations for small molecules is possible. The most important advantage of small molecules is their potential for oral activity. Such an agent would ease administration, cost less and facilitate patient compliance.
Although compounds which mimic EPO are useful in stimulating red blood cell synthesis, there are diseases where the overproduction of red blood cells is a problem. Erythroleukemia and polysythemia vera are examples of such diseases. Since EPO is an agent responsible for the maturation of red blood cell precursors, an antagonist of EPO would have utility treating either of those diseases.
SUMMARY OF THE INVENTION
The disclosed invention consists of a series of small molecules which demonstrate competitive binding with the natural ligand for the EPO receptor. As such these compounds are potentially useful in the treatment of diseases or conditions associated with this receptor. In addition, the invention contemplates methods of producing these compounds and intermediates used in their production.
The invention includes compounds of the Formula I:
wherein:
R
1
is the side chain of a natural or unnatural ax-amino acids, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C
1-5
alkyl, C
1-5
alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC
1-5
alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C
1-5
alkoxycarbonyl);
R
2
and R
3
may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
are independently selected from the group consisting of hydrogen, C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC
1-5
alkyl, phenyl C
1-5
alkoxy,
substituted phenyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
substituted phenoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
substituted phenylC
1-5
alkyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
substituted phenylC
1-5
alkoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
substituted amino (where the substituents are selected from one or more members of the group consisting of C
1-5
alkyl, halosubstitutedC
1-5
alkyl, C
1-5
alknyl, C
1-5
alkenyl, phenyl, phenylC
1-5
alkyl, C
1-5
alkylcarbonyl, halo substituted C
1-5
alkylcarbonyl, carboxyC
1-5
alkyl, C
1-5
alkoxyC
1-5
alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C
1-5
alkylsulfonyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, phenylC
1-5
alkylsulfonyl substituted phenylcarbonyl, substituted phenylC
1-5
alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC
1-5
alkylsulfonyl, substituted phenyl, and substituted phenylC
1-5
alkyl [where the aromatic phenyl, phenylC
1-5
alkyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, and phenylC
1-5
alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino]);
R
4
and R
5
may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
are independently selected from the group consisting of hydrogen, C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC
1-5
alkyl, phenyl C
1-5
alkoxy,
substituted phenyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
substituted phenoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
substituted phenylC
1-5
alkyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),
substituted phenylC
1-5
alkoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and
substituted amino (where the substituents are selected from one or more members of the group consisting of C
1-5
alkyl, halosubstitutedC
1-5
alkyl, C
1-5
alknyl, C
1-5
alkenyl, phenyl, phenylC
1-5
alkyl, C
1-5
alkylcarbonyl, halo substituted C
1-5
alkylcarbonyl, carboxyC
1-5
alkyl, C
1-5
alkoxyC
1-5
alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C
1-5
alkylsulfonyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, phenylC
1-5
alkylsulfonyl substituted phenylcarbonyl, substituted phenylC
1-5
alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC
1-5
alkylsulfonyl, substituted phenyl, and substituted phenylC
1-5
alkyl [where the aromatic phenyl, phenylC
1-5
alkyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, and phenylC
1-5
alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino]);
W is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
Q is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
X is selected from the group consisting of carbonyl, C
1-5
alkyl, C
1-5
alkenyl, C
1-5
alkenylcarbonyl, and (CH
2
)
m
—C(O)— where m is 2-5;
Y is selected from the group consisting of carbonyl, C
1-5
alkyl, C
1-5
alkenyl, C
1-5
alkenylcarbonyl, and (CH
2
)
m
—C(O)— where m is 2-5;
n is 1, 2, or 3;
Z is selected from the group consisting of hydroxy, C
1-5
alkoxy, phenoxy, phenylC
1-5
alkoxy, amino, C
1-5
alkylamino, diC
1-5
alkylamino, phenylamino, phenylC
1-5
alkylamino, piperidin-1-yl
substituted piperidin-1-yl (where the substituents are selected from the group consisting of C
1-5
alkyl, C
1-5
alkoxy, halo, aminocarbonyl, C
1-5
alkoxycarbonyl, and oxo;
substituted phenylC
1-5
alkylamino (where the aromatic substitutents are selected from the group consisting of C
1-5
alkyl, C
1-5
alkoxy, phenylC
1-5
alkenyloxy, hydroxy, halog

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