Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium ), and T ( 3 H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their non-enriched counterparts.
All percentages given for the amount of deuterium present are mole percentages.
It can be quite difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater). When 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium -enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.
The present invention provides deuterium -enriched enzastaurin or a pharmaceutically acceptable salt thereof. There are twenty-nine hydrogen atoms in the enzastaurin portion of enzastaurin as show by variables R 1 -R 29 in formula I below.
The hydrogens present on enzastaurin have different capacities for exchange with deuterium . Hydrogen atom R 1 is easily exchangeable under physiological conditions and, if replaced by a deuterium atom, it is expected that it will readily exchange for a proton after administration to a patient. Hydrogen atoms R 9 -R may be exchanged for deuterium atoms by the action of a suitable acid such as D 2 SO 4 /D 2 O. The remaining hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of enzastaurin.
The present invention is based on increasing the amount of deuterium present in enzastaurin above its natural abundance. This increasing is called enrichment or deuterium -enrichment. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound, mixture of compounds, or composition. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. Since there are 29 hydrogens in enzastaurin, replacement of a single hydrogen atom with deuterium would result in a molecule with about 3% deuterium enrichment. In order to achieve enrichment less than about 3%, but above the natural abundance, only partial deuteration of one site is required. Thus, less than about 3% enrichment would still refer to deuterium -enriched enzastaurin.
With the natural abundance of deuterium being 0.015%, one would expect that for approximately every 6,667 molecules of enzastaurin (1/0.00015=6,667), there is one naturally occurring molecule with one deuterium present. Since enzastaurin has 29 positions, one would roughly expect that for approximately every 193,343 molecules of enzastaurin (29×6,667), all 29 different, naturally occurring, mono-deuterated enzastaurins would be present. This approximation is a rough estimate as it doesn't take into account the different exchange rates of the hydrogen atoms on enzastaurin. For naturally occurring molecules with more than one deuterium , the numbers become vastly larger. In view of this natural abundance, the present invention, in an embodiment, relates to an amount of an deuterium enriched compound, whereby the enrichment recited will be more than naturally occurring deuterated molecules.
In view of the natural abundance of deuterium -enriched enzastaurin, the present invention also relates to isolated or purified deuterium -enriched enzastaurin. The isolated or purified deuterium -enriched enzastaurin is a group of molecules whose deuterium levels are above the naturally occurring levels (e.g., 3%). The isolated or purified deuterium -enriched enzastaurin can be obtained by techniques known to those of skill in the art (e.g., see the syntheses described below).
-------------------------------------------------------------------
It is another object of the present invention to provide a method for treating a disease selected from glioblastoma and/or non-Hodgkin's lymphoma, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the deuterium -enriched compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a novel deuterium -enriched enzastaurin or a pharmaceutically acceptable salt thereof for use in therapy.
It is another object of the present invention to provide the use of a novel deuterium -enriched enzastaurin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament (e.g., for the treatment of glioblastoma and/or non-Hodgkin's lymphoma).
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor's discovery of the presently claimed deuterium -enriched enzastaurin.
------------------------------------------------
Patent je od 21.3.2009
....