Semicarbazone derivatives and their use as thrombopoietin...

Details Semicarbazone derivatives and their use as thrombopoietin... Semicarbazone derivatives and their use as thrombopoietin...

2002-05-03

2004-04-13

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S404000, C548S190000, C548S198000, C548S370100

Reexamination Certificate

active

06720345

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to thrombopoietin (TPO) mimetics and their use as promoters of thrombopoiesis and megakaryocytopoiesis.
BACKGROUND OF THE INVENTION
Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al.
Proc. Natl. Acad. Aci. USA
91:11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker
J. Clin. Invest.
47:458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
The exact physiological feedback mechanism by which the mass of circulating platelets regulates the endomitrotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Specifically, TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects. Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients. In addition, recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992)
Am. J. Ped. Hematology/Oncology
14: 8-21 (1992).
The gene encoding TPO has been cloned and characterized. See Kuter et al.,
Proc. Natl. Acad. Sci. USA
91: 11104-11108 (1994); Barley et al.,
Cell
77: 1117-1124 (1994); Kaushansky et al.,
Nature
369:568-571 (1994); Wendling et al.,
Nature
369: 571-574 (1994); and Sauvage et al.,
Nature
369: 533-538 (1994). Thrombopoietin is a glycoprotein with two distinct regions separated by a potential Arg-Arg cleavage site. The amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-alpha and interferon-beta. The carboxy-terminal region shows wide species divergence.
The DNA sequences and encoded peptide sequences for human TPO receptor (TPO-R; also known as c-mpl) have been described. See, Vigon et al.
Proc. Natl. Acad. Sci. USA
89: 5640-5644 (1992). TPO-R is a member of the haematopoietin growth factor receptor family, a family characterized by a common structural design of the extracellular domain, including for conserved C residues in the N-terminal portion and a WSXWS motif close to the transmembrane region. See Bazan
Proc. Natl. Acad. Sci. USA
87: 6934-6938 (1990). Evidence that this receptor plays a functional role in hematopoiesis includes observations that its expression is restricted to spleen, bone marrow, or fetal liver in mice (see Souyri et al.
Cell
63: 1137-1147 (1990)) and to megakaryocytes, platelets, and CD34
+
cells in humans (see Methia et al.
Blood
82: 1395-1401 (1993)). Further evidence for TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34
+
cells to synthetic oligonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation. Some workers postulate that the receptor functions as a homodimer, similar to the situation with the receptors for G-CSF and erythropoietin.
The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem, and has lent urgency to the search for a blood growth factor agonist able to accelerate platelet regeneration.
It would be desirable to provide compounds which allow for the treatment of thrombocytopenia by acting as a TPO mimetic.
As disclosed herein it has unexpectedly been discovered that certain substituted thiosemicarbazone derivatives are effective as agonists of the TPO receptor, they are potent TPO mimetics.
SUMMARY OF THE INVENTION
This invention relates to compounds of Formula (I):
wherein:
R
1
and R
2
are each independently selected from hydrogen, C
1-2
alkyl, aryl, substituted aryl, and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryl, substituted aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR
7
, —S(O)
2
NR
7
R
8
, —S(O)
n
R
6
, aryloxy, nitro, cyano, halogen, and protected —OH, where
R
6
is selected from hydrogen, alkyl, cycloalkyl, C
1
-C
12
aryl, substituted alkyl, substituted cycloalkyl and substituted C
1
-C
12
aryl, and
R
7
and R
8
are independently selected from hydrogen, cycloalkyl, aryl, substituted cycloalkyl, substituted aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, —C(O)OR
6
, —S(O)
n
R
6
, —C(O)NR
6
R
6
, —S(O)
2
NR
6
R
6
, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C
1
-C
12
aryl, substituted C
1
-C
12
aryl and protected —OH where R
6
is as described above; and
n is 0-3; or R
1
and R
2
taken together with the
 group to which they are attached represent a ring of formula (A):
 where
R
4
and R
10
are each independently selected from two hydrogens, ═NR
5
, ═O, ═S, and ═CHR
5
, where R
5
is C
1
-C
12
aryl or substituted C
1
-C
12
aryl; and m is 0 to 2;
Z is a bond or selected from S or NR
5
, where R
5
is C
1
-C
12
aryl or substituted C
1
-C
12
aryl;
R
3
is selected from hydrogen, C
1
-C
10
alkyl, phenyl, substituted phenyl, carboxyl or C
1
-C
10
alkoxycarbonyl;
L is a group of formula (L):
 where
A, B, D and E independently represent CR
11
or N; where R
11
is selected from hydrogen, halogen, —CF
3
, —CN, —SO
3
H, —SO
3
Na, —SO
2
R
14
, —NO
2
, phenyl, substituted phenyl, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, C
1
-C
10
acyloxy, arylalkoxy, —COR
14
, —NR
12
R
13
, hydroxy or cycloalkyl;
where R
14
is selected from hydroxy, C
1
-C
10
alkyl, phenyl, amino, mono- or dialkylamino;
R
12
and R
13
are independently selected from hydrogen, C
1-10
alkyl, C
1
-C
12
aryl, substituted C
1
-C
12
aryl, C
1-10
acyl or cycloalkyl;
or either A═B or D═E alternatively represent O, S or NR
12
; where R
12
is as defined above;
Y is selected from —S, —O and —NR
15
, where R
15
is selected from hydrogen, C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
1
-C
6
alkylphenyl, substituted C
1
-C
6
alkylphenyl, C
1
-C
10
acyl, substituted C
1
-C
10
acyl, or SO
2
R
9
, where R
9
is C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
1
-C
12
aryl or substituted C
1
-C
12
aryl; and
X is selected from —SR
16
, —OR
16
or —NHR
17
; where

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