Myt1 kinase inhibitors

Details Myt1 kinase inhibitors Myt1 kinase inhibitors

2001-07-19

2002-05-21

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S370000, C546S256000, C548S198000

Reexamination Certificate

active

06391894

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to membrane-associated tyrosine and threonine kinase (“myt1 kinase”) enzyme inhibitors, pharmaceutical compositions comprising these compounds and methods for identifying these compounds and methods of using these compounds to treat various forms of cancer and hyperproliferative diseases.
BACKGROUND OF THE INVENTION
Entry into mitosis is initiated by the M phase-promoting factor (MPF), a complex containing the cdc2 protein kinase and cyclin B. Proper regulation of MPF ensures that mitosis occurs only after earlier phases of the cell cycle are complete. Phosphorylation of cdc2 at Tyr-15 and Thr-14 suppresses this activity during interphase (G1, S, and G2). At G2-M transition, cdc2 is dephosphorylated at Tyr-15 and Thr-14 allowing MPF to phosphorylate its mitotic substrates. A distinct family of cdc-regulatory kinases (Wee1) is known to be responsible for phosphorylation of the cdc Tyr-15. A new member of this family, Myt1 was recently described as the Thr-14 and Tyr-15-specific cdc2 kinase, and shown to be an important regulator of cdc2/cyclin B kinase activity (Science 270:86-90, 1995; Mol. Cell. Biol. vol 17:571, 1997). The inhibitory phosphorylation of cdc2 is important for the timing of entry into mitosis. Studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. Inhibition of Myt1 is predicted to cause premature activation of cdc2, and thus would kill rapidly proliferating cells. In addition, Myt1 inhibition is predicted to reduce resistance to conventional DNA-damaging chemotherapeutics, because the mechanisms by which cells avoid death involve arrest in the G2 phase of the cell cycle, and repair or DNA damage prior to division. That arrest should be prevented by blocking Myt1 inhibitory phosphorylation of cdc2. Thus forcing the cell to enter mitosis prematurely.
Myt1 kinase is an important cell cycle regulator, particularly at the G2/M phase. Inhibitors would therefore be attractive for the treatment of cancer. Current cancer therapies, including surgery, radiation, and chemotherapy, are often unsuccessful in curing the disease. The patient populations are large. For example, in colon cancer alone there are 160,000 new cases each year in the US, and 60,000 deaths. There are 600,000 new colon cancer cases each year worldwide. The number for lung cancer are twice that of colon cancer. The largest deficiency of chemotherapies for major solid tumors is that most patients fail to respond. This is due to cell cycle regulation and subsequent repair of damage to DNA or mitotic apparatus, the targets for most effective chemotherapeutic agents. Myt1 kinase offers a point of intervention downstream from these mechanisms by which tumor cells develop resistance. Inhibition of Myt1 could in and of itself have therapeutic benefit in reducing tumor proliferation, and in addition, could be used in conjunction with conventional chemotherapies to overcome drug resistance.
Based on the foregoing, there is a need to identify a potent myt1 kinase enzyme inhibitor for the treatment of various indications, including cancer, associated with the present receptor.
SUMMARY OF THE INVENTION
The present invention involves compounds represented by Formula (I) hereinbelow, pharmaceutical compositions comprising such compounds and methods of antagonizing the myt1 kinase receptor using these compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula (I), hereinbelow:
wherein A represents a covalent bond, or a 1,2, 1,3 or 1,4-disubstituted aryl amine ring selected from the group consisting of:
 wherein
R is independently selected from the group consisting of H, OMe, Cl, Br, F, NO
2
, and CN;
n is an integer from 1 to 4;
each X is independently selected from the group consisting of H, Br, CH
3
, NO
2
, CN, and NR
1
R
2
;
each Ar is independently optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring comprising one or more heteroatoms selected from N, O and S; and
R
1
and R
2
are, independently, hydrogen or C
1-4
alkyl, branched or cyclic, optionally containing O or N.
Preferred compounds of the present invention are selected from the group consisting of:
bis[2-(4-phenyl-5-methyl)thiazolyl]amine,
bis[2-(4-(2-pyridyl)thiazolyl]amine,
bis[2-[4-(3-pyridyl)thiazolyl)amine,
N,N-Bis(5(3,4-dichlorophenyl)-2-thiazolyl)amine,
N,N-bis(4-(4′-biphenyl)-2-thiazolyl)amine,
1,4-bis(4-(4′-biphenyl)-2-thiazolylamino)benzene,
1,3-bis[4-(3-pyridyl)-2-thiazolyl amino]benzene,
1,4-bis[4-fluorophenyl-2-thiazolylamino]benzene; and
1,4-bis(4-(4-methoxyphenyl)-2-thiazolylamino)benzene.
More preferred compounds of the present invention are selected from the group consisting of:
bis[2-(4-phenyl-5-methyl)thiazolyl]amine,
1,4-bis(4-(4-methoxyphenyl)-2-thiazolylamino)benzene,
N,N-bis(4-(4′-biphenyl)-2-thiazolyl)amine,
1,4-bis(4-(4′-biphenyl)-2-thiazolylamino)benzene,
1,4-bis[4-fluorophenyl-2-thiazolylamino]benzene,
bis[2-(4-(2-pyridyl)thiazolyl]amine and
bis[2-[4-(3-pyridyl)thiazolyl)amine.
The most preferred compounds of the present invention are selected from the group consisting of:
bis[2-(4-phenyl-5-methyl)thiazolyl]amine,
1,4-bis(4-(4-methoxyphenyl)-2-thiazolylamino)benzene,
N,N-bis(4-(4′-biphenyl)-2-thiazolyl)amine, and
1,4-bis(4-(4′-biphenyl)-2-thiazolylamino)benzene hydrobromide.
As used herein, “alkyl” refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Preferably, the group is saturated linear or cyclic.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
The present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof. Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered.
Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
Preferred salts include hydrobromide, dihydrobromide and bistrifluoroacetate. The present compounds are readily prepared by the schemes represented below:
The corresponding bisthiazolyl compounds are synthesized via condensation of dithiobiuret (as in eq. 1) or any other bisthiourea such as 1,3-phenyldithiourea (as in eq.2) with two equivalents of an appropriately substituted bromoketone such as 2-bromo-1-phenylpropan-1-one in a solvent such as ethanol or acetone or any other suitable solvent. The reaction mixture is heated to 70-90° C. for several hours (4-12 h). Cooling of the reaction yields de desired product as a bis-hydrobromide salts. Monobromination of the bisthiazole compounds can be accomplish for example via the reaction of N-bromosuccinimide in the presence of an acid such as fluoroboric acid, or any other suitabl

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