Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-03-04
2001-04-24
Goldberg, Jerome D. (Department: 1205)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06221873
ABSTRACT:
RELATED INFORMATION
The contents of Appendix A entitled “Cyclin Dependent Kinase Inhibitor” is expressly incorporated by reference.
The invention relates to the therapeutic uses of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine and pharmaceutically acceptable salts thereof.
It has been observed that this compound is of particular benefit in the treatment of proliferative diseases such as cancers and leukemia's. As described below it has been observed to possess a mechanism of action not previously reported that provides it with particular benefits, for example, it has been shown to inhibit cell proliferation in a manner that does not induce changes in gene transcription i.e. it functions at a level in the cell cycle regulatory control system that does not involve the regulation of gene expression.
The prior art has described several compounds that are capable of regulating the cell cycle by virtue of inhibiting cyclin dependent kinases. These compounds include butyrolactone, flavopiridol and 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine (olomoucin). Olomucin and related compounds have been shown to be inhibitors of cdc2. cdc2 (also known as cdk1) is a catalytic sub-unit of a family of cyclin dependent kinases that are involved in cell cycle regulation.
These kinases comprise at least two sub-units, namely a catalytic sub-unit (of which cdc2 is the prototype) and a regulatory sub-unit (cyclin). The cdk's are regulated by transitory association with a member of the cyclin family: cyclin A (cdc2, cdk2), cyclin B1-B3 (cdc2), cyclin C (cdk8), cycline D1-D3 (cdk2-cdk4-cdk5-ckd6), cyclin E (cdk2), cyclin H (cdk7).
Each of these complexes is involved in a phase of the cellular cycle. cdk activity is regulated by post-translatory modification, by transitory associations with other proteins and by modifications of their intra-cellular localization. The cdk regulators comprise activators (cyclins, cdk7/cyclin H, cdc25 phosphateses), the p9
CKS
and p15
cdk-BP
sub-units, and the inhibiting proteins (p16
INK4A
, p15
INK4B
, p21
Cipl
, p18, p27
Kipl
).
There is now considerable support in the literature for the hypothesis that cdk's and their regulatory proteins play a significant role in the development of human tumors. Thus, in numerous tumors a temporal abnormal expression of cyclin-dependent kinases, and a major de-regulation of protein inhibitors (mutations, deletions) has been observed.
It has now been observed that the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine is a potent in vivo inhibitor of cdk2, cdk4 and cdk7, properties that provide significant advantages in that this compound is capable of inhibiting cell proliferation in proliferating tissue and not healthy tissue and furthermore is capable of inducing apoptosis (programmed cell death) in proliferative cells.
The present invention therefore relates to a method of treating a patient suffering from leukemia comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine or a pharmaceutically acceptable salt thereof.
A further aspect of the present invention relates to a method of treating a patient suffering from cancer comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine or a pharmaceutically acceptable salt thereof.
In a further embodiment the present invention relates to a method of treating a cancerous or leukemic proliferative disease comprising inhibiting the cdk4 and/or cdk7 enzymes by the administration of a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine or 2-[(1-ethyl-2-hydroxyethyl)amino]-6-benzylamino-9-isopropylpurine or pharmaceutically acceptable salt thereof.
In an additional embodiment the present invention relates to a method of inducing cell death in proliferative cells comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-sopropylpurine or 2-[(1-ethyl-2-hydroxyethyl)amino]-6-benzylamino-9-isopropylpurine or pharmaceutically acceptable salt thereof.
In these aspects and embodiments, the proliferative cells may be cancer or leukemic cells and the cancer or leukemia is preferably p53 independent.
The compound of the present invention can be present as a salt, in particular pharmaceutically acceptable salts. These are formed, for example, with strong inorganic acids, such as mineral acids for example sulfuric acid, phosphoric acid or hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as(C
1
-C
4
)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluene sulfonic acid.
The present invention also relates to pharmaceutical compositions comprising 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine or a pharmaceutically acceptable salt thereof together with at least one a pharmaceutically acceptable excipient.
The pharmaceutical compositions of the present invention may be adapted for oral, rectal, vaginal, paraenteral, intra-muscular, intra-peritoneal, sub-cutaneous intravenous, nasal or buccal routes of administration.
For oral administration, particular use is made of compressed tablets, pills, tablets, gellules, drops and capsules. These compositions advantageously contain from 1 to 100 mg, and preferably from 10 to 40 mg, of active ingredient per dose.
Other forms of administration comprise solutions which can be injected intravenously, sub-cutaneously or intra-muscularly, and which are prepared from sterile or sterilisable solutions. They can also be in the form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels and sprays.
Injectable forms may contain between 1 and 50 mg, preferably between 10 and 30 mg, of active ingredient per dose.
Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dosage, or a multiple or sub-unit of a unit dose.
By way of example, the posology which can be used in man corresponds to the following doses: thus, for example, a patient will be administered one or more doses of 10 to 50 mg/day for the treatment of tumors.
REFERENCES:
patent: 5866702 (1999-02-01), Mackman et al.
patent: WO9720842 A1 (1997-06-01), None
De Azevedo, Walter et al. (1997) Inhibition of Cyclin-Dependent Kinases By Purinie Analogues Crystal Structure of Human cdk2 Complexed With Roscovitine Eur. J. Bichem, vol. 243, pp. 518-526.
Grant S., et al. (1998) Crystal Structure-Based Dessign of Cyclin Dependent Kinase Inhibitors Proceedings of the American Associate for Cancer Research, vol. 39, No. 1207, p. 176.
Havlicek, Libor et al. (1997) “Cytokinin-Derived Cyclin-Dependent Kinase Inhibitors: Synthesis and cdc2 Inhibitory Activity of Olomoucine and Related Compounds” J. Med. Chem., vol. 40, pp. 408-412.
Hajduch, M. et al. (1997) “Olomoucine Derived Synthetic cdk Inhibitiors: The Mechanisms of Apoptotic Death of Tumor Cells and In Vivo Anti-tumor Activity” Poster Presentation at Cell Cycle Therapeutics Conference, Nov. 6-7, 1997 Washington DC.
Hajduch, M et al. (1997) “Olomoucine Derived Synthetic cdk inhibitors: Induction of Apoptosis and Regression of Spontaneous Dog Melanoma Following In Vivo Application of Olomoucine” Poster Presentation at Cell Cycle Therapeutics Conference, Nov. 6-7, 1997 Washin
Hajduch Marian
Havlicek Libor
Strnad Miroslav
DeConti, Jr. Giulio A.
Goldberg Jerome D.
Institute of Experimental Botany of the Academy of Sciences of t
Lahive & Cockfield LLP
Williams Megan E.
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