Sphingosine kinase type 1 inhibitors and uses thereof

• US 9,974,758 B2
• Filed: 06/14/2016
• Issued: 05/22/2018
• Est. Priority Date: 04/29/2008
• Status: Active Grant

• Current Assignee: Enzo Therapeutics Incorporated (Enzo Biochem Incorporated), Virginia Commonwealth University
• Original Assignee: Enzo Therapeutics Incorporated (Enzo Biochem Incorporated), Virginia Commonwealth University
• Inventors: Spiegel, Sarah, Zipkin, Robert Elliot, Adams, Jeffrey Kroll
• Primary Examiner(s): West, Theodore R.
• Application Number:
  US15/181,826
• Publication Number:
  US 20160317472A1
• Time in Patent Office: 707 Days
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: C07C 215/28 and containing six-membered aromatic rings
• CPC Class Codes: C07C 217/64 with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 323/32 having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
• CPC Class Codes: C07D 263/06 with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 295/092 with aromatic radicals attached to the chain

Abstract

Provided are inhibitors of sphingosine kinase Type I that are useful in a number of applications, indications and diseases, as well as for monitoring pharmacokinetics and patient management. These compounds are applicable to treating tumors of the central nervous system, such as glioblastoma multiforme (GBM).

Claims

1. A method for treating a cancer in a mammal, the method comprising:

administering to a mammal in need of treatment for a cancer a sphingosine kinase Type I inhibitor having the formula

2. The method of claim 1, wherein the mammal is a human.

3. The method of claim 2, wherein the human has a cancerous tumor and said administration is performed in treatment thereof.

4. The method of claim 3, wherein the cancerous tumor is a cancerous tumor of the central nervous system.

5. The method of claim 4, wherein the cancerous tumor of the central nervous system is glioblastoma multiforme.

6. The method of claim 1, wherein

R₂ is H, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, a hetero-aromatic ring, or any combination of the foregoing;

R₃ is NR₆R₇ or N⁺R₆R₇R₈,

wherein each of R₆, R₇ and R₈ is independently H, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, a hetero-aromatic ring, or any combination of the foregoing;

R₄ is H, OH, a halide, ═

O, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, a hetero-aromatic ring, or any combination of the foregoing;

R₅ is H or comprises OH, a halide, ═

O, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, a hetero-aromatic ring, or any combination of the foregoing; and

R₉ is a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, a hetero-aromatic ring, or any combination of the foregoing.

7. The method of claim 6, wherein R₉ is a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, or a branched carbon chain comprising one or more heteroatoms.

8. The method of claim 1, wherein

R₂ is H, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, or a hetero-aromatic ring;

R₃ is NR₆R₇ or N⁺R₆R₇R₈,

wherein each of R₆, R₇ and R₈ is independently H, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, or a hetero-aromatic ring;

R₄ is H, OH, a halide, ═

O, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, or a hetero-aromatic ring;

R₅ is H, OH, a halide, ═

O, a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, or a hetero-aromatic ring; and

R₉ is a straight carbon chain, a branched carbon chain, a straight carbon chain comprising one or more heteroatoms, a branched carbon chain comprising one or more heteroatoms, a cyclic ring, a heterocyclic ring, an aromatic ring, or a hetero-aromatic ring.

9. A method for treating a cancer in a mammal, the method comprising:

administering to a mammal in need of treatment for a cancer a sphingosine kinase Type I inhibitor having the formula

10. The method of claim 9, wherein the mammal is a human.

11. The method of claim 9, wherein said administration comprises administering

12. The method of claim 11, wherein the mammal is a human.