Building IP: Patent Application re SALTS OF ISOPHOSPHORAMIDE MUSTARD AND ANALOGS THEREOF AS ANTI-TUMOR AGENTS
United States Patent Application 20110118209
Kind Code A1
Gale; Robert Peter May 19, 2011
SALTS OF ISOPHOSPHORAMIDE MUSTARD AND ANALOGS THEREOF AS ANTI-TUMOR AGENTS
Abstract
The present disclosure relates to salts and compositions of isophosphoramide mustard and isophosphoramide mustard analogs. In one embodiment the salts can be represented by the formula ##STR00001## wherein A.sup.+ represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines; and X and Y independently represent leaving groups. Also disclosed herein are methods for making such compounds and formulating pharmaceutical compositions thereof. Methods for administering the disclosed compounds to subjects, particularly to treat hyperproliferative disorders, also are disclosed.
Inventors:
Gale; Robert Peter; (Los Angeles, CA)
Assignee:
ZIOPHARM Oncology, Inc.
Charlestown
MA
Serial No.:
709319
Series Code:
11
Filed:
February 20, 2007
Current U.S. Class: 514/76; 514/137
Class at Publication: 514/76; 514/137
International Class: A61K 31/66 20060101 A61K031/66; A61P 35/00 20060101 A61P035/00
Claims
1. A method for preparing a patient for blood cell transplant comprising administering prior to the blood cell transplant a compound of the formula ##STR00016## wherein A.sup.+ represents an ammonium species selected from quaternary ammonium, the conjugate acid of a basic amino acid, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium; and X and Y independently represent leaving groups.
2. A method for preparing a patient for blood cell transplant comprising administering prior to the blood cell transplant a pharmaceutical composition comprising: a compound of the formula ##STR00017## wherein A.sup.+ represents an ammonium species selected from quaternary ammonium, the conjugate acid of a basic amino acid, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium; and X and Y independently represent leaving groups; and a pharmaceutically acceptable carrier.
3. A method for preparing a patient for blood cell transplant comprising administering prior to the blood cell transplant a compound comprising an isophosphoramide mustard anion and at least one amine, ammonium cation, or both.
4. A method for preparing a patient for blood cell transplant comprising administering prior to the blood cell transplant a pharmaceutical composition comprising: a compound comprising an isophosphoramide mustard anion and at least one amine, ammonium cation, or both; and a pharmaceutically acceptable carrier.
5. A method for preparing a patient for bone marrow transplant comprising administering prior to the bone marrow transplant a compound of the formula ##STR00018## wherein A.sup.+ represents an ammonium species selected from quaternary ammonium, the conjugate acid of a basic amino acid, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium; and X and Y independently represent leaving groups.
6. A method for preparing a patient for bone marrow transplant comprising administering prior to the bone marrow transplant a pharmaceutical composition comprising: a compound of the formula ##STR00019## wherein A.sup.+ represents an ammonium species selected from quaternary ammonium, the conjugate acid of a basic amino acid, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium; and X and Y independently represent leaving groups; and a pharmaceutically acceptable carrier.
7. A method for preparing a patient for bone marrow transplant comprising administering prior to the bone marrow transplant a compound comprising an isophosphoramide mustard anion and at least one amine, ammonium cation, or both.
8. A method for preparing a patient for bone marrow transplant comprising administering prior to the bone marrow transplant a pharmaceutical composition comprising: a compound comprising an isophosphoramide mustard anion and at least one amine, ammonium cation, or both; and a pharmaceutically acceptable carrier.
9. A conditioning regimen comprising a compound of the formula ##STR00020## wherein A.sup.+ represents an ammonium species selected from quaternary ammonium, the conjugate acid of a basic amino acid, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium; and X and Y independently represent leaving groups.
10. A conditioning regimen comprising a pharmaceutical composition comprising: a compound of the formula ##STR00021## wherein A.sup.+ represents an ammonium species selected from quaternary ammonium, the conjugate acid of a basic amino acid, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium; and X and Y independently represent leaving groups; and a pharmaceutically acceptable carrier.
11. A conditioning regimen comprising a compound comprising an isophosphoramide mustard anion and at least one amine, ammonium cation, or both.
12. A conditioning regimen comprising a pharmaceutical composition comprising: a compound comprising an isophosphoramide mustard anion and at least one amine, ammonium cation, or both; and a pharmaceutically acceptable carrier.
13. The conditioning regimen of any one of claims 9-12 wherein the conditioning regimen is for blood cell transplant.
14. The conditioning regimen of any one of claims 9-12 wherein the conditioning regimen is for bone marrow transplant.
15. The method of any of claims 1, 2, 5 or 6, wherein A.sup.- is the ammonium species of the amine base tris(hydroxymethyl)methylamine.
16. The method of any of claims 1, 2, 5 or 6, wherein X and Y independently are selected from halogens and sulfonates.
17. The method of claim 16, wherein X and Y are each halogen.
18. The method of claim 17, wherein X and Y are each chlorine.
19. The method of any of claims 1, 2, 5 or 6 wherein the compound is represented by the formula: ##STR00022##
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority of U.S. Application Ser. Nos. 60/774,857, filed Feb. 17, 2006 and 60/788,038, filed Mar. 31, 2006, the specifications of each of which are incorporated by reference in their entirety herein.
BACKGROUND
[0002] Autopsies of soldiers killed by mustard gas in World War I indicated that sulfur mustard has a disproportionate effect on rapidly dividing cells and suggested that sulfur mustard compounds might have antitumor effects. Indeed, early researchers attempted to treat cancer by direct injection of sulfur mustard into tumors. This research was limited by the extreme toxicity of sulfur mustard compounds and nitrogen mustard analogs, such as mechlorethamine, were investigated as less toxic alternatives.
##STR00002##
[0003] In general mustard compounds exert their cytotoxic effects by alkylating DNA, such as at the N-7 position of a guanine residue. The mechanism of alkylation by mustard compounds is illustrated in Scheme 1. With reference to Scheme 1, mustard compounds have an internal nucleophile that assists in chloride displacement by, as shown for the case of mechlorethamine, forming an aziridinium intermediate. Because mechlorethamine has two leaving groups, the nucleophilic substitution mechanism depicted in Scheme 1 can be repeated resulting in a DNA or protein-DNA crosslink.
##STR00003##
[0004] Mechlorethamine is extremely reactive and as a result is non-selective. Thousands of alkylating agents have been designed and prepared using mechlorethamine as a model. However, few of these compounds have demonstrated sufficient therapeutic superiority to mechlorethamine to warrant clinical trials.
[0005] Because of the lack of selectivity of most methchlorethamine analogs, prodrugs, such as phosphoramide compounds, which can be activated by the high concentration of phosphoramidases present in neoplastic cells, have been investigated. Two phophoramide alkylating agents, cyclophosphamide (CPA) and the isomeric compound Ifosfamide (Ifos) have proved to be particularly effective.
##STR00004##
[0006] The metabolic pathway of CPA is similar to that of Ifos (the metabolism of Ifos is illustrated in FIG. 1) and thus the two compounds share common drawbacks. Perhaps most important is their dose limiting toxicity due to hemorrhagic cystitis. The hemorrhagic cystitis is believed to be induced by the production of acrolein during the activation of both CPA and Ifos. Acrolein is an active electrophile that reacts with thiols under physiological conditions, which may be responsible for its liver toxicity in the form of glutathione depletion. Finally, acrolein has been demonstrated to be a teratogen and a potent mutagen, and this may be responsible for the link between CPA treatment and serious side effects, such as bladder carcinoma and other malignancies.
[0007] With reference to FIG. 1, isophosphoramide mustard (IPM) is a common metabolite of CPA and Ifos. IPM is thought to be responsible for at least a portion of the anti-tumor activity exhibited by CPA and Ifos. Efforts to use IPM as an anticancer agent directly have been unsuccessful due in part to the compound's instability. IPM has been synthesized and preliminary biological evaluations of the compound have been conducted, but unfortunately IPM is too unstable to be isolated and used for human treatment.
SUMMARY OF THE DISCLOSURE
[0008] Disclosed herein are compounds of the formula
##STR00005##
wherein A.sup.+ represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines; and X and Y independently represent leaving groups.
[0009] In one embodiment, pharmaceutical compositions are disclosed that include one or more of the compounds described above. In one aspect of this embodiment, the compositions can include one or more therapeutic agents other than those described by the formula above for use in combination therapy.
[0010] In another embodiment, methods for treating mammalian subjects, such as human subjects, having hyperproliferative disorders are disclosed. Such methods can employ one or more of the compounds and compositions described above.
[0011] In another aspect, disclosed herein are sterile pharmaceutical compositions of compounds of the formula
##STR00006##
wherein X and Y independently represent leaving groups, or a pharmaceutically acceptable salt thereof. Methods of preparing such compositions, including rendering the composition sterile by using a sterile antimicrobial filter, are also described. In certain embodiments, such filtration may be performed with less than 10% decomposition of the active ingredient, preferably less than 5%, 2%, or even less than 1% decomposition.
[0012] Also disclosed herein is a method for producing a lyophilisate comprising a compound of the formula above. In one embodiment the method comprises contacting isophosphoramide mustard or an analog thereof with an amine base in the presence of water and lyophilizing the resulting mixture.
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