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EP-3244930-B1 - PHARMACEUTICAL COMPOSITIONS COMPRISING POH DERIVATIVES

EP3244930B1EP 3244930 B1EP3244930 B1EP 3244930B1EP-3244930-B1

Inventors

  • CHEN, THOMAS
  • LEVIN, DANIEL
  • PUPALLI, Satish G.

Dates

Publication Date
20260506
Application Date
20160112

Claims (6)

  1. A perillyl alcohol carbamate for use in treating a temozolomide-resistant cancer, wherein the perillyl alcohol carbamate is perillyl alcohol conjugated with rolipram, and wherein the perillyl alcohol carbamate is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester, and the temolozomide-resistant cancer is a glioblastoma.
  2. The perillyl alcohol carbamate for use according to claim 1, wherein the perillyl alcohol carbamate is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.
  3. The perillyl alcohol carbamate for use according to claim 2, wherein the perillyl alcohol carbamate is administered using a nasal delivery device.
  4. The perillyl alcohol carbamate for use according to claim 3, wherein the nasal delivery device is an intranasal inhaler, an intranasal spray device, an atomizer, a nebulizer, a metered dose inhaler (MDI), a pressurized dose inhaler, an insufflator, a unit dose container, a pump, a dropper, a squeeze bottle, or a bi-directional device.
  5. The perillyl alcohol carbamate for use according to claim 1, further comprising use of radiation.
  6. The perillyl alcohol carbamate for use according to claim 1, further comprising use of a chemotherapeutic agent.

Description

Field of the Invention The present invention relates to POH derivatives. The present invention further relates to methods of using POH derivatives such as POH carbamates to treat a disease, such as cancer. Background of the Invention Malignant gliomas, the most common form of central nervous system (CNS) cancers, is currently considered essentially incurable. Among the various malignant gliomas, anaplastic astrocytomas (Grade III) and glioblastoma multiforme (GBM; Grade IV) have an especially poor prognosis due to their aggressive growth and resistance to currently available therapies. The present standard of care for malignant gliomas consists of surgery, ionizing radiation, and chemotherapy. Despite recent advances in medicine, the past 50 years have not seen any significant improvement in prognosis for malignant gliomas. Wen et al. Malignant gliomas in adults. New England J Med. 359: 492-507, 2008. Stupp et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England J Med. 352: 987-996, 2005. Additionally, acquired resistance of initially well-responding tumors and unwanted side effects are other problems that frequently thwart long-term treatment using chemotherapeutic agents. Hence, various analogues of chemotherapeutic agents have been prepared in an effort to overcome these problems. The analogues include novel therapeutic agents which are hybrid molecules of at least two existing therapeutic agents. For example, cisplatin has been conjugated with Pt-(II) complexes with cytotoxic codrugs, or conjugated with bioactive shuttle components such as porphyrins, bile acids, hormones, or modulators that expedite the transmembrane transport or the drug accumulation within the cell. (6-Aminomethylnicotinate) dichloridoplatinum(II) complexes esterified with terpene alcohols were tested on a panel of human tumor cell lines. The terpenyl moieties in these complexes appeared to fulfill a transmembrane shuttle function and increased the rate and extent of the uptake of these conjugates into various tumor cell lines. Schobert et al. Monoterpenes as Drug Shuttles: Cytotoxic (6-minomethylnicotinate) dichloridoplatinum(II) Complexes with Potential To Overcome Cisplatin Resistance. J. Med. Chem. 2007, 50, 1288-1293. Perillyl alcohol (POH), a naturally occurring monoterpene, has been suggested to be an effective agent against a variety of cancers, including CNS cancer, breast cancer, pancreatic cancer, lung cancer, melanomas and colon cancer. Gould, M. Cancer chemoprevention and therapy by monoterpenes. Environ Health Perspect. 1997 June; 105 (Suppl 4): 977-979. Hybridmolecules containing both perillyl alcohol and retinoids were prepared to increase apoptosis-inducing activity. Das et al. Design and synthesis of potential new apoptosis agents: hybrid compounds containing perillyl alcohol and new constrained retinoids. Tetrahedron Letters 2010, 51, 1462-1466. WO2012/027693 discloses a derivative of monoterpene or sesquiterpene, such as a perillyl alcohol derivative. The perillyl alcohol derivative may be perillyl alcohol conjugated with a therapeutic agent such as a chemotherapeutic agent. Also disclosed is a method of treating a disease such as cancer. US2013210877 also discloses a derivative of monoterpene or sesquiterpene, such as a perillyl alcohol derivative, perillyl alcohol conjugated with a therapeutic agent such as a chemotherapeutic agentand methods of treating a disease such as cancer. There is still a need to prepare perillyl alcohol derivatives including perillyl alcohol conjugated with other therapeutic agents, and use this material in the treatment of cancers such as malignant gliomas, as well as other brain disorders such as Parkinson's and Alzheimer's disease. Perillyl alcohol derivatives may be administered alone or in combination with other treatment methods including radiation, standard chemotherapy, and surgery. The administration can also be through various routes including intranasal, oral, oral-tracheal for pulmonary delivery, and transdermal. Summary of the Invention The present invention provides a perillyl alcohol carbamate for use in treating a temozolomide-resistant cancer, wherein the perillyl alcohol carbamate is perillyl alcohol conjugated with rolipram, and wherein the perillyl alcohol carbamate is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester (POH-Rolipram), and the temelozomide-resistant cancer is a glioblastoma. The pharmaceutical compositions for use in the present invention may be administered before, during or after radiation. The pharmaceutical compositions may be administered before, during or after the administration of a chemotherapeutic agent. The routes of administration of the pharmaceutical compositions include inhalation, intranasal, oral, intravenous, subcutaneous or intramuscular administration. The disclosure further provides for a therapeutically effective amount of a peri