EP3806838A1 - Compositions pharmaceutiques comprenant des dérivés de poh - Google Patents

Compositions pharmaceutiques comprenant des dérivés de poh

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Publication number
EP3806838A1
EP3806838A1 EP19818648.8A EP19818648A EP3806838A1 EP 3806838 A1 EP3806838 A1 EP 3806838A1 EP 19818648 A EP19818648 A EP 19818648A EP 3806838 A1 EP3806838 A1 EP 3806838A1
Authority
EP
European Patent Office
Prior art keywords
poh
cancer
tmz
cells
monoterpene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19818648.8A
Other languages
German (de)
English (en)
Other versions
EP3806838A4 (fr
Inventor
Thomas Chen
Daniel Levin
Satish Puppali
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Southern California USC
Original Assignee
Neonc Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/123,729 external-priority patent/US11077104B2/en
Application filed by Neonc Technologies Inc filed Critical Neonc Technologies Inc
Publication of EP3806838A1 publication Critical patent/EP3806838A1/fr
Publication of EP3806838A4 publication Critical patent/EP3806838A4/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to POH derivatives.
  • the present invention further relates to methods of using POH derivatives such as POH carbamates to treat cancer.
  • Malignant gliomas the most common form of central nervous system (CNS) cancers, is currently considered essentially incurable.
  • CNS central nervous system
  • anaplastic astrocytomas Grade III
  • GBM glioblastoma multiform
  • the present standard of care for malignant gliomas consists of surgery, ionizing radiation, and chemotherapy.
  • the poor response of tumors, including malignant gliomas, to various types of chemotherapeutic agents are often due to intrinsic drug resistance. Additionally, acquired resistance of initially well-responding tumors and unwanted side effects are other problems that frequently thwart long-term treatment using chemotherapeutic agents.
  • 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.
  • 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.
  • 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.
  • Perillyl alcohol 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.
  • Hybrid molecules 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.
  • Perillyl alcohol derivatives including perillyl alcohol conjugated with other therapeutic agents, and to 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.
  • the present invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a perillyl alcohol carbamate.
  • the perillyl alcohol carbamate may be perillyl alcohol conjugated with a therapeutic agent, such as a chemotherapeutic agent.
  • a therapeutic agent such as a chemotherapeutic agent.
  • the chemotherapeutic agents that may be used in the present invention include a DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, and a receptor antagonist.
  • the therapeutic agents are dimethyl celocoxib (DMC), temozolomide (TMZ) or rolipram.
  • the perillyl alcohol carbamates may be 4-(Bis-N,N’-4-isopropenyl cyclohex- l-enylmethyloxy carbonyl [5-(2, 5-dimethyl phenyl)- 3 -trifluoromethyl pyrazol-l-yl] benzenesulfonamide, 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-l -carboxylic acid 4-isopropenyl cyclohex- l-enylmethyl ester, and 3- methyl 4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5]tetrazine-8-carbonyl)-carbamic acid -4- isopropenyl cyclohex- l-enylmethyl ester.
  • compositions of 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.
  • routes of administration of the pharmaceutical compositions include inhalation, intranasal, oral, intravenous, subcutaneous or intramuscular administration.
  • the invention further provides for a method for treating a disease in a mammal, comprising the step of delivering to the mammal a therapeutically effective amount of a perillyl alcohol carbamate.
  • the method may further comprise the step of treating the mammal with radiation, and/or further comprise the step of delivering to the mammal a chemotherapeutic agent.
  • the diseases treated may be cancer, including a tumor of the nervous system, such as a glioblastoma.
  • the routes of administration of the perillyl alcohol carbamate include inhalation, intranasal, oral, intravenous, subcutaneous or intramuscular administration.
  • the present invention also provides for a process for making a POH carbamate, comprising the step of reacting a first reactant of perillyl chloroformate with a second reactant, which may be dimethyl celocoxib (DMC), temozolomide (TMZ) or rolipram.
  • a second reactant which may be dimethyl celocoxib (DMC), temozolomide (TMZ) or rolipram.
  • DMC dimethyl celocoxib
  • TMZ temozolomide
  • rolipram the reaction may be carried out in the presence of acetone and a catalyst of potassium carbonate.
  • the second reactant is rolipram
  • the perillyl chloroformate may also be prepared by reacting perillyl alcohol with phosgene.
  • the present invention also provides a method for treating inflammation in a mammal, comprising the step of delivering to the mammal a therapeutically effective amount of a composition including a perillyl alcohol (POH) conjugated with linoleic acid.
  • a composition including a perillyl alcohol (POH) conjugated with linoleic acid including a perillyl alcohol (POH) conjugated with linoleic acid.
  • Figure 1 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of dimethyl celecoxib (DMC) in killing U87, A172 and U251 human glioma cells.
  • DMC dimethyl celecoxib
  • Figure 2 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-DMC conjugate in killing U87, A172 and U251 human glioma cells according to the present invention.
  • FIG. 3 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of temozolomide (TMZ) in killing U87, A172 and U251 human glioma cells.
  • TMZ temozolomide
  • Figure 4 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-TMZ conjugate in killing U87, A172, and U251 human glioma cells according to the present invention.
  • Figure 5 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-Rolipram conjugate and Rolipram in killing A172 human glioma cells.
  • Figure 6 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-Rolipram conjugate and Rolipram in killing U87 human glioma cells.
  • Figure 7 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-Rolipram conjugate and Rolipram in killing U251 human glioma cells.
  • Figure 8 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-Rolipram conjugate and Rolipram in killing L229 human glioma cells.
  • Figure 9 shows the inhibition of tumor growth by butyryl-POH in mouse models.
  • Figure 9A shows the images of subcutaneous U-87 gliomas in nude mice treated with butyryl-POH, purified (S)-perillyl alcohol having a purity greater than 98.5% (“Purified POH”), POH purchased from Sigma chemicals (“Sigma”), or phosphate buffered saline (“PBS”; negative control).
  • Figure 9B shows average tumor growth over time (total time period of 60 days).
  • Figure 10 shows the results of a Colony forming Assay (CFA) demonstrating the cytotoxic effect of TMZ and TMZ-POH on TMZ sensitive (U251) and TMZ resistant (U251TR) U251 cells.
  • CFA Colony forming Assay
  • Figure 11 shows the results of a Colony forming Assay (CFA) demonstrating the cytotoxic effect of POH on TMZ sensitive (U251) and TMZ resistant (U251TR) U251 cells.
  • CFA Colony forming Assay
  • Figure 12 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-TMZ conjugate in killing U251 cells, U251TR cells, and normal astrocytes.
  • Figure 13 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of the POH-TMZ conjugate in killing normal astrocytes, brain endothelial cells (BEC; confluent and subconfluent), and tumor brain endothelial cells (TuBEC).
  • Figure 14 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of TMZ and the POH-TMZ conjugate in killing USC-04 glioma cancer stem cells.
  • Figure 15 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of POH in killing USC-04 glioma cancer stem cells.
  • Figure 16 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of TMZ and the POH-TMZ conjugate in killing USC-02 glioma cancer stem cells.
  • Figure 17 shows the results of the MTT cytotoxicity assays demonstrating the efficacy of POH in killing USC-02 glioma cancer stem cells.
  • Figure 18 shows a western blot demonstrating that TMZ-POH induces ER stress (ERS) in TMZ sensitive (“U25l-TMZs”) and resistant (“U25l-TMZr”) U251 glioma cells.
  • Figure 19A is a photograph of a mouse that received an application of asTPA on a portion of its skin for seven days and also treated with a glycerol/ethanol vehicle.
  • Figure 19B is a photograph of another mouse that received an application of asTPA on a portion of its skin for seven days and also treated with a glycerol/ethanol vehicle.
  • Figure 20A is a photograph of a mouse that received an application of asTPA on a portion of its skin for seven days and also treated with a POH-linoleic acid conjugate in a glycerol/ethanol vehicle.
  • Figure 20B is a photograph of a mouse that received an application of asTPA on a portion of its skin for seven days and also treated with a POH-linoleic acid conjugate in a
  • the present invention provides for a derivative of monoterpene or sesquiterpene, such as a perillyl alcohol derivative.
  • the present invention also provides for a pharmaceutical composition comprising a derivative of monoterpene or sesquiterpene, such as a perillyl alcohol derivative.
  • the perillyl alcohol derivative may be a perillyl alcohol carbamate.
  • the perillyl alcohol derivative may be perillyl alcohol conjugated with a therapeutic agent such as a chemotherapeutic agent.
  • the monoterpene (or sesquiterpene) derivative may be formulated into a pharmaceutical composition, where the monoterpene (or sesquiterpene) derivative is present in amounts ranging from about 0.01% (w/w) to about 100% (w/w), from about 0.1% (w/w) to about 80% (w/w), from about 1% (w/w) to about 70% (w/w), from about 10% (w/w) to about 60% (w/w), or from about 0.1% (w/w) to about 20% (w/w).
  • the present compositions can be administered alone, or may be co-administered together with radiation or another agent (e.g., a chemotherapeutic agent), to treat a disease such as cancer. Treatments may be sequential, with the monoterpene (or sesquiterpene) derivative being administered before or after the
  • a perillyl alcohol carbamate may be used to sensitize a cancer patient to radiation or chemotherapy.
  • agents may be administered concurrently.
  • the route of administration may vary, and can include, inhalation, intranasal, oral, transdermal, intravenous, subcutaneous or intramuscular injection.
  • the present invention also provides for a method of treating a disease such as cancer, comprising the step of delivering to a patient a therapeutically effective amount of a derivative of a monoterpene (or sesquiterpene).
  • compositions of the present invention may contain one or more types of derivatives of monoterpene (or sesquiterpene).
  • Monoterpenes include terpenes that consist of two isoprene units.
  • Monoterpenes may be linear (acyclic) or contain rings.
  • Derivatives of monoterpenoids are also encompassed by the present invention.
  • Monoterpenoids may be produced by biochemical modifications such as oxidation or rearrangement of monoterpenes.
  • monoterpenes and monoterpenoids examples include, perillyl alcohol (S(-)) and (R(+)), ocimene, myrcene, geraniol, citral, citronellol, citronellal, linalool, pinene, terpineol, terpinen, limonene, terpinenes, phellandrenes, terpinolene, terpinen-4-ol (or tea tree oil), pinene, terpineol, terpinen; the terpenoids such as -cymcnc which is derived from monocyclic terpenes such as menthol, thymol and carvacrol; bicyclic monoterpenoids such as camphor, borneol and eucalyptol.
  • Monoterpenes may be distinguished by the structure of a carbon skeleton and may be grouped into acyclic monoterpenes (e.g., myrcene, (Z)- and (E)-ocimene, linalool, geraniol, nerol, citronellol, myrcenol, geranial, citral a, neral, citral b, citronellal, etc.), monocyclic monoterpenes (e.g., limonene, terpinene, phellandrene, terpinolene, menthol, carveol, etc.), bicyclic monoterpenes (e.g., pinene, myrtenol, myrtenal, verbanol, verbanon, pinocarveol, carene, sabinene, camphene, thujene, etc.) and tricyclic monoterpenes (e.g.
  • Sesquiterpenes of the present invention include terpenes that consist of three isoprene units. Sesquiterpenes may be linear (acyclic) or contain rings. Derivatives of sesquiterpenoids are also encompassed by the present invention. Sesquiterpenoids may be produced by biochemical modifications such as oxidation or rearrangement of sesquiterpenes. Examples of sesquiterpenes include farnesol, famesal, farnesylic acid and nerolidol. The derivatives of monoterpene (or sesquiterpene) include, but are not limited to, carbamates, esters, ethers, alcohols and aldehydes of the monoterpene (or sesquiterpene).
  • Monoterpene (or sesquiterpene) alcohols may be derivatized to carbamates, esters, ethers, aldehydes or acids.
  • Carbamate refers to a class of chemical compounds sharing the functional group
  • R 1 , R 2 and R 3 can be a group such as alkyl, aryl, etc., which can be substituted.
  • the R groups on the nitrogen and the oxygen may form a ring.
  • R '-OH may be a monoterpene, e.g., POH.
  • the R 2 -N-R 3 moiety may be a therapeutic agent.
  • Carbamates may be synthesized by reacting isocyanate and alcohol, or by reacting chloroformate with amine. Carbamates may be synthesized by reactions making use of phosgene or phosgene equivalents. For example, carbamates may be synthesized by reacting phosgene gas, diphosgene or a solid phosgene precursor such as triphosgene with two amines or an amine and an alcohol. Carbamates (also known as urethanes) can also be made from reaction of a urea intermediate with an alcohol. Dimethyl carbonate and diphenyl carbonate are also used for making carbamates. Alternatively, carbamates may be synthesized through the reaction of alcohol and/or amine precursors with an ester- substituted diaryl carbonate, such as
  • BMSC bismethylsalicylcarbonate
  • Carbamates may be synthesized by the following approach:
  • Suitable reaction solvents include, but are not limited to, tetrahydrofuran, dichloromethane, dichloroethane, acetone, and diisopropyl ether.
  • the reaction may be performed at a temperature ranging from about -70°C to about 80°C, or from about -65°C to about 50°C.
  • the molar ratio of perillyl chloroformate to the substrate R - NH 2 may range from about 1: 1 to about 2: 1, from about 1 : 1 to about 1.5:1, from about 2: 1 to about 1 : 1 , or from about 1.05 : 1 to about 1.1:1.
  • Suitable bases include, but are not limited to, organic bases, such as triethylamine, potassium carbonate, N,N’-diisopropylethylamine, butyl lithium, and potassium-t-butoxide.
  • carbamates may be synthesized by the following approach:
  • Suitable reaction solvents include, but are not limited to, dichloromethane, dichloroethane, toluene, diisopropyl ether, and tetrahydrofuran.
  • the reaction may be performed at a temperature ranging from about 25°C to about 1 lO°C, or from about 30°C to about 80°C, or about 50°C.
  • Esters of the monoterpene (or sesquiterpene) alcohols of the present invention can be derived from an inorganic acid or an organic acid.
  • Inorganic acids include, but are not limited to, phosphoric acid, sulfuric acid, and nitric acid.
  • Organic acids include, but are not limited to, carboxylic acid such as benzoic acid, fatty acid, acetic acid and propionic acid, and any therapeutic agent bearing at least one carboxylic acid functional group
  • esters of monoterpene (or sesquiterpene) alcohols include, but are not limited to, carboxylic acid esters (such as benzoate esters, fatty acid esters (e.g., palmitate ester, linoleate ester, stearate ester, butyryl ester and oleate ester), acetates, propionates (or propanoates), and formates), phosphates, sulfates, and carbamates (e.g., N,N-dimethylaminocarbonyl).
  • a specific example of a monoterpene that may be used in the present invention is perillyl alcohol (commonly abbreviated as POH).
  • the derivatives of perillyl alcohol include, perillyl alcohol carbamates, perillyl alcohol esters, perillic aldehydes, dihydroperillic acid, perillic acid, perillic aldehyde derivatives, dihydroperillic acid esters and perillic acid esters.
  • the derivatives of perillyl alcohol may also include its oxidative and nucleophilic/electrophilic addition derivatives.
  • a POH carbamate is synthesized by a process comprising the step of reacting a first reactant of perillyl chloroformate with a second reactant such as dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram.
  • the reaction may be carried out in the presence of tetrahydrofuran and a base such as n-butyl lithium.
  • Perillyl chloroformate may be made by reacting POH with phosgene.
  • POH conjugated with temozolomide through a carbamate bond may be synthesized by reacting temozolomide with oxalyl chloride followed by reaction with perillyl alcohol.
  • the reaction may be carried out in the presence of 1 ,2-dichloroethane.
  • POH carbamates encompassed by the present invention include, but not limited to, 4-(bis- N,N’-4-isopropenyl cyclohex- l-enylmethyloxy carbonyl [5-(2, 5 -dimethyl phenyl)-3- trifluoromethyl pyrazol-l-yl] benzenesulfonamide, 4-(3-cyclopentyloxy-4-methoxy phenyl)-2- oxo-pyrrolidine- 1 -carboxylic acid 4-isopropenyl cyclohex- l-enylmethyl ester, and (3 -methyl 4- oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5]tetrazine-8-carbonyl)carbamic acid-4-isopropenyl cyclohex- l-enylmethyl ester.
  • the details of the chemical reactions generating these compounds are described in the Examples below.
  • perillyl alcohol derivatives may be perillyl alcohol fatty acid esters, such as palmitoyl ester of POH and linoleoyl ester of POH, the chemical structures of which are shown below.
  • the monoterpene (or sesquiterpene) derivative may be a monoterpene (or sesquiterpene) conjugated with a therapeutic agent.
  • a monoterpene (or sesquiterpene) conjugate encompassed by the present invention is a molecule having a monoterpene (or sesquiterpene) covalently bound via a chemical linking group to a therapeutic agent.
  • the molar ratio of the monoterpene (or sesquiterpene) to the therapeutic agent in the monoterpene (or sesquiterpene) conjugate may be 1:1, 1:2, 1:3, 1:4, 2:1, 3:1, 4:1, or any other suitable molar ratios.
  • the monoterpene (or sesquiterpene) and the therapeutic agent may be covalently linked through carbamate, ester, ether bonds, or any other suitable chemical functional groups.
  • the therapeutic agent may be any agent bearing at least one carboxylic acid functional group, or any agent bearing at least one amine functional group.
  • a perillyl alcohol conjugate is perillyl alcohol covalently bound via a chemical linking group to a
  • the therapeutic agents that may be conjugated with monoterpene (or sesquiterpene) include, but are not limited to, chemotherapeutic agents, therapeutic agents for treatment of CNS disorders (including, without limitation, primary degenerative neurological disorders such as Alzheimer’s, Parkinson’s, multiple sclerosis, Attention-Deficit Hyperactivity Disorder or ADHD, psychological disorders, psychosis and depression), immunotherapeutic agents, angiogenesis inhibitors, and anti-hypertensive agents.
  • Anti-cancer agents that may be conjugated with monoterpene or sesquiterpene can have one or more of the following effects on cancer cells or the subject: cell death; decreased cell
  • Also encompassed by the present invention is admixtures and/or coformulations of a monoterpene (or sesquiterpene) and at least one therapeutic agent.
  • Chemotherapeutic agents include, but are not limited to, DNA alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, a platinum compound, an antimetabolite, vincalkaloids, taxanes, epothilones, enzyme inhibitors, receptor antagonists, tyrosine kinase inhibitors, boron radiosensitizers (i.e. velcade), and chemotherapeutic
  • Non-limiting examples of DNA alkylating agents are nitrogen mustards, such as
  • Cyclophosphamide (Ifosfamide, Trofosfamide), Chlorambucil (Melphalan, Prednimu stine), Bendamustine, Uramustine and Estramustine; nitrosoureas, such as Carmustine (BCNU), Lomustine (Semustine), Fotemustine, Nimustine, Ranimustine and Streptozocin; alkyl sulfonates, such as Busulfan (Mannosulfan, Treosulfan); Aziridines, such as Carboquone, Triaziquone, Triethylenemelamine; Hydrazines (Procarbazine); Triazenes such as dacarbazine and Temozolomide (TMZ); Altretamine and Mitobronitol.
  • Topoisomerase I inhibitors include Campothecin derivatives including SN-38, APC, NPC, campothecin, topotecan, exatecan mesylate, 9-nitrocamptothecin, 9-aminocamptothecin, lurtotecan, rubitecan, silatecan, gimatecan, diflomotecan, extatecan, BN- 80927, DX-895lf, and MAG-CPT as decribed in Pommier Y. (2006) Nat. Rev. Cancer
  • Phenanthroline derivatives including Benzo[i]phenanthridine, Nitidine, and fagaronine as described in Makhey et al. (2003) Bioorg. Med. Chem. 11 (8): 1809-1820; Terbenzimidazole and derivatives thereof as described in Xu (1998) Biochemistry 37(l0):3558-3566; and
  • Topoisomerase II inhibitors include, but are not
  • Dual topoisomerase I and II inhibitors include, but are not limited to, Saintopin and other Naphthecenediones, DACA and other Acridine-4- Carboxamindes, Intoplicine and other Benzopyridoindoles, TAS-I03 and other 7H-indeno[2,l- c]Quinoline-7-ones, Pyrazoloacridine, XR 11576 and other Benzophenazines, XR 5944 and other Dimeric compounds, 7-oxo-7H-dibenz[f,ij]Isoquinolines and 7-oxo-7H- benzo[e]pyrimidines, and Anthracenyl- amino Acid Conjugates as described in Denny and Baguley (2003) Curr.
  • Some agents inhibit Topoisomerase II and have DNA intercalation activity such as, but not limited to, Anthracyclines (Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Valrubicin,
  • endoplasmic reticulum stress inducing agents include, but are not limited to, dimethyl-celecoxib (DMC), nelfinavir, celecoxib, and boron radiosensitizers (i.e. velcade (Bortezomib)).
  • DMC dimethyl-celecoxib
  • nelfinavir nelfinavir
  • celecoxib nelfinavir
  • boron radiosensitizers i.e. velcade (Bortezomib)
  • Platinum based compounds are a subclass of DNA alkylating agents.
  • Non-limiting examples of such agents include Cisplatin, Nedaplatin, Oxaliplatin, Triplatin tetranitrate, Satraplatin, Aroplatin, Lobaplatin, and JM-216. (see McKeage et al. (1997) J. Clin. Oncol. 201 : 1232-1237 and in general, CHEMOTHERAPY FOR GYNECOLOGICAL NEOPLASM, CURRENT THERAPY AND NOVEL APPROACHES, in the Series Basic and Clinical
  • FOLFOX is an abbreviation for a type of combination therapy that is used to treat colorectal cancer. It includes 5-FU, oxaliplatin and leucovorin. Information
  • FOLFOX/BV is an abbreviation for a type of combination therapy that is used to treat colorectal cancer. This therapy includes 5-FU, oxaliplatin, leucovorin and
  • Furthennore "XELOX/BV” is another combination therapy used to treat colorectal cancer, which includes the prodrug to 5-FU, known as Capecitabine (Xeloda) in combination with oxaliplatin and bevacizumab. Infonnation regarding these prodrug to 5-FU, known as Capecitabine (Xeloda) in combination with oxaliplatin and bevacizumab. Infonnation regarding these
  • Non-limiting examples of antimetabolite agents include Folic acid based, i.e.
  • dihydrofolate reductase inhibitors such as Aminopterin, Methotrexate and Pemetrexed;
  • thymidylate synthase inhibitors such as Raltitrexed, Pemetrexed
  • Purine based i.e. an adenosine deaminase inhibitor, such as Pentostatin, a thiopurine, such as Thioguanine and Mercaptopurine, a halogenated/ribonucleotide reductase inhibitor, such as Cladribine, Clofarabine, Fludarabine, or a guanine/guanosine: thiopurine, such as Thioguanine; or Pyrimidine based, i.e.
  • cytosine/cytidine hypomethylating agent, such as Azacitidine and Decitabine, a DNA
  • polymerase inhibitor such as Cytarabine
  • a ribonucleotide reductase inhibitor such as
  • thymine/thymidine thymidylate synthase inhibitor
  • a Fluorouracil 5- FU
  • Equivalents to 5-FU include prodrugs, analogs and derivative thereof such as 5' -deoxy-5- fluorouridine (doxifluroidine), l-tetrahydrofuranyl-5-fluorouracil (ftorafur), Capecitabine (Xeloda), S-I (MBMS-247616, consisting of tegafur and two modulators, a 5-chloro-2,4- dihydroxypyridine and potassium oxonate), ralititrexed (tomudex), nolatrexed (Thymitaq, AG337), LY231514 and ZD9331, as described for example in Papamicheal (1999) The
  • vincalkaloids examples include, but are not limited to Vinblastine, Vincristine, Vinflunine, Vindesine and Vinorelbine.
  • taxanes examples include, but are not limited to docetaxel, Larotaxel, Ortataxel, Paclitaxel and Tesetaxel.
  • An example of an epothilone is iabepilone.
  • enzyme inhibitors include, but are not limited to famesyltransferase inhibitors (Tipifamib); CDK inhibitor (Alvocidib, Seliciclib); proteasome inhibitor
  • receptor antagonists include, but are not limited to ERA (Atrasentan); retinoid X receptor (Bexarotene); and a sex steroid (Testolactone).
  • tyrosine kinase inhibitors include, but are not limited to inhibitors to ErbB: HER1/EGFR (Erlotinib, Gefitinib, Lapatinib, Vandetanib, Sunitinib, Neratinib); HER2/neu (Lapatinib, Neratinib); RTK class III: C-kit (Axitinib, Sunitinib, Sorafenib), FLT3 (Lestaurtinib), PDGFR (Axitinib, Sunitinib, Sorafenib); and VEGFR (Vandetanib, Semaxanib, Cediranib, Axitinib, Sorafenib); bcr-abl (Imatinib, Nilotinib, Dasatinib); Src (Bosutinib) and Janus kinase 2 (Lestaurtinib).
  • ErbB HER1/EG
  • Lapatinib (Tykerb®) is an dual EGFR and erbB-2 inhibitor. Lapatinib has been investigated as an anticancer monotherapy, as well as in combination with trastuzumab, capecitabine, letrozole, paclitaxel and FOLFIRI(irinotecan, 5-fluorouracil and leucovorin), in a number of clinical trials. It is currently in phase III testing for the oral treatment of metastatic breast, head and neck, lung, gastric, renal and bladder cancer.
  • lapatinib is a small molecule or compound that is a tyrosine kinase inhibitor (TKI) or alternatively a HER-l inhibitor or a HER-2 inhibitor.
  • TKI tyrosine kinase inhibitor
  • Zactima ZD6474
  • Iressa gefitinib
  • imatinib mesylate STI571; Gleevec
  • erlotinib OSI-1774; Tarceva
  • canertinib Cl 1033
  • semaxinib SU5416
  • vatalanib PTK787/ZK222584
  • sorafenib BAY 43- 9006
  • sutent SUI 1248
  • lefltmomide SET 101
  • PTK/ZK is a tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor (PDGF) receptor, c-KIT and c-Fms.
  • VEGFR VEGF receptors
  • PDGF platelet-derived growth factor
  • PTK/ZK is a targeted drug that blocks angiogenesis and lymphangiogenesis by inhibiting the activity of all known receptors that bind VEGF including VEGFR-I (Flt-l), VEGFR- 2 (KDR/Flk-l) and VEGFR- 3 (Flt-4).
  • the chemical names of PTK/ZK are l-[4-Chloroanilino]-4-[4-pyridylmethyl] phthalazine Succinate or 1- Phthalazinamine, N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-butanedioate (1:1).
  • PTK/TK Synonyms and analogs of PTK/TK are known as Vatalanib, CGP79787D, PTK787/ZK 222584, CGP-79787, DE-00268, PTK-787, PTK787A, VEGFR-TK inhibitor, ZK 222584 and ZK.
  • Chemotherapeutic agents that can be conjugated with monoterpene or sesquiterpene may also include amsacrine, Trabectedin, retinoids (Alitretinoin, Tretinoin), Arsenic trioxide, asparagine depleter Asparaginase/ Pegaspargase), Celecoxib, Demecolcine, Elesclomol, Elsamitrucin, Etoglucid, Lonidamine, Lucanthone, Mitoguazone, Mitotane, Oblimersen, Temsirolimus, and Vorinostat.
  • the monoterpene or sesquiterpene derivative may be conjugated with angiogenesis inhibitors.
  • angiogenesis inhibitors include, but are not limited to, angiostatin, angiozyme, antithrombin III, AG3340, VEGF inhibitors, batimastat, bevacizumab (avastin), BMS-275291, CAI, 2C3, HuMV833 Canstatin, Captopril, carboxyamidotriazole, cartilage derived inhibitor (CDI), CC-5013, 6-0-(chloroacetyl-carbonyl)-fumagillol, COL-3,
  • combretastatin combretastatin A4 Phosphate, Dalteparin, EMD 121974 (Cilengitide), endostatin, erlotinib, gefitinib (Iressa), genistein, halofuginone hydrobromide, Idl, M3, IM862, imatinib mesylate, IMC-IC11 Inducible protein 10, interferon-alpha, interleukin 12, lavendustin A, LY317615 or AE-941, marimastat, mspin, medroxpregesterone acetate, Meth-l, Meth-2, 2- methoxyestradiol (2-ME), neovastat, oteopontin cleaved product, PEX, pigment epithelium growth factor (PEGF), platelet factor 4, prolactin fragment, proliferin-related protein (PRP), PTK787/ZK 222584, ZD6474, re
  • Non-limiting examples of angiogenesis inhibitors also include, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-l (VEGFR1) and Flk-l/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, pentosan polysulfate, angiotensin II antagonists, cyclooxygenase inhibitors (including non-steroidal anti-inflammatory drugs
  • NSAIDs such as aspirin and ibuprofen
  • selective cyclooxygenase-2 inhibitors such as celecoxib and rofecoxib
  • steroidal anti-inflammatories such as corticosteroids
  • mineralocorticoids dexamethasone, prednisone, prednisolone, methylpred, betamethasone).
  • therapeutic agents that modulate or inhibit angiogenesis and may also be conjugated with monoterpene or sesquiterpene include agents that modulate or inhibit the coagulation and fibrinolysis systems, including, but not limited to, heparin, low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]).
  • heparin low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]).
  • TAFIa active thrombin activatable fibrinolysis inhibitor
  • Non-limiting examples of the anti-hypertensive agents include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril etc.), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan (or Cozaar), losartan potassium, eprosartan, valsartan (or Diovan), termisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine (or Amlodin), efonidipine, nicardipine etc.), diuretics, renin inhibitor (e.g., aliskiren etc.), aldosterone antagonists (e.g., spironolactone, eplerenone etc.
  • therapeutic agents that may be conjugated with monoterpene (or sesquiterpene) include, but are not limited to, Sertraline (Zoloft), Topiramate (Topamax),
  • the purity of the monoterpene (or sesquiterpene) derivatives may be assayed by gas chromatography (GC) or high pressure liquid chromatography (HPLC).
  • Other techniques for assaying the purity of monoterpene (or sesquiterpene) derivatives and for determining the presence of impurities include, but are not limited to, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), GC-MS, infrared spectroscopy (IR), and thin layer chromatography (TLC). Chiral purity can be assessed by chiral GC or measurement of optical rotation.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • IR infrared spectroscopy
  • TLC thin layer chromatography
  • the monoterpene (or sesquiterpene) derivatives may be purified by methods such as crystallization, or by separating the monoterpene (or sesquiterpene) derivative from impurities according to the unique physicochemical properties (e.g., solubility or polarity) of the derivative. Accordingly, the monoterpene (or sesquiterpene) derivative can be separated from the monoterpene (or sesquiterpene) by suitable separation techniques known in the art, such as preparative chromatography, (fractional) distillation, or (fractional) crystallization.
  • the invention also provides for methods of using monoterpenes (or sesquiterpenes) derivatives to treat a disease, such as cancer or other nervous system disorders.
  • a monoterpenes (or sesquiterpenes) derivative may be administered alone, or in combination with radiation, surgery or chemotherapeutic agents.
  • a monoterpene or sesquiterpene derivative may also be co administered with antiviral agents, anti-inflammatory agents or antibiotics. The agents may be administered concurrently or sequentially.
  • a monoterpenes (or sesquiterpenes) derivative can be administered before, during or after the administration of the other active agent(s).
  • the monoterpene or sesquiterpene derivative may be used in combination with radiation therapy.
  • the present invention provides for a method of treating tumor cells, such as malignant glioma cells, with radiation, where the cells are treated with an effective amount of a monoterpene derivative, such as a perillyl alcohol carbamate, and then exposed to radiation.
  • Monoterpene derivative treatment may be before, during and/or after radiation.
  • the monoterpene or sesquiterpene derivative may be administered continuously beginning one week prior to the initiation of radiotherapy and continued for two weeks after the completion of radiotherapy.
  • the present invention provides for a method of treating tumor cells, such as malignant glioma cells, with chemotherapy, where the cells are treated with an effective amount of a monoterpene derivative, such as a perillyl alcohol carbamate, and then exposed to chemotherapy.
  • a monoterpene derivative such as a perillyl alcohol carbamate
  • Monoterpene derivative treatment may be before, during and/or after
  • Monoterpene (or sesquiterpene) derivatives may be used for the treatment of nervous system cancers, such as a malignant glioma (e.g., astrocytoma, anaplastic astrocytoma, glioblastoma multiforme), retinoblastoma, pilocytic astrocytomas (grade I), meningiomas, metastatic brain tumors, neuroblastoma, pituitary adenomas, skull base meningiomas, and skull base cancer.
  • glioma e.g., astrocytoma, anaplastic astrocytoma, glioblastoma multiforme
  • retinoblastoma retinoblastoma
  • pilocytic astrocytomas grade I
  • Cancers that can be treated by the present monoterpene (or sesquiterpene) derivatives include, but are not limited to, lung cancer, ear, nose and throat cancer, leukemia, colon cancer, melanoma, pancreatic cancer, mammary cancer, prostate cancer, breast cancer, hematopoietic cancer, ovarian cancer, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; breast cancer; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer;
  • cancer of the head and neck gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer; leukemia including acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; liver cancer; lymphoma including Hodgkin's and Non- Hodgkin's lymphoma; myeloma; fibroma, neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma;
  • the present invention also provides methods of treating CNS disorders, including, without limitation, primary degenerative neurological disorders such as Alzheimer’s,
  • Parkinson s, psychological disorders, psychosis and depression. Treatment may consist of the use of a monoterpene or sesquiterpene derivative alone or in combination with current medications used in the treatment of Parkinson’s, Alzheimer’s, or psychological disorders.
  • the present invention also provides a method of improving immunomodulatory therapy responses comprising the steps of exposing cells to an effective amount of a monoterpene or sisquiterpene derivative, such as a perillyl alcohol carbamate, before or during
  • immunomodulatory treatment Preferred immunomodulatory agents are cytokines, such interleukins, lymphokines, monokines, interfereons and chemokines.
  • composition may be administered by any method known in the art, including, without limitation, intranasal, oral, transdermal, ocular, intraperitoneal, inhalation, intravenous, ICV, intracistemal injection or infusion, subcutaneous, implant, vaginal, sublingual, urethral (e.g., urethral suppository), subcutaneous, intramuscular, intravenous, rectal, sub-lingual, mucosal, ophthalmic, spinal, intrathecal, intra- articular, intra-arterial, sub-arachinoid, bronchial and lymphatic administration.
  • Topical formulation may be in the form of gel, ointment, cream, aerosol, etc; intranasal formulation can be delivered as a spray or in a drop; transdermal formulation may be administered via a transdermal patch or iontorphoresis; inhalation
  • compositions can be delivered using a nebulizer or similar device.
  • Compositions can also take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • a pharmaceutical acceptable carrier, adjuvant and/or excipient may be mixed with a pharmaceutical acceptable carrier, adjuvant and/or excipient, according to conventional pharmaceutical compounding techniques.
  • compositions encompass any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • the compositions can additionally contain solid pharmaceutical excipients such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
  • stabilizers and adjuvants see Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the compositions also can include stabilizers and preservatives.
  • the term "therapeutically effective amount” is an amount sufficient to treat a specified disorder or disease or alternatively to obtain a pharmacological response treating a disorder or disease.
  • Methods of determining the most effective means and dosage of administration can vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Treatment dosages generally may be titrated to optimize safety and efficacy. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents can be readily determined by those of skill in the art.
  • the composition are administered at about 0.01 mg/kg to about 200 mg/kg, about 0.1 mg/kg to about 100 mg/kg, or about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
  • a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
  • the composition may be rubbed onto a membrane of the patient, for example, the skin, preferably intact, clean, and dry skin, of the shoulder or upper arm and or the upper torso, and maintained thereon for a period of time sufficient for delivery of the monoterpene (or sesquiterpene) derivative to the blood serum of the patient.
  • composition of the present invention in gel form may be contained in a tube, a sachet, or a metered pump.
  • a tube or sachet may contain one unit dose, or more than one unit dose, of the composition.
  • a metered pump may be capable of dispensing one metered dose of the composition.
  • compositions as described above for intranasal administration can further comprise a permeation enhancer.
  • the monoterpene (or sesquiterpene) derivative may be administered intranasally in a liquid form such as a solution, an emulsion, a suspension, drops, or in a solid form such as a powder, gel, or ointment.
  • Devices to deliver intranasal medications are well known in the art.
  • Nasal drug delivery can be carried out using devices including, but not limited to, intranasal inhalers, intranasal spray devices, atomizers, nasal spray bottles, unit dose containers, pumps, droppers, squeeze bottles, nebulizers, metered dose inhalers (MDI), pressurized dose inhalers, insufflators, and bi-directional devices.
  • the nasal delivery device can be metered to administer an accurate effective dosage amount to the nasal cavity.
  • the nasal delivery device can be for single unit delivery or multiple unit delivery.
  • the ViaNase Electronic Atomizer from Kurve Technology (Bethell,
  • the compounds of the present invention may also be delivered through a tube, a catheter, a syringe, a packtail, a pledget, a nasal tampon or by submucosal infusion.
  • the monoterpene (or sesquiterpene) derivative can be formulated as aerosols using standard procedures.
  • the monoterpene (or sesquiterpene) derivative may be formulated with or without solvents, and formulated with or without carriers.
  • the formulation may be a solution, or may be an aqueous emulsion with one or more surfactants.
  • an aerosol spray may be generated from pressurized container with a suitable propellant such as,
  • aerosol refers to a suspension of fine solid particles or liquid solution droplets in a gas.
  • aerosol includes a gas-borne suspension of droplets of a monoterpene (or sesquiterpene), as may be produced in any suitable device, such as an MDI, a nebulizer, or a mist sprayer.
  • Aerosol also includes a dry powder composition of the composition of the instant invention suspended in air or other carrier gas.
  • the monoterpene (or sesquiterpene) derivative may be delivered to the nasal cavity as a powder in a form such as microspheres delivered by a nasal insufflator.
  • the monoterpene (or sesquiterpene) derivative may be absorbed to a solid surface, for example, a carrier.
  • the powder or microspheres may be administered in a dry, air-dispensable form.
  • microspheres may be stored in a container of the insufflator.
  • the powder or microspheres may be filled into a capsule, such as a gelatin capsule, or other single dose unit adapted for nasal administration.
  • the pharmaceutical composition can be delivered to the nasal cavity by direct placement of the composition in the nasal cavity, for example, in the form of a gel, an ointment, a nasal emulsion, a lotion, a cream, a nasal tampon, a dropper, or a bioadhesive strip. In certain embodiments, it can be desirable to prolong the residence time of the pharmaceutical
  • the pharmaceutical composition in the nasal cavity, for example, to enhance absorption.
  • the pharmaceutical composition can optionally be formulated with a bioadhesive polymer, a gum (e.g., xanthan gum), chitosan (e.g., highly purified cationic polysaccharide), pectin (or any carbohydrate that thickens like a gel or emulsifies when applied to nasal mucosa), a microsphere (e.g., starch, albumin, dextran, cyclodextrin), gelatin, a liposome, carbamer, polyvinyl alcohol, alginate, acacia, chitosans and/or cellulose (e.g., methyl or propyl; hydroxyl or carboxy; carboxymethyl or hydroxylpropyl).
  • a bioadhesive polymer e.g., xanthan gum
  • chitosan e.g., highly purified cationic polysaccharide
  • composition containing the purified monoterpene (or sesquiterpene) can be administered by oral inhalation into the respiratory tract, i.e., the lungs.
  • Typical delivery systems for inhalable agents include nebulizer inhalers, dry powder inhalers (DPI), and metered-dose inhalers (MDI).
  • Nebulizer devices produce a stream of high velocity air that causes a therapeutic agent in the form of liquid to spray as a mist.
  • the therapeutic agent is formulated in a liquid form such as a solution or a suspension of particles of suitable size.
  • the particles are micronized.
  • the term“micronized” is defined as having about 90% or more of the particles with a diameter of less than about 10 mih.
  • Suitable nebulizer devices are provided commercially, for example, by PARI GmbH (Starnberg, Germany).
  • nebulizer devices include Respimat (Boehringer Ingelheim) and those disclosed in, for example, U.S. Patent Nos. 7,568,480 and 6,123,068, and WO 97/12687.
  • the monoterpenes (or sesquiterpenes) can be formulated for use in a nebulizer device as an aqueous solution or as a liquid suspension.
  • DPI devices typically administer a therapeutic agent in the form of a free flowing powder that can be dispersed in a patient's air-stream during inspiration. DPI devices which use an external energy source may also be used in the present invention.
  • the therapeutic agent can be formulated with a suitable excipient (e.g., lactose).
  • a suitable excipient e.g., lactose
  • a dry powder formulation can be made, for example, by combining dry lactose having a particle size between about 1 mih and 100 mih with micronized particles of the monoterpenes (or sesquiterpenes) and dry blending.
  • the monoterpene can be formulated without excipients.
  • the formulation is loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
  • DPI devices provided commercially include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g.,
  • Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Patent No. 4,353,365). Further examples of suitable DPI devices are described in U.S. Patent Nos. 5,415,162, 5,239,993, and 5,715,810 and references therein.
  • MDI devices typically discharge a measured amount of therapeutic agent using compressed propellant gas.
  • Formulations for MDI administration include a solution or suspension of active ingredient in a liquefied propellant.
  • propellants include hydrofluoroalklanes (HFA), such as l,l,l,2-tetrafluoroethane (HFA l34a) and 1, 1,1, 2, 3,3,3- heptafluoro-n-propane, (HFA 227), and chloro fluorocarbons, such as CCl 3 F.
  • HFA formulations for MDI administration include co-solvents, such as ethanol, pentane, water; and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin.
  • co-solvents such as ethanol, pentane, water
  • surfactants such as sorbitan trioleate, oleic acid, lecithin, and glycerin.
  • the formulation is loaded into an aerosol canister, which forms a portion of an MDI device.
  • MDI devices developed specifically for use with HFA propellants are provided in U.S. Patent Nos. 6,006,745 and 6,143,227.
  • processes of preparing suitable formulations and devices suitable for inhalation dosing see U.S. Patent Nos. 6,268,533, 5,983,956, 5,874,063, and 6,221,398, and WO 99/53901, WO 00/61108, WO 99/55319 and WO 00/30614.
  • the monoterpene (or sesquiterpene) derivative may be encapsulated in liposomes or microcapsules for delivery via inhalation.
  • a liposome is a vesicle composed of a lipid bilayer membrane and an aqueous interior.
  • the lipid membrane may be made of phospholipids, examples of which include phosphatidylcholine such as lecithin and lysolecithin; acidic phospholipids such as phosphatidylserine and phosphatidylglycerol; and sphingophospholipids such as phosphatidylethanolamine and sphingomyelin. Alternatively, cholesterol may be added.
  • a microcapsule is a particle coated with a coating material.
  • the coating material may consist of a mixture of a film-forming polymer, a hydrophobic plasticizer, a surface activating agent or/and a lubricant nitrogen-containing polymer.
  • the monoterpene (or sesquiterpene) derivative may also be used alone or in combination with other chemotherapeutic agents via topical application for the treatment of localized cancers such as breast cancer or melanomas.
  • the monoterpene (or sesquiterpene) derivative may also be used in combination with narcotics or analgesics for transdermal delivery of pain medication.
  • This invention also provides the compositions as described above for ocular
  • compositions can further comprise a permeation enhancer.
  • the compositions described herein can be formulated as a solution, emulsion, suspension, etc.
  • a variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent Nos.
  • the monoterpene (or sesquiterpene) derivative can be given alone or in combination with other drugs for the treatment of the above diseases for a short or prolonged period of time.
  • the present compositions can be administered to a mammal, preferably a human. Mammals include, but are not limited to, murines, rats, rabbit, simians, bovines, ovine, porcine, canines, feline, farm animals, sport animals, pets, equine, and primates.
  • the invention also provides a method for inhibiting the growth of a cell in vitro , ex vivo or in vivo , where a cell, such as a cancer cell, is contacted with an effective amount of the monoterpene (or sesquiterpene) derivative as described herein.
  • Pathological cells or tissue such as hyperproliferative cells or tissue may be treated by contacting the cells or tissue with an effective amount of a composition of this invention.
  • the cells such as cancer cells, can be primary cancer cells or can be cultured cells available from tissue banks such as the American Type Culture Collection (ATCC).
  • the pathological cells can be cells of a systemic cancer, gliomas, meningiomas, pituitary adenomas, or a CNS metastasis from a systemic cancer, lung cancer, prostate cancer, breast cancer, hematopoietic cancer or ovarian cancer.
  • the cells can be from a vertebrate, preferably a mammal, more preferably a human.
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] cytotoxicity assay.
  • MTT assay is based on the principle of uptake of MTT, a tetrazolium salt, by metabolically active cells where it is metabolized into a blue colored formazon product, which can be read spectrometrically. J. of Immunological Methods 65: 55 63, 1983.
  • the cytoxicity of the present monoterpene (or sesquiterpene) derivative and/or the therapeutic agents may be studied by colony formation assay. Functional assays for inhibition of VEGF secretion and IL-8 secretion may be performed via ELISA. Cell cycle block by the present monoterpene (or sesquiterpene) derivative and/or the therapeutic agents may be studied by standard propidium iodide (PI) staining and flow cytometry. Invasion inhibition may be studied by Boyden chambers. In this assay a layer of reconstituted basement membrane, Matrigel, is coated onto chemotaxis filters and acts as a barrier to the migration of cells in the Boyden chambers. Only cells with invasive capacity can cross the Matrigel barrier. Other assays include, but are not limited to cell viability assays, apoptosis assays, and morphological assays.
  • Example 1 Synthesis of Dimethyl Celecoxib bisPOH Carbamate (4-(bis-N,N’-4-isopropenyl cyclohex- l-enylmethyloxy carbonyl [5-(2, 5-dimethyl phenyl)-3-trifluoromethyl pyrazol-l-yl] benzenesulfonamide)
  • the reaction scheme is the following:
  • Phosgene (20% in toluene, 13 ml, 26.2 mmol) was added to a mixture of perillyl alcohol (2.0 grams, 13.1 mmol) and potassium carbonate (5.4 grams, 39.1 mmol) in dry toluene (30 mL) over a period of 30 minutes while maintaining the temperature between 10° C to 15° C.
  • the reaction mixture was allowed to warm to room temperature and stirred for 8.0 hours under N 2 .
  • the reaction mixture was quenched with water (30 mL) and the organic layer was separated.
  • Perillyl chloroformate (0.11 grams, 0.55 mmol) was added slowly to a mixture of dimethyl celecoxib (0.2 grams, 0.50 mmol) and potassium carbonate (0.13 grams, 1.0 mmol) in dry acetone (10 mL) over a period of 5 minutes under N 2 .
  • the reaction mixture was heated to reflux and maintained for 3 hours. Since TLC analysis indicated the presence of dimethyl celecoxib (> 60%), another 1.0 equivalent of perillyl chloroformate was added and refluxed for an additional 5 hours.
  • the reaction mixture was cooled and acetone was concentrated under vacuum to give a residue.
  • Figure 1 shows the results of the MTT cytotoxicity assays performed on human malignant glioma cells U87, A172 and U251 with DMC alone.
  • the reaction scheme is the following:
  • Oxalyl chloride (0.13 grams, 1.0 mmol) was added slowly to a mixture of temozolomide (OChem Incorporation, 0.1 grams, 0.5 mmol) in l,2-dichloroethane (10 mL) over a period of 2 minutes while maintaining the temperature at 10° C under N 2 .
  • the reaction mixture was allowed to warm to room temperature and then heated to reflux for 3 hours.
  • the excess of oxalyl chloride and l,2-dichloroethane were removed by concentration under vacuum.
  • the resulting residue was re-dissolved in l,2-dichlorethane (15 mL) and the reaction mixture was cooled to 10° C under N 2 .
  • temozolomide POH carbamate was synthesized according to the following procedure. Oxalyl chloride (0.13 grams, 1.0 mmol) was added slowly to a mixture of temozolomide (OChem Incorporation, 0.1 grams, 0.5 mmol) in l,2-dichloroethane (10 mL) over a period of 2 minutes while maintaining the temperature at 10 °C under N 2 . The reaction mixture was allowed to warm to room temperature and then heated to reflux for 3 hours. The excess of oxalyl chloride and l,2-dichloroethane were removed by concentration under vacuum.
  • FIG. 3 shows the results of the MTT cytotoxicity assays performed on human malignant glioma cells U87, A172 and U251 with TMZ alone. Increasing concentrations of TMZ had minimal cytotoxicity towards the cell lines tested. Then TMZ-resistant glioma cell lines U87, A172 and U251 cells were treated with temozolomide POH carbamate (POH-TMZ) (e.g., synthesized by the method in Example 3). The MTT assay results ( Figure 4) showed that POH carbamate POH-TMZ exhibited substantially higher kill rates of the various human glioma cells compared to TMZ alone.
  • POH-TMZ temozolomide
  • the reaction scheme is the following:
  • Phosgene (20% in toluene, 13 ml, 26.2 mmol) was added to a mixture of perillyl alcohol (2.0 grams, 13.1 mmol) and potassium carbonate (5.4 grams, 39.1 mmol) in dry toluene (30 mL) over a period of 30 minutes while maintaining the temperature between 10° C to 15° C.
  • the reaction mixture was allowed to warm to room temperature and stirred for 8.0 hours under N 2 .
  • the reaction mixture was quenched with water (30 mL) and the organic layer separated.
  • Butyl lithium (2.5 M, 0.18 mL, 0.45 mmol) was added to a solution of rolipram (GF synthesis, Inc., 0.1 grams, 0.36 mmol) in dry THF at -72° C over a period of 5 minutes under N 2 . After the reaction mixture was stirred for 1.0 hours at -72° C, perillyl chloroformate (dissolved in 4 mL THF) was added over a period of 15 minutes while maintaining the temperature at -72° C. The reaction mixture was stirred for 2.5 hours and quenched with saturated ammonium chloride (5 mL). The reaction mixture was allowed to warm to room temperature and extracted with ethyl acetate (2x15 mL).
  • Rolipram alone demonstrates an IC50 of approximately 1000 uM (1 mM). In the presence of POH-rolipram, IC50 is achieved at concentrations as low as 50 uM.
  • Figure 6 shows the MTT assay for increasing concentrations of rolipram with U-87 cells. IC50 is not met at 1000 uM. On the other hand, IC50 iss achieved at 180 uM with POH-rolipram.
  • Figure 7 shows that IC50 for rolipram alone for U251 cells is achieved at 170 uM; plateau cytotoxicity is reached at 60%. POH-rolipram achieves IC50 at 50 uM, with almost 100% cytoxicity at 100 uM.
  • Figure 8 shows that IC50 for rolipram alone for FN229 cells is not achieved even at 100 uM.
  • IC50 for POH-rolipram is achieved at 100 uM, with almost 100% cytotoxicity at 10 uM.
  • Example 8 In vitro Cytotoxicity Studies of Temozolomide (TMZ) and Temozolomide POH Carbamate (POH-TMZ) on TMZ sensitive and resistant glioma cells
  • Colony forming assays were carried out after cells were treated with TMZ alone, POH alone, and the TMZ-POH conjugate. The colony forming assays were carried out as described in Chen TC, et al. Green tea epigallocatechin gallate enhances therapeutic efficacy of
  • Figure 10 shows the results of the colony forming assays performed on TMZ sensitive (U251) and TMZ resistant (U251TR) U251 cells with TMZ or TMZ-POH.
  • TMZ demonstrated cytotoxicity towards TMZ sensitive U251 cells, but had minimal cytotoxicity towards TMZ resistant U251 cells.
  • TMZ-POH demonstrated cytotoxicity towards both TMZ sensitive and TMZ resistant U251 cells.
  • Figure 11 shows the results of the colony forming assays performed on TMZ sensitive (U251) and TMZ resistant (U251TR) U251 cells with POH.
  • POH demonstrated cytotoxicity towards both TMZ sensitive and TMZ resistant U251 cells.
  • POH-TMZ Figure 10 exhibited substantially greater potency compared to POH alone ( Figure 11) in the colony forming assays
  • Example 9 In vitro Cytotoxicity Studies of Temozolomide POH Carbamate (POH-TMZ) on U251 cells, U251TR cells, and Normal Astrocytes.
  • MTT cytotoxicity assays were carried out after cells were treated with the TMZ-POH conjugate.
  • the MTT cytotoxicity assays were carried out as described in Chen TC, et al. Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. Cancer Lett. 2011 Mar 28;302(2): 100-8.
  • Figure 12 shows the results of the MTT cytotoxicity assays performed on TMZ sensitive cells (U251), TMZ resistant cells
  • TMZ-POH demonstrated cytotoxicity towards both TMZ sensitive and TMZ resistant U251 cells, but not towards normal astrocytes.
  • Example 10 In vitro Cytotoxicity Studies of Temozolomide POH Carbamate (POH-TMZ) on BEC, TuBEC, and Normal Astrocytes.
  • MTT cytotoxicity assays were carried out after cells were treated with the TMZ-POH conjugate.
  • the MTT cytotoxicity assays were carried out as described in Chen TC, et al. Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. Cancer Lett. 2011 Mar 28;302(2): 100-8.
  • Figure 13 shows the results of the MTT cytotoxicity assays performed on normal astrocytes, brain endothelial cells (BEC;
  • TMZ-POH did not induce significant cytotoxicity on normal astrocytes, confluent BEC, or TuBEC. Mild to moderate cytotoxicity was demonstrated in subconfluent BEC at high concentrations of TMZ- POH.
  • Example 11 In vitro Cytotoxicity Studies of Temozolomide (TMZ) and Temozolomide POH Carbamate (POH-TMZ) on USC-04 Glioma Cancer Stem Cells.
  • MTT cytotoxicity assays were carried out after cells were treated with the TMZ alone, POH alone, or the TMZ-POH conjugate.
  • the MTT cytotoxicity assays were carried out as described in Chen TC, et al. Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. Cancer Lett. 2011 Mar 28;302(2):l00- 8.
  • Figure 14 shows the results of the MTT cytotoxicity assays performed on USC-04 glioma cancer stem cells.
  • TMZ did not induce significant cytotoxicity with increasing concentrations (0-400 uM).
  • TMZ-POH demonstrated evidence of cytotoxicity with IC50 at 150 uM.
  • Figure 15 shows the results of the MTT cytotoxicity assays performed on USC-04 glioma cancer stem cells treated with POH. POH demonstrated cytotoxicity on USC-04 with increasing
  • Example 12 In vitro Cytotoxicity Studies of Temozolomide (TMZ) and Temozolomide POH Carbamate (POH-TMZ) on USC-02 Glioma Cancer Stem Cells.
  • MTT cytotoxicity assays were carried out after cells were treated with the TMZ alone, POH alone, or the TMZ-POH conjugate.
  • the MTT cytotoxicity assays were carried out as described in Chen TC, et al. Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. Cancer Lett. 2011 Mar 28;302(2):l00- 8.
  • Figure 16 shows the results of the MTT cytotoxicity assays performed on USC-02 glioma cancer stem cells.
  • TMZ did not induce significant cytotoxicity with increasing concentrations (0-400 uM).
  • TMZ-POH demonstrated evidence of cytotoxicity with IC50 at 60 uM.
  • Figure 17 shows the results of the MTT cytotoxicity assays performed on USC-02 glioma cancer stem cells treated with POH. POH demonstrated cytotoxicity on USC-02 with increasing concentrations (0-2 mM).
  • Example 13 In vitro Studies of ER stress by Temozolomide POH Carbamate (POH-TMZ) on TMZ sensitive and resistant glioma cells
  • mice were pre-treated with a solution of 50 microliters (pL) of a conjugate of POH and linoleic acid (e.g., linoleoyl ester of POH) in a vehicle of a
  • mice were treated solely with the glycerohethanol (90:10) vehicle.
  • mice After pre-treatment, skin inflammation was induced on the first and second groups of mice by daily cutaneous application of an acetonic solution of 12-0-Tetradecanoylphorbol- 13- acetate (asTPA) (which is a known irritant) to the backs of the mice over seven days.
  • asTPA 12-0-Tetradecanoylphorbol- 13- acetate
  • mice were anaesthetized by inhalation of isofluorane. 100 microliters of asTPA (corresponding to 20 micrograms (pg) of TPA) was then applied onto the skin of the mice. Upon evaporation of the asTPA, the mice were returned to their cages.
  • the first group continued to receive treatment of the POH-linoleic acid conjugate and vehicle solution
  • the second group continued to receive treatment of the vehicle.
  • the mice were photographed.
  • FIGS. 19A is a photograph of a first mouse of the second group that received asTPA and the vehicle but did not receive the POH-linoleic acid conjugate treatment.
  • FIG. 19B is a photograph of a second mouse of the second group that also received asTPA and the vehicle but did not receive the POH-linoleic acid conjugate treatment.
  • FIGS. 19A and 19B show, the areas of skin at the right hip of the mice (1902, 1904, respectively) where the asTPA was applied appear inflamed and desiccated.
  • FIG. 20A is a photograph of a first mouse of the first group that received combined asTPA and the POH-linoleic conjugate/vehicle treatment.
  • FIGS. 20A and 20B are photographs of a second mouse of the first group that also received combined asTPA and POH- linoleic conjugate/vehicle treatment.
  • FIGS. 20A and 20B show, the areas of skin at the right hip of the mice (2002, 2004, respectively) where the asTPA was applied display no inflammation or flaking.
  • the skin is relatively smooth at the application sites and surrounding area, providing evidence of the efficacy of the combination of POH-linoleic conjugate/vehicle treatment in comparison with the vehicle alone.
  • Example 15 Mouse studies of Anti-Inflammatory effects of POH-linoleic acid conjugate
  • mice will be divided in five (5) groups (i)-(v), with each group containing three (3) mice.
  • Groups (iii) through (v) will receive a pretreatment, while groups (i) and (ii) will be negative and positive control groups.
  • Group (iii) will receive a pretreatment of 10 mg//kg of linoleic acid;
  • group (iv) will receive a pretreatment of 10 mg/kg of POH;
  • group (v) will receive a pretreatment of 10 mg/kg of a conjugate pf linoleic acid and POH (e.g., linoleoyl ester of POH). All of the pretreatments will last three days.
  • Skin inflammation will be induced by daily cutaneous application of an acetonic solution of TPA (asTPA) to the back of mice in groups (ii), (iii), (iv) and (v) over seven consecutive days.
  • Application of the asTPA will proceed by restraining the mice in groups (ii) through (v) in an adapted device featuring a skin exposure aperture, over which 100 microliters (pL) of asTPA (corresponding to 20 micrograms (pg) of TPA) will be applied.
  • mice will be observed in a double-blind manner by two different persons unaware of the treatments given.
  • the extent and degree of dorsal cutaneous inflammation will be assessed to calculate a global macroscopic score of cutaneous inflammation.
  • a scoring system will be implemented. A macroscopic score between 0 and 12 will be assessed as an indication of the degree of inflammation observed. A score of 0 will indicate no skin inflammation; a score of 1 to 3, will indicate slight inflammation; a score of 4 to 6 will indicate medium inflammation; a score of 7 to 9 will indicate significant inflammation; and a score between 10 and 12 will indicate severe inflammation. Skin specimens will be fixed and stored in preservative for histo-pathological analysis with classical pathological methods after paraffin embedding.
  • blood samples will be taken from each mouse 4 hours after the last cutaneous treatment. About 0.5 mL of blood will be collected by cardiac puncture in a tube containing citrate as an anti-coagulant and then centrifuged at 1500g for 15 minutes to collect serum. Serum will be aliquoted in ependorf tubes and store at -80°C as preparation for cytokine analyses. The serum samples will then be thawed, and afterwards three pro-inflammatory cytokines, IL-l, IL-6 and TNF, will be assayed simultaneously with Bio-Rad mouse 3-Plex-A panel kits using the Bio-Plex technique.

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Abstract

La présente invention concerne un procédé de traitement d'une inflammation chez un mammifère. Le procédé comprend l'administration au mammifère d'une quantité thérapeutiquement efficace d'une composition comprenant un alcool périllylique (POH) conjugué à l'acide linoléique.
EP19818648.8A 2018-06-15 2019-06-17 Compositions pharmaceutiques comprenant des dérivés de poh Pending EP3806838A4 (fr)

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US16/123,729 US11077104B2 (en) 2010-08-27 2018-09-06 Pharmaceutical compositions comprising POH derivatives
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