CN103946202A - Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof - Google Patents

Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof Download PDF

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CN103946202A
CN103946202A CN201280057166.6A CN201280057166A CN103946202A CN 103946202 A CN103946202 A CN 103946202A CN 201280057166 A CN201280057166 A CN 201280057166A CN 103946202 A CN103946202 A CN 103946202A
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deuterium
rich
perillalcohol
compound
methods
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T·陈
D·莱文
S·普帕利
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Neonc Technologies Inc
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Neonc Technologies Inc
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Abstract

The present invention, provides for a deuterium-enriched monoterpene or sesquiterpene such as perillyl alcohol, or a deuterium-enriched isomer or analog of monoterpenes or sesquiterpenes, such as isoperillyl alcohol. The present invention also provides for a deuterium-enriched derivative of a monoterpene or sesquiterpene, such as a perillyl alcohol carbamate, or a deuterium-enriched derivative of an isomer or analog of a monoterpene or sesquiterpene, such as an isoperillyl alcohol carbamate. The deuterium-enriched derivative may be perillyl alcohol or isoperillyl alcohol conjugated with a therapeutic agent such as a chemotherapeutic agent. 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 deuterium-enriched compound.

Description

Comprise the pharmaceutical composition that is rich in the perillalcohol of deuterium, different perillalcohol and derivative thereof
The cross reference of related application
The application requires U.S. Provisional Application the 61/562nd, No. 105 (submission on November 21st, 2011) and U. S. application the 13/566th, the right of priority of No. 731 (submissions on August 3rd, 2012), its all by reference entirety be incorporated to herein.
Invention field
The present invention relates to be rich in deuterium perillalcohol (POH), be rich in different perillalcohol (iso-POH) and the derivative thereof of deuterium.
Background of invention
Glioblastoma (Malignant gliomas) is modal central nervous system (CNS) cancer form, and it is considered to substantially cannot cure at present.In various glioblastomas, human anaplastic astrocytoma (anaplastic astrocytomas) (III level) and glioblastoma multiforme (glioblastoma multiforme) (GBM; IV level) there is poor especially prognosis, this is due to their invasive growths and the resistance at present available therapy.At present to the nursing standard of glioblastoma by performing the operation, ionizing rays and chemotherapy form.Although get along with recently, in past 50 years, aspect the prognosis of glioblastoma, there is not any significant improvement aspect medical.The .Malignant gliomas in adults such as Wen, new England J Med.,359:492-507,2008.Stupp etc., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, new England J Med.,352:987～996,2005.
Tumour including glioblastoma to the reaction of all kinds of chemotherapeutics not good be often due to interior resistance.In addition, playing the acquisition resistance of the tumour that initial action is good and less desirable side effect is the frequent other problem that obstructs the long-term treatment that uses chemotherapeutics.Perillalcohol (POH) is a kind of naturally occurring monoterpene, has shown that it is the beneficial agents of the kinds cancer of antagonism including CNS cancer, breast cancer (breast cancer), carcinoma of the pancreas, lung cancer, melanoma and colorectal carcinoma.Gould, M., Cancer chemoprevention and therapy by monoterpenes, environ.Health Perspect.,in June, 1997; 105 (Suppl4): 977-979.Prepare the hydridization molecule that contains perillalcohol and retinoid (retinoids) to increase apoptosis induction activity.Das etc., Design and synthesis of potential new apoptosis agents:hybrid compounds containing perillyl alcoholand new constrained retinoids, tetrahedron Letters2010,51,1462-1466.
But POH is by tachymetabolism.In order to improve the performance of perillalcohol and derivative thereof, for example use lower dosage, the perillalcohol that need to prepare deuterated form (comprises isomer or analogue, for example put together perillalcohol or the different perillalcohol of (conjugated) with other therapeutical agent), and treat cancer and other encephalopathic disease such as glioblastoma with this material, for example Parkinson's disease (Parkinson ' s disease) and Alzheimer (Alzheimer ' s disease).
General introduction
The invention provides the compound that is rich in deuterium or its pharmacy acceptable salt of formula I or formula II:
Wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16independently selected from hydrogen-1 and deuterium, and R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16in at least one be deuterium.
For example, the compound that is rich in deuterium can be one of following:
The invention provides the perillalcohol or the different perillalcohol that are rich in deuterium.
The compound that is rich in deuterium of the present invention can put together to form carbamate with therapeutical agent.The present invention also provides the perillalcohol carbamate or the different perillalcohol carbamate that are rich in deuterium.For example, perillalcohol or different perillalcohol and therapeutical agent put together to form carbamate.Therapeutical agent can be chemotherapeutics, includes but not limited to DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, enzyme inhibitors and receptor antagonist.For example, therapeutical agent can be dimethyl celecoxib (dimethyl celocoxib, DMC), Temozolomide (temozolomide, TMZ) or rolipram (rolipram).
In the compound that is rich in deuterium, the abundance of deuterium can be at least about 10%, at least about 20% or at least about 30%.
The present invention also provides the pharmaceutical composition that comprises the compound that is rich in deuterium of the present invention.Pharmaceutical composition can further comprise the chemotherapeutics that is selected from DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, enzyme inhibitors and receptor antagonist.For example, pharmaceutical composition can further comprise therapeutical agent, for example dimethyl celecoxib (DMC), Temozolomide (TMZ) and rolipram.
The present invention further provides the method for the treatment of mammiferous disease, it comprises to the perillalcohol that is rich in deuterium of administration treatment significant quantity, is rich in the different perillalcohol of deuterium, the step that is rich in the perillalcohol carbamate of deuterium and/or is rich in the different perillalcohol carbamate of deuterium.
The invention provides the method for the mammiferous disease for the treatment of, the method comprises to the step of disclosed pharmaceutical composition in administration the present invention.
The method may further include by this mammiferous step of radiotherapy and/or to the step of this administration chemotherapeutics.Before can and/or using chemotherapeutics in radiation, during or drug administration composition or be rich in the compound of deuterium afterwards.Chemotherapeutics can be DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, enzyme inhibitors or receptor antagonist.For example, chemotherapeutics can be dimethyl celecoxib (DMC), Temozolomide (TMZ) or rolipram.
Disease can be cancer, for example neural tumour (as, glioblastoma multiforme (glioblastoma)).
Can be by sucking, in nose, oral, intravenously, subcutaneous or intramuscular administration pharmaceutical composition or be rich in the compound of deuterium.
Can use such as the nasal delivery devices drug administration composition of sucker, nose inner sprayer unit, spraying gun (atomizer), atomizer (nebulizer), metered dose inhaler (MDI), pressurized doses sucker, insufflator, unit-dose container, pump, dropper, squeeze bottle and two-way device in nose or be rich in the compound of deuterium.
Detailed Description Of The Invention
The invention provides and be rich in the compound of deuterium and comprise this pharmaceutical composition that is rich in the compound of deuterium.Particularly, the invention provides be rich in the monoterpene of deuterium or sesquiterpene (as, be rich in the perillalcohol of deuterium) and be rich in the monoterpene of deuterium or the isomer of sesquiterpene or analogue (as, be rich in the different perillalcohol of deuterium).
The present invention also provides is rich in the monoterpene of deuterium or the derivative of sesquiterpene, for example, be rich in the perilla alcohol derivant of deuterium.For example, the perilla alcohol derivant that is rich in deuterium can be the perillalcohol carbamate that is rich in deuterium.Perilla alcohol derivant can be and the perillalcohol of puting together such as the therapeutical agent of chemotherapeutics.
The present invention further provides the derivative that is rich in the monoterpene of deuterium or the isomer of sesquiterpene or analogue, for example, be rich in the different perilla alcohol derivant of deuterium.For example, the different perilla alcohol derivant that is rich in deuterium can be the different perillalcohol carbamate that is rich in deuterium.Different perilla alcohol derivant can be and the different perillalcohol of puting together such as the therapeutical agent of chemotherapeutics.
The present invention is also contained and is comprised the compound (or its pharmacy acceptable salt) of deuterium and the pharmaceutical composition of pharmaceutically acceptable carrier of being rich in of the present invention for the treatment of significant quantity.
The invention provides and use the compound or the pharmaceutical composition that are rich in deuterium to treat the method such as the disease of cancer or other neurological conditions.Compound of the present invention or pharmaceutical composition can be used separately, or co-administered with radiation, operation or chemotherapeutics.The molecule that is rich in deuterium can also be used jointly with antiviral agent, anti-inflammatory agent or microbiotic.These medicaments can or be used successively simultaneously.Compound of the present invention can be before one or more other promoting agents be used, during or use afterwards.
Those of skill in the art will recognize that, in the compound of all H of having atoms, H atom all represents 1h (hydrogen-l, protium) and D (deuterium, hydrogen-2, 2h) mixture, wherein approximately 0.015% is D.Therefore the level that, is rich in the deuterium that the compound (or deuterated compound) of deuterium has is higher than its natural abundance 0.015%.Used hereinly be molecular fraction for the given all percentage ratios of the abundance of deuterium.
The isomer of monoterpene or sesquiterpene or analogue can be different perillalcohol (iso-POH).Different perillalcohol comprises any isomer or the analogue of perillalcohol.In one embodiment, different perillalcohol is (4-isopropylidene hexamethylene-1-thiazolinyl) methyl alcohol.Other example of different perillalcohol includes but not limited to (4-sec.-propyl hexamethylene-1,3-dialkylene) methyl alcohol, (4-sec.-propyl hexamethylene-Isosorbide-5-Nitrae-dialkylene) methyl alcohol, (4-isopropyl phenyl) methyl alcohol and (4-pseudoallyl phenyl) methyl alcohol.
The invention provides the different perillalcohol that is rich in deuterium, wherein this compound is rich in deuterium at least one position.In one embodiment, the different perillalcohol or its pharmacy acceptable salt that are rich in deuterium are represented by formula I shown below:
Wherein: R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16independently selected from hydrogen-1 ( 1and deuterium H); And R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16in at least one be deuterium.
The limiting examples of different perillalcohol that is rich in deuterium is as follows.
The different perillalcohol that is rich in deuterium can be prepared as follows: perillalcohol or the different perillalcohol of oxidation commercial source, subsequently by the intermediate of oxidation with being rich in the hydride reducer of deuterium or by using deuterium gas (deuterohydrogen gas) and suitable catalyzer or reducing by alternate manner.
The invention provides the perillalcohol that is rich in deuterium, wherein this compound is rich in deuterium at least one position.In one embodiment, the perillalcohol or its pharmacy acceptable salt that are rich in deuterium are represented by formula II shown below:
Wherein: R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16independently selected from hydrogen-1 ( 1and deuterium H); And R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16in at least one be deuterium.
The limiting examples of perillalcohol that is rich in deuterium is as follows.
For example, as (the R of the given position for describing molecule 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16) time term " being deuterium " or symbol " D " in the time being used for the representing molecular structure given position position that means to specify be rich in the deuterium higher than its natural abundance of 0.015%.
Term " abundance of deuterium " in this article refer to the given position of molecule introduce deuterium (D or 2h) molecular fraction of replacement hydrogen.For example, the abundance of the deuterium of given position is approximately 6% to mean in given sample approximately 6% molecule and contain deuterium in the position of specifying.
In the compound that is rich in deuterium of the present invention, the abundance of deuterium can be at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, approximately 0.5% to approximately 100%, approximately 1% to approximately 100%, approximately 5% to approximately 100%, approximately 6% to approximately 100%, approximately 7% to approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100% or approximately 90% to approximately 100%.
Can use the enrichment of measuring deuterium such as the analytical procedure of mass spectroscopy, nuclear magnetic resonance spectroscopy(NMR spectroscopy) and infrared spectroscopy.In one embodiment, pass through 1h NMR measures the enrichment of deuterium.
Can synthesize the perillalcohol that is rich in deuterium of the present invention, wherein introduce deuterated for hydrogen atom.The methanol side chain place that for example, metabolic degradation can occur in vivo introduces deuterated for hydrogen atom.Compared with the metabolic rate of conventional perillalcohol or different perillalcohol, D atom postpones or slows down metabolic process.Be not subject to the restriction of any specific physiological mechanism, it is believed that this slowing down is the kinetic isotope effect due to the avtive spot place of perillalcohol desaturase.Also can introduce deuterium in the multiple different centers in molecule.In one embodiment, introduce deuterium at methyl alcohol part place, wherein can introduce 1,2 or 3 D atom and replace hydrogen atom, to obtain any isotropic substance analogue of perillalcohol or different perillalcohol.
Due to its slower mechanism, significant improvement can demonstrated compared with the not deuterated material of the deuterated form of perillalcohol or different perillalcohol and routine aspect result for the treatment of.
The compound that is rich in deuterium as herein described can contain one or more D atoms.Compound can be partly or entirely deuterated.Any compound as herein described all can be rich in deuterium.
Monoterpene comprises the terpene being made up of two isoprene units.Monoterpene can be line style (acyclic) or contain ring.The derivative of monoterpenoid (monoterpenoids) is also contained in the present invention.Monoterpenoid can for example, produce by the biochemical modification of monoterpene (oxidation or rearrangement).The example of monoterpene and monoterpenoid comprises perillalcohol (S (-)) and (R (+)), ocimene, myrcene, Geraniol, citral, Geraniol, geranial, linalool, firpene, terpinol, terpinene (terpinen), limonene, terpinene class (terpinenes), phellandrene class, terpinolene, terpinen-4-ols (or tea tree oil), firpene, terpinol, terpinene; Terpenoid, for example cymene, it is derived from the monocyclic terpene such as menthol, thymol and isothymol; Two lopps monoterpenes, for example camphor, borneol and Terpane.
Monoterpene can by the structure of carbon skeleton distinguish and can be grouped into acyclic monoterpene (as, myrcene, (Z)-and (E)-ocimene, linalool, Geraniol, vernol, geraniol, myrcenol, geranic acid, citral a, neral, citral b, geranial etc.), monocyclic monoterpene (as, limonene, terpinene, phellandrene, terpinolene, menthol, carveol etc.), two ring monoterpenes (as, firpene, myrthenol, myrthenal, verbanol, verbanone (verbanon), pinocarveol, carene, sabinene, down alkene, thujene etc.) and three ring monoterpenes (as, tricyclene).Referring to encyclopedia? of Chemical Technology, the 4th edition, the 23rd volume, 834-835 page.
The specific examples of monoterpene is perillalcohol (POH).
Sesquiterpene of the present invention comprises the terpene being made up of three isoprene units.Sesquiterpene can be line style (acyclic) or contain ring.The derivative of type sesquiterpene (sesquiterpenoids) is also contained in the present invention.Type sesquiterpene can for example, produce by the biochemical modification of sesquiterpene (oxidation or rearrangement).The example of sesquiterpene comprises farnesol, farnesal, method acid and nerolidol.PCT application number PCT/US2011/027051 and PCT/US2011/049392.U. S. application number 13/040,059.All these apply for that all entirety is incorporated to herein by reference.
The present invention also provides is rich in the monoterpene of deuterium or the derivative of sesquiterpene, for example, be rich in the perilla alcohol derivant of deuterium.For example, the perilla alcohol derivant that is rich in deuterium can be the perillalcohol carbamate that is rich in deuterium.Perilla alcohol derivant can be and the perillalcohol of puting together such as the therapeutical agent of chemotherapeutics.
The present invention further provides the derivative that is rich in the monoterpene of deuterium or the isomer of sesquiterpene or analogue, for example, be rich in the different perilla alcohol derivant of deuterium.For example, the different perilla alcohol derivant that is rich in deuterium can be the different perillalcohol carbamate that is rich in deuterium.Perilla alcohol derivant can be and the different perillalcohol of puting together such as the therapeutical agent of chemotherapeutics.
Derivative can carry out at the atom site place of any expectation deuterated, comprises the atom site of perillalcohol or different perillalcohol and the atom site of the therapeutical agent puted together with perillalcohol or different perillalcohol.
The compound that is rich in deuterium can be by for example with the preparation of getting off: use deuterium exchange hydrogen, or synthesize this compound with the initial substance or the intermediate that are rich in deuterium.In one embodiment, can, by containing deuterium reagent, include but not limited to lithium deuteride LiD aluminium, deuterium gas or other reagent, introduce deuterium.In another embodiment, depend on the deuterated site of expectation, from D 2the deuterium of O can directly exchange and enter final medical compounds, or enters the reagent for the synthesis of drug molecule.
The deuterated derivative (or deuterated derivative of the isomer of monoterpene or sesquiterpene or analogue) of monoterpene or sesquiterpene includes but not limited to carbamate, ester, ether, the alcohols and aldehydes of monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue).The present invention also provides is rich in the perillalcohol of deuterium or the derivative of different perillalcohol and conjugate.
Derivative includes but not limited to the isomer of monoterpene or sesquiterpene (as, POH) or monoterpene or sesquiterpene or analogue carbamate, ester, ether, the alcohols and aldehydes of (as, iso-POH).Alcohol can be derivatized to carbamate, ester, ether, aldehyde or acid.
Carbamate refers to a compounds with the following functional group that based on both sides is the carbonyl of oxygen and nitrogen:
R 1, R 2and R 3can be the group such as alkyl, aryl etc., it can be substituted.R group on nitrogen and oxygen can form ring.R 1-OH can be monoterpene, as POH or iso-POH.R 2-N-R 3part can be therapeutical agent.
Carbamate can be by making isocyanic ester react with alcohol or make chloro-formic ester react and synthesize with amine.Carbamate can be by synthesizing with the reaction of phosgene or phosgene equivalent.For example, carbamate can be by making phosgene, trichloromethylchloroformate or reacting and synthesize such as the solid phosgene precursor of triphosgene and two kinds of amine or amine and alcohol.Carbamate (also referred to as urethane) also can by urea intermediate and alcohol react prepare.Methylcarbonate and diphenyl carbonate are also for the preparation of carbamate.For example, or prepared by the reacting of the diaryl carbonate (two (methyl salicyl) esters (bismethylsalicylcarbonate) of carbonic acid (BMSC)) that carbamate can replace with ester by alcohol and/or amine precursor.U.S. Patent Publication No. 20100113819.
Carbamate can come to synthesize by the following method:
Suitable reaction solvent includes but not limited to tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, acetone and diisopropyl ether.Reaction can be carried out at the temperature of approximately-70 DEG C to approximately 80 DEG C or approximately-65 DEG C to approximately 50 DEG C.Different perillyl chloro-formic ester (or perillyl chloro-formic ester) and substrate R-NH 2mol ratio can be about 1:1 to about 2:1, about 1:1 to about 1.5:1, about 2:1 to about 1:1 or about 1.05:1 to about 1.1:1.Suitable alkali includes but not limited to organic bases, for example triethylamine, salt of wormwood, N, N '-diisopropylethylamine, butyllithium and potassium tert.-butoxide.
Or carbamate can come to synthesize by the following method:
Suitable reaction solvent includes but not limited to methylene dichloride, ethylene dichloride, toluene, diisopropyl ether and tetrahydrofuran (THF).Reaction can be carried out at the temperature of approximately 25 DEG C to approximately 110 DEG C or approximately 30 DEG C to approximately 80 DEG C or approximately 50 DEG C.The mol ratio of different perillalcohol and substrate R-N=C=O can be that about 1:1 is to about 2:1, about 1:1 to about 1.5:1, about 2:1 to about 1:1 or extremely about 1.1:1 of about 1.05:1.
The ester of the isomer of the ester of monoterpene or sesquiterpenoid or monoterpene or sesquiterpene or the alcohol of analogue can be derived from mineral acid or organic acid.Mineral acid includes but not limited to phosphoric acid, sulfuric acid and nitric acid.Organic acid includes but not limited to carboxylic acid, for example phenylformic acid, lipid acid, acetic acid and propionic acid, and with any therapeutical agent of at least one carboxylic acid functional.The example of the ester of alcohol include but not limited to carboxylicesters (for example benzoic ether, fatty acid ester (as; cetylate, linoleate, stearate, butyryl radicals ester and oleic acid ester), acetic ester, propionic ester (propionate or propanoate) and manthanoate), phosphoric acid ester, sulfuric ester and carbamate (as; N, N-dimethylamino carbonyl).
The derivative of perillalcohol comprises perillalcohol carbamate, purple perilla alcohol ester, perillaldehyde, dihydro perillic acid, perillic acid, perillaldehyde derivative, dihydro purple perilla acid esters and purple perilla acid esters.The derivative of perillalcohol can also comprise the derivative of its oxidation and nucleophilic/electrophilic addition.U.S. Patent Publication No. 20090031455.U.S. Patent number 6,133,324 and 3,957,856.
The derivative of different perillalcohol comprises different perillalcohol carbamate, different purple perilla alcohol ester, different purple perilla alcohol ether, different perillaldehyde, different perillic acid, different perillaldehyde derivative and different purple perilla acid esters.The derivative of different perillalcohol can also comprise its oxidized derivatives and nucleophilic/electrophilic addition derivative.In chemical literature, only report the example of the derivative of few different perillalcohol.Referring to U.S. Patent number 5,994,598 and Japanese Patent No. 07048264A.
In certain embodiments, POH carbamate (or iso-POH carbamate) is synthetic by the method that comprises following steps: make the first reactant perillyl chloro-formic ester (or different perillyl chloro-formic ester) and the second reactant reaction such as dimethyl celecoxib (DMC), Temozolomide (TMZ) and rolipram.Reaction can be carried out under tetrahydrofuran (THF) and the existence such as the alkali of n-Butyl Lithium.Perillyl chloro-formic ester (or different perillyl chloro-formic ester) can be by preparing POH (or iso-POH) and phosgene reaction.For example, the POH (or iso-POH) puting together with Temozolomide by amino-formate bond can react and synthesize with perillalcohol (or iso-POH) by then Temozolomide is reacted with oxalyl chloride.Reaction can be carried out under the existence of 1,2-ethylene dichloride.
The POH carbamate that the present invention is contained includes but not limited to 4-(two-N, N'-4-pseudoallyl hexamethylene-l-thiazolinyl methyl oxygen base carbonyl [5-(2,5-3,5-dimethylphenyl)-3-trifluoromethyl pyrazol-1-yl] benzsulfamide, 4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-oxo-tetramethyleneimine-l-carboxylic acid 4-pseudoallyl hexamethylene-1-thiazolinyl methyl ester and (3-methyl 4-oxo-3,4-glyoxalidine also [5,1-d] [1,2,3,5] tetrazine-8-carbonyl) carboxylamine-4-pseudoallyl hexamethylene-1-thiazolinyl methyl ester.
The iso-POH carbamate that the present invention is contained includes but not limited to (3-methyl 4-oxo-3,4-glyoxalidine also [5,1-d] [1,2,3,5] tetrazine-8-carbonyl)-carboxylamine-4-isopropylidene hexamethylene-l-thiazolinyl methyl ester, 4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-oxo-tetramethyleneimine-l-carboxylic acid 4-isopropylidene hexamethylene-l-thiazolinyl methyl ester, 4-(two-N, N'-4-isopropylidene hexamethylene-l-thiazolinyl methyl oxygen base carbonyl [5-(2,5-3,5-dimethylphenyl)-3-trifluoromethyl pyrazol-1-yl] benzsulfamide.The details that generates the chemical reaction of these compounds is described in embodiment below.
In certain embodiments, perilla alcohol derivant can be perillalcohol fatty acid ester, the sub-oleoyl ester of the palmitoyl ester of for example POH and POH; Different perilla alcohol derivant can be different perillalcohol fatty acid ester, the sub-oleoyl ester of the palmitoyl ester of for example iso-POH and iso-POH.
Be rich in the perillalcohol of deuterium or different perillalcohol can also by the carbamate between deuterated different perillalcohol part and other treatment part or other chemical bonds and other treatment partly (for example carcinostatic agent (for example Temozolomide)) put together, compared with the ability of arbitrary part or these two parts self, it has clean treatment benefit.
Monoterpene (or sesquiterpene) derivative can be the monoterpene (or sesquiterpene) of puting together with therapeutical agent.Monoterpene (or sesquiterpene) conjugate that the present invention is contained is the molecule having via cytotoxic compounds and the covalently bound monoterpene of therapeutical agent (or sesquiterpene).
The isomer of monoterpene or sesquiterpene or the derivative of analogue can be the monoterpene puted together with therapeutical agent or isomer or the analogue of sesquiterpene.The conjugate that the present invention is contained can be to have via cytotoxic compounds and the covalently bound monoterpene of therapeutical agent or the isomer of sesquiterpene or the molecule of analogue.
Monoterpene or sesquiterpene in conjugate (or the isomer of monoterpene or sesquiterpene or analogue) can be 1:1,1:2,1:3,1:4,2:1,3:1,4:1 or any other suitable mol ratio with the mol ratio of therapeutical agent.Monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) and therapeutical agent can be covalently bound via amino-formate bond, ester bond, ehter bond or any other suitable chemical functional group.In the time that monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) and therapeutical agent are puted together via amino-formate bond, therapeutical agent can be with any medicament of at least one carboxylic acid functional or with any medicament of at least one amine functional group.In a specific examples, perillalcohol (or iso-POH) conjugate is via cytotoxic compounds and the covalently bound perillalcohol of chemotherapeutics (or iso-POH).
According to the present invention, can include but not limited to chemotherapeutics with the therapeutical agent that monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) are puted together, be used for the treatment of CNS illness and (include but not limited to primary degeneration neurological conditions, for example Alzheimer, Parkinson's disease, multiple sclerosis, attention deficit hyperactivity disorder (Attention-Deficit Hyperactivity Disorder) or ADHD, psychological disorders (psychological disorders), psychosis (psychosis) and dysthymia disorders (depression)) therapeutical agent, immunotherapeutic agent, angiogenesis inhibitor and hypotensive agent.The carcinostatic agent that can put together with monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) can have one or more following effects to cancer cells or experimenter: necrocytosis; Cell proliferation reduces; Cell number reduces; The inhibition of Growth of Cells; Apoptosis; Downright bad; Mitotic division disaster (mitotic catastrophe); Cell-cycle arrest; Cell size reduces; Cell fission reduces; Cell survival rate reduces; Cellular metabolism reduces; Cell injury or Cytotoxic mark; Cell injury or Cytotoxic indirect instruction, for example tumour atrophy; The improvement of experimenter's survival rate; Or the disappearance of the mark relevant to less desirable, undesired or abnormal cell proliferation.U.S. Patent Publication No. 20080275057.
Chemotherapeutics includes but not limited to DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, vinca alkaloids (vincalkaloids), taxanes (taxanes), ebormycine class (epothilones), enzyme inhibitors, receptor antagonist, tyrosine kinase inhibitor, boron radiosensitizer (as, Bortezomib (velcade)) and chemotherapy combined therapy.
The limiting examples of DNA alkylating agent is nitrogen mustards, for example endoxan (Cyclophosphamide) (ifosfamide (Ifosfamide), trofosfamide (Trofosfamide)), Chlorambucil (Chlorambucil) (melphalan (Melphalan), prednimustine (Prednimustine)), bendamustine (Bendamustine), Uramustine (Uramustine) and estramustine (Estramustine); Nitrosoureas, for example carmustine (Carmustine) (BCNU), lomustine (Lomustine) (semustine (Semustine)), fotemustine (Fotemustine), nimustine (Nimustine), ranomustine (Ranimustine) and streptozocin (Streptozocin); Alkyl sulfonates, for example busulfan (Busulfan) (Mannosulfan (Mannosulfan), Treosulfan (Treosulfan)); Aziridines, for example carboquone (Carboquone), triaziquone (Triaziquone), Tretamine (Triethylenemelamine); Hydrazine class (Procarbazine (Procarbazine)); Triazenes, for example Dacarbazine (Dacarbazine) and Temozolomide; Altretamine (Altretamine) and mitobronitol (Mitobronitol).
The limiting examples of topoisomerase I inhibitor comprises camptothecin derivative, comprise SN-38, APC, NPC, camptothecine (campothecin), Hycamtin (topotecan), exatecan mesylate (exatecan mesylate), 9-nitrocamptothecin, 9-aminocamptothecin, lurtotecan (lurtotecan), rubitecan (rubitecan), silatecan, gefitinib (gimatecan), Diflomotecan (diflomotecan), Exatecan (extatecan), BN-80927, DX-8951f and MAG-CPT, as Pommier Y. (2006) nat.Rev.Cancer6 (10): described in 789-802 and U.S. Patent Publication No. 200510250854, protoberberine alkaloid and derivative thereof, comprise berberrubine and coralyne, as Li etc. (2000) biochemistry39 (24): 7107-7116 and Gatto etc. (1996) cancer Res.15 (12): described in 2795-2800, luxuriant and rich with fragrance Lip river quinoline derivant, comprises benzo [i] phenanthridines, nitidine and fagaronine, as Makhey etc. (2003) bioorg.Med.Chem.11 (8): described in 1809-1820, Terbenzimidazole and derivative thereof, as Xu (1998) biochemistry37 (10): described in 3558-3566, and anthracycline derivative, comprise Dx (Doxorubicin), daunorubicin (Daunorubicin) and mitoxantrone (Mitoxantrone), as Foglesong etc. (1992) cancer Chemother.Pharmacol.30 (2): 123-] 25, Crow etc. (1994) j.Med.Chem.37 (19): 31913194, and Crespi etc. (1986) biochem.Biophys.Res.Commun.136 (2): described in 521-8.Topoisomerase II inhibitors includes but not limited to Etoposide (Etoposide) and teniposide (Teniposide).Topoisomerase I and II double inhibitor include but not limited to Saintopin and other four benzoquinones (Naphthecenedione), DACA and other acridine-4-carboxamide class (Acridine-4-Carboxamindes), intoplicine (Intoplicine) and other benzo pyrido indoles (Benzopyridoindoles), TAS-I03 and other 7H-indeno [2, 1-c] quinoline-7-ketone, pyrazoloacridine (Pyrazoloacridine), XR11576 and other phenonaphthazine class (Benzophenazines), XR5944 and other dimeric compounds, 7-oxo-7H-dibenzo [f, ij] iloquinoline derivative and 7-oxo-7H-benzo [e] miazines and anthryl-amino acid conjugate, as Denny and Baguley (2003) curr.Top. med.Chem.3 (3): described in 339-353.Some medicaments suppress topoisomerase II and have DNA to embed activity, such as but not limited to anthracycline (aclarubicin (Aclarubicin), daunorubicin, Dx, epirubicin (Epirubicin), idarubicin (Idarubicin), amrubicin (Amrubicin), pirarubicin (Pirarubicin), valrubicin (Valrubicin), zorubicin (Zorubicin)) and amerantrone class (mitoxantrone (Mitoxantrone) and a China fir fine jade (Pixantrone)).
The example of er stress inductor includes but not limited to dimethyl-celecoxib (DMC), viracept see nelfinaivr (nelfinavir), celecoxib and boron radiosensitizer (, Bortezomib (Velcade (Bortezomib))).
Compound based on platinum is the subclass of DNA alkylating agent.The limiting examples of this class medicament comprise cis-platinum (Cisplatin), S 254 (Nedaplatin), oxaliplatin (Oxaliplatin), four nitric acid three platinum (Triplatin tetranitrate), Satraplatin (Satraplatin), Aroplatin, lobaplatin (Lobaplatin) and JM-216 (referring to McKeage etc. (1997) j.Clin.Oncol.201:1232-1237, and in general, referring to CHEMOTHERAPY FOR GYNECOLOGICAL NEOPLASM, CURRENT THERAPY AND NOVEL APPROACHES, in Series Basic and Clinical Oncology, Angioli etc., write 2004).
" FOLFOX " is the abbreviation that is used for the treatment of a kind of conjoint therapy type of colorectal carcinoma.It comprises 5-FU, oxaliplatin and formyl tetrahydrofolic acid (leucovorin).Information about this treatment can obtain on the cancer.gov of the website of National Cancer Institute, and last visit is on January 16th, 2008.
" FOLFOX/BV " is the abbreviation that is used for the treatment of a kind of conjoint therapy type of colorectal carcinoma.This therapy comprises 5-FU, oxaliplatin, formyl tetrahydrofolic acid and Avastin (Bevacizumab).In addition, " XELOX/BV " is the another kind of conjoint therapy that is used for the treatment of colorectal carcinoma, and it comprises the prodrug of 5-FU and combining of oxaliplatin and Avastin that are called as capecitabine (Capecitabine) (xeloda (Xeloda)).Information about these treatments can obtain on the cancer.gov of the website of National Cancer Institute, or obtain from the website nccn.org of 23 comprehensive cancer networks of country (National Comprehensive Cancer Network), last visit is on May 27th, 2008.
The limiting examples of metabolic antagonist medicament comprises the medicament based on folic acid, be dihydrofolate reductase inhibitor, for example aminopterin (Aminopterin), methotrexate (Methotrexate) and pemetrexed (Pemetrexed); Thymidylate synthase inhibitor, for example Raltitrexed (Raltitrexed), pemetrexed; Based on the medicament of purine, it is adenosine deaminase inhibitors, for example pentostatin (Pentostatin), sulphur purine, for example Tioguanine (Thioguanine) and mercaptopurine (Mercaptopurine), halogenation/ribonucleotide reductase inhibitors, for example CldAdo (Cladribine), Clofarex (Clofarabine), fludarabine (Fludarabine), or guanine/guanosine: sulphur purine, for example Tioguanine; Or medicament based on pyrimidine, i.e. cytosine(Cyt)/cytidine; Hypomethylation agent (hypomethylating agent), for example azacitidine (Azacitidine) and Decitabine (Decitabine), archaeal dna polymerase inhibitor, for example cytosine arabinoside (Cytarabine), ribonucleotide reductase inhibitors, for example gemcitabine (Gemcitabine), or thymus pyrimidine/thymidine: thymidylate synthase inhibitor, as Fluracil (Fluorouracil) (5-FU).The equivalent of 5-FU comprises its prodrug, analogue and derivative, for example 5'-'-Deoxy-5-fluorouridine (doxifluridine (doxifluroidine)), 1-tetrahydrofuran base-5 FU 5 fluorouracil (fluorofur (ftorafur)), capecitabine (xeloda), S-I (MBMS-247616, by Tegafur (tegafur) and two kinds of conditioning agent 5-chloro-2, 4-dihydroxy-pyridine and Oteracil Potassium composition), Reltitrexed (Tomudex (tomudex)), nolatrexed (nolatrexed) (Thymitaq, AG337), LY231514 and ZD9331, described in for example Papamicheal (1999) The Oncologist4:478-487.
The example of vinca alkaloids includes but not limited to vinealeucoblastine(VLB) (Vinblastine), vincristine(VCR) (Vincristine), Vinflunine (Vinflunine), vindesine (Vindesine) and vinorelbine (Vinorelbine).
The example of taxanes includes but not limited to docetaxel (docetaxel), La Luotasai (Larotaxel), Ao Tasai (Ortataxel), taxol (Paclitaxel) and replaces Si Tasai (Tesetaxel).An example of ebormycine is ipsapirone (iabepilone).
The example of enzyme inhibitors includes but not limited to farnesyl tranfering enzyme inhibitor (for pyrrole method Buddhist nun (Tipifarnib)); CDK inhibitor (Alvocidib, Seliciclib); Proteasome inhibitor (Velcade), phosphodiesterase inhibitor (anagrelide (Anagrelide), rolipram); IMP dehydrogenase inhibitor (tiazofurine (Tiazofurine)); And lipoxidase inhibitor (masoprocol (Masoprocol)).The example of receptor antagonist includes but not limited to ERA (atrasentan (Atrasentan)); Retinoid X receptor (bexarotene (Bexarotene)); And sex steroid (testolactone (Testolactone)).
The example of tyrosine kinase inhibitor includes but not limited to the inhibitor (Tarceva (Erlotinib), Gefitinib (Gefitinib), lapatinibditosylate (Lapatinib), ZD6474 (Vandetanib), Sutent (Sunitinib), HKI-272 (Neratinib)) of ErbB:HER1/EGFR; The inhibitor (lapatinibditosylate, HKI-272) of HER2/neu; The inhibitor (Axitinib (Axitinib), Sutent, Xarelto (Sorafenib)) of III class RTK:C-kit, the inhibitor (lestaurtinib (Lestaurtinib)) of FLT3, the inhibitor (Axitinib, Sutent, Xarelto) of PDGFR; Inhibitor (ZD6474, SU5416 (Semaxanib), AZD2171 (Cediranib), Axitinib, Xarelto) with VEGFR; The inhibitor (imatinib, nilotinib (Nilotinib), Dasatinib (Dasatinib)) of bcr-abl; The inhibitor (bosutinib (Bosutinib)) of Src and the inhibitor (lestaurtinib (Lestaurtinib)) of Janus kinases 2.
" lapatinibditosylate " eGFR and erbB-2 double inhibitor.In many clinical trials, lapatinibditosylate is combined and studied as anticancer monotherapy and with Herceptin (trastuzumab), capecitabine, letrozole (letrozole), taxol and FOLFIRI (irinotecan (irinotecan), 5 FU 5 fluorouracil and formyl tetrahydrofolic acid).At present just the oral administration of transitivity breast cancer, head and neck cancer, lung cancer, cancer of the stomach, kidney and bladder cancer is carried out to III phase test.
The chemical equivalent of lapatinibditosylate is small molecules or the compound for tyrosine kinase inhibitor (TKI) or HER-1 inhibitor or HER-2 inhibitor.Have been found that several TKI have effective antitumour active and be given the ratification or in clinical trial.Such example include but not limited to ZD6474 (Zactima) (ZD6474), Iressa (Iressa) (Gefitinib), Gleevec (STI571; Imatinib mesylate (Gleevec)), erlotinib (erlotinib) (OSI-1774; Erlotinib (Tarceva)), card how for Buddhist nun (canertinib) (CI1033), SU5416 (SU5416), PTK787 (vatalanib) (PTK787/ZK222584), Xarelto (BAY43-9006), SU11248 (sutent) (SUI1248) and leflunomide (lefltmomide) (SU101).
PTK/ZK is the extensive specific tyrosine kinase inhibitor that has of all vegf receptors of target (VEGFR), platelet-derived growth factor (PDGF) acceptor, c-KIT and c-Fms.Drevs(2003)Idrugs6(8):787-794。PTK/ZK is the targeted drug of blocking vasculogenesis and lymphatic vessel generation by inhibition in conjunction with the activity of all known receptor of VEGF, and described acceptor comprises VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4).The chemical name of PTK/ZK is 1-[4-chlorobenzene amino]-4-[4-pyridylmethyl] phthalazines succinate or 1-phthalazines amine, N-(4-chloro-phenyl-)-4-(4-pyridylmethyl)-succinate (butanedioate) are (1:1).The different name of PTK/TK and analogue are called as PTK787, CGP79787D, PTK787/ZK222584, CGP-79787, DE-00268, PTK-787, PTK787A, VEGFR-TK inhibitor, ZK222584 and ZK.
Can can also comprise amsacrine (amsacrine) with the chemotherapeutics that monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) are puted together, ET-743 (Trabectedin), retinoid (alitretinoin (Alitretinoin), vitamin A acid (Tretinoin)), white arsenic, l-asparagine depleting agents asparaginase/pegaspargase), celecoxib, Omaine (Demecolcine), department of Erie is (Elesclomol) not, elsamitrucin (Elsamitrucin), Etoglucid (Etoglucid), lonidamine (Lonidamine), lucanthone (Lucanthone), mitoguazone (Mitoguazone), mitotane (Mitotane), Ao Limeisheng (Oblimersen), temsirolimus (Temsirolimus) and Vorinostat (Vorinostat).
Monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) can be puted together with angiogenesis inhibitor.The example of angiogenesis inhibitor includes but not limited to vasculogenesis chalone (angiostatin), blood vessel enzyme (angiozyme), Antithrombin III, AG3340, VEGF inhibitor, Batimastat (batimastat), Avastin (Zarator (avastin)), BMS-275291, CAI, 2C3, HuMV833 canstatin (Canstatin), captopril (Captopril), CAI (carboxyamidotriazole), cartilage derived inhibitor (CDI), CC-5013, 6-O-(chloracetyl-carbonyl)-fumagine alcohol, COL-3, combretastatin (combretastatin), combretastatin A4 phosphoric acid ester (combretastatin A4Phosphate), DALT (Dalteparin), EMD121974 (cilengitide (Cilengitide)), Endostatin (endostatin), erlotinib, Gefitinib (Iressa), genistein (genistein), halofuginone hydrobromide (halofuginone hydrobromide), Id1, Id3, IM862, Gleevec, MC-IC11 inducible protein 10, interferon-' alpha ', interleukin 12, smoked lavendustin A (lavendustin A), LY317615 or Α Ε-941, Marimastat (marimastat), mspin, the light progesterone of acetic acid first (medroxpregesterone acetate), Meth-l, Meth-2, 2-methoxyestradiol (2-methoxyestradiol) (2-ME), Neovastat (neovastat), osteopontin split product (oteopontin cleaved product), PEX, pigment epithelium somatomedin (pigment epithelium growth factor, PEGF), platelet factor 4, prolactin fragment, proliferin associated protein (proliferin-related protein) (PRP), PTK787/ZK222584, ZD6474, the recombination human platelet factor 4 (rPF4), restin (restin), squalamine (squalamine), SU5416, SU6668, SU11248 suramin (suramin), PTX (Taxol), for Kang Lan (Tecogalan), Thalidomide (thalidomide), thrombostondin (thrombospondin), TNP-470, troponin-1, angiostatin (vasostatin), VEG1, VEGF-Trap and ZD6474.
The limiting examples of angiogenesis inhibitor also comprises tyrosine kinase inhibitor, the inhibitor of for example tyrosine kinase receptor Flt-1 (VEGFRl) and Flk-1/KDR (VEGFR2), the inhibitor of epidermis source property somatomedin, the inhibitor of inoblast source property somatomedin or the inhibitor of platelet-derived growth factor, MMP (matrix metalloproteinase) inhibitor, integrin blocker, xylan polysulfate, angiotensin-ii antagonist, cyclooxygenase inhibitors (comprises for example acetylsalicylic acid of NSAID (non-steroidal anti-inflammatory drug) (NSAID) (aspirin) and Ibuprofen BP/EP (ibuprofen), and for example celecoxib of selective cyclooxygenase-2 inhibitor and rofecoxib (rofecoxib)), and steroid anti-inflammatory agent (for example cortical steroid (corticosteroids), Mineralocorticoid (mineralocorticoids), dexamethasone (dexamethasone), prednisone (prednisone), prednisolone (prednisolone), methylprednisolone (methylpred), Betamethasone Valerate (betamethasone)).
Other therapeutical agent of adjusting or inhibition vasculogenesis comprises the medicament of adjusting or anticoagulant and fibrinolytic system, it includes but not limited to, heparin, low molecular weight heparin and Carboxypeptidase U inhibitor (also referred to as the inhibitor of active enzyme thrombin activation fiber protein dissolution inhibitor [TAFIa]).U.S. Patent Publication No. 20090328239.U.S. Patent number 7,638,549.
The limiting examples of hypotensive agent comprises that angiotensin-convertion enzyme inhibitor is (as, captopril, enalapril (enalapril), delapril (delapril) etc.), angiotensin-ii antagonist (for example candesartan cilexetil (candesartan cilexetil), Candesartan (candesartan), losartan (losartan) (or losartan (Cozaar)), Losartan Potassium (losartan potassium), Eprosartan (eprosartan), valsartan (valsartan) (or Valsartan (Diovan)), telmisartan (termisartan), irbesartan (irbesartan), Tasosartan (tasosartan), Olmesartan (olmesartan), olmesartan medoxomill (olmesartan medoxomil) etc.), calcium antagonist (as, Manidipine (manidipine), NIFEDIPINE (nifedipine), amlodipine (amlodipine) (or Amlodin), efonidipine (efonidipine), nicardipine (nicardipine) etc.), diuretic(s), renin inhibitor (as, aliskiren (aliskiren) etc.), aldosterone antagonists (as, spironolactone (spironolactone), eplerenone (eplerenone) etc.), beta blocker (for example metoprolol (metoprolol) (or Topotol), atenolol USP 23 (atenolol), Proprasylyte (propranolol), carvedilol (carvedilol), pindolol (pindolol) etc.), vasodilator (for example nitrate, soluble guanylate cyclase stimulant or activator, prostacyclin (prostacycline) etc.), Angiotensin vaccine, clonidine (clonidine) etc.U.S. Patent Publication No. 20100113780.Can include but not limited to Sertraline (Sertraline) (Zoloft (Zoloft)) with other therapeutical agent that monoterpene or sesquiterpene (or the isomer of monoterpene or sesquiterpene or analogue) are puted together, topiramate (Topiramate) (appropriate Thailand (Topamax)), duloxetine (Duloxetine) (glad hundred reach (Cymbalta)), sumatriptan (Sumatriptan) (Imitrex), lyrica (Pregabalin) (Li Ruika (Lyrica)), lamotrigine (Lamotrigine) (Lamictal (Lamictal)), valacyclovir (Valaciclovir) (Wei Desi (Valtrex)), tamsulosin (Tamsulosin) (Flomax), zidovudine (Zidovudine) (Combivir (Combivir)), lamivudine (Lamivudine) (Combivir (Combivir)), efavirenz (Efavirenz) (Sustiva), Abacavir (Abacavir) (Epzicom), rltonavir (Lopinavir) (gram force sesame (Kaletra)), pioglitazone (Pioglitazone) (Ai Ketuo (Actos)), Desloratadine (Desloratidine) (Clarinex), cetirizine (Cetirizine) (Zirtek (Zyrtec)), pantoprazole (Pentoprazole) (Protonix), lansoprazole (Lansoprazole) (Prevacid), rabeprazole (Rebeprazole) (Aciphex), Moxifloxacin (Moxifloxacin) (visiing multiple pleasure (Avelox)), meloxicam (Meloxicam) (Mobic (Mobic)), dorzolamide (Dorzolamide) (Truspot), diclofenac (Diclofenac) (diclofenac (Voltaren)), enalapril (Vasotec), Singulair (Montelukast) (Singulair (Singulair)), Virga (Sildenafil) (viagra (Viagra)), carvedilol (Carvedilol) (Coreg), Ramipril (Ramipril) (Delix) and L-DOPA.
The compound that is rich in deuterium of the present invention and at least one mixture and/or common preparation of therapeutical agent as discussed above also contained in the present invention.
The purity of compound of the present invention can be analyzed by vapor-phase chromatography (GC) or high pressure lipuid chromatography (HPLC) (HPLC).Other technology that is used for the existence of purity assay and definite impurity includes but not limited to mass spectroscopy (MS), GC-MS, infrared spectroscopy (IR), nucleus magnetic resonance (NMR) spectral method and tlc (TLC).Chiral purity can be assessed by the measurement of chirality GC or specific rotation.
Compound of the present invention can carry out purifying by the method such as crystallization, or for example, according to the physicochemical property of compound uniqueness (solvability or polarity) compound is separated purifying with impurity.Therefore, compound of the present invention can separate by suitable isolation technique well known in the prior art for example preparative chromatography, (classification) distillation method or (classification) crystallization process.
Compounds and methods for of the present invention can be for suppressing Ras albumen.Ras family is the protein family of Small GTPases (GTPases) related in cell signalling.The activation of Ras signal conduction causes Growth of Cells, differentiation and survival.The sudden change of ras gene can permanently activate it, even and do not have extracellular signal, also can cause unsuitable conduction at cell interior.Because these signals cause Growth of Cells and division, abnormal Ras signal conduction finally can cause tumour to generate and cancer.In neutralizing up to 90% specific tumors type, all human tumors of 20-25% find the activation sudden change of Ras.Goodsell DS (1999) .Downward J., " The molecular perspective:the ras oncogene ". oncologist4 (3): 263-4. (in January, 2003).“Targeting?RAS?signaling?pathways?in?cancer?therapy”· Nat.Rev.Cancer3(1):11-22。Ras family member includes but not limited to HRAS; KRAS; NRAS; DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; And RRAS.Wennerberg K, Rossman KL, Der CJ (in March, 2005). " The Ras superfamily at a glance ". j.Cell.Sci.118 (Pt5): 843-6.
The compound that is rich in deuterium of the present invention can be formulated into pharmaceutical composition.Being rich in the amount that the compound of deuterium exists in pharmaceutical composition can be for approximately 0.01% (w/w) be to approximately 100% (w/w), approximately 0.1% (w/w) is to approximately 80% (w/w), approximately 1% (w/w) is to approximately 70% (w/w), approximately 10% (w/w) is to approximately 60% (w/w), or approximately 0.1% (w/w) is to approximately 20% (w/w).
Compound of the present invention or pharmaceutical composition can be used by any approach known in the art, include but not limited to suck, nose is interior, oral, for example, through skin, in eye, intraperitoneal, suction, intravenously, ICV, intracisternal injection or infusion, subcutaneous, implantation, vagina, hypogloeeis, urethra (urethral suppositories), subcutaneous, intramuscular, intravenously, rectum, hypogloeeis, mucous membrane, intraocular, spinal cord, sheath, under intraarticular, intra-arterial, arachnoid membrane, (sub-arachinoid), segmental bronchus and lymphatic vessel are used.In nose preparation can sprays or drops form send; Sucking preparation can utilize atomizer or allied equipment to use; Topical formulations can be the forms such as gelifying agent, ointment, ointment, aerosol; Percutaneous preparation can be used by transdermal patch or iontophoresis (iontorphoresis).Composition can also adopt tablet, pill, capsule, semi-solid preparation, pulvis, sustained release preparation, solution, suspensoid, elixir, aerosol, or the form of any other suitable composition.
In order to prepare this pharmaceutical composition, can be according to conventional medicine compounding process, by one or more compounds of the present invention and pharmaceutically acceptable carrier, adjuvant and/or mixed with excipients.The pharmaceutically acceptable carrier can be used in composition of the present invention comprises any standard pharmaceutical carrier, and for example phosphate buffered salt solution, water and emulsion are as oil/water or water/fat liquor, and various types of wetting agent.Composition can contain solid pharmaceutical excipients, such as starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, glyceryl monostearate, sodium-chlor, skimmed milk powder etc. in addition.Liquid and semisolid excipient can be selected from glycerine, propylene glycol, water, ethanol and various oil, and described oil comprises those oil in oil, animal, plant or synthetic source, as peanut oil, soya-bean oil, mineral oil, sesame wet goods.Liquid vehicle, particularly injection liquid liquid vehicle, comprise water, salt solution, G/W and glycols.For the example of carrier, stablizer and adjuvant, referring to remington's Pharmaceutical Sciences, E.W.Martin writes (Mack Publishing Company, 18th ed., 1990).Composition can also comprise stablizer and sanitas.
The present invention also provides the method for the treatment of disease, it comprises to the compound that is rich in deuterium of patient's administering therapeutic significant quantity, as be rich in deuterium perillalcohol, be rich in deuterium different perillalcohol, be rich in the perillalcohol carbamate of deuterium or be rich in the step of the different perillalcohol carbamate of deuterium.
Term used herein " treatment significant quantity " is the amount that is enough to treat particular condition or disease, or is enough to the amount of the pharmacology response that obtains treatment illness or disease.The method of determining the most effective method of application and application dosage can change along with the experimenter in target cell and treatment in the object of the composition being used for the treatment of, treatment, treatment.Conventionally can adjust (titrate) therapeutic dose to optimize security and effect.Single or multiple is used dosage level and the mode that can select according to treatment doctor and is carried out.Those skilled in the art can easily determine suitable dosage particles and use the method for medicament.For example, composition is used to about 200mg/kg, about 0.1mg/kg to about 100mg/kg or about 0.5mg/kg to about 50mg/kg with about 0.01mg/kg.In the time that compound as herein described and another medicament or therapy are used jointly, significant quantity when significant quantity can be less than this reagent and uses separately.
Percutaneous preparation can for example, by being incorporated into promoting agent thixotropy or gel carrier (cellulose media, as methylcellulose gum or Natvosol) in, then the preparation of gained is put into be suitable for being fixed in skin with the transcutaneous device of wearer's skin contact in prepare.If composition is gel form, composition can be coated in to patient's for example shoulder of top layer or the skin of upper arm and/or upper torso, preferably on complete, clean and dry skin, and keep thereon one period that is enough to compound of the present invention to be delivered to patient's serum.The present composition of gel form can be included in pipe, anther sac or volume pump.This pipe or anther sac can contain a dose unit or exceed the composition of a dose unit.Volume pump can distribute the composition of a dosing.
The present invention also provides the above-mentioned composition for intranasal administration.So, composition can further comprise penetration enhancer.Southall etc. developments in Nasal Drug Delivery,2000.Compound of the present invention can be used as aerosol, with liquid form as solution, emulsion, suspension, drops, or with solid form as powder, gel or ointment intranasal administration.
The device of sending medicine in nose is as known in the art.Can use device carry out nasal cavity medicine and send, described device includes but not limited to sucker, nose inner sprayer unit, spraying gun, nasal spray bottle, unit-dose container, pump, dropper, squeeze bottle, atomizer, metered dose inhaler (MDI), pressurized doses sucker, insufflator and two-way device in nose.Can measure with the amount to the accurate effective dose of nasal administration nasal delivery devices.Nasal delivery devices can be used for that single unit sends or repeatedly unit send.In concrete example, can be used in the present invention from the ViaNase Electronic Atomizer of Kurve Technology (Bethell, Washington).Compound of the present invention can also or be sent by infusion under mucous membrane by pipe, conduit, syringe, packaging tail (packtail), swab, nasal obstruction.U.S. Patent Publication No. 20090326275,20090291894,20090281522 and 20090317377.
Compound of the present invention can use standard method to be mixed with aerosol.This compound can be prepared or not prepare together with solvent together with solvent, and prepares together with carrier or do not prepare together with carrier.Preparation can be solution, can be maybe the aqueous emulsion that contains one or more tensio-active agents.For example, can produce aerosol spray by containing for example pressurizing vessel of Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, hydro carbons, pressurized air, nitrogen, carbonic acid gas or other applicable gas of suitable propelling agent.Can be by providing valve to determine that dose unit is to send metered amount.Pump spray dispenser can distribution and computation dosage or is had the dosage of specific particle or drop size.Term used herein " aerosol " refers to the suspension that tiny solid particle in gas or liquor are dripped.Specifically, aerosol comprises that the gas of the drop of monoterpene (or sesquiterpene) carries suspension, and it can produce in as MD1, atomizer or atomizing sprayer at any applicable device.Aerosol also comprises the dry powder composite that is suspended in the present composition in air or other carrier gas.Gonda(1990) Critical? Reviews?in?Therapeutic?Drug?Carrier?Systems6:273-313。Raeburn etc., (1992) pharmacol.Toxicol.Methods27:143-159.
Compound of the present invention can be used as for example liquid aersol of aerosol or aerosol is delivered to nasal cavity.Compound of the present invention can be used as powder and is delivered to nasal cavity with the microsphere form of for example sending by nasal cavity insufflator.Compound of the present invention can be adsorbed to solid surface for example on carrier.This powder or microsphere can be used with (air-dispensable) form that be dried, can air dispersion.This powder or microsphere can be stored in the container of insufflator.Or this powder or microsphere can be loaded into capsule for example in gelatine capsule, or other is suitable in the single dose units of nasal administration.
Pharmaceutical composition can be by being for example directly placed on described composition and being delivered to nasal cavity in nasal cavity with the form of gel, emulsifiable paste, nasal cavity emulsion, lotion, ointment, nasal obstruction, dropper or bioadhesion bar.In certain embodiments, for example, in order to strengthen absorption, expect the residence time of prolong drug composition in nasal cavity.Therefore, pharmaceutical composition can be optionally and bioadhesive polymer, natural gum (as xanthan gum), chitosan (as highly purified cationic polysaccharide), pectin (or as gel maybe any carbohydrate of emulsification in the time being applied to nasal mucosa of multiviscosisty), microsphere (as starch, albumin, glucosan, cyclodextrin), gelatin, liposome, carbomer (carbamer), polyvinyl alcohol, alginate, gum arabic, chitosan and/or Mierocrystalline cellulose (for example methyl or propyl group; Hydroxyl or carboxyl; Carboxymethyl or hydroxypropyl) preparation together.
The composition that contains the compounds of this invention can be sucked and is applied in respiratory tract (, lung) by oral cavity.
Comprise nebulizer, Diskus (DPI) and metered dose inhaler (MDI) for the exemplary delivery system that can suck medicament.
Sprayer device produces high-speed air flow, and it makes the therapeutical agent of liquid form with the form ejection of mist.Therapeutical agent is formulated into liquid form, for example solution or have the suspension of the particle of suitable dimension.In one embodiment, particle is micronized.Term " micronization " be defined as have approximately 90% or more diameter be less than the particle of approximately 10 μ m.Applicable sprayer device is commercial providing, and for example, is provided by PARI GmbH (Starnberg, Germany).Other sprayer device comprises Respimat (Boehringer Ingelheim) and those disclosed in for example U.S. Patent number 7,568,480 and 6,123,068 and WO97/12687.Compound of the present invention can be mixed with the aqueous solution or liquid suspension in sprayer device.
DPI device is conventionally with the agent of free-pouring powder type administering therapeutic, and described powder can be dispersed in patient's air-flow patient intake period.The DPI device of use extra power also can be for the present invention.In order to obtain free-pouring powder, compound of the present invention can with for example, together with applicable vehicle (lactose) preparation.For example, can be by being that the dry lactose of approximately 1 μ m to 100 μ m mixes and is dry mixed with the micronized particle of the compounds of this invention and makes dry powder formulations by particle diameter.Or compound can not prepared together with vehicle.Preparation is packed in dry powder dispenser, or pack in the suction box or capsule using together with dry powder delivery apparatus.The example of the commercial DPI device providing comprise Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (referring to, for example U.S. Patent number 5,035,237); Diskus (GlaxoSmithKline) (referring to, for example U.S. Patent number 6,378,519); Turbuhaler (AstraZeneca, Wilmington, Del.) (referring to, for example U.S. Patent number 4,524,769) and Rotahaler (GlaxoSmithKline) (referring to, for example U.S. Patent number 4,353,365).The further example of applicable DPI device is described in U.S. Patent number 5,415,162,5,239,993 and 5,715,810 and reference wherein in.
MDI device utilizes the propellant gas of compression to discharge the composition of the storage of the amount of recording conventionally.The preparation of using for MDI comprises solution or the suspension of activeconstituents at liquefied propellant.The example of propelling agent comprises for example HFA 134a of hydro fluoroalkanes (HFA) (HFA134a) and the fluoro-n-propane of 1,1,1,2,3,3,3-seven (HFA227), and such as CCl of chlorofluorocarbon 3f.Other component of the HFA preparation of using for MDI comprises cosolvent, for example ethanol, pentane, water; And tensio-active agent, as anhydrosorbitol trioleate, oleic acid, Yelkin TTS and glycerine.(referring to, for example U.S. Patent number 5,225,183, EP0717987 and WO92/22286).Preparation is packed in aerosol canister, and described aerosol canister forms a part for MDI device.U.S. Patent number 6,006, provides the example for use specifically developed MDI device together with HFA propelling agent in 745 and 6,143,227.For preparing the example that is applicable to the method for preparation and is suitable for the device of inhalation, referring to U.S. Patent number 6,268,533,5,983,956,5,874,063 and 6,221,398, and WO99/53901, WO00/61108, WO99/55319 and WO00/30614.
In order to send by inhalation, compound of the present invention or pharmaceutical composition can be encapsulated in liposome or microcapsule.The vesica that liposome is made up of bilayer lipid membrane and aqueous interior.Lipid film can be made up of phosphatide, and the example of phosphatide comprises phosphatidylcholine, for example Yelkin TTS and lysolecithin; Acidic phospholipid, for example phosphatidylserine and phosphatidyl glycerol; And sphingophospholipid, for example phosphatidylethanolamine and sphingomyelin.Or, can add cholesterol.Microcapsule are the particles that are surrounded by coated material.For example, coated material can be by film-forming polymer, hydrophobicity fluidizer, tensio-active agent or/and the compositions of mixtures of lubricant polymer with nitrogen.U.S. Patent number 6,313,176 and 7,563,768.
Compound of the present invention or pharmaceutical composition also can use separately or combine with other chemotherapeutics to use and be used for the treatment of localized cancer by topical application, for example breast cancer or melanoma.Compound of the present invention also can be combined the dermal delivery for pain medication with narcotic or anodyne.
The present invention is also provided for above-claimed cpd or the composition of ocular administration.So, composition can further comprise penetration enhancer.For ocular administration, composition as herein described can be mixed with solution, emulsion, suspension etc.It is various that to be applicable to compound administration be as known in the art in the carrier of eyes.Concrete limiting examples is described in U.S. Patent number 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; In 4,882150 and 4,738,851.
Compound of the present invention or pharmaceutical composition can give separately or combine the short or longer time that gives with the other medicines that are used for the treatment of above-mentioned disease.Compound of the present invention or composition can be applied to Mammals, preferably the mankind.Mammals includes but not limited to murine, rat, rabbit, monkey, bovid, sheep, pig, Canis animals, feline, farming animals, motion use animal (sport animals), pet, equine species and primate.
Compound of the present invention or composition can be used separately, or can jointly use with radiation or other medicament (as chemotherapeutics), to treat the disease such as cancer.Treatment can be in-order, and wherein compound of the present invention or composition were used before or after the using of other medicament.For example, be rich in deuterium perillalcohol (or different perillalcohol) can for make cancer patients to radiation or chemosensitivity.Or medicament can be used simultaneously.
The compound that is rich in deuterium of the present invention can be combined use with radiotherapy.In one embodiment, the invention provides and adopt radiation to process for example method of glioblastoma cell of tumour cell, wherein for example, process cell with the compound (be rich in the perillalcohol of deuterium or be rich in the different perillalcohol of deuterium) that significant quantity of the present invention is rich in deuterium, be then exposed to radiation.With compound treatment of the present invention can radiation before, during and/or after.For example, start continuous administration the last week that compound of the present invention can start in radiotherapy, and after radiotherapy completes, continue two weeks.U.S. Patent number 5,587,402 and 5,602,184.
In one embodiment, the invention provides and adopt chemotherapeutics to process for example method of glioblastoma cell of tumour cell, wherein for example, process cell with the compound (be rich in the perillalcohol of deuterium or be rich in the different perillalcohol of deuterium) that significant quantity of the present invention is rich in deuterium, be then exposed to chemotherapeutics.With compound treatment of the present invention can be before, during and/or after chemotherapy.
Compound of the present invention or pharmaceutical composition can be used for treating nervous system cancer, for example glioblastoma (for example astrocytoma, human anaplastic astrocytoma, polymorphism collagen blastoma), retinoblastoma (retinoblastoma), pilocytic astrocytoma (pilocytic astrocytomas) (I phase), meningioma (meningiomas), metastatic brain tumor (metastatic brain tumors), neuroblastoma (neuroblastoma), pituitary adenoma (pituitary adenomas), skull base meningiomas and basis cranii cancer.
The cancer of available compound of the present invention or medicine composite for curing includes but not limited to lung cancer, ear, nose and laryngocarcinoma, leukemia (leukemia), colorectal carcinoma, melanoma, carcinoma of the pancreas, mammary cancer (mammary cancer), prostate cancer, breast cancer, hematopoietic system cancer, ovarian cancer, rodent cancer, cancer of bile ducts; Bladder cancer; Osteocarcinoma; Breast cancer; Cervical cancer; Choriocarcinoma; Coton and rectal cancer; Reticular tissue cancer; The cancer of Digestive tract; Carcinoma of endometrium; The esophageal carcinoma; Cancer eye; Head and neck cancer; Cancer of the stomach; Intraepithelial neoplasia (intra-epithelial neoplasm); Kidney; Laryngocarcinoma; Leukemia, comprises acute myelogenous leukemia (acute myeloid leukemia), acute lymphoblastic leukemia (acute lymphoid leukemia), chronic lymphocytic leukemia (chronic myeloid leukemia), lymphocytic leukemia (chronic lymphoid leukemia); Liver cancer; Lymphoma, comprises hodgkin's (Hodgkin's) and non-Hodgkin′s lymphomas (Non-Hodgkin's lymphoma); Myelomatosis; Fibroma, neuroblastoma; Oral cavity (for example lip, tongue, mouth and pharynx) cancer; Ovarian cancer; Carcinoma of the pancreas; Prostate cancer; Retinoblastoma; Rhabdosarcoma (rhabdomyosarcoma); The rectum cancer; Kidney; The cancer of respiratory system; Sarcoma (sarcoma); Skin carcinoma; Cancer of the stomach; Carcinoma of testis; Thyroid carcinoma; Uterus carcinoma; Urinary system cancer, and other cancer knurl and sarcoma.U.S. Patent number 7,601,355.
The present invention also provides the method for the treatment of CNS illness, and described CNS illness includes but not limited to, primary degeneration neurological conditions, for example Alzheimer, Parkinson's disease, psychological disorders, psychosis and dysthymia disorders.The compositions and methods of the invention can also be treated autism (Autism).Treatment can comprise that compound of the present invention uses separately or with the Drug combination that is used for the treatment of at present Parkinson's disease, Alzheimer or psychological disorders.
The present invention also provides the method for improving immune modulating treatment response, before it is included in immune modulating treatment or during cell is exposed to the compound of the present invention (the different perillalcohol that is for example rich in the perillalcohol of deuterium or is rich in deuterium) of significant quantity or the step of pharmaceutical composition.Preferred immunomodulator is cytokine, as interleukin, lymphokine, monokine, Interferon, rabbit (interfereons) and chemokine.
The present invention also provides for cytostatic method in vitro or in vivo, wherein makes cell contact with the compounds of this invention as herein described of significant quantity as cancer cells.
The cell or tissue of morbid state can be processed by the compound of the present invention or the composition that make described cell or tissue contact significant quantity as the cell or tissue of hyper-proliferative.Described cell, as cancer cells, can be primary cancer cell, can be maybe the culturing cell that can obtain as American type culture collection (ATCC) from tissue bank.Diseased cells can be the cell of general cancer, glioma, meningioma, pituitary adenoma, or from the cell of CNS metastatic carcinoma, lung cancer, prostate cancer, breast cancer, hematopoietic system cancer or the ovarian cancer of general cancer.Described cell can come from vertebrates, preferred mammal, the more preferably mankind.U.S. Patent Publication No. 2004/0087651.Balassiano etc. (2002) intern.J.Mol.Med.10:785-788.Thorne etc. (2004) neuroscience127:481-496.Fernandes etc. (2005) oncology Reports13:943-947.Da Fonseca etc. (2008) surgical Neurology70:259267.Da Fonseca etc. (2008) arch. immuno1.Ther.Exp.56:267-276.Hashizume etc. (2008) neuroncology10:112-120.
The effect of the present composition can utilize method as known in the art to measure.For example, can pass through MTT[3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene Thiazolyl blue tetrazolium bromide compound] cell toxicity test studies the cytotoxicity of the compounds of this invention.MTT tests based on following principle: metabolic activities cellular uptake MTT (tetrazolium salts), is metabolized to blue first a ceremonial jade-ladle, used in libation (formazon) product that can read by spectrography in cell. J.of?Immunological?Methods65:55-63,1983。Can study by colony-forming test the cytotoxicity of the compounds of this invention.The functional selection that suppresses VEGF secretion and IL-8 secretion can be undertaken by ELISA.Can be by the cell cycle the causing blocking-up of standard propidium iodide (PI) staining and flow cytometry research the compounds of this invention.Can pass through Boyden chamber (Boyden chambers) research invasion and attack suppresses.In this test, by the basilar membrane of one deck reconstruct---matrigel (Matrigel) is coated on chemotaxis strainer, and as the barrier of cell migration in Boyden chamber.The cell only with invasive ability can pass described matrigel barrier.Other test includes but not limited to cell viability test, apoptosis test and morphological analysis.
Be below embodiments of the invention, it should not be construed as restrictive.
Synthesizing of embodiment 1 deuterated perillalcohol
Scheme-1:
(S) synthesizing of-4-pseudoallyl-1-tetrahydrobenzene-1-first-α-d1-alcohol (2)
At N 2lower by lithium deuteride LiD aluminium (LAD, 1.0M in THF, 21.2mL, 21.3mmol) slowly add (S)-perillaldehyde (1 to, 2.0g, 13.3mmol) in the cold soln of doing in THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, is then heated to reflux, keep 2.0h.Use carefully saturated metabisulfite solution cancellation reaction mixture, and leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated and the oil of gained is passed through to the single StEP40g post of Thomson also with 7% ethyl acetate/hexane (120mL) wash-out.Clean cut is merged, and vacuum concentration, to obtain compound 2, be water white oil.Weight: 1.78g.Yield: 88%. 1H-NMR(400MHz,CDCl 3):δ1.48(m,1H),1.73(s,3H),1.84-1.99(m,2H),2.11(m,4H),3.99(d,1H),4,71(m,2H),5.71(bs,1H)。MS (APCI+ve pattern): observe molecular ion peak.
Scheme-2:
(S)-4-pseudoallyl-1-tetrahydrobenzene-1-first-α, α '-d2-alcohol (2) synthetic
At N 2lower by lithium deuteride LiD aluminium (LAD, 1.0M in THF, 16.6mL, 16.6mmol) slowly add (S)-perillic acid methyl esters (1 to, 2.0g, 11mmol) in the cold soln of doing in THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, then at room temperature stirs 2.0h.Use carefully saturated metabisulfite solution cancellation reaction mixture, and leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated and the oil of gained is passed through to the single StEP40g post of Thomson also with 5% ethyl acetate/hexane (150mL) wash-out.Clean cut is merged, and vacuum concentration, to obtain compound 2, be water white oil.Weight: 1.34g.Yield: 79%. 1H-NMR(400MHz,CDCl 3):δ1.45-1.49(m,1H),1.73(s,3H),1.84-1.98(m,2H),2.11-2.17(m,4H),4,71(m,2H),5.691(bs,1H)。MS (APCI+ve pattern): observe molecular ion peak.
Scheme-3:
(S) synthesizing of-4-pseudoallyl-1-tetrahydrobenzene-1-deuterated first-α-d1-alcohol (2)
At N 2lower by lithium deuteride LiD aluminium (LAD, 1.0M in THF, 21.2mL, 21.3mmol) slowly add (S)-perillaldehyde (1 to, 2.0g, 13.3mmol) in the cold soln of doing in THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, is then heated to reflux, keep 2.0h.Use carefully the D of 5% deuterium sodium oxide 2o solution (6.0mL) cancellation reaction.Leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated, and the oily resistates of gained is passed through to the single StEP40g post of Thomson also with 7% ethyl acetate/hexane (120mL) wash-out.Clean cut is merged, and vacuum concentration, to obtain compound 2, be water white oil.
Scheme-4:
(S)-deuterated first-α of 4-pseudoallyl-1-tetrahydrobenzene-1-, α '-d2-alcohol (2) synthetic
At N 2lower by lithium deuteride LiD aluminium (LAD, 1.0M in THF, 16.6mL, 16.6mmol) slowly add (S)-perillic acid methyl esters (1 to, 2.0g, 11mmol) in the cold soln of doing in THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, then at room temperature stirs 2.0h.Use carefully the D of 5% deuterium sodium oxide 2o solution (6.0mL) cancellation reaction mixture.Leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated.The oily resistates of gained is passed through to the single StEP40g post of Thomson also with 7% ethyl acetate/hexane (120mL) wash-out.Clean cut is merged, and vacuum concentration, to obtain compound 2, be water white oil.
The deuterated different perillalcohol of embodiment 2: 4-isopropylidene-1-tetrahydrobenzene-1-first-α, α '-d2-alcohol synthetic
Scheme:
Synthesizing of trifluoromethanesulfonic acid 4-isopropylidene hexamethylene-1-alkenyl esters (2):
At-78 DEG C, within the time of 0.5 hour, solution (5.6mL, 14.1mmol) by the n-Butyl Lithium of 2.5M in hexane slowly adds in the solution of diisopropylamine (1.98mL, 14.1mmol) in dry THF (30mL).At-78 DEG C, stir after 1.0h, within the time of 10min, add the solution of ketone (1,1.3g, 9.4mmol) in dry THF (10mL), keep temperature lower than-78 DEG C simultaneously.Reaction mixture is stirred to 1.0h at-78 DEG C.Slowly add the solution of two (fluoroform sulphonyl) imines (phenyltriflimide) (3.53g, 9.86mmol) of phenyl in dry THF (15mL), keep temperature lower than-78 DEG C simultaneously.Reaction mixture is slowly warming up to 0 DEG C, at 0 DEG C, keeps 2.0h, then use saturated ammonium chloride solution cancellation.The organic layer water (15mL), the salt solution (15mL) that separate are washed and use dried over sodium sulfate.By the organic layer vacuum concentration filtering.The resistates of gained is passed through to column chromatography purifying.[column dimension: diameter: 6.0cm, highly: 12cm, silica gel: 200 orders, with hexane (200mL) wash-out].Merging similar cut vacuum concentration, obtain 2, is oily matter.Weight: 0.9g.Weight yield: 38%. 1H-NMR(400MHz,CDCl 3):δ1.68(s,3H),1.71(s,3H),2.37(m,2H),2.46(m,2H),2.91(m,2H),5.73(m,1H)。MS (APCI+ve pattern): observe molecular ion peak.
Synthesizing of 4-isopropylidene hexamethylene-1-olefinic carboxylic acid methyl esters (3):
To compound 2 (0.2g, 0.74mmol) in the solution in N'N-dimethyl formamide (1.5mL), add methyl alcohol (1.0mL), triethylamine (0.17mL, 1.2mmol), 1, two (diphenylphosphino) propane (0.03g of 3-, 0.07mmol) and acid chloride (0.04g, 0.07mmol).Reaction mixture is degassed, then under carbon monoxide (balloon pressure) and room temperature, stir 5h.Ethyl acetate for reaction mixture (15mL) diluted and use 0.5N HCl (15mL), salt solution (5mL) washing, and using dried over sodium sulfate.By the organic layer vacuum concentration filtering, and the resistates of gained is passed through to column chromatography purifying.[column dimension: diameter: 6.0cm, highly: 12cm, silica gel: 200 orders, with hexane (100mL) wash-out, use subsequently ethyl acetate: hexane (2%, 150mL) wash-out].Merge similar cut vacuum concentration, obtain oily matter.Weight: 0.07g.Yield: 52%.
4-isopropylidene-1-tetrahydrobenzene-1-first-α, α '-d2-alcohol (4) synthetic
At N 2lower lithium deuteride LiD aluminium (1.0M in THF, 16.6mL, 16.6mmol) is slowly added in the cold soln of methyl esters (3,2.0g, 11mmol) in dry THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, then at room temperature stirs 2.0h.Use carefully saturated metabisulfite solution cancellation reaction mixture.Leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated and by the oil process column chromatography purifying of gained, obtain compound 4.
The deuterated different perillalcohol of embodiment 3: the deuterated first-α of 4-isopropylidene-1-tetrahydrobenzene-1-, α '-d2-alcohol synthetic
Scheme:
At N 2lower lithium deuteride LiD aluminium (1.0M in THF, 16.6mL, 16.6mmol) is slowly added in the cold soln of methyl esters (3,2.0g, 11mmol) in dry THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, then at room temperature stirs 2.0h.Use carefully the D of 5% deuterium sodium oxide 2o solution (6.0mL) cancellation reaction mixture.Leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated and by the oily resistates process column chromatography purifying of gained, obtain compound 4A.
The deuterated different perillalcohol of embodiment 4: 4-isopropylidene-1-tetrahydrobenzene-1-first-α-d1-alcohol synthetic
Scheme:
Synthesizing of 4-isopropylidene hexamethylene-1-thiazolinyl methyl alcohol (5)
At 10 DEG C, within the time of 5min, the solution by methyl esters (3,1.0g, 5.54mmol) in dry THF (10mL) adds in the solution of lithium aluminium hydride (0.25g, 6.6mmol) in dry THF (20mL).Mixture is slowly heated to reflux and keep 2.0h.By cooling reaction mixture and with saturated metabisulfite solution (2.0mL) cancellation.Leach lithium salts and wash with hot ethyl acetate.By organic layer dried over sodium sulfate, filter and vacuum concentration, obtain colourless oil.Weight: 0.67g.Yield: 80%. 1H-NMR(400MHz,CDCl 3):δ1.65(s,3H),1.69(s,3H),1.77(bs,OH),2.09(m,2H),2.33(t,2H),2.79(br?s,2H)。MS (APCI+ve pattern): m/e:152 (M +, 3.5%), 135.07 (100%), 107.12 (5%).
Synthesizing of 4-isopropylidene hexamethylene-1-cyclohexene carboxaldehyde (6):
At-78 DEG C, will do DMSO (0.5ml) and add in the cold soln of oxalyl chloride (0.67mL, 7.8mmol) in methylene dichloride (15mL), and mixture will be stirred to 20min.In 10min, add the solution of alcohol (5,1.0g, 6.5mmol) in 5mL DCM, and mixture is stirred to 1.0h, then add triethylamine (0.8mL).Reaction mixture is stirred to 0.5h, be then warming up to room temperature.Add water (20mL) and separate DCM layer.DCM for water layer (20mL) is extracted and separated.The DCM layer of merging is washed with water, separate, and use dried over sodium sulfate.By the organic layer vacuum concentration filtering, and the resistates of gained is passed through to column chromatography purifying, obtain compound 6.
Synthesizing of 4-isopropylidene-1-tetrahydrobenzene-1-first-α-d1-alcohol (7):
At N 2lower lithium deuteride LiD aluminium (1.0M in THF, 21.2mL, 21.3mmol) is slowly added in the cold soln of aldehyde (6,2.0g, 13.3mmol) in dry THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, is then heated to reflux, keep 2.0h.Use carefully saturated metabisulfite solution cancellation reaction mixture.Leach the lithium salts of gained and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated and by the oil process column chromatography purifying of gained, obtain compound 7.
The deuterated different perillalcohol of embodiment 5: 4-isopropylidene-1-tetrahydrobenzene-1-deuterated first-α-d1-alcohol synthetic
Scheme:
At N 2lower lithium deuteride LiD aluminium (1.0M in THF, 21.2mL, 21.3mmol) is slowly added in the cold soln of aldehyde (6,2.0g, 13.3mmol) in dry THF (20mL), keep temperature lower than 10 DEG C simultaneously.Reaction mixture is slowly warming up to room temperature, is then heated to reflux, keep 2.0h.Use carefully the D of 5% deuterium sodium oxide 2o solution (6.0mL) cancellation reaction mixture, and the lithium salts of gained is filtered and wash by ethyl acetate.By dried over sodium sulfate filtration for organic layer.Filtrate is concentrated, and by the oily resistates process column chromatography purifying of gained, obtain compound 7A.
The two POH carbamate (4-(two-N of embodiment 6 dimethyl celecoxibs, N '-4-pseudoallyl hexamethylene-1-thiazolinyl methyl oxygen base carbonyl [5-(2,5-3,5-dimethylphenyl)-3-trifluoromethyl pyrazol-1-yl] benzsulfamide) synthetic
Reaction scheme is as follows:
Within the time of 30 minutes, by phosgene, (20% in toluene, 13ml, 26.2mmol) add (2.0 grams of perillalcohols to, 13.1mmol) and (5.4 grams, salt of wormwood, 39.1mmol) in the mixture in dry toluene (30mL), keep temperature is 10 DEG C to 15 DEG C simultaneously.Make reaction mixture be warming up to room temperature, and at N 2lower stirring 8.0 hours.By reaction mixture water (30mL) cancellation, and separate organic layer.By toluene for water layer (20mL) extraction, and by the organic layer water (50mL x2) merging, salt solution (15%, 30mL) washing, and dry with sodium sulfate (20 grams).To obtain perillyl chloro-formic ester, be oily matter by the organic layer vacuum concentration of filtration.Weight: 2.5 grams; Yield: 89%. 1H-NMR(400MHz,CDCl 3):δ1.5(m,1H),1.7(s,3H),1.8(m,1H),2.0(m,1H),2.2(m,4H),4.7(dd,4H)；5.87(m,1H)。
At N 2under, within the time of 5 minutes, by (0.11 gram of perillyl chloro-formic ester, 0.55mmol) be slowly added into (0.2 gram of dimethyl celecoxib, 0.50mmol) and in the mixture of salt of wormwood (0.13 gram, 1.0mmol) in dry acetone (10mL).Reaction mixture is heated to reflux and keeps 3 hours.Because TLC analyzes exist (>60%) that shows dimethyl celecoxib, add the perillyl chloro-formic ester of 1.0 other equivalents, and reflux again 5 hours.By cooling reaction mixture and by acetone vacuum concentration with obtain resistates.
The resistates of gained is suspended in water (15mL) and uses ethyl acetate (3x15mL) extraction.By organic layer water (20mL) washing merging, use subsequently salt solution (15%, 20mL) washing, and use dried over sodium sulfate.By the organic layer vacuum concentration filtering, obtain resistates, passed through column chromatography purifying [column dimension: diameter: 1.5cm, highly: 10cm, silica gel: 230-400 order] and use hexane (100mL) wash-out, use subsequently mixture (95:5, the 100mL) wash-out of hexane/ethyl acetate.Hexane/ethyl acetate cut is merged, and vacuum concentration, gumminess material obtained.
Product P OH carbamate shows the weight of 120mg and 31% yield. 1H-NMR(400MHz,CDCl 3):δ0.9(m,2H),1.4(m,2H),1.7(m,7H*),1.95(m,8H*),2.1(m,4H),2.3(s,3H),4.4(d,2H),4.7(dd,2H),5.6(br?d,2H),6.6(s,1H),7.0(br?s,1H),7.12(d,1H),7.19(d,1H),7.4(d,2H),7.85(d,2H)；MS,m/e:751.8(M +3％),574.3(100％),530.5(45％),396(6％)。* note: the impurity of 2H and supposition is overlapping in addition, this impurity is not considered in NMR integration.
Product P OH carbamate can be by partially or completely deuterated.For example, one or more H atoms can be deuteriums.
Embodiment 7 Temozolomide POH carbamates (3-methyl 4-oxo-3,4-glyoxalidine is [5,1-d] [1,2,3,5] tetrazine-8-carbonyl also)-carboxylamine-4-pseudoallyl hexamethylene-1-thiazolinyl methyl ester) synthetic
Reaction scheme is as follows:
At N 2under, within the time of 2 minutes, by (0.13 gram of oxalyl chloride, 1.0mmol) slowly add Temozolomide (OChem Incorporation, 0.1 gram, 0.5mmol) to 1, in mixture in 2-ethylene dichloride (10mL), keep temperature is 10 DEG C simultaneously.Make reaction mixture be warming up to room temperature, be then heated to reflux, keep 3 hours.Remove excessive oxalyl chloride and 1,2-ethylene dichloride by vacuum concentration.The resistates of gained is dissolved in 1,2-ethylene dichloride (15mL) again, and at N 2lower reaction mixture is cooled to 10 DEG C.Within the time of 5 minutes, add the solution of perillalcohol (0.086 gram, 0.56mmol) in 1,2-ethylene dichloride (3mL).Make reaction mixture intensification room temperature and stir 14 hours.By 1,2-ethylene dichloride vacuum concentration, obtain resistates, it is ground with hexane.The yellow solid of gained is leached, and wash with hexane.Weight: 170mg; Yield: 89%. 1h-NMR (400MHz, CDCl 3): δ 1.4-2.2 (m, 10H), 4.06 (s, 3H), 4.6-4.8 (m, 4H), 5.88 (br s, 1H), 8.42 (s, 1H), 9.31 (br s, 1H); MS, does not observe molecular ion peak.m/e：314(100％),286.5(17％),136(12％)。
Or, according to the synthetic Temozolomide POH carbamate of following operation.At N 2under, within the time of 2 minutes, by (0.13 gram of oxalyl chloride, 1.0mmol) slowly add Temozolomide (OChemIncorporation, 0.1 gram, 0.5mmol) to 1, in mixture in 2-ethylene dichloride (10mL), keep temperature is 10 DEG C simultaneously.Make reaction mixture be warming up to room temperature, be then heated to reflux, keep 3 hours.Remove excessive oxalyl chloride and 1,2-ethylene dichloride by vacuum concentration.The resistates of gained is dissolved in 1,2-ethylene dichloride (15mL) and at N again 2lower reaction mixture is cooled to 10 DEG C.Within the time of 5 minutes, add the solution of perillalcohol (0.086 gram, 0.56mmol) in 1,2-ethylene dichloride (3mL).Make reaction mixture be warming up to room temperature, and stir 14 hours.By 1,2-ethylene dichloride vacuum concentration, obtain resistates, passed through short silica gel-stick harness purifying (column dimension: diameter: 2cm, highly: 3cm, silica gel: 230-400 order), and with mixture (1:1, the 100mL) wash-out of hexane/ethyl acetate.Hexane/ethyl acetate cut is merged, and vacuum concentration, obtain white solid resistates, it is ground with heptane, and filter, obtain white solid.Weight: 170mg; Yield: 89%. 1h-NMR (400MHz, CDCl3): 1.4-2.2 (m, 10H), 4.06 (s, 3H), 4.6-4.8 (m, 4H), 5.88 (br s, 1H), 8.42 (s, 1H), 9.31 (br s, 1H); MS, does not observe molecular ion peak, m/e:314 (100%), 286.5 (17%), 136 (12%).
Product P OH carbamate can be by partially or completely deuterated.For example, one or more H atoms can be deuteriums.
Synthesizing of embodiment 8 rolipram POH carbamates (4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-oxo-tetramethyleneimine-1-carboxylic acid 4-pseudoallyl hexamethylene-1-thiazolinyl methyl ester)
Reaction scheme is as follows:
Within the time of 30 minutes, by phosgene, (20% in toluene, 13ml, 26.2mmol) add (2.0 grams of perillalcohols to, 13.1mmol) and (5.4 grams, salt of wormwood, 39.1mmol) in the mixture in dry toluene (30mL), keep temperature is 10 DEG C to 15 DEG C simultaneously.Make reaction mixture be warming up to room temperature, and at N 2lower stirring 8.0 hours.By reaction mixture water (30mL) cancellation, and separate organic layer.By toluene for water layer (20mL) extraction, and by the organic layer water (50mL x2) merging, salt solution (15%, 30mL) washing, and dry with sodium sulfate (20 grams).To obtain perillyl chloro-formic ester, be oily matter by the organic layer vacuum concentration of filtration.Weight: 2.5 grams; Yield: 89%. 1H-NMR(400MHz,CDCl 3):δ1.5(m,1H),1.7(s,3H),1.8(m,1H),2.0(m,1H),2.2(m,4H),4.7(dd,4H)；5.87(m,1H)。
At N 2at-72 DEG C, within the time of 5 minutes, butyllithium (2.5M, 0.18mL, 0.45mmol) is added in the solution of rolipram (GL synthesis, Inc., 0.1 gram, 0.36mmol) in dry THF.Reaction mixture is stirred at-72 DEG C after 1.0 hours, within the time of 15 minutes, add perillyl chloro-formic ester (being dissolved in 4mL THF), keep temperature is-72 DEG C simultaneously.Reaction mixture is stirred 2.5 hours, and with saturated ammonium chloride (5mL) cancellation.Make reaction mixture be warming up to room temperature, and extract by ethyl acetate (2x15mL).By the organic layer water (15mL) merging, salt solution (15%, 15mL) washing, then use dried over sodium sulfate.The organic layer filtering is concentrated, obtain oily matter, passed through column chromatography purifying [column dimension: diameter: 1.5cm, highly: 10cm, silica gel: 230-400 order], and with mixture (100mL) wash-out of 8% ethyl acetate/hexane, then use 12% ethyl acetate/hexane (100mL) wash-out.12% ethyl acetate/hexane cut is merged, and vacuum concentration, gumminess solid obtained.Weight: 142mg; Yield: 86%. 1H-NMR(400MHz,CDCl 3):δ1.5(m,1H),1.6(m,2H),1.7(s,3H),1.9(m,6H),2.2(m,5H),2.7(m,1H),2.9(m,1H),3.5(m,1H),3.7(m,1H),3.8(s,3H),4.2(m,1H),4.7(m,6H),5.8(br?s,1H),6.8(m,3H)；MS,m/e:452.1(M +153％),274.1(100％),206.0(55％)。
Product P OH carbamate can be by partially or completely deuterated.For example, one or more H atoms can be deuteriums.
The Iso-POH's that embodiment 9 and Temozolomide (TMZ) are puted together is synthetic
Reaction scheme is as follows:
The preparation of (3-methyl 4-oxo-3,4-glyoxalidine is [5,1-d] [1,2,3,5] tetrazine-8-carbonyl also)-carboxylamine-4-isopropylidene hexamethylene-1-thiazolinyl methyl ester:
At N 2under, within the time of 5 minutes, slowly add oxalyl chloride (0.26 gram, 2.0mmol) to Temozolomide (source: OChem Incorporation, lot number 0711185A; 0.2g, 1.0mmol) in mixture in 1,2-ethylene dichloride (15mL), keep temperature is 10 DEG C simultaneously.Make reaction mixture be warming up to room temperature, be then heated to reflux, keep 2.5 hours.Remove excessive oxalyl chloride and 1,2-ethylene dichloride by vacuum concentration.The resistates of gained is dissolved in 1,2-ethylene dichloride (20mL) again, and at N 2lower reaction mixture is cooled to 5 DEG C.Within the time of 10 minutes, add the solution of different perillalcohol (0.17 gram, 1.12mmol) in 1,2-ethylene dichloride (5mL).Make reaction mixture intensification room temperature and stir 12 hours.By 1,2-ethylene dichloride vacuum concentration, obtain resistates, it is ground with hexane.The faint yellow solid of gained is leached, and wash with hexane.
Product iso-POH carbamate can be by partially or completely deuterated.For example, one or more H atoms can be deuteriums.
The Iso-POH's that embodiment 10 and rolipram are puted together is synthetic
Reaction scheme is as follows:
The preparation of 4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-oxo-tetramethyleneimine-1-carboxylic acid 4-isopropylidene hexamethylene-1-thiazolinyl methyl ester:
Within the time of 45 minutes, by phosgene, (20% in toluene, 19.5ml, 39.4mmol) add different perillalcohol (3.0g to, 19.7mmol) and salt of wormwood (8.1g, 58.6mmol) in the mixture in dry toluene (45mL), keep temperature is 10 DEG C to 12 DEG C simultaneously.Make reaction mixture be warming up to room temperature, and at N 2lower stirring 10 hours.By reaction mixture water (40mL) cancellation, and separate organic layer.By toluene for water layer (30mL) extraction, and by the organic layer water (40mL x2) merging, salt solution (10%, 40mL) washing, and dry with sodium sulfate (25g).To obtain different perillyl chloro-formic ester, be oily matter by the organic layer vacuum concentration of filtration.
At N 2at-72 DEG C, within the time of 10 minutes, add butyllithium (2.5M, 0.36mL, 0.90mmol) to rolipram (source: GL synthesis, Inc., lot number GLS-SH-110809; 0.2g, 0.72mmol) in the solution of doing in THF (8mL).Reaction mixture is stirred at-72 DEG C after 1.0 hours, within the time of 10 minutes, add different perillyl chloro-formic ester (0.16g, 0.76mmol are dissolved in 4mL THF), keep temperature is-72 DEG C simultaneously.Reaction mixture is stirred 3 hours, and with saturated ammonium chloride (10mL) cancellation.Make reaction mixture be warming up to room temperature, and extract by ethyl acetate (2x20mL).By the organic layer water (20mL) merging, salt solution (10%, 25mL) washing, and use dried over sodium sulfate.The organic layer filtering is concentrated, obtain oily matter, passed through column chromatography purifying [column dimension: diameter: 1.5cm, highly: 15cm, silica gel: 230-400 order], and with mixture (120mL) wash-out of 5% ethyl acetate/hexane, then use 10% ethyl acetate/hexane (150mL) wash-out.10% ethyl acetate/hexane cut is merged, and vacuum concentration, gumminess solid obtained.
Product iso-POH carbamate can be by partially or completely deuterated.For example, one or more H atoms can be deuteriums.
Synthesizing of the two iso-POH carbamate conjugates of embodiment 11 dimethyl celecoxibs
Reaction scheme is as follows:
4-(two-N, the preparation of N '-4-isopropylidene hexamethylene-1-thiazolinyl methyl oxygen base carbonyl [5-(2,5-3,5-dimethylphenyl)-3-trifluoromethyl pyrazol-1-yl] benzsulfamide:
Within the time of 45 minutes, by phosgene, (20% in toluene, 19.5ml, 39.4mmol) add different perillalcohol (3.0g to, 19.7mmol) and salt of wormwood (8.1g, 58.6mmol) in the mixture in dry toluene (45mL), keep temperature is 10 DEG C to 12 DEG C simultaneously.Make reaction mixture be warming up to room temperature, and at N 2lower stirring 10 hours.By reaction mixture water (40mL) cancellation, and separate organic layer.By toluene for water layer (30mL) extraction, and by the organic layer water (40mL x2) merging, salt solution (10%, 40mL) washing, and dry with sodium sulfate (25g).To obtain different perillyl chloro-formic ester, be oily matter by the organic layer vacuum concentration of filtration.
At N 2under, within the time of 5min, different perillyl chloro-formic ester (0.22g, 1.0mmol) is slowly added into dimethyl celecoxib (0.2g, 0.50mmol) and in the mixture of salt of wormwood (0.14g, 1.0mmol) in dry acetone (25mL).Reaction mixture is heated to reflux and keeps 4 hours.By cooling reaction mixture and by acetone vacuum concentration.The resistates of gained is suspended in water (25mL), and extracts by ethyl acetate (3x20mL).By organic layer water (40mL) washing merging, use subsequently salt solution (10%, 30mL) washing, and use dried over sodium sulfate.By the organic layer vacuum concentration filtering, obtain resistates, passed through column chromatography purifying [column dimension: diameter: 1.5cm, highly: 15cm, silica gel: 230-400 order] and use hexane (100mL) wash-out, use subsequently mixture (95:5, the 100mL) wash-out of hexane/ethyl acetate.Hexane/ethyl acetate cut is merged, and vacuum concentration, gumminess material obtained.
Product iso-POH carbamate can be by partially or completely deuterated.For example, one or more H atoms can be deuteriums.
Scope of the present invention is not limited to those of concrete demonstration above and description.Those skilled in the art can know, and for the example of described material, configuration, structure and size, have suitable replacement scheme.In description of the invention, quote and a large amount of reference have been discussed, comprising patent and multiple publication.Provide to these reference quote and discussion is only used to set forth description of the invention, and not admit that any reference is the prior art of invention discussed in this article.All reference of quoting in this specification sheets and discussing all by reference entirety be incorporated to herein.Those skilled in the art can expect variant, amendment and other embodiment of content described herein, and without departing from the spirit and scope of the present invention.Although shown and described certain embodiments of the present invention, for those skilled in the art obviously, can change and revise and without departing from the spirit and scope of the present invention.Only provide in illustrative and nonrestrictive mode the content providing in description above and accompanying drawing.

Claims (27)

1. the compound that is rich in deuterium of formula I or formula II or its pharmacy acceptable salt:
Wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16independently selected from hydrogen-1 and deuterium, and R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15and R 16in at least one be deuterium, and wherein the abundance of deuterium is at least about 10%.
2. the compound that is rich in deuterium as claimed in claim 1, it is selected from:
3. the perillalcohol or the different perillalcohol that are rich in deuterium, wherein the abundance of deuterium is at least about 10%.
4. the compound that is rich in deuterium as described in claim 1,2 or 3, itself and therapeutical agent put together to form carbamate.
5. the perillalcohol carbamate or the different perillalcohol carbamate that are rich in deuterium, wherein the abundance of deuterium is at least about 10%.
6. the compound that is rich in deuterium as described in any one in claim 1-5, wherein the abundance of deuterium is at least about 20% or at least about 30%.
7. the compound that is rich in deuterium as claimed in claim 5, wherein perillalcohol or different perillalcohol and therapeutical agent put together to form carbamate.
8. the compound that is rich in deuterium as described in claim 4 or 7, wherein said therapeutical agent is chemotherapeutics, and described chemotherapeutics is selected from DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, enzyme inhibitors and receptor antagonist.
9. the compound that is rich in deuterium as described in claim 4 or 7, wherein said therapeutical agent is selected from dimethyl celecoxib (DMC), Temozolomide (TMZ) and rolipram.
10. a pharmaceutical composition, it comprises the compound that is rich in deuterium described in any one in claims 1 to 3.
11. pharmaceutical compositions as claimed in claim 10, it further comprises chemotherapeutics, and described chemotherapeutics is selected from DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, enzyme inhibitors and receptor antagonist.
12. pharmaceutical compositions as claimed in claim 10, it further comprises therapeutical agent, and described therapeutical agent is selected from dimethyl celecoxib (DMC), Temozolomide (TMZ) and rolipram.
13. 1 kinds of pharmaceutical compositions, it comprises the compound that is rich in deuterium described in any one in claim 4 to 9.
Treat the method for mammiferous disease for 14. 1 kinds, it comprises to the step of described administration pharmaceutical composition, described pharmaceutical composition comprise treat significant quantity the perillalcohol that is rich in deuterium, be rich in deuterium different perillalcohol, be rich in the perillalcohol carbamate of deuterium and/or be rich in the different perillalcohol carbamate of deuterium.
Treat the method for mammiferous disease for 15. 1 kinds, it comprises to the step of the pharmaceutical composition described in any one in described administration claim 10-13.
16. methods as described in claims 14 or 15, wherein said disease is cancer.
17. methods as claimed in claim 16, wherein said cancer is neural tumour.
18. methods as claimed in claim 17, wherein said disease is glioblastoma multiforme.
19. methods as described in claims 14 or 15, wherein said pharmaceutical composition by sucking, nose is interior, oral, intravenously, subcutaneous or intramuscular administration.
20. methods as described in claims 14 or 15, it further comprises by mammiferous step described in radiotherapy.
21. methods as claimed in claim 20, wherein before radiation, during or use afterwards described pharmaceutical composition.
22. methods as described in claims 14 or 15, it further comprises to the step of described administration chemotherapeutics.
23. methods as claimed in claim 22, wherein before using chemotherapeutics, during or use afterwards described pharmaceutical composition.
24. methods as claimed in claim 22, wherein said chemotherapeutics is selected from DNA alkylating agent, topoisomerase enzyme inhibitor, er stress inductor, platinic compound, metabolic antagonist, enzyme inhibitors and receptor antagonist.
25. methods as claimed in claim 22, wherein said chemotherapeutics is selected from dimethyl celecoxib (DMC), Temozolomide (TMZ) and rolipram.
26. methods as described in claims 14 or 15, are wherein used nasal delivery devices to use described pharmaceutical composition.
27. methods as claimed in claim 26, wherein said nasal delivery devices is selected from sucker, nose inner sprayer unit, spraying gun, atomizer, metered dose inhaler (MDI), pressurized doses sucker, insufflator, unit-dose container, pump, dropper, squeeze bottle and two-way device in nose.
CN201280057166.6A 2011-11-21 2012-11-21 Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof Pending CN103946202A (en)

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US13/566,731 US8916545B2 (en) 2010-08-27 2012-08-03 Pharmaceutical compositions comprising POH derivatives
PCT/US2012/066379 WO2013119304A2 (en) 2011-11-21 2012-11-21 Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof

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