WO2002024705A1 - Stereoselective process for preparing cyclohexyl amine derivatives - Google Patents
Stereoselective process for preparing cyclohexyl amine derivatives Download PDFInfo
- Publication number
- WO2002024705A1 WO2002024705A1 PCT/US2001/026023 US0126023W WO0224705A1 WO 2002024705 A1 WO2002024705 A1 WO 2002024705A1 US 0126023 W US0126023 W US 0126023W WO 0224705 A1 WO0224705 A1 WO 0224705A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- optionally substituted
- alkyl
- appropriate
- Prior art date
Links
- 0 *=C(CCC1)CC1=* Chemical compound *=C(CCC1)CC1=* 0.000 description 7
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- cancers such as Hodgkin's disease, large cell lymphoma, acute lymphocytic leukemia, testicular cancer and early stage breast cancer.
- Other cancers such as ovarian cancer, small cell lung and advanced breast cancer, while not yet curable, are exhibiting positive response to combination chemotherapy.
- drug resistance After selection for resistance to a single cytotoxic drug, cells may become cross resistant to a whole range of drugs with different structures and cellular targets, e.g., ' alkylating agents, antimetabolites, hormones, platinum-containing drugs, and natural products. This phenomenon is known as multidrug resistance (MDR). In some types of cells, this resistance is inherent, while in others, such as small cell lung cancer, it is usually acquired.
- MDR multidrug resistance
- MDRl 170 kDa P-glycoprotein
- MRPl 190 kDa multidrug resistance protein
- Doxorubicin, daunorubicin, epiruhicin, vincristine, and etoposide are substrates of MRPl, i.e., MRPl can bind to these oncolytics and redistribute them away from their site of action, the nucleus, and out of the cell. Id. and Marquardt, D., and Center, M.S., Cancer Research, 52:3157, 1992. Doxorubicin, daunorubicin, and epirubicin are members of the anthracycline class of oncolytics.
- These agents are isolates of various strains of Streptomyces and act by inhibiting nucleic acid synthesis. These agents are useful in treating neoplasms of the bone, ovaries, bladder, thyroid, and especially the breast. They are also useful in the treatment of acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.
- Nincristine a member of the vinca alkaloid class of oncolytics, is an isolate of a common flowering herb, the periwinkle plant (Vinca rosea Linn). The mechanism of action of vincristine is still under investigation but has been related to the inhibition of microtubule formation in the mitotic spindle. Nincristine is useful in the treatment of acute leukemia, Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.
- Etoposide a member of the epipodophyllotoxin class of oncolytics, is a semisynthetic derivative of podophyllotoxin. Etoposide acts as a topoisomerase inhibitor and is useful in the therapy of neoplasms of the testis, and lung.
- the present invention provides a process for preparing (lR,3S)-3-(9-chloro-3- methyl-4-oxo-5H-(isoxazoloquinolin-5-yl))cyclohexanecarboxylic acid and esters thereof, as represented by formulas II and HI, wherein R is a lower alkyl group, benzyl, aryl, or heterocycle, and A and B are N or O, provided that when A is N, B is O, or when A is O, B is N:
- the invention relates to a process for converting the compounds of formulas H or HI to form a compound of formula 1(a):
- Ri is independently at each occurrence C ⁇ -C6 alkyl, Cj-C6 alkoxy, (C1-C4 alkoxy)-aryl, (C1-C4 alkoxy)-heterocycle, (C1-C4 alkoxy)-SiCH3, optionally substituted (C1-C4 alkyl)-(C3-C ⁇ cycloalkyl), optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C1-C4 alkyl)-CO-aryl, optionally substituted
- R2 is independently at each occurrence hydrogen or C j -Cg alkyl
- R 3 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle;
- R4 is independently at each occurrence hydrogen, C ⁇ -Cg alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, (CH2) U -
- R5 is independently at each occurrence hydrogen, optionally substituted C ⁇ -Cg alkyl, optionally substituted aryl, optionally substituted heterocycle, or -
- R6 is independently at each occurrence hydrogen, Cj-Cg alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-CJO bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, C(O)OR 10 , SO2R 11 , C(O)R!2, or a moiety of the formula
- R7 is independently at each occurrence hydrogen, optionally substituted Ci-C ⁇ alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted
- R ⁇ is independently at each occurrence hydrogen, Ci-C ⁇ alkyl, C1-C4 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C ⁇ -Cio bicycloalkyl, optionally substituted (C1-C
- RIO is independently at each occurrence hydrogen, optionally substituted C ⁇ -Cg alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle;
- RU is independently at each occurrence optionally substituted Cj-Cg alkyl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, or optionally substituted heterocycle;
- Rl2 is independently at each occurrence hydrogen, optionally substituted C ⁇ -Cg alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, or optionally substituted (C1-C4 alkyl)-heterocycle; or a pharmaceutical salt thereof.
- Ri 3 is independently at each occurrence Cj-Cg alkyl or optionally substituted
- the invention relates to a process for converting the compounds of formulas ⁇ or DI to form a compound of formula 1(b), wherein Rl, A, and B are as defined above:
- the invention relates to a process for converting the compounds of formulas (i) to compounds of formula 1(a), wherein Rl, A, and B are as defined above:
- the term “pharmaceutical” when used as an adjective means substantially non-toxic to living organisms.
- pharmaceutical salt refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. See, e.g., Berge, S.M, Bighley, L.D., and Monkhouse, D.C., "Pharmaceutical Salts", J. Pharm. Sci., 66:1, 1977.
- Typical pharmaceutical salts include those salts prepared by reaction of the compounds of formula I with an inorganic or organic acid or base.
- acid addition salt refers to a salt of a compound of formula I prepared by reaction of a compound of formula I with a mineral or organic acid.
- acid addition salts see, e.g., Berge, S.M, Bighley, L.D., and Monkhouse, D.C., J. Pharm. Sci., 66:1, 1977. Since compounds of this invention can be basic in nature, they accordingly react with any of a number of inorganic and organic acids to form pharmaceutical acid addition salts.
- the pharmaceutical acid addition salts of the invention are typically formed by reacting the compound of formula I with an equimolar or excess amount of acid.
- the reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like.
- the salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods.
- Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as -toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
- organic acids such as -toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic
- Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
- base addition salt refers to a salt of a compound of formula I prepared by reaction of a compound of formula I with a mineral or organic base.
- base addition salts see, e.g., Berge, S.M, Bighley, L.D., and Monkhouse, D.C., J. Pharm. Sci., 66:1, 1977.
- This invention also contemplates pharmaceutical base addition salts of compounds of formula I.
- the skilled artisan would appreciate that some compounds of formula I may be acidic in nature and accordingly react with any of a number of inorganic and organic bases to form pharmaceutical base addition salts.
- Examples of pharmaceutical base addition salts are the ammonium, lithium, potassium, sodium, calcium, magnesium, methylamino, diethylamino, ethylene diamino, cyclohexylamino, and ethanolamino salts, and the like of a compound of formula I.
- inhibitor refers to prohibiting, alleviating, ameliorating, halting, restraining, slowing or reversing the progression of, or reducing MRPl ' s ability to redistribute an oncolytic away from the oncolytic' s site of action, most often the neoplasm's nucleus, and out of the cell.
- the term "effective amount of a compound of formula I" refers to an amount of a compound of the present invention which is capable of inhibiting MRPl.
- the term “effective amount of an oncolytic agent” refers to an amount of oncolytic agent capable of inhibiting a neoplasm, resistant or otherwise.
- the term “inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance” refers to prohibiting, halting, restraining, slowing or reversing the progression of, reducing the growth of, or killing resistant neoplasms and/or neoplasms susceptible to resistance.
- resistant neoplasm refers to a neoplasm, which is resistant to chemotherapy where that resistance is conferred in part, or in total, by MRPl.
- neoplasms include, but are not limited to, neoplasms of the bladder, bone, breast, lung(small-cell), testis, and thyroid and also includes more particular types of cancer such as, but not limited to, acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.
- a neoplasm which is "susceptible to resistance" is a neoplasm where resistance is not inherent nor currently present but can be conferred by MRPl after chemotherapy begins.
- the methods of this invention encompass a prophylactic and therapeutic administration of a compound of formula I.
- chemotherapy refers to the use of one or more oncolytic agents where at least one oncolytic agent is a substrate of MRPl.
- a "substrate of MRPl” is an oncolytic that binds to MRPl and is redistributed away from the oncolytic 's site of action (the nucleus of the neoplasm) and out of the cell, thus, rendering the therapy less effective.
- Preferred oncolytic agents are doxorubicin, daunorubicin, epirubicin, vincristine, and etoposide.
- treat or “treating” bear their usual meaning which includes preventing, prohibiting, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of MRPl derived drug resistance in a multidrug resistant tumor.
- C1-C4 alkyl refers to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, cyclobutyl, s-butyl, and t-butyl.
- Ci-Cg alkyl refers to a monovalent, straight or branched saturated hydrocarbon containing from 1 to 6 carbon atoms. Additionally, the term “C -Cg alkyl” includes C1-C4 alkyl groups and C3-C6 cycloalkyls.
- C ⁇ -Cg alkyl includes, but is not limited to, cyclopentyl, pentyl, hexyl, cyclohexyl, and the like.
- C3-C8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- C5-C7 cycloalkyl refers to cyclopentyl, cyclohexyl, and cycloheptyl.
- C6-C10 bicycloalkyl refers to bicyclo-[2.1.1]hexanyl, [2.2.1]heptanyl, [3.2.1]octanyl,
- lower alkyl refers to branched or straight chain monovalent alkyl radical of one to six carbon atoms, and optionally to a cyclic monovalent alkyl radical of three to six carbon atoms.
- This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropyl-methyl, i-amyl, n-amyl, and hexyl.
- C1-C4 alkyl and “optionally substituted Cj-Cg alkyl” refers to a C1-C4 alkyl or Cj-Cg alkyl, respectively, unsubstituted or substituted from 1 to 3 times with halo or hydroxy.
- C1-C4 alkoxy and “Cj-Cg alkoxy” refer to moieties of the formula
- C3-C8 cycloalkyl refers to a C3-C8 cycloalkyl unsubstituted or substituted once with a phenyl, substituted phenyl, or CO2R 2 group.
- optionally substituted (C1-C4 alkyl)-(C3-Cg cycloalkyl) refers to optionally substituted C3-C8 cycloalkyl linked through a C1-C4 alkyl, unsubstituted or substituted with halo or hydroxy.
- optionally substituted O-(C3 ⁇ Cg cycloalkyl) refers to an optionally substituted C3-C8 cycloalkyl linked through an oxygen atom.
- Cg-Cjo bicycloalkyl refers to a Cg-Cjo bicycloalkyl unsubstituted or substituted once with a phenyl, substituted phenyl, or CO2R 2 group.
- halo or “halide” refers to fluoro, chloro, bromo, and iodo.
- aryl refers to phenyl, and naphthyl.
- optionally substituted aryl refers to a phenyl and naphthyl group, respectively, unsubstituted or substituted from 1 to 5 times independently with C ⁇ -Cg alkyl, C!-C 4 alkoxy, halo, hydroxy, trifluoromethyl, NR 8 R 9 , SO 2 N(R 10 )2, NH-Pg,
- optionally substituted (C1-C4 alkyl)-aryl refers to optionally substituted aryl linked through a C1-C4 alkyl, unsubstituted or substituted with halo, trifluoromethyl, or hydroxy.
- optionally substituted O-aryl refers to an optionally substituted aryl linked through an oxygen atom.
- phenoxy refers to a phenoxy group unsubstituted or substituted from 1 to 3 times independently with C ⁇ -Cg alkyl, halo, hydroxy, trifluoromethyl, NR 8 R 9 , SO2N(R 10 ) 2 , NH-Pg, Ci -Cg alkoxy, benzyloxy,
- optionally substituted (C1-C4 alkyl)-phenoxy refers to unsubstituted or substituted phenoxy linked through a C1-C4 alkyl, optionally substituted with halo, trifluoromethyl, or hydroxy.
- heterocycle is taken to mean stable unsaturated and saturated 3 to 6 membered rings containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said rings being optionally benzofused. All of these rings may be substituted with up to three substituents independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyano, nitro, hydroxy, -S(O)d-(C ⁇ -C4 alkyl) and -S(O)d-phenyl where d is 0, 1 or 2.
- Saturated rings include, for example, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, oxazolidinyl, morpholino, dioxanyl, pyranyl, and the like.
- Benzofused saturated rings include indolinyl, 1,2,3,4-tetrahydroquinolinyl,
- Unsaturated rings include furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like.
- Benzofused unsaturated rings include isoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl, benzofuranyl, thionaphthyl, indolyl and the like.
- heteroaryl is taken to mean an unsaturated or benzofused unsaturated heterocycle as defined in the previous paragraph.
- optionally substituted heterocycle refers to a heterocyclic ring unsubstituted or substituted 1 or 3 times independently with a Cj-Cg alkyl, halo, benzyl, phenyl, trifluoromethyl. Heterocyclic rings may be additionally substituted 1 or 2 times with an oxo group, however, total substitution of the saturated heterocyclic ring may not exceed two substituents.
- optionally substituted O-heterocycle refers to an optionally substituted heterocycle linked through an oxygen atom.
- optionally substituted (C1-C4 alkyl)-heterocycle refers to optionally substituted heterocycle linked through a C1-C4 alkyl, unsubstituted or substituted with halo or hydroxy.
- N-heterocycle refers to a nitrogen containing heterocycle linked through nitrogen atom.
- amino acid ester refers to an amino acid where the carboxy group is substituted with a Cj-Cg alkyl or benzyl group. That is, the alkyl group when taken together with the carboxy group forms a C ⁇ -Cg alkyl ester.
- amino acids have two carboxy groups that may be substituted with a C ⁇ -Cg alkyl group, for example, aspartic acid and glutamic acid.
- This invention contemplates the possibility of amino acid mono- or diesters in these circumstances.
- protecting group refers to an amino protecting group or a hydroxy protecting group.
- the species of protecting group will be evident from whether the "Pg” group is attached to a nitrogen atom (amino protecting group) or attached to an oxygen atom (hydroxy protecting group).
- leaving group refers to a group cleavable from the substrate molecule during a reaction step and comprises a halo group, sulfonates (e.g., mesylate (OMs) or tosylate (OTs)) and the like known in the art as leaving groups.
- sulfonates e.g., mesylate (OMs) or tosylate (OTs)
- leaving groups e.g., mesylate (OMs) or tosylate (OTs)
- nucleophile source as used herein describes a group capable of effecting a nucleophilic substitution on an alcohol. Such groups include halogenic acids such as HC1, HBr or HI and sulfonic acids, sulfonic anhydrides or sulfonic acid halides e.g., methanesulfonic acid chloride.
- amino protecting group refers to a substituent(s) of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
- amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the acetyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl,
- FMOC 9-fluorenylmethoxycarbonyl
- the species of amino protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule.
- Similar amino protecting groups used in the cephalosporin, penicillin, and peptide arts are also embraced by the above terms. Further examples of groups referred to by the above terms are described by T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referred to as "Greene”.
- a preferred amino protecting group is t-butyloxycarbonyl.
- hydroxy protecting group denotes a group understood by one skilled in the organic chemical arts of the type described in Chapter 2 of Greene.
- Representative hydroxy protecting groups include, for example, ether groups including methyl and substituted methyl ether groups such as methyl ether, methoxymethyl ether, methylthiomethyl ether, tert-buylthiomethyl ether, (phenyldimethylsilyl)methoxy-methyl ether, benzyloxymethyl ether, p-methoxybenzyloxy-methyl ether, and tert-butoxymethyl ether; substituted ethyl ether groups such as ethoxyethyl ether, l-(2-chloroethoxy)-ethyl ether, 2,2,2-trichloroethoxymethyl ether, and 2-(trimethylsilyl)ethyl ether; isopropyl ether groups; phenyl and substituted phenyl ether groups such as phenyl ether, ⁇ -chlor
- alkylsilyl ether groups such as trimethyl- triethyl- and triisopropylsilyl ethers, mixed alkylsilyl ether groups such as dimethylisopropylsilyl ether, and diethylisopropylsilyl ether; and ester protecting groups such as formate ester, benzylformate ester, mono-, di-, and trichloroacetate esters, phenoxyacetate ester, and /7-chlorophenoxyacetate and the like.
- the species of hydroxy protecting group employed is not critical so long as the derivatized hydroxy group is stable to the conditions of subsequent reaction(s) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other hydroxy protecting group(s).
- MTBE as used herein describes methyl tertiary-butyl ether.
- KHMDS potassium hexamethyldisilazane.
- Step a The process of step (a) of the invention is performed via the Curtius rearrangement, by converting a compound of formula D, in an appropriate solvent, with an appropriate azide, then an appropriate alcohol, to provide a compound of formula (vi).
- the compound of formula U dissolved in an appropriate solvent, is first treated with an appropriate azide and optionally a catalyst to provide the intermediate.
- the intermediate is treated with an appropriate alcohol to obtain the compound of formula (vi).
- the resulting compound of formula (vi) may be isolated by standard extractions and filtrations. If desired, the resulting compound of formula (vi) may be further purified by chromatography or crystallization as appropriate.
- Appropriate solvents must be capable of dissolving a sufficient amount of the compound of formula D and the azide for the reaction to proceed.
- Useful organic solvents include hexamethylphosphoramide, dimethylformamide, and preferably toluene.
- the skilled artisan would appreciate that the Curtius rearrangement may be performed via a number of azides and that reaction conditions may vary depending upon the azide used. For example if sodium azide, potassium azide, and the like are used the compound must first be converted to the activated acid with an appropriate activating agent, such as ethyl chloroformate or sulfuric acid.
- the substrate may need to be pretreated with the activating agent, such as the case with ethyl chloroformate, or may need to be added simultaneously.
- the activating agent such as the case with ethyl chloroformate
- diphenylphosphoryl azide is used in the process of the present invention without an activating agent.
- Appropriate alcohols for step (a) of the invention are lower alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol, benzyl, t-butanol, TMS-ethanol, and the like.
- step (a) may be carried out over a large range of concentrations, from about 0.001 molar to about 2.0 molar of the azide, dependent upon the solubility of the particular azide in the chosen solvent.
- the reaction may also be performed on slurries of the azide so long as a sufficient amount of the azide is soluble in the solvent for the reaction to proceed.
- Preferably the process is performed at a concentration from about 0.1 molar to about 1.0 molar.
- a concentration of about 0.3 to about 0.4 molar is most preferred.
- Reactions of step (a) may be performed between about 80°C and about 130°C, preferably between about 100°C and about 120°C.
- the reactants are combined at temperature of about 20°C to about 30°C, then heated to about 80°C and about 120°C, the azide is then added, and the reactants are stirred for about 0.5 to about 1.5 hours at reflux.
- An appropriate alcohol is then added and heated to about 70°C to about 90°C for about 3 to about 24 hours, preferably from about 75°C to about 85°C for about 8 to about 12 hours.
- Step (b) The deprotection process of step (b) of the invention is performed by combining the compound of formula (vi) with an appropriate deprotecting agent in an appropriate reaction medium. Once the reaction is complete, as measured by consumption of the substrate, the resulting compound of formula (vii) is isolated by standard extractions and filtrations. JJ desired, the resulting compound of formula (vii) may be further purified by chromatography or crystallization as appropriate. Methods of removing an amino- protecting group are well known in the art, for example, see T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referred to as "Greene”.
- Reaction media useful for the process of step (b) must be capable of dissolving a sufficient amount of the compound of formula (vi) for the reaction to proceed.
- Organic solvents useful as reaction media for the process of this invention depend upon the choice of deprotecting agent and may include tetrahydrofuran, acetonitrile or chlorocarbons.
- reactions of step (b) may be performed between about -30° and about 60°C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
- step (b) may be carried out over a large range of concentrations, from about 0.001 molar to about 2.0 molar of the compound of formula (vi), dependent upon the solubility of the particular product in the chosen reaction medium.
- the process is performed at a concentration from about 0.01 molar to about 1.0 molar.
- a concentration of about 0.20 molar to about 0.50 molar is most preferred.
- Step (c) The acylation process of step (c) of the invention is performed by combining the compound of formula (vii) with an appropriate acylating agent in an appropriate solvent. Once the reaction is complete, as measured by consumption of the substrate, the resulting compound of formula 1(a) is isolated by standard extractions and filtrations. Jf desired, the resulting compound of formula 1(a) may be further purified by chromatography or crystallization as appropriate.
- Reductive alkylation of primary amines are well known transformations, see, e.g., Larock, pg. 434-435.
- the skilled artisan will appreciate that the treatment of acyl halides, preferably the acyl chlorides, with amines is a very general reaction for the preparation of amides, see, e.g. March J, Advanced Organic Chemistry. 1985, 3rd edition, page 370.
- the reaction is highly exothermic and must be carefully controlled, usually by cooling.
- Reaction media useful must be capable of dissolving a sufficient amount of the compound of formula (vii) for the reaction to proceed.
- Organic solvents useful as reaction media for the process of this invention depend upon the choice of alkylating agent and may include CHCI3, hexane, cyclohexane, nitromethane, nitrobenzene, acetonitrile, ether, dioxane, trichloroacetic anhydride, dichloroacetic anhydride, and preferably tetrahydrofuran or CH2CI2.
- the overall conversion may be performed at about 0 °C to the boiling point of the mixture but room temperature is a preferred reaction temperature.
- the formation of the compounds of formulas 1(a) may take from 15 minutes to 24 hours as measured by the consumption of the acyl halide.
- acyl halides of the present invention are commercially available, and to the extent not available, may be prepared by methods well known to the skilled artisan.
- Compounds of formula 1(b) may be prepared by a process comprising the following steps: (a) reducing a compound of formula II in an appropriate solvent, with an appropriate reducing agent to provide a compound of formula (x);
- Step (a) The process of step (a) of the invention is performed by reducing a compound of formula D, in an appropriate solvent, with an appropriate reducing agent to provide a compound of formula (x).
- the resulting compound of formula (x) may be isolated by standard extractions and filtrations. Ii desired, the resulting compound of formula (x) may be further purified by chromatography or crystallization as appropriate.
- the carboxylic acid of formula H may be reduced to the corresponding alcohol by methods well known in the art, see for example Larock, pages 548-549. This reaction proceeds by combining the carboxylic acid with an appropriate reducing agent in an appropriate solvent.
- reducing agents include boron compounds such as BH3, BH3»SMe2,
- BF3*OEt2, B(OMe)3, L1BH4, and NaBH-4 are examples of solvents useful when the reducing agent is a boron compound must be capable of dissolving a sufficient amount of the carboxylic acid for the reaction to proceed.
- solvents may include the following organic solvents: dichloromethane, mixtures of DMF and dichloromethane, mixtures of tetrahydrofuran and water, dimethylformamide, and preferably tetrahydrofuran.
- Additional appropriate reducing agents include aluminum compounds such as LiAlH3 and NaH2Al(OCH2CH2OCH3)2, and other reducing agents that reduce the carboxylic acid without adversely affecting the rest of the molecule.
- solvents useful for aluminum compounds are well known in the art and include such solvents as dichloromethane, benzene, diethylamine, tetrahydrofuran, and the like.
- the reducing agent is preferably added dropwise to the substrate at about -5°C to about 10°C then slowly warmed to room temperature. The solution is stirred for about V2 to about 2 hours, then quenched.
- the resulting alcohol may be isolated by standard extractions and filtrations. Ii desired, the alcohol may be further purified by chromatography or crystallization as appropriate.
- Step (b) of the invention is performed by reacting the compound of formula (x), in an appropriate solvent, with an appropriate nucleophile source to provide a compound of formula (xi) .
- solvents must be capable of dissolving a sufficient amount of the compound of formula (x) for the reaction to proceed.
- solvent selected depends upon the nucleophile source used.
- Useful organic solvents include dichloromethane, THF, CHCI3, dioxane, benzene, MeCN, HCONM ⁇ 2, AC2O, acetone, ethanol, and preferably pyridine.
- nucleophiles include HC1, HBr or HI and sulfonic acids, sulfonic anhydrides or sulfonic acid halides e.g., methanesulfonic acid chloride or the like.
- Bromination for example, is effected by the addition of hydrogen bromide while maintaining a temperature from about 30 °C to about 100 °C, for about 2 to about 5 hours, preferably about 4 hours. The reaction mixture is then evaporated to dryness, affording the corresponding compound.
- the use of methanesulfonyl chloride is preferred.
- Step (c) The process of step (c) of the invention is performed via nucleophilic displacement, by reacting a compound of formula (xi), in an appropriate solvent, with an appropriate azide salt to provide a compound of formula (xii).
- a compound of formula (xi) dissolved in an appropriate solvent, is treated with an appropriate azide to provide a compound of formula (xii).
- the resulting compound of formula (xii) may be isolated by standard extractions and filtrations. Ii desired, the resulting compound of formula (xii) may be further purified by chromatography or crystallization as appropriate.
- Appropriate solvents must be capable of dissolving a sufficient amount of the compound of formula (xi) and the azide for the reaction to proceed.
- Useful organic solvents include hexamethylphosphoramide, toluene, and preferably dimethylformamide.
- Suitable azides for this reaction include sodium azide, potassium azide, and the like.
- sodium azide is the azide of choice
- step (c) may be carried out over a large range of concentrations, from about 0.001 molar to about 4.0 molar of the azide, dependent upon the solubility of the particular azide in the chosen solvent.
- the reaction may also be performed on slurries of the azide so long as a sufficient amount of the azide is soluble in the solvent for the reaction to proceed.
- the process is performed at a concentration from about 2.0 molar to about 4.0 molar. A concentration of about 3.0 to about 3.5 molar is most preferred.
- Reactions of step (c) may be performed between about 20 °C and about 130 °C, preferably between about 50 °C and about 70 °C. Most preferably the reactants are combined at temperature of about 20 °C to about 30 °C, then heated to a temperature of about 50 °C to about 70°C and stirred for about 1.0 to about 20.0 hours.
- Step (d) The reduction of step (d) of the invention is performed by combining the compound of formula (xii) with an appropriate reducing agent in an appropriate reaction medium. Once the reaction is complete, as measured by consumption of the substrate, the resulting compound of formula (xiv) is isolated by standard extractions and filtrations. Ii desired, the resulting compound of formula (xiv) may be further purified by chromatography or crystallization as appropriate. Methods of reducing an azide to an amine are well known in the art, for example, see Larock, (2 nd ed., 1999), pages 815-820. Compounds useful as reducing agents include NaBELj., L1BH4, triphenyl phosphine, and the like. Additionally the reducing agent may be H2 in the presence of a suitable catalyst, such as Pd/C, Pd, Raney Ni, Pd-Al2 ⁇ 3, Pd(OH)2 ⁇ C, PdO, Pt ⁇ 2, and the like.
- a suitable catalyst such as Pd/
- Reaction media useful for the process of step (e) must be capable of dissolving a sufficient amount of the compound of formula (xii) for the reaction to proceed.
- Organic solvents useful as reaction media for the process of this invention depend upon the choice of reducing agent and may include ethyl acetate and ethanol.
- reactions of step (d) may be performed between about -30° and about 60°C. Preferable the reaction is performed between about 20 °C and about 30 °C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
- Step (e) The acylation process of step (e) of the invention is performed by combining the compound of formula (xiv) with an appropriate acylating agent in an appropriate solvent. Once the reaction is complete, as measured by consumption of the substrate, the resulting compound of formula 1(b) is isolated by standard extractions and filtrations. Ii desired, the resulting compound of formula 1(b) may be further purified by chromatography or crystallization as appropriate.
- Organic solvents useful as reaction media for the process of this invention depend upon the choice of acylating agent and may include CHCI3, hexane, cyclohexane, nitromethane, nitrobenzene, acetonitrile, ether, dioxane, trichloroacetic anhydride, dichloroacetic anhydride, and preferably tetrahydrofuran or CH2CI2.
- the overall conversion may be performed at about 0°C to the boiling point of the mixture but room temperature is a preferred reaction temperature.
- the formation of the compounds of formulas 1(b) may take from 15 minutes to 24 hours as measured by the consumption of the acyl halide.
- acyl halides of the present invention are commercially available, and to the extent not available, may be prepared by methods well known to the skilled artisan.
- step (a) of the invention is performed via Curtius rearrangement by (1) converting the compound of formula (i) to the corresponding acyl azide and then (2) treating the corresponding acyl azide to form the compound of formula (ii) with an appropriate substrate.
- an appropriate substrate for examples of how to perform such reactions see Org. Rxs 3 337 (1947), TL 25 3515 (1984), JOC 51 3007, 5123 (1986); 524875 (1987), JOC 26 3511 (1961); 43 2164 (1978), and preferably JACS 94 6203 (1972) and Tetr 302151 (1974).
- the compound of formula (ii) may be isolated by standard extractions and filtrations.
- the compound of formula (ii) may be further purified by chromatography or crystallization as appropriate.
- (lR,3S)-3-(Carbonyl)cyclohexanecarboxylic acid, the compound of formula (i), is commercially available from Eastman Kodak or may be prepared as described in U.S. Patent No. 6,028,213.
- the compound of formula (i), dissolved in an appropriate solvent is first treated with an appropriate azide and optionally a catalyst. Once the reaction is complete, as measured by the consumption of substrate, then an appropriate alcohol is added.
- Appropriate solvents useful for the process of step (a) of the invention must be capable of dissolving a sufficient amount of the compound of formula (i) and then the corresponding azide for the reaction to proceed.
- Useful organic solvents include hexamethylphosphoramide, dimethylformamide, and toluene.
- Suitable azides for this reaction include sodium azide, potassium azide, and the like.
- diphenylphosphoryl azide is the azide of choice.
- the skilled artisan would appreciate that diphenylphosphoryl azide will not require a catalyst.
- the use of sodium azide and potassium azide and the like may require a activating agent, such as ethyl chloroformaate or sulfuric acid.
- the substrate may need to be pretreated with the activating agent, such as the case with ethyl chloroformate, or may need to be added simultaneously.
- the activating agent such as the case with ethyl chloroformate
- Appropriate alcohols are lower alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol, TMS-ethanol, benzyl, t-butanol, and the like.
- Methanol is the preferred alcohol.
- the process of part (1) of step a) may be carried out over a large range of concentrations, from about 0.001 molar to about 2.0 molar of the azide, dependent upon the solubility of the particular azide in the chosen solvent.
- the reaction may also be performed on slurries of the azide so long as a sufficient amount of the azide is soluble in the solvent for the reaction to proceed.
- the process is performed at a concentration from about 0.1 molar to about 1.0 molar. A concentration of about 0.3 to about 0.4 molar is most preferred.
- from about 0.1 molar to about 3.0 molar of the alcohol can be used in part (2) of step (a).
- the process is performed at a concentration from about 1.5 molar to about 2.5 molar. A concentration of about 2.0 molar is most preferred.
- Reactions of part (1) of step (a) may be performed between about 80°C and about 130°C, preferably between about 100°C and about 120°C. Most preferably the reactants are combined at temperature of about 20°C to about 30°C, then heated to about 80°C and about 120°C, the azide is added, and the reaction is stirred for about 0.5 to about 1.5 hours at reflux.
- the mixture from part (1) is allowed to cool to about 20 °C to about 100 °C, preferably from about 70 °C to about 90 °C and then the appropriate alcohol is added. This reaction mixture is then warmed to about 70°C to about 90°C, if needed, for about 3 to about 24 hours, preferably about 75°C to about 85°C for about 8 to about 12 hours.
- step b) of the invention is performed by combining the compound of formula (ii) with an appropriate deprotecting agent in an appropriate reaction medium. Once the reaction is complete, as measured by consumption of the substrate, the resulting compound of formula (iii) is isolated by standard extractions and filtrations. Ji desired, the resulting compound of formula (iii) may be further purified by chromatography or crystallization as appropriate. Methods of removing an amino- protecting group are well known in the art, for example, see T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referred to as "Greene”.
- Reaction media useful for the process of step (b) must be capable of dissolving a sufficient amount of the compound of formula (ii) for the reaction to proceed.
- Organic solvents useful as reaction media for the process of this invention depend upon the choice of deprotecting agent and may include tetrahydrofuran, acetonitrile or chlorocarbons.
- reactions of step (b) may be performed between about -30° and about 60°C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
- step (b) may be carried out over a large range of concentrations, from about 0.001 molar to about 2.0 molar of the compound of formula (iii), dependent upon the solubility of the particular product in the chosen reaction medium.
- the process is performed at a concentration from about 0.01 molar to about 1.0 molar.
- a concentration of about 0.20 molar to about 0.50 molar is most preferred.
- step (c) may be performed by reacting the compound of formula
- the order and manner of combining the reactants are not important and may be varied as a matter of convenience.
- the substrate and the acid chloride may first be combined and then the reaction medium added.
- the substrate may first be dissolved in an appropriate reaction medium and this solution added to a mixture of the acid chloride.
- a solution of the substrate in an appropriate reaction medium may be added to a slurry of the acid chloride in the same reaction medium.
- a first slurry containing part of the reactants in an appropriate reaction medium may be added to a second slurry of the remaining reactants in an appropriate reaction medium as is desired or convenient. All of these methods are useful for the process of the present invention.
- Reaction media useful for step (c) of the invention must be capable of dissolving a sufficient amount of the compound of formula (iii) products for the reaction to proceed.
- Organic solvents useful as reaction media for the process of this invention may include pyridine, triethylamine, 1:1 mixture of DMF and dichloromethane, mixture of tetrahydrofuran and water, dimethylformamide, and preferably tetrahydrofuran/water.
- Bases useful to the process of step (c) include 4- dimethylaminopyridine (DMAP) and preferably potassium carbonate.
- the acid chloride is typically employed in an equimolar amount, relative to the amine, but a slight excess (about a 0.05 to about 0.15 molar excess) is acceptable.
- Reactions of step (c) may be performed between about -30° and about 130°C. Preferably the reactants are combined between about 20°C and about 30°C, then stirred for about 10 to about 14 hours. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated. Step (d)
- Step (d) of the reaction is performed by cyclizing the compound of formula (iv), in an appropriate solvent, in the presence of an appropriate catalyst, to form the compound of formula DI.
- the resulting compound of formula DI may be isolated by standard extractions and filtrations. If desired, the compound of formula DI may be further purified by chromatography or crystallization as appropriate.
- the compound of formula DI may be prepared by dissolving or suspending the compound of formula (iv) in a suitable solvent, preferably dimethylformamide, and adding a suitable base, including potassium methoxide, potassium tert-butoxide, potassium carbonate, sodium hexamethyldisilazane, and preferably potassium hexamethyldisilazane.
- a suitable solvent preferably dimethylformamide
- a suitable base including potassium methoxide, potassium tert-butoxide, potassium carbonate, sodium hexamethyldisilazane, and preferably potassium hexamethyldisilazane.
- the base is typically employed in a one to one ratio. However, as the skilled artisan would appreciate, a slight molar excess, usually in about a 1.1 to about a 3 fold molar excess relative to the compound of formula (iv), is acceptable.
- the reactants are typically combined at a temperature from about 0°C to about 100°C.
- the reactants are preferably combined at room temperature and the resulting solution is typically mixed for about 5 minutes to about 18 hours, preferably from about 15 minutes to about 3 hours.
- step (e) of the reaction is performed by hydrolyzing the compound of formula DI to form the compound of formula D.
- the resulting compound of formula D may be isolated by standard extractions and filtrations. Ii desired, the compound of formula D may be further purified by chromatography or crystallization as appropriate.
- the hydrolysis of the ester to the carboxylic acid is performed by standard techniques in the art, see for example Org Rxs 24 187 (1976) and Tetr 36 2409.
- the ester is treated with an appropriate aqueous base in an appropriate reaction medium.
- Reaction media useful for the process of step (e) of the invention must be capable of dissolving a sufficient amount of the ester for the reaction to proceed.
- Organic solvents useful as reaction media for the process of this invention include dimethylformamide, diethyl ether, dimethoxyethane, and preferably tetrahydrofuran.
- Suitable aqueous bases for this transformation include aqueous potassium hydroxide, lithium hydroxide, and preferably sodium hydroxide.
- Reactions of step (e) may be performed between about -30° and about 100°C, preferably between about 50°C and about 70°C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
- Compounds of formula xxx, where A is O and B is N, may be prepared by scheme
- Compounds of formula xxii may be prepared by dissolving or suspending a compound of formula xxi and a suitable base in a suitable solvent and adding a compound of formula xx in a suitable solvent, dropwise.
- Toluene is a convenient solvent and is typically preferred.
- Triethylamine is the preferred base.
- the compound of formula xx is typically and preferably employed in an equimolar amount, relative to the compound of formula xxi, but a slight excess is acceptable.
- the reactants are preferably combined at about 0°C and the resulting solution is typically warmed to room temperature and mixed for from about 18 hours to about 24 hours.
- the compound of formula xxii may then be converted to the compound of formula xxiii by dissolving or suspending a compound of formula xxii in a suitable acidic solvent and adding hydroxylamine hydrochloride.
- Glacial acetic acid is a convenient acidic solvent and is typically preferred.
- the ester group is then hydrolyzed to the corresponding carboxylic acid of formula xxx through standard procedures commonly employed in the art, see for example, Larock, pgs 981-985.
- the carboxylic acid of formula xxx may be converted to the corresponding acid chloride through standard procedures commonly employed in the art, see for example, Larock, pgs 963-964.
- the reactants are preferably combined at about room temperature then heated to reflux for from about 30 minutes to about 60 minutes. Preferably the reaction is heated to reflux from about 40 to 45 minutes.
- Compounds of formula xx and xxi are known in the art and, to the extent not commercially available, are readily synthesized by standard procedures commonly employed in the art.
- THF (350 ml) was added borane-methyl sulfide complex in 140 ml of THF (26 ml, 0.27 mol) dropwise at 0 °C. After the addition, the reaction mixture was stirred at 0-5 °C for one hour. TLC (3:1 EtOAc/hexane) indicated the completion of the reaction. Methanol (50 ml) was added slowly (gas generated) with stirring, followed by aqueous 10% HCl (50 ml). After stirring for 15 minutes, the reaction mixture was poured into ice water (250 ml) and extracted with ethyl acetate (350 ml x 2).
- the reaction mixture was stirred overnight at ambient temperature and concentrated to dryness.
- the residue was partitioned between chloroform and saturated sodium bicarbonate.
- the mixture was washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to dryness.
- the residue was chromatographed on silica gel using methanol/chloroform as eluent and concentrated to dryness.
- the residue was slurried in ether/hexanes and concentrated to dryness to yield 77 mg (71%) of the desired isomer as a white foam.
- the compounds of formula I are inhibitors of MRPl.
- the compounds of the invention may be used to inhibit any neoplasm having intrinsic and/or acquired resistance, conferred in part or in total by MRPl, to an oncolytic or oncolytics.
- treatment of such a neoplasm with an effective amount of a compound of this invention will cause the neoplasm to be more sensitive to chemotherapy that was rendered less efficacious by MRPl.
- neoplasms of the bladder, bone, breast, lung(small-cell), testis, and thyroid and more specific types of cancer such as acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non- Hodgkin's lymphomas, and bronchogenic carcinoma may be inhibited with a combination of one or more of the above oncolytics and a compound of this invention.
- the biological activity of the compounds of the present invention was evaluated employing an initial screening assay, which rapidly and accurately measured the activity of the tested compound in inhibiting MRPl or MDRl.
- Assays useful for evaluating this reversing capability are well known in the art. See, e.g., T. McGrath, et al, Biochemical Pharmacology, 38:3611, 1989; D. Marquardt and M.S. Center, Cancer Research,
- HL60/Adr and HL60/Ninc are continuous cell lines, which were selected for doxorubicin and vincristine resistance respectively by culturing HL60, a human acute myeloblastic leukemia cell line, in increasing concentrations of doxorubicin or vincristine until a highly resistant variant was attained.
- HL60/Adr and HL60/Ninc cells were grown in RPMI 1640 (Gibco) containing 10% fetal bovine serum (FBS) and 50 ⁇ g ml GE ⁇ TAMICI ⁇ TM (Sigma). Cells were harvested; washed twice with assay medium (same as culture media); counted; and diluted to 1 x 10 ⁇ cells/ml in assay medium. One hundred microliters of cells were aliquoted into wells of a 96 well tissue culture plate. Two columns of each 96 well plate served as a negative control and received assay medium containing no cells. Test compounds and reference compounds were dissolved in dimethyl sulfoxide
- DMSO dimethyl methyl sulfoxide
- Samples were diluted in assay medium and 25 ⁇ l of each test compound was added to 8 wells.
- Assay standards were run in quadruplicate.
- Assay media was added to half of the wells and doxorubicin to the other half of the wells to achieve a final volume of 150 ⁇ l per well.
- the plates were incubated at 37°C for 72 hours in a humidified incubator with a 5% carbon dioxide atmosphere. Cell viability and vitality was measured by oxidation of a alamarBlueTM fluorescent dye using standard conditions. The plates were incubated for 3 hours at 37°C. Fluorescence was determined using 550 nm excitation and 590 nm emission using a microtitre plate reader.
- test compound The ability of a test compound to reverse the resistance of HL60/Adr and HL60/Vinc cells to doxorubicin was determined by comparison of the absorbance of the wells containing a test compound in addition to the oncolytic (doxorubicin) with the absorbance of wells containing the oncolytic without a test compound. Controls were used to eliminate background and to ensure the results were not artifactual. The results of the assay are expressed as percent inhibition of cell growth. The oncolytic alone at the tested concentration minimally inhibits the growth of HL60/Adr or HL60/ Vine cells. Representative compounds of formula I demonstrated a significant effect in reversing the MRPl multiple drug resistance.
- the amount of oncolytic employed will be variable. It should be understood that the amount of the oncolytic actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual oncolytic administered, the age, weight, and response of the individual patient (mammal), and the severity of the patient's symptoms. Of course, the amount of oncolytic administered should be decided and closely monitored by that patient's physician. After deciding on the oncolytic or oncolytics to employ, "The Physician' s Desk Reference®", published by Medical Economics Company at Montvale,
- ⁇ J 07645-1742 is a helpful resource to the physician in deciding on amounts of the oncolytic to administer and is updated annually.
- Preferred formulations, and the methods of this invention employing those formulations are those which do not contain an oncolytic. Thus, it is preferred to administer the compounds of this invention separately from the oncolytic.
- the oncolytics mentioned in this specification are commercially available and may be purchased in pre- formulated forms suitable for the methods of this invention.
- the compounds of formula I alone, or optionally in combination with an oncolytic, are usually administered in the form of pharmaceutical formulations.
- These formulations can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
- Such formulations are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of formula I.
- the present invention also includes methods employing pharmaceutical formulations, which contain, as the active ingredient, the compounds of formula I, and optionally an oncolytic, associated with pharmaceutical carriers.
- the active ingredient(s) is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- the formulations can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- Ji the active compound(s) is substantially water soluble, the particle size is normally adjusted by nulling to provide a substantially uniform distribution in the formulation, e.g. , about 40 mesh.
- suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
- the formulations of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- the formulations are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of each active ingredient.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the compounds of formula I are effective over a wide dosage range.
- dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
- the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
- the principal active ingredient(s) is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- the active ingredient(s) is dispersed evenly throughout the formulation so that the formulation may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid preformulation is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- novel formulations which are liquid forms may be incorporated for administration orally or by injection and include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Formulations for inhalation or insufflation include solutions and suspensions in pharmaceutical, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid formulations may contain suitable pharmaceutical excipients as described supra.
- the formulations are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutical solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine.
- Solution, suspension, or powder formulations may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
- the following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
- "Active ingredient(s)" means a compound according to formula I or a pharmaceutical salt or solvate thereof optionally with one or more oncolytics.
- the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
- Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
- the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
- Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
- the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
- the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
- Quantity Ingredient (mg/capsule)
- the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
- the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
- the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
- the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities.
- composition Example 9 An intravenous formulation may be prepared as follows:
- a topical formulation may be prepared as follows:
- Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g
- the white soft paraffin is heated until molten.
- the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
- the active ingredient is added and stirring is continued until dispersed.
- the mixture is then cooled until solid.
- Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
- the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
- the solution is cooled to about 50-55 °C and the active ingredient is slowly admixed.
- the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
- transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
- patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the- conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
- Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
- the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions, which can transiently open the blood-brain barrier.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2001294518A AU2001294518A1 (en) | 2000-09-22 | 2001-09-13 | Stereoselective process for preparing cyclohexyl amine derivatives |
EP01975165A EP1322652A1 (en) | 2000-09-22 | 2001-09-13 | Stereoselective process for preparing cyclohexyl amine derivatives |
CA002420210A CA2420210A1 (en) | 2000-09-22 | 2001-09-13 | Stereoselective process for preparing cyclohexyl amine derivatives |
JP2002529115A JP2004509897A (en) | 2000-09-22 | 2001-09-13 | Stereoselective production of cyclohexylamine derivatives |
US10/362,496 US20040010005A1 (en) | 2001-09-13 | 2001-09-13 | Stereoselective process for preparing cylcohexyl amine derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23464900P | 2000-09-22 | 2000-09-22 | |
US60/234,649 | 2000-09-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002024705A1 true WO2002024705A1 (en) | 2002-03-28 |
Family
ID=22882230
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/026023 WO2002024705A1 (en) | 2000-09-22 | 2001-09-13 | Stereoselective process for preparing cyclohexyl amine derivatives |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1322652A1 (en) |
JP (1) | JP2004509897A (en) |
AU (1) | AU2001294518A1 (en) |
CA (1) | CA2420210A1 (en) |
WO (1) | WO2002024705A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102485726A (en) * | 2010-12-02 | 2012-06-06 | 上海药明康德新药开发有限公司 | Method for preparing 1-R-1'-spiro-(piperidine-4,4'-quinoline)-2'(3'-hydrogen)ketone |
WO2012083117A1 (en) | 2010-12-16 | 2012-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2012083121A1 (en) | 2010-12-16 | 2012-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2012083122A1 (en) | 2010-12-16 | 2012-06-21 | Vertex Pharmaceutical Incorporated | Inhibitors of influenza viruses replication |
EP3427738A1 (en) | 2009-06-17 | 2019-01-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999051228A1 (en) * | 1998-04-08 | 1999-10-14 | Eli Lilly And Company | Methods for inhibiting mrp1 |
WO1999051227A1 (en) * | 1998-04-08 | 1999-10-14 | Eli Lilly And Company | Methods for inhibiting mrp1 |
-
2001
- 2001-09-13 CA CA002420210A patent/CA2420210A1/en not_active Abandoned
- 2001-09-13 AU AU2001294518A patent/AU2001294518A1/en not_active Abandoned
- 2001-09-13 WO PCT/US2001/026023 patent/WO2002024705A1/en not_active Application Discontinuation
- 2001-09-13 JP JP2002529115A patent/JP2004509897A/en not_active Withdrawn
- 2001-09-13 EP EP01975165A patent/EP1322652A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999051228A1 (en) * | 1998-04-08 | 1999-10-14 | Eli Lilly And Company | Methods for inhibiting mrp1 |
WO1999051227A1 (en) * | 1998-04-08 | 1999-10-14 | Eli Lilly And Company | Methods for inhibiting mrp1 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3427738A1 (en) | 2009-06-17 | 2019-01-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
CN102485726A (en) * | 2010-12-02 | 2012-06-06 | 上海药明康德新药开发有限公司 | Method for preparing 1-R-1'-spiro-(piperidine-4,4'-quinoline)-2'(3'-hydrogen)ketone |
CN102485726B (en) * | 2010-12-02 | 2015-07-01 | 天津药明康德新药开发有限公司 | Method for preparing 1-R-1'-spiro-(piperidine-4,4'-quinoline)-2'(3'-hydrogen) ketone |
WO2012083117A1 (en) | 2010-12-16 | 2012-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2012083121A1 (en) | 2010-12-16 | 2012-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2012083122A1 (en) | 2010-12-16 | 2012-06-21 | Vertex Pharmaceutical Incorporated | Inhibitors of influenza viruses replication |
Also Published As
Publication number | Publication date |
---|---|
EP1322652A1 (en) | 2003-07-02 |
CA2420210A1 (en) | 2002-03-28 |
JP2004509897A (en) | 2004-04-02 |
AU2001294518A1 (en) | 2002-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2276140C2 (en) | Derivatives of tetrahydropyridine and pharmaceutical composition based on thereof | |
US20040077675A1 (en) | Compounds and methods for inhibiting MRP1 | |
US6369070B1 (en) | Methods for inhibiting mrp1 | |
EP1322652A1 (en) | Stereoselective process for preparing cyclohexyl amine derivatives | |
US6673809B2 (en) | Tricyclic compounds as MRP1-inhibitors | |
US6417193B1 (en) | Methods for inhibiting MRP1 | |
US20040010005A1 (en) | Stereoselective process for preparing cylcohexyl amine derivatives | |
US6686376B2 (en) | Methods and compounds for inhibiting MRP1 | |
EP1067932A1 (en) | Methods for inhibiting mrp1 | |
US7101891B2 (en) | Compounds and pharmaceutical compositions for inhibiting MRP1 | |
EP1392702B1 (en) | Compounds and methods for inhibiting mrp1 | |
US7064131B2 (en) | Compounds and methods for inhibiting MRP1 | |
MXPA00009814A (en) | Methods for inhibiting mrp1 | |
MXPA00009825A (en) | Methods for inhibiting mrp1 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ CZ DE DE DK DK DM DZ EC EE EE ES FI FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2420210 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10362496 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001975165 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002529115 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2001975165 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2001975165 Country of ref document: EP |