EP0418292A1 - Phosphoramide zur verwendung als antitumormittel - Google Patents

Phosphoramide zur verwendung als antitumormittel

Info

Publication number
EP0418292A1
EP0418292A1 EP19890906634 EP89906634A EP0418292A1 EP 0418292 A1 EP0418292 A1 EP 0418292A1 EP 19890906634 EP19890906634 EP 19890906634 EP 89906634 A EP89906634 A EP 89906634A EP 0418292 A1 EP0418292 A1 EP 0418292A1
Authority
EP
European Patent Office
Prior art keywords
compound according
hydrogen
substituted
nitrogen
electron withdrawing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP19890906634
Other languages
English (en)
French (fr)
Other versions
EP0418292A4 (en
Inventor
Richard F. Borch
Gregory W. Canute
Ronald R. Valente
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Corp Technologies Inc
Original Assignee
Research Corp Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Research Corp Technologies Inc filed Critical Research Corp Technologies Inc
Publication of EP0418292A1 publication Critical patent/EP0418292A1/de
Publication of EP0418292A4 publication Critical patent/EP0418292A4/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2429—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of arylalkanols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates to novel phosphoramides which have useful pharmaceutical properties and are useful as anti-tumor agents.
  • Cyclophosphamide also known as cytoxan
  • Cyclophosphamide is one of the most widely used anti-cancer drugs in the world. It is administered in combination with a number of other drugs to treat a wide variety of hematolgic and solid tumors.
  • the drug requires metabolic activation in the liver to produce metabolities that are toxic to cancer cells.
  • the drug is specifically toxic to the urinary bladder and also displays the bone marrow toxicity typical of the alkylating agent class of anti-cancer drugs.
  • cyclophosphamide is a potent suppressor of the immune system at the doses used to treat cancer, thus decreasing the infection-fighting ability of patients already debilitated by their disease.
  • repeated use of cyclophosphamide frequently results in the development of resistance to the drug in a patient's cancer cells, thus rendering the drug ineffective.
  • the present invention describes new phosphoramide compounds that will circumvent one or more of these problems. Place sentence on.
  • the compounds of the present invention are effective in treating tumors in animals
  • the present invention relates to new chemical phosphoramides possessing anti-tumor activity or capable of possessing anti-tumor activity. These compounds are capable of liberating phosphoramide mustard (the cytotoxic metabolite derived from cyclophosphamides) when exposed to the reducing environment of oxygen-deficient (i.e., hypoxic) cells.
  • phosphoramide mustard the cytotoxic metabolite derived from cyclophosphamides
  • R 1 and R 2 may be the same or different and are selected from the group consisting of hydrogen, or lower alkyl which is substituted with halo, hydroxy or lower alkoxy, provided that the substituent is not on the ⁇ -carbon; or R 1 and R 2 taken together with the nitrogen to which they are attached form a morpholino ring;
  • R 3 and R 4 are independently hydrogen an electron withdrawing group or alkyl containing up to 6 carbon atoms in the main chain and up to a total of 10 carbon atoms and which is unsubstituted or monosubstituted with alkyl or an electron withdrawing group;
  • R is aryl or a nitrogen, sulfur or oxygen containing heteroaromatic group which is monosubstituted with a nitro group and a pharmaceutically acceptable salt thereof.
  • the lower alkyl groups singly or in combination with other groups containing up to six carbon atoms, which may be in the normal or branched configuration, including methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, amyl, pentyl, hexyl and the like.
  • the preferred alkyl groups contain one to three carbon atoms.
  • lower alkenyl group contains two to six carbon atoms and at least one double bond and not more than three double bonds. These groups may be in the normal or branched configuration and include such groups as ethenyl, butenyl, isobutenyl and the like.
  • alkynyl refers to a hydrocarbyl group containing up to two to six carbon atoms and contains a triple bond. These groups may be in a normal or branched configuration. These groups include ethynyl, butynyl, hexynyl, and the like.
  • the aryl groups are aromatic rings containing from 6 to 10 ring carbon atoms.
  • the aryl groups include phenyl, ⁇ -naphthyl or ⁇ -naphthyl.
  • the aryl group is preferably phenyl.
  • nitrogen, sulfur or oxygen heterocyclic ring is meant to include those heterocyclic rings which include at least one sulfur, nitrogen or oxygen ring atom but which may include one or several of said atoms.
  • the expression also includes saturated, and unsaturated heterocyclics as well as the heteroaromatic rings. These groups contain from 5 to 10 ring atoms on the heterocyclic moiety.
  • heterocyclic include furan, thiophene, pyrrole, pyridine, pyrazole, pyrazine, pyrimidine, pyridazine, oxazole, imidazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzoxazole, piperazine, tetrahydrofuran, and the like.
  • the preferred heteroaromatic is pyridyl.
  • aryl and nitrogen, sulfur or oxygen heterocyclic rings also includes the alkyl substituted aryl and heterocyclic rings.
  • said term includes toluene, ethyl benzene, alkyl imidazoles, including N-alkylimidazole, alkyl quinoline, e.g., methyl quinoline, and the like.
  • R groups as defined herein are nitro substituted aryl or heteroaromatic.
  • the nitro group may be substitued on any position of the aryl or heteroaromatic rings.
  • Preferred R groups include nitrophenyls e.g. 2-nitro or 4-nitro phenyls, nitropyridyls, such as 4-nitro-2-pyridyl or 5-nitro-2-pyridyl and nitropyrroles, nitroimidazoles and nitro quinoline.
  • the preferred nitroimidazoles are lower alkyl substituted nitroimidazoles wherein lower alkyl contains from 1 to 6 carbon atoms.
  • Especially preferred lower alkyl imidazoles are N-lower alkyl imidazoles.
  • the preferred N-alkyl imidazoles have the formula:
  • R 5 is lower alkyl
  • nitro group is on the 2,3,or 4-position of the quinoline.
  • the preferred R 1 and R 2 are hydrogen or alkyl containing 1 to 3 carbon atoms on the main chain. Both R 1 and R 2 may be monosubstituted with halogen, lower alkoxy or hydroxy at any position except at the ⁇ - position (i.e., the carbon adjacent to the nitrogen in the phosphoramide). It is preferred that the alkyl group be substituted on the omega carbon i.e., the last carbon on the chain away from the nitrogen. Preferred substituents are chloro, hydroxy or ethoxy.
  • the preferred R 1 and R 2 groups are hydrogen, CH 2 CH 2 Cl, CH 2 CH 2 OH and CH 2 CH 2 OCH 2 CH 3 . Moreover, it is preferred that R 1 is the same as R 2 .
  • R 1 and R 2 taken together with the nitrogen to which they are attached form a morpholino ring. This is also a preferred value, of R 1 and
  • R 3 and R 4 substituents are either independently hydrogen atom or an alkyl group, with said alkyl group being unsubstituted or substituted with alkyl or an electron-withdrawing group.
  • an electron withdrawing group is a group that will draw electrons to itself more than a hydrogen atom would if it occupied the same position in the molecule. See, Jerry March, "Advanced
  • Electron withdrawing groups include lower alkoxy, lower alkanoyl, formyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, hydroxy, mercapto, lower thioalkyl, carboxy, lower carbalkoxy, aryloxy, halo, nitro, cyano, lower trialkylamino, and the like.
  • the function of the electron withdrawing group is to make the hydrogen on R 4 CH-R 3 acidic, that is, easily removable by base.
  • the electron withdrawing group when present, is on the alpha carbon ofR 3 or R 4 , that is, on the first carbon atom on the R 3 or R 4 chain, respectively.
  • the preferred R 3 groups are hydrogen or carbalkyoxy, especially carbomethoxy, COOCH 3 .
  • the preferred R 4 substituent is hydrogen.
  • the compounds of the present invention can be prepared by art recognized techniques. An exemplary procedure is outlined below:
  • An alkoxide of Formula II is reacted with N,N- bis (2-chloroethyl) phosphoramidic dichloride followed by the addition of an amine R 1 R 2 NH to form the compound of Formula I. It is preferrable that the reaction take place in an inert organic solvent such as dioxane, tetrahydrofuran, hexane and the like. The reaction can take place at temperatures ranging from the melting point of the solvent to reflux temperatures, but it is preferred that the reaction take place from about - 60°C to room temperature.
  • the alkoxide of Fromula II can be prepared by reacting the corresponding alcohol with a strong base, such as alkali metal, an hydroxide or amide of an alkali metal, or a strong metal organic base, e.g., alkoxide, metal alkylamides, and the like or an organo metallic compound, such as metallic alkyls, such as n-butyl lithium, sodium methylate and the like, in accordance with procedures known to one skilled in the art.
  • a strong base such as alkali metal, an hydroxide or amide of an alkali metal, or a strong metal organic base, e.g., alkoxide, metal alkylamides, and the like or an organo metallic compound, such as metallic alkyls, such as n-butyl lithium, sodium methylate and the like, in accordance with procedures known to one skilled in the art.
  • An alternative procedure for forming the alkoxide of Formula II is to couple an aldehyde having the formula RCHO with an organometallic reagent containing a (CHR 3 R 4 ) moiety.
  • the organometallic may be on alkali metal, e.g., Li(CHR 3 R 4 ) or an Grignard reagent such as CHR 3 R 4 Mg X, wherein X is halo and the like.
  • the alkali organometallic can be generated by procedures known to one skilled in the art.
  • the Grignard can formed by reacting Mg with the halide of Formula wherein X is halo, under Grignard forming conditions.
  • CHR 3 R 4 can be metallated by active metals, such as alkali metals to form the MCHR 3 R 4 , wherein M is the active metal using metallation reagents, such as lithium bis (trimethylsilyl) amide and the like, under metallation conditions.
  • active metals such as alkali metals
  • metallation reagents such as lithium bis (trimethylsilyl) amide and the like
  • the present new compounds which contain basic nitrogen can form salts with acids. All such acid salts are contemplated by the invention but especially preferred are salts with pharmaceutically acceptable acids, such as hydrochloric, sulfuric, nitric, toluenesulfonic, acetic, propionic, tar tar ic , malic and similar such acids well known in this art.
  • quaternary salts can be formed using standard techniques of alkylation employing, for example, hydrocarbyl halides or sulfates such as methyl, ethyl, benzyl, propyl or allyl halides or sulfates.
  • the compounds of the present invention can be administered to the host in a variety of forms adapted to the chosen route of administration, i.e., orally, intravenously, intramuscularly or subcutaneous routes.
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit.
  • compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains an amount ranging from about 100mg to about 5 g of active compound.
  • Preferred dosage ranges from about 50 to about 1000 mg of active compound.
  • Especially preferred dosage ranges from about 100 to about 500mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin or a flavoring agent such as peppermint, oil of winter
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • the active compound may also be administered parenterally or intraperitoneally.
  • Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for. example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solutions thereof.
  • hypoxic cells in tumors are generally resistant to radiation and chemotherapy and thus represent a population of cells that are very difficult to eradicate.
  • Most mammaliam cells operate under conditions of oxygen excess and utilize oxidative metabolism.
  • Hypoxic cells represent a reducing environment; if a prodrug could be designed that was activated by the reducing environment inside these cells, it would provide a mechanism to deliver a cytotoxic species specifically to the tumor cell and thus offer a potential therapeutic advantage.
  • the compounds of the present invention are prodrugs that will liberate phosphoramide mustard (the cytotoxic metabolite derived from cyclophosphamide) when exposed to the reducing environment of the hypoxic cell.
  • phosphoramide mustard the cytotoxic metabolite derived from cyclophosphamide
  • the compounds of the present invention are non-cytotoxic under oxic conditions and highly cytotoxic in the presence of hypoxia.
  • the anti-tumor activity has been conducted as follows:
  • the In Vitro cytotoxic activity of representative compounds of the present invention were evalutated as follows:
  • Cultured mouse L1210 and P388 sensitive cells were purchased from EG&G Mason Research Institute, Tumor Bank, Worchester, MA.
  • Cultured cyclophosphamide resistant L1210 and P388 cells were obtained from Dr. Robert Struck of Southern Research Institute, Birmingham, Ala.
  • the desired cells (2-3 ⁇ 10 6 cells/ml) in exponential growth and suspended in 6.5 ml of Fischer's medium (Gibco Lab., Grand Island, N.Y.) were divided into six groups (1 control and 5 treated groups) containing an equal number of cells in 1 ml.
  • hypoxic cell selectivity exhibited by compounds by the present invention was evaluated as follows:
  • KHT/iv cells were adapted to cell culture from the mouse KHT sarcoma by Dietmar Siemann, University of Rochester. Cells were maintaimed in Eagle's basal medium and
  • Eagle's medium contained in stirred gas-tight vials at a final density of 2 ⁇ 10 7 cells/ml; before cells or drugs were added, the vials were pre-equilibrated with humidified gas having the composition 95:5 air:CO 2 for aerobic treatment or 95:5 nitrogen:CO 2 from hypoxic treatment. Oxygen tension in the hypoxic medium was approximately 100 ppm after the equilibration period. Drug was dissolved a volume of ethanol that would give a final ethanol concentration of 1% in the medium; this concentration of ethanol had no effect on the plating efficiency of control cell preparations. Cells were incubated with drug under aerobic or hypoxic conditions at 37° for 4 hours.
  • the cells were then removed from the vials, washed with drug-free medium, counted, and plated for cell survival using a standard clonogenic assay. Cell surviving fraction was plotted vs. drug concentration, and the LC 99 values were obtained from the least squares equation.
  • compounds of the present invention exhibit a selectivity factor of at least three in KHT sarcoma and adenocarcinoma cell lines.
  • compounds of the present invention are at least three times more toxic to these tumor lines under hypoxic conditions than to identical cells under normal oxic conditions.
  • selectivity for tumor cell killing under oxygen deficient conditions has been demonstrated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19890906634 1988-05-25 1989-05-25 Phosphoramides useful as antitumor agents Ceased EP0418292A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19840888A 1988-05-25 1988-05-25
US198408 1988-05-25

Publications (2)

Publication Number Publication Date
EP0418292A1 true EP0418292A1 (de) 1991-03-27
EP0418292A4 EP0418292A4 (en) 1991-09-25

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Application Number Title Priority Date Filing Date
EP19890906634 Ceased EP0418292A4 (en) 1988-05-25 1989-05-25 Phosphoramides useful as antitumor agents

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EP (1) EP0418292A4 (de)
JP (1) JPH04501253A (de)
WO (1) WO1989011484A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1251472B (it) * 1991-09-12 1995-05-15 Boehringer Mannheim Italia Ossaazafosforine utili come agenti antitumorali, un processo per la loro preparazione e composizioni farmaceutiche che le contengono
US5306727A (en) * 1993-04-30 1994-04-26 Research Corporation Technologies, Inc. Phosphoramidates useful as antitumor agents
US5659061A (en) * 1995-04-20 1997-08-19 Drug Innovation & Design, Inc. Tumor protease activated prodrugs of phosphoramide mustard analogs with toxification and detoxification functionalities
AU5935600A (en) 1999-07-14 2001-01-30 Richard F. Borch Phosphoramide compounds
GB0907551D0 (en) 2009-05-01 2009-06-10 Univ Dundee Treatment or prophylaxis of proliferative conditions
WO2019152955A1 (en) 2018-02-02 2019-08-08 Steven Albert Everett Small molecule drug conjugates of gemcitabine monophosphate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH372051A (de) * 1957-07-24 1963-09-30 Asta Werke Ag Chem Fab Verfahren zur Herstellung neuer cytostatisch wirksamer Verbindungen

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826830A (en) * 1985-07-31 1989-05-02 Jui Han Topical application of glyciphosphoramide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH372051A (de) * 1957-07-24 1963-09-30 Asta Werke Ag Chem Fab Verfahren zur Herstellung neuer cytostatisch wirksamer Verbindungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO8911484A1 *

Also Published As

Publication number Publication date
JPH04501253A (ja) 1992-03-05
EP0418292A4 (en) 1991-09-25
WO1989011484A1 (en) 1989-11-30

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