WO1997013748A1 - Derives sulfoxydes de l'yperite azotee et agent anticancereux les contenant - Google Patents

Derives sulfoxydes de l'yperite azotee et agent anticancereux les contenant Download PDF

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Publication number
WO1997013748A1
WO1997013748A1 PCT/KR1996/000173 KR9600173W WO9713748A1 WO 1997013748 A1 WO1997013748 A1 WO 1997013748A1 KR 9600173 W KR9600173 W KR 9600173W WO 9713748 A1 WO9713748 A1 WO 9713748A1
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WO
WIPO (PCT)
Prior art keywords
chloroethyl
ethyl acetate
sulfoxide
bis
mmol
Prior art date
Application number
PCT/KR1996/000173
Other languages
English (en)
Inventor
Jung Woo Kim
Chul-Hoon Kwon
Koo Hun Chung
Joon Kyum Kim
Jae Soo Shin
Kwan Kee Min
Original Assignee
Chong Kun Dang Corp.
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 Chong Kun Dang Corp. filed Critical Chong Kun Dang Corp.
Priority to AU73406/96A priority Critical patent/AU7340696A/en
Publication of WO1997013748A1 publication Critical patent/WO1997013748A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9

Definitions

  • the present invention relates to sulfoxide derivatives of nitrogen-mustard which are represented by a general formula:
  • R 1 represents a hydrogen, or haloethyl
  • R 2 represents a lower alkyl or phenyl group substituted or non-substituted
  • X represents a halogen atom.
  • R 1 is a chloroethyl and X is a chlorine
  • R 2 does not represent methyl group; and pharmaceutically acceptable salts thereof, and their use as an anticancer agent.
  • nitrogen mustard forms aziridinium ion based upon the following reaction formula (A) , and combines with a DNA base by alkylation reaction to form the structure as illustrated in Example (B) .
  • nitrogen mustard can optionally attack any position of oxygen or nitrogen having lone pair electrons of DNA base molecule such as cytocine, guanine, thymine and adenine, it demonstrates a strong toxicity to cells. Further, with its non-selectivity property in distinguishing tumor cells from normal cells, nitrogen mustard shows a strong toxicity to normal cells.
  • melphalan is an antineoplastic agent having phenylalanine substituent on R group of nitrogen mustard.
  • the active form of this compound is delivered to the cells in a transport system of amino acid, which is indicated for the treatment of osteoma, ovarian cancer or mastocarcinoma by the therapy of a single agent or with concurrent administration.
  • some side effects associated with the overdose of melphalan are myelosuppression, gastrointestinal disturbances, and hypersensitivity; it has relatively low selectivity with negligible effects.
  • Chlorambusil with a similar structure to melphalan has been used for a long term treatment of leukemia but its high toxicity has led to some side-effects such as myelosuppression, nausea, hepatic disorder and hepatica tocixity.
  • the present inventors have endeavored to conduct the research and development of the compounds having strong activity and high selectivity to tumor cells thus, designing and synthesizing sulfoxide derived from nitrogen mustard, which is converted to the corresponding sulfide, a physiologically active metabolite as mentioned above, to complete this invention.
  • sulfoxide derivatives of nitrogen mustard do not form a bond with a DNA base by aziridine ring formation as mentioned above, so that it has no antineoplastic activity.
  • sulfone derivatives metabolites of the sulfoxide derivatives, have no antineoplastic activity in a normal state because of the same reason.
  • sulfoxide derivatives are metabolized to a sulfide derivatives under anaerobic (hypoxic) conditions, and the sulfide group readily go through aziridine ring formation, whereby showing very selective cytotoxicity.
  • the inner tumor cells, especially a solid cancer tissue has extremely hypoxic condition is well known, the sulfoxide derivatives having the above-described property are very useful for the treatment of solid cancers.
  • R, , R- and X are defined as above.
  • the compounds of the present invention can be synthesized by the use of known methods.
  • the compounds, wherein R 2 is lower alkyl or phenyl group substituted or non-substituted and R 1 is haloethyl can be prepared by reducing the nitro group at p-position to introduce an amino group; reacting with 2-chloroethanol or ethylene oxide/ acetone to introduce a hydroxyethyl group at N- position; reacting the product with halogenating agent; and then oxidizing the resultant sulfide group, as illustrated in Scheme I.
  • R 2 is lower alkyl or phenyl group substituted or non-substituted.
  • R 1 is H
  • R 2 is an aniline group having one or more lower alkyl group with halogen substituent at N- position
  • R 2 is an aniline group having one or more lower alkyl group with halogen substituent at N- position
  • R 2 is an aniline group having one or more lower alkyl group with halogen substituent at N- position
  • n and m are 0, 1, 2, but on the other hand n and m can not be 0 simultaneously
  • Figs. 1 - 4 are graphs of plotting the survival rate of V-79 cells under normal condition or hypoxic condition with regard to the concentration of medicines, when the compound of Example 5, 10, 14 or 17 is administered (Experimental Example 1) .
  • Figs. 5 and 6 show the result of the test for tumor inhibition in vivo (Experimental Example 2) .
  • the filtered product was suspended in boiling ethyl alcohol (60 ml) , and charcoal was added thereto. The suspension was heated under reflux for 30 min. The mixture was filtered hot, and the filtrate was quickly added to ice cold water (500 ml) causing the formation of a white precipitate. The mixture was then filtered and dried to give 10.1 g of crude white powder which contained 3 substances detected by UV after TLC operation.
  • This product was dissolved in hexane/EtOAc (4:1) (25 ml) and applied to a silica gel column (40 ⁇ m; 5 x 17 cm) packed dry. Then it was wet and eluted with the same solvent. The collected corresponding fractions were dried over anhydrous sodium sulfate and evaporated to give 8.13 g (yield: 85.6%) of pure compound as yellow oil.
  • Example 3 p-(n-Propylthio) -N.N-bis(2-hvdroxyethyl)aniline p-(n-Propylthio) aniline (8.12 g, 49 mmol) was added to a suspension of CaCO- (10.00 g, 100 mmol) in water (250 ml) .
  • Example 4 p-(n-Propylthio. -N.N-bis(2-chloroethyl) aniline p-(n-Propylthio) -N,N-bis(2-hydroxyethyl) aniline (3.80 g, 15 mmol) was dissolved in P0C1- (9.0 ml) with stirring. The solution was heated under reflux at 100°C in a water bath for 40 min, then the hot reaction mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (4 x 100 ml) and washed with 10% sodium bicarbonate solution (3 x 200 ml) .
  • H 2 0 2 /trifluoroacetic acid prepared by adding 30% H 2 0 2 (8.6 ml) to trifluoroacetic acid (16.4 ml) , was added while stirring at 0°C. The reaction was allowed to proceed for 2h. The ice bath was removed and the reaction was allowed to continue for an additional 30 min. Trifluoroacetic acid was evaporated to give 0.78 g (yield : 74.3 %) of pure product as a light yellow solid.
  • Example 2 was repeated to give 11.65 g of white solid powder which contained 4 substances detected by UV after
  • Example 7 With the use of p-phenylthioaniline (50.0 mmol, 10.05 g) prepared in Example 7, the procedure of Example 3 was repeated to give 9.60 g of the crude product as a brown oil. The oil was applied to a silica gel column (40 ⁇ m, 5 x 17 cm) packed dry. Then it was wet and eluted with ethyl acetate / hexane (1:1) under a positive pressure (15 psi).
  • Example 8 the procedure of Example 4 was repeated to give 2.11 g of the crude product as a light brown viscous oil.
  • Example 10 p-(Phenylsulfinyl) -N.N-bis(2-chloroethyl) aniline
  • p-(phenylthio)-N,N-bis(2- chloroethyl)aniline (3.1 mmol, 1.00 g) prepared in Example 9
  • the procedure of Example 5 was repeated to give 0.84 g of the crude product as dark brown viscous oil.
  • the crude product was applied to a silica gel column (40 ⁇ m, 2.5 x 12.5 cm) packed dry. Then it was wet and eluted with ethyl acetate / hexane (3:1) under a positive pressure (15 psi).
  • the collected corresponding fractions were dried over anhydrous sodium sulfate and evaporated to obtain 0.71 g (yield: 68%) of the product as an light yellow crystalline product.
  • m.p. 122-124 °C
  • Example 12 4.4 ' -N . N . N ' . N ' -Tetrakis ( 2 - hydroxyethyl)dianiline sulfide
  • Example 13 4.4 ' -N . . N ' . N ' -Tetraki s ( 2 - chloroethyl)dianiline sulfide
  • 4 '-N,N,N' ,N'-tetrakis(2- hydroxyethyl)dianiline sulfide (7.4 mmol, 2.90 g) prepared in Example 12, the procedure of Example 4 was repeated to give 1.24 g of the crude product as a light brown oil. The crude product was applied to a silica gel column (40 ⁇ m, 5 x 12.5 cm) packed dry.
  • Example 14 4.5 ' -N . N . N ' . N ' -Te t r ak i s ( 2 - chloroethyl) dianiline sulfoxide
  • Example 13 With the use of 4, 4 '-N,N,N' ,N'-tetrakis (2- chloroethyl)dianiline sulfide (0.73 mmol, 0.35 g) prepared in Example 13, the procedure of Example 5 was repeated to give 0.31 g of the crude product as grey viscous oil.
  • the crude oil was diluted in ethyl acetate (2 ml) and applied to three preparative TLC plates, and was then eluted with ethyl acetate / hexane (3:2).
  • Example 15 4.4'-N.N'-bis(2-hvdroxyethyl. dianiline sulfide 4,4'-Diaminodiphenyl sulfide (5.00 g, 23.1 mmol) prepared in Example 11 and 2-chloroethanol (6.2 ml, 7.44 g, 92.4 mmol) were added to a suspension of CaC0 3 (4.10 g, 41.0 mmol) in water (150 ml) . The cloudy mixture was heated under reflux, while being protected from light for 24 h.
  • Example 17 4.4 -N.N -Bis(2-chloroethyl.dianiline sulfoxide
  • Example 18 4-[N.N-Bis(2-hydroxyethyl) 1amino-4 - nitrodiphenyl sulfide
  • Example 20 4 [N. N-Bis (2 -chloroethyl) laroino-4 '- nitrodiphenyl sulfoxide
  • Iron (19.14 g, 100 mesh) was activated by refluxing it with 1.5 ml of distilled water and 1 drop of concentrated hydrochloric acid for 0.5 h.
  • Ethanol (68.4 ml) and 4 - [N,N - bis (2 - chloroethyl) amino - 4' - nitrodiphenyl sulfoxide (13.67 g, 35.30 mmol) prepared in Example 20 were added into the mixture at 40 - 50 °C.
  • the reaction mixture was heated under reflux for 15 min.
  • Several drops of 10% NaOH was added to the reaction mixture to pH 8.
  • the hot reaction mixture was then filtered, and the residue was washed with ethanol and water.
  • Example 22 4-N.N-Bis(chloroethyl)amino-4'-(9-acridinyl. aminodiphenyl sulfide hydrochloride
  • Example 23 4- ⁇ N.N-Bis(chloroethyl) ]amino-4'-(9-acridinyl) aminodiphenyl sulfoxide hydrochloride
  • 4-[N,N-bis(2-chloroethyl) ]amino-4'- aminodiphenyl sulfoxide (1.00 g, 2.81 mmol) prepared in Example 21 and 9-chloroacridine (0.55 g, 2.57 mmol) prepared in Example 22, the procedure of Example 22 2) was repeated to give 1.3 g (yield: 88.45%) of the title compound as yellow solid, m.p. : 250-251 °C TLC : R f 0.81 (ethyl acetate) 1 H NMR (CDC1 3 / DMS0-d 6 1:4) 6 (ppm)
  • hypoxic set cells were gassed 10 min after injection of the drug, needles were pulled out and the sealed bottles were incubated for 3h in a normally aerated incubator. After drug exposure, the cells were washed twice with 5 ml sterile HBSS, and treated with 2.5% trypsin (Gibed® labs) for 2-3 min. Cells were collected by centrifugation, resuspended in 5 ml fresh solvent/or buffer and counted by trypan blue dye exclusion. Appropriate dilutions were made, and 500 cells were cultured in triplicate in a total of 10 ml medium. Dishes were incubated for 6-8 days to allow colony formation.
  • the sulfoxide derivatives according to the present invention have much lower cytotoxicity than the corresponding sulfide. It is found that the sulfoxides have rather higher cytotoxicity under hypoxic condition than under normal condition so that they have selective effects on a solid cancer having hypoxic condition as compared to the normal cells.
  • the B16 transformed cells cultured in vitro were treated with 0.25% trypsin, collected, washed with sterilized phosphate buffered saline (PBS) . And then the cell density was adjusted to 10 7 cells/ml. After 0.2 ml of cells (2 x 10 6 cells/ 0.2 ml/ mouse) were implanted into the subcutaneous tissue of the shoulder's upper part of BDF1 male mouse whose fur was previously eliminated, they were passaged in vivo per 14 days. B16 tumors were carefully isolated from the BDF1 male mouse tissue that had been passaged, necrosis cite was removed, and the weight of fresh tumor was measured.
  • PBS sterilized phosphate buffered saline
  • the mixture was ground by using a glass homogenizer to prepare a supernatant.
  • the supernatant was transplanted to a subcutaneous tissue of the shoulder's upper part of BDF1 male mouse (0.2 ml/ mouse) (0th day).
  • 45 animals having tumor tissue of 100 - 300 mm 3 volume were selected and divided into the experimental groups at random (6 animals per each group) .
  • the experimental compound(s) was administered into the abdominal cavity at the day 8 , 12, 16, and 20.
  • TGI tumor growth inhibition rate
  • Vt tumor volume of the administered group (mm 3 )
  • Vc tumor volume of the vehicle control group (mm 3 )
  • the growth of tumor can be inhibited by about 80% in case of administrating the sulfoxides of the present invention.
  • the tumor inhibition effect rises by 10% when using the compound of the present invention with the conventional compounds as compared to the case using only cyclo phosphamide (70%) , which whows the inhibition of growth of the solid cancer transplanted to mice.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des dérivés sulfoxydes de l'ypérite azotée, représentés par la formule générale (I) dans laquelle R1 représente un hydrogène ou un haloéthyle; R2 représente un groupe alkyle ou phényle inférieur, substitué ou non, et X représente un atome d'halogène. A condition que R1 soit un chloroéthyle et X un chlore, R2 ne représente pas un groupe méthyle. L'invention concerne aussi un agent anticancéreux contenant un de ces constituants en tant que promédicament. Les dérivés sulfoxydes selon l'invention se transforment en sulfure dans des conditions hypoxiques, faisant alors preuve de cytotoxicité, de telle sorte qu'ils sont très utiles comme agents anticancéreux qui agissent de manière sélective sur les cancers dans des conditions hypoxiques.
PCT/KR1996/000173 1995-10-09 1996-10-09 Derives sulfoxydes de l'yperite azotee et agent anticancereux les contenant WO1997013748A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73406/96A AU7340696A (en) 1995-10-09 1996-10-09 Sulfoxide derivatives of nitrogen-mustard and anticancer agent containing the same

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Application Number Priority Date Filing Date Title
KR1995-34486 1995-10-09
KR19950034486 1995-10-09

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WO1997013748A1 true WO1997013748A1 (fr) 1997-04-17

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005793A1 (fr) * 1999-07-19 2001-01-25 Pharmacia & Upjohn Company 1,2,3,4,5,6-HEXAHYDROAZEPINE[4,5-b]INDOLES CONTENANT DES ARYLSULFONES A LA POSITION 9
US7030109B2 (en) 1999-07-19 2006-04-18 Pharmacia & Upjohn Company 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 113, No. 25, 17 December 1990 (Columbus, Ohio, USA), page 704, Abstract No. 113:231187j, VALU, KISIONE K. et al., "DNA-Directed Alkylating Agents. 3. Structure-Activity Relationships for Acridine-Linked Aniline Mustards: Connsequences of Varying the Length of the Linker Chain"; & J. MED. CHEM., 1990, *
CHEMICAL ABSTRACTS, Vol. 114, No. 23, 10 june 1991 (Columbus, Ohio, USA), page 816, Abstract No. 114:228692k, GRAVATT, G. LANCE et al., "DNA-Directed Alkylating Agents. 4. 4-Anilinoquinoline-Based Minor Groove Directed Aniline Mustards"; & J. MED. CHEM., 1991, 34(5), 1552-60. *
CHEMICAL ABSTRACTS, Vol. 117, No. 5, 3 August 1992 (Columbus, Ohio, USA), page 32, Abstract No. 117:3991g, KWONG, CHUL HOON et al., "P-(Methyl= Sulfinyl)Phenyl Nitrogen Mustard as a Novel Bioreductive, Prodrug Selective Against Hypoxic Tumors"; & J. MED. CHEM., 1991, 35(11), 2137-9. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005793A1 (fr) * 1999-07-19 2001-01-25 Pharmacia & Upjohn Company 1,2,3,4,5,6-HEXAHYDROAZEPINE[4,5-b]INDOLES CONTENANT DES ARYLSULFONES A LA POSITION 9
US6468999B1 (en) 1999-07-19 2002-10-22 Pharmacia & Upjohn Company 1,2,3,4,5,6,-hexahydroazepino [4,5-b]indoles containing arylsulfones at the 9-position
US6878823B2 (en) 1999-07-19 2005-04-12 Pharmacia & Upjohn Company 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position
US6921823B2 (en) 1999-07-19 2005-07-26 Pharmacia & Upjohn Company Llc 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position
US7030109B2 (en) 1999-07-19 2006-04-18 Pharmacia & Upjohn Company 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position

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KR970020099A (ko) 1997-05-28
AU7340696A (en) 1997-04-30

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