WO1990001931A1 - Derives de mitomycines a toxicite reduite vis-a-vis de la moelle osseuse, leurs procedes de preparation et leur utilisation - Google Patents

Derives de mitomycines a toxicite reduite vis-a-vis de la moelle osseuse, leurs procedes de preparation et leur utilisation Download PDF

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WO1990001931A1
WO1990001931A1 PCT/US1989/003180 US8903180W WO9001931A1 WO 1990001931 A1 WO1990001931 A1 WO 1990001931A1 US 8903180 W US8903180 W US 8903180W WO 9001931 A1 WO9001931 A1 WO 9001931A1
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mitomycin
saccharide
derivative
amino
morpholinyl
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PCT/US1989/003180
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English (en)
Inventor
Abdolhossen Talebian
Diana Green
Charles Hammer
Philip S. Schein
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Georgetown University
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Priority to KR1019900700816A priority Critical patent/KR900701269A/ko
Publication of WO1990001931A1 publication Critical patent/WO1990001931A1/fr
Priority to NO910662A priority patent/NO177673C/no
Priority to DK029691A priority patent/DK29691A/da

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—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

Definitions

  • the invention is in the field of pharmaceutical agents and the uses thereof.
  • the mitomycins are a family of compounds having the following general formula (I):
  • Mitomycins A, B and C are related to one another as set forth in Table 1 below, the designations X, Y and Z being those of formula I.
  • Mitomycins are derived from mitosane compounds having the following skeleton (II):
  • the mitosanes are formed during the cultivation of the microorganism Streptomyces caespitosus in a liquid nutrient medium under artificially controlled conditions. After separating the resulting mycellium, the various mitomycins may be isolated from the latter by active carbon or preferably non-ion exchange resin adsorption, organic solvent extraction or chromatography on alumina, as disclosed in U.S. Patent No.3,660,578 to Hata et al.
  • nitosanes are excellent antibiotics, they have limited utility due to their toxicity to human blood (see U.S. Patent No. 3,450,705 to Matsui et al.).
  • the relatively highly toxin nature of the compounds has prompted search for derivatives of mitomycin to increase the antibiotic activity and to decrease toxicity.
  • Matsui et al. U.S. Patent No.
  • 3,450,705 disclose mitomycin compounds substituted at the 7-position with amino, lower alkylamino, phenylamino, or pyridyl, and substituted at the la position with haloalkanoyl, halobenzoyl, nitrobenzoyl, alkenoyl, acetyl glycyl, sorboyl, or acetyl methionyl.
  • mitomycin C While mitomycin C is active against a relatively broad spectrum of experimental tumors, its toxicity and myelosuppressive effects limit its use in clinical practice (Mitomycin C: Current Status and New Developments. Carter et al. (eds.), Academic Press, New York (1979)). In preclinical and clinical studies, mitomycin C has shown activity against a variety of murine and human neoplasms, but has also shown severe, delayed bone marrow toxicity. Goldin, A., et al., NCI -EORTC Symposium on Mitomycin C. Brussels, Belgium (1981).
  • R 1 is selected from the group consisting of NH 2 , C 1 -C 4 alkoxy and a glycosyl residue
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl, and a glycosyl residue, with the proviso that either R 1 or R 2 , but not both, contain a glycosyl group.
  • the compounds represented by formula III have excellent anti- ⁇ eoplastic activity and at the same time possess reduced bone marrow toxicity and lower overall toxicity.
  • the invention relates to a mitomycin derivative having the following general formula (IV):
  • n 0 or 1
  • Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 2-amino-1,3- cyclohexanediol, or a hydroxyl-protected peracetate derivative thereof;
  • R is hydrogen;
  • R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by phenyl, hydroxyphenyl, Indolyl, mercapto, C 1 -C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or
  • R and R 1 together form a five or six membered nitrogen containing ring.
  • the Invention also relates to a mitomycin derivative having the following general formula (V):
  • n, R, R 1 and Y are as defined above and R 2 is NH 2 - or CH 3 O-.
  • the invention also relates to a mitomycin derivative having the following structural formula (VI):
  • R 2 is as defined above;
  • R 3 is a 2-(3-cyano-4-morpholinyl)-2-deoxypyranosyl saccharide or a 2-(4-morpholinyl)-2-deoxypyranosyl saccharide.
  • the Invention also relates to a process for preparing a mitomycin derivative having the formula (IV)
  • n 1;
  • Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl, or a hydroxyl -protected peracetate derivative thereof;
  • R is hydrogen
  • R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C 1 -C 4 alkylthio, hydroxy,. carboxy, amino, guanidino, imidazole or carbamyl; or
  • R and R 1 together form a five or six membered nitrogen containing ring
  • step (b) condensing the activated ester obtained in step (a) with an amino compound to give a protected amino acid-amino compound conjugate
  • step (c) removing the protecting group of the protected amino acid-amino compound conjugate obtained in step (b) to give an amino acid-amino compound conjugate
  • the invention also relates to a process for the preparation of a mitomycin derivative having the formula (VI):
  • R 2 is NH 2 - or CH 3 O-;
  • R 3 is a 2-(3-cyano-4-morpholinyl)-2-deoxy saccharide
  • step (c) reaction of the 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide obtained in step (b) with an acetyl halide to give a 2-deoxy 1-halo-2-(3-cyano-4-morpholinyl) peracetyl saccharide;
  • step (d) treatment of the 2-deoxy-1-halo-2-(3-cyano-4-morpholinyl) peracetyl saccharide obtained in step (c) with silver thiocyanate to give a saccharide-1-thiocyanate;
  • step (e) reaction of the saccharide-1-thiocyanate obtained in step (d) with mitomycin C or mitomycin A to give a mitomycin C- or mitomycin A-saccharide peracetate carbothioamide;
  • step (f) hydrolysis of the acetate groups of the mitomycin-C-saccharide peracetate obtained in step (e) to give the mitomycin derivative.
  • the invention also relates to a process for the preparation of a mitomycin derivative having the following formula (VI)
  • R 2 is NH 2 - or CH 3 O-;
  • R 3 is a (4-morpholinyl)-2-deoxy saccharide
  • step (d) treatment of the 2-deoxy-1-halo-2-(4-morpholinyl) peracetyl saccharide obtained in step (c) with silver thiocyanate to give a saccharide-1-thiocyanate;
  • step (e) reaction of the saccharide-1-thiocyanate obtained in step (d) with mitomycin A or C to give a mitomycin A- or C-saccharide percetate carbothioamide;
  • step (f) hydrolysis of the acetate groups of the mitomycin-C-saccharide peracetate obtained in step (e) to give the mitomycin derivative.
  • the invention also relates to a process for the preparation of a mitomycin derivative having the following formula (V)
  • n 0 or 1
  • Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl;
  • R is hydrogen
  • R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C 1 -C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or
  • R and R 1 together form a five or six membered nitrogen containing ring;
  • R 2 is NH 2 -;
  • step (b) condensation of the mitomycin C-la-succinic acid ester obtained in step (a) with a compound of the Formula (VII).
  • R, R 1 and n are defined above and Y p is a hydroxyl-protected saccharide selected from the group consisting of the hydroxyl-protected derivatives of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexamediol-2-yl;
  • the invention also relates to a process for the preparation of a mitomycin derivative having the following formula (V):
  • n 0 or 1
  • Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl; R is hydrogen;
  • R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C 1 -C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or
  • R and R 1 together form a five or six membered nitrogen containing ring
  • R 2 is CH 3 O-
  • step (b) condensation of the mitomycin A-la-succinic acid ester obtained in step (a) with a compound of the Formula (VII)
  • R, R 1 and n are as defined above and Y p is a hydroxyl-protected saccharide selected from the group consisting of the hydroxyl-protected derivatives of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclohexanediol-2-yl;
  • the invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the mitomycin derivatives of the invention together with a pharmaceutically acceptable carrier.
  • the invention also relates to methods for the treatment of bacterial infections comprising administering the pharmaceutical compositions of the invention to an animal.
  • the invention also relates to methods for the treatment of cancer by suppressing growth of cancer cells susceptible to growth suppres sion comprising administering the pharmaceutical compositions of the invention to an animal.
  • Mitomycin C may be prepared according to the methods generally disclosed in Cheng et al., J. Med. Chem.20:767-770 (1977). Alternatively, mitomycin C can be obtained from mitomycin A by treatment of mitomycin A with a methanolic-ammonia solution as described by Matsui, M., et al., J. Antibiotics XXI:189 (1968).
  • the mitomycin derivatives of Formula IV may be obtained by displacement of the methoxy group of mitomycin A (VIII) with the amino group of an amino compound, for example, glucosamine (Y-NH 2 ; (IX)) under basic conditions in a polar organic solvent to give the N 7 -substituted mitomycin derivative (X) (see Scheme 1 below).
  • Amino compounds (Y-NH 2 ) which may be substituted at the 7-position include, but are not limited to glucosamine, galactosamine, mannosamine, xylosamine, cellobiosamine, maltosamine and 2-amino-1,3- cyclohexanediol and the hydroxyl -protected peracetate derivatives thereof.
  • the saccharide comprising the group "Y” is substituted at the 2-position with the amino group.
  • Polar organic solvents which may be used in the practice of the invention include methanol, ethanol, propanol, dimethylsulfoxide, and dimethylformamide.
  • Suitable bases for providing the basic conditions of the reaction include alkylamines such as C 1 -C 3 trialkyl amines, diisopropylethyl-amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and dimethylamino-pyridine (DMAP).
  • alkylamines such as C 1 -C 3 trialkyl amines, diisopropylethyl-amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and dimethylamino-pyridine (DMAP).
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DMAP dimethylamino-pyridine
  • mitomycin A and the amino derivative are present in a 1:1 molar ratio, although excess amino derivative may be present.
  • Sufficient base is present in the reaction mixture to insure that the reaction remains basic throughout.
  • Preferred mitomycin derivatives having Formula X include N 7 -(2- deoxyglucopyranosyl)mitomycin C, N 7 -(2-deoxygalactopyranosyl)mitomycin C, N 7 -(tetraacetyl-2-deoxyglucopyranosyl)mitomycin C, and N 7 -(tetra-acetyl-2-deoxygalactopyranosyl)mitomycin C.
  • Dehydrating reagents which may be used in this process include, but are not limited to dicyclohexylcarbodiimide (DCC) and diethylazodicarboxyl ate (DEAD) and triphenylphosphine.
  • Mitomycin derivatives having Formula (V), wherein R 2 is NH 2 and n is 0 may be prepared (Scheme III) by condensation of mitomycin C (XVI) with succinic anhydride to give the amide (XVII) which May then be condensed with the hydroxyl-protected amino derivative Y P -NH 2 (XVIII) using any of the above-listed dehydrating reagents followed by deprotectlon to give (XV).
  • Protecting groups for the amino derivative include, but are not limited to, C 2 -C 4 acyl esters.
  • Preferred mitomycin derivatives having Formula (XV) include N 1 - [[2-[[(2-deoxy-2-glucopyranosyl)amino]carbonyl]ethyl]carbonyl] mitomycin C.
  • Mitomycin derivatives having Formula (V), wherein R 2 is -OCH 3 and n is 0 may be prepared (Scheme IV) by treatment of mitomycin C (XVI) with sodium methoxide in absolute methanol to give mitomycin A (VIII) followed by condensation with succinic anhydride to give the mitomycin A-la-succinic add ester (XX). Condensation of the carboxylic acid group of (XX) with the hydroxyl- protected amino derivative Y P -NH 2 (XVIII), as described above, followed by deprotection gives (XIX).
  • Preferred mitomycin derivatives having Formula XVIII include N 1 - [[2-[[(2-deoxy-2-glucopyranosyl)amino]carbonyl]ethyl]carbonyl] mitomycin A.
  • the mitomycin derivatives of Formula VI may be prepared according to the sequence depicted in Scheme V.
  • Salts of cyanoborohydride may include any of the alkali metal salts of cyanoborohydride, preferably sodium cyanoborohydride.
  • Treatment of the saccharide derivative (XXIVa) with an acetyl halide gives the 2-deoxy-1-halo-(4-morpholinyl) peracetyl saccharide which may be reacted with silver thiocyanate to give a 1- thiocyanate saccharide (XXV).
  • Condensation of the thiocyanate (XXV) with mitomycin C (XVI) gives the mitomycin C-saccharide peracetate carbothioamide (XXVI).
  • Preferred mitomycin derivatives having Formula VI include 2- (3- cyano-4-morpholinyl) 2-deoxyglucopyranosyl mitomycin-la-carbothioamide and 2-(3-cyano-4-morpholinyl)-2-deoxygalactopyanosylmitomycin-la-carbothioamide.
  • the compounds of the invention may be present as pharmaceutically acceptable salts.
  • preferred anionic counter ions are those of the halides (derived from hydrohalic acids), such as chloride, bromide, or fluoride.
  • Other anions include sulfonate, or p-toluene-sulfonate.
  • the compounds of the present invention are useful against all microorganisms susceptible to the anti-bacterial action of the parent compounds, these microorganisms including, but not limited to, Pseudomonas. Staohylococcus. Sarcinia. Diolococcus. Streptococcus. Corvnebacterium. Hemophilus. Escherichia. Klebsiella. Proteus. Salmonella. Shioella. Brucella. Mycobacterium. Nocardia. Saccharomyces. Candida. Penicillium. and Asperqillus. Specific microorganism treatable with the compounds of the present invention include Pseudomonas aeruqinosa. Staphylococcus aureus.
  • the mitomycin derivatives of the present invention are useful in vitro as antiseptics, i.e. for disinfecting.
  • the compounds are also useful topically and Internally as therapeutic agents in combating pathogenic bacteria, e.g. in cases of staphylodermatitis, bacterial pneumoniae, leptopserosis, rickettsiosis, salmonellosis, and the like.
  • the mitomycins of this Invention are applied in compositions having concentrations in the range of 0.01 to 1000 ug/ml.
  • the compounds of the present invention are useful in treating a variety of cancers, including, but not limited to, those cancers susceptible to cell growth suppression b the parent compounds. Treatment of cancers with the parent compounds are described in the following references:
  • Typical cancers treated by the mitomycin derivatives of this invention include, but are not limited to gastric and pancreatic neoplasms (Schein, P.S. et al., in Mitomycin C: Current Status and New Developments, pp. 133-143, Carter et al . Eds., Academic Press, New York (1979)).
  • Other cancers that may be treated using the compounds of the invention include lung, breast, anal, colorectal, head and neck, and melanoma.
  • the compounds of the invention are also active against the following tumor systems: Leukemia L-1210, Leukemia P388, P1534 leukemia, Friend Virus Leukemia, Leukemia L4946, Mecca lymphosarcoma, Gardner lymphosarcoma, Ridgway Osteogenic sarcoma, Sarcoma 180 (ascites), Wagner osteogenic sarcoma, Sarcoma T241, Lewis lung carcinoma, Carcinoma 755, CD8F, Mammary Carcinoma, Colon 38, Carcinoma 1025, Ehrlich carcinoma (ascites & solid), Krubs 2 carcinoma (ascites), Bashford carcinoma 63, Adenocarcinoma E 0771, B16 Melanoma, Hardin-Passey melanoma, Giloma.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions within the scope of this invention include all compositions wherein the mitomycin derivative is contained in an amount effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art. Typical dosage forms contain 10 to 300 ⁇ mole/kg animal of the mitomycin derivative, or an equivalent amount of the pharmaceutically acceptable salt thereof.
  • the new pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 25 to 75 percent of active compound(s), together with the excipient.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri-calcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri-calcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, steric acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of the active compounds with a. suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • Mitomycin C (50 mg, 0.15 mmol) was dissolved in 3 ml of a solution of 50% methanol and 50% 0.1 N NaOH and stirred at room temperature for 18 hrs. After completion of the reaction (TLC, CHCl 3 :MeOH, 10:1), the reaction mixture was quenched with dry ice to neutralize sodium hydroxide. The mixture was then freeze-dried in vacuo. and the mitosane compound was removed with methanol. The methanol solution was concentrated in vacuo to dryness, and the residue was redissolved in a minimum amount of methanol and then precipitated with ether to give 20 mg of a red-purplish powder.
  • N-benzyloxycarbonylglycine (3 g, 14.3 mmol) in dioxane was added N-hydroxysuccinimide (1.65 g, 14.3 mmol) and N,N-dicyclohexylcarbodiimide (2.96 g, 14.3 mmol) with cooling.
  • the reaction mixture was stirred at 0-5oC for one hour and allowed to stand under refrigeration overnight.
  • the urea precipitate was removed by suction filtration and the filtrate was concentrated in vacuo to dryness.
  • the yellowish residue was recrystallized from ethyl acetateether to give an 84% yield of the glycine activated ester mp. 112-114oC.
  • N-protected benzyloxycarbonyl N-(2,6-dihydroxycyclohexyl) glycinamide (3g, 0.093 mol) was dissolved in 100 ml of absolute ethanol with a molar equivalent of 10% HCl.
  • Hydrogenolysis with 5% Pd/C at 30 psi, removal of the catalyst over celite, and subsequent evaporation of solvents in vacuo yielded a pale brownish solid which was triturated with ether and recrystallized from ethyl acetate and ether, m.p. 207-210oC.
  • the compound N 7 -(2-deoxyglucopyranosyl)mitomycin C prepared according to Example 2, was evaluated for both murine P388 leukemia antitumor activity and toxicity to bone marrow in normal mice.
  • the murine P388 leukemia system maintained intraperitoneally in female DBA/2 mice, was used to evaluate antitumor activity. This tumor was selected because of Its known sensitivity to the parent compound, mitomycin C (Driscoll et al., Cancer Chemotherapy Reports 4:1 (1974)). N 7 -(2-deoxyglucopyranosyl)mitomycin C was dissolved in sterile water (at 4oC) immediately prior to administration. Mitomycin C was dissolved in ethanol, and the resultant solution was adjusted to 5% ethanol, 95% sterile water. Each compound was administered intraperitoneally to groups of CD2F 1 male mice on Day 1 after intraperitoneal implantation of 1 ⁇ 10 6 P388 leukemia cells. The P388 antileukemic activity of the test compound was assessed by mean survival days and percentage increased life span (ILS). The % ILS was calculated as follows:
  • T 1 the mean survival days of the treated Mice and C is the mean survival days of the untreated mice.
  • WBC count peripheral leukocyte count was performed using a 20-ul sample of retro-orbital sinus blood obtained from normal CD2F 1 male mice on Day 3 following i.p. administration of 13.5 mg/kg of N 7 -(2-deoxyglucopyranosyl)mitomycin C or 4.5 mg/kg of mitomycin C. Blood samples obtained were diluted in 9.98 ml of Isoton (a neutral, isotonic buffer solution) and counted in a Coulter counter after lysis with Zapoglobin (an enzyme solution which lyses red blood cells, but not white blood cells). WBC counts are expressed as a percentage of values from control mice receiving drug vehicle only. The results are summarized in the following table:
  • N 7 -(2-deoxyglucopyranosyl)mitomycin C has significant activity against the murine P388 tumor system, at doses producing no significant bone marrow toxicity, as determined by depression of peripheral leukocyte (WBC) count.
  • N 7 -(2-deoxyglucopyranosyl)mitomycin C was evaluated for activity against Gram-negative bacteria, in a comparative study with the parent mitomycin C.
  • Minimum Inhibition concentration (M.I.C.) against a Gram-negative strain of bacteria (HB101) was estimated by the dilution method, with graded concentrations of drug added to agar at 37-40oC.
  • N 7 -(2-deoxyglucopyranosyl)mitomycin C was dissolved in 50% sterile water-50% ethanol at 4oC, and mitomycin C was dissolved in ethanol.

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Abstract

Quelques dérivés de mitomycines A et C et leur utilisation pour le traitement d'infections bactériennes et pour l'arrêt de la croissance de cellules cancéreuses. Procédés de préparation des dérivés de mitomycine décrits.
PCT/US1989/003180 1988-08-23 1989-07-25 Derives de mitomycines a toxicite reduite vis-a-vis de la moelle osseuse, leurs procedes de preparation et leur utilisation WO1990001931A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR1019900700816A KR900701269A (ko) 1988-08-23 1989-07-25 골수독성이 낮은 미토마이신 유도체, 그 제조방법 및 그이용
NO910662A NO177673C (no) 1988-08-23 1991-02-19 Analogifremgangsmåte for fremstilling av terapeutisk aktive N7-substituerte mitomycinderivater
DK029691A DK29691A (da) 1988-08-23 1991-02-20 Mitomycinderivater med reduceret knoglemarvstoksicitet, fremgangsmaader til deres fremstilling samt anvendelse heraf

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US23522488A 1988-08-23 1988-08-23
US235,224 1988-08-23

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EP (1) EP0431008A4 (fr)
JP (1) JPH04500513A (fr)
KR (1) KR900701269A (fr)
CN (1) CN1040593A (fr)
AU (1) AU628846B2 (fr)
CA (1) CA1327037C (fr)
DK (1) DK29691A (fr)
ES (1) ES2018726A6 (fr)
GR (1) GR1000785B (fr)
IE (1) IE63036B1 (fr)
IL (1) IL91332A0 (fr)
NO (1) NO177673C (fr)
NZ (1) NZ230343A (fr)
PT (1) PT91499B (fr)
WO (1) WO1990001931A1 (fr)
ZA (1) ZA896025B (fr)

Cited By (4)

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Publication number Priority date Publication date Assignee Title
US5091523A (en) * 1990-04-25 1992-02-25 Georgetown University Mitomycin derivatives having reduced bone marrow toxicity, processes for their preparation, and the uses thereof
EP0485904A1 (fr) * 1990-11-13 1992-05-20 Kyowa Hakko Kogyo Co., Ltd. Dérivés de la mitomiycine
WO1995005200A1 (fr) * 1993-08-18 1995-02-23 European Community Agents d'administration de medicaments comprenant de la mitomycine
US9801909B2 (en) 2015-04-06 2017-10-31 The Penn State Research Foundation Compositions and methods for combating bacterial infections by killing persister cells with mitomycin C

Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
CN104231045B (zh) * 2014-08-22 2017-10-31 亚飞（上海）生物医药科技有限公司 一种靶向激活释放的丝裂霉素衍生物及其用途
CN106715457B (zh) * 2014-08-22 2021-09-28 亚飞（上海）生物医药科技有限公司 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途

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US3226393A (en) * 1962-06-07 1965-12-28 American Cyanamid Co N-substituted derivatives of mitomycin a and mitomycin c
US3367945A (en) * 1965-05-18 1968-02-06 Kyowa Hakko Kogyo Kk Thiourea derivatives of mitomycin
US3450705A (en) * 1964-07-09 1969-06-17 Kyowa Hakko Kogyo Kk 1a- and/or 7-substituted derivatives of mitomycin
US4021449A (en) * 1973-12-17 1977-05-03 Kyowa Hakko Kogyo Co., Ltd. Derivatives of mitomycin C
US4268676A (en) * 1979-12-05 1981-05-19 University Patents, Inc. Mitomycin analogs
US4395558A (en) * 1979-08-24 1983-07-26 Kyowa Hakko Kogyo Kabushiki Kaisha 9-Epi-mitomycin B and D compounds
US4720543A (en) * 1985-06-06 1988-01-19 Georgetown University 1a-7-substituted derivatives of mitomycin and uses thereof
US4746746A (en) * 1983-02-07 1988-05-24 University Patents, Inc. Mitomycin analogs
US4771068A (en) * 1985-04-10 1988-09-13 Kyowa Hakko Kogyo Kabushiki Kaisha Mitomycin derivatives having anti-tumor and antibacterial utility
US4814445A (en) * 1984-09-04 1989-03-21 Bristol-Myers Company Process for preparing mitomycin analogs
US4820824A (en) * 1986-08-26 1989-04-11 Kyowa Hakko Kogyo Kabushiki Kaisha Mitomaycin compounds
JPH06335575A (ja) * 1993-05-28 1994-12-06 Tokyo Electric Co Ltd 電気かみそり

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JPS63246336A (ja) * 1986-11-10 1988-10-13 Kyowa Hakko Kogyo Co Ltd マイトマイシン−抗体複合体含有組成物

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US479130A (en) * 1892-07-19 Rudolf allert
US3226393A (en) * 1962-06-07 1965-12-28 American Cyanamid Co N-substituted derivatives of mitomycin a and mitomycin c
US3450705A (en) * 1964-07-09 1969-06-17 Kyowa Hakko Kogyo Kk 1a- and/or 7-substituted derivatives of mitomycin
US3367945A (en) * 1965-05-18 1968-02-06 Kyowa Hakko Kogyo Kk Thiourea derivatives of mitomycin
US4021449A (en) * 1973-12-17 1977-05-03 Kyowa Hakko Kogyo Co., Ltd. Derivatives of mitomycin C
US4395558A (en) * 1979-08-24 1983-07-26 Kyowa Hakko Kogyo Kabushiki Kaisha 9-Epi-mitomycin B and D compounds
US4268676A (en) * 1979-12-05 1981-05-19 University Patents, Inc. Mitomycin analogs
US4746746A (en) * 1983-02-07 1988-05-24 University Patents, Inc. Mitomycin analogs
US4814445A (en) * 1984-09-04 1989-03-21 Bristol-Myers Company Process for preparing mitomycin analogs
US4771068A (en) * 1985-04-10 1988-09-13 Kyowa Hakko Kogyo Kabushiki Kaisha Mitomycin derivatives having anti-tumor and antibacterial utility
US4720543A (en) * 1985-06-06 1988-01-19 Georgetown University 1a-7-substituted derivatives of mitomycin and uses thereof
US4820824A (en) * 1986-08-26 1989-04-11 Kyowa Hakko Kogyo Kabushiki Kaisha Mitomaycin compounds
JPH06335575A (ja) * 1993-05-28 1994-12-06 Tokyo Electric Co Ltd 電気かみそり

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MATSUI, M. ET AL., J. ANTIBIOTICS, vol. XXI, 1968, pages 189
See also references of EP0431008A4

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091523A (en) * 1990-04-25 1992-02-25 Georgetown University Mitomycin derivatives having reduced bone marrow toxicity, processes for their preparation, and the uses thereof
EP0485904A1 (fr) * 1990-11-13 1992-05-20 Kyowa Hakko Kogyo Co., Ltd. Dérivés de la mitomiycine
US5180825A (en) * 1990-11-13 1993-01-19 Kyowa Hakko Kogyo Co., Ltd. Mitomycin derivatives
WO1995005200A1 (fr) * 1993-08-18 1995-02-23 European Community Agents d'administration de medicaments comprenant de la mitomycine
US9801909B2 (en) 2015-04-06 2017-10-31 The Penn State Research Foundation Compositions and methods for combating bacterial infections by killing persister cells with mitomycin C

Also Published As

Publication number Publication date
PT91499B (pt) 1995-07-06
IE63036B1 (en) 1995-03-22
NO910662L (no) 1991-03-21
AU628846B2 (en) 1992-09-24
IL91332A0 (en) 1990-03-19
GR1000785B (el) 1992-12-30
CA1327037C (fr) 1994-02-15
ES2018726A6 (es) 1991-05-01
DK29691A (da) 1991-04-23
KR900701269A (ko) 1990-12-01
IE892691L (en) 1990-02-23
EP0431008A1 (fr) 1991-06-12
ZA896025B (en) 1990-05-30
NO177673C (no) 1995-11-01
JPH04500513A (ja) 1992-01-30
NO910662D0 (no) 1991-02-19
DK29691D0 (da) 1991-02-20
EP0431008A4 (en) 1992-03-11
CN1040593A (zh) 1990-03-21
AU4065089A (en) 1990-03-23
NZ230343A (en) 1992-01-29
NO177673B (no) 1995-07-24
GR890100514A (en) 1991-12-30
PT91499A (pt) 1990-03-08

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