MITOMYCIN DERIVATIVES HAVING REDUCED BONE MARROW TOXICITY, PROCESSES FOR THEIR PREPARATION, AND THE USES THEREOF

Abstract: The invention relates to certain derivatives of mitomycins A and C and the use thereof to treat bacterial infections and to suppress the growth of cancer cells. The invention also relates to processes for the preparation of the mitomycin derivatives of the invention.

Description: TITLE OF THE INVENTION HITOMYCIN DERIVATIVES HAVING REDUCED BONE MARROW TOXICITY. PROCESSES FOR THEIR PREPARATION. AND THE USES THEREOF FIELD OF THE INVENTION: The invention is in the field of pharmaceutical agents and the uses thereof. BACKGROUND OF THE INVENTION The mitomycins are a family of compounds having the following general formula (I): 2 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. TABLE 1 Mitomvcin: l 1 A B C Mitomycins are derived from mitosane compounds having the follow¬ ing skeleton (II): The itosanes are formed during the cultivation of the micro¬ organism Streptomvces 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. Although the 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.l. The relatively highly toxin nature of the compounds has prompted search for derivatives of mitomycin to increase the antibiotic activity and to decrease toxicity. For example, Matsui et al.. U.S. Patent No. 3,450,705, disclose mitomycin compounds substituted at the 7-position with amino, lower alkyla ino, phenylamino, or pyridyl, and substituted at the la position with haloalkanoyl, halobenzoyl, nitrobenzoyl, alkenoyl, acetyl glycyl, sorboyl, or acetyl methionyl. Matsui et al.. U.S. Patent No. 3,558,651, disclose mitosane derivatives comprising la-acyl-7-acyloxy-9a-methoxy compounds. Certain mitomycins and mitomycin derivatives also possess antitu or activity. Oboshi et al.. Gann £8:315-321 (1967); Usubuchi et al.. Gann £8:307-313 (1967); Matsui et al.. J. Antibiotics £XI.:189- 198 (1968); Japanese Patent No. 6806627 to Matsui et al. (Chemical Abstracts 69:86986k (1968)); and Cheng et al.. J. Med. Chem. £0:767- 770 (1977). While mitomycin C is active against a relatively broad spectrum of experimental tumors, its toxicity and yelosuppressive 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). In other studies, a combination of 5-fluorouracil, adriamycin and mitomycin C was found to be effective for the treatment of patients with advanced gastric and colorectal cancer. This regimen incor¬ porated mitomycin C administration in a single dose schedule every two months, to decrease the treatment-limiting delayed myelosuppressive effects of the compound. Schein, P.S., et al.. Mito vcin C: Current Status and New Developments, pp. 133-143, Carter et al. (eds.), Academic Press, New York (1979). Numerous synthetic derivatives of mitomycin C have been prepared in the hope of obtaining compounds with improved therapeutic proper¬ ties. These derivatives include substitution on the aziridine ring, carba oyl, or acyl group substitution on the hydroxymethyl side chain, and replacement of the 7- substituent in the quinone ring with other functional groups, especially substituted amines. However, as disclosed by Remers, U.S. Patent No. 4,268,676, none of these analogs have emerged as a clinical agent, with the possible exception of the 7-hydroxy analog of the mitomycin C, which has been involved in a recent study in Japan. This analog is asserted to be less leukopenic than mitomycin C, but is also less potent. Also disclosed by Remers, suora. are totally synthetic mitomycin analogs of the mitosane type (Mott et al.. J. Med. Chem. £1:493 (1978)), prepared mainly for their antibacterial activity. inoshita, S., et al.. J. Med. Chem. 14:103-112 (1971), disclose several derivatives of mitomycin substituted in the la, 7, and 9a positions. In particular, compounds substituted at the la position with sulfonyl, ortho-substituted benzoyl, and acyl derivatives were reported. Iyengar, B.S., et al .. J. Med. Chem. £4:975-981 (1981), disclose a series of 31 mitomycin C and porfiromycin analogues with various substituents at the 7- and la-positions. The most active substituents at the 7-position included aziridine, 2-methylaziridine, propargyl- amine, furfurylamine, methyl glycinate and 3-aminopyridine. Iyengar, B., et al.. J. Med. Chem. ££:16-20 (1983), disclose a series of 7-substituted mitomycin C and porfiromycin derivatives and the screening thereof in standard antitumor systems. The authors report that the 7- position controls the reduction of the quinone ring, thus suggesting that it would be possible to alter the substitu¬ tion of the 7- position to gain selectivity between normal cells and certain cancer cells. Iyengar, B.S., et al.. J. Med: Chem. ££:1453-1457 (1983), disclose 20 mitomycin C analogues substituted with secondary amines at the 7-position. Eleven of these analogues were more active than mitomycin C against P388 murine leukemia and two of these eleven were significantly less leukopenic. The authors report that no quantita¬ tive correlation between antitumor activity and physiochemical properties of the analogues was evident, although the relative ease of quinone reduction may be related to activity. Iyengar, B.S., et al.. J. Med. Chem. £2:1864-1868 (1986), disclose the preparation of 7-substituted amino 1,2-aziridinomito- senes. The authors reported that a Methyl group on the aziridine nitrogen gave Increased potency. The 7-amino βitosene derivatives which were difficult to reduce to hydroquinones were essentially Inactive. Sami, S., et al.. J. Med. Chem. £1:701-708 (1984), disclose a series of 30 N 7 -phenyl-substituted Mitomycin C analogs. Two of the compounds having pyrazolyl or aminopyridyl substituents at the 7- position were disclosed as clearly superior to mitomycin C in activity against P388 murine leukemia. Sami, T., et al.. J. Med. Chem. 22:247-250 (1979), also disclose N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines, including three disaccharide derivatives which exhibited strong antitumor activity against leukemia 1210 in mice. In addition, glucopyranose derivatives of N-nitrosoureas possess immunogenic and marrow-sparing properties. Anderson et al.. Cancer Research 3£:761- 765 (1975); Panasci et al.. J. Clin. Invest. 64:1103-1111 (1979). In U.S. Patent No. 4,720,543, compounds having the following general formula (III) are disclosed: where Rl is selected from the group consisting of NH2, C1-C4 al oxy and a glycosyl residue; and R 2 is selected from hydrogen, C1-C alkyl, and a glycosyl residue, with the proviso that either Rj or R∑, but not both, contain a glycosyl group. The compounds represented by formula III have excellent anti- πeoplastic activity and at the same time possess reduced bone marrow toxicity and lower overall toxicity. Despite the above-listed mitomycin derivatives, a need continues to exist for improved mitomycin derivatives having good anti-neo- plastic properties and low bone marrow and overall toxicity. SUMMARY OF THE INVENTION The invention relates to a mitomycin derivative having the followin wherein n is 0 or 1; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, annopyranosyl, xylopyranosyl, cello- biosyl, lactosyl, glucofuranosyl, maltosyl, and 2-amino-l,3- cyclohexanediol, or a hydroxyl-protected peracetate deriva¬ tive thereof; R is hydrogen; R! is hydrogen, C1-C4 alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, Indolyl, mercapto, C1-C4 alkylthio, hydroxy, carboxy, amino, guanidino, i idazole or carbayl; or R and R* together form a five or six membered nitrogen containing ring. The Invention also relates to a mitomycin derivative having the wherein n, R, R* and Y are as defined above and R 2 is NH 2 - or CH3O-. The invention also relates to a mitomycin derivative having the following structural formula (VI): wherein R 2 is as defined above; and R 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) wherein n is 1; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cello- biosyl, lactosyl, glucofuranosyl, altosyl, and 1,3-cyclo- hexanediol-2-yl, or a hydroxy!-protected peracetate deriva¬ tive thereof; R is hydrogen; Rl is hydrogen, C1-C4 alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 alkylthio, hydroxy,. carboxy, amino, guanidino, imidazole or carba yl; or R and R together form a five or six membered nitrogen containing ring; comprising: (a) condensing an N-protected amino acid with an alcohol in the presence of a dehydration reagent to give an activated ester, (b) condensing the activated ester obtained in step (a) with an amino compound to give a protected amino acid-amino compound con¬ jugate, (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, and (d) condensing the amino acid-amino compound conjugate obtained in step (c) with mitomycin A to give the mitomycin derivative. The invention also relates to a process for the preparation of a mitomycin derivative having the formula (VI): wherein R 2 is NH 2 - or CH3O-; and R^ is a 2-(3-cyano-4-morpholinyl)-2-deoxy saccharide; comprising (a) condensing bis(acetaldehyde-2-yl) ether with a 2-amino-2- deoxy saccharide in the presence of a salt of cyanoborohydride to give a 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide and a 2-deoxy-4- morpholinyl saccharide; (b) separation of the 2-deoxy-2-(3-cyano-4-morpholinyl ) saccharide from the 2-deoxy-4-morpholinyl saccharide obtained in step (a); (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 l-halo-2- (3-cyano-4-morpholinyl) peracetyl saccharide; (d) treatment of the 2-deoxy-l-halo-2-(3-cyano-4-morpholinyl) peracetyl saccharide obtained in step (c) with silver thiocyanate to give a saccharide-1-thiocyanate; (e) reaction of the saccharide-1-thiocyanate obtained in step (d) with mitomycin C or mitomycin A to give a mitomycin C- or mito¬ mycin A-saccharide peracetate carbothioamide; and (f) hydrolysis of the acetate groups of the mitomycin-C-sac- charide peracetate obtained in step (e) to give the mitomycin deriva¬ tive. The invention also relates to a process for the preparation of a mitomycin derivative having the following formula (VI) wherein R 2 is NH 2 - or CH3O-; and R 3 is a (4-morpholinyl)-2-deoxy saccharide; comprising (a) condensation of bis(acetaldehyde-2-yl) ether with a 2-amino- 2-deoxy saccharide in the presence of a salt of cyanoborohydride to give a 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide and a 2-deoxy-2- (4-morpholinyl) saccharide; (b) separation of said 2-deoxy-2-(4-morpholinyl) saccharide from said 2-deoxy-2-(3-cyano-4-morphplinyl) saccharide obtained in step (a); -li¬ te) reaction of the 2-deoxy-2-(4-morpholiny1) saccharide obtained in step (b) with an acetyl halide to give a 2-deoxy-l-halo-2- (4-morpholinyl) peracetyl saccharide; (d) treatment of the 2-deoxy-l-halo-2-(4-morpholinyl) peracetyl saccharide obtained in step (c) with silver thiocyanate to give a saccharide-1-thiocyanate; (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; and (f) hydrolysis of the acetate groups of the mitomycin-C-sac- charide peracetate obtained in step (e) to give the mitomycin deriva¬ tive. The invention also relates to a process for the preparation of a mitomycin derivative having the following formula (V) wherein n is 0 or 1; Y is selected from the group consisting of glucopyranosyl , galactopyranosyl, mannopyranosyl, xylopyranosyl , cello- biosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclo- hexanediol-2-yl; R is hydrogen; R 1 is hydrogen, 1-C alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or R and R* together form a five or six membered nitrogen containing ring; R 2 is NH 2 -; comprising: (a) condensation of mitomycin C with succinic anhydride under basic conditions to give mitomycin C-la-succinic acid ester; (b) condensation of the mitomycin C-la-succinic acid ester obtained in step (a) with a compound of the Formula (VII). wherein R, R- and n are defined above and Y-* is a hydroxyl-protected saccharide selected from the group consisting of the hydroxyl-pro¬ tected derivatives of glucopyranosyl, galactopyranosyl, mannopyrano- syl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and l,3-cyclohexamediol-2-yl; (c) removal of the hydroxyl protecting groups to give the mitomycin derivative. The invention also relates to a process for the preparation of a mitomyci wherein n is 0 or 1; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, annopyranosyl, xylopyranosyl, cello¬ biosyl, lactosyl, glucofuranosyl, maltosyl, and 1,3-cyclo- hexanediol-2-yl; R is hydrogen; R! is hydrogen, C1-C4 alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 alkylthio, hydroxy, carboxy, amino, guanidino, i idazole or carbamyl; or R and R* together form a five or six membered nitrogen containing ring; R 2 is CH3O-; comprising: (a) condensation of mitomycin A with succinic anhydride under basic conditions to give mitomycin A-la-succinic acid ester; (b) condensation of the mitomycin A-la-succinic acid ester obtained in step (a) with a compound of the Formula (VII) wherein R, R* and n are as defined above and Y p is a hydroxyl-pro¬ tected saccharide selected from the group consisting of the hydroxyl- protected derivatives of glucopyranosyl, galactopyranosyl, manno- pyranosyl, xylopyranosyl, cellobiosyl, lactosyl, glucofuranosyl, maltosyl, and l,3-cyclohexanediol-2-yl; (c) removal of the hydroxyl protecting groups to give the mitomycin derivative. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the mitomycin derivatives of the invention together with a pharmaceutically accep¬ table 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. PE$CR!PTIQN QF THE PREFERREP EMPQPWENT? The synthetic preparation of the mitomycin derivatives of the invention have, as their starting point, mitomycin C. Mitomycin C may be prepared according to the methods generally disclosed in Cheng et al.. J. Med. Chem. £fi: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, wherein n«0 (X), may be obtained by displacement of the methoxy group of mitomycin A (VIII) with the amino group of an amino compound, for example, glucosamlne (Y-NH 2 ; (IX)) under basic conditions in a polar organic sαlvent 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-l,3- cyclohexanediol and the hydroxyl-protected peracetate derivatives thereof. Preferably, 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 1-C3 trialkyl amines, diisopropylethyl- amine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and dimethylamino- pyridine (DMAP). In general, 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)mitoycin C, N 7 -(2-deoxygalactopyranosyl)mitomycin C, N 7 -(tetraacetyl-2-deoxyglucopyranosyl)mitomycin C, and N 7 -(tetra- acetyl-2-deoxygalactopyranosylJmitomycin C. Scheme I Mitomycin C 1. NaOH/MeOH 2. CH 2 2 in A Y-NH IX The amino acid linked mitomycin derivatives of formula IV, wherein n»l, may be prepared (Scheme II) from mitomycin A by condensa¬ tion of the N-protected amino acid, for example, the N-benzyloxy- carbonyl derivative (XI), with an alcohol such as N-hydroxysuc- cinamide, which 1s capable of generating an activated ester, and a dehydrating reagent to give the activated ester (XII). Dehydrating reagents which may be used in this process include, but are not limited to dicyclohexylcarbodiimide (DCC) and diethylazodicarboxylate (DEAD) and triphenylphosphine. Treatment of the activated ester (XII) with any of the above-listed amino compounds (IX) gives the protected amino acid-amino compound conjugate (XIII). Removal of the protecting group, for example, by hydrogenolysis of the N-benzyloxycarbonyl group, gives the free amino derivative (XIV). Compound (XIV) may then be condensed with mitomycin A (VIII) by displacement of -OCH3 as described above to give the amino acid linked mitomycin derivative (IV). Preferred mitomycin derivatives having Formula (IV), wherein n=l, R 1 «■ H and R • H include N 7 -[[[(2-deoxy-2-glucopyranosyl)amino] carbonyl]methyl] mitomycin C and N 7 -[[[(tetraacetyl-2-deoxy-2-glucopy¬ ranosyl)aminojcarbonyl]methyl]mitomycin C. Scheme II Mitomycin derivatives having Formula (V), wherein R 2 is NH and n is 0 (Formula (XV), below), may be prepared (Scheme III) by condensa¬ tion 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 (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, C2-C4 acyl esters. Preferred mitomycin derivatives having Formula (XV) include N 1 - [[2-[[(2-deoxy-2-glucopyranosyl)amino]carbonyl]ethyl]carbonyl] mitomycin C. Scheme III Mitomycin derivatives having Formula (V), wherein R 2 is -OCH3 and n is 0 (Formula (XIX), below), may be prepared (Scheme IV) by treat¬ ment 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. Scheme IV The mitomycin derivatives of Formula VI may be prepared according to the sequence depicted in Scheme V. Treatment of 3, -dihydrox - tetrahydrofuran (XXI) with aqueous sodium periodate in a polar organic solvent gives bis(acetaldehyde- -yl) ether (XXII) which may be con¬ densed with a 2-amino-2-deoxy-saccharide (XXIII) in the presence of a salt of cyanoborohydride to give a mixture of 2-deoxy-2-(3-cyano-4- morpholino) saccharide ((XXIVa), Q - -CN), and 2-deoxy-4-morpholinyl saccharide ((XXIVb), Q « -H) which may be separated, for example, by column chromatography. Salts of cyanoborohydride may include any of the alkali metal salts of cyanoborohydride, preferably sodium cyanobo¬ rohydride. Treatment of the saccharide derivative (XXIVa) with an acetyl halide gives the 2-deoxy-l-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 carbothioa ide (XXVI). Deacylation of (XXVI), for example, with methanolic ammonia, gives (VI) (Q « -CN or H). 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. Scheme V The compounds of the invention may be present as pharmaceutically acceptable salts. Among the preferred anionic counter ions are those of the halides (derived from hydrohalic acids), such as chloride, bromide, or fluoride. Other anions include sulfonate, or β-toluene- sulfonate. As an antibiotic, 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, Pseudo onas. Staohylococcus. Sarcinia. Diolococcus. Streptococcus. Corvnebacterium. Hemoohilus. Escherichia. Klebsiella. Proteus. Salmonella. Shioella. Brucella. Mvcobacterium. Nocardia. Saccharomvces. Candida. Penicillium. and Asperqillus. Specific microorganism treatable with the compounds of the present invention include Pseudomonas aeruαinosa. Staohylococcus aureus. Staphylococcus albus. Staphylococcus citreus. Sarcina lutea. Diolococcus pneumoniae. Streptococcus hemolvticus. Streptococcus lactis. Corvnebacterium diphtheriae. Hemophilus pertussis. Escherichia coli. Klebsiella pneumoniae. Proteus vuloaris. Salmonella tvohosa. Salmonella para- tvphi. Shioella dvsenteriae. Brucella abortus. Brucella megatherium. Brucella mvcoides. Brucella anthracius. Mvcobacterium ATCC 607. Mvcobacterium avium. Mvcobacterium ohlei. Nocardia asteroides. Saccharomvces cervisiae. Candida albicans. Penicillium qlacum, and Asperqillus niαer. 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 staphyloder atitis, bacterial pneumoniae, leptopserosis, rickettsiosis, sal onellosis, and the like. Typically, for topical application, the mitomycins of this Invention are applied in compositions having concentrations in the range of 0.01 to 1000 ug/ml. As antineoplastic agents, the compounds of the present invention are useful in treating a variety of cancers, including, but not li ited 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: Driscoll, J.S. et al .. Cancer Chemotherapy Rep. 4:1 (1974). Kojima, R., et al.. Cancer Chemotherapy Rep. 3:111 (1972). Sugiura, K., Cancer Res. 19:438 (1959). Oboshi, S., et al.. G nn 52:315 (1967). Sugiura, K., Cancer Chemotherapy Rep. 13:51 (1961). Venditti, J.M., et al .. Advances in Cancer Chemotherapy, pp. 201- 209 (1978) Editors; H. ϋmezawa et al.. Japan Soc. Press, Tokyo/Univ. Park Press, Baltimore. Usubuchi, I., et al.. Gann 58:307 (1967). 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 Mitomvcin 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 (as¬ cites), Bashford carcinoma 63, Adenocarcinoma E 0771, B16 Melanoma, Hardin-Passey melanoma, Giloma. 26, Miyona adenocarcinoma, Walker carcinosarcoma 256, Flexner-Jobling carcinoma, Jensen sarcoma, Iglesias sarcoma, Iglesias ovarian tumor, Murphy-Stum lymphosarcoma, Yoshida sarcoma, Dunning leukemia, Rous chicken sarcoma, and Crabb hamster sarcoma. The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intra¬ venous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, 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 «f optimal ranges of effective amounts of each component is with the skill of the art. Typical dosage forms contain 10 to 300 μmole/kg animal of the mitomycin derivative, or an equivalent amount of the pharmaceutically acceptable salt thereof. In addition to the pharmacologically active compounds, 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. Preferably, the preparations, particu¬ larly 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. The pharmaceutical preparations 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. Thus, 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 sac- charides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri- calciu 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, hydroxypropyl ethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, 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. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, poly¬ ethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose 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. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, 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. In addition, 1t is also possible to use 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. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be adminis¬ tered. 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. Optionally, the suspension may also contain stabilizers. The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention. EXAMPLES Example 1: Preparation of Mitomycin A 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, CHCl3: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. This was dissolved in 15 ml of ethyl acetate and cooled to 5*C, treated with diazomethane (etherial solution of diazomethane was prepared according to the procedure of Arndt, Pro. Synthesis. Collective Volume II, pp. 165-167), and stirred for 20 minutes (TLC, CHCl 3 :MeOH, 10:1). After completion of the reaction, the solvent was first removed under water aspirator reduced pressure and then dried in vacuo. The residue was recrystallized from ether to give 18 mg of reddish needles, m.p. 159-160'C. TLC (EtOAc:acetone, 1:1) gave one spot Rf - 0.91, and (acetone:benzene, 4:1) one spot Rf « 0.48. UV (methanol) 216 and 358 mu. NMR (acetone-ds, middle peak of acetone at 2.10), 5, 5.94 (br, 2H); 4.76 (dd, 1H); 4.38 (t, 1H); 4.07 (s, 3H) ; 3.96 (d, 1H); 3.54 (dd, 1H); 3.41 (d, 1H); 3.35 (d, 1H); 3.25 (s, 3H); 2.99-2.264 (mmm) ; 2.87 (s); 1.640 (s, 3H). Example 2: Preparation of N 7 -(2-deoxvolucopyranosvl .mitomvcin C To a solution of mitomycin A (10 mg, 0.028 mmol) in absolute methanol was added a methanolic solution of glucosamine'HCl (70 mg, 0.325 mmol) and diisopropylethylamine (100 ul). This mixture was stirred under N 2 atmosphere at room temperature until the reaction was complete by TLC (EtOAc: acetone, 1:1), at which time (10 hrs.) the solution had changed color from reddish to dark purple. The solution was concentrated by evaporation with a N stream and chromatographed on a preparative silica plate eluted with acetone-ethyl acetate (1:1). The purple band remaining close to the origin was scraped off and eluted with Methanol. Further purification by HPLC (Cjβ reversed phase, semi-preparative column, methanol: 0.1N phosphate buffer, 1:1) gave a purple powder, NMR (D 2 0) δ 5.32 (d, 1H, saccharide anomeric H); 3.85 (s, 3H, 9a-0CH3); and the disappearance of singlet at 4.09 (Matsui, M., et al.. J. Antibiot. £1:189 (1968); Cheng, L., and Remers, W.A., J. Med. Chem. 20:767 (1977); Vyas, D.M., et al.. J. Org. Chem. 51:4307 (1986)). Example 3: Preparation of N-.2.6-Dihvdroχycvclohexyl .qlvcinamide To a solution of N-benzyloxycarbonylglycine (3 g, 14.3 mmol) in dioxane was added N-hydroxysuccinimide (1.65 g, 14.3 mmol) and N,N- dicyclohexylcarbodii ide (2.96 g, 14.3 mmol) with cooling. The reaction mixture was stirred at 0-5'C 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 acetate- ether to give an 84% yield of the glycine activated ester p. 112- 114 * C. NMR (CHC1 3 ). The above-prepared activated ester of glycine (25 g, 0.008 mol) was dissolved in 15 ml of dry DMF (dimethyl formamide), chilled to below 5*C, and 2-amino-l,3-cyclohexanediol (2.18 g, 0.016 mol) in DMF was added drop-wise with stirring under N 2 atmosphere. After comple¬ tion of the reaction (TLC, CHCl3:MeOH, 10:1), DMF was removed under reduced pressure and the resulting solid residue was crystallized from ethyl acetate to give white crystals in 84% yield, m.p. 170-172 * C. NMR (D 2 0): 6 7.45 (s, 5H, aromatic H); 5.20 (s, 2H, benzylic-CH 2 ); 3.95 (s, 2H, -C0-CJH 2 -NH 2 ); 3.6 (t, 1H, C j H of cyclohexane ring); 3.45 (m, 2H, C H and C H of cyclohexane ring); 2.0, 1.8 and 1.35 (m,m,m, 2 to 1 to 3H; C3, C4 and C5 hydrogens of cyclohexane). The product comprises the N-protected benzyloxycarbonyl derivative of N-(2,6- dihyroxycyclohexylJglycina ide. 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 1n vacuo yielded a pale brownish solid which was triturated with ether and recrystallized from ethyl acetate and ether, m.p. 207-210'C. NMR (D 2 0) «, 3.65 (t, 3H, C j H of cyclohexane ring); 3.55 (m, 2H, C 2 H and CeH of cyclohexane); 3.4 (s, 2H, -C0-CH - NH 2 ); 2.05, 1.80, and 1.38 (m,m,m, 2 to 1 to 3H, hydrogens of C3, C4 and C5 of cyclohexane). Example 4 . Animal Studies 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. A. Determination of murine antitumor activity 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 £:1 (1974)). N 7 -(2-deoxyglucopyranosyl)mitomycin C was dissolved in sterile water (at 4*C) 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 CD2Fι male mice on Day 1 after intraperitoneal implantation of 1 x 10 6 P388 leukemia cells. The P388 antileuke ic activity of the test compound was assessed by mean survival days and percentage increased life span (ILS). The % ILS was calculated as follows: %ILS - (T-O/C x 100; where T 1s the mean survival days of the treated Mice and C is the mean survival days of the untreated mice. P388 antitumor activity for N -(2-deoxyglucopyranosyl)mitomycin C, in comparison with the parent mitomycin C, is summarized in Table 2:. 3 LDQ dose bApproximate LDJQ dose c Treated with drug vehicle B. Determination of the effects of N 7 -.2-deoxyαlucopyranosyl ) - mitomvcin C on the he atopoietic svste in mice Measurement of peripheral . leukocyte (WBC) count was performed using a 20-ul sample of retro-orbital sinus blood obtained from normal CD2Fj male mice on Day 3 following l.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: In vivo Murine WBC Depression WBC Count on Day 3 Drug pose fas percent of control) N 7 -(deoxy- 13.5 mg/kg 94% glucopyranosyl) mitomycin C Mitomycin C 4.5 mg/kg 56-66% In summary, these in vivo studies demonstrate that N 7 -(2-deoxy- glucopyranosyl)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. Example 5: Antibacterial Activity 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 37-40'C. N 7 -(2-deoxyglucopyranosylJmitomycin C was dissolved in 50% sterile water-50% ethanol at 4'C, and mitomycin C was dissolved in ethanol. The agar, containing drug, quickly solidified at room temperature, and the bacteria were plated immediately. After 24 hours at 37*C, the agar plates were observed for inhibition of bacterial growth. The results are summarized in Table 4. Tible 4 M.I.C. Compound Gram-neoative Bacteria N -(2-deoxyglucopyranosyl) 1.66-3.3 mcg/ml mitomycin C Mitomycin C 0.3 -0.5 mcg/ml Having now fully described this invention, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof.

Claims: WHAT IS CLAIMED IS: 1. A mitomycin derivative having the formula: wherein, n is 0 or 1; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, manήopyranosyl, xylopyranosyl, cellobiosyl, lac¬ tosyl, glucofuranosyl, maltosyl, and 2-amino-l,3-cyclohexanediol, or the hydroxyl-protected acetate derivatives thereof; R is hydrogen; R 1 is hydrogen, C1-C4 alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 alkylthio, hydroxy, carboxy, amino, guanidino, i idazole or carbamyl; or R and R j form a five or six membered ring containing nitrogen. 2. The mitomycin derivative of claim 1, comprising N 7 -(2- deoxyglucopyranosyl)mitomycin C. . 3. The mitomycin derivative of claim 1, comprising N 7 -(2- deoxygalactopyranosyl)mitomycin C. 4. The mitomycin derivative of claim 1, comprising N 7 -(tetra- acetyl-2-deoxyglucopyranosyl)mitomycin C. 5. The mitomycin derivative of claim 1, comprising N 7 -(tetra- acetyl-2-deoxygalactopyranosyl)mitomycin C. 6. The mitomycin derivative of claim 1, comprising N 7 -[[[(tet- raacetyl-2-deoxy-2-glucopyranosy1)amino]carbonyl]methyl]mitomycin C. 7. The mitomycin derivative of claim 1, comprising N 7 -[[[(2- deoxyglucopyranosyl)amino]carbony Jmethyl]mitomycin C. 8. A mitomycin derivative having the formula C-) n -NH-Y wherein, n is 0 or 1; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, eel1obiosyl, 1ac- tosyl, glucofuranosyl, maltosyl, and 2-amino-l,3-cyclohexanediol, or the hydroxy-protected acetate derivative thereof; R is hydrogen; K- is hydrogen, C1-C4 alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 alkylthio, hydroxy, carboxy, amino, guanidino, imidayole or carbamyl; or R and R j form a five or six membered ring containing nitrogen; and R 2 is NH 2 - or CH3O-. 9. The mitomycin derivative of claim 8, comprising N 1 -[[2-[[(2-deoxyglucopyranosyl)amino]carbonyl]ethyl]-carbonyl] mitomycin C. 10. The mitomycin derivative of claim 8, comprising N -[[2-[[(2-deoxyglucopyranosyl)amino]carbonyl]ethyl] carbonyl]mitomy- cin A. 11. A mitomycin derivative having the formula wherein, R 2 is NH 2 - or CH3O-; and R3 is a 3-cyano-4-morpholinyl-2-deoxypyranosyl saccharide or a 4- morpholinyl-2-deoxypyranosyl saccharide. 12. The mitomycin derivative of claim 11, comprising 2-(3-cyano- 4-morpholinyl)-2-deoxyglucopyranosyl-la-carbothioamide mitomycin. 13. The mitomycin derivative of claim 11, comprising 2-(3-cyano- 4-morpholinyl)-2-deoxygalactopyranosyl-la-carbothioamide mitomycin. 14. The mitomycin derivative of claim 11, comprising 2-(4- morpholinyl)-2-deoxyglucopyranosyl-la-carbothioamide mitomycin. 15. A pharmaceutical composition comprising the mitomycin derivative of any one of claims 1, 8 or 11 and a pharmaceutically acceptable carrier. 16. A method of treating bacterial Infection comprising adminis¬ tering to an animal a pharmaceutical composition comprising an antibacterial amount of the mitomycin derivative of any one of claims 1, 8 or 11 and a pharmaceutically acceptable carrier. 17. The method of claim 16, wherein said bacterial infection is caused by a bacteria selected from the group consisting of Escher¬ ichia. Pseudomonas. Salmonella. Staphylococcus. Klebsiella and Listeria. 18. A method for treating cancer by suppressing growth of cancer cells susceptible to growth suppression in an animal comprising administering to an animal a pharmaceutical composition comprising a cancer cell growth suppressing amount of the mitomycin derivative of any one of claims 1, 8 or 11, and a pharmaceutically acceptable carrier. 19. The method of claim 18, wherein said cancer is selected from the group consisting of leukemia, melanoma, sarcoma, and carcinoma. 20. A process for preparing an N -substituted mitomycin deriva¬ tive of the formula: wherein n Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, eel1obiosyl, 1acto syl, glucofuranosyl, maltosyl, and l,3-cyclohexanediol-2-yl, or th hydroxyl-protected peracetate derivative thereof; comprising: reacting mitomycin A with an amino compound under basic condi¬ tions in a polar organic solvent to give the N 7 -substituted mitomycin. 21. The process of claim 20, wherein said amino compound i selected from the group consisting of glucosamine, galactosaminε, mannosamine, xylosamine, cellobiosamine, maltosamine, and 2-amino-l,3- cyclohexanediol. 22. The process of claim 20, wherein said N -substituted mitomycin is N 7 -(2-deoxyglucopyranosyl) mitomycin C. 23. A process for preparing a mitomycin derivative having the formula wherein n is 1; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cello¬ biosyl, lactosyl, glucofuranosyl,. maltosyl, 1,3-cyclohexane- diol-2-yl, or the hydroxyl-protected peracetyl derivative thereof; R is hydrogen; R 1 is hydrogen, C1-C4 alkyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, Cι-C4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazole or carbamyl; or R and R 1 together form a five or six membered nitrogen containing ring; comprising: (a) condensing an N-protected amino acid with an alcohol in the presence of a dehydration reagent to give an activated ester, (b) condensing the activated ester obtained in step (a) with an amino compound to give a protected amino acid-amino compound con¬ jugate, (c) removing the amino acid protecting group of the protected amino acid-amino compound conjugate obtained in step (b) to give an amino acid-amino compound conjugate, and (d) condensing the amino acid-amino compound conjugate obtained in step (c) with mitomycin A to give the mitomycin derivative. 24. The process of claim 23, wherein said N-protected amino acid is selected from the group consisting of the N-benzyloxycarbonyl derivatives of alanine, valine, leucine, isoleucine, proline, phenyl- alanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamine acid, lysine, arginine and histidine. 25. The process of claim 23, wherein the amino acid protecting group is removed by hydrogenolysis. 26. The process of claim 23, wherein the hydroxyl-protected halo derivative is the 1-bromo, 1-Iodo, or 1-chloro derivative of gluco¬ pyranose peracetate, glucofuranose peracetate, galactopyranose peracetate, mannopyranose peracetate, xylopyranose peracetate, cellobiose peracetate, lactose peracetate or maltose peracetate. 27. The process of claim 23, wherein the base is a hindered amine selected from diisopropylethylamine, a C1-C3 trialkylamine, DBU or DMAP. 28. A process for the preparation of a mitomycin derivative having the formula: 0 wherein R 2 is NH 2 - or CH3O-; and R is a 2-(3-cyano-4-morpholinyl)-2-deoxy saccharide; comprising (a) condensing bis(acetaldehyde-2-yl) ether with a 2-amino-2- deoxy saccharide in the presence of a salt of cyanoborohydride to give a 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide and a 2-deoxy-4- orpholinyl saccharide; (b) separation of the 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide from the 2-deoxy-4-morpholinyl saccharide obtained in step (a); (c) reaction of the 2-deoxy-2-(3-cyano-4-morphol1nyl) saccharide obtained in step (b) with an acetyl halide to give a 2-deoxy l-halo-2- (3-cyano-4-morpholinyl) peracetyl saccharide; (d) treatment of the 2-deoxy-l-halo-2-(3-cyano-4-morpholinyl) peracetyl saccharide obtained in step (c) with silver thiocyanate to give a saccharide-1-thiocyanate; (e) reaction of the saccharide-1-thiocyanate obtained in step (d) with mitomycin C or mitomycin A to give a mitomycin C- or mito¬ mycin A-saccharide peracetate carbothioamide; and (f) hydrolysis of the acetate groups of the mitomycin-C-sac- charide peracetate obtained in step (e) to give the mitomycin deriva¬ tive. 29. A process for the preparation of a mitomycin derivative having the formula: wherein R 2 is NH 2 - or CH 3 0-; and R3 is a (4-morpholinyl)-2-deoxy saccharide; comprising (a) condensation of bis(acetaldehyde-2-yl) ether with a 2-amino- 2-deoxy saccharide in the presence of a salt of cyanoborohydride to give a 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide and a 2-deoxy-2- (4-morpholinyl) saccharide; (b) separation of said 2-deoxy-2-(4-morpholinyl) saccharide from said 2-deoxy-2-(3-cyano-4-morpholinyl) saccharide obtained in step (a); (c) reaction of the 2-deoxy-2-(4-morpholinyl) saccharide obtained in step (b) with an acetyl halide to give a 2-deoxy-l-halo-2- (4-morpholinyl) peracetyl saccharide; (d) treatment of the 2-deoxy-l-halo-2-(4-morpholinyl) peracetyl saccharide obtained in step (c) with silver thiocyanate to give a saccharide-1-thiocyanate; (e) reaction of the saccha ide-1-thiocyanate obtained in step (d) with mitomycin A or C to give a mitomycin A- or C-saccharide percetate carbothioamide; and (f) hydrolysis, of the acetate groups of the mitomycin-C-sac- charide peracetate obtained in step (e) to give the mitomycin deriva¬ tive. 30. The process of claim 28 or 29, wherein said 2-amino-2-deoxy saccharide is selected from the group consisting of glucosamine, galactosamine, mannosamine, xylosamine, cellobiosamine and maltosa¬ mine. 31. The process of claim 28, wherein said mitomycin derivative is 2-(3-cyano-4-morpholinyl)-2-deoxyglucopyranosylmitomycin-la- carbothioamide. 32. The method of claim 29, wherein said mitomycin derivative is 2-(4-morpholinyl)-2-deoxyglucopyranosylmitomycin-la-carbothioamide. 33. A process for the preparation of a mitomycin derivative n is 0; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cello¬ biosyl, lactosyl, glucofuranosyl, maltosyl, 1,3-cyclohexane- diol-2-yl; R is hydrogen; R 1 is hydrogen, C1- 4 allcyl or C1-C4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 alkylthio, hydroxy, carboxy, amino, guanidino, I idazole or carbamyl; or R and R* together form a five or six membered nitrogen containing ring; R 2 is NH 2 - or CH 3 0; comprising: (a) condensation of mitomycin C with succinic anhydride to give mitomycin C-la-succinic acid ester; (b) condensation of the mitomycin C-la-succinic acid ester obtained in step (a) with a hydroxyl-protected amino derivative selected from the group consisting of glucosamine, galactosamine, mannosamine, xylosamine, cellobiosamine, maltosamine, and 2-amino-l,3- cyclohexanediol; and (c) removal of the hydroxyl protecting groups to give the mitomycin derivative. 34. having th wherein n is 0; Y is selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, cellobiosyl, lacto¬ syl, glucofuranosyl, maltosyl, l,3-cydohexanediol-2-yl; R 1s hydrogen; K- is hydrogen, C1-C4 alkyl or C1-C alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C1-C4 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 - or CH3O-; comprising: (a) condensation of mitomycin A with succinic anhydride to give mitomycin A-la-succinic acid ester; (b) condensation of the mitomycin A-la-succinic acid ester obtained in step (a) with a hydroxyl-protected amino acid-saccharide conjugate of the formula wherein R, R* and n are as defined above and Y^ is a hydroxyl-pro¬ tected saccharide selected from the group consisting of the hydroxyl- protected derivatives of glucopyranosyl, galactopyranosyl, manno¬ pyranosyl, xylopyranosyl, eel1obiosyl, 1actosyl, glucofύranosyl, maltosyl, and l,3-cyclohexanediol-2-yl; and (c) removal of the hydroxyl protecting groups to give the mitomycin derivative.

Inventors: GREEN DIANA, HAMMER CHARLES, SCHEIN PHILIP S, TALEBIAN ABDOLHOSSEN, GREEN, DIANA, HAMMER, CHARLES, SCHEIN, PHILIP, S., TALEBIAN, ABDOLHOSSEN
Applicants: UNIV GEORGETOWN, GEORGETOWN UNIVERSITY
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61P35, C07D487