IE903347A1 - 10,11-methylenedioxy-20(rs)-camptothecin and¹10,11-methylenedioxy-20(s)-camptothecin analogs - Google Patents
10,11-methylenedioxy-20(rs)-camptothecin and¹10,11-methylenedioxy-20(s)-camptothecin analogsInfo
- Publication number
- IE903347A1 IE903347A1 IE334790A IE334790A IE903347A1 IE 903347 A1 IE903347 A1 IE 903347A1 IE 334790 A IE334790 A IE 334790A IE 334790 A IE334790 A IE 334790A IE 903347 A1 IE903347 A1 IE 903347A1
- Authority
- IE
- Ireland
- Prior art keywords
- camptothecin
- alkyl
- amino
- methylenedioxy
- nhco
- Prior art date
Links
- RPFYDENHBPRCTN-UHFFFAOYSA-N 10,11-methylenedioxy-20(rs)-camptothecin Chemical compound C1=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=CC2=C1OCO2 RPFYDENHBPRCTN-UHFFFAOYSA-N 0.000 title description 2
- 229940127093 camptothecin Drugs 0.000 claims abstract description 129
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims abstract description 80
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims abstract description 54
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims abstract description 53
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000001413 amino acids Chemical class 0.000 claims abstract description 27
- -1 cyclic diamine Chemical class 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 235000001014 amino acid Nutrition 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000008206 alpha-amino acids Nutrition 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims abstract description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 8
- 150000001371 alpha-amino acids Chemical class 0.000 claims abstract 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract 4
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims abstract 2
- 230000000802 nitrating effect Effects 0.000 claims abstract 2
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 14
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- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 3
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- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 2
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- 125000001302 tertiary amino group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
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- 239000003937 drug carrier Substances 0.000 claims 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 11
- 125000003277 amino group Chemical group 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 5
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002168 alkylating agent Substances 0.000 abstract description 3
- 229940100198 alkylating agent Drugs 0.000 abstract description 3
- 229910017604 nitric acid Inorganic materials 0.000 abstract description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical compound [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 4
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- 230000002152 alkylating effect Effects 0.000 abstract 1
- 150000001414 amino alcohols Chemical group 0.000 abstract 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 abstract 1
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
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- 239000012954 diazonium Substances 0.000 description 18
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- 238000003786 synthesis reaction Methods 0.000 description 17
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 150000001989 diazonium salts Chemical class 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 150000004985 diamines Chemical class 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 7
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- 238000003556 assay Methods 0.000 description 5
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the process for preparation of a 20(S) or 20(RS) camptothecin having the structure shown below in which Z is H or C1-8 alkyl and R is NO2, NH2, N3, H, halogen, COOH, OH, C1-3 O-alkyl, SH, C1-3 S-alkyl, CN, CH2NH2, C1-3 NH-alkyl, C1-3 CH2-NH-alkyl, N-(C1-3 alkyl)2, CH2N(C1-3 alkyl)2, O-, NH- or S-CH2CH2N(CH2CH2OH)2, O-, NH- or S-CH2CH2CH2N(CH2CH2OH)2, O-, NH- or S-CH2CH2N(CH2CH2CH2OH)2, O-, -NH- or S-CH2CH2CH2N(CH2CH2CH2OH2)2, O-, NH- or S-CH2CH2N(C1-3 alkyl)2, O-, NH- or S-CH2CH2CH2N(C1-3 alkyl)2, CHO, C1-3 alkyl or NHCOCHR1NR2R3, in which R1 is a side chain of an α-amino acid and R2 and R3 are, independently of each other, hydrogen or a lower alkyl group or R3 is a peptide unit containing l-3 amino acid units bound to nitrogen, via a peptide bond; NHCO-alkyleno-C2-8-X or NHCO-alkenyleno-C2-8-X, in which X is COOH, CONR2-(CH2)n- NR2R3, where n = 1-10 and R2 and R3 are defined as above; NHCO-B-(CH2)n-NR2R3, where B = oxygen or NH; or where m + y = 3-6. The process involves, when appropriate: diazotizing a 9-amino-10,11-methylenedioxy-20(S)- or 20(RS)-camptothecin and displacing the diazo group with a corresponding nucleophil, or reducing the group R = CN; or alkylating the group R = OH, SH, NH2 or CH2NH2 with an alkylating agent; or reacting 10,11-methylenedioxy-20(S) or 20(RS)- camptothecin with a mixture of concentrated sulphuric and nitric acid; or nitrating 10,11-methylenedioxy-20(S)- or 20(RS)- camptothecin in order to obtain 9-nitro-10,11- methylenedioxy-20(S) or 20(RS)-camptothecin and then reducing the 9-nitro group; or reacting 9-amino or 9-amino-7-alkyl C1-8-10,11- methylenedioxy-20(S)- or 20(RS)-camptothecin with an amino acid with a protected amino group or peptide containing 1-4 amino acid units, a saturated or unsaturated C4-10 carboxylic acid anhydride or phosgene, and then with a primary or secondary straight, branched- chain or cyclic diamine, or with a tertiary amino- alcohol. The invention also relates to the process for preparation of salts of the abovementioned compounds, as well as the process for preparation of pharmaceutical compositions containing the compounds or salts.
Description
The present invention relates to camptothecin analogs which are useful as antitumor agents. More specifically, the invention is directed to water-insoluble and water-soluble derivatives of 10,11-methylenedioxy-20(RS)-camptothecin and ,ll-methylenedioxy-20(S)-camptothecin. These compounds are collectively referred to as 10,11-MDOCPT below.
Discussion of the Background Camptothecin is a pentacyclic alkaloid initially isolated from the wood and bark of Camptotheca acuminata by Wall et al (M.E. Wall, M.c. Wani, C.E. cook, K.H. Palmer, A.T. McPhail, and G.A. Sim, J. Am. Chem. Soc,., 94:388 (1966)).
Camptothecin is highly biologically active and displays strong inhibitory activity toward the biosynthesis of nucleic -2acids. Additionally, camptothecin exhibits potent antitumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats.
Several methods for the synthesis of camptothecin and camptothecin analogs are known. These synthetic methods include (i) methods in which naturally occurring camptothecin is synthetically modified to produce a number of analogs and (ii) totally synthetic methods.
U.S. Patents 4,604,463; 4,545,880; and 4,473,692 as well as European Patent Application 0074256 are examples of the former type of synthetic strategy. Additional examples of this strategy can be found in Japanese Patents 84/46,284; 84/51,287; and 82/116,015. These methods require naturally J occurring camptothecin which is difficult to isolate and hence these methods are not suitable for the production of large quantities of camptothecin or analogs.
Examples of a variety of totally synthetic routes to camptothecin and camptothecin analogs can be found in the following references: Sci. Sin. (Engl, Ed ) , 21(1), 87-98 (1978) ; Fitoterpamia, 45731. 87-101 (1974); Yakucaku, Zashi, 92(6), 743-6 (1972); J, Org, Chem., 40(14), 2140-1 (1975); Hua Hsueh Hsueh Pao. 39(2), 171-8 (1981); J, Chem. Soc., Perkin Trans 1, (5) 1563-8 (1981); Heterocvcles, 14(7), 951-3 (1980); J. Amer. Chem, Soc.. 94(10), 3631-2 (1972); J. Chem. Soc, D. (7), 404 (1970) and U.S. Patent 4,031,098.
Synthetic studies directed to camptothecin analogs have also been conducted by the present inventors and are disclosed in J,. Med, chem. , 23 (5), 554-560 (1980); J. Med, chem., 29(8), -31553-1555 (1986) and J. Med, Chem., 29(11), 2358-2363(1986) for example.
Water-solubility is an. important criterion in developing potential antitumor compounds for pharmaceutical use. Most camptothecin analogs known in the art have relatively poor· water-solubility. A need exists for additional camptothecin compounds showing high anti-tumor activity and for water-soluble camptothecin analogs and methods for preparing the'same.
SUMMARY OF THE INVENTION Accordingly,^ one object of the present invention is to provide camptothecin analogs containing the .11- methylenedioxy moiety.
A further object is to provide camptothecin analogs which exhibit high cytotoxic activity and which can be readily prepared.
These and other objects which will become apparent from the following specification have been achieved by the process of the present invention and the compounds produced thereby.
More specifically, the invention is directed to compounds which are derivatives of .11- methylenedioxy-20(RS)-camptothecin (also called .11- MDO-20(RS)-CPT) and 10,ll-methylenedioxy-20(S)camptothecin (also called 10,ll-MDO-20(S)-CPT) which are highly active camptothecin analogs. — 4brief description of the drawing A more complete appreciation of the invention and many of the attendant advantages thereof will be obtained as the same becomes better understood by reference of the following detailed description when considered in connection with the accompanying drawing, wherein: Figure 1 shows the structure of CPT and derivatives thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS ,ll-MDO-20(S)-CPT is an extremely potent camptothecin analog and is one of the most potent inhibitors of the enzyme topoisoroerase I known. 10,ll-MDO-20(S)-CPT is highly active in such in vitro cytotoxicity tests as the 9KB and 9PS tests and demonstrates EDS0 values equal to or more potent than camptothecin itself. 10,ll-MDO-20(S)-CPT is also very potent in the L-1210 leukemia in vivo life prolongation assay. The synthesis of 10,ll-MDO-20(RS)-CPT is known and described in Wani et al, J. Med, Chem.. 29 (11), 2353-2363 (1986) and in U.S. 4,894,456.
Novel analogs of camptothecin have been prepared, all of which contain the 10,11-roethylenedioxy moiety. The structures of these compounds are shown below.
In the structure shown above, R is NO2, NH2, N3, hydrogen, -5halogen (F, Cl, Br, I), COOH, OH, O-C,.3 alkyl, SH, S-C,^ alkyl, CN, CH2nh2, alkyl, CH2-NH-c1<5 alkyl, N(Cv3 alkyl) 2, CH^iC^j alkyl)2, o-,nh- and s-CH2CH2N(CH2CH2OH) 2, CH2CH2CH2N(CH2CH2OH)2, 0-, NH- and S-CH2CH2N(CH2CH2CH2OH) 2, Ο-, NHand S-CH2CHzCH2N(CH2CH2CH2OH2)2, 0-, NH- and S-CH2CH2N (0,.3 alkyl) 2, 0-, NH- and S-CHjCHgCHjN(C,.j alkyl)2, CHO or Cv3 alkyl.
Preferred compounds are those in which R is halogen, nitro or amino. The compound in which R is a chlorine atom is particularly preferred.
Z in the Structure shown sbovi is Η or C,.,, alkyl with tho proviso that R and z are not both hydrogen. Preferably, z is H.
The structure shown above is understood to represent all isomers having the chemical structure indicated. The structure shown above, therefore, represents both 10,11-MDO20(S)-CPT and 10,11-MDO-20(RS)-CPT compounds.
Compounds having the structure shown above are generally prepared by first synthesizing 10,il-MDO-20(S)-cpt or 10,11MDO-20(RS)-CPT in which Ζ is hydrogen or C,.8 alkyl. The synthesis of 10,ll-MDO-20(RS)-CPT compounds in which Z is hydrogen or C,.e alkyl is possible by means of a Friedlander condensation reaction between an appropriately substituted tricyclic compound representing rings C, D and E of the camptothecin structure with an ortho-amino benzaldehyde or ketone. Friedlander condensation with an ortho-amino benzaldehyde produces compounds in which 2 is hydrogen. Condensation using corresponding ortho-amino ketones produces compounds in which Z is C,.8 alkyl. Synthesis of the 10,11IE 903347 -6MDO-20(RS)-CPT is fully described in U.S. 4,894,456 incorporated herein by reference for a complete description of the synthesis of this starting compound. The synthesis of ,ll-MDO-20(S)-CPT is described in U.S. application serial no. 07/511,953. This application is incorporated herein by reference to provide a complete description of the synthesis of the 10,ll-MDO-20(S)-CPT starting compounds in which z is hydrogen or C^g alkyl.
The 9-substituted-10,ll-MDO-20(RS)-CPT and 9-substituted10.11- MDO-20(S)-CPT compounds of the present invention can be synthesized from the 10,11-MDOCPT starting materials described above by preparing a diazonium salt at the 9-position. To prepare the diazonium salts, 10,ll-MDO-20(S)-CPT or 10,11-MDO20(RS)-CPT is nitrated to form the corresponding 9-nitro compound. This nitro compound is then reduced to form the corresponding 9-amino compound which is used to prepare the diazonium salt.
Using known mixtures of H2SO4 and HNO3 and standard nitration reaction conditions for the nitration of camptothecin (CPT) itself, one obtains a mixture of the 12nitro and 9-nitro-camptothecin analogs with the 12-nitro rTejcont: in oonoidci-ciblt . A sLiuoLuxc of 10,ll-MDO-20(S)-CPT and 10,ll-MDO-20(RS)-CPT reveals that the 9- and 12-positions are available for nitration and the .11- methylenedioxy group appears to exhibit an analogous electronic influence on both the 9- and 12-positions. An analysis of the electronic and steric environments on the potential nitration positions of 10,11- leads to the -7expectation that both 10,ll-MDO-20(S)~CPT and 10-11-MDO20(RS)-CPT will nitrate in a manner similar to camptothecin itself and provide an excess of the 12-nitro analog. Quite unexpectedly, it was found that nitration of 10,ll-MDO-20(S)CPT and 10,ll-MDO-20(RS)-cpt gives substantially the 9-nitro-10,il-MDO-analogs with only trace amounts of the 12-*nitro-10, ll-MDO analogs. The present method, therefore, provides a surprisingly effective procedure for preparing the 9-nitro-lo,11-MDOCPT analogs in high yield regioselectively.
The nitration reaction may be conducted using standard conditions for the nitration of aromatic compounds, and is generally conducted by dissolving/suspending the 10,11-MDOCPT in concentrated sulfuric acid with cooling and stirring followed by the addition of a slight excess of concentrated nitric acid. After stirring for a period of time sufficient to substantially complete the reaction, the solution is poured into water, ice or a ice/water mixture to provide the desired 9-nitro-10,11-MDOCPT compound. Purification can be effected by standard extraction and recrystallization processes.
The 9-nitro-10,11-MDOCPT may then be catalytically reduced using hydrogen and a hydrogenation catalyst such as platinum, palladium, etc., or other conventional hydrogenation reactions. Preferably, the hydrogenation catalyst is present on an inert support such as powdered carbon. Reduction of the 9-nitro analog to the 9-amino analog is conducted using standard hydrogenation solvents and hydrogen pressure conditions. Generally, the nitro compound is dissolved/ suspended in ethanol and contacted with a hydrogen atmosphere. -8The concentration of catalyst and of the nitro compound in the solvent is not critical. Concentrations of the nitro compound from about 1 mg/ml co j mg/m± may oe used with catalyst concentrations ranging from about 20-100 wt.%. The preferred solvent is absolute ethanol although other conventional inert solvents may be used.
The hydrogenation reaction is generally conducted at ambient temperature although temperatures above or below ambient temperature may be used so long as the camptothecin analog is not decomposed. Hydrogenation reaction times vary with the amount of nitro compound,to be hydrogenated and can be easily determined by one skilled in the art. Generally, reaction times ranging from 2-30 hours are sufficient to hydrogenate 9-nitro-10,li-MDOCPT.
Although catalytic hydrogenation is a preferred reduction method, other known chemical reductions such as FeSO^/NH4OH, Sn/HCl, etc. may also be employed to reduce the nitro group to an amino group.
The formation of diazonium salts is a general reaction undergone by primary aromatic amines upon treatment with sodium nitrite in acidic solution. Accordingly, the 9-amino10,11-MDOCPT can be treated with sodium nitrite in acid solution to form the corresponding diazonium salt. These diazonium salts are then reacted with nucleophiles or free radicals to generate nitrogen gas (N2) and the desired 9substituted-10,li-MDOCPT compound. The overall reaction sequence is shown in scheme 1 below. In the scheme, the diazonium salt is shown as structure II where the counter -9anion x' is derived from the acid HX.
Scheme 1 Non-limiting examples of suitable acids and reaction conditions to prepare a variety of 9-substituted-10,ll-MDOCPT compounds are shown in Table A. -10Table A Example Reactant HX Other Reagents and Conditions R in Product 2 I HBr CUBr 80 °C Br 3 I HCI CUCl 80 °C Cl 4 I hbf4 CO, Pd(OAc)2 CO2H 5 I HCI NaOAc, MeCN, 25’C HjC^NOH, CuSO4 CHO . 6 I h2so4 Na2SO3, 25 °C; aq. HCI, 80°C 80"C OH 7 1 HCI CuCN, 10 °C CN 3 I HCI NaN3, 25’C n3 9 I HCI > 120 °C F 10 I hbf4 HCI aq. KX, 100’C I 11 I hbf4 NaNO2, Cu° no2 12 I h2so4 25’C h3po2, -10’C H 13 I HCI 1) KCS2OEt, 40 °C SH 14 I hbf4 2) KOH (CH3)4Sn, ch3 Pd(OAc)2 MeCN, 2.5 °C Additional 10,11-MDOCPT compounds can be prepared by further reactions on the compounds shown in Table A or by analogous reactions. For example, the compound in which R is ethyl (C2HS) or propyl (c3H7) can be prepared by a reaction analogous to Example 14 using the reagent (C2H5)4Sn or (C3H7)4Sn in place of (CH3)4Sn. The compounds in which R is CN can be readily reduced by catalytic hydrogenation to obtain the compound in which R is CH2NH2 by hydrogenation processes analogous to the hydrogenation of 9-nitro-10, ll-MDOCPT to 9amino-10,ll-MDOCPT discussed above or other known reduction -11reactions.
Alkylation reactions of compounds in which R is oh, SH, NHj or CH2NH2 yields compounds in which R is O-C,.3 alkyl, S-C,.^ alkyl, NH-C^ alkyl or CHjNH-C^j alkyl. Dialkylation of the nitrogen-containing substituents is also possible to yield N(ct,3 alkyl)2 and cr2R(C>3 alkyl)2 substituents as R.
Alkylation may be accomplished, for example, using alkyl halides or tosylates (OT’s) . Preferred alkyl halides are the Ο,-Cj alkyl chlorides and bromides. If desired, a base such as a tertiary amine may be added to facilitate the alkylation reaction.
It is possible to incorporate additional nitrogen and oxygen atoms into the substituent R by means of alkylation reactions. For example, alkylation with a reagent having the formula (Cv3 alkyl)2N-GH2CH2-X or (CV3 alkyl)2N-CH2CH2CH2-X, where X is halogen or OTs yields the correspondingly alkylated products containing the di-Cv3 alkylaminoethyl or di-Cv3 alkylaminopropyl group. In a similar manner, introduction of an oxygen atom is possible using alkylating agents having the formula (HOCH2CH2) 2N-(CH2)2.3-X and (HOCH2CH2CH2) 2N- (CH2) 2.3-X to provide the corresponding diethanolaminoethyl, diethanol aminopropyl, dipropanolaminoethyl and dipropanolaminopropyl groups. It may be necessary to protect the hydroxyl group in these latter alkylating agents using standard hydroxyl protecting groups such as THPO-. These hydroxyl protecting groups can be conveniently removed or deprotected after alkylation by treatment with mild aqueous acid. -12It has also been discovered that water-soluble analogs of ,11-MDOCPT can be prepared by opening the lactone ring of ,11-MDOCPT compounds to form water-soluble salts. These new derivatives exhibit substantially improved water-solubility and retain a high level of cytotoxicity.
The interaction of pharmaceutical compounds with biological systems is highly specific and intimately related to the three-dimensional structure of a compound and the chemical functionality present on the pharmaceutical compound. It is well known in the pharmaceutical art that structural changes as simple as the use of an opposite enantiomer can result in complete loss of biological activity and in some instances even opposite biological activity. Surprisingly, it has been discovered that it is possible to hydrolyze the lactone ring of 10,11-ΜΠΛΟΡΤ and retain eubotantiol biological activity while also enhancing water-solubility.
The. open lactone compounds of the present invention have the structure shown below where R and Z have the same definition as given above for the closed lactone compounds and further Z and R may both be hydrogen.
The water-soluble analogs of the present invention are prepared by hydrolyzing the lactone ring of 10,11-MDOCPT or a 9-substituted-10,11-MDQCPT by utilizing one equivalent of an -13aqueous alkali metal hydroxide. The hydrolysis is preferably carried out in an aqueous solution. The resulting product is the alkali metal salt of 10,11-MDOCPT or 9-substituted-10,11MDOCPT in which the lactone ring, has been opened to form the Corresponding hydroxyl and carboxylate functional groups, as shown below, where M+ is a monovalent metal cation.
Preferred alkali metal hydroxides are potassium hydroxide and sodium hydroxide, with sodium hydroxide being particularly preferred.
Obviously, alkali metal hydroxide concentrations above or below one equivalent may be used in the present process. Concentrations below one equivalent result in incomplete formation of the metal salt.
The incomplete formation of the camptothecin salt provides a convenient purification method. Unreacted camptothecin (closed lactone form) is only slightly soluble in water and can be filtered off from the aqueous solution containing the camptothecin sodium salt in solution. This provides a convenient method for separating and purifying camptothecin salts.
The hydrolysis reaction may be conducted at any temperature which allows adequate reaction of the 10,11-MDOCPT and alkali metal hydroxide so long as the temperature is sufficiently low to prevent decomposition of the starting -14materials. Suitable temperatures are from about 5-50"C with preferred temperatures being approximately room temperature.
In the hydrolysis reaction, the 10,11-MDOCPT is generally, but not necessarily suspended in a suitable solvent such as methanol or aqueous methanol and treated with aqueous alkali metal hydroxide. To increase the rate of reaction, the reaction mixture may be gently heated. After cooling, the ,11-MDOCPT metal salt may be isolated by standard recrystallization or chromatographic processes following removal of the methanol and water solvents. Any water miscible solvent conventionally used with camptothecin analogs may be used instead of methanol.
Alkali metal salts (open lactone compounds) of other .11- MDOCPT analogs such as 9-substituted-10,11-MDOCPT compounds may also be prepared by analogous reactions. For example, 9-nitro-10,11-MDOCPT, 9-amino-lQ,11-MDOCPT, 9-chloro10.11- MDOCPT, 9-amido-10,11-MDOCPT or any other 9-substituted10.11- MDOCPT derivative may also be hydrolyzed by a process analogous to the process described above for 10,11-MDOCPT to provide the corresponding monovalent metal salts of these derivatives.
Water-soluble derivatives of 10,11-MDOCPT can also be prepared by reacting the 'amino group of 9-amino-10,11-MDOCPT with appropriately protected amino acids and peptides, ^4-10 saturated or unsaturated carboxylic acid anhydrides, or the corresponding ester-acid halide derivatives. For example, 9-amino-10,11-MDOCPT may be reacted with the carboxylic acid group of an ct-amino acid to give compounds having the -15structure shown below: in which Z is as defined above and R is the group -NHCOCHR1NR2R3, where R1 is the side-chain of an α-amino acid, preferably the side chain of a D or L-isomer of one of the naturally occurring amino acids, preferably one of the 20 commonly occurring amino acids, and R2 and R3 are, independently, hydrogen or a lower alkyl group having 1-6 carbon atoms. Additionally, R3 may be a peptide unit containing 1-3 amino acid units bonded to the nitrogen atom through a peptide bond. These water-soluble analogs, therefore, contain from 1-4 peptide units bonded to the 9-amino nitrogen atom by means of a peptide bond, obviously, amino acids which are not naturally occurring may also be used to prepare water-soluble 9-amido-10,ll-MDOCPT derivatives so long as the amino acid has a carboxylic acid, acid halide or other reactive acyl functionality to form the required peptide bond with the 9-amino group of 9-amino-lO,ll-MDOCPT. Other, preferred side chains P? ar© alkyl and axalkyl groups containing 2-20, preferably 2-10 carbon atoms.
Generally, these amino acid and peptide-containing derivatives are prepared using amino acids and peptides in which reactive functional groups such as amino groups and -16carboxylic acid groups are protected using standard amino acid and carboxylic protecting groups. For example, when preparing a derivative from an amino acid such as glycine, one can protect the amino group of glycine by reaction with tBOC chloride to prepare the reactive tBOC-protected amino acid. Appropriately protected amino acids are also available commercially. The protected amino acid is reacted with 9-amino-lO,ll-MDOCPT and the tBOC group is then removed to give the water-soluble salt of the 9- glycinamido derivative, for example.
If desired., free amino groups on the amino acids or peptides may be derivatized by known nitrogen alkylation reactions, i.e., reaction with alkyl halides, to provide mono or dialkylamino acid amido derivatives as shown above (R2 and/or R3 >=· alkyl). Preferably, free amino groups are derivatized to form C^j mono or dialkylamino groups.
Dibasic amino acids such as arginine, histidine, lysine, etc., and dicarboxylic amino acids such as aspartic acid, glutamic acid, etc., may be used for one or more of the amino acids in the amino acid or peptide derivatives described above. If desired, standard addition salts may be prepared by reacting the free amino groups of any amino acid with a mineral acid such as HCl, HBr, H3PO4 or organic acids such as malic, maleic or tartaric acids. Likewise, free carboxylic acid groups on any amino acid may be derivatized by the formation of monovalent metal cation salts, ammonium salts or quaternary ammonium salts by the addition of monovalent metal hydroxides, ammonia or amines. Quaternary ammonium salts may -17be formed with primary, secondary or tertiary amines in which the nitrogen atom of the amine contains 1, 2 or 3 lower alkyl or substituted lower alkyl groups. Substituted lower alkyl groups containing one or more hydroxyl groups are preferred. Sodium salts, triethylammonium and triethanol ammonium salts are particularly preferred.
Other water-soluble derivatives can also be prepared by reacting 9-amino-io, H-MDOCPT with a C4.10 saturated or unsaturated acid anhydride, the corresponding ester-acid halide or other reactive acyl derivatives to provide analogs having structure 1 in which n is> NIICO - C2.g-nlkylene-X auJ NHCO-C2.a~alkenylene-X where X = COOH. The reaction is optionally carried out in a suitable solvent and produces the corresponding half acid. For example, reaction of 9-amino-10,11-MDOCPT with glutaric anhydride gives the 9-glutaramide half acid. Likewise, reaction of 9-amino-10,11MDOCPT with the CV6 ester-acid halide corresponding to glutaric anhydride results in the 9-glutaramide half acid ester. Conventional hydrolysis of the ester produces the half acid. Water solubility may be imparted in each case by reaction with one equivalent of any of the bases noted above.
The reaction of 9-amino-10,11-MDOCPT with the anhydride or other reactive acyl compound is preferably carried out in the presence of a weak base such as a tertiary amine to facilitate the formation of the product amide. Suitable amines include cyclic amines such as pyridine as well as lower alkyl tertiary amines.
The free acid group of the amide half acid may be further -18coupled with a-suitable.alkylene diamine (NHR2-(CH2) n-NR2R3) to give amino amides in which the R group in structure I is -NHA1-NR2-(CH2) n-NR2R3, where n « 1-10, preferably 2-6, and A' is a C4.10 acyl-alkylene-acyl or C4.10 acyl-alkenylene-acyl group, i.e., R is NHCO-C2.8~alkylene-X or NHCO-C^.a-alkenylene-X where X is COOH or CONR2-(CH2) n-NR2Rj. For example, the reaction of 9-glutaramido-10,11-MDOCPT with a suitable diamine such as 3(dimethylamino)-1-propylamine gives the corresponding amino acid amide as shown below. ch3 / ,11-MDOCPT-NHCO(CH2)3COOH + NH2CHzCH2CH2N \ ch3 ch3 / ,11-MDOCPT-NHCO (CH2) 3CONHCH2CH2CH2N \ ch3 Acid and base addition salts of these derivatives may also be prepared in a manner analogous to that described above. -19In another embodiment, water-soluble urea and urethane analogs can be prepared by reacting 9-amino-10,ll-MDOCPT with phosgene followed by reaction with an appropriate diamine or tertiary-amino alcohol to give compounds having the formula I in which R is -NHCO-B-(CH2) n-NR2R3, where B is oxygen or NH, and compounds in which R is / NHCO-N / where m + y = 3-6 and n, R2 and R3 are as defined above.
Suitable diamines are primary and secondary straightchain, branched or cyclic diamines containing 3-15 carbon atoms. Examples of straight-chained and branched diamines include diaminoethane, 1,2- and l,3-diaminopropane, 1,4-diaminobutane, etc. Examples of cyclic diamines included pyrazolidine, iaidazolidine, piperazine, etc. Preferred diamines are diamines in which one of the amino groups is derivatized to form a di-lower-alkyl-amino group such as, for example, NH,CH2CH2CH2N(CH2CH3)2. The reaction of 9-amino-lO, llMDOCPT with phosgene followed by a diamine is represented below. 9-amino-10, ll-MDOCPT + CO(C12) -» 10,ll-MDOCPT-9-N=C=O Et Et + nh2ch2ch2ch2n io, h-mdocpt-9-nhconhch2ch2ch2n \ Et Et / -20Tertiary-amino alcohols for the preparation of urethane analogs include N,N-di-C1,6-alkylamino alkanols prepared from straight chain or branched amino alkanols having 2-10 carbon atoms, for example, N,N~diethyl-aminoethanol.
Water soluble standard acid and base addition salts can be prepared from the urea and urethane analogs in a manner oisiilar to that JeberlbeQ aoove for other amino and carboxylic acid group-containing analogs.
Preferred derivatives within the scope of the present invention are 10,11-MDOCPT analogs having glycinamido, succinamido, glutaramido, (4-methylpiperazino) carbonylamino, N,N-dimethylaminopropylamido-glutaramido and (Ν,Ν-diethylaminoethoxy)carbonylamino substituents at the 9-position and the water soluble salts thereof.
The salts of the present invention exhibit substantially improved water-solubility relative to conventional camptothecin analogs and may be formulated into solid and aqueous pharmaceutical compositions by conventional methods.
The compounds of the present invention are active in standard cytotoxicity tests and are- inhibitors of topoisomerase I.
The 10,11-methylenedioxy (MDO) group confers striking and unexpected improvements on the in vitro and in vivo activity found in the camptothecin molecule with particular reference to anti-tumor activity. Thus, Jaxel et al., Cancer Res.. 49, 1465-1469 (1939), and Hsiang et al., Cancer Res., 49, 43854309 (1965), have shown mat iu, ii-MDO-20 (RS) -CPT has three to five times the potency of camptothecin in the inhibition of topoisomerase I. inhibition of this enzyme has been shown by -21Jaxel et al. (loc. cit.) to be very well correlated with in vivo anti-tumor and anti-leukemic activity.
In contrast, a compound with quite similar structure, ,ll-dimethoxy-20(RS)-CPT, is totally inactive, Wani et al., j., Med- chem., 92: 2360 (1986). Unlike 10,ll-dimethoxy20 (Rs) -CPT, the 10,n-MDo moiety is held rigidly in the plane of ring A of CPT (See the structure in Figure 1), and this is thought to contribute to the additional biological activity unexpectedly noted with all of these compounds.
Table B shown below shows the potent topoisomerase I inhibitory activity of the compounds of the present invention The cleavable complex assay was performed according to the method described in Hsiang, Y-H. et al., J. Biol._ Chem., 260:14873-14878 (1985). The cleavable complex assay correlates well with In vivo anti-tumor activity in animal models for camptothecin analogs. See Hsiang et al., Cancer Research. 49:4385-4389 (1989) and Jaxel et al., cancer Research,. 49:1465-1469 (1989). -22Table B - Cleavable Complex Assay of Camptothecin and Analogs Name * Vf’ ** pq/^ 1 9-AMINQ-10,ll-MDO-20(S)-CPT -.01 pg/mL 2 10,ll-MDO-20(S)-CPT -.01 pg/mL 3 10/11-MDO-2 0 (RS) -CPT -.02 pg/mL 4 9-AMINO-10,11-MDO-20(RS)-CPT -.02 pg/mL 5 9-NITRO-lO,ll-MDO-20(RS)-CPT -.09 pg/mL 6 10,ll-MDO-20(S)-CPT, Na+ SALT -0.1 pg/mL 7 9-GLA-10,ll-MDO-20(RS)-CPT, HCl -0.1 pg/mL 8 10,ll-MDO-20(RS)-CPT, Na+ SALT -0.2 pg/mL 9 20(S)-CPT -0.2 pg/mL 10 20(RS)-CPT -0.8 pg/mL 11 20(RS)-CPT, Na+ SALT -0.9 pg/mL 12 9-AMINO-10,11-MD0-2 0(S)-CPT, Na+ SALT -1 pg/mL 13 9,10-MDQ-20(RS)-CPT -2 pg/mL 14 9-AMINO-10,ll-MDO-20(RS)-CPT, Na+ SALT -2 pg/mL 15 9-AMINO-10,ll-MDO-20(R)-CPT >10 pg/mL 16 20(R)-CPT >10 pg/mL * Abbreviations cpt = camptothecin MDO = Methylenedioxy gla = Glycinamido ** ECSo is the concentration of a compound which gives 50% topoisomerase I inhibition as revealed by cleavable complex formation. All EC50 values represent the mean of several independent assays? all values are normalized with respect to 2o(S)-CP'r. whicb a)«»y« assayed *s a centre! -23The present compounds are active against murine tumors, such as lymphocytic leukemia L-1210, RAW117-H10 lymphosarcoma and K1735-M2 melanoma. Activity in one or more of these tumor tests has been reported to be indicative of anti-tumor activity in man (A. Goldin et al., in Methods in Cancer Research, ed. v.T. DeVita Jr. and H. Busch, 16: 165, Academic Press, New York, 1979).
In tumor histioculture studies (See Table C) using human cancers obtained by surgery or biopsy, the compounds of the present invention demonstrate significant activity, measured as inhibition of tumor cell proliferation during treatment with the compounds of the present invention. As used herein, the term ’’cancer is synonymous with the terms malignant tumor and more generally tumor. The data shown in Table C demonstrate the activity of the present compounds against human colon cancer, which is well known to be a very resistant cancer to chemotherapy. See. _H,L^_Jlavis,. Chemotherapy of Large Bowel Cancer, Cancer (Phila.) 50: 2638-2646 (1982); J.R. Neefe and P.S. Schein, Chapter 43: The Management of Disseminated Large^B.owel Cancer in Principals of Cancer Treatment, page 402, ed. s.K. Carter, E. Glatstein and R.B. Livingston, McGraw-Hill Co., 1982; K. Mekhail-Ishak, Cancer Research. 49: 4866-4869 (1989) and P.J, Ferguson and Y.c. Cheng, Cancer Research. 49: 114.8-1153 (1989). -24Table C - HUMAN COLON TUMOR HISTIOCULTURE Inhibition of Cell Proliferation Name * **IC50 (jtg/mL) 20(S)-CPT -0.02 10.11- MDO-2G(S)-CPT 10.11- MDO-20(S)-CPT, Na+ SALT -0.003 -0.005 9-NH2-10,ll-MDO-20(S)-OPT "0.002 10.11- MDO-20(RS)-CPT 10.11- MDO-20(RS)-CPT, Na* SALT -0.005 -0.01 9-NH2-10,ll-MDO-20(RS)-CPT 9-NH2-10, ll-MDO-20 (RS)-CPT, Na* SALT -0.005 -0.01 * Abbreviations CPT « Camptothecin MDO » Methylenedioxy ** IC50: concentration of compound required to inhibit by 50% the incorporation of (H)thymidine into DNA Inhibition of tumor cell proliferation was performed in vitro on human colorectal tumors obtained from surgery or biopsy, as described by Vescio et al (Proc. Nat’l. Acad. Sci. USA 84:5029—5033, 1987) with the following modifications: Tumors were cultured l day prior to drug addition; tumors were |xposed to compounds for 24 hours, washed, and then exposed to 3[H]thymidine for 3 days. -25The compounds of the present invention exhibit antitumor activity against human colon cancer, which is known to exhibit dg ppyo drug resistance, and thus be difficult to treat chemotherapeutically. Therefore, it is believed that the present compounds will be active against a wide spectrum of mammalian (including human) cancers such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, etc. Obviously, the present compounds may be used to treat other cancers not specifically named so long as antitumor activity is demonstrated by the present compounds in the particular cancer.
The. present invention· also includes pharmaceutical compositions containing the camptothecin derivatives of the present, IjiveuiLluu. There may be luuluUeU as part oi the composition pharmaceutically acceptable binding agents, carriers and/or adjuvant materials. The active materials can also be mixed with other active materials which do not impair the desired action and/or supplement the desired action. The active materials according to the present invention can be administered by any route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in -26liguid or solid form.
For the purposes of parenteral therapeutic administration, the active ingredient may be incorporated into a solution or suspension. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Another mode of administration of the compounds of this invention, is. oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
The tablets, pills, capsules, troches and the like may cunLain Lhe following ingredients: a biadei suoli as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a -27lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange. flavoring may be added, when the dosage unit form is a capsule, it may contain, in addition to material of the above type, a liguid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various Composi t.S nrifc should be pharroaooutioally cure and non— Luaiu in the mounts used.
As known in this art, dosage values will vary with the specific cancer to be treated, the stage of tumor development, tumor location, weight and physical condition of the patient being treated, etc. Good results should be achieved when the compounds described herein are administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose of from about 0.1 to about 100 mg per day per patient. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted to the individual need in view of the patients response to treatment with the drug and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further -28understood that the dosages set forth herein are exemplary only and they do not limit the scope or practice of the invention. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary. The dosages may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
Other features of the invention will become apparent from the following descriptions of preferred embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
EXAMPLES Example 1 - Synthesis of 9-Amino-io.ii-mdogpt. .11- MDO-20(RS)-CPT and 10,ll-MDO-20(S)-CPT were prepared according to Wani et al., J..Med, Chem.. 29. 2358 (1986) and the process disclosed in U.S. application serial no. 07/511,953.
Conversion of 10,11-MDOCPT to 9-Nitro-lQ,11-MDOCPT. .11- MDOCPT (332 mg, 0.847 mmol) was dissolved/suspended in cone. H2SO4 (5 mL), stirred and cooled to o'C, and treated over 5 min with cone. HN03 (25 drops) . After 1 hr. the brown solution was poured onto ice/H20 (50 mL) to provide a yelloworange precipitate which was collected by filtration (292 mg). Extraction of the filtrate with CHC13 (2 x 50 mL) provided additional material (83 mg) for a total yield of 375 mg -29(100%). Recrystallization from MeOH/CHCl3 provided a 75% recovery of the title compound as a yellow powder: mp darkening above 255*C with no melting below 350’C: IR vmax (KBr) 3430 (br), 2920, 1741 (lactone), 1654 (pyridone), 1596 (aromatic), 1525 (N02) , 1450, 1343, 1242, 1191, 1154, 1043, 928, 785 and 565 cm'1 /1H NMR (DMSO-d6 ) ί 0.87 (t, 3, J - 7 Hz, H-18) , 1. .85 (m, 2, H- is: ) , 5.21 (S, 2, H-5), 5. 41 (s, 2, H-17), 6.52 (S, 2, -och20-) , 7. 24 (s, 1, H-14 ), 7.73 (S, 1, H-12), 3.96 (s, 1, H-7) .
Conversion Of 9-Nitro-10,11-MDOCPT to 9-Amino-10,11-MDOCPT.
A suspension of the nitro compound (139 mg) prepared above and 10% Pd/C (75 mg) in abs EtOH (40 mL) was stirred at ambient temperature under l atm H2 for 20 hr. The mixture was filtered (Celite) and the pad washed profusely with MeOH/CHCl3 and. HCl. Evaporation of the solvents afforded the crude amine as an orange-brown solid (125 mg, 97%). Recrystallization from MeOH/CHCl3 gave the title compound as a tan-orange powder (87 mg, 67%), mp darkening above 250°C with no discreet melting below 350'C. 1H NMR (DMSO-d6) <5 0.88 (t, 3, J = 7 Hz, H-18) , i. 87 (m, 2, H-19), 5 .22 (s, 2, H-5), 5.41, (s, 2, H— 17) , 5.74 (S, 2, NH2), 6.18 (s, 2, -OCSjQ-), 6.47 (S, 1, OH) , 6.91 (3/ 1, H-14), 7.2.3 (S, 1, H-12) , 8.74 (s, 1, H-7) .
Example 2 - Synthesis of 9-Bromo-10,ll-MDO-20(S)-CPT (III, R=Br).
A stirred mixture of 9-amino-lO,ll-MDO-20(S)-CPT (10.0 mg, 25.5 pmol) in 48% aq HBr (0.5 mL) at 0"C was treated with a solution of NaNO2 (2.1 mg, 30.6 prool) in H2O (25 pi). The -30cooling source was removed, and after the addition of CuBr (4.0 mg, 3 5 μχηοΐ) , the brown mixture was heated for 2 0 min at S0‘C. The mixture was cooled and poured over ice (3 g). The resulting suspension was extracted with several 10 mL portions of CHC13, and the extract was dried (Na2SO4) and evaporated under reduced pressure to afford an orange-yellow solid (10 mg) containing mostly the title compound III (R=Br) and, to a lesser extent, III (R=H). Purification was effected by flask column (1 g 23 0-400 mesh Si02, 0.25-1% MeOH in CHC13) to provide III (R=Br) as a pale yellow solid (3.8 mg) and III (R-H) in later, fractions as a cream colored solid (2.0 mg). 300 MHz 1H NMR (DMSO-d6) 6 0.84 (t, 3, J=7 Hz, H-18), 1.82 (m, 2, H-19), 5.24 (s, 2, H-5), 5.39 (S, 2, H-17), 6.36 (S, 2, OCH2O-), 6.49 (S, 1, OH), 7.24 (s, 1, H-14), 7.54 (s, 1, H-12), and 3.63 (s, 1, H-7); HRMS: calcd. for C21H15N2O6Br, 470.0114; measured, 470.0115.
Example 3 - Synthesis of 9-Chloro-iO,ll-MDQ-20(S)-CPT (III, The intermediate diazonium chloride II (X=C1) is prepared as in Example 2 except that 39% aq HCl is used. Similarly, the substitution cf CuCl leads to the expected 9-chloro compound III (R^Cl) after chromatography.
Example 4 - Synthesis of 9-Carboxy-10,ll-MDQ-20(S)-CPT (III, ExCQjH}..
The diazonium salt II (X=C1) is prepared as in Example 2. After filtration of the aq HCl solution, ag HBF4 is added to give a precipitate of II (X=BF4) . This salt is combined in a -31pressure reactor with Pd(OAc)2 and NaOAc in MeCN. Carbon monoxide (1-2 atm) is introduced and the mixture is left for l hr at ambient temperature. The mixture is concentrated by evaporation and reconstituted in H2O. Crude Ill (R=CO2H.) is isolated by extraction into CHC13, and purified by furtherextraction into dilute aq NaHCOj followed by precipitation with acid.
Example 5 - Synthesis of 9-Formvl-lQ,ll-MDO-20(S)-CPT fill, R=CHO)· The diazonium salt II (X-Cl) is .prepared as in Example 2. The salt solution is treated at room temperature with an aqueous solution of formaldoxime containing CuSO4 and Na2SO3. After 1 hr, cone. HCl is added and the intermediate oxime is collected and hydrolyzed to the product aldehyde III (F=CHO) by refluxing in cone. HCl.
Example 6 - Synthesis of 9-Hvdroxv-lQ,11-MDQ-2Q(5)-CPT (III, R—OH).
The intermediate diazonium salt II (X=HSO4) is prepared in a manner analogous to that of Example 2 by using aq H2SO4 instead of aq HBr. The mixture is then heated at 80‘C for 1 hr whereby hydrolysis occurred. On cooling, the product III (R=OH) is isolated by extraction into CHC13, Example 7 - 9-Cvano-10.ll-MDO-20(S)-CPT (III, R=CN).
The diazonium chloride II (X=Cl) is prepared as in Example 2 and treated at 20‘C with CuCN after the pH has been adjusted to 7 with Na2CO3. After 2 hr, the reaction mixture is -32extracted with CHC13. The CHC13 extract is used to isolate the title compound m (R=CNj by chromatography.
Example 8 - 9-Azjdo-lO,ll-MDO-20(g)-CPT Mil, R»N;).
The diazonium chloride II (X=CI) is prepared as described in Example 2. The resulting mixture is treated with an aqueous solution of NaN3, and after 15 min at room temperature, the azide III (R=N3) results as a precipitate. Centrifugation provides the product as a pale solid which is purified by column chromatography.
Example 9 - 9-Fluoro-10, ll-MDO-20 (S)-CPT (ΙΠ, R^Fl .
The diazonium chloride II (X=C1) is prepared as before (Example 2), and after filtration the stirred solution is treated at 0’C with a slight excess of HBF4 whereupon salt II (X—BF4) precipitates. After collection and drying, this salt is pyrolized (> 1204) over 1 hr to afford fluoro product III (R=F). Dark colored impurities can be removed by a flash column chromatography.
Example 10 - 9-Iodo-10,ll-MDO-20(5)-CPT (III, R=I) .
A solution of chloride II (X=C1, prepared as before, Example 2) in aq HCI is treated with aq KI and heated for 1 hr. Upon cooling, the mixture is extracted with CHC13, and the extract concentrated and subjected to column chromatography to provide III (R=I). -33Example 11 - 9-.Nitro-I0 , ll-MDO-20 (S) -CPT (III, R=NO,) .
The salt II (X=BF4) is isolated as in Example 4 and treated at 25° with aq NaNO2 solution followed by the addition of copper powder. After 1 hr, the mixture is extracted with CHC13 which on evaporation gives crude III (R=NO2) . Column chromatography affords pure III (R=NO2) .
Example 12 - 10,ll-MPO-20fS)-CPT (III, R-H) .
The solution of diazonium sulfate II (X=HSO4) , prepared as in Example 6, is maintained at -10’ to 0’ and treated with excess hypophosphorous acid (H3PO2) . After 1 hr, the unsubstituted product III (R=H) can be isolated in nearly pure form by extraction with a few portions of CHCl3.
Example 13 - 9-Mercapto-lQ.ll-MDO-20(S)-CPT (III, R=SH).
A diazonium chloride II (X=C1) solution, prepared as in Example 2, is treated at 40° with potassium ethyl xanthate (KCS2OEt). The intermediate ethyl xanthate is extracted into CHClj, and after evaporation of the CHC13, the xanthate is hydrolyzed with KOH in aq MeOH. The solution is neutralized with cone. HCI and the thiol III (R=SH) isolated hy extraction with CHC13.
Example 14 - 9-Methvl-10,ll-MDO-20(S)-CPT (III, R-Me).
The diazonium tetrafluoroborate salt II (X=BF4) , prepared as in Example 4, is added to MeCN and to the resulting stirred mixture is added Me4Sn and Pd(OAc)z at room temperature. After 2 hr, the MeCN is evaporated and the residue partitioned -34between H2O and CHCl3. The CHC13 is reserved and the aqueous portion is extracted twice more with CHC13. From this extract, III (R«Me) is isolated.
ExauSPle 15 - 9-EthVl-lO,ll-MDO-20(S)rCPT (III, R-Et).
The diazonium tetrafluorofcorate salt II (X-BFJ , prepared as in Example 4, is added to MeCN and to the resulting stirred mixture is added Et4Sn and Pd(OAc)z at room temperature. After 2 hr, the MeCN is evaporated and the residue partitioned between H2O and CHC13. The CHC13 is reserved and the aqueous portion is extracted twice more with CHC13. From this extract, III (R=>Et) is isolated.
Example 16 - conversion of9-Amino-io,ii-MDQCPTto 9Glvcinamido-10,11-MDOCPT Hydrochloride.
A stirred mixture of the 9-amino compound (186 mg. 0.457 mmol) and BOC-glycine (150 mg, 0.85 mmol) in pyridine (1 mL) and DMF (15 mL) was chilled to O’C and treated with Dec (200 mg, 0.971 mmol). The mixture was warmed to ambient temperature and stirred for 65 hr. The solvents were evaporated and the residue dissolved in MeOH/CHC3. Celite (3 g) was added, the mixture evaporated, and the Celite-dispersed sample placed on a silica gel column (20 g). Elution (200 mL CHC13, 500 mL 5% MeOH/CHCl3, 500 mL 12% MeOH/CHCl3) and evaporation of appropriate fractions gave the intermediate BOc-protected derivative (98 mg , 38%) . The derivative was treated with chilled cone HCl/dioxane (1:9, 5 mL), and the resulting mixture was stirred at ambient temperature for 5 hr. The solvent was evaporated, the residue sonicated in deionized -35H2O (50 mL) and filtered (0.45 micron membrane). The clear yellow solution was lyophilized to give an amber gummy solid which on trituration with abs EtOH gave the glycinamide hydrochloride salt as a yellow microcrystalline solid (57 mg, 73%), mp darkening above 230°c with no apparent melting below 340’C. IR (KBr) 3680-2300 with maxima at 3220, 2990 and 2920 (OH, amide H, amine HCl), 1740 (lactone), 1700 (amide), 1655 (pyridone), 1585, 1492, 1447, 1390, 1249, 1160, 1108, 1075, 1041., 933 and 845 cm'1; 1H NMR (DMSO-d6) δ 0.89 (t, 3, J 7 Hz, H-18), 1.87 (m, 2, H-19), 4.02 (d, 2, J = 5.4 Hz, COCHjN-) , 5.17, (s, 2, H-5), 5.42 (S, 2, H-17), 6.32 (s, 2, -OCH2O-), 07.26 (s, 1, H-14), 7.47 (s, 1, H-12), 8.38 (br s, 3,-NHj) , 8.59 (S, 1, H-7), 1075 (s, 1, amide H).
Example 17 - Synthesis of 9-Glutaramido-iO.11-MDOCPT Triethanolamine Salt..
The 9-glutaramido derivative was synthesized from 9-amino-10,ll-MDOCPT by the following method: 9-Glutaramido-10,ll-MDOCPT.
A stirred suspension of 9-amino-10,11-MDOCPT and glutaric anhydride in pyridine under nitrogen was heated at 95°C for 2 hr. The solvent was removed from the brown solution by high vacuum distillation to give the crude amide as a brown gum. Purification was effected by chromatography through silica gel employing a solvent gradient from 5% methanol/chloroform to· 50% methanol/chloroform. Evaporation of the appropriate fractions gave the 9-glutaramide half acid.
Alternatively, the 9-glutaramido derivative can be -36prepared hy hydrolysis, of its ethyl ester which is prepared by the following general method: 9-Araino-10,ll-MDOCPT in dry Ν,Ν-dimethylformamide containing pyridine is reacted at O-iO’C with a slight excess of ethylglutaryl chloride in Ν,Νdimethylformamide solution. After work-up and chromatography on silica gel, the 9-(ethyl)glutaramide derivative is obtained.
Example 18 - synthesis of 9-(4-methyipiperazj.no.).. carbonvlamino-10,ll-MDOCPT Hydrochloride.
The title compound was prepared from 9-amino-lO,li-MDOCPT in the following manner: 9-(4-Methvlpjperazino)carbonylamino-ίο,ll-MDOCPT. 9-Amino-10,ll-MDOCPT was added to chloroform (treated with alumina to remove hydroxylic components) containing triethylamine. The resulting solution was treated with phosgene gas and filtered to remove solids. The filtrate containing the intermediate carbamoyl chloride was treated with N-methylpiperazine under nitrogen and left overnight.
The turbid, mixture was washed several times with aqueous sodium bicarbonate solution, dried and evaporated to afford the crude title compound. Chromatography on silica gel provided 9-(4-methylpiperazino)carbonylamino-10,ll-MDOCPT. 9-(4-Methvlpiperazino)carbonylamino-10,ll-MDOCPT Hydrochloride.
The free base urea obtained above was suspended in methanol and treated with one equivalent of dilute aqueous -37 — hydrochloric acid. The methanol was evaporated and the aqueous residue filtered through a membrane filter. The sample was lyophilized to provide the title compound.
Example 19 - Synthesis of 9-(N.N-Diethylaminoethoxy) carbonylamino-10,11-MDOCPT.
The intermediate 9-carbamoyl chloride was prepared as in the preceding example. The resulting chloroform solution was treated with Ν,Ν-diethylaminoethanol under nitrogen. After standing overnight, the mixture was washed with aqueous sodium bicarbonate solution, dried and evaporated to afford the crude carbamate. Purification by silica gel chromatography gave the pure title carbamate as the free base.
Example 20 - 9-(N.N-Diethvlaminoethoxy)carbonvlamino10,11-MDOCPT Hydrochloride.
The free base from Example 5 was suspended in methanol and treated with one equivalent of dilute aqueous hydrochloric acid. The methanol was evaporated and the aqueous solution filtered.(membrane). Lyophilization afforded the water soluble title carbamate;.
Example 21 - 10,ll-MDO-20(RS)-camptothecin Sodium Salt The title compound was prepared from 10,11MDO-20(RS)-camptothecin (Wani et al., J. Med. Chem, 29, 2358 (1986)) by hydrolytic action of sodium hydroxide. Thus, ,ll-MDO-20(RS)-CPT (77 mg, 0.194 mmol) was suspended in 90% aqueous methanol (30 mL) and treated with 0.1 N aqueous sodium hydroxide (1.94 mL, 0.194 mmol). Upon heating at 50-60‘C for -381 h under nitrogen a clear solution resulted which was cooled to ambient temperature and evaporated to dryness. The residue was dissolved in distilled water (2 mL) and filtered (0.45 micron membrane), and the resulting solution evaporated. The residue was recrystallized from ethanol/ether to provide the title compound as a 'pale yellow solid (53 mg, 65%), mp > 300’C; IR VMX (KBr) 3400 (b£), 2970, 2920, 1640, 1610, 1560-1580, 1497, 1466, 1370, 1246, 1225, 1183, 1030, 1000, 947, 855, 810, 761, 708 and 560-580; ’h NMR (DMSO-d6) S 0.85 (t, 3, J = 7 Hz, H-18), 2.09 (m, 2, H-19), 4.74 (ABq, 2, Av = 68 HZ, J = 12, 4 Hz, H-17), 5.12 (s, 2, H-5), 5,64 (dd, 1, J = 4, 7 HZ, 17-OH), 6.17 (s, 1, 20-OH), 7.47 (s, 1, H-14), 7.54 (s, 1, H-9), 7.62 (s, 1, H-12), 8.41 (s, 1, H-7).
Example 22 - 9-Amino-lO, ll-MDO-20 (RS)-camptothecin Sodium Salt.
The title compound was prepared by an analogous alkaline hydrolysis of 9-amino-10,ll-MDO-20(RS)CPT which was prepared as described above. Thus, a suspension of 9-amino-l0,ll-MDO20 (RS) CPT in aqueous methanol was warmed with one equivalent of aqueous sodium hydroxide to provide a clear solution. Isolation as above provided the water soluble title compound as an orange-yellow solid.
The synthesis of 10,ll-MDO-20(S)-CPT, a starting material for Example 1 is disclosed in J. Med, Chem.. 1987, 30: 2317.
Claims (39)
1. WHAT IS CLAIMED AS NSW AND DESIRED TO BE SECURED BY LETTERS PATENT OF THE UNITED STATES IS: 1A 20 (S) or 20(RS)-camptothecin having the structure shown below: wherein Z is hydrogen or c V8 alkyl, R is N0 2 , NH 2 , N 3 , hydrogen, halogen, COOH, OH, o-C V3 alkyl, SH, S-C V3 alkyl, CN, CH 2 NH 2 , NH-C^J alkyl, CH 2 -NH-C V3 alkyl, N(C, 3. alkyl) 2 , CH 2 N(C Valkyl ) 2 , 0-, NH- or S-CH 2 CH 2 N(CH 2 CH 2 OH) 2 , O-, NH- or SCH 2 CH 2 CH 2 N(CH 2 CH 2 OH) 2 , O-, NH- or S-CH 2 CH 2 N (CH 2 CH 2 CH 2 OH) 2 , Ο-, NHor S~CH 2 CH 2 CH 2 N(CH 2 CH 2 CH 2 OH 2 ) 2 , 0-, NH- or S-CH 2 CH 2 N(C Valkyl) 2 , 0-, NH- or S-CH^HjCHjN/C^j alkyl) 2> CHO, C valkyl or NHCOCHI^NR^R , where R 1 is the side-chain of an α-amino acid and R 2 and R , independently, are hydrogen or a lower alkyl group or R is a peptide unit containing 1-amino acid units bonded to the nitrogen through a peptide bond; NHco-c2„a-alkylene-X or NHC0-C2.8-alkenylene-X, where X is COOH; CONR 2 -(CH2) n -NR 2 R , where n = 1-10 and R 2 and R are as defined above; NHCO-B-(CH 2 ) n -NR 2 R , where B = oxygen or NH; or (CH,)/ 2 NHCO-N N-R \ / (CH 2 ) y where m + y = 3-6, with the proviso that R and Z are not both hydrogen, and salts thereof-40IE 903347
2. The camptothecin pf claim 1, wherein R is nhcochrWr 3 .
3. The camptothecin of Claim 2, wherein R ! is the side chain of a naturally occurring α-amino acid.
4. The camptothecin of Claim 2, wherein R 2 and R 3 are, independently, hydrogen or a lower alkyl group having 1-6 carbon atoms.
5. The camptothecin of Claim 2, wherein R 3 is a peptide unit containing 1-3 amino acid units.
6. The camptothecin of Claim 2, wherein R 1 is a C 2 . 20 alkyl or aralkyl group.
7. The camptothecin of Claim 1, wherein R is NHCO-C 2 . a -alkylene-X or NHCO~C 2 , 8 -alkenylene-X.
8. The camptothecin of Claim 7, wherein X is COOH.
9. The camptothecin of claim 7, wherein X is CONR 2 - (CH z ) n -NR 2 R 3 .
10. The camptothecin of Claim l, wherein R is NHCO-B-(CH z ) n -NR ? R 3 or (CH 2 ) m / \ , NHCO-N N-R' \ / : ( GH 2>y where B is oxygen or NH and m + y = 3-6,
11. The camptothecin of Claim 10, wherein B is oxygen and m + y - 3-4.
12. The camptothecin of Claim 10, wherein B is NH and m + y - 3-4.
13. The camptothecin of Claim l, wherein said salts are mineral acid or organic acid addition salts. -4114.
14.The camptothecin of Claim 1, wherein said salts are monovalent metal cation salts, ammonium salts or quaternary ammonium salts.
15. The camptothecin of Claim l, wherein R is Cl and Z is;H.
16. The camptothecin of Claim l, wherein R is NH 2 or NO 2 and Z is H.
17. The camptothecin of Claim 1, wherein said camptothecin is a 20(S)-camptothecin.
18. A pharmaceutical composition comprising the camptothecin of Claim 1 and a pharmaceutically acceptable carrier.
19. A 20(S) or 20(RS)-camptothecin salt, wherein said salt has the structure shown below wherein z is hydrogen or c^g alkyl, R is N0 2 , NH 2 , N 3 , hydrogen, halogen, COOH, OH, 0-C v3 alkyl, SH, S-C >3 alkyl, CN, CH 2 NH 2 , NH-C V3 alkyl, CH 2 -NH-C 1 . 3 alkyl, N(C b3 alkyl) 2 , c^NfC,^ alkyl) 2 , 0-, NH- or S-CH 2 CH 2 N(CH 2 CH 2 OH) 2 , 0-, NH- or SCH 2 CH 2 CH 2 N(CH 2 CH 2 OH) 2 , 0-, NH- or S-CH 2 CH 2 N(CH 2 CH 2 CH 2 OH) 2 , ο-, NHor S-CH 2 CH 2 CH 2 N(CH 2 CH 2 CH 2 OH 2 ) 2 , 0-, NH- or S-CH 2 CH 2 N(0,.3 alkyl) 2 , 0-, NH- or S-CH 2 CH 2 CH2N.(Ci. 3 alkyl) 2> CHO, C v3 alkyl or NHCOCHR^NrV, where R 1 is the side-chain of an α-amino acid and -42R and R , independently, are hydrogen or a lower alkyl group or R is a peptide unit containing 1-3 amino acid units bonded to the nitrogen through a peptide bond; NHCO-c 2 . 8 -alkylene-X or NHCO-Cj.g-alkenylene-X, where X is COOH; CONR 2 -(CH 2 ) n -NR 2 R 3 , where n = 1-10 and R 2 and R 3 are as defined above; NHCO-B-(CH 2 ) n -NR‘R 3 , where B = oxygen or NH; or (ch 2 ). / 2 NHCO-N N-R \ / (CH,) where m + y = 3-6, M* is a monovalent metal cation and salts thereof.
20. The camptothecin salt of Claim 19, wherein M* is a sodium cation, 1
21. The camptothecin salt of Claim 19, wherein R is no 2 .
22. The camptothecin salt of Claim 19, wherein R is nh 2 .
23. The camptothecin salt of Claim 19, where R is H and 2 is H.
24. The camptothecin salt of Claim 19, wherein said salt is a 20(S)-camptothecin salt.
25. A pharmaceutical composition, comprising the camptothecin salt of Claim 19 and a pharmaceutically acceptable carrier.
26. A method for preparing 9-nitro-10,il-methylenedioxy20(S) or 20(RS)-camptothecin, comprising reacting 10,ll-methylenedioxy 20 (S) or 20(RS)- camptothecin with a mixture of concentrated sulfuric acid and concentrated nitric -43acid to obtain a product containing substantially 9-nitro10,ll-methylenedioxy-20(S) - or 20 (RS)-camptothecin.
27. A method for preparing 9-amino-10,11 methylenedioxy 20(S)- or 20(RS)-camptothecin, comprising the steps of nitrating 10,ll-methylenedioxy-20(S)- or 20(RS)-camptothecin to obtain 9~nitro-10,ll-methylenedioxy-20(S)- or 20(RS)camptothecin, and then reducing the 9-nitro group of said 9-nitro-10,ll-methylenedioxy-20(S) - or 20(RS)-camptothecin to obtain 9-amino-10,ll-methylenedioxy-20(S)- or 20(RS)camptothecin.
28. The method of Claim 27, wherein said reducing step is conducted by catalytic hydrogenation.
29. A method for preparing a 20(S) or 20(RS)camptothecin having the structure shown below: wherein Z is H or C^g alkyl and R is NHCOCHR‘NR 2 R 3 , where R 1 is 2 3 the side-chain of an α-amino acid and R and R , independently, are hydrogen or a lower alkyl group or R 3 is a peptide unit containing 1-3 amino acid units bonded to the nitrogen through a peptide bond; NHCO-C 2 „ 8 -alkylene-X or NHCOC 2 . 8 -alkenylene-X, where X is COOH and n = 1-10, comprising reacting 9-amino- or S-amino-V-C^g alkyl-10,ll-methylenedioxy-20(S) or 20(RS)camptothecin with an amino group-protected amino acid or peptide containing 1-4 amino acid units, a C 4 . 10 saturated or unsaturated carboxylic acid anhydride or with phosgene -44followed by the reaction with a primary or secondary straight-chain, branched or cyclic diamine or a tertiary-amino alcohol.
30. A method for preparing a 20(S) or 20(RS)~ camptothecin salt having the structure shown below wherein M is a monovalent metal cation, comprising hydrolyzing the lactone ring in the camptothecin of Claim 1 with an aqueous solution of a monovalent metal hydroxide.
31. A method of inhibiting the enzyme topisomerase I, comprising contacting said enzyme with an inhibitory amount of the camptothecin of Claim 1.
32. A method of inhibiting the enzyme topisomerase 1, comprising contacting said enzyme with an inhibitory amount of the' camptothecin salt of Claim 19.
33. Λ method of treating cancer, comprising administering to a mammal in need thereof an effective amount of the camptothecin of Claim 1.
34. The method of Claim 33, wherein said cancer is human colon cancer.
35. A method of treating cancer, comprising administering to a mammal in need thereof an effective amount of the camptothecin salt of Claim 19.
36.-4536. The method of claim 35, wherein said cancer is human colon cancer. ‘
37. A method for preparing a 20(S) or 20(RS)-camptothecin substantially as hereinbefore described by way of Example.
38. A 20(S) or 20(RS)-camptOthecin whenever prepared by a method as claimed in any of claims 26 to 30 or 37.
39. A compound as claimed in any of claims 1 to 17, 19 to 24 or 38 for use in the treatment of cancer.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
USUNITEDSTATESOFAMERICA15/09/19890 | |||
US40777989A | 1989-09-14 | 1989-09-14 | |
US07/581,916 US5180722A (en) | 1987-04-14 | 1990-09-13 | 10,11-methylenedioxy-20(RS)-camptothecin and 10,11-methylenedioxy-20(S)-camptothecin analogs |
Publications (2)
Publication Number | Publication Date |
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IE83632B1 IE83632B1 (en) | |
IE903347A1 true IE903347A1 (en) | 1991-04-10 |
Family
ID=27020007
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE334790A IE903347A1 (en) | 1989-09-15 | 1990-09-14 | 10,11-methylenedioxy-20(rs)-camptothecin and¹10,11-methylenedioxy-20(s)-camptothecin analogs |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU640950B2 (en) |
IE (1) | IE903347A1 (en) |
PT (1) | PT95324B (en) |
-
1990
- 1990-09-14 IE IE334790A patent/IE903347A1/en not_active IP Right Cessation
- 1990-09-14 PT PT9532490A patent/PT95324B/en not_active IP Right Cessation
- 1990-09-17 AU AU63404/90A patent/AU640950B2/en not_active Ceased
Also Published As
Publication number | Publication date |
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PT95324A (en) | 1991-05-22 |
AU6340490A (en) | 1991-04-18 |
AU640950B2 (en) | 1993-09-09 |
PT95324B (en) | 1997-06-30 |
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