WO1993023046A1 - Enantiomeric cynemicin analogs, preparation and use thereof - Google Patents
Enantiomeric cynemicin analogs, preparation and use thereof Download PDFInfo
- Publication number
- WO1993023046A1 WO1993023046A1 PCT/US1993/004708 US9304708W WO9323046A1 WO 1993023046 A1 WO1993023046 A1 WO 1993023046A1 US 9304708 W US9304708 W US 9304708W WO 9323046 A1 WO9323046 A1 WO 9323046A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- oxyacetic
- compound
- alkyl
- hydrocarbyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- -1 ring system compound Chemical class 0.000 claims abstract description 127
- 239000000203 mixture Substances 0.000 claims abstract description 31
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- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 claims abstract description 15
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 claims abstract description 15
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- 210000004881 tumor cell Anatomy 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
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- 239000002253 acid Substances 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 32
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 14
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- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- SQEGSJWWDCTFEN-UHFFFAOYSA-N o-methyl 2-phenylethanethioate Chemical compound COC(=S)CC1=CC=CC=C1 SQEGSJWWDCTFEN-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
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- GTCCGKPBSJZVRZ-UHFFFAOYSA-N pentane-2,4-diol Chemical class CC(O)CC(C)O GTCCGKPBSJZVRZ-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 108010042747 stallimycin Proteins 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
Definitions
- the present invention relates to novel DNA- cleaving, c totoxic and anti-tumor compounds, and particularly to enantiomeric fused ring compound systems that contain an enediyne macrocyclic ring and also an epoxide ring, as well as chimeras that contain such a fused ring compound system.
- Me is methyl
- a potent antibacterial and anticancer agent recently isolated from Micromonospora chersina [(a) Konishi et. al, J. Am. Chem. Soc.. 112:3715-3716 (1990); (b) Konishi et al., J. Antibiot.. 42.:1449-1452 (1989)].
- Its striking molecular structure combines characteristics of both the enediyne [Golik et al., J. Am. Chem. Soc.. 109:3461-3462 (1987); Golik et al., J. Am. Chem. Soc. 109:3462-3464 (1987); Lee et al., J. Am. Chem.
- calicheamicin and espera icin derivatives are perhaps the best known of the enediyne compounds.
- For other selected studies of model systems in the area of calicheamicins- esperamicins see: (b) Nicolaou et al, J. Am. Chem. Soc.. 110:4866-4868 (1988); (c) Nicolaou et al., J. Am. Chem. Soc.. 110:7247-7248 (1988); (d) Schoenen et al..
- the present invention relates to novel enantiomeric fused ring compound systems that contain an epoxide ring and an enediyne macrocyclic ring, and thus have structural features similar to dynemicin A.
- a contemplated enantiomeric fused ring compound is substantially free of the other enantiomer.
- the compounds have DNA-cleaving, antibiotic and antitumor activities. Compositions and methods of making and using the compounds are disclosed.
- An entio eric fused ring compound of the invention has a structure that corresponds to the formula
- R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, phenoxycarbonyl, benzyloxycarbonyl, C,-C 6 alkoxycarbonyl, substituted C--C 6 alkoxycarbonyl
- R 2 is selected from the group consisting of H, carboxyl, hydroxylmethyl and carbonyloxy C.,-C 6 alkyl;
- R 3 is selected from the group consisting of H and C--C 6 alkoxy
- R 4 is selected from the group consisting of H, hydroxyl, C,-C 6 alkoxy, oxyacetic acid, oxyacetic C--C 6 hydrocarbyl or benzyl ester, oxyacetic amide, oxyimidazilthiocarbonyl and C--C 6 acyloxy;
- R 6 and R 7 are each H or together with the unsaturated carbon atoms of the intervening vinylene group form a one, two or three fused aromatic six- membered ring system; together with the carbon atoms of the depicted, intervening vinylene group forms an aromatic hydrocarbyl ring system containing 1, 2 or 3 six- membered rings such that the fused ring compound contains 3, 4 or 5 fused rings, all but two of which are aromatic, and in which that aromatic hydrocarbyl ring system, , is joined [a, b] to the structure shown (i.e., is joined [a,b] to the nitrogen-containing rings of the structure shown) ; and
- R 8 is hydrogen or methyl, with the proviso that R 8 is hydrogen when , together with the carbon atoms of the intervening vinylene group is 9,10-dioxoanthra.
- W together with the a intervening vinylidene group forms a benzo ring so that a contemplated enantiomeric compound has the structural formula shown below.
- R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkoxy, hydroxyl, ⁇ -C 6 acyloxy, oxyethanol, oxyacetic acid, oxyacetic acid amide, oxyacetic C j -C ⁇ hydrocarbyl ester, oxyethanol tertiary amino- or quaternary ammonium-substituted CJ-CJ alkyl carboxylate, 3-hydroxyprop-l-ynyl, o-nitrobenzyloxy and halo, and A and the remaining R groups are as before described.
- R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are hydrogen so that a contemplated enantiomeric compound of the invention corresponds to the structural formula shown below, where R 1 and R 4 are as previously defined.
- R 5 is C.,-C 6 alkoxy, hydroxyl, C.,-C 6 acyloxy, carboxyl, C,-C 6 hydrocarbyl or benzyl carboxylate, oxyethanol, oxyacetic acid, oxyacetic acid amide, oxyethanol tertiary amino- or quaternary ammonium-substituted CJ-CJ alkyl carboxylate or 3-hydroxyprop-l-ynyl and R 4 is hydrogen (H) or hydroxyl so that a fused ring compound has the structural formula shown below.
- any of the above fused ring enediyne compounds can be prepared as a single enantiomer.
- R 1 group is also prepared from an individual chiral compound, as where R 1 is a 2-mono- or di-C 1 -C 6 alkyl- substituted-2-phenylsulfonyl ethoxycarbonyl group, any of the above compounds can be present as a further enantiomer.
- a chimeric compound also referred to as a chimer or chimera
- a chimeric compound that is comprised of a before-described enantiomeric fused ring compound as an aglycone portion bonded to (i) an oligosaccharide portion or (ii) a monoclonal antibody or antibody combining site portion thereof that immunoreacts with target tumor cells.
- the oligosaccharide portion comprises a sugar moiety selected from the group consisting of ribosyl, deoxyribosyl, fucosyl, glucosyl, galactosyl, N-acetylglucosaminyl, N-acetylgalactasaminyl, a saccharide whose structure is shown below, wherein a wavy line adjacent a bond indicates the position of linkage.
- a monoclonal antibody or binding site portion thereof is bonded to the enantiomeric fused ring compound aglycone portion through an R 4 oxyacetic acid amide or ester bond, an oxyacetic acid amide or ester bond or oxyethanol ester bond from W such as from an R 5 group.
- An oligosaccharide portion is glycosidically bonded to the aglycone portion through the hydroxyl of an R 4 oxyethanol group or the hydroxyl of an oxyethanol- substituent of w, e.g. an R 5 group.
- a pharmaceutical composition is also contemplated. That pharmaceutical composition contains a DNA cleaving, antibiotic or tumor cell growth- inhibiting amount of a before-defined enantiomeric compound or chimera as active agent dissolved or dispersed in a physiologically tolerable diluent.
- An enantiomeric compound, chimera or a pharmaceutical composition of either is also useful in a method for cleaving DNA, for inhibiting tumor growth and as an antimicrobial.
- the DNA to be cleaved, target tumor cells whose growth is to be inhibited or target microbial cells are contacted with a composition of the invention. That contact is maintained for a time period sufficient for the desired result to occur. Multiple administrations of a pharmaceutical composition can be made to provide the desired contact.
- Lane 1 (1.0 mM) is the DNA control; lane 2 is DNA plus Compound 21 (1.0 mM) ; lane 3 is DNA plus Compound 427 (5.0 mM) ; lane 4 is DNA plus Compound 428 (5.0 mM) ; lane 5 is DNA plus Compound 429 (5.0 mM) ; lane 6 is DNA plus 2-(phenylsulfonyl)propanol (5.0 mM) ; lane 7 is DNA plus phenyl isopropenyl sulfone (5.0 mM) ; and lane 8 is DNA plus phenyl vinyl sulfone (5.0 mM) .
- Form I is supercoiled DNA; Form II is nicked DNA; and Form III is linear DNA.
- An enantiomeric compound of the invention contains an enediyne macrocycle linked to a fused ring compound system that corresponds to structural Formula I
- R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, phenoxycarbonyl, benzyloxycarbonyl, C,-C 6 alkoxycarbonyl, substituted C 1 -C 6 alkoxycarbonyl
- R 2 is selected from the group consisting of H, carboxyl, hydroxylmethyl and carbonyloxy-C 1 -C 6 alkyl;
- R 3 is selected from the group consisting of H and C.,-C 6 alkoxy
- R 4 is selected from the group consisting of H, hydroxyl, C-,-C 6 alkoxy, oxyacetic acid (-OCH-JCOJH) , C 1 -C 6 hydrocarbyl or benzyl oxyacetic acid ester, oxyacetic amide, oxyethanol (-OCH j CH j OH) , oxyimidazylthiocarbonyl and C--C 6 acyloxy
- R 6 and R 7 are each H or together with the intervening vinylene group form a one, two or three fused aromatic six-membered ring system
- W together with the bonded, intervening, vinylene group forms a substituted aromatic hydrocarbyl ring system containing 1, 2 or 3 six-membered rings such that said fused ring compound contains 3, 4 or 5 fused 6-membered rings all but two of which rings are aromatic, and in which that aromatic hydrocarbyl ring system, W, is joined [a, b] to the structure shown; and
- R 8 is hydrogen or methyl with the proviso that R 8 is hydrogen when W together with the intervening vinylidene group is 9,10-dioxoanthra.
- a compound of Formula I and the other fused ring enediyne compounds disclosed herein are chiral, and are prepared as a single or individual enantiomer that is substantially free of the other enantiomer. Only one of the enantiomeric pair is shown in Formula I and most of the other formulas depicted herein. For ease in depiction, the depicted enantiomeric fused ring enediyne compounds are shown having the absolute stereochemistry of dynemicin A [Landley et al. , J. Am. Chem. Soc.. 113:4395 (1991) and Wender, Proc. Natl. Acad. Sci. USA. ⁇ 58_:8835 (1991)], which absolute stereochemistry is preferred.
- a contemplated enantiomer is synthesized using similar reactions to those disclosed in WO 92/02522 with different intermediate steps that permit a stereocontrolled synthesis. These different steps are outlined hereinafter.
- Racemates are useful as the data of WO 92/02522 and the literature indicate.
- separate enantiomers have also been prepared and a compound having the same absolute stereochemistry as that of dynemicin A, the (+) isomer, has been found to be more potent against some cancer cell lines, e.g. Molt-4 T cell leukemia and Capan-1 pancreatic carcinoma, than the other, (-) , enantiomer.
- Separated (+) and (-) isomers also exhibit similar potencies against other cancer cell lines such as SK-MEL-28 melanoma.
- a fused ring enediyne disclosed herein is contemplated as either or both of the separated (+) and (-) , single, enantiomeric molecules (enantiomers) .
- R 6 and R 7 groups other than hydrogen are discussed hereinafter.
- the bond. A, between the R 2 and R 3 substituents can be a double or single bond.
- the bond A is preferably a single bond.
- a C--C 6 alkyl group, as can be present in R 1 is exemplified by methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, 2-methylpentyl, hexyl, cyclohexyl, cyclopentyl and the like.
- a substituted C--C 6 alkyl group is also contemplated as an R 1 group.
- Such substituted alkyl groups include hydroxyalkyl groups such as 2-hydroxyethyl, 4-hydroxyhexyl and 3-hydroxypropyl, haloalkyl groups such as 2-chlorobutyl, 3-halopentyl such as 3-fluoropentyl, and the like.
- the above C 1 -C 6 alkyl and substituted C,-C 6 alkyl groups are further contemplated as the C 1 -C 6 alkyl portion of a carbonyloxy C 1 -C 6 alkyl group of R 2 ; i.e., a C 1 -C 6 alkyl ester of a R 2 carboxyl group, and of a R 1 urethane group.
- a C t -C 6 acyloxy group as is present in R 4 or R 5 is a carboxylic acid derivative of an appropriate alkyl group, above, except for, for example, cyclohexyl and iso-propyl, and is limited to a cyclopentylcarboxyl group for the cyclopentane derivatives.
- C 1 -C 6 acyloxy groups include for yloxy, acetoxy, propionoxy, butyryloxy, iso- butyryloxy, pentanoyloxy, 2-methylbutyryloxy, pivaloyloxy, hexanoyloxy, and the like.
- the alcohol-carbonyl portion of a urethane R 1 is typically formed by the reaction of a corresponding halo formate derivative, such as a chloroformate like phenylchloroformate, with the secondary amine nitrogen atom that is formed by addition of an acetylenic group- containing moiety to the 6-position or a correspondingly numbered position of a fused ring system such as that shown in Scheme II hereinafter.
- Such groups can also be prepared by base-catalyzed exchange from a formed carbamate using the substituted ethyl alcohol as is illustrated hereinafter.
- Exemplary C 1 -C 6 alkoxycarbonyl groups and substituted C 1 -C 6 alkoxycarbonyl groups contain a before-described C 1 -C 6 alkoxy group or substituted C 1 -C 6 alkoxy group linked to the carbonyl group and can be formed by reaction of a C,- ⁇ alkylchloroformate.
- Exemplary substituted ethoxycarbonyl groups that are a particularly preferred group of substituted C.,-C 6 alkoxycarbonyl group have a substituent other than hydrogen at the 2-position of the ethoxy group, and include 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, ⁇ - or ,S-2-(naphthylsulfonyl)ethoxycarbonyl, a- or ⁇ -2-(anthracylsulfonyl)ethoxycarbonyl, 2-propenoxycarbonyl, 2-hydroxyethoxycarbonyl, 2-(triphenylphosphoniume)thoxycarbonyl halide (e.g., chloride, bromide or iodide) and 2-(trimethylammonium)ethoxycarbonyl halide (as before).
- 2-(trimethylsilyl)ethoxycarbonyl 2-(phenylsulfony
- R 1 be a group that can be enzymatically or otherwise removed intracellularly to provide the resulting secondary amine free of a substituent group.
- a compound where R 1 contains a 2-substituted-ethoxycarbonyl group such as a 2-(phenylsulfonyl)-, 2-(naphthylsulfonyl)- and 2-(anthracylsulfonyl)- as are shown in Scheme III (shown as R- i therein) can form the free secondary amine compound via a /9-elimination under relatively mild conditions.
- An ethoxy carbonyl group can also be named an ethylene oxycarbonyl group.
- Phenylsulfonylethoxycarbonyl, o-naphthyl- and 3-naphthylsulfonylethoxycarbonyl are particularly preferred R 1 groups, with phenoxycarboxyl being a preferred R 1 group.
- an R 1 group is o-nitrobenzyloxycarbonyl
- UV light-irradiation (about 290-400 nm) provides cleavage of that group from a fused ring system, thereby providing a free amine group.
- Each of the 2-(phenylsulfonyl)-2-(mono- or di-C-,-C 6 alkyl)-ethoxy carbonyl-containing fused ring enediyne compounds was less potent than the very potent un-allylated derivatives. These differences in potency can be used to adjust the potency and selectivity of a contemplated compound.
- Exemplary R 6 and R 7 that together with the intervening vinylene group form a one, two or three fused aromatic six-membered ring system that includes benzo, naphtho and anthra rings, as well as 6,8-dimethoxynaphtho and 6,8-diazanaphtho. As noted before, it is preferred that both R 6 and R 7 be hydrogen.
- R 8 group can be methyl or hydrogen with the proviso that R 8 is hydrogen when W along with the intervening vinylene group carbon atoms forms a 9,10- dioxoanthra ring. It is particularly preferred that R 8 be methyl when W forms a benzo ring.
- R 4 groups that are hydrogen, hydroxyl, oxyethanol (-OCH 2 CH 2 OH) , oxyacetic acid (-OCH 2 C0 2 H) , oxyacetic C 1 -C 6 hydrocarbyl esters such as the before- discussed C 1 -C 6 alkyl groups such as ethyl oxyacetate (-OCH 2 C0 2 CH 2 CH 3 ) , as well as C. j -C 6 unsaturated esters such as the allyl, propargyl, 2-butenyl and the like, as well as the benzyl ester and oxyacetic amides constitute particularly preferred embodiments of the invention.
- a pharmaceutically acceptable non-toxic salt of the oxyacetic acid such as sodium, potassium, ammonium, calcium and magnesium is also contemplated.
- An oxyacetic acid amide corresponds to the chemical formula -0CH 2 C0NR 13 R u wherein R 13 is hydrogen (H) or C 1 -C 6 alkyl (as before) and R u is independently hydrogen, c ⁇ " C alkyl, phenyl, 1- or 2-napthyl, 1- or 2-anthryl, or a peptide having 1 to about six amino acid residues; or R 13 and R u together with the nitrogen atom form a 5- or 6-membered ring as is present in pyrrolidine, piperidine, morpholine, i idazole or pyrrole.
- a particularly contemplated peptide is distamycin, or a derivative thereof as discussed in Taylor et al.. Tetrahedron. 4_0:457 (1984) and Baker et al., J. Am. Chem. Soc. 111:2700 (1989). Distamycin derivatives are themselves known DNA-cleaving agents. Another particularly preferred peptide is
- Appropriate diamine and dicarboxylic acid groups can be added at the carboxy- and amino-termini of the peptides or acid labile linkers, respectively, to join the fused ring enediyne to the Mab, as is discussed below.
- Exemplary dia ines are the ⁇ , ⁇ -C 2 -C 6 alkylene diamines such as ethylene diamine, 1,3-propylene diamines and 1,6-hexylene diamine.
- Exemplary ⁇ , ⁇ -C 4 -C 6 dicarboxylic acids include succinic, maleic, glutaric and adipic acids.
- R 4 group that contains a derivatized oxyacetic acid amide or ester can also include a peptidyl spacer containing zero to about 6 residues such as (-Ala-) 3 that links the compound to a monoclonal antibody or an antibody binding site portion thereof, collectively referred to herein as a "Mab".
- An R 5 group as discussed in detail hereinafter as a substituent of W as in a compound of Formula Xlb can also constitute a useful spacer for bonding to a Mab.
- Such a Mab-linked fused ring enediyne is one type of chimeric molecule of the invention.
- the spacer portion of the enantiomeric compound-Mab construct serves to link the two portions of the molecule together.
- a lysine epsilon-amino group of the Mab forms the amido bond with an R ⁇ group as spacer.
- the spacer peptide chain when present, is typically comprised of amino acid residues having small side chains such as glycine or alanine, or relatively hydrophilic side chains such as serine, glutamine and aspartic acid.
- a peptide spacer is typically free of cysteine residues, but can contain cystine residues and otherwise can have substantially any structure that does not interfere with bonding between the two portions of the chi eric compound.
- a peptide can be prepared by an one of several synthetic methods as are well known.
- a particularly preferred peptide spacer includes an amine acid residue sequence that is recognized and cleaved by an enzyme such as a lysosomal or other proteolytic enzyme present within a target neoplastic cell so that the fused ring enediyne can be freed from the Mab after endocytosis, as is well known.
- the Mab portion of the above chimeric construct can constitute an intact antibody molecule of IgG or IgM isotype, in which case, a plurality of compounds can be present per antibody molecule.
- the binding site portions of an antibody can also be utilized, in which case, at least one compound is linked to the proteinaceous antibody binding site portion.
- An antibody binding site portion is that part of an antibody molecule that immunoreacts with an antigen, and is also sometimes referred to as a paratope.
- Exemplary antibody binding site portions include F(ab), F(ab'), F(ab , ) 2 and F v portions of an intact antibody molecule, and can be prepared by well known methods.
- An intact monoclonal antibody and a portion that includes its antibody combining site portion can be collectively referred to as a paratope- containing molecule.
- Exemplary anti-tumor Mabs are noted in the table below, listed by the name utilized in a publication, along with its deposit accession number at the American Type Culture Collection (ATCC) , 12301 Parklawn Drive, Rockville, Maryland 20852 U.S.A., and the tumor antigen with which the Mab paratope is reported to react. A citation to a discussion of each Mab and its immunoreactivity is provided by the footnote under the antigen listing.
- ATCC American Type Culture Collection
- An enantiomeric fused ring enediyne compound of the invention can also be glycosidically linked to a sugar moiety to form a second type chimeric molecule.
- the enantiomeric fused ring enediyne compound takes the place of the aglycone as in an antibiotic molecule such as doxorubicin, calicheamicin or esperamicin, with the sugar moiety taking the place of the oligosaccharide portion.
- Bonding between the enantiomeric fused ring enediyne compound aglycone and oligosaccharide is typically via a hydroxyl group of a spacer group that is itself linked to the fused ring enediyne through a reacted hydroxyl group.
- a preferred spacer group is an oxyethanol group that can be an R 4 group or can be an R 5 substituent of W as is discussed and illustrated hereinafter.
- the glycosidically bonded saccharide thus forms an ether bond via the hydroxyl group of the oxyethanol group.
- the oligosaccharide portion of the molecule is typically added after the synthesis of the fused ring enediyne compound (aglycone) portion is complete, except for any blocking groups on otherwise reactive functionalities of the aglycone that are typically removed after addition of the oligosaccharide portion.
- a sugar moiety is added by standard techniques as are discussed hereinafter.
- a glycosidically-linked sugar moiety can be a monosaccharide such as a ribosyl, deoxyribosyl, fucosyl, glucosyl, galactosyl, N-acetylglucosaminyl, N-acetylgalactosaminyl moiety or the more preferred saccharides whose structures are shown below, wherein a wavy line adjacent a bond indicates the position of linkage.
- the position of the glycosyl bond to be formed in the sugar moiety used for forming a chimeric compound is typically activated prior to linkage to the fused ring enediyne compound.
- the 1-position hydroxyl group of an otherwise protected sugar as with l BuMe 2 Si or E ⁇ Si groups
- DAST diethylaminosulfur trifluoride
- the enantiomeric enediyne having a free hydroxyl group is then reacted with the 1-fluro- protected saccharide in the presence of silver perchlorate and stannous chloride to provide a protected desired, typically blocked, enantiomeric chimer molecule.
- treatment of 1-position hydroxyl of an otherwise protected saccharide with sodium hydride and trichloracetonitrile [Grandler et al., Carbohvdr. res.. 135:203 (1985); Schmidt, Angew. Chem. Int. Ed.. Engl..
- the 1, 2 or 3 six-membered ring fused rings that along with the depicted vinylene group constitute the structure W are aromatic hydrocarbyl rings. Such rings can thus be benzo, naphtho and anthra rings, using fused ring nomenclature.
- the anthra (anthracene) derivative rings contemplated here contain 9,10-dioxo groups (are derivatives of anthraquinone) and are therefore referred to as 9,10-dioxoanthra rings.
- a benzo, naphtho or 9,10-dioxoanthra fused ring portion can also contain one or more substituents at the ring positions remaining for substitution. Those substituent groups are selected from the group consisting of hydroxyl, C--C 6 alkoxy, oxo, C,- ⁇ acyloxy and halo (chloro, bromo or iodo) .
- R 5 which designation for convenience includes hydrogen.
- R 5 is thus selected from the group consisting of hydrogen (no substituent) , C.,-C 6 alkoxy, carboxyl, C.,-C 6 hydrocarbyl or benzyl carboxylate, benzyloxy, _-nitrobenzyloxy, hydroxy, C,-C 6 acyloxy, oxyethanol, oxyethanol tertiary amino or quaternary ammonium C 2 -C 6 alkyl carboxylic acid ester, oxyacetic acid, oxyacetic acid C,- ⁇ hydrocarbyl ester, oxyacetic acid amide, 3-hydroxyprop-l-ynyl and halo.
- a hydroxyl group or a group that can form a hydroxyl group intracellularly be present, such that a hydroxyl group be present intracellularly at a position eta to the nitrogen in the adjacent ring.
- R 10 and R 11 are selected from the group consisting of C 1 -C 6 alkoxy, benzyloxy, oxo, C--C 6 acyloxy, hydroxyl and halo.
- W is more preferably a benzo group that contains a single substituent R 5 .
- R 5 is situated in the benzo ring meta or para to the nitrogen atom bonded to R 1 .
- That R 5 group is more preferably selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, benzyloxy, o-nitrobenzyloxy, C--C 6 acyloxy, carboxyl, C 1 -C 6 hydrocarbyl or benzyl carboxylate, oxyethanol, oxyacetic acid, oxycacetic C 1 -C 6 hydrocarbyl ester, oxyacetic acid amide, oxyethanol tertiary amino- or quaternary ammonium-substituted C 2 -C 6 alkyl carboxylate or 3-hydroxyprop-l-ynyl.
- R 5 oxyacetic acid or oxyethanol or 3-hydroxyprop-l-ynyl group is useful for linking the aglycone to an oligosaccharide or antibody combining site portion via an ether or ester group, as discussed previously for R 4 .
- R 5 is meta to the above nitrogen atom
- the R 5 group be an electron releasing group such as hydroxyl or a C 1 -C 6 acyloxy group that can provide a hydroxyl group intracellularly.
- a C,-C 6 acyloxy group is believed to be a pro-drug form of the hydroxyl group that is cleaved intracellularly by an endogenus esterase or the like to provide the hydroxyl group.
- the presence of such an electron releasing group appears to assist in enhancing the potency of the compound against target tumor cells. It is believed that the enhanced potency is due to enhanced triggering of the epoxide opening and cyclization reactions.
- R 5 is para to the above nitrogen atom, it is preferred that the R 5 group be an o-nitrobenzyloxy group, oxyethanol, carboxyl, C--C 6 hydrocarbyl or benzyl carboxylate, oxyacetic acid or oxyacetic acid C--C 6 hydrocarbyl ester. Those groups are particularly useful for the preparation of chimeras.
- R 5 substituent para to the nitrogen that is an oxyethanol, oxyacetic acid or oxyacetic acid amide as discussed for an R 4 group before, is also useful for providing enhanced water solubility to a fused ring enediyne compound discussed herein.
- One particularly preferred compound contains an oxyethanol R 5 group para to the nitrogen atom.
- Another particularly prefered R 5 substituent that is para to the nitrogen atom is an oxyethanol ester of a tertiary or quaternary amine substituted C 2 -C 6 alkyl carboxylic acid (carboxylate) .
- These substituents provide still further enhancements to water solubility because of the formal charge of a quaternary ammonium group or the protonation of the tertiary amine at physiological pH values, e.g. pH 7.2-7.4.
- Exemplary C 2 -C 6 alkyl carboxylic acids are those discussed in conjunction with a C 1 -C 6 acyloxy group.
- the amine substituent is preferably bonded to the carbon atom farthest down the alkyl chain from the carboxyl group and is therefore an ⁇ -(omega) substituent.
- tertiary amine and quaternary ammonium derivatives of ⁇ -amino acids such as glycine, 3-alanine, ⁇ -aminobutyric acid and 6-aminocaproic acid are preferred.
- the amine portion of an oxyethanol tertiary amine- or quaternary ammonium-substituted C 2 -C 6 alkyl carboxylic acid ester has the structure -NR 20 R 21 or - * NR 20 R 21 R 22 wherein R 20 , R 21 and R 22 are each independently C,-C 6 alkyl, or R 20 and R 21 together with the nitrogen atom form a 5- or 6-membered ring, or R 20 , R 21 and R 22 (R 20"22 ) together with the nitrogen atom form a pyridinium or pyrazinium group.
- Exemplary C,-C 6 alkyl groups have already been discussed, and methyl is preferred for each of R 20*22 .
- Exemplary 5- and 6-membered ring compounds formed by R 20 , R 21 and the nitrogen atom include piperidine, morpholine, pyrrolidine, imidazole, pyrrole and piperazine.
- exemplary -NR 20 R 21 portions of tertiary amine groups include dimethylamino, diethyla ino, hexyliso-propylamino, di-sec-butylamino, N-morpholinyl, N-piperidyl and N-imidazyl.
- Exemplary quaternary ammonium groups include trimethylammonium, ethyldimethylammonium, ethyliso-propylhexylammonium, N-methylmorpholinium, N-butylpiperidinium, pyridinium and pyrazinium.
- a suitable anion for the quaternary group is of course contemplated and includes halide ions such as chloride and bromide, sulfate, acetate or another C,-C 6 acyloxy group anion.
- An N,N,N- trimethylglycine chloride ester of an oxyethanol substituent is particularly preferred.
- a particularly preferred compound has a structure corresponding to Formula Xlb, hereinafter.
- a naphtho ring can have three substituents.
- This ring can have a 4-position radical, R 5 , selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, benzyloxy, C--C 6 acyloxy, carboxyl, C 1 -C 6 hydrocarbyl or benzyl carboxylate, and halo, and substituents at the 5- (R 10 ) and 8-positions (R 11 ) that are selected from the group consisting of hydroxyl, C--C 6 alkoxy, benzyloxy, C,-C 6 acyloxy, oxo and halo radicals.
- a 9,10- dioxoanthra ring can have three substituents at the 4- (R 5 ) , 5- (R 9 ) and 8-positions (R 12 ) that are independently selected from the group consisting of hydroxyl, C--C 6 alkoxy, benzyloxy, C 1 -C 6 acyloxy and halo.
- R 5 , R 9 and R 12 can define the same groups, and all three groups can be written as either R 5 , R 9 or R 12 , but they are shown separately herein.
- Exemplary structural formulas for a contemplated enantiomeric fused ring compound are illustrated below by structural Formulas II-IX, wherein each of the R groups is as discussed before..
- R 8 and that bond A be a single bond
- R 2 and R 3 be hydrogen
- R 6 and R 7 be hydrogen
- the fused ring system W together with the depicted vinylene group be substituted benzo, or an unsubstituted benzo, naphtho or 9,10-dioxoanthra ring.
- the fused ring compound contain a total of 3-fused six-membered rings so that W together with the depicted vinylene group forms a benzo ring.
- One particularly preferred group of enantiomeric compounds of the invention in which W is an R 5 -substituted benzo ring corresponds to structural Formula X.
- A is a double or single bond
- R 1 is selected from the group consisting of H, C ⁇ C g alkyl, phenoxycarbonyl, benzcxycarbonyl, C,- ⁇ alkoxycarbonyl, substituted C,-C 6 alkoxycarbonyl (particularly substituted ethoxycarbonyl where the substituent is phenylsulfonyl or naphthylsulfonyl, with phenylsulfonyl most particularly preferred) , ⁇ -nitrobenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl;
- R 2 is selected from the group consisting of H, carboxyl, hydroxylmethyl and carbonyloxy C 1 -C 6 alkyl;
- R 3 is selected from the group consisting of H and c,-c 6 alkoxy
- R 4 is selected from the group consisting of H, hydroxyl, oxyacetic acid (-OCl ⁇ CO ⁇ ) , oxyacetic C 1 -C 6 hydrocarbyl or benzyl ester, oxyacetic amide, oxyethanol, oxyimidazylthiocarbonyl and C.,-C 6 acyloxy;
- R 5 is selected from the group consisting of hydrogen, C,-C 6 alkoxy, benzyloxy, o-nitrobenzyloxy, hydroxyl, C,-C 6 acyloxy, carboxyl, C 1 -C 6 hydrocarbyl or benzyl carboxylate, oxyethanol, oxyacetic acid, oxyacetic acid C 1 -C 6 hydrocarbyl ester, halo, oxyacetic acid amide, oxyethanol tertiary amino- or quaternary ammonium-substituted C 2 -C 6 alkyl carboxylate and 3-hydroxyprop-l-ynyl; and R 6
- a still more preferred group of enantiomeric compounds of the invention correspond to structural Formulas XI, XIa and Xlb.
- R 1 is most preferably phenoxycarbonyl 2-(phenylsulfonyl)ethoxycarbonyl, 2-(naphthylsulfonyl)ethoxycarbonyl or hydrogen.
- R 8 is most preferably hydrogen (H) to provide a compound of Formulas XIa or Xlb.
- R 4 is most preferably H, hydroxyl, imidazylthiocarbonyloxy, benzyl oxyacetate and C 1 -C 6 hydrocarbyl oxyacetate such as ethyl oxyacetate.
- R 5 in Formulas XI and XIa is H, but is more preferably hydroxyl, C,-C 6 alkoxy, benzyloxy, C.,-C 6 acyloxy, oxyethanol, oxyacetic acid, oxyacetic acid C 1 -C 6 hydrocarbyl or benzyl ester and o-nitrobenzyloxy, oxyacetic acid amide, oxyethanol tertiary amino- or quaternary ammonium-substituted C 2 -C 6 alkyl carboxylate or 3-hydroxyprop-l-ynyl as in Formula Xlb. It is noted that an R 5 jo-nitrobenzyloxy group is not usually used in a pharmaceutical composition discussed hereinafter.
- a contemplated enantiomeric fused ring enediyne compound can be synthesized as a racemic mixture of the enantiomers as discussed in WO 92/02522 and resolved into single enantiomers for use herein, or can be synthesized as an optically pure single enantiomer, which is preferred.
- the synthesis of single enantiomeric Compounds (+)- and (-)-45 are discussed hereinafter, and analogous syntheses can be applied to the preparation of an enantiomer of any of the other compounds disclosed herein.
- the enantiomeric Compounds 45 exhibited similar DNA cleaving activities to eaoh other and to the racemate, but exhibited some startling differences between themselves and the known racemate in cytotoxicity when assayed against cancer cell lines.
- An enantiomeric compound or chimera of the invention is useful as a DNA cleaving agent, and also as an antimicrobial and a cytoxic (antitumor) agent, as are dynemicin A, calicheamicin, esperamicin and neocarzinostatin.
- a compound of the invention can also therefore be referred to as an "active agent" or "active ingredient”.
- DNA cleavage can be assayed using the techniques described hereinafter as well as those described by Mantlo et al., J. Org. Chem.. 54:2781 (1989); Nicolaou et al., J. Am. Chem. Soc.. 110:7147 (1989); Nicolaou et al., J. Am. Chem. Soc.. 110:7247 (1988) or Zein et al.. Science. 240:1198 (1988) and the citations therein.
- An enantiomeric compound or chimer of the invention is useful against Gram-positive bacteria such as s. aureus and epidermis. Micrococcus luteus and
- Bacillus subtillis as is dynemicin A Such a compound or chimer also exhibits antimicrobial activity against E. coli. Pseudomonas aeruginos. Candida albucans and Aspergillis fumigatus. Activity of an enantiomeric compound of the invention against the above microorganisms can be determined using various well known techniques. See, for example, Konishi et al., ⁇ J. Antibiotics. XLII:1449 (1989). Antimicrobial and antitumor assays can also be carried out by techniques described in U.S. Patent No. 4,837,206, whose disclosures are incorporated by reference, as well as by the procedures described hereinafter.
- a before-described enantiomeric compound can also be shown to undergo a Bergman cycloaromatization reaction in the presence of benzyl mercaptan, triethylamine and 1,4-cyclohexadiene as discussed in Haseltine et al., J. Am. Chem. Soc.. 111:7638 (1989).
- This reaction forms a tetracyclic reaction as is formed during DNA cleavage, and can be used as a co-screen to select more active compounds.
- a pharmaceutical composition is thus contemplated that contains a before-described enantiomeric compound or chimer of the invention as active agent.
- a pharmaceutical composition is prepared by any of the methods well known in the art of pharmacy all of which involve bringing into association the active compound and the carrier therefor.
- a compound or chimer of the present invention can be administered in the form of conventional pharmaceutical compositions.
- Such compositions can be formulated so as to be suitable for oral or parenteral administration, or as suppositories.
- the enantiomeric agent is typically dissolved or dispersed in a physiologically tolerable carrier.
- a carrier or diluent is a material useful for administering the active compound and must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
- physiologically tolerable and “pharmaceutically acceptable” are used interchangeably and refer to molecular entities and compositions that do not produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal.
- the physiologically tolerable carrier can take a wide variety of forms depending upon the preparation desired for administration and the intended route of administration.
- an enantiomeric compound or chimer of the invention can be utilized, dissolved or dispersed in a liquid composition such as a sterile suspension or solution, or as isotonic preparation containing suitable preservatives.
- a liquid composition such as a sterile suspension or solution, or as isotonic preparation containing suitable preservatives.
- injectable media constituted by aqueous injectable buffered or unbuffered isotonic and sterile saline or glucose solutions, as well as water alone, or an aqueous ethanol solution.
- Additional liquid forms in which these compounds or chimers can be incorporated for administration include flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles.
- flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like
- exemplary further liquid diluents can be found in Remmington s Pharmaceutical Sciences. Mack Publishing Co., Easton, PA (1980).
- liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
- the present compositions in liposome form can contain stabilizers, preservatives, excipients, and the like in addition to the agent.
- the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins) , both natural and synthetic.
- An active agent can also be used in compositions such as tablets or pills, preferably containing a unit dose of the enantiomeric compound or chimer.
- the agent active ingredient
- conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or similar materials as non-toxic, physiologically tolerable carriers.
- the tablets or pills can be laminated or otherwise compounded to provide unit dosage forms affording prolonged or delayed action.
- the pharmaceutical formulation described herein can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents. binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
- additional carrier ingredients such as diluents, buffers, flavoring agents. binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
- the tablets or pills can also be provided with an enteric layer in the form of an envelope that serves to resist disintegration in the stomach and permits the active ingredient to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings including polymeric acids or mixtures of such acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalate, and the like.
- a particularly suitable enteric coating comprises a styrene-maleic acid copolymer together with known materials that contribute to the enteric properties of the coating. Methods for producing enteric coated tablets are described in U.S. Patent 4,079,125 to Sipos, which is herein incorporated by reference.
- unit dose refers to physically discrete units suitable as unitary dosages for administration to warm blooded animals, each such unit containing a predetermined quantity of the agent calculated to produce the desired therapeutic effect in association with the pharmaceutically acceptable diluent.
- suitable unit dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and the like.
- a previously noted preferred or particularly preferred compound or chimer is preferred or particularly preferred for use in a pharmaceutical composition.
- An enantiomeric compound or chimer of the invention is present in such a pharmaceutical composition in an amount effective to achieve the desired result.
- a compound or chimer of the invention can be utilized in an amount sufficient to provide a concentration of about 1.0 to about 5000 micromolar ( ⁇ M) with a DNA concentration of about 0.02 ⁇ g/ ⁇ L.
- an effective amount of an enantiomeric compound or chimer of the invention is about 0.05 to about 50 mg per kilogram, and more preferably about 0.1 to about 15 mg per kilogram of body weight or an amount sufficient to provide a concentration of about 0.01 to about 50 ⁇ g/mL to the bloodstream.
- a compound or chimer of the invention exhibits antimicrobial activity in a concentration range of about 0.01 mg to about 50 ⁇ g/mL.
- concentrations and dosages vary with the particular compound of the invention utilized as well as with the target, e.g., DNA, tumor, microbe, as is well known.
- An enantiomeric compound or chimer of the invention is useful in cleaving DNA, as a cytotoxic agent and also in inhibiting the growth of neoplastic cells, and is utilized in a method for effecting such a result.
- An enantiomeric compound or chimer of the invention is typically utilized in a before-described composition.
- DNA to be cleaved or target cells to be killed or whose growth is to be inhibited are contacted with a compound or chimer of the invention (active ingredient) , typically in a composition as before, in an amount effective or sufficient for such a purpose, as discussed before, dissolved or dispersed in a physiologically tolerable (pharmaceutically acceptable) diluent. That contact is maintained for a time sufficient for the desired result to be obtained; i.e., DNA cleaved, cells killed or neoplastic cell growth inhibited.
- contact is maintained by simply admixing the DNA or target cells with the composition and maintaining them together under the appropriate conditions of temperature and for cell growth to occur, as for control, untreated cells.
- a single admixing and contacting is typically sufficient for in vitro purposes.
- the above method is also useful in vivo, as where a mammal such as a rodent like a rat, mouse, or rabbit, a farm animal like a horse, cow or goat, or a primate like a monkey, ape or human is treated.
- contact of a composition and the cells to be killed or whose growth is to be inhibited is achieved by administration of the composition to the mammal by oral, nasal or anal administration or by introduction intravenously, subcutaneously or intraperitoneally.
- contact in vivo is achieved via the blood or lymph systems.
- a single administration (admixture) and its resulting contact is usually sufficient to maintain the required contact and obtain a desired result in vitro, multiple administrations are typically utilized in vivo.
- contact between an active ingredient of a composition and the target cells is typically maintained by repeated administration of a compound of the invention over a period of time such as days, weeks or months, or more, depending upon the target cells.
- Exemplary methods of the invention for DNA cleavage and inhibition of MIA PaCa-2 human pancreatic carcinoma (ATCC CRL 1420) and MB49 murine bladder carcinoma target cells (obtained from Dr. Lan Bo Chen of the Dana Farber Cancer Institute, Boston, MA) as well as several other neoplastic cell lines are discussed in WO 92/02522, and in Nicolaou et al., Science. 256:1172- 1178 (1992) , and in the citations therein.
- Exemplary concentrations for in vitro cytoxicity studies vary with the cells to be killed, and can range from about 10 *5 M to about 10 *15 M, as is seen from the data in Tables 1-2 hereinafter.
- Exemplary concentrations and dosages for in vivo use can be those used for dynemicin A or calicheamicin ⁇ -, 1 .
- Typical in vivo dosages are about 1 to about 100 mg/kg body weight of the recipient mammal.
- Exemplary concentrations useful for in vitro cleavage of DNA range from about 0.1 to about 5 mM.
- An enantiomeric contemplated compound of the invention can be prepared by a number of routes, several of which are illustrated in W0 92/02522, as well as in Nicolaou et al., Science. 256:1172-1178 (1992) and the citations therein.
- the retrosynthetic plan for those syntheses is illustrated below in Scheme I.
- hydroxy quinoline Compound 400 was oxidized to ketone Compound 401 using Jones reagent [1.3 equivalents of Jones' reagent, 1.0 equivalents of H 2 S0 4 , AcOH-acetone (1:1), zero ⁇ 25°C, 30 minutes, 98 percent] , as step a, and then converted to enol silyl ether Compound 402 in high yield in step b by treatment with 1.2 equivalents of ⁇ uMeSiOTf, 1.5 equivalents of ET 3 N in CH 2 C1 2 at 25°C for three hours 99 percent.
- (2R,3R)-2,3-butanediol as used herein is not the only useful diol. Any chiral diol that contains unreactive substituents in the above reactions and can form a 5- or 6-membered ring ketal can be used.
- (2S,3S)-2,3-butanediol, (2R,4R)-2,4-pentanediol, (2S,4S)-pentanediol, (S)- or (R)-l,2-propanediol, (S)- or (R)-2-phenyl-l,2-propanediol, (S)- or (R)-1-phenyl- 1,2-ethanediol and the like can be used.
- Symmetrical diols such as the chiral 2,3-butanediols and 2,4-pentanediols are preferred.
- Diastereomeric compounds of Formulas XIII and Xlla are also contemplated as are separated enantiomers of Formulas XII and Xlla.
- stereochemistry of a 2-phenylsulfonyl-2-mono- or di-C 1 -C 6 alkyl ethoxycarbonyl R 1 substituent can also have an effect on the potency of a contemplated enantiomer.
- the discussion below illustrates an exemplary stereoselective synthesis for exemplary chiral R 1 groups.
- Racemic Compound 21 was used as the basis for the synthesis of racemic Compound 45 as discussed in regard to Scheme VIII of WO 92/02522, and was also used as a starting material for synthesis of 2-(C 1 -C 6 alkyl)- 2-(phenylsulfonyl)ethoxycarbonyl derivatives.
- each of Compounds 424-426 was separately reacted with one equivalent of WO 92/02522 Compound 21 and 1.2 equivalents of NaH in THF at 25°C for 0.5 hours in step a.
- the compounds so prepared were then separately reacted in step b with 2.5 equivalents of mCPBA in CH 2 C1 2 at zero degrees C for 0.5 hours to provide Compounds 427, 428 and 429 in 79, 79 and 66 percent yields, respectively.
- Each of Compounds 427 and 428 was an inseparable pair of diastereomers (single enantiomers at R 1 linked to a racemate) .
- phenyl vinyl sulfone (lane 8) is an alkylating agent, it was not surprising to see Form II DNA at the concentration used for these studies. Separate studies at 1.0 mM showed no DNA cleavage. The increased DNA damage from Compounds 427 and 428 at the higher pH value supports the concept of a base-catalyzed ⁇ -elimination of the R 1 group leading to formation of the DNA-cleaving material.
- the cell lines assayed were obtained from the American Type Culture Collection (ATCC) of Rockville, Maryland, except for normal human dermal fibroblasts (NHDF) that were obtained from Clonetics Corporation, San Diego, California.
- ATCC American Type Culture Collection
- NHDF normal human dermal fibroblasts
- T-cell leukemia Molt-4 1.0X10 *11 1. 0X10 "13 1. 0X10 *7
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93913966A EP0641207A4 (en) | 1992-05-21 | 1993-05-18 | Enantiomeric cynemicin analogs, preparation and use thereof. |
AU43807/93A AU680418B2 (en) | 1992-05-21 | 1993-05-18 | Enantiomeric dynemicin analogs, preparation and use thereof |
JP6503816A JPH07508037A (en) | 1992-05-21 | 1993-05-18 | Enantiomeric dynemycin analogues, their manufacture and use |
FI945427A FI945427A (en) | 1992-05-21 | 1994-11-18 | Enantiomers of dynemicin analogs, preparation and use thereof |
NO944429A NO944429L (en) | 1992-05-21 | 1994-11-18 | Enantiomeric dynemicin analogs, method of preparation and use thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/886,984 | 1992-05-21 | ||
US07/886,984 US5276159A (en) | 1990-08-01 | 1992-05-21 | Dynemicin analogs: syntheses, methods of preparation and use |
US07/939,104 | 1992-09-01 | ||
US07/939,104 US5281710A (en) | 1990-08-01 | 1992-09-01 | Dynemicin analogs: synthesis, methods of preparation and use |
Publications (1)
Publication Number | Publication Date |
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WO1993023046A1 true WO1993023046A1 (en) | 1993-11-25 |
Family
ID=27128819
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/004708 WO1993023046A1 (en) | 1992-05-21 | 1993-05-18 | Enantiomeric cynemicin analogs, preparation and use thereof |
Country Status (7)
Country | Link |
---|---|
US (2) | US5281710A (en) |
EP (1) | EP0641207A4 (en) |
JP (1) | JPH07508037A (en) |
AU (1) | AU680418B2 (en) |
CA (1) | CA2136234A1 (en) |
FI (1) | FI945427A (en) |
WO (1) | WO1993023046A1 (en) |
Cited By (4)
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WO1997007118A1 (en) * | 1995-08-18 | 1997-02-27 | William Alexander Denny | Enediyne compounds |
US5622958A (en) * | 1994-12-01 | 1997-04-22 | Sloan-Kettering Institute For Cancer Research | Enediyne quinone imines and methods of preparation and use thereof |
WO2013122823A1 (en) * | 2012-02-13 | 2013-08-22 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
US9777013B2 (en) | 2013-08-14 | 2017-10-03 | William Marsh Rice University | Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents |
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US5770736A (en) * | 1994-06-21 | 1998-06-23 | Northeastern University | Reagents for cleavage or crosslinking of biomolecules using nondiffusible reactive intermediates |
WO1996003124A1 (en) * | 1994-07-27 | 1996-02-08 | California Institute Of Technology | Dynemicin analogs |
US6248539B1 (en) | 1997-09-05 | 2001-06-19 | The Scripps Research Institute | Porous semiconductor-based optical interferometric sensor |
US7105491B2 (en) * | 1999-01-06 | 2006-09-12 | Wisconsin Alumni Research Foundation (Warf) | Biosynthesis of enediyne compounds by manipulation of C-1027 gene pathway |
ES2642179T3 (en) * | 2003-05-26 | 2017-11-15 | Hiroshi Maeda | Antitumor agent and process to produce the same |
US7122353B2 (en) * | 2003-08-05 | 2006-10-17 | Wisconsin Alumni Research Foundation | Targeted carrier fusions for delivery of chemotherapeutic agents |
US20080148906A1 (en) * | 2006-12-21 | 2008-06-26 | Proxene Tools Co., Ltd. | Driving surface configuration for hand tools |
US7955824B2 (en) * | 2007-05-11 | 2011-06-07 | Kosan Biosciences Incorporated | Methods of making epothilones |
US8030503B2 (en) * | 2007-05-11 | 2011-10-04 | Kosan Biosciences Incorporated | Process for the preparation of epothilones |
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US4837206A (en) * | 1987-04-29 | 1989-06-06 | Bristol-Myers Company | Esperamicin derivatives |
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GB846933A (en) * | 1956-07-23 | 1960-09-07 | American Cyanamid Co | New antifungal substance, pimaricin, and method of producing same |
GB1509866A (en) * | 1975-06-10 | 1978-05-04 | Johnson & Johnson | Enteric coated digestive enzyme compositions |
US4167450A (en) * | 1977-07-13 | 1979-09-11 | University Of New Hampshire | Method and apparatus for the production of secondary metabolites by the maintenance-state cultivation of microorganisms |
US4349528A (en) * | 1979-11-21 | 1982-09-14 | The Wistar Institute | Monocolonal hybridoma antibody specific for high molecular weight carcinoembryonic antigen |
US4311796A (en) * | 1980-07-14 | 1982-01-19 | Standard Oil Company (Indiana) | Method for improving specific xanthan productivity during continuous fermentation |
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JPS58201994A (en) * | 1982-05-21 | 1983-11-25 | Hideaki Hagiwara | Method for producing antigen-specific human immunoglobulin |
CA1215331A (en) * | 1983-03-04 | 1986-12-16 | Tsann M. Chu | Monoclonal antibodies to human breast carcinoma cells and their use in diagnosis and therapy |
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NZ210867A (en) * | 1984-01-31 | 1989-01-06 | Litton Bionetics Inc | Tumour-specific monoclonal antibodies, production thereof and use |
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- 1993-05-18 JP JP6503816A patent/JPH07508037A/en not_active Withdrawn
- 1993-05-18 EP EP93913966A patent/EP0641207A4/en not_active Withdrawn
- 1993-05-18 AU AU43807/93A patent/AU680418B2/en not_active Expired - Fee Related
- 1993-05-18 WO PCT/US1993/004708 patent/WO1993023046A1/en not_active Application Discontinuation
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- 1994-11-18 FI FI945427A patent/FI945427A/en unknown
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Cited By (16)
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US5622958A (en) * | 1994-12-01 | 1997-04-22 | Sloan-Kettering Institute For Cancer Research | Enediyne quinone imines and methods of preparation and use thereof |
WO1997007118A1 (en) * | 1995-08-18 | 1997-02-27 | William Alexander Denny | Enediyne compounds |
AU716920B2 (en) * | 1995-08-18 | 2000-03-09 | Auckland Uniservices Limited | Enediyne compounds |
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US9156850B2 (en) | 2012-02-13 | 2015-10-13 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
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KR20140120374A (en) * | 2012-02-13 | 2014-10-13 | 브리스톨-마이어스 스큅 컴퍼니 | Enediyne compounds, conjugates thereof, and uses and methods therefor |
CN104220441A (en) * | 2012-02-13 | 2014-12-17 | 百时美施贵宝公司 | Enediyne compounds, conjugates thereof, and uses and methods therefor |
WO2013122823A1 (en) * | 2012-02-13 | 2013-08-22 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
KR101660146B1 (en) | 2012-02-13 | 2016-09-26 | 브리스톨-마이어스 스큅 컴퍼니 | Enediyne compounds, conjugates thereof, and uses and methods therefor |
AU2013221873B2 (en) * | 2012-02-13 | 2016-11-17 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
CN104220441B (en) * | 2012-02-13 | 2017-03-29 | 百时美施贵宝公司 | Enediyne compound, its conjugate and application thereof and method |
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US9777013B2 (en) | 2013-08-14 | 2017-10-03 | William Marsh Rice University | Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents |
US10233192B2 (en) | 2013-08-14 | 2019-03-19 | William Marsh Rice University | Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents |
US10889590B2 (en) | 2013-08-14 | 2021-01-12 | William Marsh Rice University | Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents |
Also Published As
Publication number | Publication date |
---|---|
EP0641207A4 (en) | 1996-08-14 |
CA2136234A1 (en) | 1993-11-25 |
US5527805A (en) | 1996-06-18 |
FI945427A0 (en) | 1994-11-18 |
AU680418B2 (en) | 1997-07-31 |
JPH07508037A (en) | 1995-09-07 |
AU4380793A (en) | 1993-12-13 |
FI945427A (en) | 1995-01-18 |
EP0641207A1 (en) | 1995-03-08 |
US5281710A (en) | 1994-01-25 |
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