EP0957912A1 - Pharmaceutical compounds - Google Patents

Pharmaceutical compounds

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Publication number
EP0957912A1
EP0957912A1 EP97941379A EP97941379A EP0957912A1 EP 0957912 A1 EP0957912 A1 EP 0957912A1 EP 97941379 A EP97941379 A EP 97941379A EP 97941379 A EP97941379 A EP 97941379A EP 0957912 A1 EP0957912 A1 EP 0957912A1
Authority
EP
European Patent Office
Prior art keywords
group
compound
alkyl
hydrogen
ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97941379A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0957912A4 (enrdf_load_stackoverflow
Inventor
Rima S. Al-Awar
William J. Ehlhardt
Subbaraju V. Gottumukkala
Michael J. Martinelli
Eric D. Moher
Richard E. Moore
John E. Munroe
Bryan H. Norman
Vinod F. Patel
Chuan Shih
John E. Toth
Venkatraghavan Vasudevan
James E. Ray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Hawaii at Manoa
Wayne State University
Eli Lilly and Co
University of Hawaii at Hilo
Original Assignee
University of Hawaii at Manoa
Wayne State University
Eli Lilly and Co
University of Hawaii at Hilo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US1996/013855 external-priority patent/WO1997007798A1/en
Application filed by University of Hawaii at Manoa, Wayne State University, Eli Lilly and Co, University of Hawaii at Hilo filed Critical University of Hawaii at Manoa
Publication of EP0957912A1 publication Critical patent/EP0957912A1/en
Publication of EP0957912A4 publication Critical patent/EP0957912A4/xx
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to the fields of pharmaceutical and organic chemistry and provides novel cryptophycin compounds useful as anti-microtubule agents.
  • Neoplastic disease characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals.
  • Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases.
  • Such clinical experience has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells.
  • microtubule system of eucaryotic cells is a major component of the cytoskeleton and is a dynamic assembly and disassembly.
  • heterodimers of tubulin are polymerized and form microtubule.
  • Microtubules play a key role in the regulation of cell architecture, metabolism, and division.
  • the dynamic state of microtubules is critical to their normal function. With respect to cell division, tubulin is polymerized into microtubules that form the mitotic spindle.
  • agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis comprise some of the most effective cancer che otherapeutic agents in clinical use.
  • the compounds claimed herein possess fungicidal properties. Further, such agents having the ability to disrupt the microtubule system can be useful for research purposes.
  • cryptophycin compounds are known in the literature; however, cryptophycin compounds having even greater solubility, robust potency are desired for most pharmaceutical uses and a broader library of cryptophycin compounds could provide additional treatment options.
  • Applicants have now discovered novel compounds providing such desired solubility as well as compounds having the ability to disrupt the microtubule system. Such compounds can be prepared using total synthetic methods and are, therefore, well suited for development as pharmaceutically useful agents.
  • Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C1-C12 alkyl, C 1 -C 12 alkyne;
  • R 1 is halogen, OH, OR 31 , SH, amino, monoalkylamino, dialkyla ino, trialkylammonium, alkylethio, dialkylsulfonium, sulfate, or phosphate;
  • R 2 is OH, NH 2 , NR 31 , SH; or
  • R 1 and R 2 may be taken together to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, a cyclopropyl ring, or monoalkylphosphate ring; or
  • R 1 and R 2 may be taken together to form a second bond between C ]8 and Ci-.
  • R 31 is Ci-Cb alkyl and hydrogen
  • R 3 is a lower alkyl group
  • R is H
  • R" is H
  • R and R 5 may be taken together to form a second bond between C ⁇ 3 and C ]4 ;
  • R b is a substituent selected from the group consisting of B- ring heteroaromatic, substituted heteroaromatic, B-ring (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, substituted C 3 -C R cycloalkyl, substituted (C ⁇ -C e ) alkyl, a group of the formula III' :
  • R 7 is selected from the group consisting of NR 51 R 52 , R 53 NR 51 R 52 , OR 53 , H and a lower alkyl group;
  • R 51 and R 52 are independently selected from the group consisting of C 1 -C 3 alkyl;
  • R 53 is C1-C3 alkyl;
  • R 8 is H or a lower alkyl group;
  • R 7 and R 8 can optionally form a cyclopropyl ring;
  • R 9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, and lower alkyl-C-C 5 cycloalkyl;
  • R 10 is H or a lower alkyl group; R 9 and R 10 together optionally form a cyclopropyl ring; R n is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl;
  • R 14 is H or a lower alkyl group
  • R l b , R 16 and R 17 are each independently selected from the group consisting of hydrogen, (C ⁇ -C b ) alkyl, OR 18 , halo,
  • R 18 is selected from the group consisting of hydrogen, aryl, and C ⁇ -C 6 alkyl
  • R 18' is selected from the group consisting of hydrogen and
  • R 19 is C : -C b alkyl
  • R 19' is selected from the group consisting of hydrogen and (Ci-Ce) alkyl
  • R 23 is selected from the group consisting of hydrogen and
  • R 29 is (d-Cs) alkyl
  • R 30 is hydrogen or C]-C 6 alkyl; n is 0, 1, or 2; p is 0, 1, or 2; m is 0, 1, or 2;
  • X is selected from the group consisting of 0, NH and alkylamino
  • Y is selected from the group consisting of 0, NH, and alkylamino
  • Z is selected from the group consisting of -(CH 2 ) n -, -(CH 2 ) P -
  • ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof; provided that when R 6 is a group of Formula III' and n is 1, then at least one of the group consisting of R 15 , R 16 and R 17 must be a non-hydrogen group and if only one of R 15 , R 16 and R 17 is OH or OR 29 and one of the group consisting of R 15 , r lb and R 17 is halo then the remaining member of the group consisting of R 15 , R 1h , and R 17 must not be hydrogen or halo; or when R 6 is a group of Formula III' and n is 1, R 14 is a lower alkyl group.
  • Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C ⁇ -C ⁇ 2 alkyl, C]-C ⁇ 2 alkyne;
  • R 1 is halogen, OH, OR 31 , SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, or phosphate;
  • R 2 is OH, NH 2/ NR 31 , SH; or
  • R 31 is Cj-C ⁇ alkyl and hydrogen
  • R : and R 2 may be taken together to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, a cyclopropyl ring, or monoalkylphosphate ring; or R 1 and R 2 may be taken together to form a second bond between C ⁇ B and C ⁇ 9 ;
  • R 3 is a lower alkyl group;
  • R 4 is H;
  • R 5 is H;
  • R 4 and R 5 may be taken together to form a second bond between C_ 3 and C ⁇ ;
  • R 6 is a substituent selected from the group consisting of firing heteroaromatic, substituted heteroaromatic, B-ring (Ci- C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, substituted C..-C 8 cycloalkyl, substituted (C ⁇ -C 6 ) alkyl, a group of the formula III' :
  • R 7 is selected from the group consisting of H and a lower alkyl group
  • R 8 is H or a lower alkyl group
  • R 7 and R B can optionally form a cyclopropyl ring;
  • R 9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, and lower alkyl-C 3 -C 5 cycloalkyl;
  • R 10 is H or a lower alkyl group;
  • R 50 is hydrogen or R is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl;
  • R 14 is H or a lower alkyl group
  • R 15 , R 16 , and R 17 are each independently selected from the group consisting of hydrogen, (C ⁇ -C 6 ) alkyl, OR 18 , halo,
  • R 18 is selected from the group consisting of hydrogen, aryl, and C : -C 6 alkyl; R 18' is selected from the group consisting of hydrogen and (C-Ce) alkyl; R 19 is C,-C 6 alkyl; R 19' is selected from the group consisting of hydrogen and
  • R 23 is selected from the group consisting of hydrogen and
  • R 29 is (d-Ci) alkyl
  • R 30 is hydrogen or C ⁇ -C 6 alkyl
  • R is hydrogen or a group of the formula n is 0, 1, or 2; p is 0, 1, or 2; m is 0, 1, or 2;
  • X is selected from the group consisting of 0, NH and alkylamino
  • Y is selected from the group consisting of 0, NH, and alkylamino
  • Z is selected from the group consisting of -(CH 2 ) n -, -(CH 2 ) P -
  • ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof; provided that when R 6 is a group of Formula III' and n is 1, then at least one of the group consisting of R 15 , R 16 and R 17 must be a non-hydrogen group and if only one of R 15 , R 16 and
  • R 17 is OH or OR 29 and one of the group consisting of R 15 , R 16 and R 17 is halo then the remaining member of the group consisting of R 15 , R 16 and R 17 must not be hydrogen or halo; or when R 6 is a group of Formula III' and n is 1 then R 14 is lower alkyl; further provided that the compound is not a cryptophycin selected from the group consisting of cryptophycins :
  • the present invention provides pharmaceutical formulations, a method for disrupting a microtubulin system using an effective amount of a compound of Formula I or I', a method for inhibiting the proliferation of mammalian cells comprising administering an effective amount of a compound of Formula I or I', and a method for treating neoplasia in a mammal comprising administering an effective amount of a compound of Formula I or I ' .
  • the term "simple alkyl” shall refer to C ⁇ -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like.
  • B-ring C ⁇ -C b alkyl refers to saturated, unsaturated, branched and straight chain alkyl wherein the B-ring C ⁇ -C 6 alkyl group may include up to three (3) non-carbon substituents.
  • non-carbon substituents are most preferably selected from the group consisting of OH, SCH 2 phenyl, NH 2 , CO, CONH ?
  • substituted phenyl shall refer to a phenyl group with from one to three non- hydrocarbon substituents which may be independently selected from the group consisting of simply alkyl, Cl, Br, F, and I.
  • substituted benzyl shall refer to a benzyl group with from one to three non- hydrocarbon substituents which may be independently selected from the group consisting of simply alkyl, Cl, Br, F, and I wherein such substituents may be attached at any available carbon atom.
  • B-ring heteroaromatic group refers to aromatic rings which contain one or more non- carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur.
  • B-ring heterocyclic groups are selected from, but not limited to, the group consisting of:
  • R 20 is selected from hydrogen and C ⁇ -C b alkyl
  • B-ring heteroaromatic group refers to a substituent selected from the group consisting of:
  • cycloalkyl refers to a saturated C-i-C ⁇ cycloalkyl group wherein such group may include from zero to three substituents selected from the group consisting of C]-C alkyl, halo, and OR 22 wherein R 2? is selected from hydrogen and C ⁇ -C 3 alkyl. Such substituents may be attached at any available carbon atom. It is especially preferred that cycloalkyl refers to substituted or unsubstituted cyclohexyl .
  • “Lower alkoxyl group” means any alkyl group of one to five carbon atoms bonded to an oxygen atom.
  • “lower alkyl group” means an alkyl group of one to five carbons and includes linear and non- linear hydrocarbon chains, including for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, and methylated pentyl groups.
  • allylically substituted alkene means any alkene having from one to seven carbon atoms which contain an alkyl substitution on it.
  • unsaturated lower alkyl means a lower alkyl group as defined supra wherein from one to two double bonds are present in the unsaturated lower alkyl substituent.
  • lower alkyl-C 3 -C 5 cycloalkyl refers to C-C alkyl substituted with a C 3 -C ⁇ jCycloalkyl group.
  • a preferred lower alkyl-C 3 -C b cycloalkyl group is -CH 2 -cyclopropyl; wherein the group is attached to the cryptophycin core structure at R 9 via the CH 2 .
  • epoxide ring means a three- membered ring whose backbone consists of two carbons and an oxygen atom.
  • aziridine ring means a three-membered ring whose backbone consists of two carbon atoms and a nitrogen atom.
  • sulfide ring means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom.
  • episulfide ring means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom.
  • sulfate group means a five-membered ring consisting of a carbon-carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom.
  • cyclopropyl ring means a three-member ring whose backbone consists of three carbon atom.
  • monoalkylphosphate ring means a five-membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears a lower alkyl group, connected to the phosphorous atom.
  • concise unsubstituted aromatic group refers to common aromatic rings having 4n+2 electrons in a monocyclic conjugated system, for example, but not limited to: furyl, pyrrolyl, thienyl, pyridyl and the like, or a bicyclic conjugated system, for example, but not limited to: indolyl or naphthyl .
  • concise substituted aromatic group refers to a phenyl group substituted with a single group selected from the group consisting of halogen and lower alkyl group.
  • heteromatic group refers to aromatic rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur.
  • halogen or “halo” refers to those members of the group on the periodic table historically known as halogens. Methods of halogenation include, but are not limited to, the addition of hydrogen halides, substitution at high temperature, photohalogenation, etc., and such methods are known to the skilled artisan.
  • the term “mammal” shall refers to the Mammalia class of higher vertebrates.
  • the term “mammal” includes, but is not limited to, a human.
  • the term “treating” as used herein includes phophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
  • the cryptophycin compounds claimed herein can be useful for veterinary health purposes as well as for the treatment of a human patient.
  • R 8 is ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl;
  • R 7 is ethyl, propyl, isopropyl, butyl isobutyl, pentyl, or isopentyl;
  • R 7 is H, R y is methyl, R 3 is methyl, and X and Y are not both 0;
  • R 3 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl ;
  • R 9 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl;
  • R 10 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl;
  • C-16, C-17, and C-18 has R stereochemistry (numbering as set forth in Formula I supra . ) ; H) a cryptophycin compound wherein at least one of the groups selected from the group consisting of C-3, C-6, C-7, C-10, C-16, C-17, and C-18 has S stereochemistry (numbering as set forth in Formula I supra .
  • Ar is phenyl with a substituent selected from the group consisting of hydrogen, halogen, and simple alkyl; J) a compound wherein Y is O' K) a compound wherein Y is 0, R ' , R b , R ⁇ d and R 10 are each hydrogen; and R 1 and R 2 form an epoxide; L) R 7 , R 8 are each hydrogen
  • R' and R 8 are each selected from hydrogen and CH 3 ; N) Y is O; 0) R is selected from the group consisting of methyl, ethyl, n- propyl, and phenyl; P) R 1 and R 2 form an epoxide ring; Q) both X and Y are 0; R) R 4 and R b form a double bond;
  • a compound of Formula I is used as an anti-neoplastic agent
  • V) a compound of Formula I is used for the treatment of cancer in a mammal
  • W) a compound of Formula I is used as an antifungal agent
  • X) R 6 is Formula III' and is para hydroxy substituted
  • Y) R 6 is selected from the group consisting of
  • Z) Z is -(CH 2 ) n - wherein n is 0; AA) Z is ⁇ (CH 2 ) n - wherein n is 2; BB) Z is -(CH 2 ) n - wherein n is 1; CC) R 6 is Formula III' ; DD) R 6 is Formula III"; EE) R 6 is C 3 -C 6 cycloalkyl;
  • R 6 is selected from the group consisting of firing heteroaromatic, substituted heteroaromatic, B-ring alkyl, cycloalkyl, substituted cycloalkyl, Formula III' and Formula III' ' ;
  • R 1 ', R , and R 17 is selected from the group consisting of SCH ? phenyl, NH 2 , CO, C0NH 2 , C0 2 H, P0 3 H 2 , and S0 2 R 21 ; wherein R 21 is selected from hydrogen and d-d alkyl;
  • HH) Ar is phenyl
  • Ar is phenyl substituted with one or two from the group consisting of OH, 0CH 3 , halo, and methyl; and Ar is naphthyl;
  • R fc has a Z wherein the first carbon of the Z
  • R 6 is a heteroaromatic ring
  • MM is selected from the group consisting of
  • R 7 is CH 2 OCH 3 ;
  • R 7 is cyclopropyl
  • R 9 is CH 2 cyclopro ⁇ yl ;
  • RR R 6 is selected from the group consisting of
  • Ar is instead of phenyl.
  • the present invention provides a method of alleviating a pathological condition caused by hyperproliferating mammalian cells comprising administering to a subject an effective amount of a pharmaceutical or veterinary composition disclosed herein to inhibit proliferation of the cells.
  • the method further comprises administering to the subject at least one additional therapy directed to alleviating the pathological condition.
  • the pathological condition is characterized by the formation of neoplasms.
  • the neoplasms are selected from the group consisting of mammary, small-cell lung, non-small-cell lung, colorectal, leukemia, melanoma, pancreatic adenocarcinoma, central nervous system (CNS) , ovarian, prostate, sarcoma of soft tissue or bone, head and neck, gastric which includes pancreatic and esophageal, stomach, myeloma, bladder, renal, neuroendocrine which includes thyroid and non-Hodgkin' s disease and Hodgkin's disease neoplasms.
  • CNS central nervous system
  • neoplastic refers to a neoplasm, which is an abnormal growth, such growth occurring because of a proliferation of cells not subject to the usual limitations of growth.
  • anti-neoplastic agent is any compound, composition, admixture, co-mixture, or blend which inhibits, eliminates, retards, or reverses the neoplastic phenotype of a cell.
  • Anti-mitotic agents may be classified into three groups on the basis of their molecular mechanism of action. The first group consists of agents, including colchicine and colcemid, which inhibit the formation of microtubules by sequestering tubulin. The second group consists of agents.
  • Vinblastme and vmcristme which induce the formation of paracrystalline aggregates of tubulin.
  • Vinblastme and vmcristme are well known anticancer drugs: their action of disrupting mitotic spindle microtubules preferentially inhibits hyperproliferative cells.
  • the third group consists of agents, including taxol, which promote the polymerization of tubulin and thus stabilizes microtubules.
  • compositions containing a therapeutically effective amount of at least one compound of Formula I including the non-toxic addition salts thereof, which serve to provide the above recited benefits.
  • Such compositions can also be provided together with physiologically tolerable liquid, gel, or solid carriers, diluents, adjuvants and excipients. Such carriers, adjuvants, and excipients may be found in the U.S . Pharmacopeia, Vol.
  • the present invention further provides a pharmaceutical composition used to treat neoplastic disease containing at least one compound of Formula I and at least one additional anti-neoplastic agent.
  • Anti-neoplastic agents which may be utilized in combination with Formula I compounds include those provided in the Merck Index 11, pp 16-17, Merck & Co., Inc. (1989). The Merck Index is widely recognized and readily available to the skilled artisan.
  • antineoplastic agents may be antimetabolites which may include but are in no way limited to those selected from the group consisting of methotrexate, 5-fluorouracil, 6- mercaptopurine, cytosine, arabinoside, hydroxyurea, and 2- chlorodeoxyadenosine.
  • the anti-neoplastic agents contemplated are alkylating agents which may include but are in no way limited to those selected from the group consisting of cyclophosphamide, mephalan, busulfan, paraplatin, chlorambucil, and nitrogen mustard.
  • the anti-neoplastic agents are plant alkaloids which may include but are in no way limited to those selected from the group consisting of vincristine, vinblastine, taxol, and etoposide.
  • the anti-neoplastic agents contemplated are antibiotics which may include, but are in no way limited to those selected from the group consisting of doxorubicin, daunorubicin, mitomycin C, and bleomycin.
  • the anti-neoplastic agents contemplated are hormones which may include, but are in no way limited to those selected from the group consisting of calusterone, diomostavolone, propionate, epitiostanol, mepitiostane, testolactone, tamoxifen, polyestradiol phosphate, megesterol acetate, flutamide, nilutamide, and trilotane.
  • the anti-neoplastic agents contemplated include enzymes which may include, but are in no way limited to those selected from the group consisting of L-Asparginase and aminoacridine derivatives such as, but not limited to, amsacrine.
  • Additional antineoplastic agents include those provided by Skeel, Roland T., "Antineoplastic Drugs and Biologic Response Modifier: Classification, Use and Toxicity of Clinically Useful Agents" Handbook of Cancer Chemotherapy (3rd ed.), Little Brown & Co. (1991) .
  • compositions can be administered to mammals for veterinary use.
  • domestic animals can be treated in much the same way as a human clinical patient.
  • the dosage required for therapeutic effect will vary according to the type of use, mode of administration, as well as the particularized requirements of the individual hosts. Typically, dosages will range from about 0.001 to 1000 mg/kg, and more usually 0.01 to 10 mg/kg of the host body weight. Alternatively, dosages within these ranges can be administered by constant infusion over an extended period of time, usually exceeding 24 hours, until the desired therapeutic benefits are obtained.
  • drug dosage as well as route of administration, must be selected on the basis of relative effectiveness, relative toxicity, growth characteristics of tumor and effect of Formula I compound on cell cycle, drug pharmacokinetics, age, sex, physical condition of the patient and prior treatment, which can be determined by the skilled artisan.
  • the compound of Formula I with or without additional anti-neoplastic agents, may be formulated into therapeutic compositions as natural or salt forms.
  • Pharmaceutically acceptable non-toxic salts include base addition salts which may be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as for example, hydrochloric or phosphoric acids or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Additional excipients which further the invention are provided to the skilled artisan for example in the U.S. Pharmacopeia .
  • the suitability of particular carriers for inclusion in a given therapeutic composition depends on the preferred route of administration.
  • antineoplastic compositions may be formulated for oral administration. Such compositions are typically prepared as liquid solution or suspensions or in solid forms.
  • Oral formulation usually include such additives as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • These compositions may take the form of solutions, suspensions, tablets, pills, capsules, sustained relsease formulations, or powders, and typically contain 1% to 95% of active ingedient. More preferably, the composition contains from about 2% to about 70% active ingredient.
  • compositions of the present invention may be prepared as injectables, either as liquid solutions, suspensions, or emulsions; solid forms suitable for solution in or suspension in liquid prior to injection.
  • injectables may be administered subcutaneously, intravenously, intraperitoneally, intramuscularly, intrathecally, or intrapleurally.
  • the active ingredient or ingredients are often mixed with diluents, carriers, or excipients which are physiologically tolerable and compatible with the active ingredient (s) .
  • Suitable diluents and excipients are for example, water, saline, dextrose, glycerol, or the like and combinations thereof.
  • the compositions may contain minor amounts of auxilary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents.
  • the invention further provides methods for using
  • Formula I compounds to inhibit the proliferation of mammalian cells by contacting these cells with a Formula I compound in an amount sufficient to inhibit the proliferation of the mammalian cell.
  • a preferred embodiment is a method to inhibit the proliferation of hyperproliferative mammalian cells.
  • hyperproliferative mammalian cells are mammalian cells which are not subject to the characteristic limitations of growth (programmed cell death for example) .
  • a further preferred embodiment is when the mammalian cell is human.
  • the invention further provides contacting the mammalian cell with at least one Formula I compound and at least one anti-neoplastic agent. The types of antineoplastic agents contemplated are discussed supra .
  • the invention further provides methods for using a compound of Formula I to inhibit the proliferation of hyperproliferative cells with drug-resistant phenotypes, including those with multiple drug-resistant phenotypes, by contacting said cell with a compound of Formula I in an amount sufficient to inhibit the proliferation of a hyperproliferative mammalian cell.
  • a preferred embodiment is when the mammalian cell is human.
  • the invention further provides contacting a Formula I compound and at least one additional anti-neoplastic agent, discussed supra .
  • the invention provides a method for alleviating pathological conditions caused by hyperproliferating mammalian cells for example, neoplasia, by administering to a subject an effective amount of a pharmaceutical composition containing Formula I compound to inhibit the proliferation of the hyperproliferating cells.
  • pathological condition refers to any pathology arising from the proliferation of mammalian cells that are not subject to the normal limitations of growth. Such proliferation of cells may be due to neoplasms as discussed supra .
  • the neoplastic cells are human.
  • the present invention provides methods of alleviating such pathological conditions utilizing a compound of Formula I in combination with other therapies, as well as other anti-neoplastic agents.
  • the effectiveness of the claimed compounds can be assessed using standard methods known to the skilled artisan. Examples of such methods are as follows:
  • a compound of this invention is solubilized in dimethyl sulfoxide supplemented with Tween 20. Twofold dilutions are made with sterile distilled water/10 percent DMSO to obtain final drug concentrations in the agar dilution assay plates ranging from 0.008 ⁇ g/ml to 16.0 ⁇ g/ml against an expanded panel of 84 Cryptococcus neoformans strains. The minimum inhibitory concentration against the panel of 84 Cryptococcus neoformans isolates is determined to illustrate the desired antifungal activity.
  • the compounds are screened for minimum inhibitory concentrations against KB, a human nasopharyngeal carcinoma cell line, LoVo, a human colorectal adenocarcinoma cell line using The Corbett assay, see Corbett, T.H. et al. Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development, pp 35-87, Kluwer Academic Publishers: Norwell, 1992. see also, Valeriote, et al . Discovery and Development of Anticancer Agents; Kluwer Academic Publishers, Norwell, 1993 is used for the evaluation of compounds.
  • the most active compounds are further evaluated for cytotoxicity against four different cell types, for example a murine leukemia, a murine solid tumor, a human solid tumor, and a low malignancy fibroblast using the Corbett assay.
  • the compounds are further evaluated against a broad spectrum of murine and human tumors implanted in mice, including drug resistant tumors.
  • Tumor burden (mean tumor burden in treated animals versus mean tumor burden in untreated animals) are used as a further assessment. T/C values that are less than 42% are considered to be active by National Cancer Institute Standards; T/C values less than 10% are considered to have excellent activity and potential clinical activity by National Cancer Institute standards.
  • the Jurkat T cell leukemia line and A-10 rat aortic smooth muscle cells are obtained from the American Type Culture Collection and are cultured in BME containing 10%
  • gentamycin sulfate FBS and 50 ⁇ g/mL gentamycin sulfate.
  • Human ovarian carcinoma cells (SKOV3) and a sub-line which has been selected fro resistance to vinblastine (SKVLB1) were a generous gift from Dr. Victor Ling of the Ontario Cancer Institute. Both cell lines are maintained in BME containing 10% FBS and 50 ⁇ g/mL gentamycin sulfate. Vinblastine is added to a final concentration of l ⁇ g/mL to SKVLB1 cells 24 hours after passage to maintain selection pressure for P-glycoprotein- overexpressing cells.
  • Cell proliferation assays are performed as described by Skehan et al .
  • cultures are treated with the indicated drugs as described in Skehan and total cell numbers are determined by counting the cells in a hemacytometer .
  • the percentage of cells in mitosis are determined by staining with 0.4% Giemsa in PBS followed by rapid washes with PBS.
  • At least 1000 cells per treatment are scored for the presence of mitotic figures and the mitotic index is calculated as the ration of the cells with mitotic figures to the total number of cells counted.
  • A-10 cells are grown to near-confluency on glass coverslips in BME/10% FBS. Compounds in PBS are added to the indicated final concentrations and cells are incubated for an additional 24 hours. For the staining of microtubules and intermediate filaments, the cells are fixed with cold methanol and incubated with PBS containing 10% calf serum to block nonspecific binding sites. Cells are then incubated at 37_C for 60 min. with either monoclonal anti- ⁇ -tubulin or with monoclonal anti-vimentin at dilutions recommended by the manufacturer. Bound primary antibodies are subsequently visualized by a 45-minute incubation with fluorescein-conjugated rabbit antimouse IgG.
  • the coverslips are mounted on microscope slides and the fluorescence patterns are examined and photographed using a Zeiss Photomicroscope 111 equipped with epifluorescence optics for fluorescein.
  • a Zeiss Photomicroscope 111 equipped with epifluorescence optics for fluorescein.
  • cells are fixed with 3% paraformaldehyde, permeabilized with 0.2% Triton X-100 and chemically reduced with sodium borohydride (lmg/ML) .
  • PBS containing lOOnM TRITC-phalloidin is then added and the mixture is allowed to incubate for 45 min. at 37_C.
  • the cells are washed rapidly with PBS before the coverslips are mounted and immediately photographed as described above.
  • Aortic smooth muscle (A-10) cells are grown on glass coverslips and treated with PBS, 2uM cytochalasin B, lOOnM vinblastine or lOnM cryptophycin compounds . After 24 hours, microtubules and vimentin intermediate filaments are visualized by indirect immunofluorescence and microfilaments are stained using TRITC - phalloidin. The morphological effects of each drug is examined. Untreated cells displayed extensive microtubule networks complete with perinuclear microtubule organizing centers. Vimentin intermediate filaments were also evenly distributed throughout the cytoplasm, while bundles of microfilaments were concentrated along the major axis of the cell.
  • Cytochalasin B caused complete depolymerization of microfilaments along with the accumulation of paracrystalline remnants. This compound did not affect the distribution of either microtubules or intermediate filaments.
  • the cryptophycin treated microtubules and vimentin intermediates are observed for depletion of microtubules, and collapse of rimentin intermediate filaments. Effects of cryptophycins and vinblastine on taxol-stabilized microtubules
  • A-10 cells are treated for 3 hours with 0 or lO ⁇ M taxol before the addition of PBS, lOOnM vinblastine or lOnM cryptophycin compound. After 24 hours, microtubule organization is examined by immunofluorescence as described above. Compared with those in control cells, microtubules in taxol-treated cells were extensively bundled, especially in the cell polar regions. As before, vinblastine caused complete depolymerization of microtubules non-pretreated cells. However, pretreatment with taxol prevented microtubule depolymerization in response to vinblastine. Similarly, microtubules pretreated with taxol are observed with cryptophycin treatment.
  • A-10 cells are treated with either lOOnM vinblastine or lOnM cryptophycins for 24 hr . , resulting in complete microtubule depolymerization.
  • the cells are then washed and incubated in drug-free medium for periods of 1 hour or 24 hours.
  • Microtubules repolymerized rapidly after the removal of vinblastine, showing significant levels of microtubules after 1 hour and complete morphological recovery by 24 hour.
  • Cells are visualized for microtubule state after treatment with a cryptophycin compound of this invention at either 1 hour or 24 hours after removal of the cryptophycin compounds .
  • SK0V3 cells are treated with combinations of cryptophycins and vinblastine for 48 hours. The percentages of surviving cells are then determined and the IC 50 S for each combination is calculated. Toxicity of cryptophycins, vinblast e and taxol toward SK0V3 and SKVLB1 cells
  • SKVLB1 cells are resistant to natural product anticancer drugs because of their over expression of P- glycoprotem.
  • the abilities of taxol, vinblastine and cryptophycin compounds to inhibit the growth of SK0V3 and SKVLB1 cells are observed. Taxol caused dose-dependent inhibition of the proliferation of both cell lines with IC 50 s for SK0V3 and SKVLB1 cells of 1 and 8000nM, respectively. Vinblastme also inhibited the growth of both cell lines, with IC 50 s of 0.35 and 4200nM for SK0V3 and
  • Cryptophycins compounds of this invention demonstrate activity with an IC 50 S of from about 1 to about 1000pm for SK0V3 and SKVLB1 cells.
  • IC 50 S an enzyme that catalyzes cell proliferation
  • the present invention provides novel cryptophycin compounds which are potent inhibitors of cell proliferation, acting by disruption of the microtubule network and inhibition of mitosis.
  • Classic anti-microtubule agents such as colchicme and Vmca alkaloids, arrest cell division at mitosis. It seems appropriate to compare the effect of one of these agents on cell proliferation with the cryptophycin compounds.
  • the Vmca alkaloid vinblastine was selected as representative of the classic anti-microtubule agents.
  • Selected wells of a 96 well plate were seeded with GC3 human colon carcinoma cells (1x10 cells in a lOO ⁇ l assay medium/well) twenty-four hours prior to test compound addition.
  • Cell free assay medium was added to other select wells of the 96 well plate.
  • the assay medium (RPMI-1640 was the medium used; however, any medium that will allow the cells to survive would be acceptable) was supplemented with 10% dialyzed fetal bovine serum and 25 MM HEPES buffer.
  • test compound was stored in an amber bottle prior to testing.
  • Fresh dimethylsulfoxide stock solution 200 ⁇ g/ml was prepared immediately prior to preparation of test sample dilutions in phosphate-buffered saline (PBS) .
  • a dilution of 1:20 dimethylsulfoxide solution in PBS was prepared such that the final concentration was 10 ⁇ g/ml.
  • Serial 1:3 dilutions using PBS (,5ml previous sample of 1ml PBS) were prepared.
  • Falcon 2054 tubes were used for the assay.
  • a lO ⁇ l sample of each dilution of test compound was added in triplicate to wells of GC3 plates. The plates were incubated for 72 hours at about 37 °C.
  • R R 6 , R 7 , R 8 , R 9 , R 10 have the meanings set for supra in Formula I.
  • R 13 is selected from the group consisting of t- butylcarbamate (BOC) ;
  • R 24 is selected from the group consisting of
  • N-hydroxysuccinimide herein "NHS”
  • N-hydroxysulfosuccinimide and salts thereof, 2-nitrophenyl, 4- nitrophenyl, and 2, -dichlorophenyl
  • X is 0, NH or alkylamino
  • Y is 0, NH, or alkylamino.
  • R is an active ester substituent; with an acid of the formula
  • R ,27 is selected from the group consisting of H, C ⁇ -C ⁇ 2 alkyl, and aryl; and a silylating agent.
  • Bis N, O-trimethylsilyl acetamide (BSA) is an especially preferred silylating agent.
  • active ester substituent refers to a substituent which makes the OR 24 substituent a good leaving group.
  • Appropriate substituents can be selected with guidance from standard reference guides, for example, “Protective Groups in Organic Chemistry”, Plenum Press, (London and New York, 1973) ; Greene, T.W. "Protecting Groups in Organic Synthesis", Wiley (New York, 1981).
  • An especially preferred R 2S group is N- hydroxy-succinimide . (NHS)
  • R 27 should be a group that allows for the removal of the -C0 2 R 27 substituent using acidic, neutral, or mild basic conditions.
  • Preferred R 27 groups include, but are in no way limited to, hydrogen, CT-Ce alkyl, trichloromethyl, trichloroethyl, and methylthiomethyl . It is especially preferred that R 27 is hydrogen. To provide further guidance for the artisan, the following schemes are provided:
  • R 1 ' is halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, phosphate or a protected OH or protected SH group;
  • R ? is OH or SH;
  • R 2b is an alcohol protecting group introduced during a portion of the synthetic process to protect an alcohol group which might otherwise react in the course of chemical manipulations, and is then removed at a later state of the synthesis. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works, including, for example, "protective Groups in Organic Chemistry", Plenum Press, (London and New York, 1973); Greene, T.W.
  • R 6 has the meaning defined supra .
  • the ester starting material can be prepared, for example, as follows:
  • R 6 has the meaning defined supra .
  • the scheme for preparing the ester is further explained by the Preparation Section herein which provides one specific application of the scheme for the convenience of the skilled artisan.
  • the Scheme for preparing the ester is applicable to the Ar substituents claimed herein.
  • the scheme illustration is not intended to limit the synthesis scheme only to the phenyl ring illustrated. Rather, the artisan can broadly apply this process to provide desired starting materials for the compounds claimed herein.
  • the necessary reaction time is related to the starting materials and operating temperature.
  • the optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by short reaction times, and maximum yield, which is favored by long reaction times .
  • Step 1 Methyl 5-Phenylpent-2 (E) -enoate.
  • a solution of trimethyl phosphonoacetate (376 g, 417 mL, 2.7 mol) in THF (750 mL) was stirred at 0°C in a 3L 3-neck round bottom flask equipped with a mechanical stirrer and N 2 inlet.
  • To the chilled solution neat tetramethyl guanidine (239 g, 260 mL, 2.07 mol) was added dropwise via an addition funnel. The chilled clear pale yellow solution was stirred for 25 minutes at 0°C.
  • EIMS m/z 162 (1:M+) 144 (16), 129 (7), 117 (9) 108 (6), 92 (17), 91 (100), 75 (5), 65 (12), HREIMS m/z 162, 1049 (C11H14O, D -0.4 mmu) ; UV lmax (e) 206 (9900), 260 (360); IR nmax 3356, 2924, 1603, 1496, 1454, 970, 746, 700 cm -1 ; 1H NMR d 7.15-7.3 (Ph-H5;m) , 5.70 (3-H;dt, 15.6/6.0), 5.61 (2- H;dt, 15.6/4.8), 4.02 (1-H2;d 4.8), 2.68 (5-H2; t, 7.2), 2.40 (OH;bs), 2.36(4-H2; dt, 6.0/7.2); 13 C NMR dl41.6 (Ph 1'), 131.8(3), 129.5 (2), 128.3/128.2
  • the resulting mixture was cooled to - 20 °C and treated with Ti(0-i-Pr) 4 (9.2 mL, 0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M in CH 2 CI 2 , 182 mL, 0.78 mol) at a rate to maintain the temperature 2 -20°C.
  • t-butylhydroperoxide 4.0 M in CH 2 CI 2 , 182 mL, 0.78 mol
  • the reaction mixture was stirred for another 30 min, and then treated with a solution of the allylic alcohol (50 g, 0.31 mol) in CH 2 CI 2 (30 mL) at a rate to maintain the temperature 2 -20 °C.
  • the reaction was stirred at the same temperature for 5 h, then filtered into a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 mL) at 0 °C. The mixture was stirred for 20 min, then transferred to a separatory funnel and extracted with t- BuOMe (2x200 mL) . The combined organic phase was stirred with 30% NaOH solution containing NaCl, for 1 h at 0°C. The layers were again separated, and the aqueous phase extracted with t-BuOMe. The combined organic phase was washed with brine, dried over MgS ⁇ 4 and concentrated to yield 52.8 g as an amber oil.
  • Step 6. (22?, 31?) -2- [ (tert-Butyldimethylsilyl) oxy] -3-methyl- 5-phenylpent-l-yl Tosylate.
  • a solution of the tosylate (100 g, 0.29 mol) and triethylamine (81.0 mL, 0.58 mol) in CH 2 CI 2 (1200 mL) was treated with neat TBS-OTf (99 mL, 0.43 mol) dropwise with continued stirring for another 20 min.
  • the reaction was washed twice with brine, dried over MgS0 4 and concentrated to dryness.
  • the oil was dissolved in a minimal amount of hexanes and filtered over a silica pad, eluting with hexanes :EtOAc (9:1) to yield a slightly amber oil, 134 g.
  • Step 7. (22?, 32?,52?S)-2-[ ( ert-Butyldimethylsilyl) oxy] -3- methyl-5-bromo-5-phenylpent-l-yl Tosylate.
  • CCI 4 (1680 mL)
  • TBS Ts 140 g, 0.30 mol
  • NBS 65g, 0.365 mol
  • AIBN 16.5 g, 0.10 mol
  • Step 8. (22?, 32?) -2- [ (tert-Butyldimethylsilyl) oxy] -3-methyl- 5-phenylpent- (E) -en-l-yl Tosylate.
  • a solution of the bromide 100 g, 0.186 mol
  • acetonitrile 700 mL
  • Step 10 Methyl (5S, 62?) -5- [ (tert-Butyldimethylsilyl) oxy] - 6-methyl-8-phen ⁇ locta-2 (E) ,7 (E) -dienoate.
  • the nitrile 14.67 g, 46.5 mmol
  • a 1.5M solution of DIBAL in toluene (37.2 L, 55.8 mmol) was added dropwise with vigorous stirring. Upon complete addition, the cooling bath was removed and the reaction was stirred at room temperature for 1 h. The reaction mixture was carefully poured into IN HCI and the mixture stirred at room temperature for 30 min.
  • the layers were separated, and the organic phase was washed with a saturated aqueous solution of sodium potassium tartrate (2x) , brine and dried over a 2 S ⁇ 4 .
  • the volatiles were removed in vacuo, and the crude pale yellow oil was used directly in the subsequent condensation.
  • the crude aldehyde from above was dissolved in THF (90 mL) and treated with trimethyl phosphonoacetate (9.03 mL, 55.8 mmol) and tetramethylguanidine (7.0 mL, 55.8 mmol) at room temperature under nitrogen.
  • the reaction mixture was stirred for 16 h, then partitioned between EtOAc (200 mL) and water (100 mL) .
  • Boc amine as prepared by Example 2 ( 109mg, 0.154mmol ) was dissolved in trfluoracetic acid (5mL,5mM) and stirred at room temperature for 2h. The reaction was concentrated in vacuo and dried under high vacuum to give the trifluoroacetate salt of amine as a light brown foam. Crude amine salt (max. 0.154mmol) was dissolved in dry DMF (31mL) and diisopropylethylamine (80uL, 0.462mmol) , followed by pentafluorophenyl diphenyl -phosphinate (77mg, 0.2mmol) added.

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