Cryptophycin derivatives and their use as anti-microtubule agents

Abstract: The invention provides novel cryptophycin compounds which can be useful for disrupting the microtubulin system, as antineoplastic agents, and for the treatment of cancer. The invention further provides a formulation for administering the novel cryptophycin compounds. The compounds are of the formula wherein Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group; R 1 is halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, or phosphate; R 2 is OH or SH; or R 1 and R 2 may be taken together to form an epoxide ring, and aziridine ring, an episulfide ring, a sulfate ring, or monoalkylphosphate ring; or R 1 and R 2 may be taken together to form a second bond between C 18 and C 19 ; 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 13 and C 14 ; R 6 is benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group; R 7 is H or a lower alkyl group; R 8 is H or a lower alkyl group; or R 7 and R 8 may optionally be taken together to form a cyclopropyl ring; R 9 is selected from the group consisting of H, a lower alkyl group, (C 1 -C 3 ) alkylaryl, and aryl; R 10 is selected from the group consisting of H, a lower alkyl group, (C 1 -C 3 ) alkylaryl, and aryl; R 11 is H; simple alkyl; phenyl, substituted phenyl, benzyl, substituted benzyl; X is O, NH or alkylamino; Y is C, O, NH, S, SO, SO 2 or alkylamino; and a pharmaceutically acceptable salt or solvate thereof.

Description: This invention relates to novel cryptophycin compounds useful as anti-microtubule agents. Neoplastic diseases, 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. The microtubule system of eucaryotic cells is a major component of the cytoskeleton and is a dynamic assembly and disassembly; that is 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 microtubles that form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Accordingly, agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis, comprise some of the most effective cancer chemotherapeutic agents in clinical use. Further, such agents having the ability to disrupt the microtubule system can be useful for research purposes. Certain cryptophycin compounds are known in the literature U.S. Patent Nos. 4,946,835, 4,845,085, 4,845,086, and 4,868,208; however, compounds having greater metabolic stability and longer duration of action are desired for most pharmaceutical uses. Applicants have now discovered novel compounds providing such desired greater metabolic stability as well as 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. WO 95/17093 discloses cryptophycin derivatives useful to inhibit proliferation of hyperproliferative cells with drug resistant phenotypes and to treat neoplasia. The presently claimed invention provides novel cryptophycin compounds of Formula I wherein Ar is selected from the group consisting of- phenyl and a simple substituted aromatic group; R 1 is selected from the group consisting of halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, sulfate, or phosphate; R 2 is OH or SH; or R 1 and R 2 may be taken together with C 18 and C 19 to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, or monoalkylphosphate ring; or R 1 and R 2 may be taken together to form a second bond between C 18 and C 19 ; 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 13 and C 14 ; R 6 is selected from the group consisting of benzyl, hydroxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl and substituted benzyl wherein one substituent is a halogen atom and one substituent is an OR 12 group wherein R 12 is lower alkyl; R 7 is H or a lower alkyl group; R 8 is H or a lower alkyl group; R 7 and R 8 may optionally be taken together to form a cyclopropyl ring; R 9 is selected from the group consisting of H, a lower alkyl group, (C 1 -C 3 ) alkylaryl, and aryl; R 10 is selected from the group consisting of H, a lower alkyl group, (C 1 -C 3 ) alkylaryl, and aryl; R 11 is selected from the group consisting of simple alkyl; phenyl, substituted phenyl, benzyl, and substituted benzyl; X is O, NH or alkylamino; Y is C, O, NH, S, SO, SO 2 or alkylamino; or a pharmaceutically acceptable salt or solvate thereof. The presently claimed invention provides novel cryptophycin compounds of Formula III wherein Ar is selected from the group consisting of phenyl and a simple substituted aromatic group; R 1 is selected from the group consisting of halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, sulfate and phosphate; R 2 is OH or SH; or R 1 and R 2 may be taken together with C 18 and C 19 to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, or monoalkylphosphate ring; or R 1 and R 2 may be taken together to form a second bond between C 18 and C 19 ; 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 13 and C 14 ; R 6 is selected from the group consisting of benzyl, hydroxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl and substituted benzyl wherein one substituent is a halogen atom and one substituent is an OR 12 group wherein R 12 is lower alkyl; R 7 is H or a lower alkyl group; R 8 is H or a lower alkyl group; R 7 and R 8 may optionally be taken together to form a cyclopropyl ring; R 9 is selected from the group consisting of H, a lower alkyl group, (C 1 -C 3 ) alkylaryl, and aryl; R 10 is selected from the group consisting of H, a lower alkyl group, (C 1 -C 3 ) alkylaryl, and aryl; X is O, NH or alkylamino; Y is C, O, NH, S, SO, SO 2 or alkylamino; or a pharmaceutically acceptable salt or solvate thereof. The present invention provides pharmaceutical formulations, compounds for use in a method for disrupting a microtubulin system using an effective amount of a compound of Formula I or Formula III, compounds for use in a method for inhibiting the proliferation of mammalian cells comprising administering an effective amount of a compound of Formula I or Formula III, and compounds for use in a method for treating neoplasia in a mammal comprising administering an effective amount of a compound of Formula I or Formula III. As used herein, the term "simple alkyl" shall refer to C 1 -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl and methylated pentyl groups. As used herein, the term "substituted phenyl" shall refer to a phenyl group with from one to three substituents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I. As used herein, the term "substituted benzyl" shall refer to a benzyl group with from one to three substitutents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I. As used herein "lower alkyl group" means an alkyl group of one to five carbons and includes linear and nonlinear hydrocarbon chains, including for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, and methylated pentyl groups. As used herein "allylically substituted alkene" means any alkene having from one to seven carbon atoms which contains an alkyl substitution on it. As used herein "epoxide ring" means a three-membered ring whose backbone consists of two carbons and an oxygen atom. As used herein, "aziridine ring" means a three-membered ring whose backbone consists of two carbon atoms and a nitrogen atom. As used herein "sulfide ring" means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom. As used herein "episulfide ring" means a three-membered ring whose backbone consists of two carbon and a sulfur atom. As used herein "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. As used herein, "monalkylphosphate 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. As used herein "simple substituted aromatic group" refers to a phenyl group substituted with a single group selected from the group consisting of halogen and lower alkyl group. As used herein, the term " aryl" means phenyl or naphthyl. The term " C 1 -C 3 alkylaryl" represents an (C 1 -C 3 ) alkylaryl substituent wherein the alkyl group is linear, such as benzyl, phenethyl, 3-phenylpropyl, or phenyl-t-butyl; or branched. The alkylaryl moeity is attached to the parent nucleus via the alkyl group. As used herein, " alkylamino" has its common meaning. Thus, the phrase refers to N-R R' wherein R R' is C 1 -C 3 alkyl. When the alkylamino group is contained within the ring as when " X" and/or " Y" is alkylamino then such alkylamino group in the ring can be represented by the group: As used herein, "halogen" refers to those members of the group on the periodic table historically known as halogens. Methods of halogenation include the addition of hydrogen halides, substitution at high temperature, photohalogenation, etc., and such methods are known to the skilled artisan. As used herein, the term "crypto A-B-OCH 2 CCl 3 " or "cryptophycin A-Btrichloroethyl ester" shall mean a group of the formula: As used herein, the term "mammal" shall refer to the Mammalia class of higher vertebrates. The term "mammal" includes a human. The term "treating" as used herein includes prophylaxis 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 vetrinary health purposes as well as for the treatment of a human patient. Some preferred characteristics of this invention are set forth in the following tabular form wherein the features may be independently selected to provide preferred embodiments of this invention. A) R 8 is ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl; B) R 7 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl; C) R 7 is H, R 8 is methyl, R 3 is methyl, and X and Y are not both O; D) R 3 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl; E) R 9 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl; F) R 10 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl; G) 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 R stereochemistry (numbering as set forth in claim 1 infra .); 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 claim 1 infra .); I) Ar is phenyl with a substituent selected from the group consisting of hydrogen, halogen, and simple alkyl; J) a compound wherein the C-7 substituent is R configuration; K) a compound wherein the C-7 substituent is S configuration; L) R 7 , R 8 are each hydrogen; M) R 7 and R 8 are each selected from hydrogen or OH; N) R 11 is simple alkyl; O) 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 O; R) R 4 and R 5 form a double bond; S) R 6 is substituted benzyl wherein one substituent is a halogen and one is an OR 12 group wherein R 12 is lower alkyl; T) a compound of Formula I is used for disruption of a microtubulin system; U) a compound of Formula I is used as an anti-neoplastic agent; V) a compound of Formula III is used for the treatment of cancer in a mammal; W) a compound wherein Y is selected from the group consisting of O, NH, S, SO and SO 2 ; X) a compound wherein Y is C, R 7 , R 8 , R 9 , and R 10 are each hydrogen; and R 1 and R 2 form an epoxide; Y) Y is O or S; Z) Y is selected from S, SO, and SO 2 ; and Z1) R 10 is hydrogen. Examples of some preferred compounds of this invention include wherein Ar is phenyl, R 1 and R 2 taken together form a three membered epoxide ring, R 3 is methyl, R 4 and R 5 are taken together to form a double bond, R 6 is a chloro-methoxybenzyl, R 10 is hydrogen, and the remaining variables are as illustrated in the following table: X Y R 9 R 7 R 8 R 11* O O isobutyl hydrogen hydrogen hydrogen O O isobutyl hydrogen hydrogen methyl O O isobutyl hydrogen hydrogen benzyl O O isobutyl hydrogen hydrogen phenyl O O isobutyl hydrogen hydrogen p-chloro- O O isobutyl hydrogen hydrogen phenyl ethyl O O isobutyl hydrogen hydrogen m-methylbenzyl O O isobutyl hydrogen hydrogen p-methylphenyl O O isobutyl R 7 and R 8 cyclopropyl form a hydrogen O O isobutyl R 7 and R 8 cyclopropyl form a methyl O O benzyl R 7 and R 8 cyclopropyl form a benzyl O C benzyl hydrogen hydrogen hydrogen O C benzyl hydrogen hydrogen methyl O C benzyl hydrogen hydrogen benzyl O C benzyl hydrogen hydrogen phenyl O C benzyl hydrogen hydrogen p-chlorophenyl O C benzyl hydrogen hydrogen ethyl O C benzyl hydrogen hydrogen m-methylbenzyl O C benzyl hydrogen hydrogen p-methylphenyl O C benzyl R 7 and R 8 cyclopropyl form a hydrogen O C benzyl R 7 and R 8 cyclopropyl form a methyl O C isobutyl hydrogen hydrogen hydrogen O C isobutyl hydrogen hydrogen methyl O C isobutyl hydrogen hydrogen benzyl O C isobutyl hydrogen hydrogen phenyl O C isobutyl hydrogen hydrogen p-chlorophenyl O C isobutyl hydrogen hydrogen ethyl O C isobutyl hydrogen hydrogen m-methylbenzyl O C isobutyl hydrogen hydrogen p-methylphenyl O C isobutyl R 7 and R 8 cyclopropyl form a hydrogen O C isobutyl R 7 and R 8 cyclopropyl form a methyl NH C isobutyl hydrogen hydrogen hydrogen NH C isobutyl hydrogen hydrogen methyl NCH 3 O isobutyl hydrogen hydrogen benzyl NH O isobutyl hydrogen hydrogen phenyl NH C isobutyl hydrogen hydrogen p-chlorophenyl NH C isobutyl hydrogen hydrogen ethyl NH O isobutyl hydrogen hydrogen m-methylbenzyl NH C isobutyl hydrogen hydrogen p-methylphenyl NH O isobutyl R 7 and R 8 cyclopropyl form a hydrogen NH C isobutyl R 7 and R 8 cyclopropyl form a methyl NH C benzyl hydrogen hydrogen hydrogen O SO benzyl hydrogen hydrogen methyl O S benzyl hydrogen hydrogen benzyl O SO 2 benzyl hydrogen hydrogen phenyl O C benzyl hydrogen hydrogen p-chlorophenyl O NH benzyl hydrogen hydrogen ethyl O C benzyl hydrogen hydrogen m-methylbenzyl O C benzyl hydrogen hydrogen p-methylphenyl O C benzyl R 7 and R 8 cyclopropyl form a hydrogen O C benzyl R 7 and R 8 cyclopropyl form a methyl O O isobutyl methyl hydrogen hydrogen O O isobutyl methyl hydrogen methyl O O isobutyl methyl hydrogen benzyl O O isobutyl methyl hydrogen phenyl O O isobutyl methyl hydrogen p-chlorophenyl O O isobutyl methyl hydrogen ethyl O O isobutyl methyl hydrogen m-methylbenzyl O O isobutyl hydrogen methyl p-methylphenyl O O isobutyl hydrogen methyl hydrogen O O isobutyl hydrogen methyl methyl O O benzyl methyl hydrogen benzyl O C benzyl methyl methyl hydrogen O C benzyl methyl hydrogen methyl O C benzyl hydrogen methyl benzyl O C benzyl methyl hydrogen phenyl O C benzyl methyl hydrogen p-chlorophenyl O C benzyl methyl methyl ethyl O C benzyl methyl hydrogen m-methylbenzyl O C benzyl hydrogen methyl p-methylphenyl O C benzyl methyl methyl hydrogen O C benzyl methyl hydrogen hydrogen O C isobutyl methyl hydrogen methyl O C isobutyl methyl hydrogen benzyl O C isobutyl hydrogen methyl phenyl O C isobutyl hydrogen methyl p-chlorophenyl O C isobutyl methyl hydrogen ethyl O C isobutyl hydrogen methyl m-methylbenzyl O C isobutyl methyl hydrogen p-methylphenyl O C isobutyl methyl methyl hydrogen O C isobutyl methyl methyl methyl NH C isobutyl methyl hydrogen hydrogen NH C isobutyl hydrogen methyl methyl NCH 3 O isobutyl hydrogen methyl benzyl NH O isobutyl methyl hydrogen phenyl NH C isobutyl methyl hydrogen p-chlorophenyl NH C isobutyl methyl hydrogen ethyl NH O isobutyl methyl hydrogen m-methylbenzyl NH C isobutyl hydrogen methyl p-methylphenyl NH O isobutyl methyl methyl hydrogen NH C isobutyl methyl methyl methyl NH C benzyl methyl hydrogen hydrogen O SO benzyl hydrogen methyl methyl O S benzyl hydrogen methyl benzyl O SO 2 benzyl methyl hydrogen phenyl O C benzyl hydrogen methyl p-chlorophenyl O NH benzyl hydrogen methyl ethyl O C benzyl hydrogen methyl m-methylbenzyl O C benzyl hydrogen methyl p-methylphenyl O C benzyl methyl methyl hydrogen O C benzyl methyl methyl methyl The present invention provides compounds for use in 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. In a preferred embodiment of this invention, the method further comprises administering to the subject at least one additional therapy directed to alleviating the pathological condition. In a preferred embodiment of the present invention, the pathological condition is characterized by the formation of neoplasms. In a further preferred embodiment of the present invention, 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. As used herein "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. As used herein, "anti-neoplastic agent" is any compound, composition, admixture, co-mixture, or blend which inhibits, eleminates, retards, or reverses the neoplastic phenotype of a cell. Anti-mitotic agents or poisins 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, including vinblastine and vincristine, which induce the formation of paracrystalline aggregates of tubulin. Vinblastine and vincristine 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. The exhibition of drug resistance and multiple-drug resistance phenotype by many tumor cells and the clinically proven mode of action of anti-microtubule agents against neoplastic cells necessitates the development of anti-microtubule agents cytotoxic to non-drug resistant neoplastic cells as well as cytotoxic to neoplastic cells with a drug resistant phenotype. Chemotherapy, surgery, radiation therpy, therapy with biological response modifiers, and immunotherapy are currently used in the treatment of cancer. Each mode of therapy has specific indications which are known to those of ordinary skill in the art, and one or all may be employed in an attempt to achieve total destruction of neoplastic cells. Moreover, combination chemotherapy, chemotherapy utilizing compounds of Formula I or Formula III in combination with other neoplastic agents, is also provided by the subject invention as combination therapy is generally more effective than the use of a single anti-neoplastic agent. Thus, a further aspect of the present invention provides compositions containing a therapeutically effective amount of at least one compound of Formula I or Formula III, 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. XXII and National Formulary vol XVII , U.S. Pharmacopeia Convention, Inc. Rockville, MD (1989). Additional modes of treatment are provided in AHFS Drug Information , 1993 e. by the American Hospital Formulary Service, pp. 522-660. Each of these references are well known and readily available to the skilled artisan. The present invention further provides that the pharmaceutical composition used to treat neoplastic disease contains at least one compound of Formula I or Formula III and at least one additional anti-neoplastic agent. Anti-neoplastic agents which may be utilized in combination with Formula I or Formula III 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. In a further embodiment of this invention, antineoplastic agents may be antimetabolites which may include those selected from the group consisting of methotrexate, 5-fluorouracil, 6-mercaptopurine, cytosine, arabinoside, hydroxyurea, and 2-chlorodeoxyadenosine. In another embodiment of the present invention, the anti-neoplastic agents contemplated are alkylating agents which may include those selected from the group consisting of cyclophosphamide, mephalan, busulfan, paraplatin, chlorambucil, and nitrogen mustard. In a further embodiment, the anti-neoplastic agents are plant alkaloids which may include those selected from the group consisting of vincristine, vinblastine, taxol, and etoposide. In a further embodiment, the anti-neoplastic agents contemplated are antibiotics which may include those selected from the group consisting of doxorubicin, daunorubicin, mitomycin C, and bleomycin. In a further embodiment, the anti-neoplastic agents contemplated are hormones which may include those selected from the group consisting of calusterone, diomostavolone, propionate, epitiostanol, mepitiostane, testolactone, tamoxifen, polyestradiol phosphate, megesterol acetate, flutamide, nilutamide, and trilotane. In a further embodiment, the anti-neoplastic agents contemplated include enzymes which may include those selected from the group consisting of L-Asparginase and aminoacridine derivatives such as, but not limited to, amsacrine. Additional anti-neoplastic 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). These compounds and compositions can be administered to mammals for veterinary use. For example, domestic animals can be treated in much the same way as a human clinical patient. In general, 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. Indeed, 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 or Formula III compound on cell cycle, drug pharmacokinetics, age, sex, physical condition of the patient and prior treatment. The compound of Formula I or Formula III, 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. For example, anti-neoplastic 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. Such 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. In addition, if desired, the compositions may contain minor amounts of auxilary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents. The invention further provides Formula I or Formula III compounds for use to inhibit the proliferation of mammalian cells by contacting these cells with a Formula I or Formula III 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. For purposes of this invention "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 or Formula III compound and at least one anti-neoplastic agent. The types of anti-neoplastic agents contemplated are discussed supra. The invention further provides Formula I or Formula III compounds for use 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 or Formula III 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 or Formula III 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 or Formula III compound to inhibit the proliferation of the hyperproliferating cells. As used herein "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. In a further preferred embodiment the neoplastic cells are human. The present invention discloses methods of alleviating such pathological conditions utilizing a compound of Formula I or Formula III 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. One such study provided the following results: The compounds are screened for minimum inhibitory concentrations against KB, a human nasopharyngeal carcinoma cell line, LoVo, a human colorectal adenocarcinoma cell line. 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. 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 (T/C) (mean tumor burden in treated animals verses mena 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. Evaluation of compounds of Formula I and Formula III suggest that the compounds can be useful in the treatment methods described herein. Further, the compounds will be useful for disrupting the microtubule system. Compounds of this invention can be prepared as illustrated using the following schemes. The crypto-A-B trichloroethyl ester can be prepared using information known in the literature; however, the following method is provided for the convenience of the artisan: The artisan can utilize appropriate starting materials and reagents to prepare desired compounds using the guidance of the previous schemes and following examples. The artisan can utilize appropriate starting materials and reagents to prepare desired compounds using the guidance of the previous schemes and following examples. To further illustrate the invention the following examples are provided. Preparation 1 A solution containing 10.0 g (96.9 mmol) of 2,2-dimethyl-3-amino-1-propanol and 16.2 mL (116 mmol) of triethylamine in 250 mL of CH 2 Cl 2 was stirred at 0°C. To this solution was added 474 mg (4 mol %) of dimethylaminopyridine (hereinafter referred to as "DMAP") and 16.1 g (107 mmol) of tert -butyldimethylsilyl chloride (TBSCl). The reaction was allowed to warm to 25°C over one hour and stirred at that temperature for an additional 18 h. The reaction was concentrated in vacuo and dissolved in 150 mL of ethyl acetate. The organic solution was wahed three times with aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 15.0 g a light yellow oil, which was characterized as 2 . Mass Spec. (FD + ) m/e 218 (M+1 + ). Preparation 2 A solution of 3.25 g (16.7 mmol) of ( R )-2-bromo-4-methylpentanoic acid 1 in 200 mL of CH 2 Cl 2 was stirred at 0°C as 2.25 g (16.7 mmol) of hydroxybenzotriazole (HOBt) was added, followed by the addition of 3.19 g (16.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). The reaction was stirred for 1.5 h at 0°C, after which 3.62 g (16.7 mmol) of the protected amino alcohol 2 in 25 mL of CH 2 Cl 2 was added dropwise over about 5 min. The reaction was stirred an additional 2 h at 0°C, and poured into 200 mL of a saturated aqueous sodium bicarbonate solution. The organic phase was washed twice with saturated aqueous sodium bicarbonate, twice with 10% aqueous citric acid and twice with brine. The organic solution was dried over sodium sulfate and concentrated in vacuo to give 4.90 g (74 %) of a clear oil, which was characterized as 4 . Mass Spec. (FD + ) m/e 394, 396 (M+1 + ). Preparation 3 To a solution containing 1.00 g (2.54 mmol) of the protected amide 4 in 20 mL of CH 2 Cl 2 at 0°C was added 0.34 mL (2.79 mmol) of boron trifluoride etherate (BF 3 -OEt 2 ) and the reaction was warmed to 25°C. After stirring for one hour at 25°C, an additional 0.34 mL of boron trifluoride etherate was added and the reaction was stirred an additional one hour at 25°C. The reaction was poured into 100 ml water, and diluted with an additional 50 mL CH 2 Cl 2 . The organic solution was washed twice with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 560 mg (79 %) of the intermediate bromo alcohol. A solution containing 500 mg (1.78 mmol) of this material in 10 mL of anhydrous tetrahydrofuran (THF) was added to a suspension of 86 mg (2.14 mmol) of sodium hydride (60 % in mineral oil) at -78°C. The reaction was allowed to slowly warm to 25°C over one hour and quenched with 1N HCl. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. This crude material was purified by flash chromatography on silica gel, using ethyl acetate as the eluent to give 185 mg (52 %) of a clear oil, which was characterized as 5 . Mass Spec. (FD + ) m/e 199 (M + ). Preparation 4 A suspension of 1.69 g (8.48 mmol) of lactam 5 in 20 mL 5N HCl was heated to reflux for 2 h, cooled to 25°C and concentrated in vacuo to dryness. The residue was dissolved in 200 mL of methanolic HCl and stirred for 24 h at 25°C and concentrated in vacuo to give 2.20 g (97 %) of a white amorphous solid, which was characterized as 6 . Mass Spec. (FD + ) m/e 232 (M+1 + ) Preparation 5 A solution of 1.66 g (6.20 mmol) of the HCl salt 6 was dissolved in 100 mL of CH 2 Cl 2 and stirred at 25°C as 1.03 mL (7.44 mm) of triethylamine was added dropwise, followed by the addition of 1.62 g (7.44 mmol) of di- tert -butyl dicarbonate (BOC 2 O). The reaction was stirred at 25°C for 2 hours, diluted with 200 mL ethyl acetate and washed twice with 1N HCl. The organic phase was dried over sodium sulfate and concentrated in vacuo to give crude 7 , which was purified by flash chromatography on silica gel, using 50% hexane-ethyl acetate as the eluent. The major fraction was concentrated in vacuo to give 1.80 g (88%) of a clear oil, which was characterized as 7 . Mass Spec. (FD + ) m/e 331 (M + ). Preparation 6 To a solution of 1.00 g (3.02 mmol) of 7 in 10 mL of 50 % THF-water was added 253 mg (6.04 mmol) of lithium hydroxide hydrate at 25°C. The reaction was stirred for 1 h at 25°C, poured into 1N HCl and extracted with ethyl acetate. The organic extracts were dried and concentrated in vacuo to give 905 mg (94%) of a white amorphous solid, which was characterized as 8 . Mass Spec. (FD + ) m/e 318 (M+1 + ). Preparation 7 To a solution containing 323 mg (1.02 mmol) of 8 in 20 mL of CH 2 Cl 2 was added 195 mg (1.02 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), followed by 10 mg of dimethylaminopyridine (hereinafter "DMAP"). The reaction was stirred at 25°C for 30 min, after which 500 mg (0.848 mmol) of cryptophycin A-B trichloroethyl ester was added. The reaction was stirred an additional 15 min, washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography using 25% ethyl acetate-hexane as the eluent. The major fraction was concentrated in vacuo to give 451 mg (67%) of a white amorphous solid, which was characterized as 9 . Mass Spec. (FD + ) m/e 886 (M + ) Preparation 8 A 3.36g (60%in oil , 0.084 moles) sample of sodium hydride was added to a solution of 7.91g (0.07 moles) of e-Caprolactam in 220 mL of dimethylformamide and stirred for 30 minutes. 13.34 mL (0.098 moles) of p-methoxybenzoyl chloride was added and the reaction was stirred for 18 hours. The reaction was poured into 200 mL of 1N HCl and extracted two times with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to give 18.4g (100 %) of a yellow oil which was characterized as 1'. (CDCl 3 , 300 MHz) d 1.2-1.9 (series of m, 6H); 2.6(m, 2H); 3.2-3.4 (m, H-2); 3.8 (s, 3H, CH 3 ); 4.5 (s, 2H); 6.8-7.0 (m, 2H); 7.15-7.4 (m, 2H) Preparation 9 To a solution of 4.33 g (31 mmol) of diisopropylamine in 120 mL of tetrahydrofuran at ice bath temperature was added 19.3 mL (31 mmol) of butyl lithium (1.6M in hexanes). After 15 minutes the reaction was cooled to -70°C and a solution 6.0g (26 mmol) of the protected lactam 1' in 20 mL of tetrahyrofuran was added. After 25 minutes at -70°C 3.55 mL (31 mmol) of 1-iodo-2-methylpropane.were added and the reaction was allowed to warm to 25°C After 3 hours, 300 mL of 1.0N HCl were added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated in vacuo to yield 9.0 g ( 100%) of a pale oil which was characterized as 2'a . (CDCl3, 300 MHz) d 0.9 (d, J= 6.6 Hz 6H); 1.2-1.95(series of multiplets, 9H); 2.55 (m, 1H); 3.1-3.24 (m, 1H); 3.45 (m, 1H); 3.79 (s, 3H, CH3); 4.45 (d, J= 14.5 Hz,1H); 4.6(d, J= 14.4 Hz, 1H); 6.84(d, J= 8.3 Hz, 2H); 7.2(d, J= 8.4Hz, 2H). Preparation 10 To a solution of 4.33 g (31 mmol) of diisopropylamine in 120 mL of tetrahydrofuran at ice bath temperature was added 19.3 mL (31 mmol) of butyl lithium (1.6M in hexanes). After 15 minutes the reaction was cooled to -70°C and a solution of 6.0 g (26 mmol) of the protected lactam 1' in 20 mL of tetrahyrofuran was added. After 25 minutes at -70°C 3.67 mL ( 31 mmol) of benzyl bromide.were added and the reaction was allowed to warm to 25°C After 3 hours, 300 mL of 1.0N HCl were added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated in vacuo to yield 8.9 g ( 100%) of a pale oil which was characterized as 2'b . Mass Spec. (FD + ) m/e 323 (M + ) Preparation 11 Preparation 12 3'b was prepared substantially according to the method for the preparation of 3'a . Mass Spec. (FD + m/e 203 (M + ). Preparation 13 A suspension of 0.3 g (1.8 mmol) of deblocked lactam 3'a (Preparation 11) in 8.0 mL of 5N hydrochloric acid was refluxed for 4 hours. The reaction was concentrated to a residue in vacuo. The residue was dissolved in 25 mL of methanolic HCl and stirred 18 hours at 25°C and concentrated in vacuo to give 0.28 g (42%) of an amorphous white solid which was characterized as 4'a . (CDO 3 D, 300 MHz) d 0.95 (m, 6H); 1.2-1.8 (series of multiplets, 10H) ; 2.94 (m, 2H); 3.68 (m, 3H, CH 3 ) ; 4.9 (m, 3H). Preparation 14 To a solution of 0.57 g (2.4 mmol) of 4' (Preparation 13) in 10 mL of methylene chloride was added 0.4 mL (2.9 mmol) of triethylamine followed by 0.63 g (2.9 mmol) of di-tert-butyldicarbonate. The reaction was stirred for 18 hours at 25°C diluted with 50 mL of ethyl acetate and washed first with 1N HCl followed by saturated sodium bicarbonate and dried over sodium sulfate. The solution was concentrated in vacuo to a residue which was purified by flash chromatography on silica gel using hexane-ethyl acetate 6-1 as eluent to yield 0.44 g (56%) of a clear oil which was characterized as 5 ' Mass Spec. (FD + ) m/e 302 (M + ). Preparation 15 A solution of 0.44 g (1.46 mmol) of 5' (Preparation 14) was dissolved in 20 mL of methanol and 20 mL of 2N sodium hydroxide and refluxed for two hours. The methanol was removed in vacuo and the aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to yield ) 0.55 g (100%)of an oil which was characterized as 6' . Mass Spec. (FD + ) m/e 288 (M + ). Preparation 16 6'b was prepared substantially according to the method for the preparation of 6'a. Mass Spec. (FD + m/e 321 (M + ). Preparation 17 To a solution of 0.27 g (0.94 mmol) of 6'a (Preparation 15) in 10 mL of methylene chloride was added 0.162 g (0.85 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), followed by 10 mg of dimethylaminopyridine. The reaction was stirred at 25°C for 30 minutes after which 0.498 g (0.85 mmol) of cryptophycin A-B trichloroethy ester was added. The reaction was refluxed for 24 hours after which the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with 1N HCl followed by sodium bicarbonate solution and finally , brine. The solvent was removed in vacuo to yield a residue which was purified by flash chromatography on silica gel using hexane-ethyl acetate 2-1 as eluent to yield 0.28 g (35 %) of a white residue which was characterized as 7'a Mass Spec. (FD + ) m/e 858 (M + ) Preparation 18 7'b was prepared substantially according to the method for the preparation of 7'a . Mass Spec. (FD + m/e 892 (M + ). Preparation 19 To a solution of 341 mg (1.47 mmol) of 6-BOC-aminocaproic acid (15') in 25 mL of CH 2 Cl 2 was added 283 mg (1.47 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), followed by 10 mg (catalytic) of 4-dimethylaminopyridine (DMAP) at 25°C. The reaction was stirred at 25°C for 30 min. and 290 mg (0.492 mmol) of cryptophycin A-B trichloroethyl ester ( 16' ) was added. The reaction was stirred an additional 15 min, washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography using 25% ethyl acetate-hexane as the eluent. The major fraction was concentrated in vacuo to give 205 mg (52%) of a white amorphous solid, which was characterized as 17' . Mass Spec. (FD + ) m/e 802 (M + ). Example 1 To a solution of 426 mg (0.537 mmol) of 9 (Preparation 7) in 5 mL CH 2 Cl 2 was added 2 mL of trifluoroacetic acid (TFA). The reaction was strirred at 25°C for 30 min, after which it was poured into 25 mL of a saturated aqueous sodium bicarbonate solution. An additional 25 mL of CH 2 Cl 2 was added and the organic phase was washed with 1N NaOH, dried over sodium sulfate and concentrated in vacuo. This crude material was dissolved in 10 mL of toluene and stirred at 25°C as 255 mg (2.68 mmol) of 2-hydroxypyridine was added. The reaction was stirred at 25°C for 18 h. The reaction was diluted with 50 mL of ethyl acetate and the organic phase washed twice with 1N HCl, twice with brine and twice with saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using 50% ethyl acetate-hexane as the eluent. Two fractions were collected, which correspond to the epimers at the isobutyl substitution site adjacent to the ether moiety. The major fraction was concentrated in vacuo to give 106 mg (31%) of a white amorphous solid, which was characterized as 10 . Mass Spec. (FD + ) m/e 638 (M + ). Example 2 To a solution containing 47 mg (0.074 mmol) of 10 (Example 1) in 10 mL of CH 2 Cl 2 was added 22.3 mg (0.11 mmol) of 85% m -chloroperbenzoic acid (mCPBA). The reaction was strirred at 25°C and monitored by HPLC (reverse phase, C 18 , 70% acetonitrile-water). After about 5 h, the reaction slowed and an additional 44 mg m CPBA was added. The reaction was stirred at 25°C and after another 12 h, was complete. The reaction was diluted with 25 mL CH 2 Cl 2 and washed twice with a saturated sodium meta-bisulfite solution and twice with a saturated sodium bicarbonate solution. The organic layer was dried and concentrated in vacuo to give 38 mg (79%) of a white amorphous solid, which was charaterized as a 2:1 mixture of diastereomeric epoxides of 11 . HPLC (Reverse Phase, C18, 70% acetonitrile-water, isocratic, 1.0 ml/min.). Retention Times: Major Isomer: 9.58 min. Minor Isomer: 10.28 min. Example 3 A solution of 0.11 g (0.128 mmol) of 7' (Preparation 17) and 2.0 mL of trifluoroacetic acid in 2.0 mL of methylene chloride was stirred at 25°C for 45 minutes. The solvent was removed in vacuo and the residue was dissolved in 20 mL of methylene chloride, washed with sodium bicarbonate solution and dried over sodium sulfate. After the solvent was removed in vacuo, the residue was dissolved in 10 mL of toluene .and 0 061 g (0.64 mmol) of 2-hydroxypyridine was added. After stirring 18 hours at 25°C, the solvent was removed in vacuo, the residue dissolved in ethyl acetate and washed with 1N HCl then sodium bicarbonate solution, then brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using hexane-ethyl acetate 1-1 as eluent to yield 0.032 g (41%) of a white residue which was characterized as 8'a Mass Spec. (FD + ) m/e 609 (M + ). Example 4 8'b was prepared according to the method for the preparation of 8'a . Mass Spec. (FD + ) m/e 642 (M + ). Example 5 To a solution containing 26 mg (0.043 mmol) of 8'a (Example 3) in 5.0 mL of methylene chloridewas added 8.1 mg (0.047 mmol) of m -chloroperbenzoic acid. The reaction was stirred 18 hours at 25°C and monitored by HPLC (reverse phase, C18, 70% acetonitrile-water). An additional 8.1 mg (0.047 mmol) of m -chloroperbenzoic acid was added and the reaction was stirred another 18 hours. The reaction was diluted with 10 mL of methylene chloride and washed with a saturated sodium bisulfite solution followed by sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 27 mg (100%) of a white residue which was characterized as a mixture of diastereomeric epoxides of 9'a Mass Spec. (FD + ) m/e 624 (M + ) Example 6 9'b was prepared substantially according to the method for the preparation of 9'a . Mass Spec. (FD + m/e 658. (M + ). Example 7 To a solution of 97 mg (0.121 mmol) of 17' (Preparation 19) in 5 mL CH 2 Cl 2 was added 2 mL of trifluoroacetic acid (TFA). The reaction was strirred at 25°C for 30 min, after which it was poured into 25 mL of a saturated aqueous sodium bicarbonate solution. An additional 25 mL of CH 2 Cl 2 was added and the organic phase was washed with 1N NaOH, dried over sodium sulfate and concentrated in vacuo. This crude material was dissolved in 10 mL of toluene and stirred at 25°C as 58 mg (0.605 mmol) of 2-hydroxypyridine was added. The reaction was stirred at 25°C for 18 h. The reaction was diluted with 50 mL of ethyl acetate and the organic phase washed twice with 1N HCl, twice with brine and twice with saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated in vacuo . The crude material was purified by flash chromatography on silica gel using 50% ethyl acetate-hexane as the eluent. The major fraction was concentrated in vacuo to give 28 mg (43%) of a white amorphous solid, which was characterized as 18' . Mass Spec. (FD + ) m/e 552 (M + ). HPLC (Reverse Phase, C18, 70% acetonitrile-water, isocratic, 1.0 ml/min.). Retention Times: 6.35 min. Example 8 To a solution containing 23 mg (0.043 mmol) of 18' (Example 7) in 5 mL of CH 2 Cl 2 was added 20.8 mg (0.103 mmol) of 85% m -chloroperbenzoic acid (mCPBA). The reaction was strirred at 25°C and monitored by HPLC (reverse phase, C 18 , 70% acetonitrile-water). After about 15 h, the reaction was complete. The reaction was diluted with 25 mL CH 2 Cl 2 and washed twice with a saturated sodium meta-bisulfite solution and twice with a saturated sodium bicarbonate solution. The organic layer was dried and concentrated in vacuo to give 15 mg (62%) of a white amorphous solid, which was charaterized as a 2:1 mixture of diastereomeric epoxides (ration determined from NMR) of 19' . HPLC (Reverse Phase, C18, 70% acetonitrile-water, isocratic, 1.0 ml/min.). Retention Time: 4.82 min. (isomers were coincident).

Claims: A compound of Formula I wherein Ar is phenyl or phenyl substituted with a single group selected from the group consisting of halogen and alkyl of from one to five carbons; R 1 is halogen, SH, amino, mono(C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, tri (C 1 -C 3 )alkylammonium, sulfate, or phosphate; R 2 is OH or 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, or a five membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears an alkyl group of from one to five carbons, connected to the phosphorous atom; or R 1 and R 2 may be taken together to form a second bond between C 18 and C 19 ; R 3 is an alkyl group of from one to five carbons; R 4 is H; R 5 is H; R 4 and R 5 may be taken together to form a second bond between C 13 and C 14 ; R 6 is benzyl, hydroxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, or substituted benzyl wherein one substituent is a halogen atom and one substituent is an OR 12 group wherein R 12 is alkyl of from one to five atoms; R 7 is H or an alkyl group of from one to five carbons; R 8 is H or an alkyl group of from one to five carbons; or R 7 and R 8 may optionally be taken together to form a cyclopropyl ring; R 9 is selected from the group consisting of H, an alkyl group of one to five carbons, (C 1 -C 3 ) alkylaryl, and aryl, in which aryl means phenyl or naphthyl; R 10 is selected from the group consisting H, an alkyl group of one to five carbons, (C 1 -C 3 ) alkylaryl, and aryl, in which aryl means phenyl or naphthyl; R 11 is C 1 -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched or straight chain, phenyl, a phenyl group with one to three substituents which may be independently selected from C 1 -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched or straight chain, Cl, Br, F, and I, benzyl, and a benzyl group with one to three substituents which may be independently selected from C 1 -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched or straight chain, Cl, Br, F, and I; X is O, NH or C 1 -C 3 alkylamino; Y is C, O, NH, S, SO, SO 2 or C 1 -C 3 alkylamino; or a pharmaceutically acceptable salt or solvate thereof. A compound as claimed by Claim 1 wherein Y is O. A compound as claimed by any one of Claims 1 to 2 wherein X is O. A compound as claimed by any one of Claims 1 to 3 wherein R 6 is a group of the formula: A compound as claimed by any one of Claims 1 to 4 wherein R 8 and R 7 are each methyl. A compound as claimed by any one of Claims 1 to 5 wherein R 9 is isobutyl and R 10 is hydrogen. A compound as claimed by any one of Claims 1 to 6 wherein R 11 is C 1 -C 4 alkyl. A compound as claimed by any one of Claims 1 to 6 wherein R 11 is phenyl. A compound as claimed by any one of Claims 1 to 8 wherein R 1 and R 2 form an epoxide group. A compound as claimed by any one of Claims 1 to 9 wherein Y is C. A compound as claimed by any one of Claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. A compound as claimed by any one of Claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for use in disrupting a microtubule. A compound as claimed by any one of Claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for use in treating a neoplasm. A pharmaceutical formulation comprising as active ingredient a compound as claimed by any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, associated with one or more excipients or carriers therefor. A compound of Formula III wherein Ar is phenyl or phenyl substituted with a single group selected from the group consisting of halogen and alkyl of from one to five carbons; R 1 is halogen, SH, amino, mono(C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, tri (C 1 -C 3 )alkylammonium, sulfate, or phosphate; R 2 is OH or SH; or R 1 and R 2 may be taken together with C 18 and C 19 to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, or or a five membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears an alkyl group of from one to five carbons, connected to the phosphorous atom; or R 1 and R 2 may be taken together to form a second bond between C 18 and C 19 ; R 3 is an alkyl group of from one to five carbons; R 4 is H; R 5 is H; R 4 and R 5 may be taken together to form a second bond between C 13 and C 14 ; R 6 is benzyl, hydroxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, or substituted benzyl wherein one substituent is a halogen atom and one substituent is an OR 12 group wherein R 12 is alkyl of from one to five atoms; R 7 is H or an alkyl group of from one to five carbons; R 8 is H or an alkyl group of from one to five carbons; or R 7 and R 8 may optionally be taken together to form a cyclopropyl ring; R 9 is selected from the group consisting of H, an alkyl group of from one to five carbons, (C 1 -C 3 ) alkylaryl, and aryl, in which aryl means phenyl or naphthyl; R 10 is selected from the group consisting H, an alkyl group of from one to five carbons, (C 1 -C 3 ) alkylaryl, and aryl, in which aryl means phenyl or naphthyl; X is O, NH or C 1 -C 3 alkylamino; Y is C, O, NH, S, SO, SO 2 or C 1 -C 3 alkylamino; or a pharmaceutically acceptable salt or solvate thereof. A compound of Claim 15 wherein Y is O. A compound as claimed by any one of Claims 15 to 16 wherein X is O. A compound as claimed by any one of Claims 15 to 17 wherein R 6 is a group of the formula: A compound as claimed by any one of Claims 15 to 18 wherein R 8 and R 7 are each methyl. A compound as claimed by any one of Claims 15 to 19 wherein R 9 is isobutyl and R 10 is hydrogen. A compound as claimed by any one of Claims 15 to 20 wherein R 1 and R 2 form an epoxide group. A compound as claimed by any one of Claims 15 to 21 wherein Y is C. A compound as claimed by any one of Claims 15 to 22 , or a pharmaceutically acceptable salt thereof, 1 for use as a pharmaceutical. A compound as claimed by any one of Claims 15 to 22 , or a pharmaceutically acceptable salt thereof, for use in disrupting a microtubule. A compound as claimed by any one of Claims 15 to 22 , or a pharmaceutically acceptable salt thereof, for use in treating a neoplasm. A pharmaceutical formulation comprising as active ingredient a compound as claimed by any one of Claims 15 to 22 , or a pharmaceutically acceptable salt thereof, associated with one or more excipients or carriers therefor. A compound selected from the group consisting of and

Inventors: KROIN JULIAN STANLEY, NORMAN BRYAN HURST, SHIH CHUAN, KROIN, JULIAN STANLEY, NORMAN, BRYAN HURST, SHIH, CHUAN
Applicants: LILLY CO ELI, UNIV HAWAII, UNIV WAYNE STATE, ELI LILLY AND COMPANY, UNIVERSITY OF HAWAII, WAYNE STATE UNIVERSITY
Application year: 1997
Main classification: C07D255
IPC codes: C07D273, C07D413