MXPA00008090A - Antitumor agents - Google Patents

Abstract

The present invention provides compounds of general formula (I) or (II):wherein R1, R2, R3, R4, R5, R6, and R7 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising compounds of formula (I) or (II), intermediates and processes useful for preparing compounds of formula (I) or (II), and methods comprising inhibiting tumor growth or treating cancer by administering one or more compounds of formula (I) or (II).

Description

ANTITUMOR AGENTS FIELD AND BACKGROUND OF THE INVENTION A list of human cancers for which chemotherapy has played a predominant role in increasing the length of life, posing a normal life expectancy, includes Bur itt's lymphoma, acute lymphocytic leukemia and Hodgkin's disease, along with approximately other 10-15 types of tumor. For example, see A. Golden et al., Eur J. Cancer, 17, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in the selection of antitumor agents that are effective in man, these response tumors represent only a small fraction of the various types of cancer and, notably, these are relatively few highly active drugs against solid tumors such as ovarian cancer, breast cancer, lung cancer and the like. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylamine, and the like. Therefore, REF .: 122616 Patients with any of the types of malignancies remain at a significant risk for relapse and mortality. After relapse, some patients may be re-induced in remission with their initial treatment regimen. However, high dosages of the agent that is required or the use of additional agents are frequently required, indicating the development of at least the partial resistance of the drug. Recent evidence indicates that drug resistance can simultaneously develop several agents, including ones to which the patient was not exposed. The development of tumors (mdr) resistant to multiple drugs can be a function of the mass of the tumor and constitutes a major cause of the deficiency of the treatment. To extend this drug resistance, high-dose chemotherapy with or without radiation and bone marrow transplantation from self-derived or allogeneic bone can be employed. High-dose chemotherapy may employ the original drug (s) or be altered to include additional agents. The development of new drugs, resistant not obstructed with The mdr phenotypes are required to promote the healing potential of current regimens and to facilitate curative interventions in previously treated patients. The in vitro anti-tumor activity of the new class of natural products called iludins have been examined by Kelner, M. et al., Cancer Res-, 47, 3186 (1987). Illudin M was purified and submitted for evaluation by the National Cancer Institute Division of Center Treatment (Division of the National Cancer Institute for Cancer Treatment, NCI DCT) in the drug screening or screening program. alive . Illudin M significantly increases the lifespan of rats with Dunning's leukemia, but has a low therapeutic index in solid tumor systems. The extreme toxicity of the illudins has prevented any of the applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit prominent antitumor activity, including those analogously described in the ^^^ However, despite these developments, there is a continuing need for chemotherapeutic agents which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index. to be effective for in vivo treatment.

DESCRIPTION OF THE INVENTION The invention provides a compound of formula I: (D where Ri is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or - (CH? Ln- (X) - (Y); n is 0 to 4; X is oxy (-O-), thio (-S -), -N (Ra) -, or absent; Y is (C3-C6) cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a branched or unbranched carbon chain of 1 to 15 elements that optionally comprises 1, 2 or 3 oxy without peroxide, thio, or - N (Ra) -; wherein said chain may be optionally substituted on the carbon with 1, 2, or 3, oxo (= 0), hydroxy, carboxy, halo, mercapto, nitro, -N (Rb) (Rc), (Ca-Cβ) cycloalkyl , aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may be optionally saturated or unsaturated; R2 is carboxy, (Ci-Cβ) alkanoyl, (Ci-Ce) alkoxycarbonyl, halo (CI-CÍ) alkyl, C (= 0) NRdRe, a saccharide, an amino acid, a peptide, or (Ci-Ce) alkyl substituted by 1 or 2 hydroxy, (Ci-Cβ) alkoxy, (Ci-Ce) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or C (= 0) NRdRe; R3 is hydrogen, (Ci-Cβ) alkyl or, (Ci-CÍ] alkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R is hydrogen or (Ci-Cβ) alkyl, and Rs is hydroxy, (CI-CÍ) alkoxy, or (Ci-Cd) alkanoyloxy, or R. and Rs taken together are ethylenedioxy, R6 is hydrogen, carboxy, (Ci-Cβ) alkanoyl, (Ci-Cβ) alkoxycarbonyl, halo (C?-Chalkyl, -C (= 0) NRfR3, a saccharide, an amino acid, a peptide, or (Ci-Cβ) alkyi optionally substituted by 1 or 2 hydroxy, (Ci-Celalkoxy, (Ci-Cβ) alkanoyloxy , carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Ra is hydrogen, (Ci-Cß) to the one, (C? -Ce) alkanoyl, phenyl or benzyl; and Rb, Rc, Rd , Re, Rf and Rg are each independently hydrogen, (Ci-Cd) alkyl, (Ci-Cß) to the canoe, phenyl or benzyl; or Rb and Rc, Rd, and Re, or Rf and Rg, together with the nitrogen to which they are attached, they are pyrrolidino, piperidino, or morpholino, wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 can be optionally substituted by 1, 2 or 3 (Ci-Cdlalquilo, (Ci-Cß) alkoxy, (Ci-Cß) alkanoyl, (Ci- Ce) alkanoyloxy, (Ci-Cβ) alkoxycarbonyl, hydroxy (Ci-Ce) alkyl, halo (Ci-Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (R.), wherein each Rh and R is independently hydrogen, (Ci-Cβ) alkyl, (Ci-Ct) alkanoyl, phenyl or benzyl, or Rh and R] together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same. The invention also provides a compound of formula I wherein: Ri is - (CH 2) n- (X) - (Y); n is 0 to 4; X is oxy, thio, -N (Ra) -, or absent; Y is a monopronected amino acid, a diprotected amino acid, a peptide, or a branched or unbranched carbon chain of 1 to 15 elements optionally comprising 1, 2, or 3 oxy without peroxide, thio, or -N (Ra) -; wherein said chain is substituted with 1,2, or 3 peptides; and wherein said chain may be optionally saturated or unsaturated; R2 is hydrogen or (Ci-C.) Alkyl; R 3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) alkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R. is hydrogen or (Ci-Cβ) alkyl; and Rs is hydroxy, (Ci-Cβ) alkoxy, or (Ci-Cβ) alkanoi loxy; or R and Rs taken together are ethylenedioxy; Re is hydrogen, carboxy, (C 1 -C 1) alkanoyl, (Ci-Ce) alkoxycarbonyl, halo (Ci-Cs) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or ( Ci-Cs) is optionally substituted by 1 or 2 hydroxy, (Ci-Cejalkoxy, (Ci-Ce) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Ra is hydrogen, (Ci-) Cß) alkyl, (Ci-Ce) alkanoyl, phenyl or benzyl, and Rb, R, Rd, Re, Rf and Rg are each independently hydrogen, (Ci-CÍ) alkyl, (Ci-Cs) alkanoyl, phenyl or benzyl, oby Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino, wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1,2 or 3 (Ci-Cd) alkyl, (Ci-Ce) alkoxy, (Ci-Cd) alkanoyl, (Ci-Cβ) alkanoyloxy, (Ci- Cdlalkoxycarbonyl, hydroxyCi-Cßalkyl, halo (Ci -Cß) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (Rj), in of each Rh and R] is independently hydrogen, (Ci-Clylalkyl, (C 1 -C 6) alkanoyl, phenyl or benzyl; or Rh and] together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof. Preferably, Y is (Ci-Cs) alkyl substituted with a peptide. The invention also provides a compound of formula I wherein: Ri is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or - (CH2) n- (X) - ()); n is 0 to 4; X is 0x1, thio, - N (Ra) -, or absent; Y is (C3-C6) cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a branched or unbranched carbon chain of 1 to 15 elements optionally comprising 1, 2 or 3 oxy without peroxide, thio, o - N (Ra) -; wherein said chain may be optionally substituted on the carbon with 1,2, or 3, oxo, hydroxy, carboxy, halo, mercapto, nitro, -N (Rb) (Rc), (C3-Cs-cycloalkyl, aryl, heteroaryl, saccharides , amino acids, or peptides, and wherein said chain may be optionally saturated or unsaturated, R2 is hydrogen or (Ci-Cs) alkyl, R3 is hydrogen, (Ci-Cs) alkyl, (Ci-C) alkoxy, Cß) alkyl thio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R. is hydrogen or (Ci-Cβ) alkyl, and Rs is hydroxy.

(Ci-Cβ) alkoxy, or (Ci-Cβ) alkanoyloxy; or R. and Rs taken together are ethylenedioxy; Rd is carboxy, (Ci-Cβ) alkanoyl, (Ci-Ce) alkoxycarboni 1 or, C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cs) alkyl substituted by 1 or 2 (Ci -Ce) alkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Ra is hydrogen, (Ci-Ce) alkyl, (Ci-C.) Alkanoyl, phenyl or benzyl; and Rb, Rc, Rd, Re, Rf and R are each independently hydrogen, (Ci-Cβ) alkyl, (Ci-Cd) alkanoyl, phenyl or benzyl; or Rb and Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any alkyl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1,2 or 3 (Ci-Cβ) alkyl, (Ci-Cβ) alkoxy, (Ci-Ce) alkanoyl, (Ci -Ce) alkanoi loxi, (Ci- Csalkoxycarbonyl, hydroxy (C? -C? S) alkyl, halo (Ci-Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (Rj), wherein each Rh and R: is independently hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) alkanoyl, phenyl or benzyl; or Rh and R3 together with the nitrogen to which they are attached; united are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof.

The invention also provides dimeric compounds comprising two compounds of formula (I), linked by a bond. The binder can be, for example, an alkyl or ester based on a linking group. Examples of suitable binders include - (CH2) p-0- (CH2) q-, - (CH2) r-, and -CH2-S-CH2C (O) -0- (CH2) 2-0-C ( 0) CH2-S-CH2-; where p and q are each indi-idually an integer from 1 to 8, inclusive; and r is an integer from 1 to 16, inclusive. Preferably, r is an integer from 1 to 8, inclusive. As would be apparent to one skilled in the art, other linkers of approximately the same length can also be used. Two compounds of the formula I can conveniently be linked, for example, by replacing Ri, R3, R. or Rs, independently, in each compound of the formula I, with the bifunctional linker. When the bond is through Ri, the binder is preferably -CH2-O-CH2- or -CH2-S -CH2C (O) -O- (CH2) 2-0-C (O) CH2-S-CH- .

"^" - • * - * • The invention also provides the compounds of formula I wherein Ri is - (CH? Jn- (X) - (Y); n is 1 to 4 (preferably n is 1); X is oxy, thio, or -N (Ra ) - (preferably X is thio), Y is a branched or unbranched carbon chain of 2 to 15 elements optionally comprising 1,2, or 3 oxy without peroxide, thio, or -N (Ra) -; The chain can be substituted at carbon with 1, 2, or 3, oxo, carboxy, mercapto, -N (Rb) (R), (C3-Cs) cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; wherein said chain may be optionally saturated or unsaturated (preferably Y is a branched or unbranched carbon chain of 2 to 6 elements which is substituted on carbon with 1,2, or 3, oxo, heteroaryl, amino acids, or peptides); R2 is hydrogen or (Ci-C.) Alkyl, R3 is hydrogen, (Ci-C6) alkyl, (Ci-Cs) alkoxy, (Ci-Ct) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R. is hydrogen or (Ci-Cß) alkyl, and R5 is hydroxy, (Ci-Cß) alkoxy, or (C? -C s) alkanoyloxy; or R, and Rs taken together are ethylenedioxy; R6 is hydrogen, carboxy, (Ci-Cs) to the canoyl, (Ci-Cβ) alkoxycarbonyl, halo (Ci-Ce) alkyl, -C (= 0) NRfRg, a saccharide, a amino acid, a peptide, or (Ci-Cβ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cβ) alkoxy, (Ci-Cβ) alkanoyl oxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Ra is hydrogen, (Ci-Cβ) alkyl, (Ci-Cß alkanoyl, phenyl or benzyl, and Rb, R, Rf and Rg are each independently hydrogen, (Ci-Cβ) alkyl, (Ci-Ce) alkanoyl , phenyl or benzyl, or Ru and Rc, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino, wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1, 2 or 3 (Ci-Cs) alkyl, (Ci-Cß) alkoxy, (Ci-Cß) alkanoyl, (Ci-Ce) al canoi loxi, (Ci-Csl alkoxycarbonyl, hydroxy (Ci-Cß) alkyl, halo (Ci-Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (Rj), wherein each Rh and R3 is independently hydrogen, (Ci-Cβ) alkyl, (Ci) -Ce) alkanoi, phenyl or benzyl; or Rh and R] together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof. The invention also provides a compound of formula II: wherein R2 is (Ci-Cd) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cd) alkoxy, (Ci-Cβ) alkyl thio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R. is hydrogen or (Ci-Cβ) alkyl; and Rs is hydroxy, (Ci-Cβ alkoxy, or (Ci-Cβ) alkanoyloxy, or R and Rs taken together are ethylendioxy, Re is hydrogen, carboxy, (C-Cβ) al canoi lo, (Ci-C.) alkoxycarbonyl, halo (Ci-Cß) alkyl, -C (= 0) NRtRg, a saccharide, an amino acid, a peptide, or (Ci-Ce) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Ce) alkoxy , (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; R7 is carboxy, (Ci-Cd) alkanoyl, (Ci-Cß) alkoxycarbonyl, halo (C? -Cs) alkyl, C (= 0) NRdRe, a saccharide, an amino acid, a peptide, or (CI-CÍ) alkyl substituted by 1 or 2 hydroxy, (CI-CÍI alkoxy, (Ci-Csl alkanoyloxy, carboxy, amino acids, peptides, saccharides, or C (= 0) NRdRe; Rd, Re, Rf and Rg are each independently hydrogen, (Ci-Cs) alkyl, (Ci- C) alkanoyl, phenyl or benzyl; or Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be optionally substituted by 1, 2 or 3 (Ci-Ce) alkyl, (C? -C) alkoxy, (Ci-C) to 1-canoil or, (Ci) -Ce) alkanoyloxy, (Ci-Cβ) alkoxycarbonyl, hydroxy (Ci-Cβ) alkyl, halo (C? -Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (R-j), wherein each Rh and R] is independently hydrogen, (Ci-Cβ) alkyl, (Ci-Ce) alkanoyl, phenyl or benzyl; or Rh and R] together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same. The compounds of the invention are useful as antineoplastic agents, i.e. to inhibit the growth of tumor cells in vitro or in vivo, in mammalian hosts, such as humans or pets, and are particularly effective against solid tumors and tumors resistant to multiple drugs. Accordingly, the invention provides a method comprising the inhibition of cancer cells, by contacting said cells, in vivo or in vivo, with an effective amount of a compound of the invention. The invention also provides a therapeutic method comprising the treatment of cancer (i.e., the inhibition of tumor cell growth) by administering a compound of the invention to a mammal (e.g., a human) in need of such therapy. The present compounds can be fcl directed to a particular tumor by binding the compound to a reagent which is capable of binding to an antigen associated with the tumor. The antigen can be located on a tumor or in the area of the tumor cell. Suitable reagents include polyclonal or monoclonal antibodies. The compound or reagent-conjugate may additionally comprise a binder (e.g. a binder such as described here before) for the binding of the compound to the reagent. Accordingly, the invention also provides a compound comprising a compound of formula I or formula II and a reagent (eg, a monoclonal or polyclonal antibody) which is capable of binding to an antigen associated with the tumor. The present invention also provides a pharmaceutical composition (e.g., a unique pharmaceutical dosage form), which comprises one or more compounds of the invention in combination with a pharmaceutically acceptable diluent or carrier. The invention also provides a compound of the invention (for example a compound of formula I or II, a dimer thereof, or a conjugate comprising a compound of formula I or II and a reagent which is capable of binding to an antigen associated with the tumor, or a salt thereof) for use in medical therapy (preferably for use in the treatment of cancer, for example solid tumors), as well as the use of a compound of the invention for the production of a medicine useful for the treatment of cancer, for example solid tumors. The invention also provides processes and novel intermediates described herein that are useful for the preparation of the compounds of the invention. Some of the compounds of the invention are useful for preparing other compounds of the invention.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the representative compounds of the invention (compounds 1 to 9) and intermediate compounds 10 or 11.

Figure 2 shows the representative compounds of the invention (compounds 13 to 16). Figure 3 shows the representative compounds of the invention (compounds 17 and 18).

DETAILED DESCRIPTION The following definitions are used, unless otherwise described: Halo is fluorine, chlorine, bromine, or iodine. Alkyl, alkoxy, alkenyl, etc. they denote both straight and branched groups, but with respect to an individual radical such as "propyl" it embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine or ten ring atoms in which at least one ring is aromatic. Heteroaryl contains a radical linked via a carbon ring of a monocyclic aromatic ring containing five or six atoms consisting of carbon and one to four oxygen without peroxide, sulfur, or N (Ry) wherein Ry is absent or is H , O, (Ci-C.) Alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz derivative or a derivative fusing a diradical propylene, trimethylene, or tramethylene of this type. The term "inhibit" or "inhibition" means the decrease in the speed of growth of the tumor cell from the rate at which it could occur without treatment, and / or causing the tumor mass to decrease. Inhibition also includes the principle of complete regression of the tumor. Accordingly, the present analogues can either be cytostatic or cytotoxic to the tumor cells. The method of the invention can be practiced in any mammal having a susceptible cancer, i.e., a population or tumor of the malignant cell. The compounds of the invention are effective in human in vivo tumors as well as in the in vitro lines of human tumor cells. The present compounds may be particularly useful for the treatment of solid tumors for which relatively few treatments are available. Such tumors include epidermoid and myeloid, chronic (CML) or acute (AML) tumors. Such tumors also include, non-small cell, squamous, liver, cervical, renal, adrenal, stomach, esophageal, oral and mucosal tumors, as well as carcinoma of the lung, ovaries, breast and colon, and melanomas (including amelanotic subtypes). The present compounds can also be used against endometrial tumors, bladder cancer, pancreatic cancer, lymphoma, Hodgkin's disease, prostate cancer, cancer of the testes and sarcomas as well as tumors of the central nervous system, such as tumors of the brain cancers of the hematopoietic and neurological cells such as 1 eukemia / 1 B cell infoma, myelomas, leukemia / 1 T cell infoma, leukemia / l small cell infomation, as well as null, sezary, monocytic, myelomonocytic cells and hairy cell leukemia. These 1 eukemia / 1 infoma can be either acute (ALL) or chronic (CLL). The term "saccharide" includes monosaccharides, disaccharides, trisaccharides and polysaccharides. The term includes glucose, sucrose, fructose and ribose, as well as deoxy sugars such as deoxyribose and the like. The saccharide derivatives can be conveniently prepared as described in International Patent Application Publication Nos. WO 96/34005 and 97/03995. A saccharide may be conveniently linked to the remainder of a compound of formula I or II through an ether linkage. The term "amino acid", comprises the residues of the natural amino acids (for example Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in the form D or L, as well as also non-natural amino acids (for example phosphoserine, photosonine, phosphorus, hydroxyproline, gamma-carboxyglytherm, hippuric acid , acid oc tahidr oí ndol -2 -carboxy li c, stanine, acid 1, 2, 3, 4 - te tr ahidroi soquinol ina -3-carboxylic acid, penicillin, ornithine, citrulline, -methyl-alanine, couple -benzoi 1 f eni 1 alanin, f enilglicina, propargi lgli ciña, sarcosina, and t er c-bu t ilgl i ciña). The term also comprises natural and non-natural amino acids in the presence of a conventional amino protecting group (eg, acetyl or benzyloxycarbonyl), as well as also natural and unnatural amino acids protected at the carboxy terminus (eg, as a (Ci-Cβ) alkyl , phenyl or benzyl ester or amide, or as an a-methybenzylidene). Other protective groups Suitable carboxy and amino are known to those skilled in the art (see, for example, T.W. Greene, Pro t e c t in g Gro ups In Orga n i c Syn t h e s i; Wiley: Ne York, 1981, and references cited herein). An amino acid may be annealed to the remnant of a compound of formula I through the carboxy terminus, the amino terminus, or through any other convenient point in the junction, such as, for example, through the sulfur of cysteine. The term "peptide" describes a sequence of 2 to 5 amino acids (for example as defined hereinbefore) or peptidyl residues. The sequence can be linear or cyclical. For example, a cyclic peptide can be prepared or it can result from the formation of the disulfide bridges between two cysteine residues in a sequence. A peptide may be linked to the remainder of a compound of formula I through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of a cysteine. Preferably a peptide comprises 3 to 25, or 5 to 21 amino acids. Peptide derivatives can be prepared as US 4,612,302 was described in US Patent Nos. 4,612,302; 4,853,371; and 4,684,620, or as described in the Examples below. The peptide sequences specifically cited here are written with the amino terminus on the left and the carboxy terminus on the right. It has been shown that certain peptides specifically bind to specific antigens associated with the tumor in a manner analogous to the ligament of antibodies to such antigens. See Arap et al. S c i en ce, 1998, 279, 5349, 377-380. Accordingly, pharmaceutical agents which comprise a peptide that is capable of binding specific receptors in tumor cells can be administered preferentially to such tumor cells. As a result, a preferred embodiment of the invention provides a compound of formula I or II comprising a peptide capable of binding especially to an antigen associated with the tumor. Preferred peptides include -Cys-Asp-Cys-Arg-Gly-Asp-Cy s-Phe-Cy s (SEQ ID NO: 1), -Cys-Asp-Gly-Arg-Cys (SEQ ID NO: 2) and -Cy s -Asp-Gl y-Cys - Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys (SEQ ID NO: 3). It will be appreciated by those skilled in the art that the compounds of the invention having a chiral center may exist in and be isolated in racemic and optically active forms. Some compounds may exhibit polymorphism. It will be understood that the present invention includes any racemic, optically active, polymorphic, or is ter eoi form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein., being well known in the art to prepare the optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by the synthesis of the optically active starting materials, by the chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine the anti-tumor activity using a Test A or Test B, described below, or using other tests which are well known in the art. In the preferred compounds of formula I, the absolute stereochemistry in the presence of carbon R. and R5 is (R). The specific values listed below for the radicals, substituents, and ranges, are for illustration only, these do not exclude other defined values or other values with defined ranges for the radicals and substituents. Specifically, (Ci-C.) Alkyl 1 or can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or sec-butyl; (Ci-Cβ) alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (Ci-Cβ) alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, septyl, or octyl; (C3-C6) ciel oal quil o can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C 1 -Ci) alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or sec-butoxy; (C1-C6) alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6) alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-2-butenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, or 4-methyl-3-pentyl; (Ci-Cdlalcanoyl can be acetyl, propanoyl or butanoyl; halo (C? -Ce) alkyl can be iodomomethyl, bromomethyl, chloromethyl, f-loromethyl, t ici or omet i 1, trifluoromethyl, 2-chloroethyl, 2-fluoro Oet i lo, 2, 2, 2 - 1 rif 1 uor oe t il o, or pentafluoroethyl; hydroxy (Ci-Cß) alkyl can be hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1-hydroxymethyl opyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypropyl, 5-hydroxynthoxy, 1-hydroxyhexyl or, or hydroxyhexyl; (Ci-C 1 -lalkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or, pent oxycarbonyl, or hexyloxycarbonyl; (Ci-Cß) alkylthio can be methylthio, ethylthio, propylthio, and thiopropylthio, butylthio , isobutylthio, pentthylthio, or hexylthio; (Ci-Ce) alkanoi loxy can be formyloxy, acetoxy, prosoxyloxy, butanoyloxy, isobutyl, pentanoyloxy, or hexanoyloxy; be phenyl, indenyl, or naphthyl; and heteroaryl may be furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl , isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). A specific value for Ri is hydroxy, halo, carboxy, aryl, heteroaryl, a saccharide, an amino acid, or a peptide. Another specific value for Ri is - (CH2) n- (X) - (Y); where n is 0 to 4; X is oxy, thio, N (Ra) -, or absent; and Y is a peptide, or (C i -C e) alkyl substituted with a peptide. Another specific value for Ri is hydrogen or (Ci-Cβ) alkyl, optionally substituted with 1 or 2 hydroxy, halo, methoxy, or ethoxy. Another specific value for Ri is - (CH2) n- (X) - (Y); X is oxy, thio, or -N (Ra) -; and Y is CH2OC (0) (Ci-Ci) alkyl, CH2C (0) -O- (CH2) 2-0- C (0) CH2SH, (CH2) 2-0- (CH2) 2halo, (Ci-C) .) alkyl, (C 1 -C) alkyl, CH 2 CO 2 (C 1 -C 4) alkyl, CH 2 CO 2 H, aryl (C 1 -C 4) alkyl, a saccharide, an amino acid, or (Ci-Cβ) alkyl optionally substituted with 1 or 2 hydroxy or halo; wherein any aryl or heteroaryl may be optionally substituted with 1 or 2 hydroxy, halo, (Ci-C.Jalkyl or (Ci-C.) coxi.) Another specific value for Ri is -CH2- (X) - (Y ), wherein X is oxy, thio, or -N (Ra) -; and Y is (Ci-Cβ) alkyl optionally substituted with 1 or 2 hydroxy, halo, carboxy, oxo, mercapto, N (Rb) (Rc) , (C3-C6) cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides, wherein any aryl or heteroaryl of Y may be optionally substituted by 1,2, or 3 (Ci-Ct) alkyl, (Ci-Cß) alkoxy, (Ci-Cs) alkanoyl, (Ci-Cβ) alkanoyloxy, (Ci-Cßalkoxycarbonyl, hydroxy (C 1 -C 6) alkyl, halo (Ci-Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N ( Rh) (R3); where every Rh and R_? is independently hydrogen, (Ci-Cß) alkyl, (Ci-Cdlalcanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical.) Another specific value for Ri is - (CHz) n- (X) - (Y), n is 1 or 2, X is oxy, thio, or -N (Ra) -, and Y is (Ci-Cí) alkyl or (C2-C6) alqueni it, optionally substituted with 1 or 2 oxo, hydroxy. carboxy, halo, mercapto, nitro, -N (Rb) (Rc), (C3-Cd) cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; wherein any aryl or heteroaryl of Y may be optionally substituted by 1,2, or 3 (Ci-Cβ) alkyl, (Ci-C-alkoxy, (Ci-Cβ) alkanoyl, (Ci-C) alkanoyloxy, (Ci-Cβ) alkoxycarbonyl, hydroxy (Ci-Ce) alkyl, halo (Ci-Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, and -N (Rh) (R3), wherein each Rh and R: is independently hydrogen , (Ci-Cß) alkyl, (C? -C () alkanoyl, phenyl and benzyl, or Rh and] together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical.Another specific value for Ri is - CH2- [ci s teína- enla zada aa zu fre] -Rx where Rx is an amino acid or a peptide comprising 2 to 24 amino acids Another specific value for Ri is -CH2- [N-aci Ici s teí na-enlaz ada-sulfur] -Rx wherein Rx is an amino acid or a peptide comprising 2 to 24 amino acids.Another specific value for Ri is -CH2- [glut at ion-bonded a-sulfur].

Another specific value for Ri is 2 - [(R) -a-methylbenzyl-aminocarbonyl] -2 - (acylamino) ethyl thiomethyl lo. Preferably, the 2-position of the ethyl group has the (S) configuration of the cysteine. A more specific value for Ri is hydrogen, hydroxymethyl, methoxymethyl, or acetoxymethyl. A specific value for R2 is hydroxymethyl, methoxymethyl, or acetoxymethyl. Another specific value for R2 is carboxy, (Ci-Ce) alkanoyl, (Ci-Cí) alkoxycarbonyl, or C (= 0) RdRe. Another specific value for R2 is (Ci-Cd) alkyl substituted by 1 or 2 hydroxy, (Ci-Cd] alkoxy, (C 1 -C 6) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRdRe.

Another specific value for R2 is -CH2- [ci s te-nada a-a zuf r e] -Rx where Rx is an amino acid or a peptide comprising 2 to 24 amino acids. Another specific value for R2 is -CH2-.N-aci lei s t eí na-bin z a a-sulfurJ-R, where Rx is an amino acid or a peptide comprising 2 to 24 amino acids.

Another specific value for R2 is -CH2- [gluta t ione-linked to-sulfur]. A specific value for R3 is hydrogen. A specific value for R. is methyl. A specific value for Rs is hydroxy. A specific value for R e is hydrogen. A specific value for Re is carboxy, (Ci-Cβ) alkanoyl, (Ci-Cβ) alkoxycarbonyl, or C (= 0) RfRg. A specific value for R e is (Ci- Cd) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cβ) alkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or C (= 0) NRfRg . Another specific value for Re is -CH2- [cis t e n-linked to a-sulfur] -R x wherein R x is an amino acid or peptide comprising 2 to 24 amino acids. Another specific value for R e is -CH 2 -. N-acylcyl stein na-bound to-sulfur] -R x wherein R x is an amino acid or a peptide comprising 2 to 24 amino acids. A more specific value for Re is methyl or hydroxymethyl.

A specific value for R7 is (Ci-Cdlalkyl substituted by 1 or 2 hydroxy, (Ci-Cdlalkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRaRe. R7 is hydroxymethyl, specifically, Rx can be a peptide comprising 4 to 20 amino acids.Another specific value for Rx is -Leu-Gly-Phe, -Phe-Leu-Gly, -Leu-Leu-Phe, -Gly-Phe, or -Leu Another specific value for Rx is -Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (SEQ ID NO: 4), Asp-Gly-Arg-Cys (SEQ ID NO: 5), or -Asp-Gl y-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys (SEQ ID NO: 5) A specific compound of the invention is a compound of formula I in where R2 is (Ci-Cd) alkyl, substituted with hydroxy, (Ci-Ce) alkoxy, (Ci-Cd) alkanoyloxy, or carboxy; R3 is H, (Ci-Cd) alkyl, (Ci-Cβ) alkoxy, ( Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R, and hydrogen or (Ci-Cβ) alkyl, Rs is hydroxy, and Re is (Ci-Cd) alkyl, optionally substituted with hydroxy i, (Ci-Cd) alkoxy, | C? -Cs) alkanoyloxy, or carboxy; or a pharmaceutically acceptable salt thereof. Another specific compound of the invention is a compound of formula I wherein Ri is hydrogen or (Ci-Cβ) alkyl, optionally substituted with hydroxy, halo, methoxy, ethoxy, or acetoxy; R 2 is hydrogen oxime, methoxymethyl, or acetoxymethyl; R3 is hydrogen; R. is methyl; Rs is hydroxy; and Re is methyl or hydroxymethyl; or a pharmaceutically acceptable salt thereof. Another specific compound of the invention is a compound of formula I wherein Ri is (CH2) n- (X) - (Y); n is 0 to 4; X is oxy, uncle, N (Ra) -, or absent; And it is a monoprotected amino acid or a diprotected amino acid; and R2 is hydrogen or (Ci-Cβ) alkyl; or a pharmaceutically acceptable salt thereof. Another specific compound of the invention is a compound of formula I wherein R 1 is CH 2 [- (1-cycloalkyl-α-sulfur), (S) -2- [(R) -a-methylbenzylaminocarbonyl] - 2 - (aci lamino) eti 11 iomet i lo, or (R) -2 - [(R) -a-me ti lbenc i laminocarbonil] - 2 - (aci lamino) eti lt iomet i lo; and R2 is hydrogen or (Ci-Cβ) alkyl; or a pharmaceutically acceptable salt thereof. A specific compound of formula I is a compound which is: or a pharmaceutically acceptable salt thereof.

A specific compound of formula II is a compound which is or a pharmaceutically acceptable salt thereof.

A preferred compound is a compound of formula I wherein R. is hydrogen or (Ci-Cd) alkyl; and Rs is hydroxy or acetoxy; wherein the absolute stereochemistry of carbon in the presence of R, and Rs is (R); or a pharmaceutically acceptable salt thereof. Processes for the preparation of the compounds of the invention are provided as further embodiments of the invention and are illustrated by the following procedures in which the meaning of the generic radicals is as given above unless otherwise qualified. The compounds of the present invention (compounds of formula I and II and salts thereof) can be derivatives of iludine ?, hydroxymethyl acylfulvene (HMAF, ie, a compound of formula (I) wherein Ri is CH2OH, R2 is CH3, R3 is hydrogen, R. is CH3, R5 is OH and R6 is CH3) and fulvene (ie, a compound of formula (I) wherein Ri is H, R2 is CH3, R3 is H, R. is CH3, Rs is OH and R e is CH3) the syntheses of which are known in the art (see, for example, WO 9104754, WO 94/18151). i ^ | ¡^ ¡| ^^^ A compound of formula I wherein R2 is hydroxymethyl can be prepared by oxidation of a corresponding compound of formula I wherein R2 is methyl. The oxidation can be conveniently carried out using selenium dioxide and tere-butyl hydroperoxide under conditions similar to those described in Example 1. A compound of formula I wherein Ri is hydroxymethyl can be prepared from a corresponding compound of Formula I wherein Ri is hydrogen by treatment with paraformaldehyde and sulfuric acid, the reaction can be conveniently carried out under conditions similar to those described in Example 2. A compound of formula I wherein R2 is acetoxymethyl can be prepared by the acylation of a corresponding compound of formula I wherein R2 is hydroxymethyl. The acylation can be conveniently carried out using acetic anhydride, under conditions similar to those described in Example 3. A compound of formula I wherein R2 is methoxymethyl can be prepared by reacting a corresponding compound of formula I wherein R2 is hydroxymethyl with methyl iodide and silver oxide. The reaction can be conveniently carried out under conditions similar to those described in Example 7. A compound of formula I wherein Ri is methoxymethyl can be prepared by reacting a corresponding compound of formula I wherein Ri is hydroxymethyl with methanol and sulfuric acid. The reaction can be conveniently carried out under conditions similar to those described in Example 8, subpast a. A compound of formula I in which Ri is -CH 2 - [ci s t-n-a-sulfur] can be prepared by reacting a corresponding compound of formula I wherein Ri is hydroxymethyl by the binding of cysteine. The reaction can be conveniently carried out under conditions similar to those described in Example 10. A compound of formula I in which Ri is -CH2- [N-acylcyl and n-bonded a-sulfur] can be prepared by reacting a corresponding compound of formula I wherein Ri is hydroxymethyl by the union with N-acylci te tina. The reaction can be conveniently carried out under conditions similar to those described in Example 11. A compound of formula I wherein Ri is 2- [(R) -a-methylbenzyl-aminocarbonyl] -2 - (acylamino) eti 11 ome thyl can be prepared by reacting a corresponding compound of formula I wherein Ri is -CH2- [N-acylcii linked to-sulfur] with a-me t ilbenci lami na. The reaction it can be carried out readily under conditions similar to those described in Example 12. A compound of formula I in which Ri is -CH2- [glut ationa-a-sulfur] can be prepared by reacting a corresponding compound of formula I wherein Ri is hydroxymethyl with glutathione. The reaction can be conveniently carried out under conditions similar to those described in Example 14. A compound of formula I wherein Ri is -CH2- [n-linked to-to-zuf e] -Rx, or -CH2-.N-acylcyl stearylated to sulfur] -Rx can be prepared by reacting a compound UjgfraijmÉtm e corresponding to the formula I wherein Ri is -CH2- [steared na-enl a-sulfur] or -CH2-N-aci lei stei na-bound to-sulfur] with the necessary amino acid or peptide (Rx). The reaction can be conveniently carried out under conditions similar to those described in Example 15.

The compounds of formula II can be conveniently prepared from the iludin S using procedures similar to those described in Example 17. The compounds of the invention can also be prepared using techniques and intermediates similar to those described by T. McMorris et al. to the. Te t ra h e dron, 1997, 53, 44, 14579-14590; T. McMorris et al. J. Org. Ch em. 1997, 62, 3015-3018; T. McMorris et al Ch em. Comm. 1997, 315-316; and T. McMorris et al. Experen t i a 1996, 52, 75-80; and those described in U.S. Patent 5,439,942; U.S. Patent 5,439,936; U.S. Patent 5,523,490; U.S. Patent 5,536,176; WO 91/04754; WO 94/18151 and WO 98/03458. Some compounds of formula I or II can be used to prepare other compounds of formula I or II.

In cases where the compounds are sufficiently basic or acidic to form the non-toxic base or acid salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, me tansul fonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate , and α-glycerophosphate. Suitable inorganic salts can also be formed, including the hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable anion. Salts of alkali metal (eg, sodium, potassium or lithium) or alkaline earth metal (eg calcium) of the carboxylic acids can also be produced.

The compounds of the invention can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of dosage forms adapted to the chosen route of administration, i.e., orally or parenterally, intravenous, intramuscular routes, topical or subcutaneous. Accordingly, the present compounds can be administered if appropriate, for example, orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an edible assimilable carrier. These can be included in hard or soft shell gelatin capsules, can be compressed into tablets, or can be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the effective compound. The percentage of Compositions and preparations may, by the way, be varied and conveniently be from about 2 to about 60% by weight of a given single dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. Tablets, pills, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, a disintegrating agent such as corn starch, starch potato, alginic acid and the like, a lubricant such as magnesium stearate, and a sweetening agent such as sucrose, fructose, lactose, or aspartame or a sabotating agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the single dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Several other materials may be present as / • ttitm ÍI? I m • i ¡y- coatings or otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules can be coated with gelatin, wax, lacquer or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and pr opilpar abenos as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release preparations and devices. The active compound can also be administered intravenously or intraperitoneally by infusion or injection. The solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils.

Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or sterile dispersions or powders comprising the active ingredient which is adapted for the extemporaneous preparation of solutions for infusion or sterile injectables or dispersions, optionally encapsulated in liposomes. In all cases, the last dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a liquid dispersion medium or solvent comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The appropriate fluid can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be conducted approximately by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be conducted approximately by the use in the compositions of delayed absorption agents, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients listed above, when required, followed by sterilization by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are: vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any ingredient desired additional present in previously sterile filtered solutions. For topical administration, the present compounds can be applied in the pure form, that is, when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which can be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-to-1-alcohol / glycol mixtures, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid compositions can be applied from absorbent pads, used to impregnate bandages and other wipes, or sprayed on the affected area using spray or spray or pump type sprayers. Thickeners such as synthetic polymers, fatty acids, salts of fatty acids and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form expandable pastes, gels, ointments, soaps, and the like, for application directly to the user's skin. Examples of useful dermatological compositions which can be used to administer the compounds of the invention to the skin are known in the art; for example, see Jacquet et al. (U.S. Patent No. 4,608,392), Geria (U.S. Patent No. 4,992,478), Smith et al. (U.S. Patent No. 4,559,157) and Wortzman (U.S. Patent No. 4,820, 508). Useful dosages of the compounds of the invention can be determined by correlating their in vitro activity, and in vivo activity in animal models, such as dog or murine models as taught for iludine analogues such as those of U.S. Patent Nos. 5,439,936 and 5,523,490, for activity in higher mammals, such as human adults and children as taught, for example, in Borch et al. (North American Patent No. 4,938,949). The therapeutically effective amount of the analogue varies with the subject and the tumor to be treated. It has been found that relatively high doses of representative compounds of the invention can be administered due to the decreased toxicity compared to iludin S and M. For example, the maximum tolerated dose of illudin S is approximately 250 μg / kg, whereas the Compound 2 can be administered chronically at 35 mg / kg without toxicity. A therapeutic amount between 30 to 112,000 μg per kg of body weight is especially effective for intravenous administration although 300 to 112,000 μg per kg of body weight is effective if administered intraperitoneally. As one skilled in the art could recognize, the amount can be varied depending on the method of administration. The amount of the compound, or a active salt or derivative thereof, required for use in the treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be the discretion of the attending physician or clinical doctor. The compound can be conveniently administered in the unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, more conveniently, 50 to 500 mg of active ingredient per unit dosage form. Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 0.5 to about 75 μM, preferably, from about 1 to 50 μM, most preferably about 2 to about 30. μM. This can be achieved, for example, by the intravenous injection of a solution of 0.05 to 5% of the active ingredient, optionally in saline, or orally administered as a bolus containing approximately 1-100 mg of the active ingredient. Desirable blood levels can be maintained by continuous infusion to provide approximately 0.01-5.0 mg / kg / hr or by intermittent infusions containing approximately 0.4-15 mg / kg of the active ingredient (s). The desired dose may be conveniently presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The cytotoxic and antitumor properties of a compound of the invention can be determined using pharmacological models which are well known in the art, or using Test A and Test B described below.

Testing Studies In Vi t r o To verify the cytotoxic effects, various concentrations of compounds of the - < r - * "'•" • invention were added to cultures of MV522 (human lung carcinoma cell line), HL60 (myeloid leukemia cells), and 8392 (lymphoma / 1 B cell eukemia) cells for 48 hours, then cell viability / growth was determined by exclusion with tppane blue. As an alternative to continuous exposure studies for 48 hours, cells were plated in liquid culture in 96-well plates, exposed to various concentrations of compounds of the invention for 2 hours, pulsed with [3H] -thymidine for one to two hours and were collected on filter paper. The filter papers were added to vials containing scintillation fluid and residual radioactivity determined in a beta counter. The data of Test A, for the representative compounds of the invention, are shown in Table 1. The values are reported as average + _ 1 standard deviation; the units are nanomoles per liter; and NT means unproven.

Table 1 Test B. In Vi Studies Several representative compounds of the invention are chosen for in vivo studies. The anticancer agent mitomycin C was used as a pharmaceutical control. Drug therapy is started 10 days after incubation on a daily basis via IP route for 5 consecutive days. The animals were observed for 3 weeks after the start of therapy. The MTD was reached by mitomycin C of the control agent but not by compounds 1 or 2. The 4-week-old female BALB / c nu / nu mice weighing 18.22 g were obtained from Simonsen, Inc. (Gilroy, CA ) and were maintained in the colony of the athymic mouse of the University of California (San Diego, CA) ba or pathogen-free conditions using HEPA filtering hoods. The animals were provided with sterilized food and water ad l ibi t um in groups of 5 in ventilated plastic boxes with polyester fiber filter covers. All personnel handling or handling the animals wear: sterile gowns, covers mouths, gloves and shoes and hoods, clean. All the studies were conducted in accordance with NH guidelines "Guide for Care and Use of Animáis" and were approved by the University I ns t t ional Animal Care and Use Committee (Protocol 3-006-2). The MV522 lung carcinoma line used for xenograft studies is derived as described by Keiner et al. (Anticancer Res., 15: 867-872; 873-878 (1995)) and maintained in antibiotic-free RPMI 1640 (Mediatech, Herndon, VA) supplemented with 10% fetal bovine serum and 2 mM glutamine in humidified carbon dioxide at 37 ° C. Mice were randomly selected in treatment groups of five animals each for initial studies and groups of 16-20 animals to confirm analogous efficacy. Each animal was marked on the ear and followed individually in all experiments. The mice receive s.c. of the parental cell line MV522 using 10 million cell s / inoculation on the shoulders. Ten days after implantation s.c. of MV522 cells, when s.c. had a size of approximately 3 x 3 mm, the animals received the desired drug and dosage. The effect of the compound on the course of life was calculated from average survival. Although MV522 cells kill mice by metastasis, the tumor growth s.c. primary over the shoulder was observed to start on the first day of treatment and at intervals weekly later. The size of the tumor was measured in two perpendicular diameters. The tumor weights were estimated according to the formula w = (width) x length / 2). The relative weights (-R &) were calculated for the standardized variability in tumor size between test groups at the initiation of treatment using the formula RW = fit / wi, where Wi is the tumor weight for an animal given at the beginning of drug treatment and Wt is the tumor weight at a subsequent time. The animals were necropsied, and the organs were examined for evidence of metastasis. The comparison of the survival curves between groups of animals was by the method of Kaplan and Meier. For comparison of relative tumor weights between multiple groups of animals, ordinary ANOVA followed by post-ANOVA multiple comparison analysis of Tukey-Kramer was performed (Kelner et al. (An ti ca n cer Re s., 15: 867- 872; 873-878 (1995)). Probability values (p) less than 0.05 were considered statistically significant.

The data of Test B, for representative compounds of the invention, are shown in Table 2. The data were collected using eight animals in the control studies and four animals in each study of the compound. The values represent the weight of the relative tumor or Wt / Wi (day ten by definition is 1.0). The drug was administered i.p. on days 10, 11, 12, 13, and 14 (QD x 5 days).

Table 2 The data in Tables 1 and 2 show that the representative compounds of the invention are potent cytotoxic and anti tumor agents. The invention will now be illustrated by the following non-limiting Examples, wherein, a unless stated otherwise: the melting points are incorrect; the XH and 13C NMR spectra were measured at 300 and 75 MHz; the high resolution mass spectrum was determined at the University of Minnesota Mass Spectrometry Service Laboratory; chromatography was performed on silica gel (Davisil 230-425 mesh, Fisher Scientific), with ethyl acetate: hexanes as the eluent; the analytical TLC was performed on Whatman 4420 222 silica gel plates; and Reactions were routinely observed by TLC. Synthesis of iludin S, hydr oxime ti 1 aci 1 ful ene (HMAP) and fulvene were prepared as previously described (see, for example, WO 91/04754, WO 94/18151).

E empl os E ppl 1. Compound 1 (formula I wherein Ri is hydrogen, R 2 is hydroxymethyl, R 3 is hydrogen, R is methyl, R 5 is hydroxy, and R 6 is methyl) To a stirred solution of acrilfulvene (6.9 g, 32 mmoles) ) in 7.0 ml of EtOAc, 99% selenium dioxide (1.75 g, 15.8 g. mmoles), and 90% tere-butyl hydroperoxide (6 ml, d 0.901, 60 mmol). The mixture was stirred at room temperature for 24 hours and then partitioned between EtOAc and saturated sodium sulfite (3 x 3 ml), followed by saturated brine. The organic extract was then dried over MgSO .. After concentration, the crude product was subjected to chromatography to give 922.5 mg of the title compound (12%) as a yellow-orange gum, and 5.8 g of Acilfulvene (84%).; lH NMR (CDCl 3) d 0.76 (ddd, 1H), 1.14 (ddd, 1H), 1.27 (ddd, 1H), 1.36 (s, 3H), 1.54 (ddd, 1H), 2.03 (s, 3H), 4.02 ( s, 1H), 4.56 (s, 2H), 6.67 (s, 1H), 7.29 (s, 1 H); 13 C NMR (CDCl 3) d 197.9, 161.5, 146.0, 140.2, 132.9, 127.0, 119.8, 76.6, 59.9, 37.5, 27.7, 17.0, 14.7, 9.9; MS m / e 232 (M +); UV? max (EtOH) 327.2 nm (e-7631). 2. Use 2. Compound 2 (formula I where Ri is hydroxymethyl, R2 is hydroxymethyl, R3 is hydrogen, R A is methyl, R5 is hydroxy, and R is methyl).

^^ ¡- ^. - - Paraformaldehyde (36.3 g) was added to a solution of dilute H2SO4 (1.5 M, 75 ml), and Me? CO (300 ml). The mixture was stirred and heated to dissolve all the solid. Compound 1 was added to the cooled solution (0 ° C) (922.50 mg, 3.98 mmol), the resulting solution was stirred and allowed to warm to room temperature. After 24 hours, the orange-yellow mixture was extracted with EtOAc (2 x 300 ml) and the combined extracts were washed with saturated NaHCO3 (30 ml), followed by saturated brine. The organic extracts were then dried over MgSO .. Removal of the solvent and chromatography of the residue on Si gel with EtOAc-hexanes yielded 357.3 mg (34%) of the title compound as a dark yellow-orange gum; 1 H NMR (CDCl 3) d 0.79 (ddd, 1H), 1.16 (ddd, 1H), 1.26 (ddd, 1H), 1.38 (s, 3H), 1.41 (ddd, 1H), 2.20 (s, 3H), 3.90 ( s, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 7.25 (s, 1H), MS m / e 262 (M +); UV? max (EtOH) 330.0 nm (e 5011).

Compound 3. Compound 3 (formula 1 wherein Ri is hydrogen, R2 is acetoxymethyl, R3 is hydrogen, R is methyl, R5 is hydroxy, and Re is methyl) to a stirred solution of compound 1 (76.0 mg, 0.328 mmoles) in 2 ml of acetic anhydride at room temperature, add anhydrous sodium acetate (126.2 mg, 1.54 mmoles). The mixture was stirred at room temperature for 24 hours, filtered to remove the NaOAc. The solution was placed under reduced pressure for 4 hours. The crude product was then partitioned between EtOAc and saturated NaHCO 3, followed by saturated brine, and dried over MgSO 4. After concentration the residue was chromatographed on Si gel with E tOAc-hexanes to give the title compound (50 mg, 56%) as a yellow gum; 1 H NMR (CDCl 3) d 0.77 (ddd, 1H), 1.16 (ddd, 1H), 1.34 (ddd, 1H), 1.38 (s, 3H), 1.58 (ddd, 1H), 2.06 (s, 3H), 2.11 ( s, 3H), 4.99 (s, 2H), 6.69 (s, 1H), 7.27 (s, 1H); 13C NMR (CDCI3) d 197.9, 170.8, 163.6, 140.5, 140.0, 132.8, 126.7, 121.9, 76.7, 61.3, 37.9, 27.8, 20.9, 17.3, 15.3, 10.3.

E 4. 4. Compound 4 (formula I wherein Ri is acetoxymethyl, R2 is hydroxymethyl, R3 is hydrogen, R4 is methyl, Rs is hydroxy, and Re is methyl) to a stirred solution of compound 10. (430 mg, 1.49 mmol) in 3 mL of EtOAc, 99% selenium dioxide (186 mg, 1.67 mmol) was added, followed by 90% tere-butyl hydroperoxide (0.40 mL, d 0.901, 4.0 mmol). . The mixture is allowed to stir at room temperature for 4 days, and then partitioned between EtOAc and saturated sodium sulfite (3 x 3 ml), followed by saturated brine, and dried over magnesium sulfate. After concentration, the crude product was subjected to chromatography to give the title compound (8.5 mg, 2%) as a yellow gum; 1 H NMR (CDCl 3) d 0.79 (ddd, 1H), 1.17 (ddd, 1H), 1.39 (s, 3H), 1.43 (ddd, 1H), 1.52 (ddd, 1H), 2.09 (s, 3H), 2.14 ( s, 3H), 3.93 (s, 1H), 4.65 (q, 2H), 5.21 (q, 2H), 7.32 (s, 1H); MS m / e (M +); UV? max (EtOH) 330.6 nm (e 5950). The intermediate compound 10 was prepared as follows: a. Compound 10. Anhydrous sodium acetate was added to a stirred solution of HMAF (1.4 g, 5.7 mmoles) in acetic anhydride (6 ml) at room temperature. After 18 hours, the mixture was filtered and the resulting solution was placed under reduced pressure for 4 hours. The resulting material was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, followed by brine, and the resulting ethyl acetate solution was dried over magnesium sulfate. The solution was concentrated and purified by chromatography on silica gel with ethyl acetate: hexanes as the eluent to give compound 10 (1.4 g, 85%) as a yellow-orange gum; H NMR (CDC13) d 0.74 (ddd, 1H), 1.11 (ddd, 1H), 1.36 (s, 3H), 1.51 (ddd, 1H), 2.04 (s, 3H), 2.09 (s, 3H), 2.17 ( s, 3H), 3.90 (s, 1H), 5.10 (s, 2h), 7.11 (s, 1H).

Example 5. Compound 5 (formula I wherein Ri is acetoxymethyl, R2 is acetoxymethyl, R3 is hydrogen, R4 is methyl, R5 is hydroxy, and R is methyl) to a stirred solution of compound 4 (2 mg, 0.0066). mmoles) in 15 μl of CH 2 Cl 2 and 135 μl of acetic anhydride, anhydrous NaOAc was added (3.1 mg, 0.038 mmol). The reaction was allowed to stir at room temperature for 4 hours, filtered to remove the NaOAc. The mixture was placed under reduced pressure to remove the acetic anhydride. The crude product was then partitioned between EtOAc and NaHC 3, followed by saturated brine, and dried over MgSO 4. After concentration the residue was chromatographed on Si gel with EtOAc-hexane to give the title compound (0.9 mg, 40%) as a yellow gum. 1 H NMR (CDCl 3) d 0.79 (ddd, 1H), 1.15 (ddd, 1H), 1.39 (s, 3H), 1.40 (ddd, 1H), 1.58 (ddd, 1H), 2.09 (s, 3H), 2.093 ( s, 3H), 2.10 (s, 3H), 3.89 (s, 1H), 5.08 (s, 2H), 5.17 (s, 2H), 7.25 (s, 1H); MS m / e 346 (M +); UV? max (EtOH) 332.1 nm (e 8378).

Example 6. Compound 6 (formula I wherein Ri is hydroxymethyl, R2 is acetoxymethyl, R3 is hydrogen, R4 is methyl, R5 is hydroxy, and Re is methyl) to a stirred solution of compound 2 (76.0 mg, 0.290 mmol) in 1.5 ml of acetic anhydride, anhydrous NaOAc (45.3 mg, 0. 552 mmol). The reaction mixture was stirred at room temperature for 75 min, then filtered to remove the NaOAc. The mixture was partitioned between EtOAc and NaHCO 3, followed by saturated brine, and dried over MgSO .. The extracts were concentrated under reduced pressure and the residue was chromatographed on Si gel with EtOAc-hexane to give compound 4 (6.9 mg, 40%) as a yellow gum, compound 2 (10.0 mg) as an orange yellow gum, 3 minor products including compound 5, and the title compound (10.0 mg, 11.3%) as a yellow gum; 1R NMR (CDCI3) d 0.81 (ddd, 1H), 1.17 (ddd, 1H), 1.38 (s, 3H), 1.60 (ddd, 1H), 2.06 (s, 3H), 2.24 (s, 3H), 3.89 ( s, 1H), 4.47 (m, 2H), 5.03 (m, 2H), 7.23 (1H); MS m / e 304 (M +); UV? max (EtOH) 331.3 nm (e 5921).

E 7. Compound 7 (formula I wherein Ri is hydrogen, R 2 is methoxymethyl, R 3 is hydrogen, R 4 is methyl, Rs is hydroxy, and R e is methyl) To a stirred solution of compound 1 (300 mg, 1.29 mmoles) in 10 ml of CH3CN, added 1 ml of CH3I, and Ag20 (110 mg, 0.475 mmoles). The mixture was stirred at room temperature for 3 days, then filtered and concentrated. The residue was chromatographed on Si gel with EtOAc-hexanes to give compound 1 (133 mg) and the title compound (53 mg, 17%) as a dark orange gum. ! NMR (CDCls) d 0.76 (ddd, 1H), 1.13 (ddd, 1H), 1.34 (ddd, 1H), 1.38 (s, 3H), 2.05 (s, 3H), 3.41 (s, 3H), 3.96 ( s, 1H), 4.35 (s, 2H), 6.66 (s, 1H), 7.28 (s, 1H), 13C NMR (CDCI3) d 197.8, 161.8, 143.3, 140.2, 133.1, 126.7, 120.9, 76.6, 69.6, 58.3, 37.6, 27.8, 17.1, 14.9, 10.0.

Example 8. Compound 8 (formula I wherein Ri is methoxymethyl, R 2 is hydroxymethyl, R 3 is hydrogen, R is methyl, R 5 is hydroxy, and R e is methyl) to a stirred solution of compound 11 (830 mg, 3.19 mmoles) in 10 mL of EtOAc, 99% selenium dioxide (150 mg, 1.35 mmol) was added, followed by 90% of tert-butyl hydroperoxide (1 mL, d 0.901, 10.0 mmol). The reaction mixture was stirred at room temperature for 5 days, divided between diethyl ether and sulfite of saturated sodium, followed by saturated brine, and dried over MgSO4. After concentration the crude material was subjected to chromatography to give the title compound (47.2 mg, 5%) as a dark gum. 1H NMR (CDC13) d 0.74 (ddd, 1H), 1.08 (ddd, 1H), 1.32 (s, 3H), 1.33 (ddd, 1H), 1.47 (ddd, 1H), 2.08 (s, 3H), 3.14 ( br s, 1H), 3.35 (s, 3H), 4.41 (q, 2H), 4.51 (br s, 2H), 7.28 (s, 1H). to. Compound 11. Intermediate compound 11 (formula I wherein Ri is methoxymethyl, R 2 is methyl, R 3 is hydrogen, R 4 is methyl, Rs is hydroxy, and Re is methyl) is prepared as follows. To a stirred solution of HMAF (320 mg, 1. 3 mmoles) in 3 ml of Me2CO, MeOH (3 ml), and dilute H2O4 (1M, 3 ml) were added. The reaction mixture was stirred at room temperature for 24 hours and extracted with diethyl ether. The combined extracts were washed (saturated NaHCO3, followed by brine), and dried over MgSO4. After concentration, the residue was chromatographed on Si gel with EtOAc-hexane to give compound 50 (290 mg, 86%) as a dark orange gum; 1 HOUR NMR (CDCI3) d 0.62 (ddd, 1H), 0.98 (ddd, 1H), 1.24 (ddd, 1H), 1.27 (s 3H), 1.37 (ddd, 1H), 2.00 (s, 3H), 2.04 (s, 3H), 3.26 (s, 3H), 3.91 (br s, 1H), 4.29 (q, 2H), 7.0 (s, 1H); 13C NMR (CDCI3) d 197.6, 159.7, 142.6, 138.8, 134.3, 129.7, 126.6, 75.9, 65.3, 57.3, 37.3, 27.3, 15.7, 13.9, 12.9, 9.1.

E pple 9. Compound 9 (formula I wherein Ri is methoxymethyl, R 2 is methoxymethyl, R 3 is hydrogen, R 4 is methyl, Rs is hydroxy, and Re is methyl o) to a stirred solution of compound 8 (240 mg, 0.87. mmoles) in 15 ml of CH3CN, 1.5 ml of CH3I, and Ag20 (150 mg, 0.647 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours, a concentrate was filtered. The residue was subjected to chromatography on Si gel with EtOAc-hexane to give the title compound (25 mg, 10%) as a yellow gum la -ana ran j ada. 1H NMR (CDCl 3) d 0.76 (ddd, 1H), 1.11 (ddd, 1H), 1.37 (s, 3H), 1.40 (ddd, 1H), 1.53 (ddd, 1H), 2.13 (s, 3H), 3.36 ( s, 3H), 3.38 (s, 3H), 3.91 (s, 1H), 4.37 (q, 2H), 4.43 (q, 2H), 7.27 (s, 1H); C NMR (CDC13) d 198.0, 163.4, 142.8, 139.1, 132.6, 132.0, 127.2, 76.6, 67.2, 67.2, 65.5, 58.3, 57.8, 38.1, 27.5, 16.3, 14.8, 9.8.

Example 10. Compound 12 (formula I wherein Ri is -CH2-, cysteine bonded to sulfur), R2 is methyl, R3 is hydrogen, R4 is methyl, Rs is hydroxy, and Re is methyl). To a solution of HMAF in acetone and 1M H2SO4 (1: 1) was added one equivalent of cysteine. Mix. The mixture was stirred at room temperature overnight. A large amount of EtOAc was added and the water was removed by adding MgSO4. The solid NaHC03 was also added to neutralize the sulfuric acid. The solution was filtered, concentrated, and subjected to chromatography, to give compound 102 as a yellow gum: 1 H NMR (CDCl 3) d 0.78 (m, 1 H), 0.89 (m, 1 H), 1.06 (m, 1 H) , 1.31 (s, 3H), 1.43 (m, 1H), 2.15 (s, 3H), 2.21 (s, 3H), 2.91-4.02 (m, 8H), 7.04 (s, 1H).Example 11. Compound 13 (formula I wherein Ri is -CH2- [N-acylcysteine bonded to sulfur], R2 is methyl, R3 is hydrogen, R4 is methyl, Rs is hydroxy, and R is methyl). HMAF solution (36 mg, 0.146 mmol) in 1: 1 1M H2SO4 / acetone (3 ml) was added N-acetyl cysteine (22.4 mg, 0.137 mmol) at room temperature, the mixture was stirred for 22 hours and the mixture was stirred for 22 hours. The organic extracts were washed with saturated NaHC03 and saline respectively The solution was dried over MgSO4 After concentration, the crude product was subjected to chromatography (addition of 2-5% acetic acid to the mixture of the normal solvent, ethyl acetate and hexanes) to give 45.5 mg of compound 103 (85% yield) as a yellow gum; XH NMR (CDCl 3) d 0.72 (m, 1H), 1.09 (m, 1H), 1.23 (m, 1H), 1.36 (s, 3H), 1.47 (m, 1H), 2.07 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 2.97 (m, 1H), 3.14 ( m, 1H), 3.82 (dd, 3.82), 4.80 (m, 2H), 6.56 (d, J = 7.2 Hz) 7.10 (s, 1 H); MS m / e 391 (M +), 373, 229, 185; HRMS for C20H25NO3S calculated 391.1455, found 391.1452.

Example 12. Compound 14 (formula I wherein Ri is (S) -2- [(R) -a-methylbenzyl-a-inocarbonyl] -2- (acylamino) eti 11 iometri, R2 is methyl, R3 is hydrogen R4 is methyl, R5 is hydroxy, and Re is 5methyl) To a solution of compound 13 (40 mg, 0.102 mmol) in methylene chloride (1 ml) was added N-hydroxybenzot riazol (20 mg, 0.132 mmoles), N, N-di i sopropi 1 carbodi imi da (20 μL, 0.12 mmol) and (d) - (+) -a -methyl benzylamine (12 μl, 0.093 mmol). The mixture was stirred for 1.5 hours at room temperature. The mixture was partitioned between EtOAc and water, The organic extract was dried over MgSO4. After the concentration the product Crude was subjected to chromatography to give 33.6 mg of compound 14 (73%) as a yellow gum; and NMR (CDCl 3) d 0.70 (m, 1H), 1.07 (m, 1H), 1.29 (m, 1H), 1.35 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H), 1.51 (m, 1H), 1.93 (s, 3H), 2.09 (s, 3H), 2.10 (s, 3H), 2.91 (m, 2H), 3.84 (dd, 2H), 4.61 (m, 1H), 5.03 (m, 1H), 6.64 (d, J = 7.8 Hz, 1H), 7.07 (s) , 1H), 7.26 (m, 5H); 13C NMR (CDCI3) d 197.5, 170.4, 169.2, 159.7, 142.6, 142.0, 138.3, 134.9, 129.8, 128.7, 127.4, 126.4, 125.9, 77.4, 52.5, 49.3, 37.7, 34.4, 29.8, 27.6, 23.1, 22.1, 16.3, 14. 3, 13.1, 9.5; HRMS for C28H34N2O4? calculated 494.2241, found 494.2225.

Use 13. Compound 15 (formula I wherein Ri is (R) -2- [(R) -a-methylbenzyl-aminocarbonyl] -2- (acylamino) eti 111 omethi, R2 is methyl, R3 is hydrogen; R4 is methyl, Rs is hydroxy, and R is methyl). Chromatography of Example 12 also provides 5.3 mg of compound 15 (13%) as a yellow gum; 1 H NMR (CDCl 3) d 0.70 (m, 1 H), 1.07 (m, 1 H), 1.32 (m, 1 H), 1.34 (s, 3 H), 1.45 (, 1 H), 1.48 (d, J = 6.9 Hz, 3 H ), 2.03 (s, 3H), 2.05 (s, 6H), 2.76 (m, 1H), 2.87 (m, 1H), 3.73 (dd, 2H), 4.50 (m, 1H), 5.03 (m, 1H) , 6.46 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 7.31 (m, 5H); HRMS for C28H34N2O4S calculated 494.2241, found 494.2238.

Example 14. Compound 16 (formula I wherein Ri is - (CH2) - [glutathione linked to sulfur], R2 is methyl, R3 is hydrogen, R4 is methyl, Rs is hydroxy, and Re is methyl).

Using a procedure similar to that described in Example 10 except that the cysteine used here with glutathione is replaced, compound 16 was prepared.

E emp l o 15. General procedure for the synthesis of the compounds wherein R is -CH2- [cysteine linked to a zuf re] -peptide, -CH2- [cysteine linked to a zufr e] - (amino acid), -CH2 - [N-aci Ici s tein linked to the sulfur] -peptide gone, or -CH2- [N-aci Ici s tein bonded to sulfur] - (amino acid). Using the solid phase peptide synthesis techniques, which are well known in the art, the amino acids Leu, Phe and Gly combine to give the following resin bound to tripeptides and dipeptides. -Leu-Leu-Leu -Leu-Leu-Phe -Leu-Leu-Gly -LLeeuu-PPhhee -Leeuu -Leu-Phe-Phe -Leu-Phe-Gly -Leu-Gly-Leu -Leu-Gly- Phe-Leu-Gly-Gly - Phe-Leu-Leu-Leu-Leu- Phe -Phe-Leu-Gly -Phe-Phe-Leu -Phe-Phe-Phe -Phe-Phe-Gly -Phe-Gly-Leu - Phe-Gly-Phe -Phe-Gly-Gly --GGllyy - LLeeuu - LLeeuu -Gly-Leu-Phe -Gly-Leu-Gly -Gly-Phe-Leu -Gly-Phe-Phe -Gly-Phe-Gly -Gly-Gly-Leu -Gly-Gly-Phe -Gly-Gly-Gly -Leu-Leu -Leu-Phe -Leu-Gly -Phe-Leu -Phe-Phe -Phe-Gly -Gly-Leu -Gly-Phe -Gly-Gly A rink acid resin having the following structure, wherein "P" represents a polystyrene di-inylbenzene resin, was used in the solid phase reactions.

The first amino acid protected with N- (9-f luor enylme toxicar boni lo) was coupled to the resin via a bond formation or union between its C-terminal and the hydroxyl group of the resin using DIPC (Dii s opropylcarbodiimide) / DMAP ( 4-Dimethylaminopyridine). The percent yield was calculated after the coupling, and if it was below 90% itself, the coupling was repeated until the yield percent exceeded 90%. The group N- (9- f luorenylmethoxycarbonyl) (Fmoc group) of the first amino acid was removed by treatment with 20% piperidine in 1-Me t i 1 -2-Pir r ol idinone (NMP). A Kaiser Test was performed to verify the result of the deprotection. The three Kaiser reagents (Ninhydrin, Phenol and Potassium Cyanide) were added to an aliquot of the resin sample to give a light yellowish solution. The mixture was heated to 100 ° C for 3 minutes, and if the solution became dark purple (positive), the Fmoc group was considered to have been removed. The following amino acid was coupled by the formation of the peptide bond using DIP / HOBT (1-Hydroxy-Benzotriazole). NMP was used as the solvent for deprotection, coupling, and washing and, dichloromethane was used as the drying reagent. Another Kaiser test was performed, without color change (negative result) indicating that the coupling was successful. The coupling reaction was repeated to add additional amino acids. Compound 13 was bound or bound to the final resin attached to the amino acid or peptide using dichloromethane as the solvent. NMP was not used as the solvent for the reaction of coupling or binding to compound 13, because NMP has been shown to cause the inversion of the chiral center into cysteine, producing a racemic mixture. Additionally, HOBT was not used in the coupling reaction with compound 13, because it can also contribute to the formation of a product mixture. Cleavage of the resin from the peptide was achieved by treatment with 10% of etidic acid in dichloromethane. The products were tested by UV and Mass Spectroscopy. HMAF produced two maximum UV absorbances at approximately 210 nm and 330 nm, thus the presence of products was confirmed by the presence of these two absorbencies. Mass Spectroscopy was also used to confirm the presence of the desired products. Using this general procedure, compound 13 was coupled with the 36 tri- and dipeptides shown above, and with the individual amino acids Leu, Phe and Gly, to give a total of 39 compounds of the invention. The N-acetyl group of these 39 compounds can also be removed using conditions similar to those described in Example 11 to give 39 additional compounds of the invention. Accordingly, in a compound of formula I Rx may preferably represent Leu, Phe, Gly, or any of the 36 tri- and dipeptides shown above.

E pple 16. Compound 17 (formula I wherein Ri is (S) -2- (2-carboxymethyl) i-1 -carbonyl 1) pr opyl ether, R 2 is methyl, R 3 is hydrogen; R4 is methyl, R5 is hydroxy, and Re is me tyl). Using a procedure similar to that described in Example 10 except replacing the cysteine used therein with 1 - (3-mer cap to-2 -me ti 1-1 -oxopr opi 1) -L-pr olin (captopril), he prepared the compuete 17.

Use 17. Compound 18 (formula II wherein R 2 is methyl, R 3 is hydrogen, R 4 is methyl, R 5 is hydroxy, R 4 is methyl, and R is hydroxymethyl). Illudin S (178.5 mg) was dissolved in acetic anhydride (2.0 ml) and sodium acetate (96 mg) was added. After 24 hours a mixture of mono and diacetate. The monoacetate (171 mg) was dissolved in dichloromethane and pyridinium dichromate (695 mg) was added. The mixture was stirred at room temperature for 21 hours. Work-up produced dehydroyludine monoacetate S (118 mg), which was dissolved in acetone (5 ml) and 1M sulfuric acid (3 ml) for 12 hours to give compound 18 (66 mg); 1 tt NMR (CDCl 3) d 0.63 (1H), 1.13 (1H), 1.23 (4H), 1.38 (4H), 2.05 (3H), 3.62 (1H), 3.76 (1H), 6.82 (1H).

E empl o 18. The following illustrates the representative pharmaceutical dosage forms, which contains a compound of the formula I or II ("Compound X"), for therapeutic or prophylactic use in humans.

(I) Table 1 mq / tablet 'Compound X' 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet 2 mq / table ta 'Compues t o X' 20.0 Cellulose micr ocr is taima 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg / capsule 'Compound X' 10.0 Colloidal silica dioxide 1.5 Lac cough at 465.5 Proprietary starch t ini z ada 120.0 Magnesium stearate 3.0 600.0 (x) Injection 1 (1 mq / ml) mq / ml 'Compound X' (acid form 1 Ibr e 1.0 Dibasic sodium phosphate 12.0 Sodium phosphate monobasic 0.7 Sodium chloride 4.5 Sodium hydroxide solution 1.0 N (pH adjusted a 7.0-7.5) cs Water for injection cs ad 1 ml (v) Injection 2 (10 mq / ml) mg / ml 'Compound X' (free acid form) 10.0 Sodium phosphate monobasic 0.3 Sodium phosphate dibasic 1.1 Polyethylene glycol 400 200.0 Sodium hydroxide solution 01 N (pH adjusted to 7.0 -7.5) cs Water for injection c.s. ad 1 ml (vi) Aerosol mq / t a 'Compound X' 20.0 Oleic acid 10.0 Trichlor omonof luoromet ano 5,000.0 Dichlorodi fl uor omene 10,000.0 Diclorotetraf luoroethane 5,000.0 The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. All publications, patents, and patent documents are incorporated herein by reference, however they are incorporated individually as a reference. The invention has been described with reference to several specific and preferred techniques and modalities. Without However, it should be understood that many variations and modifications can be made as long as they remain within the scope of the invention.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (51)

1. A compound of formula I (D characterized in that Ri is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or - (CHzln- (X) - (?); n is 0 to 4; X is oxy, uncle, -N (Ra) -, or absent; Y is (C3-C6) cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a branched or unbranched carbon chain of 1 to 15 elements optionally comprising 1.2 or 3 oxy without peroxide, uncle, or N (R ») -; wherein said chain may be optionally substituted on the carbon with 1, 2, or 3, oxo, hydroxy, carboxy, halo, mercapto, ^ ¡^^^ s ^^ nitro, -N (Rb) (Rc), (C.-Cβ) cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may be optionally saturated or unsaturated; R2 is carboxy, (Ci-Cd) alkanoyl, (Cid) alkoxycarbonyl, halo (Ci-Cd) alkyl, C (= 0) NRdRe, a saccharide, an amino acid, a peptide, or (Ci-Cβ) substituted alkyl by 1 or 2 hydroxy, (Ci-Cd) alkoxy, (Ci-Cd) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or C (= 0) NRdRe; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) alkoxy, (Ci-Cβ) alkyl thio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or (Ci-Ce) alkyl; and Rs is hydroxy, (Ci-Cβ) lkoxy, or (Ci-Cβ) alkanoyloxy; or R4 and Rs taken together are ethylenedioxy; Re is hydrogen, carboxy, (Ci-C6) alkanoyl, (Ci-Cß) to lcoxycar bonyl, halo (C? -C-dlalkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci) -Cβ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cdlalkoxy, (Ci-Cd) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; f ^ í ........ A, ... Ra is hydrogen, (Ci-Cβ) alkyl, (Ci-Cdlalcanoyl, phenyl or benzyl, and Rb, Rc, Rd, Re, Rf and Rg are each independently hydrogen, (Ci-Cdi alkyl, (Ci-Cβ ) alkanoyl, phenyl or benzyl, or R and Rc, Rd, and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino, wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1, 2 or 3 (Ci-Cβ) alkyl, (Ci-Cß) alkoxy, (Ci-Ce) alkanoyl, (Ci-Cß) alkanoyloxy, (C? -Cd) alkoxycarbonyl , hydroxy (Ci -Ce) alkyl, halo (Ci-Cß) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (R.), wherein each Rh and R] is independently hydrogen, (Ci-Ce) alkyl, (Ci-Cβ) alkanoyl, phenyl or benzyl; or Rh and R3 together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same.
2. A compound of formula I JU ^^ tiÉ ^ characterized in that Ri is - (CH2) n- (X) - (Y); n is 0 to 4; X is oxy, thio, -N (Ra) -, or absent; Y is a monopronected amino acid, a diprotected amino acid, a peptide, or a branched or unbranched carbon chain of 1 to 15 elements optionally comprising 1,2, or 3 oxy without peroxide, thio, or -N (Ra) -; wherein said chain is substituted with 1,2, or 3 peptides; and wherein said chain may be optionally saturated or unsaturated; R 2 is hydrogen or (C 1 -C 5 alkyl, R 3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Ce) alkoxy, (Ci-Cβ) alkyl thio, aplo, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or ( Ci-Cd) alkyl, and Rs is hydroxy, (Ci-Ce) coxy, or (Ci-Cß) to lcanoi loxi; or R4 and Rs taken together are ethylenedioxy; Rd is hydrogen, carboxy, (Ci-C e) alkanoyl, (Ci-Ce) alkoxycarbonyl, halo (C? -Cislalkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or Ce) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cdlalkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Ra is hydrogen, (Ci-Cd) alkyl, (Ci-Cd) alkanoyl, phenyl or benzyl; and Rb, Rc, Rd, Re, Rf and Rg are each independently hydrogen, (Ci-Cβ) alkyl, (Ci-Cß) to the canoe, phenyl or benzyl; or Rb and Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1,2 or 3 (Ci-Celalkyl, (Ci-Cβ) alkoxy, (Ci-Cβ) alkanoyl, (Ci-Ce) alkanoyloxy, (Ci-Cß) to lcoxycarbonyl, hydroxy (C? -Cd) alkyl, halo (C? -Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (Rj), wherein each Rh and R] is independently hydrogen, (Ci-Cβ) alkyl, (Ci-Ce) alkanoyl, phenyl or benzyl; or Rh and R: together with the nitrogen to which they are attached are pyrrolidino, piper i alno, or morpholino; or a pharmaceutically acceptable salt of the same.
3. 3. A compound of formula I: (D characterized in that Ri is hydrogen, hydroxy, mercapto, ammo, halo, carboxy, nitro, or - (CH2) n- (X) - (Y); n e s 0 to 4; X is oxy, thio, -N (Ra) -, or absent; Y is (C3-C6) cycloalkyl, aplo, heteroaryl, a saccharide, an amino acid, a peptide, or a branched or unbranched carbon chain of 1 to 15 elements optionally comprising 1,2 or 3 oxy without peroxide, uncle, or N (Ra) -; wherein said chain may be optionally substituted at the carbon with 1, 2, or 3, oxo, hydroxy, carboxy, halo, mercapto, nitro, -N (Rb) (Rc), (C3-C6) cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may be optionally saturated or saturated; R2 is hydrogen or (Ci-Cd) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cd] alkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R 4 is hydrogen or (Ci-Cβ) alkyl, and R 5 is hydroxy, (Ci-Cß) alkoxy, or (Ci-Cβ) alkanoyloxy, or R and R 5 taken together are ethylenedioxy, R 6 is carboxy, (Ci-Cβ) alkanoyl, (C 1 -C 15 alkoxycarbonyl, -C (= 0) NR.Rg , a saccharide, an amino acid, a peptide, or (Ci-Cβ) alkyl substituted by 1 or 2 (Ci-Cß) to lcoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Ra is hydrogen, (Ci-Cß) alkyl, (Ci-Ce) alkanoyl, phenyl or benzyl, and Rb, Rc, Rd, Re, Rf and Rg are each independently hydrogen, (Ci-Cs ) alkyl, (C1-C6) alkanoyl, phenyl or benzyl, or Rb and Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aploxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1, 2 or 3 (Ci-Cdl alkyl, (Ci-Cβ) alkoxy, (Ci-Cd) alkanoyl, (Ci-Cβ) ) alkanoyloxy, (C? -Cd) alkoxcarbonyl, hydroxy (Ci-Cß) alkyl, halo (C? -Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (R)), wherein each Rh and R3 is independently hydrogen, (Ci-Cd) alkyl, (Ci-Cdlalcanoyl, phenyl or benzyl; or Rh and R3 together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof.
4. 4. The compound according to claim 1, 2, or 3 characterized in that Ri is - (CH2) n- (X) - (Y); n is 0 to 4; X is oxy, thio, -N (Ra) ~, or absent; and Y is a peptide, or (Ci-Cd) alkyl substituted with a peptide.
5. # 5. The compound according to claim 1 or 3 characterized in that Ri is hydroxy, halo, carboxy, aryl, heteroaryl, a saccharide, an amino acid, or a peptide.
6. 6. The compound according to claim 1 or 3 characterized in that Ri is hydrogen or (Ci-Cß) alkyl, optionally substituted with 1 or 2 hydroxy, halo, methoxy or ethoxy.
7. 7. The compound according to claim 1 or 3 characterized in that Ri is - (CH2) n- (X) - (Y); n is 1 or 2; X is oxy, thio, or - N (Ra) -; and Y is (Ci-Cβ) alkyl or (C? -Cd) alkenyl, optionally substituted with 1 or 2, oxo, hydroxy, carboxy, halo, mercapto, nitro, N (Rb) (Rc), (C3-C6) cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein any aryl or heteroaryl of Y may be optionally substituted by 1, 2, or 3 (Ci-Cß) alkyl, (Ci-Cß) alkoxy, (Ci-Cβ) alkanoyl, (Ci-Cdl alkanoyloxy, (C? -Cd) alkoxy carboni lo, hydroxy (Ci-Cβ) alkyl, • halo (C? -Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, and N (Rh) (R)); wherein each Rh and j is independently hydrogen, (Ci-Cβ) alkyl, (Ci-C-alkanoyl, phenyl and benzyl; or Rh and R: together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morphol radical or .
8. 8. The compound according to claim 1, 2, or 3, characterized in that Ri is -CH2- [t-linked to-sulfur] -Rx or -CH2- [N-acyl-the-t-na) α-sulfur] -R x wherein R x is an amino acid or a peptide comprising 2 to 24 amino acids.
9. 9. The compound according to claim 8, characterized in that Rx is Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (SEQ ID NO: 4), -Asp-Gly-Arg-Cys (SEQ ID NO: 5) ), or -Asp-Gl y-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys (SEQ ID NO: 6).
10. 10. The compound according to claim 8, characterized in that Rx is a peptide consisting of 4 to 20 amino acids.
11. 11. The compound according to claim 1, or 3, characterized in that Ri is -CH2- [tis-n-linked to -sulfur] or -CH2-N-acylcyl-nale-to-sulfur ]
12. 12. The compound according to claim 1, 2 or 3, characterized in that Ri is 2- [(R) -a-methylbenzylaminocarbonyl] -2- (acylamino) eti lt iomet i lo.
13. 13. The compound according to claim 1, 2, or 3, characterized in that Ri is -CH 2 - [glutathione-bonded a-sulfur].
14. 14. The compound according to claim 1 or 3, characterized in that Ri is hydrogen, methyl, hydroxymethyl, methoxymethyl, or acetoxymethyl.
15. 15. The compound according to claim 1, characterized in that R 2 is hydroxymethyl, methoxymethyl, or acetoxymethyl.
16. 16. The compound according to claim 1, characterized in that R2 is carboxy, (Ci-Cß) to the canoyl, (Ci-Cd) alkoxycarbonyl, or -C (= 0) NRdRe.
17. 17. The compound according to claim 1, characterized in that R2 is (Ci-Cβ) alkyl substituted by 1 or 2 hydroxy, (Ci-C-alkoxy, (Ci-Cβ) to the canoil oxy, carboxy, amino acids, peptides, saccharides, or - C (= 0) NRdRe.
18. 18. The compound according to claim 1, 2, or 3, characterized in that R 4 is methyl.
19. 19. The compound according to claim 1, 2, or * 3, characterized in that Rs is hydroxyl.
20. 20. The compound according to claim 1 or 2, characterized in that Re is hydrogen.
21. 21. The compound according to claim 1, 2, or 3, characterized in that Re is carboxy, (Ci-Cβ) alkanoyl, (Ci-Cd) alkoxycarbonyl, or -C (= 0) NRfRg.
22. 22. The compound according to claim 1 6 2, characterized in that Rd is (Ci-Cd) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cβ) alkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides , or C (= 0) NRfRg.
23. 23. The compound according to claim 1 or 2, characterized in that R e is methyl or hydroxymethyl.
24. 24. The compound according to claim 1, characterized in that R2 is (Ci-Cd) alkyl, substituted with hydroxy, (Ci-Cd) alkoxy, (C? -Cd) alkanoyloxy, or carboxy; R3 is H, (Ci-Ce) alkyl, (Ci-Ce) alkoxy, (Ci-Ce) alkyl t i or, aryl, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or (Ci-Cβ) alkyl; R5 is hydroxy; R6 is (Ci-Cβ) alkyl, optionally substituted with hydroxy, (Ci-C 6) coxy, (Ci-Cd) alkanoyloxy, or carboxy; or a pharmaceutically salt thereof.
25. 25. The compound according to claim 1, characterized in that Ri is hydrogen or (Ci-Cβ) alkyl, optionally substituted with hydroxy, halo, methoxy, ethoxy, or acetoxy; R2 is hydroxymethyl, methoxymethyl, or acetoxymethyl; R3 is hydrogen; R is methyl; Rs is hydroxy; and Re is methyl or hydroxymethyl, or a pharmaceutically acceptable salt thereof.
26. 26. The compound according to claim 2, characterized in that Ri is (CH2) n- (X) - (Y), n is 0 to 4; X is oxy, thio, N (Ra) -, or absent; and Y is a monoprone amino acid or a diprotected amino acid.
27. 27. The compound according to claim 2, characterized in that Ri is CH2-. N-aci 1 ci s teí na-enla zada a-sulfur], (S) -2- [(R) -a-methylbenzylaminocarbonyl] -2 - (acylamino) ethyl thiomethyl, or (R) -2 - [(R ) -a-methylbenzylaminocarbonyl] -2- (acylamino) ethylthiomethyl.
28. 28. A dimeric compound characterized in that it comprises two compounds in accordance with the rei indication 1 linked by a linker.
29. 29. A compound of formula I: (D characterized in that Ri is- (CH2) n- (X) - (Y); n is 1; X is a thio, • - Y is a branched or unbranched carbon chain of 2 to 6 elements that is substituted on carbon with 1, 2 or 3 oxo, heteroaryl, amino acids, or peptides; R2 is hydrogen or (C? -Cd) alkyl; R 3 is hydrogen, (Ci-Cs) alkyl, (Ci-Cdl alkoxy, (Ci-Ce) alkyl thio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R 4 is hydrogen or (Ci-Cβ) alkyl, and Rs is hydroxy, (Ci-Cdl alkoxy, or (Ci-Cβ) alkanoyloxy, or R4 and Rs taken together are ethylenedioxy, Re is hydrogen, carboxy, (Ci- C) to lcanoi lo, (Ci-Ce) to 1 coxycar bonyl, halo (Ci- Cd) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cß) alkyl optionally substituted by 1 6 2 hydroxy, (Ci-Cdlalkoxy, (Ci-Ce) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) RfRg; Ra is hydrogen, (Ci-Cβ) alkyl, (Ci-Cdlalcanoyl, phenyl or benzyl, and Rb, Rc, Rf and Rg are each independently hydrogen, (Ci-Cß) alkyl, (Ci-Cdl alkanoyl, phenyl or benzyl; or Rb and Rc, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino, wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may optionally be substituted by 1, 2 or 3 (Ci-Cß) alkyl, (Ci-Cß) alkoxy, (Ci-Ce) to lcanoi lo, (Ci-C) alkanoi loxi, (Ci-Cß) alkoxycarbonyl, hydroxy (Ci-Cd) alkyl, halo (Ci-Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (Rj), wherein each Rh and Rj is independently hydrogen, (Ci-Cs) alkyl, ( Ci-Ce) alkanoyl, phenyl or benzyl, or Rh and Ri together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino, or a pharmaceutically acceptable salt thereof.
30. 30. A compound characterized because it is a pharmaceutically acceptable salt thereof.
31. 31. A compound of formula II characterized in that R2 is (Ci-Cβ) alkyl; R 3 is hydrogen, (Ci-Ce) alkyl, (Ci-Cβ] alkoxy, (Ci-Cs) alkylthio, aryl, heteroaryl, aryloxy, or heteroactoxy; R 4 is hydrogen or (Ci-Cd) alkyl; and Rs is hydroxy, (Ci-Cβ) alkoxy? ,. or (Ci-Cβ) alkanoyloxy; or R4 and Rs taken together are ethylenedioxy; Re is hydrogen, carboxy, (Ci-C e) to the canoi lo, (Ci-Ce) alkoxycarboni lo, halo (Ci-Cd) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Ce) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cßalkoxy, (Ci-Cd) alkanoi 1 oxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; R7 is carboxy, (Ci-Cd) alkanoyl, (Ci-Cβ alkoxycarbonyl, halo (Ci-Cd) alkyl, C (= 0) NRdRe, a saccharide, an amino acid, a peptide, or (Ci-Cd) alkyl substituted by 1 or 2 hydroxy, (Ci-C.) Coxy, (Ci-Cd) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or C (= 0) NRdRe; Rd, Re, Rf and Rg are each independently hydrogen, (Ci-Cß) alkyl, (Ci-Cd) alkanoyl, phenyl or benzyl; or Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be optionally substituted by 1, 2 or 3 (Ci- # Celalkyl, (Ci-Cβ) alkoxy, (Ci-Cd) alkanoyl, (Ci-C-alkanoyloxy, "^ (Ci-Cβ) alkoxycarbonyl, hydroxy (Ci-Cβ) alkyl, halo (C? -Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (R :), wherein each, Rh and Rj is independently hydrogen, (Ci-Cβ) alkyl, (Ci-C e) alkanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidmo, or morpholino, or a pharmaceutically acceptable salt thereof.
32. 32. The compound according to claim 31, characterized in that R7 is (Ci-Cßl alkyl substituted by 1 or 2 hydroxy, (Ci-Cd) alkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRdRe.
33. 33. The compound according to claim 32, characterized in that R7 is hydroimethylene.
34. 34. The compound according to claim 32, characterized in that it is a pharmaceutically acceptable salt thereof.
35. 35. A compound characterized in that it comprises a compound of claim 1, 2, 3, 29, or 32 and a reagent that is capable of binding to an antigen associated with the tumor.
36. 36. A compound of formula I CD characterized in that A: Ri is - (CH2) n- (X) - (Y); n is 0 to 4; X is oxy, thio, or -N (Ra) -; And it is a peptide, or (Ci-Ce) alkyl substituted with a peptide; R2 is hydrogen or (Ci-Cβ) alkyl; R 3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) alkoxy, (Ci-Cβ) alkylthio, aplo, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or (Ci-Cβ) alkyl; and Rs is hydroxy, (C? -Cd) alkoxy, or (Ci-C?) alkanoyloxy; or R4 and Rs taken together are ethylenedioxy; Re is hydrogen, carboxy, (Ci-C e) alkanoyl, (Ci-Cd) alkoxycarbonyl, halo Ci-Cdlalkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cβ) ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cdlalkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Cs) alkyl, (Ci-Cd) alkanoyl, phenyl or benzyl; or Rf and Rg together with the nitrogen to which they are they are united, they are pi r r il, piperidino, or morph ol; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1, 2 or 3 (Ci-Cd-alkyl, (Ci-Ce) alkoxy, (Ci-C) alkanoyl, (Ci-C)) alkanoyloxy, (C? -Cd) alkoxycarbonyl, hydroxy (Ci-Cß) alkyl, halo (Ci-Cß) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (Rj), wherein each Rh and 3 is independently hydrogen, (Ci-Cß) alkyl, (Ci-Cß) to the canoe, phenyl or benzyl, or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; pharmaceutically acceptable salt of the same.
37. 37. A compound of formula I: (D characterized in that - 'Ri is - (CH2) n- (X) - (Y); n e s 1 to 4; X is oxy, thio, or -N (Ra) -; Y is (C2-C6) alkyl, optionally substituted with 1 or 2 oxo, hydroxy, carboxy, halo, mercapto, nitro, -N (Rb) (Rc), (Ci-Cβ) cycloalkyl, aryl, heteroaryl, saccharides , amino acids, or peptides; R 2 is hydrogen or (Ci-C 1 alkyl, R 3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cdlalkoxy, (Ci-Cd) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or (Ci-Cβ) ) alkyl, and Rs is hydroxy, (Ci-Cdl alkoxy, or (Ci-Cβ) alkanoyloxy, or R4 and Rs taken together are ethylenedioxy, Re is hydrogen, carboxy, (Cid) alkanoyl, (C1-C6) alkoxylate boni lo, halo (Ci-Cdlalkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cs) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-C4alkoxy, Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) RfRg; Rb, Rc, Rf and Rg are each independently hydrogen, (Ci-Cs) alkyl, (Ci-) C e) alkanoyl, phenyl or H jpcilo; or Rb and Rc or Rf and Rg together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy * 'of Y, or R3 may be optionally substituted by 1, 2 or 3 (Ci- C) alkyl, (Ci-C) alkoxy, (Ci-Cd) alkanoyl, ( Ci- C) alkanoyloxy, (C? -Cs) alkoxycarbonyl, hydroxy (Ci-C e) alkyl, halo (C? -Cd) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (Rj), wherein each Rh and R] is independently hydrogen, (Ci-Cβ) alkyl, (Ci-Cdlalcanoyl, phenyl or benzyl; or Rh and R3 together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino, or a pharmaceutically acceptable salt of the same.
38. A compound of formula I: characterized in that Ri is -CH2- [sulfur-linked steine] -Rx wherein Rx is amino acid or a peptide comprising 2 to 24 amino acids; R2 is hydrogen or (Ci-Cβ) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cdlalkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R4 is hydrogen or (Ci-Cs) alkyl, and Rs is hydroxy, (Ci -Cβ) alkoxy, or (Ci-Cβ) alkanoyloxy, or R4 and Rs taken together are ethylenedioxy; R e is hydrogen, carboxy, (Ci- C) alkanoyl, (Ci-Cβ) to the coxy carbonyl, halo (Ci-) Cd) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cβ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cd) alkoxy, (Ci-Cd) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Ci) alkyl, (Ci-Cdlalcanoyl, phenyl or benzyl; or Rf and Rg together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any heteroaryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be optionally substituted by 1, 2, 3 (Ci-Cd-alkyl, (Ci-Cβ) alkoxy, (Ci-Cβ) alkanoy, or Cd) alkanoi loxi, (Ci-Ce) alkoxycarbonyl, hydroxy (C6-6) alkyl, halo (Ci-Cd) alkyl, hiaroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (R .?), wherein each Rh and Rj is independently hydrogen, (Ci-Cß) alkyl, (C? ~ Ce] alkanoyl, phenyl or benzyl; or Rh and Ri together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same.
39. 39. A compound of formula I (0 characterized because Ri is -CH2- [N-acijlcistein bonded to sulfur] -Rx, wherein Rx is an amino acid or a peptide comprising 2 to 24 amino acids; R2 is hydrogen or (Ci-Cd) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci- Cd) alkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or (Ci-Cβ) alkyl; and Rs is hydroxy, (Ci-Cβ) alkoxy, or (Ci-Cβ) alkanoyloxy; or R and R5 taken together are ethylenedioxy; Re is hydrogen, carboxy, (C-Cjalkanoyl, (Ci-Cd) a lcoxycarboni lo, halo (Ci-Cdlalkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cβ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cd) alkoxy, (Ci-Cβ) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Cβ) alkyl, (Ci-C-alkanoyl, phenyl or benzyl; or Rf and Rg together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be optionally substituted by 1, 2 or 3 (Ci-Cdlalkyl, (Ci-Cd) alkoxy, (Ci-Ce) to lcanoyl, (Ci-C-alkanoyloxy, (C? -C) alkoxycarbonyl, hydroxy (Ci-C) alkyl, halo (Ci-Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (R) l, wherein each R and R_ is independently hydrogen, (Ci-Cß) alkyl, ( Ci-Cd) alkanoyl, phenyl or benzyl, or R and R: together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino, or a pharmaceutically acceptable salt thereof.
40. 40. A compound of formula I (0 characterized because -ftf '' - -: te * ~ - Ri is -CH2- [glutathione linked to sulfur]; R2 is hydrogen or (Ci-Cd) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cslalkoxy, (Ci-Cβ) alkylthio, aplo, heteroaryl, aryloxy, or heteroaryloxy, R 4 is hydrogen or (Ci-Cβ) alkyl, and Rs is hydroxy, (Ci -Cd) alkoxy, or (Ci-Cβ) alkanoyloxy, or R and Rs taken together are ethylenedioxy, Re is hydrogen, carboxy, (Ci- C e) alkanoy 1, (C- C e) to 1 coxy carbonyl, halo (Ci-Cd) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cβ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Ce) alkoxy, Ce) alkanoyl oxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Ce) alkyl, (Ci-Cβ) alkanoyl, phenyl or benzyl; or Rf and Rg together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be optionally substituted by 1, 2, or 3 (Ci- C6) alkyl, (C? -Ce) alkox iflr (C i -Cß) alkanoyl, (C i -C β) alkanoyloxy, (Ci-C β) alkoxycarbonyl, hydroxy (Ci-Ce) alkyl or halo (Ci-C β) alkyl , hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (Ri); in each Rh and R] donation is independently hydrogens', (Ci-Cd) alkyl, (Ci-Cβ) alkanoyl, phenyl or benzyl; or Rh and R-j together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same.
41. 41. A compound of formula I (D characterized in that Ri is 2- [(R) -o.-methylbenzyl-aminocarbonyl] -2- (acylamino) ethylthiomethyl; R2 is hydrogen or (Ci-Cβ) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) alkoxy, (Ci-Cd) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R 4 is hydrogen or (Ci-Cβ) alkyl; and R 5 is hydroxy, (Ci-Cβ) alkoxy, or (C? -Cd) alkanoyloxy; or R4 and Rs taken together are ethylenedioxy; R e is hydrogen, carboxy, (Ci- C e) alkanoyl, (Ci-Cd) coxiyl carboni, halo (Ci-Cd) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide , or (Ci-Cd) alkyl optionally substituted by 1 6 2 hydroxy, (Ci-Cd] alkoxy, (Ci-Ce) alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf R. are each independently hydrogen, (Ci-Cd) alkyl, (Ci-Cd) alkanoyl, phenyl or benzyl, or Rf and Rg together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be optionally substituted by 1, 2 or 3 (Ci-Cd-alkyl, (Ci-C) alkoxy, (Ci-C) alkanoyl, (Ci-Ce) alkanoyloxy, Cβ) alkoxycarbonyl, hydroxy (Ci-Ce) alkyl, halo (Ci-Cβ) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (R;,), wherein each Rh and R] is independently hydrogen, (Ci-Cβ) alkyl, (Ci-C ") alkanoyl, phenyl or benzyl; or Rh and Ri together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same.
42. 42 A compound of formula I (D characterized in that Ri is - (CH2) n- (X) - (Y); n e s 1 to 4; X is oxy, thio, or -N (Ra) -; And it is a carbon chain of 2 to 15 elements, branched or unbranched, where the chain is substituted with 1 6 2 carboxy, (C3-Ce) cycloalkyl, heteroaryl, saccharides, amino acids, or peptides; and wherein the chain may be optionally saturated or unsaturated; R2 is hydrogen or (Ci-Cβ) alkyl; R3 is hydrogen, (Ci-Cd) alkyl, (Ci-Cβ) alkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R is hydrogen or (Ci-Ce) alkyl; and Rs is hydroxy, (Ci-Cβ) alkoxy, or (Ci-Ce) to lcanoi loxy; or R4 and R5 taken together are ethylenedioxy; R e is hydrogen, carboxy, (Ci- Ce) to canoi lo, (Ci- C e) to 1 coxi carboni 1, halo (Ci-Cd) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid , a peptide, or (Ci-Cd) alkyl optionally substituted by 1 6 2 hydroxy, (Ci-Cβ) alkoxy, (Ci-C) alkanoi 1 oxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Cβ) alkyl, (Ci-Cd) alkanoyl, phenyl or benzyl; or Rf and Rg together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1, 2, or 3 (Ci-C-alkyl, (Ci-Ce) alkoxy, (Ci-C) alkanoyl, (Ci-C e) ) to 1 canoxi loxi, (C i - C) to coxi carboni 1, hydroxy (Ci-Cß) alkyl, halo (Ci-Ce) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (Rj), wherein each Rh and R3 is independently hydrogen, (Ci-Cß) alkyl, (Ci-Cejalcanoyl, phenyl or benzyl; or Rh and R3 together with the nitrogen to which they are attached are pyrrolidino, piperidino , or morpholino, or a pharmaceutically acceptable salt of the same.
43. 43. A compound of formula I: 0) characterized because '^ ¿^ ¿^ ¿_ Ri is - (CH2) n- (X) - (Y); n is 1; X is a guy; Y is a branched or unbranched carbon chain of 2 to 6 elements that is substituted on the carbon with 1,2, or 3, oxo, heteroaryl, or peptides; R2 is hydrogen or (Ci-Ce) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-Cdlalkoxy, (Ci-Ce) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R4 is hydrogen or (Ci-Ce) alkyl, and Rs is hydroxy, (Ci -Ce) alkoxy, or (Ci-Cβ) alkanoyloxy, or 4 and R5 taken together are ethylenedioxy, Re is hydrogen, carboxy, (Ci-) alkanoyl, (Ci-C) a 1 coxycarboni 1, halo (Ci) -Ce) alkyl, -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cβ) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Ce) alkoxy, (Ci-C) al canoil oxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Ce) alkyl or, (Ci-Cd) alkanoyl, phenyl or benzyl; or Rf and Rg, together with the nitrogen to which they are attached, they are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may be optionally substituted by 1, 2 or 3 (Ci-Cβ) alkyl, (Ci-Ce) alkoxy, (Ci-Cβ) alkanoyl, (Ci-) Ce) alkanoyloxy, (C? -Ce) alkoxycarbonyl, hydroxy (C? -Ce) alkyl, halo (Ci-Cß) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or -N (Rh) (R) ), wherein each Rh and R: is independently hydrogen, (Ci-Cs) alkyl, (Ci-Ce) alkanoyl, phenyl or benzyl; or Rh and R] together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same.
44. 44. A compound of formula I (0 adjusts characterized in that Ri is hydroxy, carboxy, aryl, heteroaryl, a saccharide, an amino acid, or a peptide; R2 is hydrogen or (Ci-Cd) alkyl; R3 is hydrogen, (Ci-Cβ) alkyl, (Ci-CeJalkoxy, (Ci-Cβ) alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy, R is hydrogen or (Ci-Ce) alkyl, and Rs is hydroxy, (Ci -Ce) alkoxy, or (Ci-Cs) alkanoyloxy, or R4 and Rs taken together are ethylenedioxy, Re is hydrogen, carboxy, (Ci-Cd) alkanoyl, (Ci-Ce) alkoxycarbonyl, halo (Ci-Ce) alkyl , -C (= 0) NRfRg, a saccharide, an amino acid, a peptide, or (Ci-Cd) alkyl optionally substituted by 1 or 2 hydroxy, (Ci-Cβ) alkoxy, (Ci-Cß alkanoyloxy, carboxy, amino acids, peptides, saccharides, or -C (= 0) NRfRg; Rf and Rg are each independently hydrogen, (Ci-Cβ) alkyl, (Ci-, C-alkanoyl, phenyl or benzyl; or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, pipepdino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may be ^^ ¡^^^^ ¿^ optionally substituted by 1, 2 or 3 (Ci-Cdlalkyl, (Ci-Cß) alkoxy, (Ci-Ce) to the canoil, (Ci-Ce) alkanoyloxy, (Ci-Ce) alkoxycarbonyl, hydroxy (Ci-Ce) alkyl, halo (Ci-Ce) alkyl, hydroxy, halo, carboxy, mercapto, nitro, or N (Rh) (R)), wherein each Rh and R: is independently hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) alkanoyl, phenyl or benzyl; or Rt, and R: together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt of the same.
45. 45. A pharmaceutical composition characterized in that it comprises one or more compounds according to claim 1, 2, 3, 29, 30, 31, 34, 36, 37, 38, 39, 40, 41, 42, 43, or 44 in combination with a pharmaceutically acceptable diluent or carrier.
46. 46. A compound according to claim 1, 2, 3, 29, 30, 31, 34, 36, 37, 38, 39, 40, 41, 42, 43, or 44 for use in medical therapy.
47. 47. The compound according to claim 46, characterized in that medical therapy is the treatment of cancer.
48. 48. The use of a compound according to claim 1, 2, 3, 29, 30, 31, 34, 36, 37, 38, 39, 40, 41, 42, 43, or 44 to prepare a medicament for the treatment of the cancer
49. 49. The use according to claim 48 wherein the cancer is a solitary tumor.
50. 50. A method characterized in that it comprises the inhibition of cancer cells, by contacting said cells, in vivo or in vivo, with an effective amount of a compound according to claim 1, 2, 3, 29, 30, 31, 34, 36, 37, 38, 39, 40, 41, 42, 43, or 44.
51. 51. A therapeutic method characterized in that it comprises the treatment of cancer by administering an effective amount of a compound according to claim 1, 2, 3, 29, 30, 31, 34, 36, 37, 38, 39, 40, 41, 42, 43, or 44 to a mammal in need of such therapy.