ZA200301439B - Fused pyrrolocarbazoles against inflammation. - Google Patents

Description

SELECTED FUSED PYRROLOCARBAZOLES

» . FIELD OF THE INVENTION

The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.

BACKGROUND OF THE INVENTION

Publications cited throughout this disclosure are incorporated in their entirety herein by reference.

Various synthetic small organic molecules that are biologically active and generally known in the art as “fused pyrrolocarbazoles” have been prepared (See U.S.

Patent Nos. 5,475,110; 5,591,855; 5,594,009; and 5,616,724). In addition, U.S. Patent 5,705,511 discloses fused pyrrolocarbazole compounds which possess a variety of functional pharmacological activities. The fused pyrrolocarbazoles were disclosed to be used in a variety of ways, including: enhancing the function and/or survival of cells of neuronal lineage, either singularly or in combination with neurotrophic factor(s) and/or indolocarbozoles; enhancing trophic factor-induced activity; inhibition of protein kinase

C ("PKC") activity; inhibition of rk tyrosine kinase activity; inhibition of proliferation of a prostate cancer cell-line; inhibition of the cellular pathways involved in the inflammation process; and enhancement of the survival of neuronal cells at risk of dying.

The present inventors have found that certain selected fused pyrrolocarbazoles ’ selected from the generic formulas of U.S. Patent 5,705,511 but not specifically ] disclosed therein possess surprising and unexpected biological activities compared to the compounds described in U.S. Patent 5,705,511.

SUMMARY OF THE INVENTION

- Accordingly, one object of the invention is to provide novel fused pyrrolocarbazole compounds represented by the general Formula I:

H

No

S10 \

R FR

Formula

Constituent members of Formula I are disclosed in detail, infra.

Preferred fused pyrrolocarbazoles are represented by the following Formula II:

H

N.__o eulen

R'" R?

Formula ll : Constituent members of Formula II are disclosed in detail, infra.

The fused pyrrolocarbazoles of the present invention may be used in a variety of ways, including: inhibition of angiogenesis; antitumor agents; enhancing the function * and/or survival of cells of neuronal lineage, either singularly or in combination with neurotrophic factor(s) and/or indolocarbozoles; enhancing trophic factor-induced ' 5 activity; inhibition of kinases; inhibition of vascular endothelial growth factor receptor (VEGFR) kinase, preferably VEGFR2; inhibition of mixed lineage kinase (MLK); rk kinase; inhibition of platelet derived growth factor receptor (PDGFR) kinase; inhibition of NGF-stimulated #rk phosphorylation; inhibition of protein kinase C ("PKC") activity; inhibition of #rk tyrosine kinase activity; inhibition of proliferation of a prostate cancer cell-line; inhibition of the cellular pathways involved in the inflammation process; and enhancement of the survival of neuronal cells at risk of dying. In addition, the fused pyrrolocarbazoles may useful for inhibition of c-met, c-kit, and mutated Flt-3 containing internal tandem duplications in the juxtamembrane domain. Because of these varied activities, the disclosed compounds find utility in a variety of settings, including research and therapeutic environments.

Another object of the present invention is to provide pharmaceutical compositions comprising a fused pyrrolocarbazole of the present invention wherein the compositions comprise a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt or ester form thereof.

It is another object of the present invention to provide methods of treating or preventing diseases or disorders comprising administering a therapeutic or preventative effective amount of at least one of the compounds of the present invention to a subject in need thereof.

These and other objects, features and advantages of the fused pyrrolocarbazoles will be disclosed in the following detailed description of the patent disclosure. ] DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

One embodiment of the present invention are the fused pyrrolocarbazoles represented by Formula I:

No assis \

R' R?

Formula wherein:

R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons (inclusive), preferably an alkyl of 1-4 carbons (inclusive), substituted with OH, or ~OR* where R* is an alkyl of 1-4 carbons (inclusive), aryl, preferably phenyl or naphthyl, or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R’ is -CH,OH; -CH,0R’; -(CH,),SR’; -(CH,),S(0),R*; -CH,SR’; or alkyl of 1-8 carbons (inclusive), preferably an alkyl of 1-4 carbons (inclusive), substituted with —OH, -OR’, -OR%, -CH,0R’, -S(O),R°® or SR’; and wherein

R’ is alkyl of 1-4 carbons (inclusive), or aryl, preferably phenyl or naphthyl;

R® is H, alkyl of 1-4 carbons (inclusive), aryl of 6-10 carbons, preferably phenyl or naphthyl, or heteroaryl;

R’ is H or alkyl of 1-4 carbons (inclusive);

R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4 (inclusive); and ’ yis1or?2.

In certain preferred embodiments, the compounds of Formula I are those of

Formula II:

No

TS

Sesey I

R" R

Formula ll wherein R!, R?, and R? are as defined for Formula I above.

In certain referred embodiments, R' is an alkyl of 1-4 carbons (inclusive), substituted with -OH or -OR* where R* is an alkyl of 1-4 carbons (inclusive), aryl, preferably phenyl or naphthyl, or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

R? is H; and R’ is -CH,0H; -CH,0R’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons (inclusive), preferably an alkyl of 1-4 carbons (inclusive), substituted with —

OH, -OR’, -OR?, -CH,0R’, -S(0),R® or SR’; wherein R%, R®, R” and R® are as defined for Formula I above.

In certain other preferred embodiments, R' is -CH,CH,CH,OH or -

CH,CH,CH,0COCH,N(CH,),, R? is H and R® is -CH,0OR’; wherein R’ is alkyl of 1-4 carbons (inclusive).

In certain even further preferred embodiments the fused pyrrolocarbazoles of

Formula I and Formula II are those represented in Table I:

Tablel : ww we wm

I cc NA Wc 0 omomomoR |W | crooCHonon mem |W [woman

I A ELA LA

CH,CH,CH,0H H ®)

I Ea BL poo

I cc EOL Wc vow || oom

I =o a I CC

I cL IL Le coc)

CH,CH,CH,0H H CH(CH3)OCH,CH,CH,CH

TI I i id

I Ec 0M 19 | CH,CH,CH,OCOCH(NH,)CH,- H CH,OCH(CHz),

Mal I Bal

Cem, | | ono 21 | CHpCH,CH,OCOCH,CH,- H CH,OCH(CH3),

J i I 23 | CHyCH,CH,OCOCH,CH,CHy- CH,OCH(CHz),

Em

I I vc

I cc NO Cc

I NL

IE IS SO LI RL rw memo

I Ec I cc

EN A

CHORE:

CT CHOC

CH,CH,CH,OCOCF, CH,SCH,CH,CHj3

CH,CH,CH,OH [HO] CH, S(2-pyrimidyl)

CH,CH,CH,0H CH,OH CHyOCH(CH3),

Preferred fused pyrrolocarbazoles of Formula II are represented structurally in Table II:

Table IT

H

\ N lo) 0}

Saves es

H

~o N 0 ? 30 has ".

H

—L N fo) 0] ’ ealet . N

Aw

+/-

LA eaves , ® )

E N (o] : 80 ,

R) !

NEG ANI sel “ 1A 3-10 ~,

ones , +/- L " ) $0) chiral H \, NI 11 Q $1) chiral y \ Noo 12 ones “a +- ° 8-00) pw - p=

+/- H eves “, +/- ]

NU z $0 ~,

So do " $0 ,

A A, is oats ld

Sm

Le 19 ) $20)

A,

A n 2 ones ~ fo) am

A A, 21 eaves ) RNP

A a 2 ened

LR we,

A A, 23 onYel

RR SP

LA

24 0 ~, , b_ ned . } ( 0 3 ; 26 2) $21) “

H

27 | or $010 ,

Hl

N

OH 0O y ei $210) \,

H

OH N 6}

Reslss nu

H

N

OH 0] 0 fof

H i

N o 31 5-0

H

H

1 A ’ 32 5-0

H

H

OH N 0 53 ened ' ,

H

OH N (0) 4 ones ,

H

N

OH 0) onle®

Bi &h } o N 0 36 ones

H

N

. S 0 i

Ra

Vo

Ss 0] 2

CL-CI2

L

SO

Ns M=o 39 vay

LI-CI0 \,

H

_L N fo} (o} ~~ OH

OH

Particularly preferred compounds of Table II include compounds 1, 3, 4, 5, 6, 7 and 22 with compounds 3 and 22 being most preferred.

The compounds represented by Formula I and II and depicted in Tables I and II may also be referred to herein as “the compounds,” “the compound(s) of the present invention,” “fused pyrrolocarbazole(s),” “fused pyrrolocarbazole(s) of the present invention” and the like.

Certain compounds of U.S. Patent 5,705,511 are depicted in Table lia.

Table Tia ———— o

N

0

A ones “on

H

N

Sores ee w pe

H

N o

LIL-C ~ 0

NN

NH,

H

N

0) genYs®

Ra

H

As used herein with reference to the definitions of R! and R2 , the term “amino acid” denotes a molecule containing both an amino acid group and a carboxyl group. It includes an “a.-amino acid” which has its usual meaning as a carboxylic acid which bears an amino functionality on the carbon adjacent to the carboxyl group. a-Amino acids can

S be naturally occurring or non-naturally occurring. Amino acids also include “dipeptides” which are defined herein as two amino acids which are joined in a peptide linkage Thus constituents of dipeptides are not limited to a-amino acids, and can be any molecule containing both an amino group and a carboxyl group. Preferred are o.-amino acids, dipeptides such as lysyl-f-alanine, and aminoalkanoic acids of 2-8 carbons, e.g., 3- dimethylaminobutyric acid.

Pharmaceutically acceptable salts of the fused pyrrolocarbazoles of the present invention also fall within the scope of the compounds as disclosed herein. The term “pharmaceutically acceptable salts” as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.

Examples of pharmaceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine.

Compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients or carriers. As noted above, such compositions may be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, via, for example, trans-dermal patches.

Accordingly, another aspect of the present invention are pharmaceutical compositions comprising a compound of the present invention optionally in admixture with one or more pharmaceutically acceptable excipients or carriers. Preferably, the pharmaceutical compositions comprise a compound of Formula II. More preferably, the pharmaceutical compositions comprise a compound of Table I or Table II.

In certain preferred pharmaceutical compositions, the composition is for ] inhibiting one or more of #rk kinase activity, VEGFR kinase activity, PKC or PDGFR activity wherein the composition comprises a compound of Formula I, Formula II, Table

I or Table II and optionally one or more pharmaceutically acceptable carrier(s). In other preferred pharmaceutical compositions the composition is for enhancing tropic factor or spinal chord ChAT activity wherein the composition comprises a compound of Formula

I, Formula II, Table I or Table II and a pharmaceutically acceptable carrier.

In other preferred pharmaceutical compositions, the composition is for treating or preventing angiogenesis and angiogenic disorders such as cancer of solid tumors, endometriosis, retinopathy, diabetic retinopathy, psoriasis, hemangioblastoma, ocular disorders or macular degeneration. In other preferred pharmaceutical compositions, the composition is for treating or preventing neoplasia, theumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis. In other preferred pharmaceutical compositions, the composition is for treating or preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington’s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AIDS related peripheral neuropathy, or injuries of the brain or spinal chord.

In other preferred pharmaceutical compositions, the composition is for treating or preventing prostate disorders such as prostate cancer or benign prostate hyperplasia. In still other preferred pharmaceutical compositions, the composition is used for treating or preventing multiple myeloma and leukemias including, but not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia.

The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington’s Pharmaceutical Sciences (Mack Pub. Co., Easton,

PA, 1980). Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or ’ polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations for trans-dermal patches are preferably lipophilic emulsions.

The compounds of the present invention can be employed as the sole active agent ina pharmaceutical or can be used in combination with other active ingredients, e.g., other growth factors which could facilitate neuronal survival or axonal regeneration in diseases or disorders or other angiogenesis or antitumor agents.

The concentrations of the compounds described herein in a therapeutic or pharmaceutical composition will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration. In general terms, the compounds of this invention may be provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration.

Typical dose ranges are from about 1 pg/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day.

The preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.

In other embodiments, the present invention provides a method for inhibiting rk kinase activity comprising providing a compound of the present invention in an amount sufficient to result in effective inhibition. In a preferred embodiment, the compound of the present invention is provided to treat inflammation, for example, neurological inflammation and chronic arthritis inflammation. In another preferred embodiment, the ] trk kinase receptor is rk A.

In other embodiments, the present invention provides a method for treating or preventing prostate disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of the present invention. In a preferred embodiment, the prostate disorder is prostate cancer or benign prostate hyperplasia.

In other embodiments, the present invention provides a method for treating or preventing angiogenic disorders where VEGFR kinase activity contributes to pathological conditions, the method comprising providing a compound of the present invention in an amount sufficient to result in the vascular endothelial growth factor receptor being contacted with an effective inhibitory amount of the compound. In another embodiment, the present invention provides a method for treating or preventing angiogenic disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of the present invention.

In a preferred embodiment, the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

In other embodiments, the present invention provides a method for treating or preventing disorders where PDGFR activity contributes to pathological conditions, the method comprising providing a compound of the present invention in an amount sufficient to result in the platelet derived growth factor receptor being contacted with an effective inhibitory amount of the compound. In another embodiment, the present invention provides a method for treating or preventing pathological disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of the present invention. In preferred embodiments, the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

: In other embodiments, the present invention provides a method for treating disorders characterized by the aberrant activity of trophic factor responsive cells, the ’ method comprising providing a compound of Formula I, Formula II, Table I or Table II in an amount sufficient to result in the trophic factor cell receptor being contacted with an effective activity inducing amount of the compound. In preferred embodiments, the activity of the trophic factor responsive cells is ChAT activity. In another embodiment, the present invention provides a method for treating or preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington’s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I, Formula II, Table I and Table II.

As used herein, the term “effect”. when used to modify the terms “function” and “survival” means a positive or negative alteration or change. An effect which is positive can be referred to herein as an “enhancement” or “enhancing” and an effect which is negative can be referred to herein as “inhibition” or “inhibiting.”

As used herein, the terms “enhance” or “enhancing” when used to modify the terms “function” or “survival” means that the presence of a fused pyrrolocarbazole has a positive effect on the function and/or survival of a trophic factor responsive cell compared with a cell in the absence of the fused pyrrolocarbazole. For example, and not by way of limitation, with respect to the survival of, e.g., a cholinergic neuron, the fused pyrrolocarbazole would evidence enhancement of survival of a cholinergic neuronal population at risk of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when compared to a cholinergic neuronal population not presented with such fused pyrrolocarbazole, if the treated population has a comparatively greater period of functionality than the non-treated population. As a further example, and again not by way of limitation, with respect to the function of, e.g., a sensory neuron, the fused pyrrolocarbazole would evidence enhancement of the function (e.g. neurite extension) of a sensory neuronal population when compared to a : sensory neuronal population not presented with such fused pyrrolocarbazole, if the neurite extension of the treated population is comparatively greater than the neurite extension of the non-treated population.

As used herein, “inhibit” and “inhibition” mean that a specified response of a designated material (e.g., enzymatic activity) is comparatively decreased in the presence of a fused pyrrolocarbazole of the present invention.

As used herein the term “neuron,” “cell of neuronal lineage” and “neuronal cell” includes, but is not limited to, a heterogeneous population of neuronal types having singular or multiple transmitters and/or singular or multiple functions; preferably, these are cholinergic and sensory neurons. As used herein, the phrase “cholinergic neuron” means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholine; exemplary are basal forebrain and spinal cord neurons. As used herein, the phrase “sensory neuron” includes neurons responsive to environmental cues (e.g., temperature, movement) from, e.g., skin, muscle and joints; exemplary is a neuron from the DRG.

As used herein a “trophic factor” is a molecule that directly or indirectly affects the survival or function of a trophic factor responsive cell. Exemplary trophic factors include Ciliary Neurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF), insulin and insulin-like growth factors (e.g., IGF-I, IGF-II, IGF-II), interferons, interleukins, cytokines, and the neurotrophins, including Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5) and Brain Derived Neurotrophic

Factor (BDNF).

A “trophic factor-responsive cell,” as defined herein, is a cell which includes a receptor to which a trophic factor can specifically bind; examples include neurons (e.g., cholinergic and sensory neurons) and non-neuronal cells (e.g., monocytes and neoplastic cells).

As used herein, “trophic factor activity” and “trophic factor induced activity” are defined as any response which directly or indirectly results from the binding of a trophic factor (e.g., NGF) to a cell comprising a trophic factor receptor (e.g., neuron comprising of a trk). In the case of], e.g., NGF binding with rk, an exemplary response would include autophosphorylation of tk tyrosine residues leading to increased ChAT activity which results in enhanced neuron survival, and/or function.

As used in the phrases “trophic factor activity” and “trophic factor-induced activity,” the term “trophic factor” includes both endogenous and exogenous trophic ’ factors, where “endogenous” refers to a trophic factor normally present and “exogenous” refers to a trophic factor added to a system. As defined, “trophic factor induced activity” includes activity induced by (1) endogenous trophic factors; (2) exogenous trophic factors; and (3) a combination of endogenous and exogenous trophic factors.

As used herein, the term “sk” refers to the family of high affinity neurotrophin receptors presently comprising trk A, trk B and #k C, and other membrane associated proteins to which a neurotrophin can bind.

As used herein the phrase “hyperproliferative state” in reference to the term “cells” means cells whose unregulated and/or abnormal growth can lead to the development of an unwanted condition, for example, a cancerous condition or a psoriatic condition.

As used herein, “cancer” and “cancerous” refer to any malignant proliferation of cells in a mammal. Examples include prostate, benign prostate hyperplasia, ovarian, breast and other recognized cancers. As used herein the term “psoriasis” and “psoriatic condition” refer to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration and cytokine alteration.

As used herein, the phrase “at risk of dying” in conjunction with a biological material, e.g., a cell such as a neuron, means a state or condition which negatively impacts the biological material such that the material has an increased likelihood of dying due to such state or condition. For example, compounds disclosed herein can “rescue” or enhance the survival of motoneurons which are naturally at risk of dying in an in ovo model of programmed cell death. Similarly, for example, a neuron may be at risk of dying due to the natural aging process which occasions the death of a neuron, or due to an injury, such as a trauma to the head, which may be such that neurons and/or glia, for example, impacted by such trauma may be at risk of dying. Further, for example, a neuron may be at risk of dying due to a disease state or condition, as in the case of neurons at risk of dying as occasioned by the disease ALS. Thus, by enhancing the survival of a cell at risk of dying by use of a compound of the claimed invention is meant that such compound decreases or prevents the risk of the death of the cell.

As used herein the term “contacting” means directly or indirectly causing placement together of moieties, such that the moieties directly or indirectly come into ’ physical association with each other, whereby a desired outcome is achieved. Thus, as used herein, one can “contact” a target cell with a compound as disclosed herein even though the compound and cell do not necessarily physically join together (as, for example, is the case where a ligand and a receptor physically join together), as long as the desired outcome is achieved (e.g., enhancement of the survival of the cell).

Contacting thus includes acts such as placing moieties together in a container (e.g., adding a compound as disclosed herein to a container comprising cells for in vitro studies) as well as administration of the compound to a target entity (e.g., injecting a compound as disclosed herein into a laboratory animal for in vivo testing, or into a human for therapy or treatment purposes).

As used herein, “prodrug” is intended to include any covalently bonded carriers which release the active parent drug as a compound of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention contemplates prodrugs of the compounds of the present invention, compositions containing the same, and methods of treating diseases and disorders with such prodrugs. Prodrugs of a compound of the present invention, for example Formula I, may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively.

Examples include, but are not limited to, the residue of an amino acid after the hydroxyl } group of the carboxyl group is removed acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.

The fused pyrrolocarbazoles of the present invention have important functional pharmacological activities which find utility in a variety of settings, including both ’ research and therapeutic arenas. For ease of presentation, and in order not to limit the range of utilities for which these compounds can be characterized, we generally describe the activities of the fused pyrrolocarbazoles as follows: 6. Inhibition of enzymatic activity 6. Effect on the function and/or survival of trophic factor responsive cells 6. Inhibition of inflammation-associated responses 6. Inhibition of cell growth associated with hyperproliferative states 6. Inhibition of developmentally programmed motoneuron death

Inhibition of enzymatic activity can be determined using, for example, VEGFR inhibition (e.g., VEGFR2 inhibition), MLK inhibition (e.g., MLK1, MLK2 or MLK3 inhibition), PDGFR kinase inhibition, NGF-stimulated tk phosphorylation, PKC inhibition, or rk tyrosine kinase inhibition assays. Effect on the function and/or survival of trophic factor responsive cells, e.g., cells of a neuronal lineage, can be established using any of the following assays: (1) cultured spinal cord choline acetyltransferase (“ChAT”) assay; (2) cultured dorsal root ganglion (“DRG”) neurite extension assay; (3) cultured basal forebrain neuron (“BFN”) ChAT activity assay. Inhibition of inflammation-associated response can be established using an indoleamine 2,3- dioxygenase (“IDO”) mRNA assay. Inhibition of cell growth associated with hyperproliferative states can be determined by measuring the growth of cell lines of . interest, such as an AT2 line in the case of prostate cancer. Inhibition of developmentally programmed motoneuron death can be assessed in ovo using embryonic chick somatic motoneurons, which cells undergo naturally occurring death between embryonic days 6 and 10, and analyzing inhibition of such naturally occurring cell death as mediated by the compounds disclosed herein. ’ The inhibition of enzymatic activity by the fused pyrrolocarbazole compounds of the present invention can be determined using, for example, the following assays:

VEGFR Inhibition Assay

MLK Inhibition Assay } PKC Activity Inhibition Assay trkA Tyrosine Kinase Activity Inhibition Assay

Inhibition of NGF-stimulated trk phosphorylation in a whole cell preparation

Platelet Derived Growth Factor Receptor (PDGFR) inhibition assay

Particularly, inhibition of the Vascular Endothelial Growth Factor Receptor (VEGFR) implies utility in, for example, diseases where angiogenesis plays important roles, such as cancer of solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, as well as other ocular diseases and cancers. Inhibition of MLK implies utility in, for example, neurological diseases. Inhibition of rk implies utility in, for example, diseases of the prostate such as prostate cancer and benign prostate hyperplasia, and treatment of inflammatory pain. Inhibition of the Platelet Derived

Growth Factor Receptor (PDGFR) implies utility in, for example, various forms of neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, diseases with cardiovascular end points, such as atherosclerosis, restenosis, post- angioplasty restenosis, and the like. } Fused pyrrolocarbazoles have also been shown to have positive effects on the function and survival of trophic factor responsive cells by promoting the survival of neurons. With respect to the survival of a cholinergic neuron, for example, the compound may preserve the survival of a cholinergic neuronal population at risk of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when compared to a cholinergic neuronal population not presented with such compound, if the treated population has a comparatively greater period of functionality than the non-treated population.

A variety of neurological disorders are characterized by neuronal cells which are dying, injured, functionally compromised, undergoing axonal degeneration, at risk of dying, etc. These disorders include, but are not limited to, neurological diseases and disorders, Alzheimer’s disease; motor neuron disorders (e.g. amyotrophic lateral sclerosis); Parkinson’s disease; cerebrovascular disorders (e.g., stroke, ischaemia);

Huntington’s disease; AIDS dementia; epilepsy; multiple sclerosis; peripheral neuropathies (e.g., those affecting DRG neurons in chemotherapy-associated peripheral neuropathy) including diabetic neuropathy and AIDS related peripheral neuropathy; disorders induced by excitatory amino acids; and disorders associated with concussive or penetrating injuries of the brain or spinal cord.

The compounds are not only useful for enhancing trophic factor-induced activities of trophic responsive cells, e.g., cholinergic neurons, but also may function as survival promoting agents for other neuronal cell types, e.g., dopaminergic or glutamatergic. Growth factor may regulate survival of neurons by signaling cascades downstream of the small GTP binding proteins ras, rac, and cdc42 (Denhardt, D.T.,

Biochem. J., 1996, 318, 729). Specifically, activation of ras leads to phosphorylation and activation of extracellular receptor-activated kinase (ERK), which has been linked to biological growth and differentiation processes.

Stimulation of rac/cdc42 leads to an increase in activation of JNK and p38, responses that are associated with stress, apoptosis, and inflammation. Although growth factor responses are primarily via the ERK pathway, affecting these latter processes may lead to alternative mechanisms of neuronal survival which may mimic growth factor enhancing survival properties (Xia et al., Science, 1995, 270, 1326). The compounds of the present invention may also function as survival promoting agents for neuronal and non-neuronal cells by mechanisms related to, but also distinct from, growth factor mediated survival, for example, inhibition of the JNK and p38 MAPK pathways which may lead to survival by inhibition of apoptotic cell death processes. The present.

compounds are also useful in the treatment of disorders associated with decreased ChAT activity or the death, injury to spinal cord motoneurons, and also have utility in, for ) example, diseases associated with apoptotic cell death of the central and peripheral nervous system, immune system and in inflammatory diseases. ChAT catalyzes the synthesis of the neurotransmitter acetylcholine, and it is considered an enzymatic marker fora functional cholinergic neuron. A functional neuron is also capable of survival.

Neuron survival is assayed by quantitation of the specific uptake and enzymatic conversion of a dye (e.g., calcein AM) by living neurons. The compounds described herein may also find utility in the treatment of disease states involving malignant cell proliferation, such as many cancers.

Because of their varied utilities, the properties of isomeric fused pyrrolocarbazoles and isoindolones may be exploited in other settings, such as research.

For example, the compounds can be used in the development of in vitro models of neuronal cell survival, function, identification, or for the screening of other synthetic compounds which have activities similar to that of the of isomeric fused pyrrolocarbazole and isoindolone compounds. Thus, the compounds provided by this invention are useful as standard or reference compounds for use in tests or assays for determining the activity of an agent in a pharmaceutical research program.

The compounds can also be utilized to investigate, define and determine molecular targets associated with functional responses. For example, by radiolabelling an isomeric fused pyrrolocarbazole or isoindolone compound associated with a specific cellular function (e.g., mitogenesis), the target entity to which the derivative binds can be identified, isolated, and purified for characterization. By way of further illustration, compounds may be used in the development of assays and models for further enhancement of the understanding of the roles that inhibition of serine/threonine or tyrosine protein kinase (e.g., PKC, trk tyrosine kinase) play in the mechanistic aspects of the associated disorders and diseases. Thus, the compounds of the present invention are ) useful as diagnostic reagents in diagnostic assays, such as the assays described herein.

The results obtained in the VEGFR and MLK assays are set forth below. Other assays are described in more detail as well. They are not intended, nor are they to be construed, as limiting the scope of the disclosure. Certain abbreviations used to delineate the results below are defined as follows: “pg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “pL” denotes microliter, “mL” denotes milliliter, “L” ’ denotes liter, “nM” denotes nanomolar, “uM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar and “nm” denotes nanometer.

Synthesis

The present invention also provides a method for preparing the fused pyrrolocarbazoles of the present invention. The compounds of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods described in the Schemes below, or variations thereon as appreciated by the skilled artisan. The appropriate modifications and substitutions being readily apparent and well known or readily obtainable from the scientific literature to those skilled in the art. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.

It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from active starting materials or by deliberate chiral synthesis of target centers.

As will be readily understood, functional groups present on the compounds of the present invention may contain protecting groups. For example, the amino acid side chain substituents of the compounds can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups according to the invention may be found in Greene, T.W. and

Wats, P.G.M., “Protective Groups in Organic Synthesis” 2d. Ed., Wiley & Sons, 1991.

Scheme 1 y ! ) ae DBU : pTSOH { ethyl acrylate DMB-OH q L200) CH3CN q L230) NMP 9g LI0) lL Benzene . L,

CHEH;O CHEHO

I 0] mn 1.LiBHg

THF QV) 2. NBS

THF

; : v co N ° 0 ° NaOAc 5 ) ©

HO a DIBALH ~~"o {) PACIp(PPha)2 Br -— E —— 9 N ss CH2CI2 9 N 8 2-methoxyethanol 9 N es { { 1550C {

HO HO HO

TEA Example 29 TFA vi v

Cristi mer ° Thioanisole C. vil

Scheme 2 : ; " H

N__o o No o

H HO

OD — "0 — on 20

Ls Ls {

CHCH,0 CHECH,0 HG i X Example 29 h ! y

N__o o NC o No

H HO ao 0 — Senate 0 — eas 00 lu lw Gs

XVI Xvil Example 28

Scheme 3 i ! !

AN lo) N_o OH NO

R, R,

QC — OR — RO k, k, 1S

R1=H, (CH)30H XI Rp = (CH2)30H Example 30 R2=H, R7 =H ’ Xl Ry=H Example35 R2 =H, R7 = Me

Example34 R2 = (CHp)3OH, Ry = Et

R Example33 R2 = (CH)30H, Ry = Me

Scheme 4

H

ORs N_o esse i ’ sop” L,

OH N_o

Rents \ :, \ H

RgSH SRs N__o

General Structure IX R ) Os 7)

R2 =H, (CH)20H, (CHp)30H N

R7 = H, Me, Et %

Scheme 5

H H

. N 0 NaH N 0 0

Rests cRE Aas ous

I=)

N DMF N

{ 0

Example 31 xm

Super hydride

THF

H j

N 0 hess

N ond

Example 7

Scheme 6

DMB DMB

N CsCO. 0 0 ) N 0]

Ao) Se

LIC) OST)

CH,Cl,/ MeOH $

N Cl N

H Ho

Xv XV

TFA

CHCl, 0

N_o

Re & 2) ha

Ho

Example 14

Scheme 7

TBS

) H

N__o No

PR TBSCI,Et;N PR

OLD

—_— ees k TBS = tBuMe,Si- (

HO TBSO

Example 3 Xvill

Triton B/pyridine, paraformaldehyde

H TBS

N 0 N o

PS 9 C) ® Pro, TMS! (A) —— TP) : LL ( on { ~

Ho TBSO

Example 40 XIX

Claims (97)

- 58 - PCT/US01/26266 CLAIMS

1. Compounds of Formula I: H N_-0 QC N RR? Formula} wherein: R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0H; -CH,OR’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,OR’, -S(O),R® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; Réis H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yis1or2; with the proviso that when R' is (CH,);OH and R? is H, then R? cannot be - CH,OH, -CH,0CH,CH,, or -CH,SCH,CH,.

2. Compounds of Formula II: AMENDED SHEET 2004-05-20

-59- PCT/US01/26266 H N__0 rrr anise R'" R? Formula ll wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0H; -CH,0R’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,OR’, -S(O),R°® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1or2; with the proviso that when R! is (CH,),0H and R? is H, then R® cannot be -CH,0H, -CH,0CH,CH,, or -CH,SCH,CH,.

3. The compounds of claims 1 or 2 wherein: R! is an alkyl of 1-4 carbons, substituted with -OH or -OR* where R* is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; R? is H; and AMENDED SHEET 2004-05-20

- 60 - PCT/US01/26266 R® is alkyl of 1-4 carbons, substituted with -OR’, -OR®, -CH,OR’, -S(O),R® or -SR®; and wherein R® is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; and R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed.

4. The compounds of claims 1 or 2 wherein: R! is -CH,CH,CH,OH or -CH,CH,CH,0COCH,N(CH,),; R? is H; and R’ is -CH,OR’ wherein R’ is alkyl of 1-4 carbons.

5. The compounds of claims 1 or 2 represented in Table I: Table I 4 CH,CH,CH,0H H CH,OCH(CH3)C CL] eT CH,CH,CH,OH H (S)- I Ed CH,CH»CH70H H (R)- CT CH,CH,CHOH H CH,OCHCHC I il vl CH,CH,CH,0OH H CH,OCH,CH,C ME AMENDED SHEET 2004-05-20

-61- PCT/US01/26266 CH,CH»CH7OH H CH(CH3)OCH;C I El 11 CH,CH,CH70OH H (chiral) Hl Br 12 CH,CH»CHpOH H (chiral) CT 14 H CH,CHOH CH»OCHCHj3 RE Bad CH,CH,CH,OH H CH(CH3)OCH,C ME 16 CH»CHCH0H H CH(CH3)OCH(C I al I 18 CH,CHCHpOCOC H CH7OCH(CH3), a a 19 CH>CH,CH,OCOC H CH>OCH(CH3)» H(NH)CHj- CH,CH,CH,NH» CH,CH,CHpOCOC H CH,0CH(CH3), Ml El 21 CHpCH»CH,0COC H CHpOCH(CH3)> pe 22 CHpCH»CH0COC H CHOCH(CH3)» I I 23 CHpCH,CH70COC H CHpOCH(CH3), AMENDED SHEET 2004-05-20

-62 - PCT/US01/26266 26 CH,CH,CH0H H CH»S(O)CH(CH3 CH,CH,CH,0H CH,SCH(CH3), CH,CH,CH,OH CH(OH)CH,CH3 36 H H (+/-) CH(OCH3)CH3 CH,CH,CH,OH CH,OH CH,OCH(CH3),

6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or carrier.

7. A method for preventing prostate disorders which comprises administering to a host an effective amount of a compound of Formula I: H NO == \ R' R? Formula wherein: AMENDED SHEET 2004-05-20

-63- PCT/US01/26266 R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R} is -CH,0H; -CH,0R’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR?®, -CH,OR’, -S(O),R® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yis 1 or 2.

8. The method of claim 7 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

9. A method for preventing angiogenic disorders which comprises administering to a host an effective amount of a compound of Formula I: No Nonacs ie Formula wherein: R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and AMENDED SHEET 2004-05-20

-64 - PCT/US01/26266 R’ is -CH,0H; -CH,0R’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,0R’, -S(O),R® or -SR®; and wherein R® is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2.

10. The method of claim 9 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

11. A method for preventing pathological disorders which comprises administering to a host an effective amount of a compound of Formula I: No S00 in R? Formula wherein: R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R? is -CH,0H; -CH,OR’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR®, -OR®, -CH,0R’, -S(O),R® or -SR®; and wherein AMENDED SHEET 2004-05-20

- 65 - PCT/US01/26266 R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yis 1or2.

12. The method of claim 11 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

13. A method for preventing neurodegenerative diseases and disorders, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AIDS related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host an effective amount of a compound of Formula I: H NO --C \ R' R Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and AMENDED SHEET 2004-05-20 }

- 66 - PCT/US01/26266 R® is -CH,OH; -CH,0R’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,0R’, -S(O),R® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2.

14. A method for preventing multiple myeloma and leukemias which comprises administering to a host an effective amount of a compound of Formula I: No R® 9 C10 No RR Formula wherein: R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R® is -CH,0H; -CH,0R’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,0R’, -S(O),R® or -SR’; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl! of 1-4 carbons; AMENDED SHEET 2004-05-20 }

-67 - PCT/US01/26266 R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yis lor2.

15. The method of claim 14 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

16. Use of a compound of Formula I: No 5-010 Ne oo R" R Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxy! group of the carboxyl group is removed; and R® is -CH,0H; -CH,0R’; (CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR?®, -CH,0R’, -S(O),R° or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yislor2; AMENDED SHEET 2004-05-20 i

- 68 - PCT/US01/26266 in the manufacture of a preparation for treating or preventing prostate disorders

17. Use of claim 16 wherein the prostate disorder is cancer or benign prostate hyperplasia.

18. Use of a compound of Formula I: No aeelss No RR Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0H; -CH,0R’; -(CH,) SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,OR’, -S(O),R® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2. in the manufacture of a preparation for treating or preventing angiogenic disorders AMENDED SHEET 2004-05-20 }

- 69 - PCT/US01/26266

19. Use of claim 18 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

20. Use of a compound of Formula I: No CC No R R Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0H; -CH,OR’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR?®, -CH,OR’, -S(O),R°® or -SR°®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2; in the manufacture of a preparation for treating or preventing pathological disorders. AMENDED SHEET 2004-05-20 }

-70 - PCT/US01/26266

21. Use of claim 20 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

22. Use of a compound of Formula I: No ~Q-CI0 No oo RR Formulal wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R® is -CH,0H; -CH,0OR’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,OR’, -S(0),R® or -SR®; and wherein R? is alkyl of 1-4 carbons or aryl; RS is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2; in the manufacture of a preparation for treating or preventing neurodegenerative diseases and disorders, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced AMENDED SHEET 2004-05-20 ]

-71- PCT/US01/26266 peripheral neuropathy, AIDS related peripheral neuropathy or injuries of the brain or spinal chord.

23. Use of a compound of Formula I: No 0 No RR Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0H; -CH,OR’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR?®, -CH,0R’, -S(O),R°® or -SR’; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R? is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yis 1lor2; in the manufacture of a preparation for treating or preventing multiple myeloma and leukemias.

24. Use of claim 23 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia. AMENDED SHEET 2004-05-20 i

-72 - PCT/US01/26266

25. A substance or composition for use in a method for treating or preventing prostate disorders, said substance or composition comprising a compound of Formula I: No = No od RR Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R} is -CH,OH; -CH,OR’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR?, -CH,OR’, -S(O),R® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and yis 1 or 2; and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

26. A substance or composition for use in a method of treatment of claim wherein the prostate disorder is prostate cancer or benign prostate hyperplasia. AMENDED SHEET 2004-05-20 i

-73 - PCT/US01/26266

27. A substance or composition for use in a method for treating or preventing angiogenic disorders, said substance or composition comprising a compound of Formula I: No 5-010 No RR Formula wherein: R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0OH; -CH,0R’; -(CH,), SR’; -(CH,),S(0O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR?®, -CH,0R’, -S(O),R® or -SR®; and wherein R’ is alkyl of 1-4 carbons or aryl; RS is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2; and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

28. A substance or composition for use in a method of treatment of claim 27 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, AMENDED SHEET 2004-05-20 ]

-74 - PCT/US01/26266 macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

29. A substance or composition for use in a method for treating or preventing pathological disorders, said substance or composition comprising a compound of Formula I: No = Noo R R Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,0OH; -CH,0R’; -(CH,),SR’; -(CH,),S(O),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,0R’, -S(O),R° or -SR°®; and wherein R? is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1or2; and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition. AMENDED SHEET 2004-05-20 i

-75- PCT/US01/26266

30. A substance or composition for use in a method of treatment of claim 29 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

31. A substance or composition for use in a method for treating or preventing neurodegenerative diseases and disorders, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AIDS related peripheral neuropathy or injuries of the brain or spinal chord, said substance or composition comprising a compound of Formula I: No R® 9g C1 \ 1 2 RR Formula wherein: R! and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R’ is -CH,OH; -CH,0R’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR?, -OR®, -CH,OR’, -S(O),R® or -SR%; and wherein R’ is alkyl of 1-4 carbons or aryl; RS is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R2 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; AMENDED SHEET 2004-05-20 .

-76 - PCT/US01/26266 n is an integer of 1-4; and y is 1 or 2; and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

32. A substance or composition for use in a method for treating or preventing multiple myeloma and leukemias, said substance or composition comprising a compound of Formula I: No R 9g C1 No R R Formula wherein: R' and R? are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with -OH, or -OR* where R* is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and R® is -CH,OH; -CH,OR’; -(CH,),SR’; -(CH,),S(0),R’; -CH,SR’; or alkyl of 1-8 carbons substituted with -OH, -OR’, -OR®, -CH,0R’, -S(O),R® or -SR®; and wherein R® is alkyl of 1-4 carbons or aryl; R® is H, alkyl of 1-4 carbons or aryl of 6-10 carbons; R’ is H or alkyl of 1-4 carbons; R® is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is an integer of 1-4; and y is 1 or 2; and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition. AMENDED SHEET 2004-05-20 )

-77 - PCT/US01/26266

33. A substance or composition for use in a method of treatment of claim 32 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

34. The compound of claim 2 wherein R' is (CH,);OH, R? is H, and R’ is CH,0CH(CH,),.

35. The compound of claim 2 wherein R' is (CH,);OCOCH,N(CH,),, R? is H, and R? is CH,OCH(CH.,),.

36. A pharmaceutical composition comprising a compound of claim 34.

37. A pharmaceutical composition comprising a compound of claim 35.

38. A method for preventing prostate disorders which comprises administering to a host an effective amount of a compound of claim 34.

39. A method for preventing prostate disorders which comprises administering to a host an effective amount of a compound of claim 35.

40. The method of claim 38 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

41. The method of claim 39 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

42. A method for preventing angiogenic disorders which comprises administering to a host an effective amount of a compound of claim 34.

43. A method for preventing angiogenic disorders which comprises administering to a host an effective amount of a compound of claim 35. AMENDED SHEET 2004-05-20 3

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44. The method of claim 42 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

45. The method of claim 43 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

46. A method for preventing pathological disorders which comprises administering to a host an effective amount of a compound of claim 34.

47. A method for preventing pathological disorders which comprises administering to a host an effective amount of a compound of claim 35.

48. The method of claim 46 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

49. The method of claim 47 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

50. A method for preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host an effective amount of a compound of claim 34.

51. A method for preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, AMENDED SHEET 2004-05-20

-79 - PCT/US01/26266 ischaemia, Huntington’s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host an effective amount of a compound of claim 35.

52. A method for preventing multiple myeloma and leukemias which comprises administering to a host an effective amount of a compound of claim 34.

53. A method for preventing multiple myeloma and leukemias which comprises administering to a host an effective amount of a compound of claim 35.

54. The method of claim 52 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

55. The method of claim 53 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

56. Compounds of the following table: H N 0 Re nded \ R' R? AMENDED SHEET 2004-05-20 }

- 80 - PCT/US01/26266 CH, CH,CH,0COCF, CH»SCH,CH,CHj3 CH, CHCH,0H CH, S(2-pyridyl) CH,CH,CH,0H CH, S(2-pyrimidyl)

57. Use of a compound of claim 35 in the manufacture of a preparation for treating or preventing prostate disorders.

58. Use of a compound of claim 35 in the manufacture of a preparation for treating or preventing prostate disorders.

59. Use of claim 57 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

60. Use of claim 58 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

61. Use of a compound of claim 34 in the manufacture of a preparation for treating or preventing angiogenic disorders.

62. Use of a compound of claim 35 in the manufacture of a preparation for treating or preventing angiogenic disorders.

63. Use of claim 61 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma. AMENDED SHEET 2004-05-20 ]

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64. Use of claim 62 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

65. Use of a compound of claim 34 in the manufacture of a preparation for treating or preventing pathological disorders.

66. Use of a compound of claim 35 in the manufacture of a preparation for treating or preventing pathological disorders.

67. Use of claim 65 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

68. Use of claim 66 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

69. Use of a compound of claim 34 in the manufacture of a preparation for treating or preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington’s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord.

70. Use of a compound of claim 35 in the manufacture of a preparation for treating or preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord. AMENDED SHEET 2004-05-20 ]

- 82 - PCT/US01/26266

71. Use of a compound of claim 34 in the manufacture of a preparation for treating or preventing multiple myeloma and leukemias.

72. Use of a compound of claim 35 in the manufacture of a preparation for treating or preventing multiple myeloma and leukemias.

73. Use of claim 71 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

74. Use of claim 72 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

75. A substance or composition for use in a method for treating or preventing prostate disorders, said substance or composition comprising a compound of claim 34, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

76. A substance or composition for use in a method for treating or preventing prostate disorders, said substance or composition comprising a compound of claim 35, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

77. A substance or composition for use in a method of treatment or prevention of claim 75 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia. AMENDED SHEET 2004-05-20 ]

- 83 - PCT/US01/26266

78. A substance or composition for use in a method of treatment or prevention of claim 76 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

79. A substance or composition for use in a method for treating or preventing angiogenic disorders, said substance or composition comprising a compound of claim 34, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

80. A substance or composition for use in a method for treating or preventing angiogenic disorders, said substance or composition comprising a compound of claim 35, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

81. A substance or composition for use in a method of treatment or prevention of claim 79 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

82. A substance or composition for use in a method of treatment or prevention of claim 80 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

83. A substance or composition for use in a method for treating or preventing pathological disorders, said substance or composition comprising a compound of claim 34, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition. AMENDED SHEET 2004-05-20

-84 - PCT/US01/26266

84. A substance or composition for use in a method for treating or preventing pathological disorders, said substance or composition comprising a compound of claim 35, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

85. A substance or composition for use in a method of treatment or prevention of claim 83 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

86. A substance or composition for use in a method of treatment or prevention of claim 84 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

87. A substance or composition for use in a method for treating or preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington’s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord, said substance or composition comprising a compound of claim 34, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

88. A substance or composition for use in a method for treating or preventing neurodegenerative diseases and disorders, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, ischaemia, Huntington’s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord, said substance or composition comprising a AMENDED SHEET 2004-05-20 ]

- 85 - PCT/US01/26266 compound of claim 35, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

89. A substance or composition for use in a method for treating or preventing multiple myeloma and leukemias, said substance or composition comprising a compound of claim 34, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

90. A substance or composition for use in a method for treating or preventing multiple myeloma and leukemias, said substance or composition comprising a compound of claim 35, and said method comprising administering to a host in need of such treatment or prevention a therapeutically effective amount of said substance or composition.

91. A substance or composition for use in a method of treatment or prevention of claim 89 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

92. A substance or composition for use in a method of treatment or prevention of claim 90 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

93. A compound according to any one of claims 1 to 5, or 56, substantially as herein described and illustrated.

94. A composition according to claim 6 or claim 36 or claim 37, substantially as herein described and illustrated. AMENDED SHEET 2004-05-20 ]

- 86 - PCT/US01/26266

95. A method according to any one of claims 7 to 15 or 38 to 55, substantially as herein described and illustrated.

96. Use according to any one of claims 16 to 24 or 57 to 74, substantially as herein described and illustrated.

97. A substance or composition for use in a method of treatment or prevention according to any one of claims 25 to 33 or 75 to 92, substantially as herein described and illustrated.

08. A new compound, a new composition, a new non-therapeutic method of treatment, a new use of a compound as claimed in claim 1 or claim 34 or claim 35, or a substance or composition for a new use in a method of treatment or prevention, substantially as herein described. AMENDED SHEET 2004-05-20 }