# Patent

## Title
Anti-cancer compounds

## Abstract

The invention provides bradykinin antagonists and pharmaceutically acceptable salts thereof having anti-cancer activity. These anti-cancer compounds are particularly useful for inhibiting the growth of lung and prostate cancers.

## Background
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation in part of U.S. patent application Ser. No. 10/035,662, filed Dec. 28, 2001, now U.S. Pat. No. 7,071,168, which is a continuation of U.S. patent application Ser. No. 09/378,019, filed Aug. 19, 1999, now U.S. Pat. No. 6,388,054, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 60/141,169 filed Jun. 25, 1999. These priority documents are incorporated herein in their entirety by this reference.


GOVERNMENT INTEREST
This invention was made with Government support under grant numbers HL-26284 awarded by the National Heart, Lung and Blood institute and CA-78154 awarded by the National Cancer Institute of the U.S. National Institutes of Health. The Government has certain rights in this invention.


REFERENCE TO SEQUENCE LISTING
This application contains a Sequence Listing submitted as an electronic text file named “2848-41-CON-CIP_ST25.txt”, having a size in bytes of 1kb, and created on 20 Dec. 2007. The information contained in this electronic file is hereby incorporated by reference in its entirety pursuant to 37 CFR §1.52(e)(5).
FIELD OF THE INVENTION
The invention relates to anti-cancer compounds and methods of making and using these compounds.
BACKGROUND OF THE INVENTION
Many lung and prostate cancers, of which small cell lung cancer (SCLC) is a prime example, have a neuroendocrine phenotype, and their growth is stimulated by neuropeptides. Antagonists of several peptides (e.g. bradykinin, substance P, bombesin) have been used in experimental treatment of models of SCLC in animals. Among the most potent of the peptides examined thus far, crosslinked dimers of bradykinin antagonist peptides have been efficacious both in vitro and in vivo against strains of SCLC and other tumors (Chan et al., Immunopharmacology 33: 201-204, 1996; Stewart et al., Can. J. Physiol. Pharmacol. 75: 719-724, 1997; Stewart et al., U.S. Pat. No. 5,849,863). Prostate cancers show a similar neuroendocrine phenotype and are susceptible to these neuropeptide antagonists.
Bradykinin (BK: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (SEQ ID NO: 1) is an important growth factor for many types of cancers. Many cancers express receptors for BK and overproduce BK to stimulate their growth. In addition to direct stimulation of cancer growth, BK stimulates angiogenesis in solid tumors by stimulating release of vascular endothelial growth factor (VEGF) and facilitates tumor spreading and invasion by stimulating release of matrix metalloproteases (MMPs). Thus, antagonists of BK have three potential tumor-inhibiting activities.
The first BK antagonists developed were peptides which did not show any anti-cancer activity. Thereafter, several non-peptide BK antagonists were reported from several laboratories (Inamura et al., Can. J. Physiol. Pharmacol. 75: 622-628, 1997). The present inventors also discovered a group of acylated amino acid amides having BK antagonist activity that are also potent anti-cancer agents (see U.S. Pat. No. 6,388,054). Following the discovery that certain dimerized bradykinin antagonist peptides are cytotoxic for cancer cells and inhibit tumor growth, interest grew in finding smaller, non-peptide BK antagonists with similar anti-cancer efficacy but lower cost of synthesis as well as the possibility non-parenteral routes of administration.
SUMMARY OF THE INVENTION
The present invention provides anti-cancer agents comprised of a range of novel acyl amino acid amide derivatives having BK antagonist activity and having the ability to inhibit growth of small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and prostate cancer (PC) cells in standard in vitro tests as well as to inhibit growth of these cancers in vivo in tumors implanted subcutaneously in athymic nude mice. The anti-cancer agents in this application are derivatives of compound M570, which has the chemical structure: Pentafluorocinnamoyl-O-(2,6-dichlorobenzyl)tyrosine-4-amino-2,2,6,6-tetramethylpiperidine (Abbreviated F5C—OC2Y-Atmp).
M570 was disclosed in U.S. Pat. No. 6,388,054, and is a potent inhibitor of SCLC, NSCLC and PC growth, both in vitro and in vivo. The compounds of the present invention were obtained by replacement of one or two of the three functional groups in M570 to produce more potent anti-cancer compounds that are advantageously more soluble and may preferably be administered orally.
The present invention also provides methods of inhibiting cancer growth by administering to a subject afflicted with cancer a therapeutically effective amount of one or more of the compounds of the present invention.


DETAILED DESCRIPTION OF THE INVENTION
Non-peptide compounds have recently been described as antagonists for a variety of peptide hormones, including bradykinin. Such peptide mimetics are pharmaceutically desirable, as they are more likely to be orally available and are less likely to be susceptible to enzymatic degradation. Although there are few guidelines to direct a search for such compounds, the present inventors synthesized various molecules containing the presumed requisite hydrophobic and basic groups and examined these compounds for anti-bradykinin and anti-cancer activity. Several potent anti-cancer compounds were found in this search.
Anti-cancer activity was determined on cultured human cancer cell lines using the standard tetrazolium (MTT) assay and in human cancers implanted subcutaneously in athymic nude mice. Potent compounds were found to stimulate apoptosis in SCLC cells. They inhibited implanted tumors by inhibiting growth directly, by inhibiting neovascularization and by inhibiting matrix metalloproteases, which are important for tumor extension and migration.
The anti-cancer compounds of the present invention have the chemical formula:

A-B-R  (Formula I)

wherein,

A is an acylating group, and preferably a hydrophobic acylating group, or an anti-inflammatory substituent;
B is an amino acid or substituted amino acid; and,
R is a substituted amide, preferably having additional polar character.
Abbreviations of the chemical entities that compose the anti-cancer compounds of the present invention that are used in this disclosure are listed in Table 1.
With reference to Table 1, the group A acylating groups may be chosen from: Aaa, Aba, Aca, Acrc, Aic, Amts, 6Ani, Aq2c, Arac, Aspr, Atfb, 4Atfb, B6, B6P, Baaa, Bbz, Bcin, Bcpa, Bcpoa, Biot, Bipa, 4Bpc, Bphs, tBua, Bzac, Chbu, Chc, CHFB, Chl, Chpa, 2Cln, Cmioc, Cpcpc, Dbhc, Dca, Dcla, tDecl, Dfc, Dhq, Dmc, Dmo, 22Dp, Esul, 2-Fa, 3-Fa, F5b, F5bs, F5bz, F3c, F5c, Fcin, aFcn, Fmoc, F5pa, Fmpi, F5po, F5pt, Gbz, Hcn, Hmqc, Hor, 2Hyb, 3Iac, 3Ibu, 2Ina, Indo, Inp, Ktlc, Ktpf, Mca, aMcn, Mcoa, 34Mdc, MTPA, 1Nac, 1Nala, Nap, Napr, Nba, Octe, Otac, Pac, Pas, Pcin, Pcn, Pcnl, βPhc, 3Php, 5Phv, Pic, Piva, Ppr, Ptmb, αPtpa, Pya, Pyrc, Pyz, 13cR, Ret, Rio, Saa, Sab, cSdc, Sibu, cSsa, tβSts, Taa, Tchc, Tcpa, Tf2c, 4Tfmb, Thia, Th2n, Tic, Tmb, 4Tmbs, Tmbz, Tmcc, or ZPcn.
Group A anti-inflammatory substitutents may include indomethacin (Indo), aspirin (Aspr), naproxen (Napr), diclofenac (Dfc), ketoprofen (Ktpf) or ketorolac (Ktlc). Because solid tumors are surrounded by a zone of inflammation, anti-cancer analogs having the F5C moiety of M570 replaced by non-steroidal anti-inflammatory drugs (NSAIDS) were synthesized. Although standard NSAIDS are typically administered as free acids, esters or amides of these are also effective. Some of these anti-inflammatory compounds are potent anti-cancer agents in their own right. Combined in the structure of the anti-cancer bradykinin antagonists of the present invention, the resulting compounds are particularly effective anti-cancer agents.
Group B amino acids may be chosen from: Bip, Ddip, F5F, F3MF, hPhe, MC2Y, Nal, NMF, OBPY, OBrZY, OC2Y, OCIY, Pal, PBF, PCNF, PFF, PIF, PNF, Tic, or Tyr(Bzl).
Group R amide groups may be chosen from: Abzp, Aem, Alp, Ambi, Apia, Apyr, AquR, Atmp, BapR, BapS, Bdbh, Bhp, Btmb, Cbp, Chmp, tCip, 4Clbp, Cpp, Cypp, Daep, Dasd, Dcpp, cDmap, cDmbp, cDmm, Dmmp, Dmpz, Dpic, Fbhp, 4Fbp, Fpmp, Fpdh, Matp, 4Mbp, Mpz, Ocp, Pep, Pipe, Pipp, Pipz, Pmpz, Ppp, Pypz, 3Qum, or Tmbp.







TABLE 1





Abbreviations for Chemical Groups Used to Synthesize


the Anti-Cancer Compounds of the Present Invention
















Aaa =
1-Adamantaneacetyl


Aba =
2-cis-4-trans-Abscisic acid


Abzp =
4-Amino-1-benzylpiperidine


Aca =
1-Adamantanecarboxyl


Acrc =
Acridine-9-carboxyl


Aem =
4-(2-Aminoethyl)-morpholine


Aic =
2-Aminoindane-2-carboxylic acid


Alp =
1-Allylpiperazine


Ambi =
2-(Aminomethyl)benzimidazole


Amp =
1-(3-Aminopropyl)-4-methylpiperazine


Amts =
2-Acetamido-4-methyl-5-thiazolesulfonyl


6Ani =
6-Aminonicotinoyl


Apia =
1-(3-Aminopropyl)imidazole


Apyr =
3-Amino-pyrrolidine


Aq2c =
Anthraquinone-2-carboxyl


AquR =
(R)-(+)-3-Aminoquinuclidine


Arac =
Arachidonyl


Aspr =
O-Acetylsalicyl: 2-acetoxybenzoyl


Atfb =
3-Amino-2,5,6-trifluorobenzoyl


4Atfb =
4-Amino-2,3,5,6-tetrafluorobenzoyl


Atmp =
4-Amino-2,2,6,6-tetramethylpiperidine


AtmpO =
4-Amino-2,2,6,6-tetramethylpiperidinyloxy


B6 =
3-Hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridylmethyl



(Vitamin B6, Pyridoxamine)


B6P =
3-Hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridylmethyl-



5-phosphate


Baaa =
2,2-Bis(acrylamido)acetyl


BapR =
(R)-(−)-1-Benzyl-3-aminopyrrolidine


BapS =
(S)-(+)-1-Benzyl-3-aminopyrrolidine


Bbz =
4-Boronobenzoyl


Bcin =
4-Boronocinnamoyl


Bcpa =
bis(4-Chlorophenyl)acetyl


Bcpoa =
bis(4-Chlorophenoxy)acetyl


Bdbh =
(1S,4S)-(+)-2-Benzyl-2,5-diazabicyclo[2.2.1]heptane


Bhp =
1-Benzylhomopiperazine


Biot =
Biotinyl


Bip =
β-(4-Biphenylyl)alanine


Bipa =
4-Biphenylacetyl


4Bpc =
4-Biphenylcarboxyl


Bphs =
4-Biphenylsulphonyl


Btmb =
3,5-Bis(trifluoromethyl)benzylamine


tBua =
tert-Butylacetyl


Bzac =
3-Benzoylacryloyl


Cbp =
1-(4-Chlorobenzhydrylpiperazine)


2Ccn =
2-Chlorocinnamoyl


Chbu =
2-Cyclohexylbutyryl


Chc =
α-Cyano-4-hydroxycinnamoyl


CHFB =
4-Carboxy-hexafluorobutyryl


Chl =
Chlorambucil: 4-[p-(bis[2-Chloroethyl]amino)-



phenyl]butyryl


Chmp =
1-Cyclohexylmethylpiperazine


Chpa =
α-Cyclohexylphenylacetyl


tCip =
trans-1-Cinnamylpiperazine


4-Clbp =
1-(4-Chlorobenzyl)piperazine


2Cln =
2-Chloronicotinoyl


Cmioc =
3-(2-Chlorophenyl)-5-methylisoxazole-4-carbonyl


Cpcpc =
1-(4-Chlorophenyl)-1-cyclopropanecarboxyl


Cpp =
1-(4-Chlorophenyl)piperazine


Cypp =
1-(4-Cyanophenyl)piperazine


Daep =
1-(2-(Diallylamino)ethyl)piperazine


Dasd =
1,4-Dioxa-8-azaspiro[4.5]decane


Dbhc =
3,6-Di-tert-butyl-4-hydroxycinnamoyl


Dca =
Dicyclohexylacetyl


Dcla =
Dichloroacetyl


Dcpp =
1-(2,3-dichlorophenyl)piperazine


tDecl =
trans-4-(Diethylamino)cinnamyl


Dfc =
Diclofenac: 2-[(2,6-Dichlorophenyl)amino]phenylacetyl


Dhq =
2,3-Dehydroquinuclidine-3-carboxyl


Dip =
3,3-Diphenylalanine


cDmap =
cis-2,6-Dimethyl-1-allyl-piperazine


cDmbp =
cis-2,6-Dimethyl-1-benzylpiperazine


Dmc =
Dimethoxycinnamoyl


CDmm =
cis-2,6-Dimethylmorpholine


Dmmp =
cis-2,6-Dimethyl-1-(methoxycarbonylmethyl)piperazine)


Dmo =
3,7-Dimethyl-6-octenoyl: R-+-Citronellyl


Dmpz =
2,6-Dimethylpiperazine


22Dp =
2,2-Diphenylpropionyl


Dpic =
Di-(2-picoyl)amine


Esul =
Exisulindacyl: (Z)-5-Fluoro-2-methyl-[[4-



(methylsulfonyl)phenyl]methylene]-1H-indene-3-acetyl;



(cis)


2-Fa =
2-Furanacryloyl


3-Fa =
trans-3-Furanacryloyl


F5b =
2,3,4,5,6-Pentafluorobenzyl


Fbhp =
1-(4-Fluorobenzyl)homopiperazine


4-Fbp =
1-(4-Fluorobenzyl)piperazine


F5bs =
Pentafluorobenzenesulfonyl


F5bz =
Pentafluorobenzoyl


F3c =
2,3,5-Trifluorocinnamoyl


F5c =
2,3,4,5,6-Pentafluorocinnamoyl


Fcin =
4-Formylcinnamoyl


αFcn =
αFluorocinnamoyl


F5F =
Pentafluorophenylalanine


F3MF =
4-Trifluoromethylphenylalanine


Fmoc =
9-Fluorenylmethoxycarbonyl


F5pa =
2,3,4,5,6-Pentafluorophenylacetyl


Fpmp =
1-bis(4-Fluorophenyl)methylpiperazine


Fmpi =
(Z)-5-Fluoro-2-methyl-(4-pyridylidene)-3-indenylacetyl


F5po =
2,3,4,5,6-Pentafluorophenoxyacetyl


F5Pt =
Pentafluorophenylthiocarbamyl


Fpdh =
(1S,4S)-(−)-2-(4-Fluorophenyl)-2,5-



diazabicyclo[2.2.1]heptane


Gbz =
4-Guanidinobenzoyl


Gun =
Guanidyl


Hcn =
9-(N-Hydroxycarbamoyl)-nonanoyl


Hmqc =
3-Hydroxy-2-methyl-4-quinolinecarboxyl


Hor =
(S)-(+)-Hydroorotic acid


HPhe=
Homo-phenylalanine


2Hyb =
2-Hydroxybenzoyl


3Iac =
3-β-Indoleacryloyl


3Ibu =
Indole-3-butyryl


Igl =
α-2-Indanylglycine


2Ina =
2-Indanylacetyl


Indo =
Indomethacin: 1-[p-Chlorobenzoyl]-5-methoxy-2-



methylindole-3acetyl


Inp =
Isonipecotic acid: hexahydroisonicotinic Isoquinolineacetyl


Ktlc =
Ketorolac: (±)5-benzoyl-2,3dihydro-1H-pyrrolizine-1-



carboxyl: Toradol


Ktpf =
Ketoprofen: 2-(3-benzoylphenyl)propionyl


Matp =
4-(Methylamino)-2,2,6,6-tetramethylpiperidine


4-Mbp =
1-(4-Methylbenzyl)piperazine


Mca =
2-Methylcinnamoyl


αMcn =
α-Methylcinnamoyl


Mcoa =
7-Methoxycoumarin-4-acetyl


MC2Y =
N-Methyl-O-2,6-dichlorobenzyl-tyrosine


34Mdc =
3,4-(methylenedioxy)cinnamoyl


Mpz =
1-Methylpiperazine


MTPA =
α-Methoxy-α-trifluoromethylphenylacetyl


1Nac =
3-(1-Naphthyl)acryloyl


Nal =
β-Naphthylalanine


1Nala =
Naphthylacetyl


Nap =
Naphthoyl


Napr =
Naproxen: 6-Methoxy-α-methyl-2-Naphthaleneacetyl


Nba =
Norbornane-2-acetyl


Nif =
Niflumic acid, 2-(3-[Trifluoromethyl]aniline)nicotinic



acid


NMF =
N-Methylphenylalanine


OBPY =
O-Benzyl-phosphotyrosine


OBrZY =
(O-2-Bromo-Cbz)-tyrosine


OCIY =
O-2,6-Dichlorobenzyl-3,5-diiodo-tyrosine


OC2Y =
O-2,6-dichlorobenzyl tyrosine


Ocp =
1-Octylpiperazine


Octe =
2-Octenoyl


Otac =
(−)-2-Oxo-4-thiazolidinecarboxyl


Pac =
4-Aminocinnamic acid


Pal =
β-(3-Pyridyl)alanine


Pas =
p-Aminosalicyloyl


PBF =
p-Bromophenylalanine


Pcin =
4-Phenylcinnamoyl


Pcn =
α-Phenylcinnamoyl


PCNF =
p-Cyano-L-phenylalanine


Pcnl =
β-Phenylcinnamyl


Pen(Mbzl) =
S-(4-methylbenzyl)Penicillamine


Pep =
1-(2-Phenylethyl)piperazine


PFF =
p-Fluorophenylalanine


βPhc =
β-Phenylcinnamoyl


3Php =
3-Phosphonopropionyl


5Phv =
5-Phenylvaleroyl


Pic =
Picolinoyl


PIF =
p-Iodophenylalanine


Pipe =
Piperidine


Pipp =
4-Piperidinopiperidine


Pipz =
Piperazine


Piva =
Pivaloyl (Trimethylacetyl)


Pmpz =
1-2-Pyrimidylpiperazine


PNF =
p-Nitro-phenylalanine


Ppp =
1-(3-Phenylpropyl)piperazine


Ppr =
Phenylpropiolyl


Ptmb =
4-(Trifluoromethyl)benzoyl


αPtpa =
α-(Phenylthio)phenylacetyl


Pxa =
Pyridoxamine [4-(aminomethyl)-5-hydroxy-6-methyl-



3-pyridinemethanol]


Pya =
trans-3-(3-Pyridyl)acryloyl


Pypz =
1-2-Pyridylpiperazine


Pyrc =
Pyridine-3-carboxyl


Pyz =
Pyrazinoyl


3Qum =
Quinoline-3-methyl


13cR =
13-cis-Retinoyl


Ret =
trans-Retinoyl


Rio =
Ricinoleyl


Saa =
trans-Styrylacetyl


Sab =
4-Sulphamidobenzoyl


cSdc =
cis-Stilbene-4,4′-dicarboxylic


Sibu =
S-(+)-Ibuprofen


CSsa =
cis-Styrenesulphonylacetyl


tβSts =
trans-β-Styrenesulfonyl


Taa =
1,2,4-Triazole-acetyl


Tchc =
(1R,3R,4S,5R)-1,3,4,5-Tetrahydrocyclohexane-1-carboxyl


Tcpa =
2,4,5-Trichlorophenoxyacetyl


Tf2c =
trans-3,5-bis(Trifluoromethyl)cinnamoyl


4Tfmb =
4-(Trifluoromethoxy)benzoyl


Thia =
3-(2-Thienyl)acryloyl


Th2n =
1,2,3,4-Tetrahydro-2-naphthoyl


Tic =
Tetrahydroisoquinoline-3-carboxylic acid


Tmb =
Trimethoxybenzoyl


Tmbp =
1-(2,4,6-Trimethylbenzyl)piperazine


4Tmbs =
4-(Trifluoromethoxy)benzenesulfonyl


Tmbz =
Trimethoxybenzyl


Tmcc =
2,2,3,3-Tetramethylcyclopropanecarboxyl


Tmpc =
Carboxy-TEMPO: 4-carboxy-2,2,6,6-



tetramethylpiperidinyloxy


Tyr(Bzl) =
O-Benzyl-tyrosine


ZPcn =
(Z)-α-Phenylcinnamoyl; (cis)









It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in, and be isolated in, optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of the anti-cancer compounds of the invention, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine anti-cancer and anti-tumor activity using the in vitro and in vivo tests described herein, or using other similar tests which are well known in the art.
Prodrugs of the compounds of Formula I may be identified using routine techniques known in the art. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32: 692 (1984), each of which is specifically incorporated herein by reference.
In addition, the invention also includes solvates, metabolites, and pharmaceutically acceptable salts of compounds of Formula I.
The term “solvate” refers to an aggregate of a molecule with one or more solvent molecules. A “metabolite” is a pharmacologically active product produced through in vivo metabolism in the body of a specified compound or salt thereof. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of Formula I, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
A “pharmaceutically acceptable salt” as used herein, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, pheylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, .gamma.-hydroxybutyrates, glycollates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. Since a single compound of the present invention may include more than one acidic or basic moieties, the compounds of the present invention may include mono, di or tri-salts in a single compound.
In the embodiments of the present invention in which the anti-cancer compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an acidic compound, particularly an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alphahydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
In the embodiments of the present invention in which the anti-cancer compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base. Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and the like. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglusoamine, plus salts formed with basic amino acids such as ornithine, histidine, lysine and arginine.
Whereas most of the results of in vivo anti-cancer activity of compounds reported in this application were obtained by intraperitoneal injection of compounds into nude mice bearing implanted tumors, reference compound M570 was shown to be active after oral administration.
The active anti-cancer compounds are effective over a wide dosage range and are generally administered in a therapeutically-effective amount. The dosage and manner of administration will be defined by the application of the anti-cancer agent and can be determined by routine methods of clinical testing to find the optimum dose. These doses are expected to be in the range of 0.001 mg/kg to 100 mg/kg of active compound. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
When employed as pharmaceuticals, the compounds of Formula I are administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Preferably, the anti-cancer compounds of the present invention are administered via intratracheal instillation or aerosol inhalation when used to treat lung cancer. Such pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active anti-cancer compound of Formula I.
The pharmaceutical compositions of the present invention contain, as the active ingredient, one or more of the compounds of Formula I above, associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 30% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the anti-cancer compound to provide the appropriate particle size prior to combining with the other ingredients. If the anti-cancer compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the anti-cancer compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably these compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are not intended to be limiting.
EXAMPLES
Example I
Synthesis of Compounds
Compounds were synthesized by standard organic chemistry procedures well known in the art. Compounds were purified by HPLC and were characterized by analytical HPLC, TLC, and LDMS. Examples of structures of compounds tested are given in Tables 2 and 3.
Example II
Synthesis of M570 Hydrochloride: F5c-OC2Y-Atmp.HCl
4-Amino-2,2,6,6-tetramethylpiperidine (Aldrich) was coupled with Boc-(O-2,6-dichlorobenzyl)-tyrosine, using BOP in DMF solution. The Boc protecting group was removed by TFA and the product coupled with 2,3,4,5,6-pentafluorocinnamic acid in DMF, using BOP in the presence of excess DIEA at room temperature for 3 hours. The DMF was removed in vacuo, the product was extracted into ethyl acetate and the solvent was evaporated. The residue was treated with 0.1-1.0 N HCl or 20% ethanolic HCl. The solvent was removed by evaporation in vacuo at room temperature. The residue was lyophilized from water-dioxane or crystallized from ethanol-ether.
Example III
In Vitro Colorimetric Assay for Cell Survival
Cell growth and survival were measured by a rapid colorimetric assay based on the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) (Mosmann, J. Immunol. Methods 65: 55-63, 1983, with minor modifications). Briefly, 1,000 normal lung fibroblasts or normal epithelial BEAS-2B cells, 1,000 or 5,000 viable non-SCLC cells or 10,000 viable SCLC cells were plated in 100 μL of growth medium in 96-well flat-bottomed microtiter plates. Cells were incubated overnight to allow recovery. Compounds to be tested were added to the cells in triplicate in a range of concentrations and the cells were incubated at 37° C., 5% CO2, with 100% humidity. Control cells were treated in the same way without antagonists. All wells had a final volume of 200 μL. Plates were incubated for 4 days, allowing sufficient time for cell replication and compound-induced cell death to occur. On day 5, 25 μL of a 2 mg/mL solution of MTT (Sigma) dissolved in RMPI-1640 was added to each well. The plate was incubated for 4 h at 37° C. The supernatant liquid was removed and the blue formazan complex was dissolved by adding 100 μL of 0.02 N HCl in 75% isopropanol to all wells. Absorbance was immediately determined using a scanning multiwell plate reader. M570 caused 50% cell death at a concentration of 0.15 μM under these conditions. Examples of structures of compounds tested and their biological activities on cancers in vitro are given in Tables 2 and 3.
Example IV
Inhibition of Tumor Growth in vivo in Nude Mice
Compounds having high in vitro cytotoxic activity were tested against implanted tumors in vivo. Athymic nude mice were implanted subcutaneously with suspensions (2 million SHP-77 SCLC cells, 1 million A549 NSCLC cells or 1.5 million PC3 PC cells) in Matrigel suspension. On the eighth day after tumor implantation groups of 5 mice bearing implants were injected intraperitoneally with the compounds being tested at 5 mg/kg/every second day or at 10 mg/kg/every fourth day; control animals were injected with an equal volume of isotonic saline. Less soluble compounds were initially dissolved in dimethyl sulfoxide (DMSO) and diluted with medium. In those cases the control injections contained the same concentration of DMSO. Tumor size was measured with a caliper three times per week. Tumor volume was calculated by the formula:

Volume(cc)=3.14×(length)×(width)2/6

At autopsy tumors were removed and weighed. Tumor inhibition was calculated on both weight and measurement basis. Results of representative in vivo tests are given in Tables 2 and 3.In each Table, an IC50 value of “0” represents no detectable anti-cancer activity for a drug in a given cell line and “Stim.” indicates the observation of a stimulatory activity on the growth of the cancer cell line. For comparison, reference compound M570 caused 85% inhibition of growth of the SCLC line SHP-77 and 65% inhibition of PC cell line PC3 tumors at a dose of 5 mg/kg/every second day or at 10 mg/kg/every fourth day.








TABLE 2







Structures and Activities of Anti-Cancer Compounds of the Present Invention














SHP-77
SHP-77
A-549
PC3


Analog

In vitro
In vivo
In vivo
In vivo


Number
Structure
IC50, μMa
% inhib.c
% inhib.c
% inhib.c















M-1052
F5c-Igl-Atmp
7.3


27


M-1054
F5c-F5F-Atmp
4.6


47


M-1080
F5c-OBPY-Atmp
0


M-1092
F5BS-OC2Y-Atmp
14


Stim.


M-1094
F5PT-OC2Y-Atmp
3.2


52


M-1096 #1
IMP-OC2Y-Atmp
7.0


M-1096 #2
IMP-OC2Y-Atmp
4.0


M-1098 #1
CHFB-OC2Y-Atmp
0


M-1098 #2
CHFB-OC2Y-Atmp
6.8


M-1100
Gun-Cys-OC2Y-Matp
13


13


M-1108
F5c-D-OC2Y-Atmp
0


46


M-1110
F5c-PCNF-Atmp
0.9


54


M-1112
F5c-PNF-Atmp
30


24


M-1114
F5c-Trp-Atmp
0


28


M-1116
Dca-OC2Y-Atmp
7.5


19


M-1118
F5c-OC2Y-Atmp(2Me)
1.8


M-1120
Glu-Trp-Atmp
0


M-1124 #1
Chpa-OC2Y-Atmp
1.7

50
Stim


M-1124 #2
Chpa-OC2Y-Atmp
3.5

4.5


M-1126
22Dp-OC2Y-Atmp
4.0

36


M-1128
Rio-OC2Y-Atmp
1.6

48
44


M-1140
F5c-PFF-Atmp
15


M-1142
F5c-PIF-Atmp
7.2


M-1144
F5c-PBF-Atmp
7.2


20


M-1146
F5c-F3MF-Atmp
12


M-1148
F5c-NMF-Atmp
15.5


M-1150
F5c-Dip-Atmp
5


M-1152
3-Fa-PFF-Atmp
0


M-1154
2-Fa-PFF-Atmp
0


Stim


M-1156
F5c-PFF-Abzp
7.5


56


M-1158
F5c-PFF-Mpz
28


M-1160
F5c-PFF-Dmpz
24


M-1162
F5c-PFF-Pmpz
15


M-1164
F5c-PFF-Pypz
14


M-1174
F5c-Bip-Atmp
3.7

57
37


M-1176
F5c-hPhe-Atmp
14


M-1178
F5c-Phe-Atmp
15


M-1180
F5c-PIF-Abzp
3.2

23
53


M-1182
F5c-F5F-Abzp
19.5


M-1186
F5c-F5F-Dmpz
11


M-1188
Bcpa-F5F-Abzp
4.5

17


M-1200
F5c-Nal-Dpic
5.0

Stim


M-1202
F5c-PFF-Cbp
30


M-1204
Pya-Nal-Cbp
7.5


M-1208
F5c-PFF-Cpp
30


M-1212
Pya-PFF-Cpp
10


M-1214
Bcpa-Nal-Dpic
7.3

24
37


M-1216
F5c-Nal-Pypz
0

32
22


M-1218
F5c-Aic-Dpic
14


M-1242
Bcpa-Nal-Pypz
0

19
36


M-1244
Bcpa-Bip-Atmp
1.3


59


M-1246
Bcpa-Nal-Pipp
3.6


Stim


M-1248
F5c-PIF-Pypz
13


M-1250
F5c-Nal-Pipp
7.6


M-1252
Tf2c-PIF-Pypz
0


M-1254
F5c-PIF-Dmpz
10


M-1256
F5c-PIF-Dpic
13


M-1258
F5c-Bip-Pypz
48


10


M-1260
F5c-Bip-Pmpz
10


60


M-1268
F5c-Bip-Bdbh
3


36
















TABLE 3







Structures and Activities of Anti-Cancer Compounds of the Present Invention















NSCLC
SCLC
SHP-77
A-549
PC3


Analog

A-549
SHP-77
In vivo
In vivo
In vivo


Number
Structure
IC50, μMb
IC50, μMa
% inhib.c
% inhib.c
% inhib.c
















M-1272
F5c-Bip-Fpdh
22
10


71


M-1274
Bcpa-Bip-Atmp
7.3
2.1


M-1276
Bcpa-Bip-Bdbh
20
0


56


M-1278
F5c-Bip-Aqu


M-1280
F5c-PIF-Bdbh
20
10


40


M-1284
F5c-PIF-Dasd
20
22


Stim.


M-1286
F5c-PIF-(R)-(+)-Aqu
9.0
4.3


M-1288
F5c-Bip-(R)-(+)-Aqu
7.3
4.3


M-1290
F5c-PIF-(S)-(−)-Aqu
14


M-1292
F5c-Bip-(S)-(−)-Aqu
9.8


M-1294
F5c-PIF-Bhp
22



44


M-1296
F5c-Bip-Bhp


M-1298
F5c-PIF-Cpp
21


M-1300
F5c-PIF-Cbp
21


M-1304
F5c-PIF-Pep
17


M-1306
F5c-PIF-3-Abzp
18


M-1308
F5c-PIF-Ppp
14


M-1310
F5c-PIF-4-Clbp
12



Stim.


M-1312
F5c-PIF-BapS
13



33


M-1314
F5c-PIF-Chmp
21


M-1316
F5c-PIF-Alp
20


M-1318
F5c-PIF-Daep
8.4


M-1320
F5c-PIF-4-Cypp
17


M-1322
F5c-PIF-Fbp
13



46


M-1324
F5c-PIF-Chep
15



44


M-1326
F5c-PIF-BapR
10



0.6


M-1328
F5c-PIF-2-Cypp
14


M-1330
F5c-PIF-Ocp
17



40


M-1332
F5c-PIF-4-Mbp
7.8



63


M-1334
F5c-PIF-Tmbp
19



50


M-1336
F5c-PIF-Fpmp
12



71


M-1342
F5c-PIF-Fbhp


M-1350
Pic-OC2Y-Atmp

6.1

36


M-1352
Pic-PCNF-Atmp

0

21


M-1354
Pic-Igl-Atmp

0


M-1356
F5pa-OC2Y-Atmp

4.4

0


M-1358
F5po-OC2Y-Atmp

4.1


30


M-1360
F5bz-OC2Y-Atmp

4.1


Stim.


M-1362
3,4Dmc-OC2Y-Atmp

4.0

21


M-1364
3Ibu-OC2Y-Atmp

7.2

50
9


M-1366
Dmo-OC2Y-Atmp

3.8

14


M-1368
2Pyz-OC2Y-Atmp

3.2

47
Stim.


M-1372
Bbz-OC2Y-Atmp

0

64


M-1374
Bbz-Igl-Atmp

0


M-1376
Indo-OC2Y-Atmp
1.8
1.5

18
44


M-1378
Aspr-OC2Y-Atmp
3.5
2.9

9
Stim.


M-1380
Napr-OC2Y-Atmp
1.6
1.7


26


M-1382
Dfc-OC2Y-Atmp

2.9

46


M-1384
Chl-OC2Y-Atmp
1.9
1.8

46
Stim.


M-1386
Tmpc-OC2Y-Atmp

12


20


M-1388
F3c-OC2Y-Atmp

1.6

21
Stim.


M-1390
Gbz-OC2Y-Atmp
4.3
>40


Stim.


M-1392
Ktpf-OC2Y-Atmp

2.9

28
18


M-1394
Ktlc-OC2Y-Atmp
4.9
2.9

68
Stim.


M-1396
Dhq-OC2Y-Atmp

15


9


M-1398
Ppr-OC2Y-Atmp

8.0


65


M-1400
Pcn-OC2Y-Atmp

1.3


Stim.


M-1402
Hcn-OC2Y-Atmp

0


Stim.


M-1406
Tmcc-OC2Y-Atmp

5.3


25


M-1408
3,4,5Tmb-OC2Y-Atmp

8.0


Stim.


M-1412
2Octe-OC2Y-Atmp

12


38


M-1414
34Mdc-OC2Y-Atmp

7.1


Stim.


M-1416
Tchc-OC2Y-Atmp

0


0


M-1418
Thia-OC2Y-Atmp

8.6


9


M-1420
Atfb-OC2Y-Atmp

12


Stim.


M-1422
Cpcpc-OC2Y-Atmp

13


31


M-1430
F5c-Pen(Mbzl)-Atmp

6.1


50


M-1432
F5c-PFF-Dmmp

18


M-1434
3Pal-OC2Y-Atmp

3.8
Stim.


M-1436
Biot-OC2Y-Atmp

0


M-1440
Th2n-OC2Y-Atmp

3.5


15


M-1442
Arac-OC2Y-Atmp

6.4


31


M-1444
Tf2c-OC2Y-Atmp

1.4


11


M-1446
Ret-OC2Y-Atmp

6.7


60


M-1448
2Ina-OC2Y-Atmp

13


11


M-1450
2Hyb-OC2Y-Atmp

13


Stim.


M-1452
Atfb-OC2Y-Atmp

7.2


Stim.


M-1456
Fcin-OC2Y-Atmp

4.0


17


M-1458
Sab-OC2Y-Atmp

0


Stim.


M-1460
Bcin-OC2Y-Atmp

23


38


M-1462
Hor-OC2Y-Atmp

0


7


M-1464
Aba-OC2Y-Atmp

14


14


M-1466
Biot-PCNF-Atmp

0


29


M-1468
Biot-Pen(Mbzl)-Atmp

0


46


M-1470
Ret-Pen(Mbzl)-Atmp


M-1472
Ret-PCNF-Atmp


M-1474
3Ibu-Pen(Mbzl)-Atmp

7.8


Stim.


M-1476
3Ibu-PCNF-Atmp

0


M-1478
Rio-PCNF-Atmp

14


M-1480
Tmpc-Pen(Mbzl)-Atmp

0


Stim.


M-1482
Tmpc-PCNF-Atmp

0


M-1484
Ptmb-OC2Y-Atmp

1.8


Stim.


M-1486
F5po-Pen(Mbzl)-Atmp

4.2


21


M-1488
F5po-PCNF-Atmp

0


M-1490
F5bz-PCNF-Atmp

>60


M-1492
Aca-Pen(Mbzl)-Atmp

3.4


15


M-1494
Aca-OC2Y-Atmp

1.6


40


M-1496
Aca-PCNF-Atmp

>60


2


M-1498
Chl-Pen(Mbzl)-Atmp

3.5


20


M-1500
Chl-PCNF-Atmp

25


M-1502
F3c-Pen(Mbzl)-Atmp

3.4


11


M-1504
F3c-PCNF-Atmp

>60


M-1506
Napr-Pen(Mbzl)-Atmp

4.7


13


M-1508
Napr-PCNF-Atmp

23


45


M-1510
22Dp-Pen(Mbzl)-Atmp

4.2


Stim.


M-1512
22Dp-PCNF-Atmp

22


48


M-1514
Dca-Pen(Mbzl)-Atmp

7.3


M-1516
Dca-PCNF-Atmp

11


M-1518
Indo-Pen(Mbzl)-Atmp

6.0


Stim.


M-1520
Indo-PCNF-Atmp

13


Stim.


M-1522
2Pyz-Pen(Mbzl)-Atmp

31


Stim.


M-1524
2Pyz-PCNF-Atmp

>60


M-1528
Fmpi-OC2Y-Atmp

1.7


M-1532
Esul-OC2Y-Atmp
5
4.0

54
42


M-1536
4Tmbs-OC2Y-Atmp

3.2


Stim.


M-1538
4Tfmb-OC2Y-Atmp

1.8


Stim.


M-1542
4Bpc-OC2Y-Atmp

6.4


Stim.


M-1544
F5c-OC2Y-(R)-Aqu

6.0


28


M-1546
F5c-OC2Y-(S)-Aqu

1.8


29


M-1548 #1
Chpa-OC2Y-(R)-Aqu

4.0


M-1548 #2
Chpa-OC2Y-(R)-Aqu

13


M-1550 #1
Chpa-OC2Y-(S)-Aqu

2.5


36


M-1550 #2
Chpa-OC2Y-(S)-Aqu

4.0


Stim.


M-1552
F5c-OC2Y-Abzp

13


52


M-1554
F5c-OC2Y-Pmpz

6.8


Stim.


M-1556
F5c-OC2Y-cDmbp

18


59


M-1558
Indo-OC2Y-Abzp

9.6


Stim.


M-1560
Indo-OC2Y-cDmbp

0


Stim.


M-1562
Indo-OC2Y-Pmpz

0


2


M-1564
F5c-OC2Y-tCip

4.0


M-1566
Indo-OC2Y-tCip

0


57


M-1568
Cmioc-OC2Y-Atmp

3.6


Stim.


M-1574
Dbhc-OC2Y-Atmp

1.6


Stim.


M-1576
Bzac-OC2Y-Atmp

6.2


57


M-1578
F5c-OC2Y-Dcpp




Stim.


M-1580
Indo-OC2Y-Dcpp


M-1582
F5c-OC2Y-Amp

6.7


60


M-1584
Indo-OC2Y-Amp

1.5


32


M-1586
Indo-D-OC2Y-Atmp

1.7


38


M-1588
Indo-OC2Y-(R)-Aqu

3.9


8


M-1590
Indo-OC2Y-(S)-Aqu

4.1


Stim.


M-1592
Pas-OC2Y-Atmp

7.2


Stim.


M-1594
F5b-OC2Y-Atmp

3.1


20


M-1596
6Ani-OC2Y-Atmp

0


M-1598
tDecl-OC2Y-Atmp

4.1


M-1600
Pcnl-OC2Y-Atmp

4.1


44


M-1602
Acrc-OC2Y-Atmp

1.6


Stim.


M-1604
3Qum-OC2Y-Atmp

7.4


Stim.


M-1606
F5c-OC2Y-Bhp

17


M-1608
F5c-ObrZY-Atmp

10


29


M-1610
B6-OC2Y-Atmp

0


Stim.


M-1612
B6P-OC2Y-Atmp

0


Stim.


M-1614
F5c-OC2Y-cDmap

2.0


54


M-1616
3Php-OC2Y-Atmp

0


18


M-1618
Aq2c-OC2Y-Atmp

2.2


10


M-1622
F5c-OC2Y-Pxa

22


58


M-1624
F5c-OC2Y-Ambi

50


68


M-1628
Amts-OC2Y-Atmp

45


M-1630
Otac-OC2Y-Atmp

60


71


M-1632
F5c-OC2Y-Aem

7.8


32


M-1634
F5b-OC2Y-tCip

0


Stim.


M-1636
F5c-OC2Y-Pipz


M-1638
Chc-OC2Y-Atmp

18


39


M-1642
F5c-OC2Y-Apia

42


M-1648
Pac-OC2Y-Atmp

7.6


28


M-1650
Nba-OC2Y-Atmp

4.3


40


M-1652
2Ccn-OC2Y-Atmp

4.1


M-1654
Pcn-OC2Y-tCip

0


M-1656
Biot-OC2Y-tCip

5.5


M-1658
Pcn-OC2Y-Amp

10


M-1660
Pcn-OC2Y-Abzp

31


M-1662
Pcn-OC2Y-cDmbp

20


M-1664
Ktlc-OC2Y-cDmbp

0


M-1666
Ktlc-OC2Y-tCip

0


M-1668
Ktlc-OC2Y-Abzp

4.6


M-1670
Pcn-OC2Y-Pmpz

50


M-1672
Aaa-OC2Y-Pmpz

>50


M-1674
Ktlc-OC2Y-Amp

3.2


M-1676
Aca-OC2Y-Amp

6.2


M-1678
Aca-OC2Y-Abzp

7.8


M-1680
Aca-OC2Y-Pmpz

33.


M-1682
Pcn-D-OC2Y-Atmp

1.8


M-1684
Pcn-Igl-Atmp

4.2


M-1686
Ktlc-Igl-Atmp

14


M-1688
Indo-Igl-Atmp

4.0


M-1690
F5c-Igl-Pipz(F5b)

25


M-1692
Dcla-OC2Y-Atmp

7.2


M-1698
Dbhc-OC2Y-Amp

4.2


M-1700
Acrc-OC2Y-Amp

7.3


M-1702
Aq2c-OC2Y-Amp

3.6


M-1704
Pyrc-OC2Y-Atmp

25


M-1706
1Nap-OC2Y-Atmp

4.2


M-1708
1Nala-OC2Y-Atmp

7.2


M-1710
2Nala-OC2Y-Atmp

1.7


M-1712
5Phv-OC2Y-Atmp


M-1714
2Cln-OC2Y-Atmp

4.0


M-1716
Hmqc-OC2Y-Atmp

7.2


M-1718
Baaa-OC2Y-Atmp

0


M-1720
Tcpa-OC2Y-Atmp


M-1722
F5c-OC2Y-Pipe(Btmb)

26


M-1724
Pcn-OC2Y-Pipe(Btmb)

0


M-1726
F5c-OC2Y-Pipz(Tmbz)

26


M-1728
Pcn-OC2Y-Pipz(Tmbz)

26


M-1730
F5c-F5F-Pipz(F5b)

21


M-1732
F5c-OC2Y-Pipz(F5b)

24


M-1734
Pcn-OC2Y-Pipz(F5b)

24


M-1736
Piva-OC2Y-Atmp

13


M-1738
F5c-OC2Y-Apyr(Tmbz)

24


M-1742
Otac-OC2Y-Ambi


M-1744
Mcoa-OC2Y-Atmp

7.1


M-1746
Chbu-OC2Y-Atmp

1.6


M-1748
tBua-OC2Y-Atmp

7.1


M-1750
(S)-MTPA-OC2Y-Atmp

4.2


M-1752
(R)-MTPA-OC2Y-Atmp

4.0


M-1754
Bcpa-OC2Y-Atmp

1.5


M-1756
Bcpoa-OC2Y-Atmp


M-1758
αMcn-OC2Y-Atmp


M-1760
Pcn-OCIY-Atmp

2.0


M-1762
Bcpa-OCIY-Atmp

3.0


M-1764
Pcn-Bip-Atmp

2.5


M-1766
Bcpoa-Bip-Atmp

2.0


M-1770
Pcn-Tic-Atmp

5.4


M-1772
Pcn-Tyr(Bzl)-Atmp


M-1774
13cR-OC2Y-Atmp


M-1776
Pcin-OC2Y-Atmp

1.4


M-1778
Mca-OC2Y-Atmp

1.5


M-1780
Saa-OC2Y-Atmp

1.8


M-1782
Bipa-OC2Y-Atmp

3.0


M-1786
Taa-OC2Y-Atmp

0


M-1788
Pcn-PFF-Atmp

2.3


M-1790
Pcn-F3MF-Atmp

2.2


M-1796
Bipa-Bip-Atmp

1.5


M-1798
Fmoc-Leu-Atmp

7.6


M-1800
Fmoc-OC2Y-Atmp

1.7


M-1804
Pcn-MC2Y-Atmp


M-1806
αPtpa-OC2Y-Atmp


M-1808
cSsa-OC2Y-Atmp


M-1810
1Nac-OC2Y-Atmp


M-1812
cSdc-OC2Y-Atmp


M-1816
Bcpa-Dip-Atmp


M-1832
3Iac-Bip-Atmp


M-1834
F5c-OC2Y-AtmpO


M-1836
ZPcn-OC2Y-Atmp


M-1838
tβSts-OC2Y-Atmp


M-1840
βPhc-OC2Y-Atmp


M-1842
αFcn-OC2Y-Atmp


M-1844
Nif-OC2Y-Atmp


M-1846
Nif-Bip-Atmp


M-1848
SIbu-OC2Y-Atmp


M-1850
SIbu-Bip-Atmp


M-1852
Fmoc-Bip-Atmp


M-1854
Bphs-OC2Y-Atmp


M-1856
Bphs-Bip-Atmp


M-1858
αFcn-Bip-Atmp


M-1862
2Nac-OC2Y-Atmp


M-1864
Bipa-F3MF-Atmp


M-1868
Pcn-PIF-Atmp





Footnotes:


aED50 for killing of SCLC strain SHP-77 in vitro, μM.


bED50 for killing of NSCLC strain A-549 in vitro, μM.


cPercent inhibition of tumor growth in vivo in nude mice. PC3 is prostate cancer.






The foregoing description of the present invention has been presented for purposes of illustration and description. Furthermore, the description is not intended to limit the invention to the form disclosed herein. Consequently, variations and modifications commensurate with the above teachings, and the skill or knowledge of the relevant art, are within the scope of the present invention. The embodiment described hereinabove is further intended to explain the best mode known for practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with various modifications required by the particular applications or uses of the present invention. It is intended that the appended claims be construed to include alternative embodiments to the extent permitted by the prior art.

## Claims

1. An anti-cancer compound selected from the group consisting of:
(−)-2-Oxo-4-thiazolidinecarboxyl-O-2,6-dichlorobenzyl tyrosine-4-amino-2,2,6,6-tetramethylpiperidine (Otac-OC2Y-Atmp);
9-Fluorenylmethoxycarbonyl-O-2,6-dichlorobenzyl tyrosine-4-amino-2,2,6,6-tetramethylpiperidine (Fmoc-OC2Y-Atmp);
2,3,4,5,6-Pentafluorocinnamoyl-O-2,6-dichlorobenzyl tyrosine-2-(Aminomethyl)benzimidazole (F5c-OC2Y-Ambi); and,
5-benzoyl-2,3dihydro-1H-pyrrolizine-1-carboxyl-O-2,6-dichlorobenzyl tyrosine-4-amino-2,2,6,6-tetramethylpiperidine (Ktlc-OC2Y-Atmp).

2. A prodrug of the anti-cancer compound of claim 1.

3. A pharmaceutically-acceptable salt of the anti-cancer compound of claim 1.

4. A pharmaceutical composition comprising an anti-cancer compound of claim 1 and at least one of an excipient and a pharmaceutically-acceptable carrier.