# US 11,440,917 B2 · EIF4A-inhibiting compounds and methods related thereto

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- Number: US 11,440,917 B2
- Document ID: US11440917B2
- Status: Granted
- Kind: B2
- Application number: 16/804,937
- Filed: 2020-02-28
- Published: 2020-10-29
- Granted: 2022-09-13
- Earliest claimed: 2015-11-25
- Assignees: eFFECTOR Therapeutics, Inc.
- Applicants: eFFECTOR Therapeutics Inc.
- Inventors: Justin T. Ernst; Siegfried H. Reich; Paul A. Sprengeler; Chinh Viet Tran; Garrick Kenneth Packard; Alan X. Xiang; Christian Nilewski; Theo Michels
- Web page: https://patentgrep.com/patent/US11440917B2

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 307/93: condensed with a ring other than six-membered
- C07D 333/78: condensed with rings other than six-membered or with ring systems containing such rings
- C07D 491/153: the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
- C07D 491/16: Peri-condensed systems
- C07D 491/20: Spiro-condensed systems
- C07D 498/14: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds X, Y, R1, R2, R3a, R3b, R4a, R4b and R5 are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4A and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.

## Claims

### Claim 1

A method for treating an eIF4A dependent condition in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of at least one compound according to Formula (I)
or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
X is O, S, S(O) or S(O)2;
Y is a 5-membered heteroaryl or a 6-membered aryl or heteroaryl;
R1 and R2 independently are aryl;
R3a, R3b, R4a and R4b independently are H, halogen, CN, C1-C8(alkyl), (C1-C8)haloalkyl, C2-C8(alkenyl), (C2-C8)alkynyl, OR9, NHR9, NR9R9, [(C1-C8)alkylene]OR9, [(C1-C8)alkylene]NHR9, [(C1-C8)alkylene]NR9R9, C(O)R8, C(O)NHR9, C(O)NR9R9, C(O)[(C1-C8)alkylene]NHR9, C(O)[(C1-C8)alkylene]NR9R9, CO2R9, C(S)NHR9, C(S)NR9R9, SR9, S(O)R9, SO2R9, SO2NHR9, SO2NR9R9, NH(CO)R8, NR9(CO)R8, NH(CO)NHR9, NH(CO)NR9R9, NR9(CO)NHR9, NR9(CO)NR9R9, P(O)(OH)(OR9), P(O)(OR9) (OR9), aryl, heteroaryl, cycloalkyl or heterocyclyl;
R3a and R3b, and R4a and R4b independently combine to form oxo or alkenyl, or a cycloalkyl or heterocyclyl ring; or
R3a and R4a, R3b and R4b or R4a and R5 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;
R5 is H, halogen, OH, CN, N3, SR9, (C1-C8)alkyl, (C1-C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkynyl, NHC(O)(C1-C8)alkyl or heteroaryl;
R6 and R7 independently are H, CN, halogen, OR9, SR9, (C1-C8)alkyl, NH(R9) or NR9R9;
R8 is H, (C1-C8)alkyl, (C1-C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, cycloalkyl, O(cycloalkyl), heterocyclyl, O(heterocyclyl), aryl, O(aryl), heteroaryl or O(heteroaryl);
R9 is H, (C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, [(C1-C8)alkylene]heterocyclyl, aryl, [(C1-C8)alkylene] aryl or heteroaryl;
wherein the two R9's together with the nitrogen atom to which they are attached of NR9R9, [(C1-C8)alkylene]NR9R9, C(O)NR9R9, C(O)[(C1-C8)alkylene]NR9R9, C(S)NR9R9, SO2NR9R9, NH(CO)NR9R9 or NR9(CO)NR9R9, optionally form a heterocyclyl ring;
wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy;
or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo;
“m” and “p” are 1, 2, 3, 4, 5 or 6; and
wherein when Y is a 6-membered aryl then X is not O,
in combination with at least one other therapeutic agent;
wherein the eIF4A dependent condition is breast cancer.

### Claim 2 (depends on 1)

The method according to claim 1 wherein X is O.

### Claim 3 (depends on 1)

The method according to claim 1 wherein the 6-membered aryl or heteroaryl is
wherein
A1 is N or CR10;
A2 is N or CR11;
A3 is N or CR12;
A4 is N or CR13; and
R10, R11, R12 and R13 independently are H, halogen, C1-C8(alkyl), (C1-C8)haloalkyl, C(O)O(C1-C8)alkyl, C(O)(C1-C8)alkyl, SO2(C1-C8)alkyl, C1-C8(alkenyl), (C1-C8)alkynyl, OR9, NHR9, NR9R9, CN, [(C1-C8)alkylene]OR9, [(C1-C8)alkylene]NHR9, [(C1-C8)alkylene]NR9R9, C(O)R8, C(O)NHR9, C(O)NR9R9, C(O)[(C1-C8)alkylene]NHR9, C(O)[(C1-C8)alkylene]NR9R9, CO2R9, C(S)NHR9, C(S)NR9R9, SR9, S(O)R9, SO2R9, SO2N(H)(R9), SO2NR9R9, NH(CO)R8, NR9(CO)R8, NH(CO)NHR9, NH(CO)NR9R9, NR9(CO)NHR9, NR9(CO)NR9R9, P(O)(OH)(OR9), P(O)(OR9) (OR9), aryl, heteroaryl, cycloalkyl, or heterocyclyl.

### Claim 4 (depends on 3)

The method according to claim 3 wherein
A2 and A4 are N, A1 is CR10 and A3 is CR12, wherein R10 and R12 independently are H, CN, halogen or OR9;
A2 is N, A1 is CR10, A3 is CR12 and A4 is CR13, wherein R10, R12 and R13 independently are H, CN, halogen or OR9;
A3 is N, A1 is CR10, A2 is CR11 and A4 is CR13, wherein R10, R11 and R13 independently are H, CN, halogen or OR9; or
A4 is N, A1 is CR10, A2 is CR11 and A3 is CR12, wherein R10, R11 and R12 independently are H, CN, halogen or OR9.

### Claim 5 (depends on 4)

The method according to claim 4 wherein A2 is N, A1 is CR10, A3 is CR12 and A4 is CR13, wherein R10, R12 and R13 independently are H, CN, halogen or OR9; or
A3 is N, A1 is CR10, A2 is CR11 and A4 is CR13, wherein R10, R11 and R13 independently are H, CN, halogen or OR9.

### Claim 6 (depends on 1)

The method according to claim 1 wherein R3a, R3b, R4a and R4b independently are H, halogen, C1-C8(alkyl), (C1-C8)haloalkyl, OH, CN, [(C1-C8)alkylene]OR9, [(C1-C8)alkylene]NHR9, [(C1-C8)alkylene]NR9R9, C(O)NH2, C(O)NHR9, C(O)NR9R9, C(O)R9, CO2R9, C(S)NH2, S(O)R9, SO2R9, SO2NHR9, SO2NR9R9, heteroaryl or cycloalkyl, wherein R9 is a C1-C8(alkyl) or (C1-C8)haloalkyl, or wherein the two R9's together with the nitrogen atom to which they are attached of [(C1-C8)alkylene]NR9R9, C(O)NR9R9 or SO2NR9R9, optionally form a heterocyclyl ring.

### Claim 7 (depends on 1)

The method according to claim 1 wherein R3b is [(C1-C8)alkylene]NHR9 or [(C1-C8)alkylene]NR9R9, wherein R9 is C1-C8(alkyl) or (C1-C8)haloalkyl, or wherein the two R9's together with the nitrogen atom to which they are attached of [(C1-C8)alkylene]NR9R9 optionally form a heterocyclyl ring.

### Claim 8 (depends on 7)

The method according to claim 7 wherein R3b is [(C1-C8)alkylene]NR9R9 and R9 is C1-C8(alkyl).

### Claim 9 (depends on 1)

The method according to claim 1 wherein R4b is OH.

### Claim 10 (depends on 1)

The method according to claim 1 wherein R5 is OH.

### Claim 11 (depends on 1)

The method according to claim 1 wherein R6 and R7 are H or C1-C8(alkyl).

### Claim 12 (depends on 1)

The method according to claim 1 wherein R9 is H or C1-C8(alkyl).

### Claim 13 (depends on 1)

The method according to claim 1 where the compound is selected from
(5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 147F),
4-((5aR,6S,7S,8R,8aS)-3-Chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 198aF),
(5aR,6S,7S,8R,8aS)-7-(Azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 212F),
(5aR,6S,7S,8R,8aS)-5a-(4-Chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 145F),
Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 144F),
Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 143F),
Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 142F),
Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 196F),
(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 139F),
Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 207bF),
Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 152F),
Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 157bF),
Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 158bF),
4-((5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 231F),
Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 159bF),
4-((5aR,6S,7S,8R,8aS)-3-Chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 140F),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 146F),
(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 151F),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 197F),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 207aF),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 157cF),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 153F),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 159cF),
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 158cF),
Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 180F),
Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 206F),
4-((4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 66F),
(4bS,5R,6S,7S,7aR)-7a-(4-Chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 272F),
(4bS,5R,6S,7S,7aR)-7a-(4-(Difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 106F), and
(4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 107F),
or pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 1)

The method of claim 1 wherein the at least one additional therapeutic agent is an anti-cancer agent.

### Claim 15 (depends on 14)

The method of claim 14, wherein the anti-cancer agent is a chemotherapeutic drug.

### Claim 16 (depends on 15)

The method of claim 15, wherein the chemotherapeutic drug is selected from the group consisting of an inhibitor of chromatin function, a topoisomerase inhibitor, a microtubule inhibiting drug, a DNA damaging agent, an antimetabolite, a DNA synthesis inhibitor, a DNA interactive agent, and a DNA repair inhibitor.

### Claim 17 (depends on 16)

The method of claim 16, wherein the chemotherapeutic drug is selected from the group consisting of pyrimidine analogs, purine analogs, folate antagonists, antiproliferative/antimitotic agents, vinca alkaloids, epidipodophyllotoxins, antibiotics, anthracyclines, enzymes, antiplatelet agents, antiproliferative/antimitotic alkylating agents, nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates-busulfan, nitrosoureas, trazenes, antimetabolites, platinum coordination complexes, hormones, hormone analogs, aromatase inhibitors, anticoagulants, fibrinolytic agents, antisecretory agents, immunosuppressives, anti-angiogenic compounds, growth factor inhibitors, angiotensin receptor blocker, nitric oxide donors, anti-sense oligonucleotides, antibodies, chimeric antigen receptors, cell cycle inhibitors, differentiation inducers, mTOR inhibitors, topoisomerase inhibitors, corticosteroids, growth factor signal transduction kinase inhibitors, mitochondrial dysfunction inducers, toxins, caspase activators, and chromatin disruptors.

### Claim 18 (depends on 15)

The method of claim 15, wherein the chemotherapeutic drug is selected from the group consisting of 5-fluorouracil, floxuridine, capecitabine, gemcitabine, cytarabine, mercaptopurine, thioguanine, pentostatin, cladribine, vinblastine, vincristine, vinorelbine, taxane, paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilones, navelbine, etoposide, teniposide, actinomycin, amsacrine, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin, procarbazine, taxol, taxotere, temozolamide, triethylenethiophosphoramide, dactinomycin, daunorubicin, doxorubicin, adriamycin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin, mitomycin, L-asparaginase, mechlorethamine, cyclophosphamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, carmustine, dacarbazinine, methotrexate, cisplatin, carboplatin, procarbazine, hydroxyurea, mitotane, aminoglutethimide, estrogen, tamoxifen, goserelin, bicalutamide, nilutamide, letrozole, anastrozole, heparin, synthetic heparin salts, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, breveldin, cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil, TNP470, genistein, trastuzumab, rituximab, tretinoin, doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, irinotecan, cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, prednisolone, Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, and diphtheria toxin.

### Claim 19 (depends on 18)

The method of claim 18, wherein the chemotherapeutic drug is an antibody.