WO1998005315A1 - Pentafluorobenzenesulfonamides and analogs - Google Patents

Pentafluorobenzenesulfonamides and analogs Download PDF

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Publication number
WO1998005315A1
WO1998005315A1 PCT/US1997/012720 US9712720W WO9805315A1 WO 1998005315 A1 WO1998005315 A1 WO 1998005315A1 US 9712720 W US9712720 W US 9712720W WO 9805315 A1 WO9805315 A1 WO 9805315A1
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WIPO (PCT)
Prior art keywords
pentafluorophenylsulfonamidobenzene
methoxy
substituted
compound
unsubstituted
Prior art date
Application number
PCT/US1997/012720
Other languages
French (fr)
Inventor
John Flygare
Julio Medina
Bei Shan
David Clark
Terry Rosen
Original Assignee
Tularik, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP50793798A priority Critical patent/JP3421350B2/en
Priority to AU38877/97A priority patent/AU710173B2/en
Priority to BR9710737-9A priority patent/BR9710737A/en
Priority to CA002260777A priority patent/CA2260777C/en
Priority to DE69724811T priority patent/DE69724811T2/en
Priority to AT97936133T priority patent/ATE249214T1/en
Application filed by Tularik, Inc. filed Critical Tularik, Inc.
Priority to EP97936133A priority patent/EP0939627B1/en
Priority to IL12796597A priority patent/IL127965A0/en
Priority to DK97936133T priority patent/DK0939627T3/en
Publication of WO1998005315A1 publication Critical patent/WO1998005315A1/en
Priority to IL127965A priority patent/IL127965A/en
Priority to HK00100662A priority patent/HK1021699A1/en

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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the field of the invention is pentafluorobenzenesulfonamide derivatives and analogs and their use as pharmacologically active agents.
  • a number of human diseases stem from processes of uncontrolled or abnormal cellular proliferation. Most prevalent among these is cancer, a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neopiastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer.
  • anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5- fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, fiutamide).
  • DNA-alkylating agents e.g., cyclophosphamide, ifosfamide
  • antimetabolites e.g., methotrexate, a folate antagonist, and 5- fluorouracil, a pyrimidine antagonist
  • microtubule disruptors e.g., vincristine, vinblastine, paclitaxel
  • DNA intercalators e
  • Psoriasis a common chronic skin disease characterized by the presence of dry scales and plaques, is generally thought to be the result of abnormal cell proliferation. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeutic cure exists for psoriasis.
  • Milder cases are often treated with topical corticosteroids, but more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea. and the microtubule disrupter colchicine.
  • antiproliferative agents such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea. and the microtubule disrupter colchicine.
  • Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like.
  • Infectious and parasitic agents per se e.g. bacteria, trypanosomes, fungi, etc
  • a further object of the present invention is to provide therapeutic compositions for treating said conditions. Still further objects are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions. A further object is to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders. Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.
  • the invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, bacterial infections and psoriasis, or as lead compounds for the development of such agents.
  • the invention provides for the pharmaceutical use of compounds of d e general formula I and for pharmaceutically acceptable compositions of compounds of formula I:
  • Y is -S(O)- or -S(O) 2 -;
  • Z is -NR'R 2 or -OR 3 , where R 1 and R 2 are independently selected from hydrogen, substituted or unsubstituted (C l -ClO)alkyl, substituted or unsubstituted (C 1 -C 10)alkoxy, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or un
  • E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene
  • the ring formed by R l , E, R 2 and the nitrogen contains no more than 8 atoms, or preferably the R 1 and R 2 may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR'R 2 ; and where R 3 is a substituted or unsubstituted aryl or heteroaryl group.
  • Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl. heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienyl radicals are selected independently from
  • Substituents for the aryl and heteroaryl groups are selected independently from -halo -OH -O-R'
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) -X-
  • the invention provides novel methods for the use of pharmaceutical compositions containing compounds of the foregoing description of the general formula I.
  • the invention provides novel methods for treating pathology such as cancer, bacterial infections and psoriasis, including administering to a patient an effective formulation of one or more of the subject compositions.
  • the invention provides chemically-stable, pharmacologically active compounds of general formula I: or a pharmaceutically acceptable salt thereof, wherein: Y is -S(O)- or -S(O 2 )-; and
  • Z is NR'R 2 , wherein R 2 is an optionally substituted aryl or heteroaryl group, and R 1 is selected from: hydrogen, substituted or unsubstituted (Cl-ClO)alkyl, substituted or unsubstituted (Cl-ClO)alkoxy, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted
  • E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene. and the ring formed by R', E, R 2 and the nitrogen contains no more than 8 atoms, or preferably the R 1 and R 2 may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR'R 2 ; provided that: in the case that Y is -S(O 2 )-, and R 1 is hydrogen or methyl, then R 2 is substituted phenyl or heteroaryl group; in the case that Y is -S(O 2 )- and R 2 is a ring system chosen from 1-naphthyl.
  • R' is not hydrogen or R 2 is substituted by at least one substituent that is not hydrogen; in the case that Y is -S(O 2 )-, R 2 is phenyl, and R' is a propylene unit attaching the nitrogen of -NR'R 2 - to the 2- position of the phenyl ring in relation to the sulfonamido group to form a 1,2,3,4-tetrahydroquinoline system, one or more of the remaining valences on the bicvclic system so formed is substituted with at least one substituent that is not hydrogen; in the case that Y is -S(O 2 )- and R 2 is phenyl substituted with 3-(l-hydroxyethyl),
  • R 1 is not hydrogen or when R' is hydrogen, one or more of the remaining valences on the phenyl ring of R 2 is substituted with a substituent that is not hydrogen; in the case that Y is -S(O 2 )- and R 2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy- 1 -phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-l
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons) and includes straight or branched chain groups such as methyl, ethyl, n-propyl. isopropyl, n-butyl, t-butyl. isobutyl. sec-butyl, homologs and isomers of n-pentyl, n-hexyl. 2-methylpentyl.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH ⁇ CH-,CH 7 -.
  • a "lower alkyl” is a shorter chain alkyl, generally having six or fewer carbon atoms.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O. N, and S. and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -OH,
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH,-CH 2 -NH-.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively.
  • Examples of cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yI, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • alkenyl employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched monounsaturated or diunsaturated hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1 ,4-pentadienyl, and the higher homologs and isomers.
  • -CH CH-CH 2 -OH
  • -CH 2 -CH N-OCH 3
  • -CH CH-N(CH 3 )-CH 3
  • -CH 2 -CH CH-CH,-SH.
  • alkynyl employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched hydrocarbon group having the stated number of carbon atoms, and containing one or two carbon-carbon triple bonds, such as ethynyl, 1- and 3-propynyl, 4-but- 1 -ynyl. and the higher homologs and isomers.
  • alkoxy employed alone or in combination with other terms, means, unless otherwise stated, an alkyl group, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers.
  • halo or halogen by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthyl group.
  • the maximal number of substituents allowed on each one of these ring systems is five, seven, and seven, respectively. Substituents are selected from the group of acceptable substituents listed above.
  • heteroaryl by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or bicyclic heterocyclic aromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S. and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized.
  • the heterocyclic system may be attached, unless otherwise stated at any heteroatom or carbon atom which affords a stable structure.
  • the heterocyclic system may be substituted or unsubstituted with one to four substituents independently selected from the list of acceptable aromatic substituents listed above.
  • heterocycles examples include 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl.
  • Pharmaceutically acceptable salts of the compounds of Formula I include salts of these compounds with relatively nontoxic acids or bases, depending on the particular substituents found on specific compounds of Formula I.
  • base addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulftiric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic. malonic. benzoic. succinic. suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic. and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like gluconic or galactunoric acids and the like (see, for example, Berge, S.M.. et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science. Vol. 66, pages 1-19 (1977)).
  • Certain specific compounds of Formula I contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the free base form may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers); the racemates, diastereomers, and individual isomers are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) or carbon- 14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • Y is S(O 2 ) and Z is NR'R 2 , wherein R 1 is hydrogen or methyl, and R 2 is a substituted phenyl, preferably mono-, di-, or trisubstituted as follows.
  • R 1 is hydrogen or methyl
  • R 2 is a substituted phenyl, preferably mono-, di-, or trisubstituted as follows.
  • Y is S(O 2 ) and Z is NR'R 2 , wherein R' is hydrogen or methyl, and R 2 is a phenyl group, preferably substituted in the para position by one of the following groups: hydroxy. amino, (C 1 -C 10)alkoxy, (Cl-ClO)alkyl, (Cl-ClO)alkylamino.
  • compositions and compounds of the subject pharmaceutical methods include: 2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfinamidobenzene;
  • Pentafluorophenylsulfonamidobenzene 5-Pentafiuorophenylsulfonamidoindazole;
  • compositions and compounds of the subject pharmaceutical methods include: 4-(NN-Dimethylamino)-l-pentafluorophenylsulfonamidobenzene;
  • the invention provides for certain novel compounds of general Formula I that possess one or more valuable biological activities such as a pharmacologic, toxicologic, metabolic, etc.
  • Exemplary compounds of this embodiment of the invention include: 2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfinamidobenzene;
  • Preferred compounds of this embodiment of the invention have specific pharmacological properties. Examples of the most preferred compounds of this embodiment of the invention include:
  • the invention provides methods of making the subject compounds and compositions.
  • the methods involve combining pentafluorophenylsulfonyl chloride with an amine having the general formula R'R 2 NH under conditions whereby the pentafluorophenylsulfonyl chloride and amine react to form the desired compound, and isolating the compound.
  • Compounds with the generic structure 1 or 3 may be prepared by reacting the appropriate starting amine in a solvent such as tetrahydrofuran (THF). dimethylformamide (DMF), ether, toluene or benzene in the presence of a base such as pyridine, /?-dimethylaminopyridine, triethylamine, sodium carbonate or potassium carbonate and pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively.
  • a solvent such as tetrahydrofuran (THF).
  • DMF dimethylformamide
  • ether ether
  • toluene or benzene in the presence of a base such as pyridine, /?-dimethylaminopyridine, triethylamine, sodium carbonate or potassium carbonate and pentafluorophenylsulfonyl chloride or pentafluorophenylsul
  • This reaction can be carried out at a temperature range of 0 °C to 100 °C, conveniently at ambient temperature.
  • Compounds of the generic structure 1 can also be obtained by treating the starting sulfonamide (Scheme II) with a base such as LDA, NaH, dimsyl salt, alkyl lithium, potassium carbonate, under an inert atmosphere such as argon or nitrogen, in a solvent such as benzene, toluene, DMF or THF with an alkylating group containing a leaving group such a CI, Br, I, MsO-, TsO-, TFAO-, represented by E in Scheme II.
  • a preferred solvent for this reaction is THF and the preferred base is lithium bis(trimethylsilyl)amide.
  • This reaction can be carried out at a temperature range of 0 °C to 100 °C. conveniently at ambient temperature.
  • Sulfonic esters (2) and sulfinic esters (4) may be prepared by reacting the appropriate starting phenol in a solvent such as THF, DMF, toluene or benzene in the presence of a base such as pyridine, triethylamine, sodium carbonate, potassium carbonate or 4- dimethylaminopyridine with pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively.
  • Pyridine itself may also be used as the solvent.
  • Preferred solvents are pyridine and DMF and preferred bases are sodium carbonate and potassium carbonate. This reaction can be carried out at a temperature range of 0 °C to 100 °C, conveniently at ambient temperature.
  • the substrates for the transformations shown in Schemes I-III may contain functional groups (for example, amino, hydroxy or carboxy) which are not immediately compatible with the conditions of the given reaction.
  • these groups may be protected with a suitable protective group, and this protective group removed subsequent to the transformation to give the original functionality using well know procedures such as those illustrated in T.W. Greene and P.G. M. Wuts. Protective Groups in Organic Synthesis. Second Edition, John Wiley & Sons. Inc., 1991.
  • the compounds used as initial starting materials in this invention may be purchased from commercial sources or alternatively are readily synthesized by standard procedures which are well know to those of ordinary skill in the art.
  • Some of the compounds of formula I may exist as stereoisomers. and the invention includes all active stereoisomeric forms of these compounds.
  • optically active isomers such compounds may be obtained from corresponding optically active precursors using the procedures described above or by resolving racemic mixtures. The resolution may be carried out using various techniques such as chromatography, repeated recrystallization of derived asymmetric salts, or derivatization. which techniques are well known to those of ordinary skill in the art.
  • the compounds of formula I which are acidic or basic in nature can form a wide variety of salts with various inorganic and organic bases or acids, respectively. These salts must be pharmacologically acceptable for administration to mammals. Salts of the acidic compounds of this invention are readily prepared by treating the acid compound with an appropriate molar quantity of the chosen inorganic or organic base in an aqueous or suitable organic solvent and then evaporating the solvent to obtain the salt. Acid addition salts of the basic compounds of this invention can be obtained similarly by treatment with the desired inorganic or organic acid and subsequent solvent evaporation and isolation.
  • the compounds of the invention may be labeled in a variety of ways.
  • the compounds may be provided as radioactive isotopes; for example, tritium and the 14 C-isotopes.
  • the compounds may be advantageously joined, covalently or noncovalently, to a wide variety of joined compounds which may provide pro-drugs or function as carriers, labels, adjuvents, coactivators. stabilizers, etc.
  • compounds having the requisite structural limitations encompass such compounds joined directly or indirectly (e.g. through a linker molecule), to such joined compounds.
  • a wide variety of indications may be treated, either prophylactically or therapeutically, with the compounds and compositions of the present invention.
  • the subject compounds and compositions have been found to be effective modulators of cell proliferation.
  • Limitation of cell growth is effected by contacting a target cell, in or ex vivo, with an effective amount of one or more of the subject compositions or compounds.
  • Compounds may be assayed for their ability to modulate cellular proliferation using cell and animal models to evaluate cell growth inhibition and cytotoxicity, which models are known in the art, but are exemplified by the method of S.A. Ahmed et al. ( 1994) J. Immunol. Methods 170: 21 1-224, for determining the effects of compounds on cell growth.
  • Conditions amenable to treatment by the compounds and compositions of the present invention include any state of undesirable cell growth, including various neoplastic diseases, abnormal cellular proliferations and metastatic diseases, where any of a wide variety of cell types may be involved, including cancers such as Kaposi's sarcoma, Wilms tumor, lymphoma, leukemia, myeloma, melanoma, breast, ovarian, lung, etc, and others such as cystic disease, cataracts, psoriasis, etc.
  • cancers such as Kaposi's sarcoma, Wilms tumor, lymphoma, leukemia, myeloma, melanoma, breast, ovarian, lung, etc, and others such as cystic disease, cataracts, psoriasis, etc.
  • Other conditions include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like.
  • Infectious and parasitic agents per se e.g. trypanosomes, fungi, etc
  • compositions may be advantageously combined and/or used in combination with other antiproliferative chemotherapeutic agents, different from the subject compounds (see Margolis et al. (1993) US Pat No. 5.262.409). Additional relevant literature includes: Woo et al. (1994) WO94/08041; Bouchard et al. (1996) WO96/13494; Bombardelli et al. (1996) WO96/11184; Bonura et al. (1992) WO92/15291.
  • compositions were demonstrated to have pharmacological activity in in vitro and in vivo assays, e.g. are capable of specifically modulating a cellular physiology to reduce an associated pathology or provide or enhance a prophylaxis.
  • Preferred compounds display specific toxicity to various types of cells.
  • Certain compounds and compositions of the present invention exert their cytotoxic effects by interacting with cellular tubulin.
  • that interaction is covalent and irreversible.
  • tissue and cell samples e.g. human breast carcinoma MCF7 cells
  • tritiated forms of these preferred compounds e.g. Compound 7 (Example 72).
  • tubulin This protein is a key component of microtubules, which constitute the cytoskeleton and also play critical roles in many other aspects of the cell's physiology, including cell division.
  • the labeling of tubulin by the subject preferred compounds is also shown to be dose-dependent.
  • the site of covalent binding on tubulin is identified as Cysteine-239 on the ⁇ -tubulin chain.
  • Cys-239 residue is selectively covalently modified when present in a wide variety of Cys-239 containing ⁇ -tubulin petides (e.g. Ser-234 to Met-267) provided in vitro or in vivo. Consistent with the ability of these compounds to bind to ⁇ -tubulin, treatment of a wide variety of cell and tissue types with various concentrations of the compounds resulted in widespread, irreversible disruption of the cytoskeleton of most cells.
  • tubulin defines a family of heterodimers of two polypeptides, designated ⁇ and ⁇ .
  • animals express multiple forms (isotypes) of each ⁇ and ⁇ polypeptides from multiple a and ⁇ genes.
  • Many ⁇ isotypes comprise a conserved cysteine, Cys-239 (of human ⁇ 2 tubulin: because of upstream sequence variations, the absolute position of Cys-239 is subject to variation, though Cys-239 is readily identified by those in the art by its relative position (i.e. context within encompassing consensus sequence, e.g. at least 8, preferably 12.
  • Cys-239 is preferentially bound relative to all other residues, including cysteins of the protein, by at least at least a factor of 2, preferably 10, more preferably 100. most preferably 1,000. In a particularly prefered embodiment. Cys-239 is substantially exclusively and preferably exclusive bound.
  • selective binding to or modification of tubulin is meant that tubulin is preferentially modified relative to all other proteins, by at least a factor of 2, preferably 10, more preferably 100, most preferably 1 ,000. In a particularly prefered embodiment, tubulin is substantially exclusively and preferably exclusive modified.
  • Compounds may be evaluated in vitro for their ability to inhibit cell growth, for example, as described in S.A. Ahmed et al. (1994) J. Immunol. Methods 170:21 1-224.
  • established animal models to evaluate antiproliferative effects of compounds are known in the art.
  • several of the compounds disclosed herein are shown to inhibit the growth of human tumors, including MDR and taxol and/or vinblastine-restistant tumors, grafted into immunodeficient mice (using methodology similar to that reported by J. Rygaard and CO. Povlsen (1969) Acta Pathol. Microbiol. Scand. 77:758-760, and reviewed by B.C. Giovanella and J. Fogh (1985) Adv. Cancer Res. 44:69-120.
  • the invention provides methods of using the subject compounds and compositions to treat disease or provide medicinal prophylaxis, to slow down and/or reduce the growth of tumors, to treat bacterial infections, etc. These methods generally involve contacting cells with or administering to the host an effective amount of the subject compounds or pharmaceutically acceptable compositions.
  • compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral or topical routes.
  • the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration.
  • Preferred dosages are administered orally in the range of about 0.05 mg/kg to about 20 g kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
  • the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions.
  • a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc.
  • the compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages.
  • Useful carriers include solid, semi-solid or liquid media including water and non-toxic organic solvents.
  • the invention provides the subject compounds in the form of a pro-drug, which can be metabolically converted to the subject compound by the recipient host.
  • a pro-drug which can be metabolically converted to the subject compound by the recipient host.
  • compositions may be provided in any convenient form including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc.
  • compositions in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers.
  • dosage units may be included in a variety of containers including capsules, pills, etc.
  • compositions may be advantageously combined and/or used in combination with other antiproliferative therapeutic or prophylactic agents, different from the subject compounds.
  • administration in conjunction with the subject compositions enhances the efficacy of such agents.
  • antiproliferative agents include cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine. vinblastine. vinarelbine, paclitaxel, docetaxel. tamoxifen. flutamide, hydroxyurea, and mixtures thereof.
  • the compounds and compositions also find use in a variety of in vitro and in vivo assays, including diagnostic assays. In certain assays and in in vivo distribution studies, it is desirable to used labeled versions of the subject compounds and compositions, e.g. radioligand displacement assays. Accordingly, the invention provides the subject compounds and compositions comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
  • a detectable label which may be spectroscopic (e.g. fluorescent), radioactive, etc.
  • Examples 20 through 26 were prepared by a protocol similar to that of Example 19 by replacing -phenetidine with the appropriate amine.
  • Example 27 1 ,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene . l,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene. 5-Pentafluorophenylsulfonamido-l,2.3-trihydroxybenzene. l,2,3-Methoxy-5-pentafluorophenylsulfonamidobenzene (269mg, 0.65mmol) was suspended in dry CH-.C1-. (5mL) at 0 °C under nitrogen. To the mixture was added BBr 3 as a IM solution in CH 2 C1 2 (3.26mmol.
  • N-(5-hydroxypentyl)-2-hydroxy-l-methoxy-4-aminobenzene was prepared by reductive amination of 5-amino-2-methoxy phenol with glutaric dialdehyde with ⁇ aBH 4 in MeOH.
  • Example 72 4-[ 3 H]- 1 -Fluoro-2-methoxy-5-pentafluorosulfonamidobenzene.
  • the sample purity was characterized by HPLC using a Microsorb silica (250x4.6mm) 5 mm column and 15% ethyl acetate/hexane as the mobile phase.
  • the elution of material was detected using a UV detector at 254 nm and a Beta Ram detector.
  • the chemical purity of this material was determined to be 100%. and the radiochemical purity was 99.3%.
  • the specific activity of this material was Ci/mmol. 71
  • HeLa cells an immortal cell line derived from a human cervical carcinoma commonly used to evaluate the cytotoxicity of potential therapeutic agents.
  • the following data reflect the cytotoxicity of selected examples of the present invention.
  • the values given represent the concentration of test compound required to inhibit by 50% the uptake of Alamar Blue (Biosource International, Camarillo. CA) by HeLa cell cultures, which correlates directly with the overall levels of cellular metabolism in the culture, and is generally accepted as an appropriate marker of cell growth.
  • the test was conducted according to the method of S.A. Ahmed et al. (1994) J. Immunol. Methods 170: 211-224.
  • the following selected examples display potent cytotoxic activity in this assay, with IC 50 values ranging from less than 0.05 ⁇ M to 10 ⁇ M.
  • Example 1 ⁇ 0.05
  • Example 2 0.15
  • Example 7 ⁇ 0.05
  • Example 8 ⁇ 0.05

Abstract

The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, vascular restenosis, microbial infections, and psoriasis, or as lead compounds for the development of such agents. The compositions include compounds of general formula (I).

Description

Pentafluorobenzenesulfonamides and Analogs
INTRODUCTION Field of the Invention
The field of the invention is pentafluorobenzenesulfonamide derivatives and analogs and their use as pharmacologically active agents. Background
A number of human diseases stem from processes of uncontrolled or abnormal cellular proliferation. Most prevalent among these is cancer, a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neopiastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer. The most commonly used types of anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5- fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, fiutamide). The ideal antineoplastic drug would kill cancer cells selectively, with a wide therapeutic index relative to its toxicity towards non-malignant cells. It would also retain its efficacy against malignant cells even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies possess an ideal profile. Most possess very narrow therapeutic indexes, and in practically every instance cancerous cells exposed to slightly sublethal concentrations of a chemotherapeutic agent will develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents.
Psoriasis, a common chronic skin disease characterized by the presence of dry scales and plaques, is generally thought to be the result of abnormal cell proliferation. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeutic cure exists for psoriasis. Milder cases are often treated with topical corticosteroids, but more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea. and the microtubule disrupter colchicine.
Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. bacteria, trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds. Accordingly, it is one object of the present invention to provide compounds which directly or indirectly are toxic to actively dividing cells and are useful in the treatment of cancer, viral and bacterial infections, vascular restenosis. inflammatory diseases, autoimmune diseases, and psoriasis.
A further object of the present invention is to provide therapeutic compositions for treating said conditions. Still further objects are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions. A further object is to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders. Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims. SUMMARY OF THE INVENTION The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, bacterial infections and psoriasis, or as lead compounds for the development of such agents.
In one embodiment, the invention provides for the pharmaceutical use of compounds of d e general formula I and for pharmaceutically acceptable compositions of compounds of formula I:
Figure imgf000005_0001
or a physiologically acceptable salt thereof, wherein: Y is -S(O)- or -S(O)2-;
Z is -NR'R2 or -OR3, where R1 and R2 are independently selected from hydrogen, substituted or unsubstituted (C l -ClO)alkyl, substituted or unsubstituted (C 1 -C 10)alkoxy, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(Cl-C4)alkyl, substituted or unsubstituted aryl-(Cl-C4)alkoxy, substituted or unsubstituted aryl-(Cl-C4)heteroalkyl, substituted or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted aryloxy-(Cl-C4)alkyl, substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl-(Cl-C4)alkyl, substituted or unsubstituted heteroaryl-(Cl-C4)alkoxy, substituted or unsubstituted heteroaryl-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(Cl -C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein R1 and R2 may be connected by a linking group E to give a substituent of the formula
Figure imgf000006_0001
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring formed by Rl, E, R2 and the nitrogen contains no more than 8 atoms, or preferably the R1 and R2 may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR'R2; and where R3 is a substituted or unsubstituted aryl or heteroaryl group.
Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl. heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienyl radicals are selected independently from
-H
-OH
-O-(C1-C10)alkyl =O
-NH2 -NH-(C1-C10)alkyl -N[(Cl-C10)alkyl]2
-SH
-S-(C1-C10)alkyl -halo
-Si[(Cl-C10)alkyl]3 in a number ranging from zero to (2N+1), where N is the total number of carbon atoms in such radical.
Substituents for the aryl and heteroaryl groups are selected independently from -halo -OH -O-R'
-O-C(O)-R' -NH2 -NHR'
-NR'R"
-SH
-SR'
-R' -CN
-NO2
-CO2H
-CO^R'
-CONH, -CONH-R'
-CONR'R"
-O-C(O)-NH-R'
-O-C(O)-NR'R"
-NH-C(O)-R' -NR"-C(O)-R' -NH-C(O)-OR' -NR"-C(O)-R'
-NH-C(NH2)=NH
-NR'-C(NH2)-=NH -NH-C(NH2)=NR'
-S(O)-R' -S(O)2-R'
-S(O)2-NH-R'
-S(O)2-NR'R" -N3
-CH(Ph)2 substituted or unsubstituted aryloxy substituted or unsubstituted arylamino substituted or unsubstituted heteroarylamino substituted or unsubstituted heteroaryloxy substituted or unsubstituted aryl-(Cl -C4)alkoxy, substituted or unsubstituted heteroaryl-(Cl-C4)alkoxy, perfluoro(C l-C4)alkoxy, and perfluoro(Cl-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system: and where R' and R" are independently selected from : substituted or unsubstituted (Cl-ClO)alkyl, substituted or unsubstituted (Cl-ClO)heteroalkyl, substituted or unsubstituted (C2-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkenyl, substituted or unsubstituted (C2-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)heterocycloalkyl, substituted or unsubstituted (C5-C6)cycloalkenyl, substituted or unsubstituted (C5-C6)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-(Cl-C4)alkyl, substituted or unsubstituted aryl-(Cl-C4)heteroalkyl, substituted or unsubstituted aryi-(C2-C6)alkenyl, substituted or unsubstituted aryloxy-(Cl-C4)alkyl, substituted or unsubstituted aryloxy-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl-(Cl-C4)alkyl, substituted or unsubstituted heteroaryl-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C2-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(Cl-C4)alkyl, and substituted or unsubstituted heteroaryloxy-(Cl-C4)heteroalkyl.
Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)n-U-, wherein T and U are independently selected from N, O, and C, and n = 0-2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)p-B-, wherein A and B are independently selected from C, O, N, S, SO, SO-,, and SO2NR\ and p = 1-3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2) -X-
(CH2)r-, where q and r are independently 1-3, and X is selected from O, N, S. SO, SO, and
SO2NR\ The substituent R' in SO,NR' is selected from hydrogen or (Cl-C6)alkyl. In another embodiment, the invention provides novel methods for the use of pharmaceutical compositions containing compounds of the foregoing description of the general formula I. The invention provides novel methods for treating pathology such as cancer, bacterial infections and psoriasis, including administering to a patient an effective formulation of one or more of the subject compositions.
In another embodiment, the invention provides chemically-stable, pharmacologically active compounds of general formula I:
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -S(O)- or -S(O2)-; and
Z is NR'R2, wherein R2 is an optionally substituted aryl or heteroaryl group, and R1 is selected from: hydrogen, substituted or unsubstituted (Cl-ClO)alkyl, substituted or unsubstituted (Cl-ClO)alkoxy, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C 1 -C4)alkyl, substituted or unsubstituted aryl-(Cl-C4)alkoxy, substituted or unsubstituted aryl-(Cl-C4)heteroalkyl, substituted or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted aryloxy-(Cl -C4)alkyl, substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl-(Cl-C4)alkyl, substituted or unsubstituted heteroaryl-(Cl-C4)alkoxy, substituted or unsubstituted heteroaryl-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(Cl-C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein R' and R2 may be connected by a linking group E to give a substituent of the formula
Figure imgf000011_0001
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene. and the ring formed by R', E, R2 and the nitrogen contains no more than 8 atoms, or preferably the R1 and R2 may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR'R2; provided that: in the case that Y is -S(O2)-, and R1 is hydrogen or methyl, then R2 is substituted phenyl or heteroaryl group; in the case that Y is -S(O2)- and R2 is a ring system chosen from 1-naphthyl. 5-quinolyl, or 4-pyridyl. then either R' is not hydrogen or R2 is substituted by at least one substituent that is not hydrogen; in the case that Y is -S(O2)-, R2 is phenyl, and R' is a propylene unit attaching the nitrogen of -NR'R2- to the 2- position of the phenyl ring in relation to the sulfonamido group to form a 1,2,3,4-tetrahydroquinoline system, one or more of the remaining valences on the bicvclic system so formed is substituted with at least one substituent that is not hydrogen; in the case that Y is -S(O2)- and R2 is phenyl substituted with 3-(l-hydroxyethyl),
3-dimethylamino. 4-dimethylamino. 4-phenyl, 3-hydroxy, 3-hydroxy-4-diethylaminomethyl. 3,4-methylenedioxy, 3,4-ethylenedioxy, 2-(l-pyrrolyl), or 2-methoxy-4-(l-morpholino), then either R1 is not hydrogen or when R' is hydrogen, one or more of the remaining valences on the phenyl ring of R2 is substituted with a substituent that is not hydrogen; in the case that Y is -S(O2)- and R2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy- 1 -phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl-l ,3,4-thiadiazol-5-yl, 5,6,7,8- tetrahydro-2-naphthyl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methy 1-1.8- naphthyridin-2-yl, 5,7-dimethyl-l,8-naphthyridin-2-yl, or 3-cyanopyrazol-4-yl, R' is a group other than hydrogen.
DETAILED DESCRIPTION OF THE INVENTION The term "alkyl" by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons) and includes straight or branched chain groups such as methyl, ethyl, n-propyl. isopropyl, n-butyl, t-butyl. isobutyl. sec-butyl, homologs and isomers of n-pentyl, n-hexyl. 2-methylpentyl. 1,5-dimethylhexyl, l-methyl-4-isopropylhexyl and the like. The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CHιCH-,CH7-. A "lower alkyl" is a shorter chain alkyl, generally having six or fewer carbon atoms.
The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O. N, and S. and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-O-CH3, -CH2-CH2-CH2-OH,
-CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3,
-O-CH2-CH2-CH2-NH-CH3, and -CH2-CH2-S(O)2-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH,-CH2-NH-.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Examples of cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yI, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The term "alkenyl" employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched monounsaturated or diunsaturated hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1 ,4-pentadienyl, and the higher homologs and isomers. A divalent radical derived from an alkene is exemplified by -CH=CH-CH2-.
The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O. N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quarternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-O-CH3,
-CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH,-SH.
The term "alkynyl" employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched hydrocarbon group having the stated number of carbon atoms, and containing one or two carbon-carbon triple bonds, such as ethynyl, 1- and 3-propynyl, 4-but- 1 -ynyl. and the higher homologs and isomers.
The term "alkoxy" employed alone or in combination with other terms, means, unless otherwise stated, an alkyl group, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers.
The terms "halo" or "halogen" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The term "aryl" employed alone or in combination with other terms, means, unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthyl group. The maximal number of substituents allowed on each one of these ring systems is five, seven, and seven, respectively. Substituents are selected from the group of acceptable substituents listed above.
The term "heteroaryl" by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or bicyclic heterocyclic aromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S. and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heterocyclic system may be attached, unless otherwise stated at any heteroatom or carbon atom which affords a stable structure. The heterocyclic system may be substituted or unsubstituted with one to four substituents independently selected from the list of acceptable aromatic substituents listed above. Examples of such heterocycles include 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl. 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl. 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl.
Pharmaceutically acceptable salts of the compounds of Formula I include salts of these compounds with relatively nontoxic acids or bases, depending on the particular substituents found on specific compounds of Formula I. When compounds of Formula I contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of Formula I contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulftiric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic. malonic. benzoic. succinic. suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic. and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like gluconic or galactunoric acids and the like (see, for example, Berge, S.M.. et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science. Vol. 66, pages 1-19 (1977)). Certain specific compounds of Formula I contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The free base form may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers); the racemates, diastereomers, and individual isomers are all intended to be encompassed within the scope of the present invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H) or carbon- 14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In various preferred embodiments of the pharmaceutical compositions of compounds of formula I, Y is S(O2) and Z is NR'R2, wherein R1 is hydrogen or methyl, and R2 is a substituted phenyl, preferably mono-, di-, or trisubstituted as follows. In one group of preferred compounds, Y is S(O2) and Z is NR'R2, wherein R' is hydrogen or methyl, and R2 is a phenyl group, preferably substituted in the para position by one of the following groups: hydroxy. amino, (C 1 -C 10)alkoxy, (Cl-ClO)alkyl, (Cl-ClO)alkylamino. and [di(Cl-C10)alkyl]amino. with up to four additional substituents independently chosen from hydrogen, halogen, (Cl-ClO)alkoxy, (Cl-ClO)alkyl, and [di(Cl-C10)alkyl]amino. Also preferred are compounds of formula I where there is no linking group E between R1 and R2. Illustrative examples of pharmaceutical compositions and compounds of the subject pharmaceutical methods include: 2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfinamidobenzene;
4-Dimethylamino- 1 -pentafluorophenylsulfinamidobenzene ;
4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;
4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine; 2-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidopyridine;
4-Pentafluoropheny lsulfonamidopyridine ;
4-(N N,-Dimethy lamino)- 1 -(N-ethy Ipentafluoropheny lsulfonamido)-benzene; 4-tert-Butoxy- 1 -pentafluoropheny lsulfonamidobenzene;
3-tert-Butoxy- 1 -pentafluoropheny lsulfonamidobenzene;
2-tert-Butoxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Isopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
3-Isopropoxy- 1 -pentafluoropheny lsulfonamidobenzene; 2-Isopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-Methoxy- 1 ,3-difluoro-5-pentafluorophenylsulfonamidobenzene;
4-Cyclopropoxy- 1 -pentafluoropheny lsulfonamidobenzene;
3-Fluoro-4-cyclopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
3-Hydroxy-4-cyclopropoxy- 1 -pentafluoropheny lsulfonamidobenzene; l-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene: l-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene; l-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene; l,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonylindole; 1 -Pentafluoropheny lsulfonyl(2,3-dihydro)indole;
1 -Pentafluoropheny lsulfonyl( 1 ,2-dihydro)quinoline;
1 -Pentafluoropheny lsulfonyl( 1 ,2,3,4-tetrahydro)quinoline;
3,4-Difluoro- 1 -pentafluorophenylsulfonamidobenzene;
4-Trifluoromethoxy- 1 -pentafluorophenylsulfonamidobenzene; 2-Chloro-5-pentafluorophenylsulfonamidopyridine;
2-Hydroxy- 1 -methoxy-4-[Ν-5-hydroxypent- 1 -yl)pentafluorophenyl-sulfonamido]benzene; 4-( 1 , 1 -Dimethyl)ethoxy- 1 -pentafluorophenylsulfonamidobenzene;
1 -Bromo-3-hydroxy-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-l-pentafluorophenylsulfonamidobenzene; l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene; 3-Chloro- 1 -pentafluorophenylsulfonamidobenzene;
4-Chloro- 1 -pentafluoropheny lsulfonamidobenzene;
3 -Nitro-1 -pentafluoropheny lsulfonamidobenzene;
4-Methoxy-l-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene;
4-Methoxy- 1 -[N-(2-propeny l)pentafluorophenylsulfonamido]benzene; 1 -(N-(3-Butenyl)pentafluoropheny lsulfonamido)-4-methoxybenzene;
4-Methoxy- l-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene; l-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene; l-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene: l-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene; 1 -(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
4-Methoxy- l-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;
3-Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Butoxy- 1 -pentafluoropheny lsulfonamidobenzene; l-Pentafluorophenylsulfonamido-4-phenoxybenzene; 6-Pentafluorophenylsulfonamidoquinoline;
2,3-Dihydro-5-pentafluorophenylsulfonamidoindole;
5-Pentafluorophenylsulfonamidobenzo[a]thiophene;
5-Pentafluorophenylsulfonamidobenzo[a]furan;
3-Hydroxy-4-( 1 -propenyl)- 1 -pentafluorophenylsulfonamidobenzene; 4-Benzyloxy- 1 -pentafluoropheny lsulfonamidobenzene;
4-Methylmercapto- 1 -pentafluorophenylsulfonamidobenzene;
2-Methoxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Allyloxy- 1 -pentafluorophenylsulfonamidobenzene; l-Pentafluorophenylsulfonamido-4-propoxy benzene; 4-( i -Methy l)ethoxy- 1 -pentafluorophenyisulfonamidobenzene; l,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene: l,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;
4-(NN-Diethylamino)- 1 -pentafluorophenylsulfonamidobenzene;
4-Amino- 1 -pentafluorophenylsulfonamidobenzene;
Pentafluorophenylsulfonamidobenzene; 5-Pentafiuorophenylsulfonamidoindazole;
4-(NN-Dimethylamino)-l-(N-methylpentafluorophenylsulfonamido)-benzene; l,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;
3,5-Dimethoxy- 1 -pentafluorophenylsulfonamidobenzene;
3-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene; 7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;
3-Phenoxy- 1 -pentafluorophenylsulfonamidobenzene:
4-( 1 -Morpholino)- 1 -pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido- 1 ,2,3-trimethoxy benzene;
2-Hydroxy- 1 ,3-methoxy-5-pentafluorophenylsulfonamidobenzene; 1 ,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido- 1 ,2, 3-trihydroxy benzene;
3-Hydroxy-5-methoxy- 1 -pentafluorophenylsulfonamidobenzene;
3 ,5-Dihydroxy- 1 -pentafluoropheny lsulfonamidobenzene;
2-Fluoro-l -methoxy -4-(N-methylpentafluorophenylsulfonamido)benzene; 4-(N N-Dimethylamino)- 1 -pentafluoropheny lsulfonamidobenzene, hydrochloride:
2-Methoxy-5-pentafluorophenylsulfonamidopyridine; and
2-Anilino-3-pentafluorophenyisulfonamidopyridine.
Examples of the most preferred pharmaceutical compositions and compounds of the subject pharmaceutical methods include: 4-(NN-Dimethylamino)-l-pentafluorophenylsulfonamidobenzene;
3-(N,N-Dimethylamino)-l-pentafluorophenylsulfonamidobenzene; l,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;
2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene;
2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene; 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt; 2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
4-Methoxy- 1 -pentafluoropheny lsulfonamidobenzene;
3 -Hydroxy- 1 -pentafluorophenylsulfonamidobenzene; 4-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene; l,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamidoindole;
4-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene;
3-Methoxy- 1 -pentafluorophenylsulfonamidobenzene; 2-Bromo- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Chloro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Bromo-3-hydroxy-4-methoxy-l-pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-l-pentafluorophenylsulfonamidobenzene; l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene; 4-Chloro- 1 -pentafluorophenylsulfonamidobenzene; and
3-Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene.
The invention provides for certain novel compounds of general Formula I that possess one or more valuable biological activities such as a pharmacologic, toxicologic, metabolic, etc.
Exemplary compounds of this embodiment of the invention include: 2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfinamidobenzene;
4-Dimethy lamino- 1 -pentafluorophenylsulfinamidobenzene;
4-Methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;
4,6-Dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;
2-Pentafluorophenylsulfonamidothiophene; 3-Pentafluorophenylsulfonamidothiophene;
3-Pentafluorophenylsulfonamidopyridine;
4-Pentafluorophenylsulfonamidopyridine;
4-(N N,-Dimethy lamino)- 1 -(N-ethylpentafluorophenylsulfonamido) benzene;
4-tert-Butoxy- 1 -pentafluorophenylsulfonamidobenzene; 3-tert-Butoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-tert-Butoxy- 1 -pentafluorophenylsulfonamidobenzene; 4-Isopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
3-Isopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-Isopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-Methoxy- 1 ,3-difluoro-5-pentafluorophenylsulfonamidobenzene; l-Hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene; l-Hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene; l-Hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene; l,3-Dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;
1-Pentafluorophenylsulfonylindole; 1 -Pentafluorophenylsulfonyl(2,3-dihydro)indole;
1 -Pentafluorophenylsulfony 1( 1 ,2-dihydro)quinoline;
1 -Pentafluorophenylsulfonyl( 1 ,2,3,4-tetrahydro)quinoline;
3,4-Difluoro- 1 -pentafluorophenylsulfonamidobenzene;
4-Trifluoromethoxy- 1 -pentafluorophenylsulfonamidobenzene; 2-Chloro-5-pentafluorophenylsulfonamidopyridine;
2-Hydroxy- 1 -methoxy-4-[N-5-hydroxypent- 1 -yl)pentafluoropheny l-sulfonamido]benzene;
4-( 1 , 1 -Dimethy l)ethoxy- 1 -pentafluorophenylsulfonamidobenzene;
1 -Bromo-3-hydroxy-4-methoxy- 1 -pentafluoropheny lsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy-l-pentafluorophenylsulfonamidobenzene: l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene:
3-Chloro- 1 -pentafluorophenylsulfonamidobenzene;
4-Chloro- 1 -pentafluoropheny lsulfonamidobenzene;
3-Nitro- 1 -pentafluoropheny lsulfonamidobenzene;
4-Methoxy-l-pentafluorophenylsulfonamido-3-(trifluoromethyl)benzene; 4-Methoxy- l-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene; l-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene;
4-Methoxy- 1 -(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene; l-[N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido]-4-methoxy-benzene; l-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene; l-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene; l-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxy benzene; 4-Methoxy- l-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)-benzene;
3-Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Butoxy- 1 -pentafluoropheny lsulfonamidobenzene; l-Pentafluorophenylsulfonamido-4-phenoxybenzene; 4-Benzyloxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Methylmercapto- 1 -pentafluorophenylsulfonamidobenzene;
2-Methoxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Allyloxy- 1 -pentafluorophenylsulfonamidobenzene; l-Pentafluorophenylsulfonamido-4-propoxybenzene; 4-( 1 -Methy l)ethoxy- 1 -pentafluoropheny lsulfonamidobenzene;
1.2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene: l,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene;
4-(NN-Diethylamino)- 1 -pentafluorophenylsulfonamidobenzene;
4-Amino- 1 -pentafluorophenylsulfonamidobenzene; Pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamidoindazole:
4-(NN-Dimethylamino)-l-(N-methylpentafluorophenylsulfonamido)-benzene; l,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene;
3,5-Dimethoxy- 1 -pentafluorophenylsulfonamidobenzene; 3-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene:
7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene;
3-Phenoxy- 1 -pentafluorophenylsulfonamidobenzene;
4-( 1 -Mo holino)- 1 -pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido- 1 ,2,3-trimethoxybenzene; 2-Hydroxy- 1 ,3-methoxy-5-pentafluorophenylsulfonamidobenzene: l,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;
5-Pentafluorophenylsulfonamido- 1 ,2,3-trihydroxy benzene:
4-Cyclopropoxy- 1 -pentafluorophenylsulfonamidobenzene;
3-Fluoro-4-cyclopropoxy- 1 -pentafluorophenylsulfonamidobenzene: 6-Pentafluorophenylsulfonamidoquinoline;
2,3-Dihydro-5-pentafluorophenylsulfonamidoindole: 5-Pentafluorophenylsulfonamidobenzo[a]thiophene;
5-Pentafluorophenylsulfonamidobenzo[a]furan;
3-Hydroxy-4-(l-propenyl)-l-pentafluorophenylsulfonamidobenzene;
3-Hydroxy-5-methoxy- 1 -pentafluorophenylsulfonamidobenzene: 3,5-Dihydroxy-l-pentafluorophenylsulfonamidobenzene;
2-Fluoro-l-methoxy-4-(N-methylpentafluorophenylsulfonamido)benzene;
4-(N N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene, hydrochloride; and,
2-Analino-3-pentafluorophenylsulfonamidopyridine.
Preferred compounds of this embodiment of the invention have specific pharmacological properties. Examples of the most preferred compounds of this embodiment of the invention include:
4-(N,N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene;
3-(NN-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene; l,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene; 2-Hydroxy- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene;
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene;
2-Hydroxy- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene. sodium salt;
2-Hydroxy- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene, potassium salt;
2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene. sodium salt; 2-Fluoro- l-methoxy-4-pentafluorophenylsulfonamidobenzene. potassium salt;
4-Methoxy- 1 -pentafluoropheny lsulfonamidobenzene;
3-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene;
4-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene; l,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene; 5-Pentafluorophenylsulfonamidoindole;
4-Ethoxy- 1 -pentafluoropheny lsulfonamidobenzene;
3-Methoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-Bromo- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene;
2-Chloro- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene; 2-Bromo-3-hydroxy-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene;
2-Bromo-4-methoxy-5-hydroxy- 1 -pentafluorophenylsulfonamidobenzene; l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene; -Chloro- 1 -pentafluorophenylsulfonamidobenzene; and -Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene.
SYNTHESIS
Scheme I
Syntheses of pentafluorophenylsulfonamides, sulfonic esters, sulfinamides, and sulfinic esters
Figure imgf000024_0001
Sulfonamide
Figure imgf000024_0002
Sulfonic ester
Figure imgf000024_0003
Sulfinamide
Figure imgf000024_0004
Scheme II
Alternative synthesis of -Y-V-disubstituted pentafluorophenylsulfonamides.
Figure imgf000025_0001
Scheme III
Syntheses of phenols
Figure imgf000025_0002
x=l-3
The invention provides methods of making the subject compounds and compositions. In one general embodiment, the methods involve combining pentafluorophenylsulfonyl chloride with an amine having the general formula R'R2NH under conditions whereby the pentafluorophenylsulfonyl chloride and amine react to form the desired compound, and isolating the compound.
Compounds with the generic structure 1 or 3 (Scheme I) may be prepared by reacting the appropriate starting amine in a solvent such as tetrahydrofuran (THF). dimethylformamide (DMF), ether, toluene or benzene in the presence of a base such as pyridine, /?-dimethylaminopyridine, triethylamine, sodium carbonate or potassium carbonate and pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively. Pyridine itself may also be used as the solvent. Preferred solvents are pyridine and DMF and preferred bases are pyridine. triethylamine, and potassium carbonate. This reaction can be carried out at a temperature range of 0 °C to 100 °C, conveniently at ambient temperature. Compounds of the generic structure 1 can also be obtained by treating the starting sulfonamide (Scheme II) with a base such as LDA, NaH, dimsyl salt, alkyl lithium, potassium carbonate, under an inert atmosphere such as argon or nitrogen, in a solvent such as benzene, toluene, DMF or THF with an alkylating group containing a leaving group such a CI, Br, I, MsO-, TsO-, TFAO-, represented by E in Scheme II. A preferred solvent for this reaction is THF and the preferred base is lithium bis(trimethylsilyl)amide. This reaction can be carried out at a temperature range of 0 °C to 100 °C. conveniently at ambient temperature.
Sulfonic esters (2) and sulfinic esters (4) may be prepared by reacting the appropriate starting phenol in a solvent such as THF, DMF, toluene or benzene in the presence of a base such as pyridine, triethylamine, sodium carbonate, potassium carbonate or 4- dimethylaminopyridine with pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively. Pyridine itself may also be used as the solvent. Preferred solvents are pyridine and DMF and preferred bases are sodium carbonate and potassium carbonate. This reaction can be carried out at a temperature range of 0 °C to 100 °C, conveniently at ambient temperature. Compounds of the general structure 5, in which Ar is an aromatic group and x is from one to three, can be obtained from the corresponding methyl ethers (Scheme III) by reaction with boron tribromide in a solvent of low polarity such as hexanes or CH2C12 under an inert atmosphere at a temperature ranging from -45° to 30 °C. In a preferred embodiment, the reaction is carried out in CH2C12 at about 30 °C.
Occasionally, the substrates for the transformations shown in Schemes I-III may contain functional groups (for example, amino, hydroxy or carboxy) which are not immediately compatible with the conditions of the given reaction. In such cases, these groups may be protected with a suitable protective group, and this protective group removed subsequent to the transformation to give the original functionality using well know procedures such as those illustrated in T.W. Greene and P.G. M. Wuts. Protective Groups in Organic Synthesis. Second Edition, John Wiley & Sons. Inc., 1991.
The compounds used as initial starting materials in this invention may be purchased from commercial sources or alternatively are readily synthesized by standard procedures which are well know to those of ordinary skill in the art.
Some of the compounds of formula I may exist as stereoisomers. and the invention includes all active stereoisomeric forms of these compounds. In the case of optically active isomers. such compounds may be obtained from corresponding optically active precursors using the procedures described above or by resolving racemic mixtures. The resolution may be carried out using various techniques such as chromatography, repeated recrystallization of derived asymmetric salts, or derivatization. which techniques are well known to those of ordinary skill in the art.
The compounds of formula I which are acidic or basic in nature can form a wide variety of salts with various inorganic and organic bases or acids, respectively. These salts must be pharmacologically acceptable for administration to mammals. Salts of the acidic compounds of this invention are readily prepared by treating the acid compound with an appropriate molar quantity of the chosen inorganic or organic base in an aqueous or suitable organic solvent and then evaporating the solvent to obtain the salt. Acid addition salts of the basic compounds of this invention can be obtained similarly by treatment with the desired inorganic or organic acid and subsequent solvent evaporation and isolation.
The compounds of the invention may be labeled in a variety of ways. For example. the compounds may be provided as radioactive isotopes; for example, tritium and the 14C-isotopes. Similarly, the compounds may be advantageously joined, covalently or noncovalently, to a wide variety of joined compounds which may provide pro-drugs or function as carriers, labels, adjuvents, coactivators. stabilizers, etc. Hence, compounds having the requisite structural limitations encompass such compounds joined directly or indirectly (e.g. through a linker molecule), to such joined compounds. A wide variety of indications may be treated, either prophylactically or therapeutically, with the compounds and compositions of the present invention. For example, the subject compounds and compositions have been found to be effective modulators of cell proliferation. Limitation of cell growth is effected by contacting a target cell, in or ex vivo, with an effective amount of one or more of the subject compositions or compounds. Compounds may be assayed for their ability to modulate cellular proliferation using cell and animal models to evaluate cell growth inhibition and cytotoxicity, which models are known in the art, but are exemplified by the method of S.A. Ahmed et al. ( 1994) J. Immunol. Methods 170: 21 1-224, for determining the effects of compounds on cell growth. Conditions amenable to treatment by the compounds and compositions of the present invention include any state of undesirable cell growth, including various neoplastic diseases, abnormal cellular proliferations and metastatic diseases, where any of a wide variety of cell types may be involved, including cancers such as Kaposi's sarcoma, Wilms tumor, lymphoma, leukemia, myeloma, melanoma, breast, ovarian, lung, etc, and others such as cystic disease, cataracts, psoriasis, etc. Other conditions include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.
Many of the subject compounds have been shown to bind to the β-subunit of tubulin and interfere with normal tubulin function. Hence, the compounds provide agents for modulating cytoskeletal structure and/or function. Preferred compounds bind irreversibly or covalently, and hence provide enhanced application over prior art microtubule disruptors such as colchicine. The compositions may be advantageously combined and/or used in combination with other antiproliferative chemotherapeutic agents, different from the subject compounds (see Margolis et al. (1993) US Pat No. 5.262.409). Additional relevant literature includes: Woo et al. (1994) WO94/08041; Bouchard et al. (1996) WO96/13494; Bombardelli et al. (1996) WO96/11184; Bonura et al. (1992) WO92/15291.
ANALYSIS
The subject compositions were demonstrated to have pharmacological activity in in vitro and in vivo assays, e.g. are capable of specifically modulating a cellular physiology to reduce an associated pathology or provide or enhance a prophylaxis. Preferred compounds display specific toxicity to various types of cells. Certain compounds and compositions of the present invention exert their cytotoxic effects by interacting with cellular tubulin. For certain preferred compounds and compositions of the present invention, that interaction is covalent and irreversible. For example, exposure of a wide variety of tissue and cell samples, e.g. human breast carcinoma MCF7 cells, to tritiated forms of these preferred compounds, e.g. Compound 7 (Example 72). results in the irreversible labeling of only one detectable cellular protein, which was found to be tubulin. This protein is a key component of microtubules, which constitute the cytoskeleton and also play critical roles in many other aspects of the cell's physiology, including cell division. The labeling of tubulin by the subject preferred compounds is also shown to be dose-dependent. The site of covalent binding on tubulin is identified as Cysteine-239 on the β-tubulin chain. The same Cys-239 residue is selectively covalently modified when present in a wide variety of Cys-239 containing β-tubulin petides (e.g. Ser-234 to Met-267) provided in vitro or in vivo. Consistent with the ability of these compounds to bind to β-tubulin, treatment of a wide variety of cell and tissue types with various concentrations of the compounds resulted in widespread, irreversible disruption of the cytoskeleton of most cells.
As discribed inter alia in Luduena (1993) Mol Biol of the Cell 4, 445-457. tubulin defines a family of heterodimers of two polypeptides, designated α and β. Moreover, animals express multiple forms (isotypes) of each α and β polypeptides from multiple a and β genes. Many β isotypes comprise a conserved cysteine, Cys-239 (of human β2 tubulin: because of upstream sequence variations, the absolute position of Cys-239 is subject to variation, though Cys-239 is readily identified by those in the art by its relative position (i.e. context within encompassing consensus sequence, e.g. at least 8, preferably 12. more preferably 16, most preferably 20 residue consensus peptide region of the isotype or fragment thereof, which region contains Cys-239). By selective binding to Cys-239 is meant that Cys-239 is preferentially bound relative to all other residues, including cysteins of the protein, by at least at least a factor of 2, preferably 10, more preferably 100. most preferably 1,000. In a particularly prefered embodiment. Cys-239 is substantially exclusively and preferably exclusive bound. By selective binding to or modification of tubulin is meant that tubulin is preferentially modified relative to all other proteins, by at least a factor of 2, preferably 10, more preferably 100, most preferably 1 ,000. In a particularly prefered embodiment, tubulin is substantially exclusively and preferably exclusive modified.
Compounds may be evaluated in vitro for their ability to inhibit cell growth, for example, as described in S.A. Ahmed et al. (1994) J. Immunol. Methods 170:21 1-224. In addition, established animal models to evaluate antiproliferative effects of compounds are known in the art. For example, several of the compounds disclosed herein are shown to inhibit the growth of human tumors, including MDR and taxol and/or vinblastine-restistant tumors, grafted into immunodeficient mice (using methodology similar to that reported by J. Rygaard and CO. Povlsen (1969) Acta Pathol. Microbiol. Scand. 77:758-760, and reviewed by B.C. Giovanella and J. Fogh (1985) Adv. Cancer Res. 44:69-120.
FORMULATION AND ADMINISTRATION
The invention provides methods of using the subject compounds and compositions to treat disease or provide medicinal prophylaxis, to slow down and/or reduce the growth of tumors, to treat bacterial infections, etc. These methods generally involve contacting cells with or administering to the host an effective amount of the subject compounds or pharmaceutically acceptable compositions.
The compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral or topical routes. Generally, the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration. Preferred dosages are administered orally in the range of about 0.05 mg/kg to about 20 g kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
In one embodiment, the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions. The compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages. Useful carriers include solid, semi-solid or liquid media including water and non-toxic organic solvents.
In another embodiment, the invention provides the subject compounds in the form of a pro-drug, which can be metabolically converted to the subject compound by the recipient host. A wide variety of pro-drug formulations are known in the art.
The compositions may be provided in any convenient form including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc. As such the compositions, in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers. For example, dosage units may be included in a variety of containers including capsules, pills, etc.
The compositions may be advantageously combined and/or used in combination with other antiproliferative therapeutic or prophylactic agents, different from the subject compounds. In many instances, administration in conjunction with the subject compositions enhances the efficacy of such agents. Exemplary antiproliferative agents include cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine. vinblastine. vinarelbine, paclitaxel, docetaxel. tamoxifen. flutamide, hydroxyurea, and mixtures thereof.
The compounds and compositions also find use in a variety of in vitro and in vivo assays, including diagnostic assays. In certain assays and in in vivo distribution studies, it is desirable to used labeled versions of the subject compounds and compositions, e.g. radioligand displacement assays. Accordingly, the invention provides the subject compounds and compositions comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
The following examples are offered by way of illustration and not by way of limitation. EXAMPLES ■H NMR spectra were recorded on a Varian Gemini 400MHz NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant(s) in Hertz, number of protons. Electron Ionization (El) mass spectra were recorded on a Hewlett Packard 5989A mass spectrometer. Fast Atom Bombardment (FAB) mass spectroscopy was carried out in a VG analytical ZAB 2-SE high field mass spectrometer. Mass spectroscopy results are reported as the ratio of mass over charge, and the relative abundance of the ion is reported in parentheses.
Example 1
Figure imgf000032_0001
4-(N,N-Dimethylamino)-l -pentafluorophenylsulfonamidobenzene. To N,N-dimethyl-l,4-phenyldiamine dihydrochloride (3g, 14.6mmol) suspended in pyridine (50mL) at 0 °C under argon was added dropwise pentafluorophenylsulfonyl chloride (2.38mL, lόmmol). The reaction mixture was stirred for 30 min at 0 °C and allowed to warm to ambient temperature. The reaction mixture was stirred at room temperature for 3h. The volume of the mixture was then reduced to 10 mL under reduced pressure. The mixture was diluted with ethyl acetate and the reaction quenched with water. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The organic layers were combined and washed with brine and dried with MgSO4. The solvent was evaporated and the residue purified by chromatography on silica, eluting with CH-,C1-,. The title product was obtained as a white solid in 63% yield (3.4g). Η ΝMR (CDC13): 7.01(d. J=8.9Hz. 2H), 6.77(s. 1H),
6.59(d, J=8.3Hz, 2H), 2.92ppm(s, 6H). FAB m/z (relative abundance): 367(100%. M+H+). 135(30%). 121(25%). Anal, calcd. for C14H1 1F5Ν,O,S: C 45.95, H 3.03. N 7.65. Found C
45.83, H 2.99, N 7.62 Example 2
Figure imgf000033_0001
3-(N,N-Dimethylamino)-l-pentafluorophenylsulfonamidobenzene. Η ΝMR (CDC13): 7.12(t, J=8Hz, 1 H), 7.05(s. 1 H). 6.57(s. 1 H) 6.53(d, J=8Hz, 1 H), 6.40(d, J=8Hz, 1 H),
2.94ppm (s, 6H). FAB nvz: 366 (100%. M+). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l,4-phenyldiamine dihydrochloride with 3-(NN-dimethylamino (aniline.
Example 3
Figure imgf000033_0002
l,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene. *H ΝMR (CDC13): 6.97(s, IH), 6.76(d, J=8.6Hz, IH), 6.72(d, J=2.6Hz, IH), 6.62(dd, J=8.6, 2.6Hz, IH), 4.21ppm (s, 4H). FAB m/z: 381(100%, M+H+). Anal calcd. for C14H8F5NO4S: C 44.09, H 2.12. N 3.68, S 8.39. Found: C 43.83. H 2.19, N 3.62, S 8.20. The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l,4-phenyldiamine dihydrochloride with 3,4-ethylenedioxyaniline. Example 4
Figure imgf000034_0001
l,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene. Η NMR (CDC13): 6.85(s,
IH), 6.78 (s, IH), 6.70(d,J=8Hz, IH), 6.57(d, J=8Hz. IH), 5.97ppm(s, 2H). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l ,4-phenyldiamine dihydrochloride with 3,4-methylenedioxyaniline.
Example 5
Figure imgf000034_0002
l,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene. Η ΝMR (CDC13): 6.98(s, IH),
6.85(d, IH), 6.74(d, IH). 6.60(dd, IH), 3.85(s, 3H). 3.83ppm (s. 3H). EL m/z: 383(50, M+). 152(100). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l,4-phenyldiamine dihydrochloride with 3,4-dimethoxyaniline.
Example 6
Figure imgf000035_0001
2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene. Η NMR (CDC13): 6.93(s.
IH), 6.7-6.8(m, 3H), 5.68(bs, IH). 3.85ppm(s, 3H). EL m z: 333(20, M+), 138(100). mp 118-120 °C. The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l ,4-phenyldiamine dihydrochloride with 3 -hydroxy -4-methoxyaniline .
Example 7
Figure imgf000035_0002
2-Fluoro- 1 -methoxy-4-pentafluorosulfonamidobenzene.
■H ΝMR (DMSO) 11.15 (broad s. IH), 7.13 (t, J=9Hz, IH), 7.02 (dd, J=9.5 2.5 Hz, IH), 6.94ppm (dd, J=8.8 1.5Hz, IH), 3.79ppm (s, 3H). El, m/z: 371 (20, M+), 140 (100). Anal, calcd. for C13H7HF6Ν]O3S,: C 42.06, H 1.90, N 3.77. S 8.64. Found: C 42.19. H 1.83, N
3.70, S 8.60. Mp 1 18-1 19°C. The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l,4-phenyldiamine dihydrochloride with 3-fluoro-p-anisidine. Example 8
Figure imgf000036_0001
4-Methoxy- 1 -pentafluoropheny lsulfonamidobenzene. -H NMR (CDC13): 6.99 (s, IH),
6.96(d, J=4Hz, 2H), 6.88 (d, J=4Hz, 2H). 3.83ppm(s. 3H). El, m/z: 353 (60, M+), 122 (100). M.p. 102-103 °C. The compound was prepared by a protocol similar to that of example 1 by replacing NN-dimethyl-l,4-phenyldiamine dihydrochloride with 4-methoxyaniline.
Example 9
Figure imgf000036_0002
3-Hydroxy-l-pentafluorophenylsulfonamidobenzene. Η ΝMR (CD-OD): 7.15(t. J=8.1Hz.
IH), 6.67(t, J=2.2Hz. IH) 6.60(dd. J=1.3Hz. 7.8Hz. IH). 6.52ppm (dd. J=2.4Hz 8.3Hz. IH). El, m z: 339 (80, M~), 256 (50), 81 (100). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-1.4-phenyldiamine dihydrochloride with 3 -hydroxy aniline.
Example jo
Figure imgf000037_0001
4-Hydroxy-l-pentafluorosulfonamidobenzene. Η NMR (CD3OD): 6.95(d, J=8.9Hz, 2H), 6.65ppm (d, J=8.9Hz, 2H). EL m/z: 339 (30, M+). The compound was prepared by a protocol similar to that of example 1 by replacing N.N-dimethyl-1.4-phenyldiamine dihydrochloride with 4-hydroxyaniline.
Example 1
Figure imgf000037_0002
l,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene. lH ΝMR (CDC13): 7.03(d, J=7.9Hz.
IH), 6.92(s, I H). 6.85-6.82(m. 2H). 2.18(s, 3H). 2.16ppm(s. 3H). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-1.4-phenyldiamine dihydrochloride with 3,4-dimethylaniline.
Example 12
Figure imgf000038_0001
4-(N,N-Diethylamino)-l-pentafluorophenylsulfonamidobenzene. -H ΝMR (CDC13): 6.93(d.
J=8.8Hz, 2H), 6.78(s. 1), 6.45(d, J=8.7Hz. 2H), 3.25(dd, J=7.0Hz, 7.3Hz,4H), l.lOppm (t, J=7.2Hz, 6H). The compound was prepared by a protocol similar to that of example 1 by replacing N N-dimethyl- 1.4-pheny Idiamine dihydrochloride with 4-(N,N-diethylamino)aniline.
Example 13
Figure imgf000038_0002
4-Amino-l -pentafluoropheny lsulfonamidobenzene. *H ΝMR (CDC13): 6.82(d, J=8.7Hz,
2H), 6.49ppm(d. J=8.7Hz. 2H). EL m/z: 338(7. M+), 107(100). 80(40). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethy 1-1, 4-pheny Idiamine dihydrochloride with 1 ,4-diaminobenzene.
Example H
Figure imgf000039_0001
Pentafluorophenylsulfonamidobenzene. "H NMR (CDC13): 7.30(d, J=8Hz. 2H), 7.13-7.2(m.
3H), 7.0ppm(s, IH). El, m/z: 323(90, M+), 92(100). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethy 1-1, 4-pheny Idiamine dihydrochloride with aniline.
Example 15
H
Figure imgf000039_0002
5 -Pentafluoropheny lsulfonamidoindazole. 'H ΝMR (CD3OD): 7.98(s, IH). 7.69(s. IH), 7.47(d, J=8.3Hz, IH), 7.23ppm(d. J=8.3Hz, IH). El m/z: 364(50, M+H+), 133(100). The compound was prepared by a protocol similar to that of example 1 by replacing NN-dimethy 1-1, 4-pheny Idiamine dihydrochloride with 5-aminoindazole. Example 16
H
Figure imgf000040_0001
5-Pentafluorophenylsulfonamidoindole. -H NMR (CDC13): 8.2(s, IH), 7.43(s, IH), 7.3(d, J=8 Hz, IH), 7.22(s, IH)), 6.98 (d, J=8 Hz, IH). 6.92ppm (s, IH), 6.50ppm(s, IH). El m/z: 362(M+), 131(100). The compound was prepared by a protocol similar to that of example 1 by replacing N.N-dimethyl-1.4-phenyldiamine dihydrochloride with 5-aminoindole.
Example 17
Figure imgf000040_0002
4-(NN-Dimethylamino)-l-(N-methylpentafluorophenylsulfonamido)benzene.
4-(N N-Dimethylamino)- l-(pentafluorophenylsulfonamido)benzene (lOOmg, 0.273mmol) was dissolved in dry THF (2.5mL) and to the system was added under Ν2 at room temperature a IM solution of lithium όw(trimethylsilyl)amide (0.274mL). The reaction mixture was stirred for 10 min followed by addition of Mel (65mg, 0.028mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20%EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62mg). El m/z: 380(35. M+), 149(100). 'H NMR (CD3OD) 7.05(d. J=8Hz. 2H), 6.68(d. J=8Hz, 2H), 3.33(s. 3H) 2.93(s, 6H). Anal, calcd. for
C15H.3F5SO2N2: C 47.37. H 3.45, N 7.37. Found: C 47.37. H 3.49, N 7.32. Example 1
Figure imgf000041_0001
l,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene. l-Hydroxy-2-methoxy-4-pentafluorophenylsulfonamidobenzene (250mg, 0.678mmol) was suspended in dry CH-.C1-, (5mL) at 0 °C under nitrogen. To the mixture was added BBr3 as a
IM solution in CH-.C1-, (0.746mmol. 1.leq.). The mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was poured over ice (75mL) and extracted 3 times with 30 mL portions of CH2C1,. The organic layer was dried with MgSO4 and the solvent was evaporated. The crude product was purified by chromatography over silica eluting with 30% (v/v) EtO Ac/Hex to afford the product as a white solid in 41% yield (98mg). -H NMR (DMSO): 10.63(s, IH), 9.15(s, IH), 8.91(s. IH). 6.61(d. J=9Hz, IH), 6.58(d, J=3Hz. IH), 6.39ppm(dd, J= 9Hz 3Hz, IH).
Example 19
Figure imgf000042_0001
4-Ethoxy-l -pentafluoropheny lsulfonamidobenzene. To a stirred solution of p-phenetidine (0.1 OOg, 0.729mmol) in dimethylformamide (3.65 mL) at 25 °C was added pentafluoropheny 1 sulfonyl chloride (0.135mL, 0.91 lmmol), followed by sodium carbonate (0.116g, 1.09mmol), and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (50mL) and washed with 20% ammonium chloride (2 x 20mL) and saturated sodium chloride (2 x 20mL). The organic layer was dried (sodium sulfite), and the ethyl acetate was removed under reduced pressure to yield a reddish-brown oil. Column chromatography (3:1 ethyl acetate hexane) yielded the title compound (0.222g, 83%). *H NMR (CDC13) 7.08 (d, J = 9Hz, 2H), 7.04 (s, IH), 6.80 (d. J-= 9Hz. 2H). 3.96 (q, J=7Hz, 2H), 1.37 ppm (t, J=7Hz. 2H). IR (neat) 3000-3600, 1750 cm"1. El m/z : 367(M+), 154, 136.
The compounds of Examples 20 through 26 were prepared by a protocol similar to that of Example 19 by replacing -phenetidine with the appropriate amine.
am le 20
Figure imgf000043_0001
3,5-Dimethoxy-l-pentafluorophenylsulfonamidobenzene . The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with
3,5-dimethoxyaniline. lH NMR (CDC13) 6.91(s, IH), 6.32(s. 2H), 6.25(s, IH), 3.72ppm(s.
6H).
Example 21
Figure imgf000043_0002
3-Ethoxy-l-pentaf uorophenylsulfonamidobenzene . The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with 3-ethoxyaniline. 'H NMR (CDC13) 7.35 (t, J= 8Hz, IH). 7.21( s, IH), 6.92( s, IH), 6.86(d. J=8Hz, IH),
6.83(d, J=8Hz, IH), 4.15( q, J=6Hz. 2H), 1.56ppm ( t, J=6Hz, 3H). Example 22
Figure imgf000044_0001
7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene. The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with
2-amino-7-hydroxynaphthalene. - H NMR (CDC13) 8.15 ( t. J = 8Hz. 1 H), 7.55( d. J=8Hz.
IH), 7.44 (s, IH). 7.42 (d. J=8Hz. IH). 7.40 (s, IH). 6.88ppm (q. J=8Hz. IH).
Example 23
Figure imgf000044_0002
3-Phenoxy-l -pentafluoropheny lsulfonamidobenzene. The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with 3-phenoxyaniline. 'H NMR (CDC13) 7.34 ( t. J= 8Hz, 2H), 7.26 ( t, J=8Hz. IH). 7.16 ( t, J=8Hz. IH), 6.94 (d, J=8Hz, 2H), 6.86 ( d, J=8Hz, IH). 6.82 ( d, J=8Hz. IH), 6.74 (s. IH ). Example 24
Figure imgf000045_0001
3-Methoxy-l-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with 3-methoxyaniline. *H NMR (CDC13) 7.20 (d, J = 8Hz. IH, ), 6.95 (s, IH), 6.78 ( d, J=8Hz, IH,), 6.70 ( t, J=8Hz.
IH), 3.79 ppm (s. IH).
Example 25
Figure imgf000045_0002
4-(l-Mo holino)-l-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with 4-(l-morpholino)aniline. *H NMR (CDCI3) 7.09 (d, J-= 8Hz, 2H), 6.85 (d. J=8Hz, 2H),
3.85 (t, J=8Hz, 4H), 3.15ppm (t. J=8Hz, 4H). Examnle 26
Figure imgf000046_0001
5-Pentafluorophenylsulfonamido-l,2.3-trimethoxybenzene. The compound was prepared by a protocol similar to that of Example 19 by replacing p-phenetidine with
3,4,5-trimethoxyaniline. -H NMR (CDC13) 8.14 (s, IH). 6.46 (s, 2H). 3.69 (s. 6H), 3.59 (s.
3H).
Example 27 1 ,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene . l,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene. 5-Pentafluorophenylsulfonamido-l,2.3-trihydroxybenzene. l,2,3-Methoxy-5-pentafluorophenylsulfonamidobenzene (269mg, 0.65mmol) was suspended in dry CH-.C1-. (5mL) at 0 °C under nitrogen. To the mixture was added BBr3 as a IM solution in CH2C12 (3.26mmol. 5eq.). The mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was poured over ice (75mL) and extracted 3 times with 30 mL portions of CH-.C1-.. The organic layer was dried with MgSO4, evaporated, and the residue was subjected to chromatography over silica eluting with 30% (v/v) EtOAc/Hex to afford the three products. The compounds of Examples 28 and 29 were prepared in a manner similar to that described above beginning with the product of Example 20 and treating it with BBr3.
Figure imgf000047_0001
l,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene.
-H NMR (CDCI3) 10.85 (s, IH), 8.31 (s, IH), 6.41 (s, 2H), 3.66 ppm (s, 6H).
Figure imgf000047_0002
l,2-Dihydroxy-3-methoxy F
-5-pentafluorophenylsulfonamidobenzene. 'H NMR (CDC13) 10.73 (s, IH), 8.31 (s, IH),
6.27 (s, IH). 6.26 (s. IH). 3.66 ppm (s, 3H).
5-Pentafluorophenylsulfonamido- 1,2,3-trihydroxybenzene. Η NMR (CDC13) 11.0 (s, IH). 9.03 (s, 2H), 8.06 (s, IH), 6.13 ppm (s, 2H). Example 23
Figure imgf000048_0001
3-Hydroxy-5-methoxy-l-pentafluorophenylsulfonamidobenzene. *H NMR (CDC13) 1 1.2 (s, IH), 9.63 (s, IH), 6.23 (s. IH), 6.21 (s, IH), 6.08 (s, IH), 3.63 (s, 3H).
Example 29
Figure imgf000048_0002
3.5-Dihydroxy-l -pentafluoropheny lsulfonamidobenzene. *H NMR (CDC13) 7.15 (s. lH), 6.25 (s, 2H), 6.15 (s, IH), 5.31 (s, 2H).
Example 30
Figure imgf000049_0001
2-Fluoro- 1 -methoxy -4-(N-methylpentafluorophenylsulfonamido)benzene. Prepared using a procedure similar to that of Example 18 replacing
4-(N,N-dimethylamino)-l-pentafluorophenylsulfonamidobenzene with the appropriate non-substituted sulfonamide (product of Example 7). -H ΝMR (CDC13): 6.97-6.94(m, 2H),
6.89(t, J=9Hz, IH). 3.87(s, 3H). 3.35ppm (t, J=lHz). El m/z: 385(20, M+), 154(100). Anal, calcd. for C|4H9F6ΝO3: C 43.64. H 2.35. N 3.64. Found C 43.55, H 2.38. N 3.65.
Example 31
Figure imgf000049_0002
2-Bromo-l-methoxy-4-pentafluorophenylsulfonamidobenzene. -H NMR (CDC13): 7.35(d. J=3Hz, IH), 7.15(dd, J=9Hz, 3Hz, IH). 6.97 (s, IH). 6.81(d. J=9Hz, IH), 3.88 ppm (s, 3H). El m/z: 433(35, MT), 202(100). The compound was prepared by a protocol similar to that of example 1 by replacing N.N-dimethy 1-1, 4-pheny Idiamine dihydrochloride with 3-bromo-4-methoxvaniline. Example 32
Figure imgf000050_0001
2-Chloro-l -methoxy -4-pentafluorophenylsulfonamido benzene. -H NMR (CDC13): 7.19(d,
J=3Hz, IH), 7.08(dd. J=9Hz. 3Hz. IH), 7.01 (s. IH). 6.84(d. J=9Hz, IH). 3.85 ppm (s. 3H). El m/z(rel. abundance): 387(10, M+). 156(100). The compound was prepared by a protocol similar to that of example 1 by replacing N,N-dimethyl-l,4-phenyldiamine dihydrochloride with 3-chloro-4-methoxyaniline.
Example 33
Figure imgf000050_0002
4-(N N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene hydrochloride. 4-(N N-Dimethylamino)- 1-pentafluorophenylsulfonamidobenzene (2g, 5.5mmol) was dissolved in 15mL of diethyl ether at ambient temperature under nitrogen. Gaseous HCl was bubbled into the reaction mixture for 5 min. The mixture was filtered and the resulting solid washed twice with 15mL portions of ice cold diethyl ether to afford the product as a white solid (1.89g, 86% yield). Η ΝMR (CD3OD): 7.62(dd, J=9.0Hz. 1.6Hz. 2H), 7.44(dd,
J=9.0Hz, 1.6Hz, 2H), 3.28ppm(s, 6H). FAB m/z: 367(100%, M+H+), 135(90%), 121(45%). Anal, calcd. for C|4H,3ClF5Ν2O2S: C 41.79, H 3.01, N 6.97, S 7.95. Found C 41.71, H 3.05.
N 7.01, S 7.96. Example 34
Figure imgf000051_0001
3,4-Difluoro-l-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to that of example 1 by replacing N,N-dimethy 1-1.4-pheny Idiamine dihydrochloride with 3,4-difluoroaniline. *H ΝMR (CDC13) 7.13 (m. 3H), 6.91 ppm (m, IH). El, m/z (relative abundance) : 359 (20). 128 (100). Anal, calcd. for C13H4F7ΝO2S: C 40.12. H 1.12, N 3.90. Found: C 40.23, H 1.17, N 3.89.
Example 35
Figure imgf000051_0002
4-Trifluoromethoxy-l -pentafluoropheny lsulfonamidobenzene. The compound was prepared in a manner similar to that of example 1 by replacing NN-dimethy 1-1, 4-pheny Idiamine dihydrochloride with 4-(trifluoromethoxy)aniline. -H ΝMR (CDC13) 7.18ppm (m. 4H). EL m/z (relative abundance) : 407 (20), 176 (100). Anal, calcd. for C,3H5FgΝO3S: C 38.34, H
1.24, N 3.44. Found: C 38.33, H 1.30, N 3.43. Example 36
Figure imgf000052_0001
2-Chloro-5-pentafluorophenylsulfonamidopyridine. The compound was prepared in a manner similar to that of example 1 by replacing N,N-dimethyl-l,4-phenyldiarnine dihydrochloride with 5-amino-2-chloropyridine. H ΝMR (DMSO-d6): 8.18 (d. J=2.68 Hz. IH), 7.64 (dd, J=8.75. 2.89 Hz. IH), 7.50ppm (d, J=8.75 Hz. IH). El m/z 358 (20. M+). 127 (100). Anal, calcd. for C..H4ClF5Ν2O,S: C 36.83, H 1.12. N 7.81, S 8.94. CI 9.90.
Found: C 37.00, H 1.16. N 7.78. S 8.98, CI 10.01. White crystals with M.P.= 144- 145 °C.
Example 37
Figure imgf000052_0002
2-Hydroxy- l-methoxy-4-(N-(5-hydroxypentyl)-pentafluorophenylsulfonamido)benzene. N-(5-hydroxypentyl)-2-hydroxy-l-methoxy-4-aminobenzene was prepared by reductive amination of 5-amino-2-methoxy phenol with glutaric dialdehyde with ΝaBH4 in MeOH.
2-Hydroxy- 1 -methoxy -4-(N-(5-hydroxypentyl)-pentafluorophenylsulfonamido)benzene was prepared in a manner similar to that of example 1 by replacing NN-dimethyl-1.4-pheny Idiamine dihydrochloride with N-(5-hydroxypentyl)- 2-hydroxy- l-methoxy-4-aminobenzene. -H ΝMR (CDC13): 6.78(d. J=8.6 Hz. IH). 6.71(dd.
J=8.59, 2.48 Hz. IH), 6.63(d, J=2.48 Hz, IH), 3.88(s, 3H). 3.7(t, J=6.8 Hz, 2H). 3.6(t, J=6.39 Hz, 2H), 1.5ppm (m, 6H). Anal, calcd. for C18H,8F5ΝO5S: C 47.47, H 3.98, N 3.08. S 7.04. Found: C 47.47, H 4.04, N 3.1 1, S 6.97. White crystals with M.P.=118°. Example 38
Figure imgf000053_0001
4-( 1 , 1 -Dimethyl)ethoxy- 1 -pentafluorophenylsulfonamidobenzene.
The compound was prepared in a manner similar to example 46 by replacing 3-chloroaniline with 4-t-butoxyaniline. 4-t-Butoxyaniline was prepared by the method of Day (J. Med. Chem. 1975, 18, 1065). -H NMR (CDC13): d 7.07 (m, 2), 6.92 (m, 2), 6.88 (m, 1 ), 1.31 (s, 9). MS (El): m/z 395 (1. W). 339 (28), 108 (100). Anal. Calcd. for C,6H]4F5NO3S: C. 48.61; H. 3.57: N, 3.54; S. 8.1 1. Found: C. 48.53; H. 3.60; N. 3.50: S. 8.02.
Example 39
Figure imgf000053_0002
l-Bromo-3-hydroxy-4-methoxy-l -pentafluoropheny lsulfonamidobenzene. The compound was prepared by bromination of the compound of example 6 with N-bromosuccinimide in dichloromethane. lH ΝMR (CDC13) 7.28 (br s, IH), 7.21 (d. J=9Hz, 1 H). 6.80 (d, J=9Hz,
IH), 6.05 (s, IH), 3.89ppm (s, 3H). El, m/z (relative abundance) : 449 (25), 447 (25), 218 (100), 216 (100). Anal, calcd. for C,3H8BrF5ΝO4S: C 34.84. H 1.57, N 3.13, S 7.15. Found:
C 34.75, H 1.60, N 3.07. S 7.08. Example 40
Figure imgf000054_0001
2-Bromo-4-methoxy-5-hydroxy- 1 -pentafluorophenylsulfonamidobenzene. The compound was prepared by bromination of the compound of example 6 with N-bromosuccinimide in dichloromethane. >H ΝMR (CDC1-,) 7.28 (s, IH). 7.16 (br s, IH), 6.91 (s, IH), 5.63 (s, IH),
3.85ppm (s, 3H). El, m/z (relative abundance) : 449 (25), 447 (25), 218 (100), 216 (100). Anal, calcd. for C13HgBrF5ΝO4S: C 34.84, H 1.57, N 3.13. S 7.15. Found: C 34.84. H 1.57, N 3.05, S 7.06.
Example 41
Figure imgf000054_0002
l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene. The compound was prepared by bromination of the compound of example 7 with bromine water. -H NMR (CDC13): 7.49 (d. J=l 1.72 Hz, IH), 7.21 (s, IH), 7.04 (d, J=8.2 Hz, IH), 3.84 ppm (s. 3H).
El m/z: 449 (20, M+), 451 (20 ). 228 (100), 230 (100). Anal. Calcd. for C,3H6BrF6NO3S: C
34.69, H 1.34, N 3.1 1, S 7.12. Br 17.75. Found: C34.76, H 1.29, N 3.05, S 7.12, Br 17.68. White crvstals with M.P.= 109 °C. Example 42
Figure imgf000055_0001
2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene sodium salt. The compound was prepared by treating the compound of example 6 with an equimolar amount of IN NaOH, ,. The mixture was then lyophilized and the residue recrystallyzed from ethyl acetate/ ether. *H NMR (DMSO) 8.40 (s, IH), 6.57 (d. J=9Hz. IH), 6.39 (d. J=2Hz. IH). 6.24 (dd. J=9, 2Hz. IH), 3.62ppm (s, 3H). Anal, calcd. for C,3H7F5NNaO4S: C 39.91. H
1.80, N 3.58, Na 5.88, S 8.19. Found: C 39.79, H 1.86, N 3.50. Na 5.78, S 8.07.
Example 43
Figure imgf000055_0002
2-Hydroxy- l-methoxy-4-pentafluoropheny lsulfonamidobenzene potassium salt. The compound was prepared in a manner similar to that of example 42 by replacing IN NaOH with IN KOH. -H NMR (DMSO) 8.30 (br s, IH), 6.55 (d, J=9Hz, IH), 6.36 (d. J=2Hz. IH), 6.25 (dd, J=9, 2Hz, IH), 3.61ppm (s, 3H). Anal, calcd. for C13H7F5KNO4S: C 38.33.
H 1.73. N 3.44, S 7.87. Found: C 38.09, H 1.79, N 3.39. S 7.97. Scheme IV
Figure imgf000056_0001
β1-, 32-, and 34-tubulin [3H]-compound 7 31-, 32-, and 34-tubuli
53/2
Figure imgf000057_0001
Figure imgf000057_0002
54
Example 4
Figure imgf000058_0001
2-Fluoro- l-methoxy-4-pentafluorophenylsulfonamidobenzene potassium salt. The compound was prepared in a manner similar to that of example 43 by replacing the compound from example 6 with example 7. *H NMR (DMSO) 6.80 (t. J=10Hz, IH). 6.72 (dd. J=9, 2Hz, IH). 6.54 (dd, =9. 2Hz, IH), 3.68ppm (s, 3H). Anal, calcd. for C,3H6F6 NO3S: C 38.15, H 1.48. N 3.42. S 7.83. Found: C 38.09, H 1.51. N 3.35, S 7.73. M.P.=202-205 °C.
Example 45
Figure imgf000058_0002
2-Fluoro- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene sodium salt. The compound was prepared in a manner similar to that of example 44 by replacing IN KOH with IN NaOH. -H NMR (DMSO) 6.80 (t, J=10Hz, I H), 6.71 (dd, J=9, 2Hz, IH), 6.53 (dd. J=9, 2Hz, IH), 3.69ppm (s, 3H). Anal, calcd. for C] 3H6F6NNaO3S: C 39.71, H 1.54. N 3.56, Na 5.85, S 8.15. Found: C 39.56, H 1.62, N 3.49, Na 5.88, S 8.08. M.P. > 250 °C. 55
Example 46
Figure imgf000059_0001
3-Chloro-l-pentafluorophenylsulfonamidobenzene. To a solution of pentafluorophenylsulfonyl chloride (0.15 mL, 1.00 mmol) in MeOH (4 mL) was added 3-chloroaniline (260 mg, 2.04 mmol). After stirring at rt for 1 h, the reaction mixture was concentrated under reduced pressure and the residue was taken up in EtOAc and then filtered through a plug of silica gel. The filtrate was concentrated to give a yellow oil that upon chromatography provided 265 mg (74%) of product. Η NMR (CDC13): d 7.28-7.24 (m,
IH), 7.21-7.17 (m, 2H), 7.10-7.08 (m. IH). 7.07 (s, IH). MS (El): m/z 357 (42, M+). 258 (76), 126 (87), 99 (100). Anal. Calcd. for C12H5ClF5NO2S: C, 40.30; H, 1.41 ; N, 3.92; S, 8.96. Found: C, 40.18; H. 1.35; N, 3.84; S, 8.90.
Exampl 47
Figure imgf000059_0002
4-Chloro- 1 -pentafluoropheny lsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 46 by replacing 3-chloroaniline with
4-chloroaniline. >H NMR (CDC13): d 7.30 (m, 2H). 7.20 (m. IH). 7.14 (m. 2H). MS (El): m/z 357 (27, M+). 258 (38), 126 (100), 99 (85). Anal. Calcd. for C12H5ClF5NO2S: C. 40.30: H, 1.41; N. 3.92; S. 8.96. Found: C. 40.19: H, 1.37; N, 3.87; S. 8.88. 56
Example 48
Figure imgf000060_0001
3-Nitro-l-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 46 by replacing 3-chloroaniline with 3-nitroaniline. *H NMR (CDC13): d 8.14 (s, IH), 8.06-8.03 (m, 2H), 7.66-7.63 (m, IH), 7.55 (m, IH). MS
(El): m/z 368 (54. Mτ), 137 (70). 91 (100). Anal. Calcd. for C] 2H5F5N2O4S: C. 39.14: H,
1.37; N, 7.61 ; S, 8.71. Found: C. 39.39: H. 1.45: N. 7.46; S. 8.58.
Example 49
Figure imgf000060_0002
4-Methoxy- 1 -pentafluoropheny lsulfonamido-3-trifluoromethylbenzene. The compound was prepared in a manner similar to that described in example 46 by replacing 3-chloroaniline with 4-methoxy-3-trifluoromethylaniline which was obtained by the hydrogenation of the corresponding nitro compound. White solid, mp 121-123 °C. Η NMR (CDC13): d 7.43-7.37 (m, 2H), 6.96 (d, J = 8.8. IH), 3.88 (s, 3H). MS (El): m/z 421 (16, M+), 190 (100). Anal. Calcd. for C,4H7F8NO3S: C, 39.92; H, 1.67: N. 3.32: S. 7.61. Found: C. 40.17; H,
1.68; N, 3.28; S, 7.67. 57
Example 50
Figure imgf000061_0001
4-Methoxy- l-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene. To a solution of 4-methoxy-l -pentafluoropheny lsulfonamidobenzene (448 mg, 1.27 mmol) in THF (3 mL) was added triphenylphosphine (333 mg, 1.27 mmol) and allyl alcohol (0.09 mL. 1.27 mmol). Diethylazodicarboxylate (0.20 mL, 1.27 mmol) was added and the mixture was stirred at rt. After 1 h. the reaction mixture was poured onto saturated ΝaCl ( 10 mL) and extracted with CH-,C12 (3 x 10 mL). The combined organic extracts were washed with saturated ΝaHCO3
(10 mL) and dried (MgSO4). Concentration followed by flash chromatography
(25:25: l/hexanes:CH2Cl-,:EtOAc) provided 451 mg (90%) of product as a white solid, mp
59-60 *C. 'H NMR (CDC13): d 7.06 (m, 2H), 6.85 (m, 2H). 5.79 (m, IH). 5.15 (s, IH), 5.1 1
(m, lH). 4.37 (d, J= 6.3, 2H), 3.80 (s, 3H). MS (El): m/z 393 (33, M+), 162 (100). 134 (66). Anal. Calcd. for C,6HnF5NO3S: C 48.98; H, 2.83; N, 3.57: S, 8.17. Found: C, 49.13; H,
3.15; N, 3.63; S, 8.15.
58
Example 51
Figure imgf000062_0001
l-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene. The compound was prepared in a manner similar to that described in example 50 by replacing allyl alcohol with 3-buten-l-ol. White solid, mp 64-66 °C. 'H ΝMR (CDC13): d 7.08 (m, 2H), 6.86 (m, 2H),
5.74 (m, IH), 5.10-5.04 (m. 2H), 3.83 (m. 2H). 3.81 (s, 3H), 2.25 (q, J= 6.9. 2H). MS (El): m/z 407 (13, M+). 366 (24), 135 (100). Anal. Calcd. for C| 7H,4F5ΝO3S: C. 50.13; H. 3.46:
N, 3.44; S, 7.87. Found: C. 50.25: H. 3.51 ; N, 3.43; S, 7.81.
Example 52
Figure imgf000062_0002
4-Methoxy- l-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. The compound was prepared in a manner similar to that described in example 50 by replacing allyl alcohol with 4-penten-l-ol. Low melting semi-solid. *H ΝMR (CDC13): d 7.08 (m. 2H). 6.87 (m. 2H),
5.74 (m, IH), 5.02-4.96 (m, 2H). 3.81 (s, 3H), 3.76 (t,J= 7.04, 2H), 2.11 (q, J= 6.9. 2H), 1.60 (pentet, J= 7.3, 2H). MS (El): m/z 421 (30, M+), 190 (100). Anal. Calcd. for C18H]6F5ΝO3S: C, 51.31; H. 3.83: N. 3.32; S, 7.61. Found: C, 51.44; H. 3.89; N, 3.38; S,
7.54. 59
Example 53
Figure imgf000063_0001
l-(N-(2,3-Dihydroxy propyl)pentafluorophenylsulfonamido)-4-methoxybenzene. To a solution of 4-methoxy- l-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene (101 mg, 0.26 mmol) in acetone:water (8:1, 1 mL) at rt was added N-methylmorpholine N-oxide (34.0 mg. 0.29 mmol) and OsO4 (0.10 mL of 0.16 M solution in H,O. 1.60 x 10"2 mmol). After stirring at rt for 18 h. the reaction mixture was treated with saturated ΝaHSO3 (5 mL) and allowed to stir at rt. After 1 h, the reaction mixture was poured onto saturated NaHSO3 (5 mL) and extracted with CH-,C12 (3 x 10 mL). The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1 :1, 1 :2/hexanes:EtOAc) afforded 90 mg (83%) of product as a white solid, mp 130-131 °C. 'H NMR (CDC13): d 7.11 (m. 2H), 6.85 (m, 2H), 3.78 (s. 3H), 3.90-3.65 (m, 5H). Anal. Calcd. for C,6H13F5NO5S: C, 45.08; H, 3.07; N, 3.29; S, 7.52. Found: C, 45.09; H, 3.33; N. 3.27; S, 7.46.
60
Example ?4
Figure imgf000064_0001
l-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxy benzene. The compound was prepared in a manner similar to that described in example 53 by replacing 4-methoxy- 1 -(N-(2-propeny l)pentafluorophenylsulfonamido)benzene with l-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene. White solid, mp 126-128 °C. Η ΝMR (CDC13): d 7.10 (m, 2H), 6.88 (m. 2H), 4.13 (m, IH), 3.96 (m, IH),
3.81 (s. 3H), 3.78-3.73 (m, lH). 3.64 (dd, 1, J = 2.9, 10.7. IH), 3.47 (dd, J= 7.3, 11.2; IH). 2.67 (bs, IH), 1.92 (bs, IH), 1.62 (m, 2H).
Example 55
Figure imgf000064_0002
l-(N-(4.5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxybenzene. The compound was prepared in a manner similar to that described in example 53 by replacing 4-methoxy- 1 -(N-(2-propenyl)pentafluorophenylsulfonamido)benzene with 4-methoxy- l-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. White solid, mp 116-118 °C. lH ΝMR (CDC13): d 7.07 (m. 2H), 6.86 (m. 2H), 3.80 (s, 3H), 3.78 (m. 2H), 3.71-3.62 (m. 2H), 3.43 (dd. J*= 7.5, 10.8; IH), 1.90 (bs. 2H), 1.66-1.49 (m, 4H). Anal. 61
Calcd. for C18H18 F5NO5S: C. 47.48; H. 3.98; N. 3.08; S, 7.04. Found: C. 47.58; H, 3.95; N. 3.06: S, 6.95.
Example 56
Figure imgf000065_0001
l-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene. To a solution of l-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene (410 mg, 1.01 mmol) in THF (6.5 mL) at -78 X was added BH3.THF (1.00 mL of a 1 M solution in THF, 1.00 mmol). After stirring at -78 °C for 1 h and at 0 °C for 1 h. the reaction mixture was treated with H?O (20 mL) and sodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, the mixture was poured onto H-,0 (20 mL) and extracted with CH-C1-, (3 x 15 mL). The combined organic extracts were washed with sat. ΝaCl (20 mL) and dried (MgSO4). Concentration followed by chromatography (2:l hexanes:EtOAc) afforded 270 mg (64%) of product as a white solid, mp 88-90 °C. 'H ΝMR (CDC13): d 7.08 (m. 2H). 6.85 (m, 2H), 3.80 (s, 3H), 3.77 (m, 2H), 3.64 (t. J = 6.0; 2H), 1.63-1.55 (m. 5H), 1.50 (bs, IH). Anal. Calcd. for C17H,6F5ΝO4S: C. 48.00; H, 3.79; N, 3.29; S, 7.54. Found: C, 48.08; H. 3.76; N.
3.34; S, 7.46. 62
Example 57
Figure imgf000066_0001
4-Methoxy- 1 -(N-(5-hydroxypentyl)pentafluoropheny lsulfonamido)benzene. The compound was prepared in a manner similar to that described in example 56 by replacing l-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene with 4-methoxy- l-(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene. White solid, mp 96-97 °C. 'H ΝMR (CDC13): d 7.08 (m, 2H), 6.86 (m, 2H), 3.81 (s, 3H), 3.76 (t. J = 6.8, 2H), 3.62 (t, J = 6.4; 2H), 1.58-1.43 (m. 6H). Anal. Calcd. for C18H18F5ΝO4S: C. 49.20; H, 4.13; N. 3.19; S, 7.30. Found: C, 49.11; H. 4.09; N, 3.14; S, 7.19.
Example 58
Figure imgf000066_0002
4-Methoxy-3-nitro-l-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to example 46 by replacing 3-chloroaniline with 4-methoxy-3-nitroaniline which was prepared by the method of Norris (Aust. J. Chem. 1971, 24, 1449). Orange-yellow solid, mp 95-97 °C. 'H NMR (CDC13): d 7.64 (d, J = 2.7; IH), 7.51 (dd, J =
2.7, 9.0; IH), 7.09 (s. IH). 7.09 (d, J= 9.0: IH), 3.95 (s, 3H). Anal. Calcd. For C]3H7F5N2O5S: C. 39.21 : H, 1.77; N, 7.03; S, 8.05. Found: C. 39.19: H, 1.73; N. 6.97; S,
7.95. 63
E ample 59
Figure imgf000067_0001
3-Amino-4-methoxy-l-pentafluorophenylsulfonamidobenzene. To a solution of 4-methoxy-3-nitro-l-pentafluorophenylsulfonamidobenzene (627 mg, 1.58 mmol) in ethanol (10 mL) was added 10% Pd/C (51 mg). The resulting mixture was stirred under an atmosphere of hydrogen gas at 1 atm pressure. After 14 h, the mixture was passed through a pad of celite and the filtrate was concentrated to give a solid residue. Silica gel chromatography (2:1, 1 : l/hexanes:EtOAc) yielded 542 mg (93%) of product as a white solid, mp 142-143 °C. »H NMR (DMSO-d6): 10.64 (s, 1), 6.68 (d, J = 8.4; IH). 6.44 (d. J = 2.1 ; IH), 6.30 (d, J = 2.1, 8.4; IH), 4.88 (bs. 2H), 3.69 (s, 3H). Anal. Calcd. for C] 3H9F5N2O3S:
C, 42.40; H. 2.46; N, 7.61; S, 8.71. Found: C, 42.29; H. 2.36; N, 7.52; S, 8.60.
64
Example <?Q
Figure imgf000068_0001
4-Butoxy-l-pentafluorophenylsulfonamidobenzene. To a solution of pentafluorophenylsulfonyl chloride (203 mg, 0.763 mmol) in MeOH (4 mL) was added 4-butoxyaniline (0.26 mL, 1.53 mmol). After stirring at rt for 1 h, the reaction mixture was poured onto 1 HC1 (15 mL) and extracted with CH2C1, (3 x 10 mL). The combined organic extracts were washed with saturated NaCl (10 mL) and dried (MgSO4). Concentration followed by flash chromatography (25:25:l hexanes: CH,Cl-,:EtOAc) provided 189 mg (63%) of product. lH NMR (CDC!3): d 7.07 (m. 2H), 6.86 (s, IH), 6.80 (m, 2H). 3.89 (t, J = 6.5; 2H), 1.73 (m, 2H), 1.46 (m. 2H), 0.95 (t, J= 7.5; 2H). MS (El): m/z 395 (30. M+), 164 (35), 108 (100). Anal. Calcd. for C16H14F5NO3S: C, 48.61 : H. 3.57; N, 3.54; S, 8.1 1. Found: C,
48.54; H. 3.53; N, 3.50; S, 8.02.
Example 61
Figure imgf000068_0002
l-Pentafluorophenylsulfonamido-4-phenoxybenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with 4-phenoxyaniline. ]H NMR (CDC13): 7.36-7.30 (m, 2H), 7.15-7.10 (m, 3H), 6.99 (s. IH),
6.98-6.90 (m, 4H). MS (El): m/z 415 (32, M+), 184 (100). 77 (66). Anal. Calcd. for C18H10F5NO3S: C. 52.05: H, 2.43; N, 3.27; S, 7.72. Found: C, 51.78; H, 2.45; N, 3.25; S. 65
7.53.
Example
Figure imgf000069_0001
4-Benzyloxy- 1 -pentafluor ophenylsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with 4-benzyloxy aniline. 4-Benzyloxyaniline was obtained from the commercially available hydrochloride salt by treatment with aqueous NaOH. Η NMR (CDC13): 7.38-7.37 (m. 4H), 7.36-7.32 (m, IH),
7.10-7.08 (m, 2H), 7.91-7.88 (m, 2H), 6.78 (s, IH), 5.01 (s. IH). MS (El): m/z 429 (19, M+), 91 (100). Anal. Calcd. for C19H12F5NO3S: C, 53.14; H. 2.82; N. 3.26; S. 7.45. Found: C, 53.07; H. 2.78; N, 3.21 ; S, 7.35.
66
Example 63
Figure imgf000070_0001
4-Methylmercapto-l-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with 4-(methylmercapto)aniline. -H NMR (CDC13): 7.17 (m. 2H), 7.09 (m, 2H), 6.89 (m, IH).
2.44 (s, 3H). MS (El): m/z 369 (24. M+). 138 (100), 77 (66). Anal. Calcd. for C13H8F5NO2S2: C. 42.28: H, 2.18; N. 3.79; S, 17.36. Found: C. 42.20; H. 2.21 ; N. 3.72; S.
17.28.
Example 64
Figure imgf000070_0002
2-Methoxy-l -pentafluoropheny lsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with oanisidine. •H NMR (CDCl3): d 7.54 (dd, J= 1.5. 8.0; IH), 7.13 (dt J = 1.5. 8.0; IH), 6.94 (dt, J = 1.2.
8.0; IH), 6.84 (dd. J = 1.2. 8.0; IH). 3.79 (s. 3H). MS (El): m/z 353 (82. M+), 122 (100), 94 (95). Anal. Calcd. for C,3H8F5NO3S: C. 44.19; H, 2.28; N. 3.97: S. 9.06. Found: C. 44.10:
H, 2.26; N, 3.92; S, 9.03. 67
Example 65
Figure imgf000071_0001
4-Allyloxy-l -pentafluoropheny lsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with 4-allyloxyaniline. 4-Allyloxyaniline was prepared by the method of Butera (J. Med. Chem. 1991 , 34. 3212). Η NMR (CDC13): 7.08 (m. 2H), 6.87 (m. IH), 6.82 (m, 2H), 6.04-5.94 (m.
IH), 5.39-5.34 (m. IH). 5.29-5.25 (m. IH). 4.48-4.46 (m. 2H). MS (El): m/z 379 (1 1. M+). 148 (32). 41 (100). Anal. Calcd. for C,5H10F5NO3S: C, 47.50; H. 2.66; N. 3.96; S. 8.45. Found: C, 47.53; H, 2.68; N. 3.62; S. 8.37.
Example 66
Figure imgf000071_0002
l-Pentafluorophenylsulfonamido-4-propoxybenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with 4-propoxy aniline. 4-Propoxyaniline was obtained by catalytic hydrogenation of 4-allyloxynitrobenzene. 4-Allyloxynitrobenzene was prepared by the method of Butera (J. Med. Chem. 1991. 34. 3212). »H NMR (CDC13): 7.09 (m. 2H), 6.82 (m, 2H), 6.78 (m, IH),
3.87 (t, J= 6.5: 2H), 1.78 (m, 2H), 1.02 (t, J= 7.4: 3H). MS (El): m/z 381 (20. M~), 150 (40), 108 (100). Anal. Calcd. for C15H,2F5NO3S: C. 47.25: H, 3.17; N, 3.67; S. 8.41.
Found: C. 47.01: H, 3.20: N, 3.61; S. 8.31. 68
Example 67
Figure imgf000072_0001
4-(l-Methyl)ethoxy-l-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to that described in example 60 by replacing 4-butoxyaniline with 4-isopropoxyaniline. 4-Isopropoxyaniline was prepared from 4-fluoronitrobenzene in analogy to the method of Day (J. Med. Chem. 1975, 18, 1065). lH NMR (CDC13): 7.08 (m. 2H),
7.00 (s. IH), 6.81 (m, 2H). 4.48 (heptet. J = 6.1 : IH). 1.30 (d, J = 6.04: 6H). MS (El): m/z 381 (7, M"), 339 (8), 108 (100). Anal. Calcd. for C,5HI2F5NO3S: C, 47.25; H. 3.17; N,
3.67; S, 8.41. Found: C, 47.08; H. 3.18; N, 3.60; S. 8.34.
Example 68
Figure imgf000072_0002
1-Pentafluorophenylsulfonyloxybenzene. To a stirred solution of phenol (0.068g, 0.729mmol) in dimethylformamide (3.65 mL) at 25 °C is added pentafluorophenyl sulfonyl chloride (0.135mL, 0.91 lmmol). followed by sodium carbonate (0.116g, 1.09mmol), and the reaction mixture is stirred for 18 hours. The reaction mixture is diluted with ethyl acetate
(50mL), washed with 20% ammonium chloride (2 x 20mL). and saturated sodium chloride (2 x 20mL). The organic layer is dried (sodium sulfite), and the ethyl acetate removed under vacuum. Column chromatography (3/1 ethyl acetate/hexane) yields the title compound. 69
Example 69
Figure imgf000073_0001
1-Pentafluorophenylsulfonylindole. To a stirred solution of indole (0.085g, 0.729mmol) in dimethylformamide (3.65 mL) at 25 °C is added pentafluorophenyl sulfonyl chloride (0.135mL, 0.91 lmmol), followed by sodium carbonate (0.116g, 1.09mmol), and the reaction mixture is stirred for 18 hours. The reaction mixture is diluted with ethyl acetate (50mL), washed with 20% ammonium chloride (2 x 20mL), and saturated sodium chloride (2 x 20mL). The organic layer is dried (sodium sulfite), and the ethyl acetate removed under vacuum. Column chromatography (3/1 ethyl acetate/hexane) yields the title compound.
Example 7Q
Figure imgf000073_0002
2-Fluoro- l-methoxy-4-pentafluorophenylsulfιnamidobenzene. To 3-fluoro- -anisidine (3g, 21.2mmol) suspended in THF (50mL) with pyridine (1.84g. 23.3mmol) at 0 °C under argon is added dropwise pentafluorophenylsulfinyl chloride (5.3g, 21.2mmol). The reaction mixture is stirred for 30 min. at 0 °C and allowed to warm to ambient temperature. The reaction mixture is strirred at room temperature and followed by TLC. After the reaction is completed the mixture is diluted with ethyl acetate and the reaction quenched with water. The layers are separated and the aqueous layer extracted twice with ethyl acetate. The organic layers are combined and dried with brine and with Na,SO4. The solvent is evaporated and the residue purified by chromatography on silica to give the title compound. 70
Example 71
Figure imgf000074_0001
2-Anilino-3-pentafluorophenylsulfonamidopyridine. To a solution of pentafluorophenylsulfonyl chloride (863 mg, 3.24 mmol) in pyridine (9 mL) at rt was added 3-amino-2-analinopyridine (600 mg, 3.24 mmol). After stirring at rt overnight the reaction mixture was concentrated at reduced pressure and the residue partitioned between 1 M Hel (50 mL) and CH2C12 (50 mL). The organic extract was dried and concentrated to give an oil which was purified by MPLC to give 377 mg (28%) of product as an orange solid. H1 NMR (CDC13): 8.50 (bs, IH), 7.80 (d. J=5.1, IH), 7.61 (d, J=8.0, IH), 7.32 (t. J=8.0, 2H). 7.25 (d,
J=8.0, 2H), 7.11 (t, J=7.3. I H), 6.80 (dd. J=5.6, 7.7, IH), 4.20 (bs, IH). MS (FAB): m/z 438 (M+Na), 416 (M+H).
Example 72 4-[3H]- 1 -Fluoro-2-methoxy-5-pentafluorosulfonamidobenzene.
A solution of l-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene (27.8 mg, 0.058 mmol; prepared in Example 41) in ethyl acetate (2 mL) was treated with 100 mg of 10% palladium on charcoal. The air in the reaction vessel was evacuated and replaced with tritium gas. After 2 h of stirring at room temperature, the catalyst was filtered, the solvent was evaporated, and the crude product purified by preparative thin layer chromatography (TLC) using dichloromethane as the eluent. The sample purity was characterized by HPLC using a Microsorb silica (250x4.6mm) 5 mm column and 15% ethyl acetate/hexane as the mobile phase. The elution of material was detected using a UV detector at 254 nm and a Beta Ram detector. The chemical purity of this material was determined to be 100%. and the radiochemical purity was 99.3%. The specific activity of this material was Ci/mmol. 71
Example 7
Compounds were evaluated for their ability to inhibit in vitro the growth of HeLa cells, an immortal cell line derived from a human cervical carcinoma commonly used to evaluate the cytotoxicity of potential therapeutic agents. The following data reflect the cytotoxicity of selected examples of the present invention. The values given represent the concentration of test compound required to inhibit by 50% the uptake of Alamar Blue (Biosource International, Camarillo. CA) by HeLa cell cultures, which correlates directly with the overall levels of cellular metabolism in the culture, and is generally accepted as an appropriate marker of cell growth. The test was conducted according to the method of S.A. Ahmed et al. (1994) J. Immunol. Methods 170: 211-224. The following selected examples display potent cytotoxic activity in this assay, with IC50 values ranging from less than 0.05 μM to 10 μM.
Compound IC50 (μM)
Example 1 < 0.05 Example 2 0.15
Example 3 1.5
Example 4 10
Example 6 < 0.05
Example 7 < 0.05 Example 8 < 0.05
Example 9 1
Example 12 0.15
Example 15 1
Example 17 10 Example 25 10
Example 30 1.5
Example 31 0.5
Example 32 0.1
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and 72
individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

73WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I:
Figure imgf000077_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -S(O)- or -S(O)2-; and
Z is -NR-R2 or -OR3; wherein R1 and R2 are independently selected from hydrogen, substituted or unsubstituted (C 1 -C 10)alky 1, substituted or unsubstituted (Cl-ClO)alkoxy, substituted or unsubstituted (C3-C6)alkenyl. substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6 heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl. substituted or unsubstituted (C3-C8)cycloalkyl. substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl. substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C5-C7)cycloalkenyl. substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl. substituted or unsubstituted aryl-(Cl-C4)alkyl. substituted or unsubstituted aryl-(Cl-C4)alkoxy, substituted or unsubstituted aryl-(Cl-C4)heteroalkyl, 74
substituted or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted aryloxy-(Cl -C4)alkyl, substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl-(Cl -C4)alkyl, substituted or unsubstituted heteroaryl-(Cl-C4)alkoxy, substituted or unsubstituted heteroaryl-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(Cl-C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein R1 and R2 may be connected by a linking group E to give a substituent of the formula
Figure imgf000078_0001
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene. and the ring formed by R1, E, R2 and the nitrogen atom contains no more than 8 atoms: and where R3 is a substituted or unsubstituted aryl or heteroaryl group, wherein said compound I has pharmacological activity.
2. The composition of claim 1 , wherein, in the compound of formula I. Y is SO2 and
Z is NR*R2; wherein R2 is optionally substituted aryl or optionally substituted heteroaryl.
3. The composition of claim 2. wherein R1 is hydrogen or lower alkyl, R2 is optionally substituted phenyl or optionally substituted pyridyl, and there is no linking group E between R- and R2.
4. The composition of claim 3, wherein R1 is hydrogen or methyl and R2 is substituted phenyl, wrherein the substituents on R2. ranging in number from one to four, are 75
independently chosen from lower alkyl, hydroxy, lower alkoxy, amino optionally substituted with one or two lower alkyls, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted phenoxy, and halogen.
5. The composition of claim 4, wherein R1 is hydrogen and R2 is substituted phenyl. wherein the substituents on R2 are independently chosen from amino, (lower)alkylamino, and di(lower)alkylamino, and are located at one or more of positions 3- and 4- of the phenyl ring, in relation to the sulfonamido group.
6. The composition of claim 5, wherein the compound is
4-(N,N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene,
4-(N,N-Diethylamino)- 1 -pentafluorophenylsulfonamidobenzene,
3-(N,N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene,
4- Amino- 1 -pentafluorophenylsulfonamidobenzene, or 4-(N N-Dimethy lamino)- 1 -pentafluoropheny lsulfonamidobenzene hydrochloride.
7. The composition of claim 6, wherein the compound is 4-(N N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene.
8. The composition of claim 2. wherein the compound is Pentafluorophenylsulfonamidobenzene.
9. The composition of claim 3, wherein R1 is hydrogen, and R2 is phenyl substituted at positions 3- and 4-, in relation to the sulfonamido group, with a divalent moiety that forms a 5- or 6- membered ring together with carbons 3- and 4- of the phenyl ring.
10. The composition of claim 9, wherein the divalent moiety is: -OCH2CH,O-. -OCH2O-. -C=CΝH-, or -C=NNH-.
11. The composition of claim 10. wherein the compound is 1.2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene. 76
l,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene, 5-Pentafluorophenylsulfonamidoindazole, or 5-Pentafluorophenylsulfonamidoindole.
12. The composition of claim 4. wherein R1 is hydrogen, and the substituents on R2 are independently selected from halogen, hydroxy, lower alkyl, lower alkoxy. amino, (lower)alkylamino, and di(lower)alkylamino.
13. The composition of claim 12. wherein the substituents on R2 are independently selected from bromo, chloro. fluoro. hydroxy, methoxy, ethoxy, amino. and dimethy lamino.
14. The composition of claim 13. wherein the substituents on R2 are independently selected from bromo, chloro, fluoro. hydroxy, methoxy, and ethoxy.
15. The composition of claim 12. wherein the substituents on R2 are at one or more of positions 3- and 4- of the phenyl ring, in relation to the sulfonamido group.
16. The composition of claim 15. wherein R2 is monosubstituted phenyl.
17. The composition of claim 16. wherein the compound is
4-Methoxy- 1 -pentafluorophenylsulfonamidobenzene.
3-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene,
4-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene,
4-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene, 3-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene,
3-Phenoxy- 1 -pentafluoropheny lsulfonamidobenzene,
3-Methoxy- 1 -pentafluoropheny lsulfonamidobenzene, or
4-tert-Butoxy- 1 -pentafluorophenylsulfonamidobenzene.
18. The composition of claim 16, wherein the compound is 3-Chloro- 1 -pentafluorophenylsulfonamidobenzene. or 77
4-Chloro- 1 -pentafluoropheny lsulfonamidobenzene.
19. The composition of claim 15. wherein R2 is disubstituted phenyl.
20. The composition of claim 19. wherein the compound is l,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene, 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, l,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene,
2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene. monosodium salt, or 2-Hydroxy- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene. monopotassium salt.
21. The composition of c laim 1 9, wherein the compound is 2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene,
2-Bromo- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, 2-Chloro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene,
2-Fluoro- l-methoxy-4-pentafluoropheny lsulfonamidobenzene. sodium salt, or 2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt.
22. The composition of claim 20. wherein the compound is 2-Hydroxy- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene.
23. The composition of claim 20, wherein the compound is
2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, monosodium salt.
24. The composition of claim 21. wherein the compound is 2-Fluoro-l-methoxy-4-pentafluorophenylsulfonamidobenzene.
25. The composition of claim 21 , wherein the compound is
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt.
26. The composition of claim 21. wherein the compound is 78
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt.
27. The composition of claim 12, wherein R2 is a trisubstituted phenyl.
28. The composition of claim 21, wherein the compound is 2-Bromo- l-methoxy-4-pentafluorophenylsulfonamidobenzene. or 2-Chloro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene.
29. The composition of claim 12, wherein the compound is 1 ,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene.
30. The composition of claim 1. wherein in the compound of formula I, Y is SO, and
Z is NR'R2, where R1 is hydrogen or lower alkyl. and R2 is an unsubstituted or optionally substituted naphthyl group.
31. The composition of claim 30. wherein the compound is 7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene.
32. The composition of claim 4. wherein R2 is a phenyl group substituted by phenoxy or optionally substituted phenoxy.
33. The composition of claim 32, wherein the compound is 3-Phenoxy- 1 -pentafluorophenylsulfonamidobenzene.
34. The composition of claim 3, wherein R2 is a phenyl ring substituted by a heterocyclic group at the 4- position, in relation to the sulfonamido group.
35. The composition of claim 17. wherein the compound is 4-Methoxy- 1 -pentafluorophenylsulfonamidobenzene. 79
36. The composition of claim 2, wherein R1 and R2 are covalently joined in a moiety that forms a 5- or 6- membered heterocyclic ring with the nitrogen atom of NR'R2.
37. The composition of claim 36, wherein R1 is a -CH=CH- group linked to the 2- position of the R2 phenyl group, in relation to the sulfonamido group, forming an optionally substituted indole.
38. The composition of claim 37, wherein the compound is 1-pentafluorophenylsulfonylindole.
39. The composition of claim 36. wherein R1 is a -(CH2)3- group linked to the 2- position of the R2 phenyl group, in relation to the sulfonamido group, forming an optionally substituted 1 ,2,3,4-tetrahydroquinoline.
40. The composition of claim 39, wherein the compound is 1 -pentafluorophenylsulfonyl-1 ,2,3.4-tetrahydroquinoline.
41. The composition of claim 2. wherein R1 is an optionally substituted (C2-C10)alkyl or optionally substituted (C2-C6)heteroalkyl.
42. The composition of claim 41. wherein the compound is
2-Hydroxy- 1 -methoxy-4-[N-(5-hydroxypent-l -yl)pentafluorophenyl-sulfonamido]benzene, 4-Methoxy- l-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene, 4-Methoxy- 1 -[N-(4-pentenyl)pentafluorophenylsulfonamido]benzene. 1 -[N-(2,3-Dihydroxypropyl) pentafluorophenylsulfonamido]-4-methoxybenzene. l-[N-(3.4-Dihydroxybutyl)pentafluorophenylsulfonamido]-4-methoxybenzene. l-[N-(4.5-Dihydroxypentyl)pentafluorophenylsulfonamido]-4-methoxybenzene. l-[N-(4-hydroxybutyl)pentafluorophenylsulfonamido]-4-methoxybenzene. or 4-Methoxy - 1 - [N -( 5 -hydroxy penty 1 )pentafluoropheny 1 sulfonamido] benzene .
43. A method of treating or preventing a disease state characterized by an abnormal or 80
undesired level of cell proliferation, which method comprises administering to a mammalian subject in need thereof a therapeutically effective amount of a composition containing a compound of formula I
Figure imgf000084_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -S(O)- or -S(O)2-;
Z is -NR'R2 or -OR3; where R1 and R2 are independently selected from hydrogen, substituted or unsubstituted (Cl-ClO)alkyl, substituted or unsubstituted (C 1 -C 10)alkoxy . substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl. substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycioalkyl. substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(Cl-C4)alkyl. substituted or unsubstituted aryl-(Cl-C4)alkoxy, substituted or unsubstituted aryl-(Cl-C4)heteroalkyl. substituted or unsubstituted aryl-(C3-C6)alkenyl, 81
substituted or unsubstituted aryloxy-(Cl -C4)alkyI. substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl-(Cl-C4)alkyl, substituted or unsubstituted heteroaryl-(Cl-C4)alkoxy, substituted or unsubstituted heteroaryl-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(Cl-C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein R1 and R2 may be connected by a linking group E to give a substituent of the formula
Figure imgf000085_0001
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene. and the ring formed by R1, E, R2 and the nitrogen contains no more than 8 atoms; and where R3 is optionally substituted aryl or optionally substituted heteroaryl.
44. The method of claim 43 wherein, in the compound of formula I. Y is SO, and
Z is NR' R2; where R2 is optionally substituted aryl or optionally substituted heteroaryl.
45. The method of claim 44. wherein R1 is hydrogen or lower alkyl, R2 is optionally substituted phenyl. and there is no linking group E between R1 and R2.
46. The method of claim 45. wherein R1 is hydrogen or methyl, and the substituents on R2 are independently chosen from lower alkyl, hydroxy. lower alkoxy, amino, amino optionally substituted with one or two lower alkyls, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted phenoxy. and halogen. 82
47. The method of claim 46. wherein the compound is chosen from:
4 - ( N ,N - D i met hy l am i n o ) - ! -p en t afluo rop h en y l s u l f onami d o b en z e n e,
3-(N,N-Dimethy lamino)- 1 -pentafluorophenylsulfonamidobenzene, 1 ,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene, l,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene, l,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene,
2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene,
2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene, 4-Methoxy- 1 -pentafluoropheny lsulfonamidobenzene,
3-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene.
4-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene, l,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene.
4-(N,N-Diethylamino)-l-pentafluorophenylsulfonamidobenzene, 4-Amino- 1 -pentafluorophenylsulfonamidobenzene,
Pentafluoropheny 1 sulfonamidobenzene .
5-Pentafluorophenylsulfonamidoindazole,
5-Pentafluorophenylsulfonamidoindole,
4-(N,N-Dimethylamino)-l-(N-methylpentafluorophenylsulfonamido)benzene. 4-(N,N-Dimethy lamino)- 1 -(pentafluorophenylsulfonamido)benzene,
1 ,2 -D ihy droxy-4-pentafluoropheny 1 sul f onamidobenzene ,
4-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene,
3,5-Dimethoxy- 1 -pentafluorophenylsulfonamidobenzene,
3-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene. 7-Hydroxy-2-pentafluorophenylsulfonamidonaphthalene.
3-Phenoxy- 1 -pentafluorophenylsulfonamidobenzene,
3-Methoxy- 1 -pentafluorophenylsulfonamidobenzene,
4( 1 -Morpholino)- 1 -pentafluoropheny lsulfonamidobenzene,
5-Pentafluorophenylsulfonamido-1.2.3-trimethoxybenzene, 2-Hydroxy- 1 ,3-methoxy-5-pentafluorophenylsulfonamidobenzene, l,2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene, 83
5-Pentafluoropheny Isulfonamido- 1 ,2,3 -trihydroxybenzene, l,3-Dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene, 1.2-Dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene, 5-Pentafluorophenylsulfonamido- 1 ,2,3-trihydroxybenzene, 5 3-Hydroxy-5-methoxy- 1 -pentafluorophenylsulfonamidobenzene, 3 ,5-Dihydroxy- 1 -pentafluorophenylsulfonamidobenzene. 2-Fluoro- 1 -methoxy -4-(N-methylpentafluorophenylsulfonamido)benzene, 2-Bromo- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, 2-Chloro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene, o 4-(N,N-Dimethy lamino)- 1 -pentafluorophenylsulfonamidobenzene hydrochloride. 3 ,4-Difluoro- 1 -pentafluoropheny lsulfonamidobenzene, 4-Trifluoromethoxy- 1 -pentafluorophenylsulfonamidobenzene, 2-Chloro-5-pentafluorophenylsulfonamidopyridine, 2-Hydroxy- l-methoxy-4-[N-(5-hydroxypentyl)pentafluorophenylsulfonamido]benzene, 5 4-( 1 , 1 -Dimethyl)ethoxy- 1 -pentafluorophenylsulfonamidobenzene,
2-Bromo-3-hydroxy-4-methoxy- 1 -pentafluoropheny lsulfonamidobenzene, 2-Bromo-4-methoxy-5-hydroxy-l-pentafluorophenylsulfonamidobenzene, l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene, 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene; sodium salt, 0 2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene; potassium salt. 2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene: sodium salt, 2-Fluoro- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene; potassium salt, 3 -Chloro- 1 -pentafluorophenylsulfonamidobenzene, 4-Chloro- 1 -pentafluorophenylsulfonamidobenzene, 5 3-Nitro- 1 -pentafluorophenylsulfonamidobenzene,
4-Methoxy-l-pentafluorophenylsulfonamido-3-trifluoromethylbenzene, 4-Methoxy-l-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene, l-(N-(3-Butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene, 4-Methoxy- 1 -(N-(4-pentenyl)pentafluorophenylsulfonamido)benzene, 0 l-(N-(2,3-Dihydroxypropyl)pentafluorophenylsulfonamido)-4-methoxybenzene. l-(N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene. 84
l-(N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido)-4-methoxy benzene. l-(N-(4-hydroxybutyl)pentafluorophenylsulfonamido)-4-methoxybenzene,
4-Methoxy- l-(N-(5-hydroxypentyl)pentafluorophenylsulfonamido)benzene.
4-Methoxy-3-nitro- 1 -pentafluoropheny lsulfonamidobenzene. 3-Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene,
4-Butoxy- 1 -pentafluorophenylsulfonamidobenzene, l-Pentafluorophenylsulfonamido-4-phenoxy benzene.
4-Benzyloxy- 1 -pentafluorophenylsulfonamidobenzene,
4-Methylmercapto- 1 -pentafluorophenylsulfonamidobenzene. 2-Methoxy- 1 -pentafluorophenylsulfonamidobenzene,
4-Allyloxy- 1 -pentafluorophenylsulfonamidobenzene, l-Pentafluorophenylsulfonamido-4-propoxy benzene,
4-( 1 -Methyl)ethoxy- 1 -pentafluorophenylsulfonamidobenzene,
1-Pentafluorophenylsulfonyloxybenzene. 1 -Pentafluorophenylsulfonylindole,
1 -Pentafluoropheny lsulfony 1-1.2,3, 4-tetrahydroquinoline.
2-Methoxy-5-pentafluorophenylsulfonamidopyridine.
2-Fluoro- 1 -methoxy -4-pentafluoropheny lsulfinamide,
4-tert-Butoxy- 1 -pentafluorophenylsulfonamidobenzene, and 2-Anilino-3-pentafluorophenylsulfonamidopyridine.
48. The method of claim 47, wherein the compound is chosen from:
4-(N,N-Dimethylamino)- 1 -pentafluorophenylsulfonamidobenzene,
3-(N,N-Dimethy lamino)- 1 -pentafluorophenylsulfonamidobenzene. 1 ,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene.
2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene.
2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene.
4-Methoxy- 1 -pentafluorophenylsulfonamidobenzene.
3-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene. 4-Hydroxy- 1 -pentafluorosulfonamidobenzene, l,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene, 85
5-Pentafluorophenylsulfonamidoindole.
4-(N,N-Dimethylamino)-l-(N-methylpentafluorophenyisulfonamido)benzene,
4-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene,
3-Methoxy- 1 -pentafluorophenylsulfonamidobenzene, 2-Bromo- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene.
2-Chloro- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene.
2-Bromo-3-hydroxy-4-methoxy- l-pentafluorophenylsulfonamidobenzene,
2-Bromo-4-methoxy-5-hydroxy-l-pentafluorophenylsuIfonamidobenzene, l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene, 2-Hydroxy- l-methoxy-4-pentafluorophenylsulfonamidobenzene; monosodium salt,
2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene: monopotassium salt.
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene; sodium salt.
2-Fluoro- 1 -methoxy-4 -pentafluoropheny lsulfonamidobenzene; potassium salt.
4-Chloro- 1 -pentafluoropheny lsulfonamidobenzene. and 3-Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene.
49. The method of claim 48. wherein the compound is:
2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene.
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene. 4-Methoxy- 1 -pentafluorophenylsulfonamidobenzene. l,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene.
5-Pentafluorophenylsulfonamidoindole,
4-Ethoxy- 1 -pentafluoropheny lsulfonamidobenzene,
2-Bromo- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene, 2-Chloro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene.
2-Bromo-3-hydroxy-4-methoxy-l-pentafluorophenylsulfonamidobenzene,
2-Bromo-4-methoxy-5-hydroxy-l-pentafluorophenylsulfonamidobenzene, l-Bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene,
2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene: monosodium salt. 2-Hydroxy- l-methoxy-4-pentafluorophenylsulfonamidobenzene; monopotassium salt,
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene: sodium salt. 86
2-Fluoro- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene; potassium salt, or 3-Amino-4-methoxy- 1 -pentafluorophenylsulfonamidobenzene.
50. The method of claim 49. wherein the compound is 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene.
2-Hydroxy- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene; monosodium salt, or 2-Hydroxy- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene; monopotassium salt.
51. The method of claim 49, wherein the compound is 2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene.
52. The method of claim 49. wherein the compound is
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene. sodium salt.
53. The method of claim 49. wherein the compound is
2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene. potassium salt.
54. The method of claim 43 in which the growth of a target cell is inhibited, which method comprises contacting said cell with an effective amount of a composition containing a compound of formula I.
55. The method of claim 43. wherein the proliferative disease state is cancer or a cancerous condition.
56. The method of claim 43, wherein the proliferative disease state is infection by a microorganism.
57. The method of claim 43, wherein the proliferative disease state is psoriasis.
58. The method of claim 43, wherein the proliferative disease state is vascular restenosis. 87
59. The method of claim 43, wherein the composition is administered orally.
60. The method of claim 43, wherein the compound is administered intravenously.
61. The method of claim 43 wherein the subject is administered intramuscularly.
62. The method of claim 43 wherein the composition is administered in combination with a therapeutically effective amount of an antineoproliferative, chemotherapeutic, or cytotoxic agent that is not represented by formula I.
63. The method of claim 43. wherein the compound is administered as a prodrug.
64. The method of claim 43. wherein the compound is conjugated to a targeting molecule which preferentially directs the compound to a targeted cell.
65. A compound having the formula I:
Figure imgf000091_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is -S(O)- or -S(O2)-; and Z is NR'R2, wherein R2 is an optionally substituted aryl or heteroaryl group, and R 1 is selected from hydrogen, substituted or unsubstituted (Cl-ClO)alkyl, substituted or unsubstituted (Cl-ClO)alkoxy, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, 88
substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted (C5-C7)cycloalkadienyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted aryl-(Cl-C4)alkyl, substituted or unsubstituted aryl-(Cl-C4)alkoxy. substituted or unsubstituted aryl-(Cl-C4)heteroalkyl, substituted or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted aryloxy-(C 1 -C4)alkyl, substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl-(Cl -C4)alkyl, substituted or unsubstituted heteroaryl-(C 1 -C4)alkox\\ substituted or unsubstituted heteroaryl-(Cl-C4)heteroalkyl, substituted or unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or unsubstituted heteroaryloxy-(C 1 -C4)alkyl, and substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein R' and R2 may be connected by a linking group E to give a substituent of the formula
wherein E represents a bond, (C 1 -
Figure imgf000092_0001
C4) alkylene, or (C1-C4) heteroalkylene, and the ring formed by R1, E, R2 and the nitrogen contains no more than 8 atoms; 89
provided that: in the case that Y is -S(O2)-, and R1 is hydrogen or methyl, then R2 is substituted phenyl or heteroaryl group; in the case that Y is -S(O,)- and R2 is a ring system chosen from 1 -naphthyl, 5- quinolyl, or 4-pyridyl, then either R1 is not hydrogen or R2 is substituted by at least one substituent that is not hydrogen; in the case that Y is -S(O2)-, R2 is phenyl, and R1 is a propylene unit attaching the nitrogen of -NR'R2- to the 2- position of the phenyl ring in relation to the sulfonamido group to form a 1,2,3,4-tetrahydroquinoline system, and one or more of the remaining valences on the bicyclic system so formed is substituted with at least one substituent that is not hydrogen; in the case that Y is -S(O2)- and R2 is phenyl substituted with 3-(l-hydroxyethyl),
3-dimethylamino, 4-dimethylamino, 4-phenyl, 3-hydroxy, 3-hydroxy-4-diethylaminomethyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 2-(l-pyrrolyl), or 2-methoxy-4-(l-morpholino), then either R1 is not hydrogen or when R1 is hydrogen, one or more of the remaining valences on the phenyl ring of R2 is substituted with a substituent that is not hydrogen; in the case that Y is -S(O2 )- and R2 is 2-methylbenzothiazol-5-yl,
6- hy droxy -4-met hy l-p y r imidin - 2 - y l, 3 - c arbo met ho xy py raz in - 2- y l, 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-l-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidin-6-yl, 2-trifluoromethyl- 1.3,4-thiadiazol-5-yl, 5,6,7.8- tetrahydro-2-naphthyl. 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, 7-chloro-5-methy 1-1.8- naphthyridin-2-yl, 5,7-dimethyl-l,8-naphthyridin-2-yl, or 3-cyanopyrazol-4-yl, then R 1 is a group other than hydrogen; wherein said compound has pharmacological activity.
66. The compound of claim 65. wherein R1 is hydrogen or lower alkyl, Y is -S(O2)-, and there is no linking group E between R1 and R2.
67. The compound of claim 66, wherein R1 is hydrogen or methyl and R2 is substituted phenyl, wherein the substituents on R2, ranging in number from one to four, are 90
independently chosen from lower alkyl, hydroxy, lower alkoxy, amino optionally substituted with one or two lower alkyls, optionally substituted arylamino, optionally substituted heteroary lamino, optionally substituted phenoxy, and halogen.
68. The compound of claim 67, wherein R' is hydrogen and R2 is substituted phenyl, wherein the substituents on R2 are independently chosen from amino, (lower )alkylamino, and di(lower)alky lamino, and are located at one or more of positions 3- and 4- of the phenyl ring, in relation to the sulfonamido group.
69. The compound of claim 68, wherein the compound is
4-(NN-Diethy lamino)- 1 -pentafluoropheny lsulfonamidobenzene, or 4- Amino- 1 -pentafluorophenylsulfonamidobenzene.
70. The compound of claim 65, wherein R ' is hydrogen, and R2 is phenyl substituted at positions 3- and 4-, in relation to the sulfonamido group, with a divalent moiety that forms a
5- or 6- membered ring together with carbons 3- and 4- of the phenyl ring.
71. The compound of claim 70, wherein the divalent moiety is: -C=CΝH-, or -C=NNH-.
72. The compound of claim 71 , wherein the compound i s 5- Pentafluorophenylsulfonamidoindazole or 5-Pentafiuorophenylsulfonamidoindole.
73. The compound of claim 65, wherein R ' is hydrogen, and the substituents on R2 are independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, amino, (lower)alky lamino, and di(lower)alky lamino.
74. The compound of claim 73, wherein the substituents on R2 are independently selected from bromo, chloro, fluoro, hydroxy, methoxy, ethoxy, amino, or dimethy lamino.
75. The compound of claim 74, wherein the substituents on R2 are independently selected from bromo, chloro, fluoro, hydroxy, methoxy, and ethoxy. 91
76. The compound of claim 75, wherein the substituents on R2 are at one or more of positions 3- and 4- of the phenyl ring, in relation to the sulfonamido group.
77. The compound of claim 76, wherein R2 is monosubstituted phenyl.
78. The compound of claim 77, wherein the compound is 4-Methoxy- 1 -pentafluorophenylsulfonamidobenzene, 3-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene, 4-Hydroxy- 1 -pentafluorophenylsulfonamidobenzene, 4-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene, 3-Ethoxy- 1 -pentafluorophenylsulfonamidobenzene, or 3-Methoxy- 1 -pentafluorophenylsulfonamidobenzene.
79. The compound of claim 77, wherein the compound is 3 -Chloro- 1 -pentafluoropheny lsulfonamidobenzene, or 4-Chloro- 1 -pentafluorophenylsulfonamidobenzene.
80. The compound of claim 76, wherein R2 is disubstituted phenyl.
81. The compound of claim 80, wherein the compound is l,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene, 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, l,2-Dihydroxy-4-pentafluorophenylsulfonamidobenzene, 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, monosodium salt, or 2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, monopotassium salt.
82. The compound of claim 80, wherein the compound is 2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene, 2-Bromo- 1 -methoxy-4-pentafluorophenylsulfon-ιmidobenzene, 2-Chloro- 1 -methoxy -4-pentafluoropheny lsulfonamidobenzene, 92
2-Fluoro- l-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt, or 2-Fluoro- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt.
83. The compound of claim 81, wherein the compound is 2-Hydroxy- l-methoxy-4-pentafluorophenylsulfonamidobenzene, or
2-Hydroxy- 1 -methoxy-4-pentafluorophenylsulfonamidobenzene, monosodium salt.
84. The compound of claim 82, wherein the compound is 2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene, or 2-Fluoro- 1 -methoxy-4-pentafluoropheny lsulfonamidobenzene, sodium salt.
85. The compound of claim 84, wherein the compound is 2-Fluoro-l-methoxy-4-pentafluorophenylsulfonamidobenzene.
86. The compound of claim 84, wherein the compound is
2-Fluoro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene, sodium salt.
87. The compound of claim 76. wherein R2 is trisubstituted phenyl.
88. The compound of claim 82, wherein the compound is 2-Bromo- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene, or 2-Chloro- 1 -methoxy -4-pentafluorophenylsulfonamidobenzene.
89. The compound of claim 73, wherein the compound is 1 ,2-Dimethyl-4-pentafluorophenylsulfonamidobenzene.
90. The compound of claim 67, wherein the compound is 3-Phenoxy-l-pentafluorophenylsulfonamidobenzene.
91. The compound of claim 66, wherein R2 is a phenyl ring substituted by a heterocyclic group at the 4- position, in relation to the sulfonamido group. 93
92. The compound of claim 78, wherein the compound is 4-Methoxy- 1 -pentafluorophenylsulfonamidobenzene.
93. The compound of claim 65. wherein R1 and R2 are covalently joined in a moiety that forms a 5- or 6- membered heterocyclic ring with the nitrogen atom of NR'R2.
94. The compound of claim 93, wherein R' is a -CH=CH- group linked to the 2- position of the R2 phenyl group, in relation to the sulfonamido group, forming an optionally substituted indole.
95. The compound of claim 94 , wherein the compound is l-(Pentafluorophenylsulfonyl)indole.
96. The compound of claim 93, wherein R1 is a -(CH2)3- group linked to the 2- position of the R2 phenyl group, in relation to the sulfonamido group, forming an optionally substituted 1 ,2,3,4-tetrahydroquinoline.
97. The compound of claim 65, wherein the compound is 2-Hydroxy- l-methoxy-4-[N-(5-hydroxypent-l-yl)pentafluorophenylsulfonamido]benzene. 4-Methoxy- l-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene, 4-Methoxy- 1 -[N-(4-pentenyl)pentafluorophenylsulfonamido]benzene, l-[N-(2,3-Dihydroxy propyl) pentafluorophenylsulfonamido]-4-methoxybenzene, l-[N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido]-4-methoxybenzene, l-[N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido]-4-methoxybenzene. l-[N-(4-hydroxybutyl)ρentafluorophenylsulfonamido]-4-methoxy benzene, or 4-Methoxy-l-[N-(5-hydroxypentyl)pentafluorophenylsulfonamido]benzene.
98. The composition of any of claim 1-42, or a method of any of claim 43-64, or a compound of any of claim 65-97, wherein the compound prevents cancerous cell growth. 94
99. A method for controlling cell proliferation, which method comprises covalently modifying selectively a β tubulin.
100. The method of claim 99, which method comprises covalently modifying selectively Cys-239 of a β tubulin.
101. A method for disrupting microtubule formation, which method comprises covalently modifying selectively a β tubulin.
102. The method of claim 101, which method comprises covalently modifying selectively Cys-239 of a β tubulin.
103. A natural β tubulin covalently modified at selectively Cys-239.
104. A compound which covalently modifies selectively a β tubulin.
PCT/US1997/012720 1996-07-19 1997-07-18 Pentafluorobenzenesulfonamides and analogs WO1998005315A1 (en)

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IL127965A0 (en) 1999-11-30
AU3887797A (en) 1998-02-25
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