WO1999038846A1 - Immunosuppressive agents - Google Patents

Immunosuppressive agents Download PDF

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Publication number
WO1999038846A1
WO1999038846A1 PCT/US1999/000361 US9900361W WO9938846A1 WO 1999038846 A1 WO1999038846 A1 WO 1999038846A1 US 9900361 W US9900361 W US 9900361W WO 9938846 A1 WO9938846 A1 WO 9938846A1
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WIPO (PCT)
Prior art keywords
substituted
group
structural formula
compound
ring
Prior art date
Application number
PCT/US1999/000361
Other languages
French (fr)
Inventor
Timothy D. Ocain
Cecilia M. Bastos
Zhan Shi
Raymond Patch
Bainian Feng
Original Assignee
Procept, Inc.
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Publication date
Application filed by Procept, Inc. filed Critical Procept, Inc.
Priority to AU21080/99A priority Critical patent/AU2108099A/en
Publication of WO1999038846A1 publication Critical patent/WO1999038846A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • 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
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/55—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C323/39—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 at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • One embodiment of the present invention is a method of suppressing the immune system in a subject in need of immune system suppression.
  • the method comprises administering to the subject an effective amount of a compound represented by Structural Formula (I) , (II) , (III) or (IV) :
  • Ring A, Ring B and Ring C are substituted or unsubstituted.
  • Ring B has one or two nitrogen atoms.
  • the "dotted line" in Ring B indicates the presence or absence of a double bond.
  • Ring D is a substituted or unsubstituted aromatic group . - 3 -
  • Ring D is substituted on adjacent ring carbon atoms (ortho, carbon atoms if Ring D is a phenyl ring) with the carboxylic acid and amide group.
  • Ar x and Ar 4 are independently an aromatic group or a substituted aromatic group.
  • Ar 2 and Ar 3 are independently an aromatic group, substituted aromatic group, a cycloalkyl group, a substituted cycloalkyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.
  • X 2 is a covalent bond, -C(O)-, -CH 2 -, -CH(R 2 )-, -CH 2 -CH(R 2 )- or -CH 2 -C (R 3 ) (R 2 ) - .
  • X 3 is a covalent bond or -CH 2 -, -CH(R 2 )-, -NH- , and -N(R 2 ) .
  • X 4 is -0-, -S-, -0CH 2 - or -CH 2 CH 2 - .
  • R ⁇ is an aliphatic or substituted aliphatic group.
  • R 2 and R 3 are independently -H,a C1-C3 alkyl or halogenated alkyl group, or wherein R 2 and R 3 , taken together with the carbon atom to which they are attached, are a C3-C6 cycloalkyl group.
  • the invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as immune system suppressants and a suitable pharmaceutical carrier.
  • the invention further relates to novel compounds which can be used to suppress the immune system in a subject in need of immune system suppression.
  • the method of the present invention can be used to treat subjects having an autoimmune disease, such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus . It is expected that the methods disclosed herein will not cause the undesirable side effects associated with other immunosuppressive drugs such as cyclosporin.
  • the method of the present invention can be used to treat tumors in a subject in need thereof.
  • the compound is represented by Structural Formula (V) :
  • Rj_ is an aliphatic group such as a C1-C3 aliphatic group or a substituted C1-C3 aliphatic group. More preferably, R ⁇ is a C1-C3 alkyl group or a C1-C3 halogenated alkyl group .
  • X x is a covalent bond or -CH 2 -.
  • Ring A, rj . and Ar 2 are as defined for Structural Formula (I) .
  • the compound is represented by Structural Formula (VI) : - 5 -
  • X is a covalent bond or -CH 2 - .
  • Ring A, Ar x and Ar 2 are as defined for Structural Formula (I) .
  • the compound is represented by Structural Formula (VII) :
  • X-_ is a covalent bond or -CH 2 - .
  • Ring A, Ar x and Ar 2 are as defined for Structural Formula (I) .
  • the compound is represented by Structural Formula (VIII) :
  • Ring A, R 1# X 2 and Ar 3 are as defined above for
  • Rj_ in Structural Formula (VIII] is preferably -H, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group, more preferably, -H, methyl or ethyl.
  • X 2 in Structural Formula (VIII) is preferably -CH 2 -.
  • Ar 3 is preferably a substituted or unsubstituted aromatic group .
  • the compound is represented by Structural Formula (IX) :
  • Ring D, R 2 and Ar 3 are as defined in Structural Formula (III) .
  • R 2 is preferably -H, methyl or ethyl.
  • the compound is represented by Structural Formula (X) :
  • Ring D, R 2 and Ar 3 are as defined in Structural Formula (III) .
  • R 2 is preferably -H or methyl.
  • Ring D is preferably a carbocyclic aromatic ring.
  • the compound is represented by Structural Formula (XI) :
  • the compound is represented by Structural Formulas (XII) or (XIII) :
  • Ar 4 in Structural Formulas (XII) and (XIII) are as defined in Structural Formula (IV) .
  • Ar 4 is preferably a substituted or unsubstituted carbocyclic aromatic group.
  • Another embodiment of the present invention is a method of suppressing the immune system in a subject in need of immune system suppression.
  • the method comprises administering an effective amount of a compound represented by Structural Formula (XIV) :
  • Ar lf Ar 2 and X x are as defined above for Structural Formula (I) .
  • X x is a covalent bond or -CH 2 -
  • Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like.
  • a suitable organic or inorganic acid such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like.
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base, for example, a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium, potassium and the like.
  • aliphatic groups include straight chained, branched or cyclic C-x-Cg hydrocarbons which are completely saturated or which contain one or more units of unsaturation.
  • An "alkyl” group is a saturated aliphatic group.
  • Aromatic groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2 -naphthyl, 1-anthracyl and
  • 2-anthracyl and heterocyclic aromatic groups such as N- imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl, 2- furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4- oxazolyl and 5-oxazolyl.
  • Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • Examples include 2-benzothienyl , 3-benzothienyl, 2-benzofuranyl , 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl , 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2- • 10 -
  • quinolinyl 3-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridintyl .
  • Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring.
  • the ring can be five, six, seven or eight-membered. Examples include 2-tetrahydrofuranyl, 3 -tetrahydrofuranyl , 2 -tetrahyrothiophenyl , 3-tetrahyrothiophenyl, 2-morpholino, 3-morpholino, 4- morpholino, 2-thiomorpholino,
  • Suitable substituents on an alkyl, aliphatic, aromatic or non-aromatic heterocyclic ring include, for example,
  • -0 (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -CN, - N0 2 , -C00H, -NH 2 , -NH (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) 2 , -COO (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -CONH 2 , -CONH (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group)), -SH, -S (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) and -NH-C
  • a substituted non- aromatic heterocyclic ring, or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent.
  • a substituted aromatic or non-aromatic heterocyclic group can have another ⁇ l i ⁇
  • a substituted alkyl or aliphatic group can also have a non-aromatic heterocyclic ring, benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent.
  • a substituted aliphatic, substituted aromatic or substituted non-aromatic heterocyclic ring can have more than one substituent.
  • Subjects in need of treatment to suppress the immune system include subjects with an autoimmune disease.
  • autoimmune diseases include insulin dependent diabetes mellitus, asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus .
  • Subjects with an organ transplant are also in need of treatment to suppress the immune system in order to suppress or prevent organ transplant rejection.
  • An "organ transplant” refers to transferring or "transplanting" an internal organ (e.g. heart, lung, kidney, liver, pancreas, stomach, large intestine and small intestine) or external organ (e.g. skin) from a donor to a recipient, wherein the donor is genetically distinct from the individual or animal who has received the transplant.
  • An “organ transplant” also includes cross species transplants.
  • An effective amount is the dosage of compound required to achieve the desired therapeutic and/or prophylactic effect, for example the dosage of the compound which results in suppression of an immune response in the individual or animal, or which results in suppression of an organ transplant rejection in the subject.
  • prophylactic effect includes, for example, increasing the life span or ameliorating the symptoms of an individual or animal having or likely to have an autoimmune disease such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus .
  • autoimmune disease such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus.
  • symptoms which can be ameliorated include hyperglycemia in diabetes, joint pain, stiffness and immobility in rheumatoid arthritis, paralysis in multiple sclerosis and rash and skin lesion in lupus erythematosus.
  • a "desired therapeutic or prophylactic effect” includes mitigating or preventing secondary complications resulting from the disease, such as vascular disorders, arise.
  • Suitable dosages can be determined by methods known in the art and can be dependent, for example, upon the individual's age, weight, sensitivity, tolerance and overall well-being. For example, dosages can be from about 10 mg/kg/day to about 1000 mg/kg/day.
  • An effective amount of the compound can be administered by an appropriate route in a single dose or multiple doses.
  • a "subject” is preferably a mammal, such as a human, but can also be an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, chickens and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • domestic animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, chickens and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • the compound can be administered alone or in conjunction with other pharmacologically active agents, e.g., together with other immunosuppressive agents or together with antibiotics and/or antiviral agents.
  • Compounds that can be coadministered include steroids, (e.g. methyl prednisolone acetate) , NSAIDS and other known immunosuppressants such as azathioprine, 15- deoxyspergualin, cyclosporin, mizoribine, mycophenolate ⁇ 13 -
  • mofetil brequinar sodium, leflunomide, FK-506, rapamycin and related compounds. Dosages of these drugs will also vary depending upon the condition and individual to be treated. A variety of routes of administration are possible including, but not necessarily limited to parenteral (e.g., intravenous, intraarterial , intramuscular, subcutaneous injection), oral (e.g., dietary), nasal, slow releasing microcarriers, topical or rectal, depending on the disease or condition to be treated. Oral, parenteral and intravenous administration are preferred modes of administration.
  • parenteral e.g., intravenous, intraarterial , intramuscular, subcutaneous injection
  • oral e.g., dietary
  • nasal, slow releasing microcarriers e.g., topical or rectal, depending on the disease or condition to be treated.
  • Oral, parenteral and intravenous administration are preferred modes of administration.
  • Formulation of the compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, gels, creams, ointments, oils, aerosoles, capsule) .
  • An appropriate composition comprising the compound to be administered can be prepared in a physiologically acceptable vehicle or carrier.
  • suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
  • Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. (1980) ) .
  • the compound can be applied topically as a cream, ointment or gel.
  • Tetronic acid 1.00 g, 10 mmoles
  • triethylamine 1.01 g, 10 mmoles
  • DMAP 1.22 g, 10 mmoles
  • Trifluoromethylthiophenyl isocyanate ( 2.20 g, 10.05 mmoles ) was dropwise added over 20 minutes. The solution was continuously stirred at room temperature for 48 hours. Ice-chilled IN HCl aqueous solution ( 30 ml ) was added. The mixture was extracted with solution of EtOAc:MeOH ( 19 : 1, 500 ml ) and washed with 2N HCl solution for four times ( 200 ml each ) . The organic layer then was dried with anhydrous Na 2 S0 4 , filtered. Solvent was removed from the filtrate in vacuo .
  • the compounds of the present invention were tested by an enzyme assay, an MLR assay and an in vivo

Abstract

Disclosed are methods of suppressing the immune system in a subject in need of immune system suppression. The method comprises administering to the subject an effective amount of a compound represented by Structural Formulas (I, II, III or IV) and physiologically acceptable salts thereof.

Description

IMMUNOSUPPRESSIVE AGENTS
BACKGROUND OF THE INVENTION
Replacement of diseased or severely injured tissue and organs with transplanted tissue or organs has become a common medical practice. Grafts from an individual to self almost invariably succeed, and are especially important in the treatment of burn patients. Likewise, grafts or organ transplants between two genetically identical individuals have a high success rate. However, grafts or organ transplants between two genetically dissimilar individuals generally do not succeed without immunosuppressive drug therapies .
A number of drugs are currently being used or investigated for their immunosuppressive properties. Among these drugs, the most commonly used immunosuppressant is cyclosporin A. However, usage of cyclosporin has numerous side effects such as nephrotoxicity, hepatotoxicity and other central nervous system disorders. Thus, there is presently a need to investigate new immunosuppressive agents that are less toxic but equally as effective as those currently available.
There are a number of autoimmune disease states for which present treatments are inadequate. Examples include asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus . Consequently, there is a need for new drugs which can treat these autoimmune disorders. SUMMARY OF THE INVENTION
One embodiment of the present invention is a method of suppressing the immune system in a subject in need of immune system suppression. The method comprises administering to the subject an effective amount of a compound represented by Structural Formula (I) , (II) , (III) or (IV) :
V0H
B
"ARi -Ar5
Figure imgf000004_0001
( I ) ( ID
OH
or
Figure imgf000004_0003
Figure imgf000004_0002
(III) (IV) and physiologically acceptable salts amd esters thereof . Ring A, Ring B and Ring C are substituted or unsubstituted.
Ring B has one or two nitrogen atoms. The "dotted line" in Ring B indicates the presence or absence of a double bond.
Ring D is a substituted or unsubstituted aromatic group . - 3 -
Ring D is substituted on adjacent ring carbon atoms (ortho, carbon atoms if Ring D is a phenyl ring) with the carboxylic acid and amide group.
Arx and Ar4 are independently an aromatic group or a substituted aromatic group.
Ar2 and Ar3 are independently an aromatic group, substituted aromatic group, a cycloalkyl group, a substituted cycloalkyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.
Xx is a covalent bond, -CH2-, -CH2CH2-, -CH=CH- or a cycloalkyl group to which Arx and Ar2 are both fused.
X2 is a covalent bond, -C(O)-, -CH2-, -CH(R2)-, -CH2-CH(R2)- or -CH2-C (R3) (R2) - . X3 is a covalent bond or -CH2-, -CH(R2)-, -NH- , and -N(R2) .
X4 is -0-, -S-, -0CH2- or -CH2CH2- .
R± is an aliphatic or substituted aliphatic group.
R2 and R3 are independently -H,a C1-C3 alkyl or halogenated alkyl group, or wherein R2 and R3, taken together with the carbon atom to which they are attached, are a C3-C6 cycloalkyl group.
The invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as immune system suppressants and a suitable pharmaceutical carrier. The invention further relates to novel compounds which can be used to suppress the immune system in a subject in need of immune system suppression.
The method of the present invention can be used to treat subjects having an autoimmune disease, such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus . It is expected that the methods disclosed herein will not cause the undesirable side effects associated with other immunosuppressive drugs such as cyclosporin. In another embodiment, the method of the present invention can be used to treat tumors in a subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment, the compound is represented by Structural Formula (V) :
-Ar2
Figure imgf000006_0001
(V)
Rj_ is an aliphatic group such as a C1-C3 aliphatic group or a substituted C1-C3 aliphatic group. More preferably, Rλ is a C1-C3 alkyl group or a C1-C3 halogenated alkyl group . Xx is a covalent bond or -CH2-.
Ring A, rj. and Ar2 are as defined for Structural Formula (I) .
In another preferred embodiment, the compound is represented by Structural Formula (VI) : - 5 -
Figure imgf000007_0001
AT, -X-i Ar2
(VI )
X: is a covalent bond or -CH2- .
Ring A, Arx and Ar2 are as defined for Structural Formula (I) .
In another preferred embodiment, the compound is represented by Structural Formula (VII) :
-Ar?
Figure imgf000007_0002
(VII :
■ 6 -
X-, is a covalent bond, -CH2-, -CH2CH2-, -CH=CH- or a cyclpentyl group to which Arx and Ar2 are both fused. Preferably, X-_ is a covalent bond or -CH2- .
Ring A, Arx and Ar2 are as defined for Structural Formula (I) .
In another preferred embodiment, the compound is represented by Structural Formula (VIII) :
X?
Figure imgf000008_0001
Ar3
(VIII)
Ring A, R1# X2 and Ar3 are as defined above for
Structural Formula (II) . Rj_ in Structural Formula (VIII] is preferably -H, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group, more preferably, -H, methyl or ethyl. X2 in Structural Formula (VIII) is preferably -CH2-. Ar3 is preferably a substituted or unsubstituted aromatic group .
In another preferred embodiment, the compound is represented by Structural Formula (IX) :
Figure imgf000008_0002
(IX) - 7 -
In Structural Formula (IX) , Ring D, R2 and Ar3 are as defined in Structural Formula (III) . R2 is preferably -H, methyl or ethyl.
In another preferred embodiment, the compound is represented by Structural Formula (X) :
Figure imgf000009_0001
(X)
In Structural Formula (X) , Ring D, R2 and Ar3 are as defined in Structural Formula (III) . R2 is preferably -H or methyl. Ring D is preferably a carbocyclic aromatic ring.
In another preferred embodiment, the compound is represented by Structural Formula (XI) :
Figure imgf000009_0002
(XI)
Ar3 in Structural Formula (XI) is as defined in Structural Formula (III) . • 8 -
In another preferred embodiment, the compound is represented by Structural Formulas (XII) or (XIII) :
Figure imgf000010_0002
Figure imgf000010_0001
(XII) (xiii :
Ar4 in Structural Formulas (XII) and (XIII) are as defined in Structural Formula (IV) . Ar4 is preferably a substituted or unsubstituted carbocyclic aromatic group.
Another embodiment of the present invention is a method of suppressing the immune system in a subject in need of immune system suppression. The method comprises administering an effective amount of a compound represented by Structural Formula (XIV) :
O^OH
-Ar?
(XIV) Ring A is substituted or unsubstitued.
Arlf Ar2 and Xx are as defined above for Structural Formula (I) . Preferably, Xx is a covalent bond or -CH2-
Also included in the present invention are physiologically acceptable salts of the compounds represented by Structural Formulas (I) through (XIV) . Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base, for example, a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium, potassium and the like.
As used herein, aliphatic groups include straight chained, branched or cyclic C-x-Cg hydrocarbons which are completely saturated or which contain one or more units of unsaturation. An "alkyl" group is a saturated aliphatic group.
Aromatic groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2 -naphthyl, 1-anthracyl and
2-anthracyl, and heterocyclic aromatic groups such as N- imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl, 2- furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4- oxazolyl and 5-oxazolyl.
Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include 2-benzothienyl , 3-benzothienyl, 2-benzofuranyl , 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl , 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2- • 10 -
quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridintyl .
Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring can be five, six, seven or eight-membered. Examples include 2-tetrahydrofuranyl, 3 -tetrahydrofuranyl , 2 -tetrahyrothiophenyl , 3-tetrahyrothiophenyl, 2-morpholino, 3-morpholino, 4- morpholino, 2-thiomorpholino,
3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl , 2- pyrrolidinyl, 3 -pyrrolidinyl, 1-piperazinyl, 2- piperazinyl, 1-piperidinyl , 2-piperidinyl, 3- piperidinyl, 4-piperidinyl and 4-thiazolidinyl . Suitable substituents on an alkyl, aliphatic, aromatic or non-aromatic heterocyclic ring include, for example,
-OH, one or more halogens (-Br, -Cl, -I and -F) ,
-0 (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -CN, - N02, -C00H, -NH2, -NH (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) 2, -COO (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -CONH2, -CONH (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group)), -SH, -S (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) and -NH-C (=NH) -NH2. A substituted non- aromatic heterocyclic ring, or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent. In addition, a substituted aromatic or non-aromatic heterocyclic group can have another ■ l i ¬
aromatic group, substituted aromatic group, non-aromatic heterocyclic group or substituted non-aromatic heterocyclic group as a substituent. A substituted alkyl or aliphatic group can also have a non-aromatic heterocyclic ring, benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent. A substituted non-aromatic heterocyclic ring (for example, Ring B in Structural Formula (I) can also have =0, =S, =NH or =N (aliphatic, aromatic or substituted aromatic group) as a substituent. A substituted aliphatic, substituted aromatic or substituted non-aromatic heterocyclic ring can have more than one substituent.
Subjects in need of treatment to suppress the immune system include subjects with an autoimmune disease. Examples of autoimmune diseases include insulin dependent diabetes mellitus, asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus . Subjects with an organ transplant are also in need of treatment to suppress the immune system in order to suppress or prevent organ transplant rejection. An "organ transplant" refers to transferring or "transplanting" an internal organ (e.g. heart, lung, kidney, liver, pancreas, stomach, large intestine and small intestine) or external organ (e.g. skin) from a donor to a recipient, wherein the donor is genetically distinct from the individual or animal who has received the transplant. An "organ transplant" also includes cross species transplants. "An effective amount" is the dosage of compound required to achieve the desired therapeutic and/or prophylactic effect, for example the dosage of the compound which results in suppression of an immune response in the individual or animal, or which results in suppression of an organ transplant rejection in the subject. A "desired therapeutic effect and/or ■ 12 -
prophylactic effect" includes, for example, increasing the life span or ameliorating the symptoms of an individual or animal having or likely to have an autoimmune disease such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus . Examples of symptoms which can be ameliorated include hyperglycemia in diabetes, joint pain, stiffness and immobility in rheumatoid arthritis, paralysis in multiple sclerosis and rash and skin lesion in lupus erythematosus. With respect to insulin dependent diabetes mellitus, a "desired therapeutic or prophylactic effect" includes mitigating or preventing secondary complications resulting from the disease, such as vascular disorders, arise. Suitable dosages can be determined by methods known in the art and can be dependent, for example, upon the individual's age, weight, sensitivity, tolerance and overall well-being. For example, dosages can be from about 10 mg/kg/day to about 1000 mg/kg/day. An effective amount of the compound can be administered by an appropriate route in a single dose or multiple doses.
A "subject" is preferably a mammal, such as a human, but can also be an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, chickens and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
The compound can be administered alone or in conjunction with other pharmacologically active agents, e.g., together with other immunosuppressive agents or together with antibiotics and/or antiviral agents. Compounds that can be coadministered include steroids, (e.g. methyl prednisolone acetate) , NSAIDS and other known immunosuppressants such as azathioprine, 15- deoxyspergualin, cyclosporin, mizoribine, mycophenolate ■ 13 -
mofetil, brequinar sodium, leflunomide, FK-506, rapamycin and related compounds. Dosages of these drugs will also vary depending upon the condition and individual to be treated. A variety of routes of administration are possible including, but not necessarily limited to parenteral (e.g., intravenous, intraarterial , intramuscular, subcutaneous injection), oral (e.g., dietary), nasal, slow releasing microcarriers, topical or rectal, depending on the disease or condition to be treated. Oral, parenteral and intravenous administration are preferred modes of administration. Formulation of the compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, gels, creams, ointments, oils, aerosoles, capsule) . An appropriate composition comprising the compound to be administered can be prepared in a physiologically acceptable vehicle or carrier. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. (1980) ) . To avoid systemic exposure, the compound can be applied topically as a cream, ointment or gel.
The invention is illustrated by the following examples which are not intended to be limiting in any way. - 14 -
EXEMPLIFICATION
Example 1 -Preparation of exemplary compounds of the present invention
Trifluoromethylphenyl) phenyl] -4-carboxy-l (2H) isoquinolinone (I)
A) 4- (4-Bromophenyl) aminomethylene homophthalic anhydride
Homophthalic anhydride (6.48 g) , triethylorthoformate (30 ml), 4-bromoaniline (6.88 g) and 1,4-dioxane (25 ml) were mixed and refluxed for 30 min. The reaction mixture was cooled to room temperature. The resulting precipitate was collected by filtration and washed with a small amount of dioxane. The filtrate was stirred at room temperature for 48 more hours, with collection of the precipitate by filtration every 24 hour. The combined precipitate was dried over in vacuo and 7.68 g of pale yellow solid was obtained. ""Η-nmr (DMSO-d6/CDCl3, 250MHz) : 8.92 (t, IH) , 8.16 (d, IH) , 8.02 (d, IH) , 7.75-7.58 (m, 5H) , 7.33 (t, 2H) .
B) 2- (4-Bromophenyl) -4-carboxy-l (2H) isoquinolinone:
4- (4-Bromophenyl) aminomethylene homophthalic anhydride (7.68 g) , with NaOH ( 4.0 g) , was suspended in the solution of EtOH (300 ml) and H20 (15 ml) , and stirred at room temperature for 3 hours . Solvent was removed in vacuo and the residue was suspended in ice-water (100 ml), acidified with 36% HCl (8 ml) to pH 2. The suspension was filtered and the collected white solid was washed with water, dried over in vacuo overnight.
The given crude product (5.9 g) was subject to ■ 15 -
recrystallization by refluxing in AcOH (100 ml) , cooling to room temperature and adding of water (100 ml) . 3.54 g of fine powder was afforded after collected by filtration, washed with water and dried in vacuo . 'H-nrnr (DMSO-d6, 250 MHZ): 8.85 (d, IH) , 8.31 (d, IH) , 8.18 (s, IH) , 7.86 (t, IH) , 7.75 (q, 2H) , 7.62 (t, IH) , 7.53 (q, 2H) .
C) 2- [4- (3-Trifluoromethylphenyl) phenyl] -4- carboxy-1 (2H) isoquinolinone:
The mixture of 2- (4-Bromophenyl) -4-carboxy-l (2H) isoquinolinone (690 mg) , 3-trifluoromethylphenylboronic acid (600 mg) , tetrakis (triphenylphosphine) -palladium (0) (80 mg) , 2 M Na2C03 solution (4 ml) and toluene (6 ml) was refluxed under argon for 16 hours. The reaction mixture was quenched with 2N HCl (20 ml) at room temperature, extracted with EtOAc (500 ml), washed with 0.5 N HCl (3x200 ml) . The organic layer was dried with anhydrous Na2S04, filtered. Solvent was removed from the filtrate. The resulted residue was subject to silica gel flash column purification, with elution by chloroform: acetic acid (99.5: 0.5 to 98:2). 360 mg of title product was afforded upon solvent was removed from the pure fraction and dried in vacuo overnight. 1H-nmr (DMSO-d6, 250MHz) :
8.88 (d, IH) , 8.34 (d, IH) , 8.23 (s, IH) , 8.06 (m, 2H) , 7.96-7.83 (m, 3H) , 7.77-7.60 (m, 5H) . The acid product was suspended in MeOH (25 ml) and neutralized with 1.00 N NaOH (0.88 ml) at room temperature for 2 hours. Solvent was removed from the resulted solution under reduced pressure and 380 mg of sodium salt was given after dried in vacuo overnight. MS (FAB-) : m/z
408 (M - Na+) . - 16 -
Sodium 2- (3 'methoxy-1, 1 ' -biphenyl-4-yl) -6-fluoro- quinazoline-4-carboxylate (II)
A)
2- (4-bromophenyl) -β-fluoro-quinazoline-4-carboxylate : A mixture of 4-fluoroaniline (7.40 mL, 0.067 mmol), p-bromobenzoyl chloride (14.53g, 0.067 and diisopropylethylamine (11.6 mL, 0.067 mmol) in THF (100 mL) was stirred at rt . for 4 h. The solvent was removed to dryness and ethanol (200 mL) added. The mixture was filtered, the solid washed with ethanol (3 X 25 mL) and then dried under vacuum overnight. The solid was suspended in S0C12 (40 mL) and the mixture refluxed for 2 h. The solvent was removed to dryness and the solid dried under vacuum for 1 h. The solid was redissolved in 1, 2-dichlorobenzene (30 mL) and ethylcyanoformate
(6.2 mL, 0.063 mmol) added. A solution of SnCl4 (7.6 mL, 0.65 mmol) in 1, 2-dichlorobenzene (20 mL) was added dropwise over a period of lh. The mixture was placed in a preheated bath (135 °C) for 15 min. The mixture was cooled down to rt . and poured slowly into a cold (0 °C) solution of NaOH (1M, 100 mL) . The mixture was extracted with EtOAc (3 X 200 mL) . The solvent was dried over MgS04, filtered and the solvent removed to dryness. The mixture was purified by column chromatography using 2% EtOAc/hexane . The product was suspended in a 6/1 solution of EtOH/NaOH (20%) and the mixture refluxed for 2h. The mixture was filtered and the solid washed with EtOH (3 X 20 mL) . Crude yield 4.53 g (20.7 %, more than 95 % pure by HPLC). A small sample was purified by column chromatography using first EtOAc and then 1/1 EtOAc/hexane 1% HOAC . CHN calculated (found) for C15H8N202BrF: C, 51.82 (51.82); H, 2.32 (2.48) ; N, 8.07 (7.93) . 17 -
B) Sodium 2- (3 'methoxy-1, 1 ' -biphenyl-4-yl) -6-fluoro- quinazoline-4-carboxylate: Pd(PPh3)4 (0.9540, 0.76 mmol) was added to a degassed solution of A (1.0478, 2.84 mmol) and 3-methoxyphenylboronic acid (1.0212 g, 6.72 mmol) in a suspension of THF (100 mL) /Na2C03 (2 M, 10 ml) . The mixture was refluxed for 2 days, the solvent was removed to dryness and HCl (1M, 100 mL) added. The mixture was filtered and the solid redissolved in EtOAc (400 mL) , dried over MgS04, filtered and the solvent removed to dryness. The mixture was purified by column chromatography using EtOAc until the boronic acid was eluted and then 1/1 EtOAc/hexane 1% HOAc . The product (0.5316 g, 1.432 mmol, 50% yield) was suspended in 3/1 EtOH/H20 (40 mL) and a solution of NaOH (1.370 mL, 1.036M) was added. The mixture was heated to reflux for 30 min, cooled down to rt . , filtered and the solvent removed to dryness. CHN calculated (found) for C22H1403FN2-2H20: C, 61.11 (60.97); H, 4.20 (3.81); N, 6.48 (6.22) .
Sodium 6-fluoro-2- (4-fluorobenzyloxy) quinoline-4- carboxylate (III)
A) 5-fluoro-1-acetylisatin : A mixture of
5-fluoroisatin (4.00 g, 24.2 mmol) in acetic anhydride
(8 mL) was heated to reflux for 1.5 h. The mixture was cooled down to rt . and let stand for 12 h. The mixture was filtered and the solid washed with acetic anhydride and then dried under high vacuum to yield 1.8 g. The filtrate was concentrated to dryness and the mixture purified by column chromatography using 1/1 EtOAc/hexane to yield an extra 1.1 g. Total yield 2.9 g (57 %). ■ 18 -
B) 4-carboxy-6-fluoroquinolin-2-one : A mixture of A (2.00 g, 9.65 mmol) in NaOH (20 %, 40 mL) was refluxed for lh, cooled down and the pH was adjusted to 2 with HCl (IM) . The mixture was filtered and the solid washed with water and then cold acetone to give 1.2 g (60 % yield) of crude material. The solid was dried under vacuum and used without purification in the next step.
C) 2-chloro-4-carboxy-6-fluoroquinoline : A suspension of B (1.00 g, 4.98 mmol) in P0C13 (5 L) was refluxed for 2 h. The mixture was cooled down to rt . , and poured slowly into iced-water. The solid was filtered, suspended in NaOH (IM, 50 mL) and the mixture stirred at rt. overnight. The pH was adjusted back to 3 with HCl (IM) and the mixture filtered. The solid was dried under high vacuum overnight. Yield 1.037 g (95%) .
D) sodium 6-fluoro-2- (4-fluorobenzyloxy) quinoline- 4-carboxylate: 4-fluorobenzyl alcohol (0.29 L, 2.67 mmol) was added to a cooled (0 °C) suspension of NaH
(320 mg, 13.4 mmol, 60 % in mineral oil) . The mixture was stirred for 10 min. and C (600 mg, 2.67 mmol) was added and stirred to rt. and for 5 h. The solvent was removed to dryness and the mixture partitioned between HCl/EtOAc (IM, 50 mL/ 150 mL) . The aqueous layer was extracted with EtOAc (3 X 50 ml), the organic layer was dried over MgS04, filtered and the solvent removed to dryness. The product was purified by column chromatography using 3/1 Hexane/EtOAc 1 % HOAc . Yield; 0.5884 g (70 %). The acid was dissolved in EtOH (10 mL) and NaOH (1.803 mL, 1.036 N) added. The mixture was filtered and the solvent removed to dryness. CHN ■ 19 -
calculated (found) for C17H10NF2O3Na'll/2 H20: C, 56.05 (56.37); H,3.60 (3.53); N, 3.85 (3.68).
N- (2-carboxyphenyl) -N' - [2-methyl-4- (2 ' -methylphenyl) ] phe nyl urea (PRO 8644) (IV) To a cooled (-78° C) solution of
4-amino-3, 2 ' -dimethylbiphenyl (200mg; lmmol), diisopropylethylamine (262mL; 1.5mmol) and methylene chloride (5mL) was added phenyl chloroformate (138 mL; 1. lmmol) and the resulting mixture was allowed to slowly warm to room temperature. After 3h, tic analysis
[hexane/EtOAc (4:1)] indicated complete reaction. The mixture was extracted with IN HCl (2X) , water (IX), dried (K2C03) and concentrated affording the crude carbamate as a solid. The solid was washed with hexane to afford the carbamate (316mg; quant.) which was used directly without further purification. The solid carbamate was taken up in N, N-dimethylacetamide (5mL); anthranilic acid (137mg; lmmol) and dimethylaminopyridine (pinch) were added sequentially and the resulting mixture was heated to 100° C for 2h. The solution was then cooled to room temperature and treated with IN HCl (50mL) , generating a white precipitate. The solid was filtered, washed with water and dried. Purification by silica gel flash chromatography, eluting with CHC13 followed by
CHCL3/MeOH/HOAc (10:1:0.1) afforded the desired urea (143mg; 40%) as a white solid. H NMR (DMSO- 6) d 10.30 (s, IH, exch.), 9.05 (s, IH, exch) , 8.33 (d, IH, J = 9.0Hz), 7.93 (dd, IH, J = 7.5, 1.5Hz), 7.6-7.4 (m, 2H) , 7.3-7.1 (m, 6H) , 7.03 (td, IH, J = 7.5, 1.5Hz), 2.30 (s, 3H) , 2.25 (s, 3H) . FAB" MS : 359 [M-H] . -20-
PRO 8 658 ( V )
A) 4- (1-naphthyl) phenylacetic acid:
To a solution of 4-bromophenylacetic acid (323mg; 1.5mmol) and tetrakis ( triphenylphosphine) -palladium( 0) (52mg; 0.045mmol) in dimethoxyethane (5mL) was added 1-naphthaleneboronic acid (284mg; 1.65mmol) followed by a IM aqueous solution of sodium bicarbonate (4.5mL; 4.5mmol) and the resultant mixture was refluxed. After 3h, tic analysis [hexane/EtOAc (3:2) + 1% HOAc] indicated complete reaction. The solution was cooled to room temperature, acidified with IN HCl and extracted with EtOAc (3X) . The combined organic solution was extracted with IN aqueous NaOH (3X) and the aqueous extract was back-extracted once with EtOAc. The aqueous phase was then acidified with IN HCl and extracted with EtOAc (3X) . The combined organic extracts were then dried (MgS04) and concentrated under reduced pressure affording a yellow oil. The oil was taken up in a mixture of hexane/EtOAc (3:2) and passed through a plug of silica gel, then further eluted with hexane/EtOAc/HOAc (75:50:0.25). Concentration of the combined eluents afforded the desired biaryl acetic acid (343mg; 87%) as a light yellow foam. XH NMR (CDC13) d 8.0-7.8 (m, 3H) , 7.6-7.4 (m, 8H) , 3.78 (s, 2H) .
B) 4- (l-naphthyl)phenylacetyl anthranilamide (PRO 8568):
A solution of 4- (1-naphthyl) phenylacetic acid (340mg; 1.3mmol), thionyl chloride (300mL) and toluene (5mL) was refluxed for 2.5h, at which time IR analysis indicated complete conversion to the acid chloride (1798cm"1) . The solution was then concentrated under vacuum to afford the crude acid chloride as a straw-colored syrup. This - 21 -
residue was taken up in acetonitrile (5mL), anthranilic acid (162mg; 1.18mmol) was added and the mixture was refluxed for 2h, then kept warm overnight. The solution was cooled in an ice bath, and the resulting precipitate was then filtered, washed with cold acetonitrile and dried, affording the pure amide product (368mg; 82%) as an off-white solid. λE NMR (DMSO-d6) d 11.23 (s,lH, exch.), 8.52 (d,lH. J= 8.6Hz), 8.1-7.9 (m, 3H) , 7.82 (br. d, IH, J = 8.0 Hz), 7.7-7.4 (m, 9H) , 7.16 (br. t, IH, J = 8.0Hz), 3.88 (s, 2H) . FAB" MS: 380 [M-H] .
3-Biphenyl carbonyl amino-2-thiophene carboxylic acid (VI)
370 mg of methyl 3-amino-2-thiophene carboxylate in 3 ml of Pyridine was added cat. amount of DMAP followed by 765 mg of biphenyl carbonyl chloride. After stirring at room temp, for 18 hours, the mixture was concentrated down to dryness. The residue was dissolved in CH2C12 and washed with IN HCl followed by sat. NaHC03 then brine. The organic phase was then dried over MgS04 and concentrated to dryness under vacuum. 500 mg of the resulting materiel was dissolved in 15 ml of mixture solvent of MeOH:H20:THF (1:1:1). The mixture was added 50 mg of KOH and heated to 55C for 3 hours. After cooling down to room temp, the mixture was adjusted to pH=l, extracted with CH2C12. The organic phase was concentrated under vacuum to give the essentially pure title compound as a solid. The total yield for two steps was 78%. *H-NMR (CDC13) : 7.40-7.55 (3H, m) , 7.70 (2H, brd, J=8.20), 7.90 (2H, d, J=10.0), 7.93 (IH, d, J=6.27), 8.10 (2H, d, J=10.0), 8.15 (IH, d, J=6.27). FAB-MS: (M-H) "=322 - 22 -
4-hydroxy-2-oxo-2, 5-dihydro-furan-3-carboxylic acid-4-trifluoromethylthiophenylamide (VII )
Tetronic acid ( 1.00 g, 10 mmoles ), triethylamine ( 1.01 g, 10 mmoles ), and DMAP ( 1.22 g, 10 mmoles ) in anhydrous chloroform ( 30 ml ) was stirred at room temperature for 30 minutes.
Trifluoromethylthiophenyl isocyanate ( 2.20 g, 10.05 mmoles ) was dropwise added over 20 minutes. The solution was continuously stirred at room temperature for 48 hours. Ice-chilled IN HCl aqueous solution ( 30 ml ) was added. The mixture was extracted with solution of EtOAc:MeOH ( 19 : 1, 500 ml ) and washed with 2N HCl solution for four times ( 200 ml each ) . The organic layer then was dried with anhydrous Na2S04, filtered. Solvent was removed from the filtrate in vacuo . The residue was subject to silica gel flash column purification, with elution by EtOAc: AcOH ( 99.5 : 0.5 to 98.5 : 1.5 ) . 690 mg of the product was given from the pure fraction. XH-NMR (DMSO-d6 ): 7.73 (d, 2H) ,
7.57 (d, 2H) , 4.26 (s, 2H) ; MS (FAB-): m/z 318 (M-H+
Example 2 - Biological Data
The compounds of the present invention were tested by an enzyme assay, an MLR assay and an in vivo
GvH model according to a modification of procedures disclosed in Copeland et al . , Arch . Biochem . Biophyε .
323 : 79 - 86 (1995), Colligan et al . , Current Protocils in Immunology 1994, 1 and Ford et al . , Transplantation - 23
10:258. The entire teachings of these references are incorporated herein by reference. The results are reported in the Table .
■24- id IMOLSTRUCTURE eπz ic50 imlr ic50 in vivo
7749 O 14 nM 12 uM
■> v
7750 160 nM 9uM
i , χ -•
7831 | ' T : 5 nM 8 uM
7851 αQ 15 nM 3 uM
V • ED50 - 80 mg/kg
7854 30 nM 3uM
0 'v ^--^ p.o. in GvH
0^0"
7871 50 nM 13 uM
8537 inactive n.a. o
0γ0-
V @ 80 mg/kg
8538 ! . I! 140 nM 18 uM
0 "r*o p.o. in GvH
25% @ 120
8539 37 nM 13 uM mg/kg p.o. in GvH
Figure imgf000026_0001
8634 m. inactive
N^N,
^3'
<> V5
8637 γ\ 1.2 uM 17 uM
63% @ 100
8651
Figure imgf000026_0002
3.7 nM 6 uM mg/kg p.o. in GvH -25-
I
8652 150 nM j 31 uM
I =-
8668 ! 1.6 nM 0.48 uM i I
I
!
8669
= (^J 1.7 nM 0.36 uM
V
8670 j 5.5 nM 11 uM
8677
8678
8679 i
8680
1 • "cP i I
8681 ) !
I
Figure imgf000027_0001
•26-
id i MO ..STRUCTURE enz ic50 (uM) mir ιc50 (uM) in vivo
7371
0 _... IED50 - 40 mpk p.o.
0.019
! GvH
Ά
7708! y^„**-~^. 0J4 0.52
78091 xo 3.6 X
7810
1.6 10
7846
1.1 3.4
7847 Y"
0.058 1.6
78551 °^="
'XXX.
LA 0.82 11
X)
8567ι
ED5020- 40 mpk
^■ Ύ*, 0.02 0.46 p.o. GvH
8568
0.04C ^y^*,
8609
19% I @ 80 mpk
0.66 p.o. GvH
8610'
C.009 1J
8611 %•
0.6: >60 -27-
id MPLS ■ RUCTURE eπz icsO (uM) mir ιc50 (uM) in vivo
7745 '-" >,-,
0.51 29
7709
0.55 >60
7773
—-/* 0.51 2* w
7774
1.5 51 Jtf
7775 a^Λ"
0.49 24
7776 pΛ 2.6 15
7780
8.8 36
.^
7806
1.2
7807 =w
3.2 27
7808
6.6 >50
/an
0 is
75-^51 -28-
7853
2 % @ 4-0 mpk
V*^^- 0.013 poGvH
7875 V
0.012
■J
7895
I
0.011 τ?^a 8.8
XL
8002!
0.012
80031
Figure imgf000030_0001
0.049
8004:
25% @ 80 mpk
0.16
-^ poGvH
8005i 5 0.07 38% @ 80 mpk
Λ poGvH
8530
0.11 17.2
Figure imgf000030_0002
8531
0.0014 0% @ 80 mpk po
5.9 GvH
8532
«- J ' 1.3
:,'*yY.
8533
■ ^v^..' 0.025 10
•%
85^6
2.5 25
8547 α ^S »^
0.57 20
-^V*\ -29-
Figure imgf000031_0001
8608' °ϊ : ι 0.89 1.6
-y>
8626!
0.003 3.1
Figure imgf000031_0002
8627 <V"
AXλ 0.002 6.1-
8628! o^o- »• 'w. 0.016
8629
0% @ 40 mpk po
0.062 GvH
Figure imgf000031_0003
8630 °γβ'
;16% @ 100 mpk
0.025 po GvH
Figure imgf000031_0004
8633
19° @ 100 mpk
0.012 poGvH
8642
2*% @ 100 mpk
0.031 po GvH
86<i3 u«v ■sy II 9% © 50 mpk pc
0.021 GvH
^Z^^.,
86*8, =^-
(^ 0.15 17 ■30-
86531 α^o
0.214 33
Figure imgf000032_0001
Figure imgf000032_0002
8654 <v- 0H
Figure imgf000032_0004
0.0055 14
Figure imgf000032_0003
8655. V-α
0.344 27
IA •O
8656!
0.086 18
Figure imgf000032_0005
8657!
∞, 0.024 14 ^*
■31- id ; MOLSTRUCTURE enz ic5Q (uM) mir ic50 (uM) in vivo
5^62 y 0.03 .
7840 r 0.034 o
Figure imgf000033_0001
7856, CH, HO
' ^s-^JI. /
;/ TV 0.018
7857 rv 0.016 22% ! @ 80
1.5
^ mpk p.o. GvH
7894,
P-T-f
0.022 >60
Figure imgf000033_0002
Figure imgf000033_0003
7904 s^ 0.001 29% I @ 80
0.052 mpk p.o. GvH
7907 όrTϋ inactive n.t.
8006
1.4
Figure imgf000033_0004
0
Figure imgf000033_0005
8008 inactive n.t.
Figure imgf000033_0006
8009 ii^ " N' ^ r^S* 0.17 11 ^"
8010 0^s.--O OuO 0.052 14% I © 30
0.71 mpk p.o. Gvh
8011
0.013
Figure imgf000033_0007
-32-
85691 °γ0H CH.
V 0.011 12% I @ 100
7.4
U° mpk p.o. Gvh
8570 i O^OH
-v 0.04 20
Figure imgf000034_0001
85711
0.016 14
Figure imgf000034_0002
8572'
Figure imgf000034_0003
* 0.011 4.3
8573
0.001
Figure imgf000034_0004
0.2
Figure imgf000034_0005
8585!
0.01 15
Figure imgf000034_0006
8586 i
0% I β 100
0.005 0.59
° *A3 mpk p.o. Gvh
8587 o^o-1*.
-v ^ in act
8602 °γ° y 0.217
Figure imgf000034_0007
8603 J inact
8604 O-^CH inact
8605 i . I J • 0.0014 -33-
1.78
Figure imgf000035_0001
8607 j γ»
(Yr" inact
6
8617' °γα
U S W 0.057 3.4
8618,
13% I @ 80
Figure imgf000035_0002
mpk p.o. Gvh
8619
..o
0.77 >60
"Yo
8638!
-o^ 0.038 0.16
8644
0.001 0.018
Figure imgf000035_0003
8645 o ^ 0.3 0
8650 V*
CrTD 0.061 6
8659 i
18% I @ 80 mpk p.o. Gvh
8667', 'V"
0.009 4.3
Amices
8571 y* * ~^s**.t 0.016 14
Λ
KJ -34-
8614. 0-v*
0J3 13
Figure imgf000036_0001
86151
0J7 14
Figure imgf000036_0002
0.021 23
Figure imgf000036_0003
8636 0>- -OH
I 17% I @ 100
0.019 16 | mpk p.o. Gvh
Figure imgf000036_0004
8658
11% I @ 100
0.002 0.034 mpk p.o. Gvh
Figure imgf000036_0005
- 35 -
id i MOLSTRUCTURE 1 enz ic50 (uM) > mir ic50 (uM) in vivo
1
21% @ 20
7832 0.9 1 5 mpk p.o. GvH
J;
! c
7849 ! 0Λ_ 0.55 21 ly ,
7852 0.82 51
7862 0.53 27
7882 0.53 31
Figure imgf000037_0001
■36-
i 'MOLSTRUCTURE enz ic50 (uM) ' mir ic50 (uM) ι in i o
6788
Y^ 15 >35 y~~o
6789
^ ° P 35 =
67901
OH
' ., 32
A-o
0.59 16
Figure imgf000038_0001
7723 CH
} 49
0
77261 r . ' I 6% I @ 80 mpk
0.12 p.o. GvH
Figure imgf000038_0002
7763
^1 9
NV 0.11 13
.^-s>
7777
CH / ^ N N 0.37 33 y~-a
7834
^ 0
^A-vA ^ 0.25 27 jrs
7850
0.71
7870 as ,c ^^, 0J4
„^-= -37-
78961
^Λxy 0.66 7
7898 ^i^ 0 OH
0J8 2
7899
2 >60
^ %
Figure imgf000039_0001
■ 3 8 -
EQUIVALENTS
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims .

Claims

■ 3 9 -
What is claimed is:
1. A method of suppressing the immune system in a subject comprising administering to the subject an effective amount of a compound represented by a structure selected from:
<V0H
B
"AR, -Aio
Figure imgf000041_0001
Ar3
or
Figure imgf000041_0003
Figure imgf000041_0002
and physiologically acceptable salts thereof, wherein:
Ring A, Ring B, Ring C are substituted or unsubstituted;
Ring B has one or two nitrogen atoms;
Ring D is a substituted or unsubstituted aromatic group; -40-
Arx and Ar4 are independently an aromatic group or a substituted aromatic group;
Ar2 and Ar3 are independently an aromatic group, substituted aromatic group, a cycloalkyl group, a substituted cycloalkyl group, a non- aromatic heterocyclic group or a substituted non- aromatic heterocyclic group;
X-L is a covalent bond, -CH2-, -CH2CH2-, - CH=CH- or a cycloalkyl group to which Ar. and Ar2 are both fused;
X2 is a covalent bond, -C(O)-, -CH2-, - CH(R2) -, -CH2-CH(R2)- or -CH2-C (R3) (R2) -
X3 is a covalent bond or -CH2-, -CH(R2)-, - NH-, and -N(R2) ;
X4 is -0-, -S-, -OCH2- or -CH2CH2-;
R: is an aliphatic or substituted aliphatic group ;
R2 is -H,a C1-C3 alkyl or halogenated alkyl group, or wherein R2 and R3, taken together with the carbon atom to which they are attached, is a C3-C6 cycloalkyl group.
The method of Claim 1 wherein the compound is represented by the following structural formula:
-X -Ar,
Figure imgf000042_0001
- 41 -
wherein :
Rx is a C1-C3 aliphatic group or a substituted C1-C3 aliphatic group; and X- is a covalent bond or -CH2- .
The method of Claim 1 wherein the compound is represented by the following structural formula:
"Xi -Ar?
Figure imgf000043_0001
wherein X, is a covalent bond or -CH,
The method of Claim 1 wherein the compound is represented by the following structural formula: O^OH
-Ar?
wherein Xx is a covalent bond, -CH2-, - CH2CH2-, -CH=CH- or a cyclpentyl group to which Arx and Ar2 are both fused. -42 -
The method of Claim 1 wherein the compound is represented by the following structural formula:
,X5
Figure imgf000044_0001
"Αr3
The method of Claim 1 wherein the compound is represented by the following structural formula:
Figure imgf000044_0002
7. The method of Claim 6 wherein Ring D is a substituted or unsubstituted carbocyclic aromatic ring and R2 is -H or methyl .
8. The method of Claim 1 wherein the compound is represented by the following structural formula:
Figure imgf000044_0003
- 43 -
9. The method of Claim 7 wherein Ring D is a substituted or unsubstituted carbocyclic aromatic ring and R2 is
-H or methyl .
10. The method of Claim 1 wherein the compound is represented by the following structural formula:
Figure imgf000045_0001
11. The method of Claim 10 wherein the compound is represented by the following structural formula:
Figure imgf000045_0002
-44 -
12. The method of Claim 1 wherein the compound is represented by the following structural formula:
Figure imgf000046_0001
13. The method of Claim 12 wherein Ar4 is a substituted or unsubstituted carbocyclic aromatic group .
14. The method of Claim 1 wherein the compound is represented by the following structural formula:
0 OH
Figure imgf000046_0002
15. The method of Claim 14 wherein Ar4 is a substituted or unsubstituted carbocyclic aromatic group .
- 45 -
16. A method of suppressing the immune system in a subject comprising administering to the subject an effective amount of a compound represented by the following structural formula:
"AΓH -XI -Ar,
and physiologically acceptable salts thereof, wherein:
Ring A is substituted or unsubstituted;
Ar-,. is an aromatic group or a substituted aromatic group;
Ar2 is an aromatic group, substituted aromatic group, a cycloalkyl group, a substituted cycloalkyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; and
X1 is a covalent bond, -CH2-, -CH2CH2-, - CH=CH- or a cycloalkyl group to which Arx and Ar2 are both fused.
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WO2000047577A1 (en) * 1999-02-12 2000-08-17 Smithkline Beecham Plc Phenyl urea and phenyl thiourea derivatives as orexin receptor antagonists
JP2002114751A (en) * 2000-08-04 2002-04-16 Aventis Cropscience Sa Fungicidal derivative of phenyl(thio)urea or phenyl(thio) carbamate
WO2003006425A2 (en) 2001-07-10 2003-01-23 4Sc Ag Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2004046090A3 (en) * 2002-11-21 2004-08-19 Neurosearch As Aryl ureido derivatives and their medical use
WO2006085112A1 (en) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Anthranilic acid derivatives as hm74a receptor agonists
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US8686048B2 (en) 2010-05-06 2014-04-01 Rhizen Pharmaceuticals Sa Immunomodulator and anti-inflammatory compounds
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