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WO1990009787A1 - Nouveaux sulfamides servant de radiosensibilisateurs - Google Patents

Nouveaux sulfamides servant de radiosensibilisateurs Download PDF

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Publication number
WO1990009787A1
WO1990009787A1 PCT/US1990/001054 US9001054W WO9009787A1 WO 1990009787 A1 WO1990009787 A1 WO 1990009787A1 US 9001054 W US9001054 W US 9001054W WO 9009787 A1 WO9009787 A1 WO 9009787A1
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Prior art keywords
compound
phenyl
chloro
alkynyl
alkenyl
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PCT/US1990/001054
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English (en)
Inventor
Carl Henry Behrens
Shih-Fong Chen
Jack Bau Chien Jiang
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The Du Pont Merck Pharmaceutical Company
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Publication of WO1990009787A1 publication Critical patent/WO1990009787A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • 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
    • A61K31/18—Sulfonamides
    • 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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K31/40—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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids

Definitions

  • This invention relates to sulfonamides, their preparation, pharmaceutical compositions containing them and methods of using them in the treatment of tumors as radiosensitizers and chemosensitizers. Background:
  • the currently known radiosensitizers that are in clinical trials are hypoxic cell sensitizers and exert their radiation sensitizing effect only when given before the irradiation of tumors (G. E. Adams and I. J. Stratford, "Hypoxia-Dependent Radiation Sensitizers", Molecular Actions and Targets for Cancer Chemotherapeutic Agents, 1981, Page 401, Academic Press) .
  • the repair of radiation damage to DNA may be an important factor in the radiocurability of human tumors (K. K. Fu, "Biological Basis for the Internation of Chemotherapeutic Agents and Radiation Therapy", Cancer, May 1 Suppl., V. 55, 2123, 1985; S. Nakatsugawa and T. Sugahara, "Effects of Inhibitors of Radiation-Induced Potentially Lethal Damage Repair on Chemotherapy in
  • U.S. Patent 4,603,133 discloses amides and esters of 2-[N-(morpholinoalkyl)aminosulfonyl]-6-nitrobenzoic acids and compositions as useful adjuncts to radiation therapy.
  • R! is hydroxy-(lower alkoxy), lower alkoxy, allyloxy, amino, monoalkylamino, dialkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, or allylamino;
  • R ⁇ is hydrogen, lower alkyl from 1-4 carbon atoms, hydroxy-(lower alkyl), allyl;
  • R3 is a morpholino radical of the formula 0 ( CH2CH2)2N ( CH2) n ; and n is 2 or 3.
  • U.S. Patent 4,731,369 discloses amides and esters of 2-[N-(hydroxypi ⁇ eridinoalkyl) and
  • R 1 is hydroxy-(lower alkoxy), lower alkoxy, allyloxy, amino, alkylamino, di(lower alkyl)-alkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, or allylamino;
  • R2 is hydrogen, lower alkyl from 1-4 carbon atoms, hydroxy-(lower alkyl), allyl; n is 2 or 3; m is 0, 1, or 2; and p is 1 or 2.
  • U.S. Patent 4,694,020 discloses amides and esters of 2-(substituted sulfamyl)-6-nitrobenzoic acids and pharmaceutical compositions useful for increasing the sensitivity of hypoxic tumor cells to therapeutic radiation. These compounds have the formula:
  • R is hydroxy-(lower alkoxy), lower alkoxy, alkoxy- (lower alkoxy) , allyloxy, amino, monoalkylamino. dialkyla ino, (hydroxyalkyl)amino, di(hydroxyalkyl)- amino, or allylamino;
  • R2 and R-3 are each separately hydrogen, lower alkyl from 1-4 carbon atoms, hydroxy-(lower alkyl), allyl, amino-(lower alkyl), (lower alkyl)-amino-(lower alkyl), di(lower alkyl)-amino-(lower alkyl), (hydroxyalkyl)-amino(lower alkyl), (hydroxyalkyl)- alkylamino(lower alkyl), or di(hydroxyalkyl)- amino(lower alkyl) or when taken together along with the nitrogen to which they are attached represent a heterocyclic ring selected from morpholino, aziridinyl, azet
  • R! is hydrogen or loweralkyl of 1-4 carbons
  • R ⁇ and R 4 are the same or different and are each hydrogen, loweralkyl of 1-4 carbons, or hydroxyloweralky1;
  • R ⁇ is loweralkyl of 1-4 carbons substituted with NQ!Q2 wherein Q 1 is the same or different from Q ⁇ and both Q 1 and ⁇ - are hydrogen, loweralkyl of 1-4 carbons, or hydroxyloweralkyl, or Q ⁇ and Q2 taken together with the nitrogen atom in NQ ⁇ Q ⁇ form a heterocyclic ring such as aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl.
  • a broad class of sulfonamides have been described in the patent art and literature as pharmaceuticals and as agricultural agents. The closest ones are the following:
  • the compounds of the present invention are believed to exert their effect by inhibiting the repair of DNA strand breaks caused by radiation, thus the compounds are classified as postradiation sensitizers.
  • This postradiation sensitizer terminology is descriptive of the mechanism of action of these compounds but should not be a temporal limitation for administration of the compounds. In order for the compounds to be effective they must be present after the radiation therapy.
  • these compounds are believed to inhibit the repair of DNA strand breaks, they will be effective chemosensitizer agents when given in combination with chemotherapeutic agents which cause DNA strand breaks.
  • the compounds of the present invention may enhance or sensitize the activity of intercalators, alkylating agents, DNA cross-linker agents and any other agents which exert their anticancer activity by interacting with DNA, causing strand breaks.
  • R6 and R 7 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R ⁇ and R 7 taken together can form (CH2)pNR 8 (CH2)q (P and q independently are 2-6);
  • R8 and R 9 independently are H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms;
  • R 1 ⁇ is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl or substituted phenyl;
  • R 1 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 13 R 14 ;
  • R 2 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 1 ⁇ 17
  • R 3 and R 14 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl or CF3, or R 13 and R 14 taken together can form (CH2)r R 1 ⁇ (CH2)s (r and s independently are 2-6);
  • R 1 ⁇ is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms
  • R 1 ⁇ and R 17 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 16 and R 17 taken together can form (CH2)tNR 18 (CH2)u (t and u independently are 2-6);
  • R 18 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms;
  • Y is N or CR 5 ; * each X independently is H, F, Cl, Br, I, NO2, CN, CF3, alkyl, alkenyl, alkynyl of 1-4 carbon atoms, phenyl, substituted phenyl, (CH2) C NR 19 R 20 (c is 0-10), CO2R 22 , OR 23 , COR 24 , or S(0)d
  • R 19 and R 2 ⁇ independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 19 and R 20 taken together can form (CH2)eNR 21 (CH2)f (e and f independently are 2-6) ;
  • R 21 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms;
  • R 22 is H, alkyl, alkenyl or alkynyl of 1-10 carbon atoms;
  • R 23 is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl or substituted phenyl;
  • R 24 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR ⁇ R 27 ;
  • R 2 ⁇ is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 2 R 3u ;
  • R 2 > and ' R 27 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 2 ⁇ > and R 27 taken together can form (CH2)gNR 28 .(CH2)h (9 and h independently are 2-6) ;
  • R 28 is H, alkyl, alkenyl, alkynyl or
  • A is NR 32 or NR 32 QNR 33 ;
  • Q is (CH2)w, (CH2) x CO or (CH2) X S0 2 ; w is 2-10; x is 0-10; R 32 and R 33 independently are H, Na + , K + , Li + , alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, benzyl or substituted benzyl; with the following provisos: (a) when X, R 1 , R 3 and R 4 are H, R 2 is H, methyl,
  • compositions containing compounds of Formula (I) are also provided.
  • Preferred compounds of the present invention are those compounds of Formula (I) wherein: -SO2A is at the 1 or 2 position; and/or
  • Z is CH; and/or
  • X is 2-halogen, provided that when X is 2-halogen, -SO2A is at the 1 position.
  • Specifically preferred compounds of the present invention are:
  • j N-[3-(Aminosulfonyl)phenyl]-2-chloro-l- naphthalenesulfonamide
  • k 3- [ (2-Chloro-l-naphthalenyl) sulfonylamino] -4- methoxybenzamide
  • m N- (3-Methylphenyl) -1-naphthalenesulfonamide
  • n N-(3-Acetylphenyl)-l-naphthalenesulfonamide
  • o N-(3-Hydroxyphenyl) -1-naphthalenesulfon
  • the compounds of the present invention can be prepared according to Scheme I.
  • the compounds of Formula (I) can be prepared by the reaction of the sulfonyl chlorides of Formula (2) with the amines of Formula (3) in a suitable solvent such as pyridine, acetone or methylene chloride, with or without the addition of a suitable base, at a temperature from room temperature to the reflux temperature of the solvent.
  • the compounds of Formula (I) can be prepared by the simultaneous addition of a solution of an amine of Formula (3) in a suitable solvent, such as tetrahydrofuran (THF) , and a solution of a suitable base, such as potassium carbonate, in a suitable solvent, such as water, to a solution of an appropriate sulfonyl chloride of Formula (2) in a suitable solvent, such as THF at a temperature from room temperature to the reflux temperature of the solvent.
  • a suitable solvent such as tetrahydrofuran (THF)
  • a suitable base such as potassium carbonate
  • Physiologically acceptable salts include but are not limited to acid addition salts such as hydrochloric, sulfuric, acetic, succinic, citric, and benzene sulfonic acid salts of the compounds of Formula (I) which contain one or more basic functional groups, and the lithium, sodium or potassium salts which may be derived by the addition of a suitable base such as a metal hydroxide or metal hydride.
  • Materials of increased water solubility can be prepared by the addition of one or two equivalents of an aqueous sodium hydroxide solution to a suspension of a sulfonamide of the present invention in an appropriate solvent such as water, methanol or ethanol, followed by evaporation to dryness.
  • an appropriate solvent such as water, methanol or ethanol
  • Example 1 N-(3-Amidophenyl )-2-chloro-l-naphthalenesulfonamide To a solution of 3-aminobenzamide (6 g, 50 mmole) in THF (150 ml) was added dropwise simultaneously a solution of 2-chloro-l-naphthalenesulfonyl chloride (13 g, 50 mmole) in THF (100 ml) and a solution of K2CO3
  • the title compound was also prepared by adding dropwise for 30 minutes, a solution of 2-chloro- naphthalenesulfonyl chloride (9.7 g, 37 mmole) in acetonitrile (30 ml) into a mixture of 3-aminobenzamide (4.8 g, 35 mmole) and 3-dimethylaminopyridine (0.78 g, 6.5 mmole) in pyridine (40 ml) at 25°C under nitrogen. Then the reaction mixture was stirred at 25°C for 30 minutes and water (250 ml) was added dropwise and then poured into another 250 ml of water.
  • N- 3- ⁇ nidophenyl)-5-chloro-l-naph ha1enesulfonamide A solution of 3-aminobenzamide (5.5 g, 40 mmole) in acetone (75 ml) was added dropwise at 25°C into a solution of 5-chloro-l-naphthalene sulfonyl chloride (10 g, 40 mmole) in acetone (50 ml) over a period of 45 min.
  • reaction mixture was stirred for 20 hours and filtered to give a yellowish solid which was washed in sequence with acetone (25 ml) , water (25 ml) , and hot methanol (25 ml), and yielded the title compound (5.7 g, 40%) after drying in vacuo at 50°C for 2 hours, m.p. 257-259°C.
  • EMT6 tumors in female BALB/c mice are used. These mice are bred in the Stanford Radiobiology colony under specific pathogen-free conditions and are 3 to 4 months old at the beginning of each experiment.
  • the EMT6 tumor is grown intradermally in the flank from an inoculation of 2x10 ⁇ tumor cells taken from the 2nd to 8th in vitro passage of tumor cells since removed from a previous tumor in BALB/c mice.
  • Two tumors per mouse are implanted. These are used at a volume of approximately 100 mm 3 . At this point, the tumors contain approximately 20% hypoxic cells.
  • the first in vivo radiosensitization experiment is done with a fixed dose of intraperitoneally (ip) injected drug (usually 2 mmole/kg or 2/3 LD50, whichever is lower) , a fixed radiation dose (20 Gy) , and a variable interval between irradiation and injection, or between injection and irradiation. If tumor drug concentrations are required, one of the two tumors in each mouse is cut in half, and one half is immediately frozen for subsequent analysis of drug levels by high pressure liquid chromatography (HPLC) .
  • HPLC high pressure liquid chromatography
  • Irradiation of the EMT6 tumors is done by irradiating nonanesthetized, tumor-bearing mice in a Plexiglas® box. Irradiation conditions are low LET 250- kVp X-rays, 15 mA, FSD 33 cm, added filtration of 0.35 mm Cu, half value layer 1.3 mm Cu, and a dose rate of 130 rad/min.
  • the tumor-bearing mice are killed immediately after irradiation.
  • the tumors are dissected from the skin, cut into several pieces, and made into a fine brei by high-speed chopping with a razor blade attached to a jigsaw.
  • the brei is then added to 30 ml of Hank's Balanced Salt Solution (HBSS) containing the following enzyme concentrations: 0.02% DNase, 0.05% pronase, and 0.02% collagenase.
  • HBSS Hank's Balanced Salt Solution
  • the cell pellet is resuspended in complete Waymouth's medium plus 15% Fetal Calf Serum (FCS) , and an aliquot is mixed with trypan blue and the cells are counted with the use of a hemacytometer. Suitable dilutions of this single-cell suspension are then made in complete Waymouth's medium plus serum and plated into 60- or 100-mm polystyrene Petri dishes (Lux Scientific Corp.) in 5 or 15 ml of medium. After incubation for 13 days, the colonies are fixed and stained, and those containing 50 cells or more are counted. The dilution yielding an average count of 25 to 100 colonies in a 60- mm dish is used in the calculation of results. Results are determined as the ratio of cells killed with radiation versus cells killed with radiation plus sensitizer (Table IV) .
  • SER Sensitizer Enhancement Ratio
  • This assay is performed with the SCCVII carcinoma transplanted in C3H mice. It is an excellent tumor for regrowth delay studies because it has a low spontaneous metastasis rate, it is relatively nonimmunogenic in its syngeneic host, and grows to a large volume without compromising the health of its host.
  • test sensitizer For tumor inoculation, cells are taken from the 2nd to the 5th in vitro passage of a SCCVII tumor previously removed from a C3H mouse. Between 1 and 2x10 ⁇ cells are inoculated in a volume of 0.05 ml HBSS intradermally in the dorsum approximately 1 cm proximal to the base of the tail.
  • the assays for each test sensitizer result in two growth delay curves (one for vehicle controls and one for the test drug) , in which the mean number of days delay for the tumor to reach 4X its volume at the time of radiation is plotted as function of time.
  • the test sensitizer was given at a dose selected in the tumor cell survival assay experiment and at its optimal time interval (also determined in the tumor cell survival assay) .
  • mice are irradiated in a specially designed lead shield, with only the tumor and lower part of the dorsum exposed. The mice are retained by taping the tail to the side of the shield.
  • Four mice are irradiated simultaneously with 250-KVp X-rays, FSD 31 cm, dose rate of 167 rad/min.
  • Each growth delay curve is produced from five groups (four radiation doses + unirradiated control) of 6 mice each. Radiation dose used was 20 Gy.
  • Tumor diameter is measured daily in three dimensions with a vernier caliper and tumor volume calculated. At treatment tumors were about 300 mm 3 to 500 mm 3 . After treatment tumors were measured three times per week until each tumor reaches four-fold its initial volume. The mean number of days after treatment for tumors in each group to reach four times their treatment volume is calculated. This growth delay to four times initial tumor volume which is the difference between the mean in irradiated and unirradiated controls, or between irradiated pulse drug versus unirradiated control, is shown in Table V.
  • Human colon cancer clone A cells (1 x 106) were plated in 60-mm tissue culture dishes in RPMI-C medium on day 0. The cells were incubated in a humidified atmosphere of 5%C ⁇ 2 ⁇ 95% air at 37°C for 24 hrs. The culture " medium was then removed and replaced with 4 ml of fresh RPMI-C medium. The cells were irradiated with or without 5.7 Gy of radiation. Test analogs (1 ml, 5X concentration) were added to two similar plates (+/- radiation) immediately after radiation. The cultures were incubated at 37°C for 2 hrs and then the cells were harvested with trypsin (0.033%) and centrifuged.
  • the cells were resuspended in RPMI-C and the cell concentrations were adjusted for appropriate seeding density (depending on concentrations of testing analogs and whether the cells were treated with radiation) . After seeding, cultures were maintained for 10 days and then the cells were washed with 0.9% NaCl and stained with crystal violet (0.5% in absolute alcohol) and the number of colonies with more than 50 cells/colony were counted.
  • the plating efficiency (PE) was defined as the percentage of colonies formed from the total number of cells seeded.
  • PE (rad) plating efficiency of cells treated with radiation alone
  • PE (rad+analog) plating efficiency of cells treated with radiation and test analog
  • PE analog
  • control plating efficiency of control (no treatment) cells
  • Any test analog with a SR > 1.5 is considered positive in this- clonogenic survival assay.
  • Data are shown in Table VI.
  • L1210 Cells (3 x 10 5 cells/ml) were incubated with 0.02 ⁇ Ci/ l of [2- 14 C]thymidine (sp. act. 54.0 Ci/mmol) in a humidified atmosphere of 5% C ⁇ 2 ⁇ 95% air at 37°C for 24 hrs. The cells were then harvested and centrifuged. The cells were resuspended and adjusted to a concentration of 1 x 106 cells/ml. The cells were irradiated on ice for 1 hour in a Gamma cell 40 irradiator at a flux rate of 1.14 Gy/min. The cell suspensions were then incubated with or without test analogs for 2 hr at 37°C.
  • the DNA double-strand breaks in each sample were measured by neutral elution procedures (Kohn "X-ray Induced DNA Double Strand Break Production and Repair in Mammalian Cells as Measured by Neutral Filter Elution, " Nucleic Acids Research, 2, p. 793-804 (1979)).
  • the cells were diluted with cold phosphate buffered saline (PBS) and loaded onto a Smokestack funnel fitted with a 2 ⁇ polycarbonate filter. After washing the cells three times with cold PBS, the cells were lysed with 5 ml of SDS-EDTA lysis solution.
  • PBS cold phosphate buffered saline
  • the cell lysates were deproteinized with SDS-EDTA lysis solution containing 0.5 mg/ml proteinase K.
  • the amount of radioactive DNA retained on the filter after 10 hr elution was determined.
  • the inhibition of DNA repair by test analog is calculated by the following formula:
  • DNA a is %DNA retained when cells were incubated at
  • DNA ⁇ is %DNA retained when cells remained on ice for 2 hrs after irradiating with 68.4 Gy of radiation (designated as 0% repair) If a testing analog produced a >50% inhibition of DNA repair, the analog was considered active and a "+" sign was assigned in Table VI. Table VI
  • the postradiation and/or chemotherapeutic sensitizing compounds (active ingredients) of this invention can be administered to enhance radiation or chemotherapy treatment by any means that produces contact of the active ingredient with the agent's site of action in the body of a mammal after such radiation or chemotherapy treatment. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual active ingredients or in a combination of active ingredients. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage administered will be a radiation or chemotherapy enhancing amount of active ingredient and will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular active ingredient, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a dosage of active ingredient can be about 5 to 1000 milligrams per kilogram of body weight administered after radiation.
  • a typical dose is about 400 mg/kg.
  • compositions suitable for internal administration contain from about 5 milligrams to about 1000 milligrams of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions, it can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene, glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceu ical Sciences. A. Osol, a standard reference text in this field.
  • Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
  • Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 175 milligrams of lactose, 24 milligrams of talc, and 6 milligrams magnesium stearate. A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried. Tablets
  • a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of comstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
  • Consisting essentially of in the present disclosure is intended to have its customary meaning: namely, that all specified material and conditions are very important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

L'invention concerne de nouveaux sulfamides utiles en tant que radiosensibilisateurs et/ou chimiosensibilisateurs, une composition pharmaceutique contenant ces composés, des procédés d'utilisation de ceux-ci pour traiter une tumeur chez un mammifère, ainsi que des procédés de préparation desdits composés.
PCT/US1990/001054 1989-02-27 1990-02-27 Nouveaux sulfamides servant de radiosensibilisateurs WO1990009787A1 (fr)

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US5354562A (en) * 1992-01-21 1994-10-11 Sri International Process for preparing micronized polypeptide drugs
EP0682016A1 (fr) * 1994-05-13 1995-11-15 Zeneca Limited Dérivés de pyridine
US5663174A (en) * 1991-09-05 1997-09-02 Pharno-Wedropharm Gmbh Aromatic sulfonamide derivatives, their use as enzyme inhibitors and pharmaceutical compositions containing them
US5668137A (en) * 1995-06-22 1997-09-16 Zeneca Ltd. N-heterocyclic sulfonamides having endothelin receptor activity
WO1998027081A1 (fr) * 1996-12-19 1998-06-25 Smithkline Beecham Plc Derives de sulfamide, procede de preparation de ces derives et utilisation de ces derniers en tant que medicaments
US5861401A (en) * 1994-03-31 1999-01-19 Zeneca Limited N-heterocyclyl sulphonamide derivatives and their use as endothelin antagonists
US5866568A (en) * 1995-06-07 1999-02-02 Zeneca Limited Heterocyclic compounds
WO1999037608A1 (fr) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Nouveaux sulfonamides a substitution naphtyle et heterocyclique
WO1999037609A1 (fr) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Nouveaux sulfamides a substitution par naphtyle et anilide
WO2000066553A1 (fr) * 1999-04-30 2000-11-09 Bayer Aktiengesellschaft Indolsulfonamides substitues utilises comme produits antiviraux
WO2004074438A3 (fr) * 2003-02-14 2005-02-24 Smithkline Beecham Corp Antagonistes de ccr8
US7307089B2 (en) 2005-07-27 2007-12-11 Roche Palo Alto Llc Aryloxy quinolines and uses thereof
EP2054056A4 (fr) * 2006-08-16 2010-08-25 J David Gladstone Inst A Testa Petits inhibiteurs moleculaires de la kynurenine-3- monooxygenase
US7994338B2 (en) 2006-08-16 2011-08-09 The J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US8470810B2 (en) 2004-10-14 2013-06-25 Abbott Gmbh & Co. Kg Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
CN116675684A (zh) * 2023-08-02 2023-09-01 上海翰森生物医药科技有限公司 含炔基稠环类衍生物拮抗剂、其制备方法和应用

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DE3823318A1 (de) * 1988-07-09 1990-02-22 Bayer Ag (hetero)aryloxynaphthaline mit ueber schwefel gebundenen substituenten

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GB981286A (en) * 1962-10-25 1965-01-20 Hoffmann La Roche Sulphonamides and a process for the manufacture thereof
GB1185616A (en) * 1968-02-28 1970-03-25 Nordmark Werke Gmbh 2-Sulfanilamido-3-Halogeno-Pyridines
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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663174A (en) * 1991-09-05 1997-09-02 Pharno-Wedropharm Gmbh Aromatic sulfonamide derivatives, their use as enzyme inhibitors and pharmaceutical compositions containing them
US5354562A (en) * 1992-01-21 1994-10-11 Sri International Process for preparing micronized polypeptide drugs
US5861401A (en) * 1994-03-31 1999-01-19 Zeneca Limited N-heterocyclyl sulphonamide derivatives and their use as endothelin antagonists
US6083951A (en) * 1994-03-31 2000-07-04 Zeneca Limited Aryl-substituted pyrimidine sulphonamide compounds as endothelin antagonists
EP0682016A1 (fr) * 1994-05-13 1995-11-15 Zeneca Limited Dérivés de pyridine
US5641793A (en) * 1994-05-13 1997-06-24 Zeneca Limited Pyridine compounds which have useful pharmaceutical activity
US6060475A (en) * 1995-06-07 2000-05-09 Zeneca Limited Substituted pyrazin-2-yl-sulphonamide-(3-pyridyl) compounds and uses thereof
US6258817B1 (en) 1995-06-07 2001-07-10 Zeneca Ltd. Substituted pyrazin-2-yl-sulphonamide (-3-pyridyl) compounds and uses thereof
US5866568A (en) * 1995-06-07 1999-02-02 Zeneca Limited Heterocyclic compounds
US5668137A (en) * 1995-06-22 1997-09-16 Zeneca Ltd. N-heterocyclic sulfonamides having endothelin receptor activity
WO1998027081A1 (fr) * 1996-12-19 1998-06-25 Smithkline Beecham Plc Derives de sulfamide, procede de preparation de ces derives et utilisation de ces derniers en tant que medicaments
AU729056B2 (en) * 1996-12-19 2001-01-25 Smithkline Beecham Plc Sulphonamide derivatives, process for their preparation, and their use as medicaments
US6599904B2 (en) 1996-12-19 2003-07-29 Smithkline Beecham P.L.C. Sulphonamide derivatives, process for their preparation, and their use as medicaments
EA002351B1 (ru) * 1996-12-19 2002-04-25 Смитклайн Бичам Плс Производные сульфонамида, способ их получения и их использование в качестве лекарственных средств
US6423717B1 (en) 1996-12-19 2002-07-23 Smithkline Beecham P.L.C. Sulphonamide derivatives, process for their preparation, and their use as medicaments
AP1277A (en) * 1996-12-19 2004-05-05 Smithkline Beecham Plc Sulphonamide derivatives, process for their preparation, and their use as medicaments.
WO1999037609A1 (fr) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Nouveaux sulfamides a substitution par naphtyle et anilide
WO1999037608A1 (fr) * 1998-01-23 1999-07-29 Bayer Aktiengesellschaft Nouveaux sulfonamides a substitution naphtyle et heterocyclique
US6417181B1 (en) 1998-01-23 2002-07-09 Bayer Aktiengesellschaft Naphthyl-substituted and anilide-substituted sulfonamides
WO2000066553A1 (fr) * 1999-04-30 2000-11-09 Bayer Aktiengesellschaft Indolsulfonamides substitues utilises comme produits antiviraux
US6498183B1 (en) 1999-04-30 2002-12-24 Bayer Aktiengesellschaft Substituted indole sulfonamides as anitviral agents
WO2004074438A3 (fr) * 2003-02-14 2005-02-24 Smithkline Beecham Corp Antagonistes de ccr8
US8470810B2 (en) 2004-10-14 2013-06-25 Abbott Gmbh & Co. Kg Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
US7307089B2 (en) 2005-07-27 2007-12-11 Roche Palo Alto Llc Aryloxy quinolines and uses thereof
US7994338B2 (en) 2006-08-16 2011-08-09 The J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US8466182B2 (en) 2006-08-16 2013-06-18 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase
EP2054056A4 (fr) * 2006-08-16 2010-08-25 J David Gladstone Inst A Testa Petits inhibiteurs moleculaires de la kynurenine-3- monooxygenase
US8710237B2 (en) 2006-08-16 2014-04-29 The J. David Gladstone Institute Small molecule inhibitors of kynurenine-3-monooxygenase
US8071631B2 (en) 2006-08-16 2011-12-06 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
CN116675684A (zh) * 2023-08-02 2023-09-01 上海翰森生物医药科技有限公司 含炔基稠环类衍生物拮抗剂、其制备方法和应用
CN116675684B (zh) * 2023-08-02 2023-11-07 上海翰森生物医药科技有限公司 含炔基稠环类衍生物拮抗剂、其制备方法和应用

Also Published As

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AU5175490A (en) 1990-09-26
EP0462179A1 (fr) 1991-12-27
EP0462179A4 (en) 1992-03-18

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