WO2004112779A1 - New use vii - Google Patents

New use vii Download PDF

Info

Publication number
WO2004112779A1
WO2004112779A1 PCT/SE2004/000994 SE2004000994W WO2004112779A1 WO 2004112779 A1 WO2004112779 A1 WO 2004112779A1 SE 2004000994 W SE2004000994 W SE 2004000994W WO 2004112779 A1 WO2004112779 A1 WO 2004112779A1
Authority
WO
WIPO (PCT)
Prior art keywords
thien
chloro
amino
benzenesulfonamide
sulfonyl
Prior art date
Application number
PCT/SE2004/000994
Other languages
French (fr)
Inventor
Cecilia Nilsson
Catrine Dreifeldt
Original Assignee
Biovitrum Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2004112779A1 publication Critical patent/WO2004112779A1/en

Links

Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to the use of chemical compounds for wound healing, said compounds acting on the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (ll ⁇ HSDl).
  • Cortisol performs a broad range of metabolic functions and other functions.
  • the multitude of glucocorticoid action is exemplified in patients with prolonged increase in plasma glucocorticoids, so called "Cushing's syndrome".
  • Patients with Gushing' s syndrome have prolonged increase in plasma glucocorticoids and exhibit impaired glucose tolerance, type 2 diabetes, central obesity, and osteoporosis. These patients also have impaired wound healing and brittle skin (1).
  • Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds (2). Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery (3).
  • EP 0902288 discloses a method for diagnosing the status of wound healing in a patient, comprising detecting cortisol levels in said wound.
  • the authors suggest that elevated levels of cortisol in wound fluid, relative to normal plasma levels in healthy individuals, correlates with large, non-healing wounds (4).
  • 11 ⁇ -HSD catalyzes the conversion of cortisol to cortisone, and vice versa.
  • the parallel function of 11 ⁇ -HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5).
  • Two isoenzymes of 11 ⁇ -HSD, l l ⁇ - HSD1 and 1 l ⁇ -HSD2 have been characterized, and differ from each other in function and tissue distribution (6).
  • 11 ⁇ -HSD 1 is expressed in numerous tissues like liver, adipose tissue, adrenal cortex, gonads, lung, pituitary, brain, eye etc (7-9).
  • the function of 11 ⁇ -HSDl is to fine-tune local glucocorticoid action.
  • 11 ⁇ -HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).
  • Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, angiogenesis, wound contraction and epithelialization. It can be divided in three phases; inflammatory, proliferative and remodeling phase (reviewed in (2)).
  • glucocorticoids In surgical patients, treatment with glucocorticoids increases risk of wound infection and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF- ⁇ , EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).
  • WO 03/044009 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 11 ⁇ -HSDl, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders.
  • Other l l ⁇ -HSDl inhibitors are disclosed in e.g. WO 01/90090; WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/043999; and Swedish patent application No. SE 0301504-7, filed on May 21, 2003.
  • WO 02/072084 relates to glycyrrhetinic acid derivatives, progesterone and progesterone derivatives as ll ⁇ -HSDl inhibitors for wound healing.
  • 11 ⁇ -HSDl inhibitors according to the present invention for wound healing has not previously been disclosed.
  • this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 11 ⁇ -hydroxysteroid dehydrogenase type 1 , wherein the inhibitor of 11 ⁇ - hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
  • T is an aryl ring or heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C ⁇ -6 -alkyl, optionally halogenated C ⁇ -6 -alkoxy, C ⁇ -6 - alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di- substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by C 1-6 -acyl, C ⁇ -6 -alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C ⁇ -6
  • Bi and B 2 are B or Z, provided that Bi and B 2 have different meanings, wherein: • Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, C ⁇ -6 - alkyl, halogenated C ⁇ -6 -alkyl, halogen, C ⁇ -6 -alkoxy, nitro, C ⁇ -6 -alkoxycarbonyl, C ⁇ -6 - alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R 2 , wherein
  • R 2 is selected from C ⁇ -6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C ⁇ -6 -alkoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl; NR 3 R 4 , wherein R 3 and R 4 are each independently selected from hydrogen, C ⁇ -6 - alkyl, optionally halogenated C ⁇ -6 -alkylsulfonyl, C ⁇ -6 -alkoxy, 2-methoxyethyl, 2- hydroxyethyl, 1-methylimidazolylsulfonyl, C ⁇ -6 -acyl, C - ⁇ o-cycloalkyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsul
  • R .5/ O wherein R >5 i •s hydrogen, optionally halogenated C ⁇ _ 6 -alkyl, aryl, heteroaryl, Ci- 6 -acyl, C ⁇ -6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; • B 3 is hydrogen, C ⁇ -6 -alkyl or dimethylaminomethyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
  • T is selected from 5-chloro-l,3-dimethyl-lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, l-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3-
  • R 1 is hydrogen or methyl
  • Bi and B 2 are B 3 or Z, provided that Bi and B 2 have different meanings, wherein:
  • Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl;
  • phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y- R 2 , wherein
  • Y is CH 2 , CO or a single bond
  • 5 • R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
  • NR 3 R 4 wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, l,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, 0 cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-ind
  • R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
  • R 5 O wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl;
  • B 3 is hydrogen, methyl or dimethylaminomethyl.
  • N-(3'-chloro-2,2'-bithien-3-yl)-4-propylbenzenesulfonamide 3-chloro-N-(3'-chloro-2,2'-bithien-3-yl)-2-methylbenzenesulfonamide, 2,4,6-trichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide, 2,4-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)-6-methylbenzenesulfonamide, 2,4-dichloro-N-[2-(2-chlorophenyl)thien-3-yl]-6-methylbenzenesulfonamide, 4-bromo-2-methyl-N-[2-(2-mo ⁇ holin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
  • the said method is a method for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids.
  • the method according to the invention is also intended for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • the compounds referred to above may also be used in the manufacture of a medicament for promoting wound healing, e.g. for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • a medical condition involving delayed or impaired wound healing.
  • medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids.
  • the compounds referred to above may also be used for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • aryl in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph) and naphthyl, which optionally may be substituted by C ⁇ -6 -alkyl.
  • substituted aryl groups are benzyl, and 2-methylphenyl.
  • heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system.
  • heteroaryl rings examples include pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3- benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indan
  • Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
  • heterocyclic in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms having one or more heteroatoms (e.g., oxygen, sulfur, or nitrogen) as part of the ring system and the reminder being carbon, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings.
  • exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine and 1,4- oxazepane.
  • C ⁇ -6 -alkyl in the compound of formula (I) according to the present application is preferably C ⁇ -4 -alkyl.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
  • C ⁇ -6 -alkyl For parts of the range "C ⁇ -6 -alkyl" all subgroups thereof are contemplated such as Ci-s-alkyl, C ⁇ -4 -alkyl, C ⁇ -3 -alkyl, C ⁇ -2 -alkyl, C 2-6 -alkyl, C 2 . 5 - alkyl, C 2-4 -alkyl, C 2- -alkyl, C 3-6 -alkyl, C -5 -alkyl, etc.
  • C 3 - ⁇ o-cycloalkyl in the compound of formula (I) according to the present application may be straight or branched, is preferably C 3-8 -cycloalkyl.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
  • C 3- ⁇ )-cycloalkyi all subgroups thereof are contemplated such as C 3-9 -cycloalkyl, C 3-8 -cycloalkyl, C 3-7 -cyclo alkyl, C 3-6 - cycloalkyl, C 3-5 -cycloalkyl, C 4- ⁇ o-cycloalkyl, C 5- ⁇ o-cycloalkyl, C 6- ⁇ 0 -cycloalkyl, C 7- ⁇ o- cycloalkyl, C 8-9 -cycloalkyl, etc.
  • C ⁇ - 6 -alkoxy in the compound of formula (I) according to the present application may be straight or branched, is preferably C ⁇ -4 -alkoxy.
  • Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
  • C ⁇ -6 -alkoxy For parts of the range "C ⁇ -6 -alkoxy" all subgroups thereof are contemplated such as C ⁇ -5 -alkoxy, C ⁇ -4 -alkoxy, C ⁇ - 3 -alkoxy, C ⁇ -2 - alkoxy, C 2-6 -alkoxy, C -5 -alkoxy, C 2 - 4 -alkoxy, C 2-3 -alkoxy, C 3-6 -alkoxy, C 4-5 -alkoxy, etc.
  • C ⁇ -6 -acyl in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably C ⁇ -4 -acyl.
  • exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3- butenoyl), hexenoyl (e.g. 5-hexenoyl).
  • C ⁇ -6 -acyl all subgroups thereof are contemplated such as C ⁇ -5 -acyl, C ⁇ - -acyl, C ⁇ - -acyl, C ⁇ -2 -acyl, C 2-6 -acyl, C 2 . 5 -acyl, C 2- -acyl, C 2-3 -acyl, C 3-6 -acyl, C 4-5 -acyl, etc.
  • C 2-6 -alkenyl in the compound of formula (I) according to the present application is preferably C 2-4 -alkenyl.
  • Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl.
  • C -6 -alkenyl all subgroups thereof are contemplated such as C 2-5 -alkenyl, C 2-4 -alkenyl, C 2-3 -alkenyl, C 3- 6 -alkenyl, C 4-5 -alkenyl, etc.
  • halogen in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • sulfanyl in the present description means a thio group.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the pu ⁇ oses detailed herein (e.g., therapeutic administration to a subject for the treatment of disease, 11- ⁇ -HSDl inliibition, 11 - ⁇ -HSDl -mediated disease).
  • prodrug forms in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15).
  • “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
  • Base addition salts may be formed with organic and inorganic bases,: such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
  • the compounds of formula (I) can be prepared according to the methods described in WO 03/044009.
  • the compounds of formula (I) can preferably be topically administered.
  • the compounds could also be administered by other routes, for instance orally, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
  • Diabetic KKA y mice underwent surgery during anesthesia whereby a catheter was inserted in the jugularis vein. Oral treatment twice daily (200 mg/kg/day) with the 1 l ⁇ - HSD1 inhibitor BVT.2733 (disclosed as Example 172A in WO 01/90090), or vehicle started 4-6 days later and continued for 3.5 days.
  • ll ⁇ -HSDl inl ibitors e.g. BVT.2733
  • BVT.2733 ll ⁇ -HSDl inl ibitors
  • 1 cm full-thickness wounds, including the panniculus carnosus muscle are cut with a scalpel on the back of the mice.
  • Mice are treated with BVT.2733 for 5 days.
  • On day 2 and 9 of treatment wounds are harvested, embedded and sectioned. Histological staining of the sections with hematoxylin/eosin are made to determine degree of re-epithelialization and immunostaining against the von Willebrand factor to determine revascularisation.
  • Hutchinson TC Swaniker HP. Wound diagnosis by quantitating cortisol in wound fluids.
  • Beer HD Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm 2000;59:217-39.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of such promotion an effective amount of an inhibitor of 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), said 11β-HSD1 inhibitor having the formula (I) wherein T, B1, B2, B3 and R1 are as defined in the specification. These compounds may also be used in the manufacture of a medicament for promoting wound healing.

Description

NEW USE VΠ
RELATED APPLICATIONS
This application claims priority to Swedish application number 0301888-4, filed on June 25, 2003, the contents of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to the use of chemical compounds for wound healing, said compounds acting on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (llβHSDl).
BACKGROUND ART
Cortisol performs a broad range of metabolic functions and other functions. The multitude of glucocorticoid action is exemplified in patients with prolonged increase in plasma glucocorticoids, so called "Cushing's syndrome". Patients with Gushing' s syndrome have prolonged increase in plasma glucocorticoids and exhibit impaired glucose tolerance, type 2 diabetes, central obesity, and osteoporosis. These patients also have impaired wound healing and brittle skin (1).
Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds (2). Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery (3).
The European patent application No. EP 0902288 discloses a method for diagnosing the status of wound healing in a patient, comprising detecting cortisol levels in said wound. The authors suggest that elevated levels of cortisol in wound fluid, relative to normal plasma levels in healthy individuals, correlates with large, non-healing wounds (4).
h humans, the 11 β-HSD catalyzes the conversion of cortisol to cortisone, and vice versa. The parallel function of 11 β-HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5). Two isoenzymes of 11 β-HSD, l lβ- HSD1 and 1 lβ-HSD2, have been characterized, and differ from each other in function and tissue distribution (6). Like GR, 11 β-HSD 1 is expressed in numerous tissues like liver, adipose tissue, adrenal cortex, gonads, lung, pituitary, brain, eye etc (7-9). The function of 11 β-HSDl is to fine-tune local glucocorticoid action. 11 β-HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).
Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, angiogenesis, wound contraction and epithelialization. It can be divided in three phases; inflammatory, proliferative and remodeling phase (reviewed in (2)).
In surgical patients, treatment with glucocorticoids increases risk of wound infection and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF-β, EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).
WO 03/044009 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 11 β-HSDl, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders. Other l lβ-HSDl inhibitors are disclosed in e.g. WO 01/90090; WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/043999; and Swedish patent application No. SE 0301504-7, filed on May 21, 2003. WO 02/072084 relates to glycyrrhetinic acid derivatives, progesterone and progesterone derivatives as llβ-HSDl inhibitors for wound healing. However, the use of the 11 β-HSDl inhibitors according to the present invention for wound healing has not previously been disclosed. DISCLOSURE OF THE INVENTION
It has surprisingly been found that the present inhibitors of llβ-HSDl are useful for the promotion of wound healing. Consequently, in a first aspect this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 11 β-hydroxysteroid dehydrogenase type 1 , wherein the inhibitor of 11 β- hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
Figure imgf000004_0001
wherein
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Cι-6-alkyl, optionally halogenated Cι-6-alkoxy, Cι-6- alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di- substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by C1-6-acyl, Cι-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Cι-6- alkyl, optionally halogenated Cι-6-alkoxy, amide which is optionally mono- or di- substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2- oxoethyl)-l,3-thiazol-2-yl]amino}carbonyl); R1 is hydrogen or C1-6-alkyl;
Bi and B2 are B or Z, provided that Bi and B2 have different meanings, wherein: • Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, Cι-6- alkyl, halogenated Cι-6-alkyl, halogen, Cι-6-alkoxy, nitro, Cι-6-alkoxycarbonyl, Cι-6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R2, wherein
• X is CH2 or CO; • Y is CH2, CO or a single bond;
• R2 is selected from Cι-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, Cι-6-alkoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl; NR3R4, wherein R3 and R4 are each independently selected from hydrogen, Cι-6- alkyl, optionally halogenated Cι-6-alkylsulfonyl, Cι-6-alkoxy, 2-methoxyethyl, 2- hydroxyethyl, 1-methylimidazolylsulfonyl, Cι-6-acyl, C -ιo-cycloalkyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or Cι-6-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR3R4 represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomo holine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(lH)isoquinolinyl), or (lS,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by Cι-6-alkyl, Cι-6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR3R4, wherein R3 and R4 are each independently selected from hydrogen, .
6-alkyl or form together with the N-atom to which they are attached morpholinyl;
R .5/ O, wherein R >5 i •s hydrogen, optionally halogenated Cι_6-alkyl, aryl, heteroaryl, Ci- 6-acyl, Cι-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; • B3 is hydrogen, Cι-6-alkyl or dimethylaminomethyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
It is preferred that:
T is selected from 5-chloro-l,3-dimethyl-lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, l-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3-
5 acetylphenyl, benzeneammo, l,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro- 2-cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4- (2-ethoxy-2-oxoethyl)-l,3-thiazol-2-yl]amino}carbonyl), fluoro, 5-fluoro-2- methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, l o 4-methyl- 1 -piperazinyl, 4-methyl- 1 -piperidinyl, 4-methylsulfanylphenyl, 5 -methyl-2- thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl;
15 R1 is hydrogen or methyl;
Bi and B2 are B3 or Z, provided that Bi and B2 have different meanings, wherein:
• Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl;
20 phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y- R2, wherein
• X is CH2 or CO;
• Y is CH2, CO or a single bond; 5 • R2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR3R4, wherein R3 and R4 are each independently selected from acetyl, benzhydryl, l,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, 0 cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (lS)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR > 3r R>4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-dimethylmoφholinyl, (2R)-2,4-dimethyl-l- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-l,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1 , 1 -dioxido-thiomorpholinyl;
OCONR3R4, wherein R3 and R4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R5O, wherein R5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; • B3 is hydrogen, methyl or dimethylaminomethyl.
The following compounds are especially preferred:
ethyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetate,
(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetic acid,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N- methylacetamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-ethylacetamide,
2,5-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, isopropyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetate,
3-chloro-N-[4-(2-hydiOxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[4-(2-ethoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- diethylacetamide, methyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetate,
3-chloro-N-[4-(2-isopropoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[4-(2-methoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl methanesulfonate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetamide, 3-chloro-N- {4-[2-(2-fluoroethoxy)ethyl]thien-3-yl} -2- methylbenzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(2,2,2-trifluoroethoxy)ethyl]thien-3- yl } benzenesulfonamide,
2-(4- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-3-yl)ethyl acetate,
3-chloro-2-methyl-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
N-[4-(2-bromoethyl)thien-3-yl]-3-chloro-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl morpholine-4- carboxylate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl diethylcarbamate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl propionate,
2-(4- {[(3 -chloro-2-methylphenyl)sulfonyl] amino} thien-3 -yl)ethyl 2- methylpropanoate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl 2-furoate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl benzoate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-methoxy-N- methylacetamide,
3-chloro-N-{4-[2-(diethylamino)ethyl]thien-3-yl}-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl ethylcarbamate,
N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]-N- ethylacetamide,
3-chloro-2-methyl-N-[4-(2-oxopentyl)thien-3-yl]benzenesulfonamide,
N- {4-[2-(l , 1 -dioxidothiomorpholin-4-yl)-2-oxoethyl]thien-3-yl} -4- propylbenzenesulfonamide,
2,4,6-trichloro-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
2,4-dichloro-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(3-oxomorpholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-morpholin-4-ylethyl)thien-3- yl]benzenesulfonamide, N-[4-(2-morpholin-4-ylethyl)thien-3-yl]-4-proρylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2,4,6-trichloro-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3- yljbenzenesulfonamide,
N- [4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] -1,1 '-biphenyl-4-sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-propylbenzenesulfonamide,
N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide,
N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-oxo-2-piperidin-l-ylethyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide,
N-[4-(2-oxo-2-piperidin-l-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
2,4,6-trichloro-N-[4-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
N-(4-phenylthien-3-yl)-4-propylbenzenesulfonamide, ethyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)(oxo)acetate,
3-chloro-2-methyl-N-(4-phenylthien-3-yl)benzenesulfonamide,
3-chloro-N-[4-(4-fluoro-3-methylphenyl)thien-3-yl]-2- methylbenzenesulfonamide,
2,4,6-trichloro-N-(4-phenylthien-3-yl)benzenesulfonamide,
N-(4-phenylthien-3 -yl)- 1 , 1 '-biphenyl-4-sulfonamide,
2,4-dichloro-6-methyl-N-(4-phenylthien-3-yl)benzenesulfonamide,
2- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3-yl)acetamide,
2-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-3-yl)-N-ethyl-N- methylacetamide, N-ethyl-N-methyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3- yl)acetamide,
2,4,6-trichloro-N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yTJbenzenesulfonamide,
2- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N-isopropyl-N- methylacetamide,
2- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N,N-diethylacetamide,
N,N-diethyl-2-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3-yl)acetamide,
2-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- diethylacetamide,
N,N-diethyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3-yl)acetamide,
2-{4-[(l,r-biphenyl-4-ylsulfonyl)amino]thien-3-yl}-N,N-diisopropylacetamide,
N,N-diisopropyl-2-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3-yl)acetamide,
2-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- diisopropylacetamide,
N,N-diisopropyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3- yl)acetamide,
N-[4-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3~yl)phenyl]acetamide,
4-propyl-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide,
N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
N-[4-(2-chlorophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
3-chloro-N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3-chloro-N-(5-chloro-2,3'-bithien-4'-yl)-2-methylbenzenesulfonamide,
3-chloro-N-[4-(2-chlorophenyl)thien-3-yl]-2-methylbenzenesulfonamide,
N-[4-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3-yl)phenyl]acetamide,
2,4,6-trichloro-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide,
2,4,6-1richloro-N-[4-(2-chloro-5-mtiOphenyl)thien-3-yl]benzenesulfonamide,
2,4,6-trichloro-N-(5-chloro-2,3'-bithien-4'-yl)benzenesulfonamide,
2,4,6-trichloro-N-[4-(2-chlorophenyl)thien-3-yl]benzenesulfonamide,
N-(4- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl}phenyl)acetamide,
N-(4-pyridin-3 -ylthien-3 -yl)- 1 , 1 '-biphenyl-4-sulfonamide, N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]- 1 , 1 '-biρhenyl-4-sulfonamide,
N-[4-(2-chlorophenyl)thien-3-yl]- 1 , 1 '-biphenyl-4-sulfonamide,
N-[4-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-3- yl)phenyl] acetamide,
2,4-dichloro-6-methyl-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide,
2,4-dichloro-N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
2,4-dichloro-N-(5-chloro-2,3'-bithien-4'-yl)-6-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- dipropylacetamide,
3-chloro-2-methyl-N-[4-(2-oxo-2-piperazin-l-ylethyl)thien-3- yl]benzenesulfonamide,
2,4-dichloro-N-[4-(2,5-dimethyl-3-furyl)thien-3-yl]-6- methylbenzenesulfonamide,
N-(3-chloro-2,3'-bithien-4'-yl)-4-propylbenzenesulfonamide,
3-chloro-N-(3-chloro-2,3'-bithien-4'-yl)-2-methylbenzenesulfonamide,
2,4,6-trichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide,
2,4-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)-6-methylbenzenesulfonamide,
2,4-dichloro-N-[4-(2-chlorophenyl)thien-3-yl]-6-methylbenzenesulfonamide,
4-bromo-2-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide,
2-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-
(trifluoromethoxy)benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-phenoxybenzenesulfonamide,
4-chloro-2,6-dimethyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yljbenzenesulfonamide,
2,4-dichloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yljbenzenesulfonamide, tert-butyl 4-[(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3- yl)acetyl]piperazine- 1 -carboxylate, 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- dimethylacetamide,
3-chloro-2-methyl-N-{4-[2-(ρyridin-3-yloxy)ethyl]thien-3- yl}benzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-isopropyl-N- methylacetamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-ethyl-N- methylacetamide,
3-chloro-2-methyl-N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yljbenzenesulfonamide,
3-chloro-2-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- diisopropylacetamide,
3-chloro-2-methyl-N-[4-(2-oxo-2-pyrrolidin-l-ylethyl)thien-3- yljbenzenesulfonamide,
3 -chloro-2-methyl-N- [4-(2-oxo-2-piperidin- 1 -ylethyl)thien-3 - yl]benzenesulfonamide,
3-chloro-2-methyl-N-[4-(moφholin-4-ylmethyl)thien-3-yl]benzenesulfonamide,
3-chloro-N- {4-[2-(lH-imidazol-l-yl)ethyl]thien-3-yl} -2- methylbenzenesulfonamide,
2,4,5-trichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide,
2,3,4-trichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide,
2,3,4-trichloro-N-[4-(2-chlorophenyl)thien-3-yl]benzenesulfonamide,
N- [4-(4- { [(4-bromo-2,5 -difluorophenyl)sulfonyl] amino } thien-3 - yl)phenyl] acetamide,
4-bromo-N-(3-chloro-2,3'-bithien-4'-yl)-2,5-difluorobenzenesulfonamide,
4,5-dichloro-N-[4-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide,
N-[4-(4-{[(2,4,5-trichlorophenyl)sulfonyl]amino}thien-3-yl)phenyl]acetamide,
4-bromo-5-chloiO-N-(3-chloro-2,3'-bithien-4'-yl)thiophene-2-sulfonamide,
3-bromo-5-chloro-N-[4-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide,
N-[4-(4-{[(2,6-dichlorophenyl)sulfonyl]amino}thien-3-yl)phenyl]acetamide, 2,6-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide,
N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]acetamide,
3-chloro-2-methyl-N-(4-{2-[(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(2-oxopyrrolidin-l-yl)ethyl]thien-3- yl } benzenesulfonamide,
2,3,4-trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl } benzenesulfonamide,
N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
4-bromo-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3-yl}-2,5- difluorobenzenesulfonamide,
4,5-dichloro-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]thiophene-2- sulfonamide,
4-bromo-5-chloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl } thiophene-2-sulfonamide,
2,4-dichloro-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
4-bromo-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3 -chloro-2-methyl-N-(4- {2- [methyl(methylsulfonyl)amino] ethyl} thien-3 - yl)benzenesulfonamide,
N- [2-(4- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-3 -yl)ethyl] -N- methylcyclopropanecarboxamide,
3-chloro-2-methyl-N- {4- [2-(4-methyl-2-oxopiperazin- 1 -yl)ethyl]thien-3 - yl}benzenesulfonamide,
3-chloro-2-methyl-N-[4-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3- yl]benzenesulfonamide,
N-[4-(4-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}thien-3- yl)phenyl] acetamide,
2,4-dichloro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,4,6-trichloro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
4-(2-furyl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]benzenesulfonamide,
5 '-fluoro-2'-methoxy-N- [4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] - 1 , 1'- biphenyl-4-sulfonamide,
4-(5-methylthien-2-yl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
3 '-acetyl-N- [4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] -1,1 '-biphenyl-4- sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4'-(trifluoromethoxy)-l,r- biphenyl-4-sulfonamide,
3',4'-dichloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)tlιien-3-yl]-l,r-biphenyl-4- sulfonamide,
4-(l,3-benzodioxol-5-yl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
4-(5-chlorothien-2-yl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-pyridin-4- ylbenzenesulfonamide,
N- [4'-( { [4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] amino } sulfonyl)- 1,1'- biphenyl-3-yl]acetamide,
N- [4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] -4-thien-3 -ylb enzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-2-ylbenzenesulfonamide,
4'-(methylthio)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] -1,1 '-biphenyl-4- sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3,,5'-bis(trifluoromethyl)-l,l'- biphenyl-4-sulfonamide,
4'-chloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l, -biphenyl-4- sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3'-nitro-l,r-biphenyl-4- sulfonamide, 3-chloro-2-methyl-N-[4-(2-
{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3-yl]benzenesulfonamide,
N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]-l-methyl-
1 H-imidazole-4-sulfonamide,
3-chloro-N-{4-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
4, 5 -dichloro-N- {4- [2-(3 -oxomoφholin-4-yl)ethyl]thien-3 -yl} thiophene-2- sulfonamide,
N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}-4- phenoxybenzenesulfonamide,
3-fluoro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}benzenesulfonamide,
N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}-5-pyridin-2-ylthiophene-2- sulfonamide,
N-{2-chloro-4-[({4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl} amino)sulfonyl]phenyl} acetamide, ethyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate,
(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} thien-2-yl)acetic acid,
2-(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)-N- methylacetamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N-ethylacetamide,
2,5-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide, isopropyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate,
3-chloro-N-[2-(2-hydroxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[2-(2-ethoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diethylacetamide, methyl (3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yf)acetate,
3-chloro-N-[2-(2-isopropoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[2-(2-methoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl methanesulfonate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetamide, 3-chloro-N-{2-[2-(2-fluoroethoxy)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(2,2,2-trifluoroethoxy)ethyl]thien-3- yl } benzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl acetate,
3-chloro-2-methyl-N-[2-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
N-[2-(2-bromoethyl)thien-3-yl]-3-chloro-2-methylbenzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl moφholine-4- carboxylate,
2-(3 - { [(3-chloro-2-methylphenyl)sulfonyl] amino } thien-2~yi)ethyl diethylcarbamate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethylpropionate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl 2- methylpropanoate,
2-(3- { [(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl 2-furoate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl benzoate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N-methoxy-N- methylacetamide,
3-chloro-N-{2-[2-(diethylamino)ethyl]thien-3-yl}-2-methylbenzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl ethylcarbamate,
N-[2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl]-N- ethylacetamide,
3-chloro-2-methyl-N-[2-(2-oxopentyl)thien-3-yl]benzenesulfonamide,
N-{2-[2-(l,l-dioxidothiomoφholin-4-yl)-2-oxoethyl]thien-3-yl}-4- propylbenzenesulfonamide,
2,4,6-trichloro-N-[2-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
2,4-dichloro-N-[2-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,4-dichloro-6-methyl-N-[2-(2-moφholin-4-ylethyl)thien-3- yl]benzenesulfonamide, N-[2-(2-moφholin-4-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide, N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-propylbenzenesulfonamide, N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-l , 1 '-biphenyl-4-sulfonamide, N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide, N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
N-(2-phenylthien-3-yl)-4-propylbenzenesulfonamide, ethyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)(oxo)acetate, 3-chloro-2-methyl-N-(2-phenylthien-3-yl)benzenesulfonamide, 3-chloro-N-[2-(4-fluoro-3-methylphenyl)thien-3-yl]-2- methylbenzenesulfonamide,
2,4,6-trichloro-N-(2-phenylthien-3-yl)benzenesulfonamide, N-(2-phenylthien-3-yl)-l,l'-biphenyl-4-sulfonamide, 2,4-dichloro-6-methyl-N-(2-phenylthien-3-yl)benzenesulfonamide, 2- {3-[(l , 1 '-biρhenyl-4-ylsulfonyl)amino]thien-2-yl} -N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(3-{[(4-propylphenyl)sulfonyl]amino}thien-2-yl)acetamide, 2-(3- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino } thien-2-yl)-N-ethyl-N- methylacetamide, N-ethyl-N-methyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2- yl)acetamide,
2,4,6-trichloro-N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
2-{3-[(l,r-biphenyl-4-ylsulfonyl)amino]thien-2-yl}-N-isopropyl-N- methylacetamide,
2- {3-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N,N-diethylacetamide,
N,N-diethyl-2-(3 - { [(4-propylphenyl)sulfonyl] amino} thien-2-yl)acetamide,
2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diethylacetamide,
N,N-diethyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2-yl)acetamide,
2- {3-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N,N-diisopropylacetamide,
N,N-diisopropyl-2-(3-{[(4-propylphenyl)sulfonyl]amino}thien-2-yl)acetamide,
2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diisopropylacetamide,
N,N-diisopropyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2- yl)acetamide,
N-[4-(3-{[(4-propylphenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide,
4-propyl-N-(2-pyridin-3-ylthien-3-yl)benzenesulfonamide,
N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
N-[2-(2-chlorophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
3-chloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3-chloro-N-(5'-chloro-2,2'-bithien-3-yl)-2-methylbenzenesulfonamide,
3-chloro-N-[2-(2-chlorophenyl)thien-3-yl]-2-methylbenzenesulfonamide,
N-[4-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide,
2,4,6-trichloro-N-(2-pyridm-3-ylthien-3-yl)benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]benzenesulfonamide,
2,4,6-trichloro-N-(5'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-chlorophenyl)thien-3-yl]benzenesulfonamide,
N-(4- {3-[(l ,r-biphenyl-4-ylsulfonyl)amino]thien-2-yl}phenyl)acetamide,
N-(2-pyridin-3 -ylthien-3 -yl)- 1 , 1 '-biphenyl-4-sulfonamide, N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide, N-[2-(2-chlorophenyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide, N-[4-(3 - { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino} thien-2- yl)phenyl] acetamide,
2,4-dichloro-6-methyl-N-(2-pyridin-3-ylthien-3-yl)benzenesulfonamide, 2,4-dichloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
2,4-dichloro-N-(5'-chloro-2,2'-bithien-3-yl)-6-methylbenzenesulfonamide, 2-(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yT)-N,N- dipropylacetamide,
3 -chloro-2-methyl-N-[2-(2-oxo-2-piperazin- 1 -ylethyl)thien-3 - yl]benzenesulfonamide,
2,4-dichloro-N-[2-(2,5-dimethyl-3-furyl)thien-3-yl]-6- methylbenzenesulfonamide,
N-(3'-chloro-2,2'-bithien-3-yl)-4-propylbenzenesulfonamide, 3-chloro-N-(3'-chloro-2,2'-bithien-3-yl)-2-methylbenzenesulfonamide, 2,4,6-trichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide, 2,4-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)-6-methylbenzenesulfonamide, 2,4-dichloro-N-[2-(2-chlorophenyl)thien-3-yl]-6-methylbenzenesulfonamide, 4-bromo-2-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide, 2-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4- (trifluoromethoxy)benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-phenoxybenzenesulfonamide, 4-chloro-2,6-dimethyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2,4-dichloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide, tert-butyl 4- [(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2- yl)acetyl]piperazine- 1 -carboxylate, 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- dimethylacetamide,
3-chloro-2-methyl-N-{2-[2-(pyridin-3-yloxy)ethyl]thien-3- yl } benzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N-isopropyl-N- methylacetamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N-ethyl-N- methylacetamide,
3-chloro-2-methyl-N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diisopropylacetamide,
3-chloro-2-ιnethyl-N-[2-(2-oxo-2-pyrrolidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[2-(moφholin-4-ylmethyl)thien-3-yl]benzenesulfonamide,
3-chloro-N-{2-[2-(lH-imidazol-l-yl)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
2,4,5-trichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
2,3 ,4-trichloro-N-(3 '-chloro-2,2'-bithien-3 -yl)benzenesulfonamide,
2,3,4-trichloro-N-[2-(2-chlorophenyl)thien-3-yl]benzenesulfonamide,
N-[4-(3-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}thien-2- yl)phenyl] acetamide,
4-bromo-N-(3'-chloro-2,2'-bithien-3-yl)-2,5-difluorobenzenesulfonamide,
4,5-dichloro-N-[2-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide,
N-[4-(3-{[(2,4,5-trichlorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide,
4-bromo-5-chloro-N-(3'-chloro-2,2'-bithien-3-yl)thiophene-2-sulfonamide,
3-bromo-5-chloro-N-[2-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide,
N-[4-(3-{[(2,6-dichlorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide, 2,6-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
N-[2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl]acetamide,
3-chloro-2-methyl-N-(2-{2-[(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(2-oxopyrrolidin-l-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,3,4-trichloro-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl}benzenesulfonamide,
N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
4-bromo-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3-yl}-2,5- difluorobenzenesulfonamide,
4,5-dichloro-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]thiophene-2- sulfonamide,
4-bromo-5-chloro-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl } thiophene-2-sulfonamide,
2,4-dichloro-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
4-bromo-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3-chloro-2-methyl-N-(2-{2-[methyl(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
N-[2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl]-N- methylcyclopropanecarboxamide,
3-chloro-2-methyl-N-{2-[2-(4-methyl-2-oxopiperazin-l-yl)ethyl]thien-3- yl}benzenesulfonamide,
3-chloro-2-methyl-N-[2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3- yl]benzenesulfonamide,
N- [4-(3 - { [(4-bromo-5 -chlorothien-2-yl)sulfonyl] amino } thien-2- yl)phenyl] acetamide,
2,4-dichloro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide, 2,4-dichloro-6-methyl-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,4,6-trichloro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
4-(2-furyl)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]benzenesulfonamide, 5'-fluoro-2'-methoxy-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,l'- biphenyl-4-sulfonamide,
4-(5-methylthien-2-yl)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
3'-acetyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r-biphenyl-4- sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)tlιien-3-yl]-4'-(trifluoromethoxy)-l, - biphenyl-4-sulfonamide,
3',4'-dichloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,l'-biphenyl-4- sulfonamide,
4-(l,3-benzodioxol-5-yl)-N-[2-(2-mόφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
4-(5-chlorothien-2-yl)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-pyridin-4- ylbenzenesulfonamide,
N-[4'-( { [2-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] amino} sulfonyl)- 1 , 1 '- biphenyl-3 -yl] acetamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-3-ylbenzenesulfonamide, N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-2-ylbenzenesulfonamide, 4'-(methylthio)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] -1,1 '-biphenyl-4- sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3',5'-bis(trifluoromethyl)- 1,1'- biphenyl-4-sulfonamide,
4'-chloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r-biphenyl-4- sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3'-nitro- 1 , 1 '-biphenyl-4- sulfonamide, 3-chloro-2-methyl-N-[2-(2-
{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3-yl]benzenesulfonamide,
N-[2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl]-l-methyl-
1 H-imidazole-4-sulfonamide,
3-chloro-N-{2-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
4,5-dichloro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}thiophene-2- sulfonamide,
N- {2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl} -4- phenoxybenzenesulfonamide,
3-fluoro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}benzenesulfonamide,
N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}-5-pyridin-2-ylthiophene-2- sulfonamide,
N-{2-chloro-4-[({2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl} amino)sulfonyl]phenyl} acetamide, methyl (3-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate, methyl (3-{[(3-cyanophenyl)sulfonyl]amino}thien-2-yl)acetate, methyl (3- {[(4-butoxyphenyl)sulfonyl]amino}thien-2-yl)acetate, methyl (3-{[(2-methylsulfanylpyrimidin-4-ylthiophene)sulfonyl]amino}thien-2- yl)acetate, methyl (3-{[(l-methylimidazol-4-yl)sulfonyl]amino}thien-2-yl)acetate, and methyl (3- {[(4-methylphenyl)sulfonyl]amino}thien-2-yl)acetate.
In one aspect of the invention, the said method is a method for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing. Examples of such medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids. The method according to the invention is also intended for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
The compounds referred to above may also be used in the manufacture of a medicament for promoting wound healing, e.g. for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing. Examples of such medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids. The compounds referred to above may also be used for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
The various terms used, separately and in combinations, in the above definition of the compounds having the formula (I) will be explained.
The term "aryl" in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph) and naphthyl, which optionally may be substituted by Cι-6-alkyl. Examples of substituted aryl groups are benzyl, and 2-methylphenyl.
The term "heteroaryl" means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3- benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5- naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene. Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
The term "heterocyclic" in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms having one or more heteroatoms (e.g., oxygen, sulfur, or nitrogen) as part of the ring system and the reminder being carbon, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, moφholine, thiomoφholine and 1,4- oxazepane.
Cι-6-alkyl in the compound of formula (I) according to the present application, which may be straight, branched or cyclic, is preferably Cι-4-alkyl. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl. For parts of the range "Cι-6-alkyl" all subgroups thereof are contemplated such as Ci-s-alkyl, Cι-4-alkyl, Cι-3-alkyl, Cι-2-alkyl, C2-6-alkyl, C2.5- alkyl, C2-4-alkyl, C2- -alkyl, C3-6-alkyl, C -5-alkyl, etc.
C3-ιo-cycloalkyl, in the compound of formula (I) according to the present application may be straight or branched, is preferably C3-8-cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. For parts of the range "C3-κ)-cycloalkyi" all subgroups thereof are contemplated such as C3-9-cycloalkyl, C3-8-cycloalkyl, C3-7-cyclo alkyl, C3-6- cycloalkyl, C3-5-cycloalkyl, C4-ιo-cycloalkyl, C5-ιo-cycloalkyl, C6-ι0-cycloalkyl, C7-ιo- cycloalkyl, C8-9-cycloalkyl, etc.
Cι-6-alkoxy, in the compound of formula (I) according to the present application may be straight or branched, is preferably Cι-4-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy. For parts of the range "Cι-6-alkoxy" all subgroups thereof are contemplated such as Cι-5-alkoxy, Cι-4-alkoxy, Cι-3-alkoxy, Cι-2- alkoxy, C2-6-alkoxy, C -5-alkoxy, C2-4-alkoxy, C2-3-alkoxy, C3-6-alkoxy, C4-5-alkoxy, etc.
Cι-6-acyl, in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably Cι-4-acyl. Exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3- butenoyl), hexenoyl (e.g. 5-hexenoyl). For parts of the range "Cι-6-acyl" all subgroups thereof are contemplated such as Cι-5-acyl, Cι- -acyl, Cι- -acyl, Cι-2-acyl, C2-6-acyl, C2. 5-acyl, C2- -acyl, C2-3-acyl, C3-6-acyl, C4-5-acyl, etc.
C2-6-alkenyl in the compound of formula (I) according to the present application, which may be straight, branched or cyclic, is preferably C2-4-alkenyl. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl. For parts of the range "C -6-alkenyl" all subgroups thereof are contemplated such as C2-5-alkenyl, C2-4-alkenyl, C2-3-alkenyl, C3- 6-alkenyl, C4-5-alkenyl, etc.
The term "halogen" in the present description is intended to include fluorine, chlorine, bromine and iodine.
The term "sulfanyl" in the present description means a thio group.
With the expression "mono- or di-substituted" is meant in the present description that the functionalities in question may be substituted with independently Cι-6-acyl, C2-6- alkenyl, Cι-6-(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, moφholine and thiomoφholine, which heterocyclic rings optionally may be substituted with Cι-6-alkyl. With the expression "optionally mono- or disubstituted" is meant in the present description that the functionalities in question may also be substituted with independently hydrogen.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the puφoses detailed herein (e.g., therapeutic administration to a subject for the treatment of disease, 11-β-HSDl inliibition, 11 -β-HSDl -mediated disease).
The term "prodrug forms" in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15).
"Pharmaceutically acceptable" means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases,: such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
The compounds of formula (I) can be prepared according to the methods described in WO 03/044009.
For use according to the invention, the compounds of formula (I) can preferably be topically administered. However, the compounds could also be administered by other routes, for instance orally, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
EXAMPLES
EXAMPLE 1
Diabetic KKAy mice underwent surgery during anesthesia whereby a catheter was inserted in the jugularis vein. Oral treatment twice daily (200 mg/kg/day) with the 1 lβ- HSD1 inhibitor BVT.2733 (disclosed as Example 172A in WO 01/90090), or vehicle started 4-6 days later and continued for 3.5 days.
Advantageous effects on wound healing of the surgical wounds were observed during treatment. In BVT.2733 treated mice, less complication were observed in and around the wound area as compared to control mice. Examples of advantageous effects were less pus in the wound, as well as better wound strength. 58 % of the vehicle treated animals showed complications during treatment period whereas complications were present in only 24 % of the BVT.2733 treated animals.
EXAMPLE 2
(a)
Advantageous effects of llβ-HSDl inl ibitors (e.g. BVT.2733) on wound healing are confirmed in diabetic KKAy mice employing the excisional wound-healing model. 1 cm full-thickness wounds, including the panniculus carnosus muscle, are cut with a scalpel on the back of the mice. Mice are treated with BVT.2733 for 5 days. On day 2 and 9 of treatment wounds are harvested, embedded and sectioned. Histological staining of the sections with hematoxylin/eosin are made to determine degree of re-epithelialization and immunostaining against the von Willebrand factor to determine revascularisation.
(b)
Advantageous effects of llβ-HSDl inhibitors are confirmed in in vitro studies. Proliferation of human keratinocytes and fibroblasts, which are important cell types in the wound healing process, are studied after incubation with the 11 β-HSDl inhibitor.
(c)
Effects on wound healing after treatment with 11 β-HSDl inhibitors are also studied in wounds on explants from human breast skin. The proliferative effect of the substance and the effect on re-epithelialization are determined.
REFERENCES 1. Ganong WF. Review of Medical Physiology. Eighteenth edition ed. Stamford, Connecticut: Appleton & Lange; 1997.
2. Anstead GM. Steroids, retinoids, and wound healing. Adv Wound Care 1998;l l(6):277-85.
3. Diethelm AG. Surgical management of complications of steroid therapy. Ann Surg 1977;185(3):251-63.
4. Hutchinson TC, Swaniker HP. Wound diagnosis by quantitating cortisol in wound fluids. European patent application No. EP 0 902 288, published 17.03.1999.
5. Frey FJ, Escher G, Frey BM. Pharmacology of 11 beta-hydroxysteroid dehydrogenase. Steroids 1994;59(2):74-9.
6. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994;105(2):Rll-7.
7. Monder C, White PC. 11 beta-hydroxysteroid dehydrogenase. Vitam Horm 1993;47:187-271.
8. . Stewart PM, Krozowski ZS. 11 beta-Hydroxysteroid dehydrogenase. Vitam Horm 1999;57:249-324.
9. Stokes J, Noble J, Brett L, Phillips C, Seckl JR, O'Brien C, et al. Distribution of glucocorticoid and mineralocorticoid receptors and 1 lbeta-hydroxysteroid dehydrogenases in human and rat ocular tissues. Invest Ophthalmol Vis Sci 2000;41(7):1629-38.
10. Hammami MM, Siiteri PK. Regulation of 11 beta-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J Clin Endocrinol Metab 1991;73(2):326-34.
11. Cooper MS, Moore J, Filer A, Buckley CD, Hewison M, Stewart PM. 1 lbeta- hydroxysteroid dehydrogenase in human fibroblasts: expression and regulation depends on tissue of origin. ENDO 2003 Abstracts 2003.
12. Teelucksingh S, Mackie AD, Burt D, Mclntyre MA, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990;335(8697):1060-3.
13. Slight SH, Chilakamarri VK, Nasr S, Dhalla AK, Ramires FJ, Sun Y, et al. Inhibition of tissue repair by spironolactone: role of mineralocorticoids in fibrous tissue formation. Mol Cell Biochem 1998;189(l-2):47-54. 14. Mercado AM, Quan N, Padgett DA, Sheridan JF, Marucha PT. Restraint stress alters the expression of interleukin-1 and keratinocyte growth factor at the wound site: an in situ hybridization study. J Neuroimmunol 2002;129(l-2):74-83.
15. Rojas IG, Padgett DA, Sheridan JF, Marucha PT. Stress-induced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav Lm un 2002;16(l):74-84.
16. Beer HD, Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm 2000;59:217-39.
17. Hamon GA, Hunt TK, Spencer EM. In vivo effects of systemic insulin-like growth factor-I alone and complexed with insulin-like growth factor binding protein-3 on corticosteroid suppressed wounds. Growth Regul 1993;3(l):53-6.
18. Laato M, Heino J, Kahari VM, Niinikoski J, Gerdin B. Epidermal growth factor (EGF) prevents methylprednisolone-induced inhibition of wound healing. J Surg Res 1989;47(4):354-9.
19. Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Gramates P, Deuel TF. Transforming growth factor beta reverses the glucocorticoid-induced wound-healing deficit in rats: possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci U S A 1989;86(7):2229-33.
20. Oishi Y, Fu ZW, Ohnuki Y, Kato H, Noguchi T. Molecular basis of the alteration in skin collagen metabolism in response to in vivo dexamethasone treatment: effects on the synthesis of collagen type I and III, coUagenase, and tissue inhibitors of metalloproteinases. Br J Dermatol 2002;147(5):859-68.

Claims

Claims
1. A method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 11-β-hydroxysteroid dehydrogenase type 1, wherein the inhibitor of 11-β- hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
Figure imgf000031_0001
wherein
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Cι-6-alkyl, optionally halogenated Cι-6-alkoxy, Cι-6- alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di- substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by Cι-6-acyl, Cι-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Cι-6- alkyl, optionally halogenated Cι-6-alkoxy, amide which is optionally mono- or di- substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2- oxoethyl)-l,3-thiazol-2-yl]amino}carbonyl); R1 is hydrogen or Cι-6-alkyl;
Bi and B2 are B or Z, provided that Bi and B2 have different meanings, wherein: • Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, Cι-6- alkyl, halogenated Cι-6-alkyl, halogen, Cι-6-alkoxy, nitro, Cι-6-alkoxycarbonyl, Cι-6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R2, wherein • X is CH2 or CO;
• Y is CH2, CO or a single bond;
• R2 is selected from Cι-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- moφholinolinylmethylene, Cι-6-alkoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl;
NR3R4, wherein R3 and R4 are each independently selected from hydrogen, Cι-6- alkyl, optionally halogenated Cι-6-alkylsulfonyl, Cι-6-alkoxy, 2-methoxyethyl, 2- hydroxyethyl, 1-methylimidazolylsulfonyl, Cι-6-acyl, C3-ιo-cycloalkyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or Cι-6-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR3R4 represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, moφholine, oxazepine, oxazole, thiomoφholine, 1,1- dioxidothiomoφholine, 2~(3,4-dihydro-2(lH)isoquinolinyT), or (lS,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by
Cι-6-alkyl, Cι-6-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR3R4, wherein R3 and R4 are each independently selected from hydrogen, Ci- 6-alkyl or form together with the N-atom to which they are attached moφholinyl; R5O, wherein R5 is hydrogen, optionally halogenated Cι-6-alkyl, aryl, heteroaryl, Cι_ 6-acyl, Cι-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl;
• B3 is hydrogen, Cι-6-alkyl or dimethylaminomethyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
2. The method according to claim 1, wherein
T is selected from 5 -chloro- 1,3 -dimethyl- lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)- 1-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneammo, l,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro- 2-cyanophenoxy, 4-chlorophenyl, 5 -chloro-2 -thienyl, cyano, 3,4-dichlorophenyl, ({[4- (2-ethoxy-2-oxoethyl)-l,3-thiazol-2-yl]amino}carbonyl), fluoro, 5-fluoro-2- methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- 1 -piperazinyl, 4-methyl- 1 -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2- thienyl, 4-moφholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3 -thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl;
R1 is hydrogen or methyl;
Bi and B2 are B3 or Z, provided that Bi and B2 have different meanings, wherein: • Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-
R , wherein • X is CH2 or CO;
• Y is CH2, CO or a single bond;
• R2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- moφholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR3R4, wherein R3 and R4 are each independently selected from acetyl, benzhydryl, l,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (lS)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR3R4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-dimethylmoφholinyl, (2R)-2,4-dimethyl-l- piperazinyl, 2-hydroxy-3-oxomoφholinyl, imidazolyl, 2-methyl-3-oxomoφholinyl, 4- methyl-2-oxopiρerazinyl, 4-methylpiperazinyl, moφholinyl, (lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomoφholinyl, 3-oxo-l,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomoφholinyl; 1 , 1 -dioxido-thiomoφholinyl;
OCONR3R4, wherein R3 and R4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached moφholinyl; R5O, wherein R5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; • B3 is hydrogen, methyl or dimethylaminomethyl.
3. The method according to any one of claims 1 or 2, wherein the compound is selected from:
ethyl (4- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-3-yl)acetate,
(4-{[(3-chloro-2-methylphe'nyl)sulfonyl]amino}thien-3-yl)acetic acid,
2-(4-{[(3-chloro-2-methylphenyl)sulfdnyl]amino}thien-3-yl)-N- methylacetamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-ethylacetamide,
2,5-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, isopropyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetate,
3-chloro-N-[4-(2-hydroxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3 -chloro-N- [4-(2-ethoxyethyl)thien-3 -yl] -2-methylb enzenesulfonamide,
2-(4- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} thien-3 -yl)-N,N- diethylacetamide, methyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)acetate,
3-chloro-N-[4-(2-isopropoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[4-(2-methoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl methanesulfonate,
2-(4- { [(3-chloro-2-methylphenyl)sulfonyl] amino } thien-3 -yl)acetamide,
3-chloro-N- {4-[2-(2-fluoroethoxy)ethyl]thien-3-yl} -2- methylbenzenesulfonamide, • 3-chloro-2-methyl-N- {4-[2-(2,2,2-trifluoroethoxy)ethyl]thien-3- yl}benzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl acetate,
3-chloro-2-methyl-N-[4-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
N-[4-(2-bromoethyl)thien-3-yl]-3-chloro-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl moφholine-4- carboxylate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl diethylcarbamate, • 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl propionate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl 2- methylpropanoate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl 2-furoate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl benzoate, • 2-(4- {[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-methoxy-N- methylacetamide,
3-chloro-N-{4-[2-(diethylamino)ethyl]thien-3-yl}-2-methylbenzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl ethylcarbamate, • .N-[2-(4- {[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]-N- ethylacetamide,
3-chloro-2-methyl-N-[4-(2-oxopentyl)thien-3-yl]benzenesulfonamide,
N- {4-[2-(l , 1 -dioxidothiomoφholin-4-yl)-2-oxoethyl]thien-3-yl} -4- propylbenzenesulfonamide, • 2,4,6-trichloro-N-[4-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
2,4-dichloro-N-[4-(2-moφholin-4-ylethyl)tlτien-3-yl]benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-moφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-moφholin-4-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2,4,6-trichloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]- 1 , 1 '-biphenyl-4-sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-propylbenzenesulfonamide,
N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-l, -biphenyl-4-sulfonamide,
N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-oxo-2-piperidin- 1 -ylethyl)thien-3-yl]-l , 1 '-biphenyl-4-sulfonamide,
N-[4-(2-oxo-2-piperidin-l-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[4-(2-oxo-2-piperidin- 1 -ylethyl)thien-3 - yl]benzenesulfonamide,
2,4,6-trichloro-N-[4-(2-oxo-2-piperidin- 1 -ylethyl)thien-3- yl]benzenesulfonamide,
N-(4-phenylthien-3-yl)-4-propylbenzenesulfonamide, ethyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)(oxo)acetate,
3-chloro-2-methyl-N-(4-phenylthien-3-yl)benzenesulfonamide,
3-chloro-N-[4-(4-fluoro-3-methylphenyl)thien-3-yl]-2- methylbenzenesulfonamide,
2,4,6-trichloro-N-(4-phenylthien-3-yl)benzenesulfonamide,
N-(4-phenylthien-3 -yl)- 1 , 1 '-biphenyl-4-sulfonamide,
2,4-dichloro-6-methyl-N-(4-phenylthien-3-yl)benzenesulfonamide,
2- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3-yl)acetamide,
2-(4- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino } thien-3-yl)-N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3- yl)acetamide, 2,4,6-trichloro-N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
2- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N-isopropyl-N- methylacetamide,
2- {4-[(l , 1 ?-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N,N-diethylacetamide,
N,N-diethyl-2-(4- { [(4-propylphenyl)sulfonyl] amino } thien-3-yl)acetamide,
2-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- diethylacetamide,
N,N-diethyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3-yl)acetamide, • 2- {4-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N,N-diisopropylacetamide,
N,N-diisopropyl-2-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3-yl)acetamide, 2-(4- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino } thien-3 -yl)-N,N- diisopropylacetamide, N,N-diisopropyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3- yl)acetamide,
N- [4-(4- { [(4-propylphenyl)sulfonyl] amino } thien-3 -yl)phenyl] acetamide, 4-propyl-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide, N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-4-propylbenzenesulfonamide, N-[4-(2-chlorophenyl)thien-3-yl]-4-propylbenzenesulfonamide, • 3-chloro-N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3-chloro-N-(5-chloro-2,3'-bithien-4'-yl)-2-methylbenzenesulfonamide, 3-chloro-N-[4-(2-chlorophenyl)thien-3-yl]-2-methylbenzenesulfonamide, N-[4-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-3-yl)phenyl]acetamide, • 2,4,6-trichloro-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide,
2,4,6-trichloro-N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]benzenesulfonamide, 2,4,6-trichloro-N-(5-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, 2,4,6-trichloro-N-[4-(2-chlorophenyl)thien-3-yl]benzenesulfonamide, N-(4-{4-[(l, -biphenyl-4-ylsulfonyl)amino]thien-3-yl}phenyl)acetamide, • N-(4-pyridin-3-ylthien-3-yl)-l,r-biphenyl-4-sulfonamide,
N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]- 1 , 1 '-biphenyl-4-sulfonamide, N- [4-(2-chlorophenyl)thien-3 -yl] -1,1 '-biρhenyl-4-sulfonamide, N-[4-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-3- yl)phenyl]acetamide,
2,4-dichloro-6-methyl-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide, 2,4-dichloro-N-[4-(2-chloro-5 -nitrophenyl)thien-3 -yl] -6- methylbenzenesulfonamide,
2,4-dichloro-N-(5-chloro-2,3'-bithien-4'-yl)-6-methylbenzenesulfonamide, 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- dipropylacetamide,
3-chloro-2-methyl-N-[4-(2-oxo-2-piperazin-l-ylethyl)thien-3- yl]benzenesulfonamide,
2,4-dichloro-N-[4-(2,5-dimethyl-3-furyl)thien-3-yl]-6- methylbenzenesulfonamide,
N-(3 -chloro-2,3 '-bithien-4'-yl)-4-propylbenzenesulfonamide, 3-chloro-N-(3-chloro-2,3'-bithien-4'-yl)-2-methylbenzenesulfonamide, 2,4,6-trichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, 2,4-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)-6-methylbenzenesulfonamide, 2,4-dichloro-N-[4-(2-chlorophenyl)thien-3-yl]-6-methylbenzenesulfonamide, 4-bromo-2-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide, 2-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4- (trifluoromethoxy)benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-phenoxybenzenesulfonamide, 4-chloro-2,6-dimethyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2,4-dichloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide, tert-butyl 4-[(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3- yl)acetyl]piperazine- 1 -carboxylate,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- dimethylacetamide, 3-chloro-2-methyl-N-{4-[2-(pyridin-3-yloxy)ethyl]thien-3- yl}benzenesulfonamide,
2-(4-{[(3-chloro-2-methylρhenyl)sulfonyl]amino}thien-3-yl)-N-isopropyl-N- methylacetamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N-ethyl-N- methylacetamide,
3-chloro-2-methyl-N-[4-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)-N,N- diisopropylacetamide,
3 -chloro-2-methyl-N- [4-(2-oxo-2-pyrrolidin- 1 -ylethyl)thien-3 - yl]benzenesulfonamide,
3-chloro-2-methyl-N-[4-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[4-(moφholin-4-ylmethyl)thien-3-yl]benzenesulfonamide, 3-chloro-N-{4-[2-(lH-imidazol-l-yl)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
2,4,5-trichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, 2,3,4-trichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, 2,3,4-trichloro-N-[4-(2-chlorophenyl)thien-3-yl]benzenesulfonamide, N-[4-(4-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}thien-3- yl)phenyl] acetamide,
4-bromo-N-(3-chloro-2,3'-bithien-4,-yl)-2,5-difluorobenzenesulfonamide, 4,5-dichloro-N-[4-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide, N- [4-(4- { [(2 ,4,5 -trichlorophenyl)sulfonyl] amino } thien-3 -yl)phenyl] acetamide, 4-bromo-5 -chloro-N-(3 -chloro-2,3 ,-bithien-4'-yl)thiophene-2-sulfonamide, 3-bromo-5-chloro-N-[4-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide, N-[4-(4-{[(2,6-dichlorophenyl)sulfonyl]amino}thien-3-yl)phenyl]acetamide, 2,6-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide, N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]acetamide, 3-chloro-2-methyl-N-(4-{2-[(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(2-oxopyrrolidin-l-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,3,4-trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl}benzenesulfonamide,
N- [4-(2-chloro-6-fluorophenyl)thien-3 -yl] -4-propylbenzenesulfonamide, • 4-bromo-N- {4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3-yl}-2,5- difluorobenzenesulfonamide,
4,5-dichloro-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]thiophene-2- sulfonamide,
4-bromo-5-chloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl}thiophene-2-sulfonamide,
2,4-dichloro-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
4-bromo-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]-2- methylbenzenesulfonamide, • 3-chloro-2-methyl-N-(4- {2-[methyl(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
N-[2-(4- { [(3-chloro-2-methylphenyl)sulfonyl] amino} thien-3 -yl)ethyl] -N- methylcyclopropanecarboxamide,
3-chloro-2-methyl-N-{4-[2-(4-methyl-2-oxopiperazin-l-yl)ethyl]thien-3- yl}benzenesulfonamide,
3 -chloro-2-methyl-N- [4-(2- { [(trifluoromethyl)sulfonyl] amino} ethyl)thien-3 - yl]benzenesulfonamide,
N- [4-(4- { [(4-bromo-5 -chlorothien-2-yl)sulfonyl] amino } thien-3 - yl)phenyl] acetamide, • 2,4-dichloro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,4-dichloro-6-methyl-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide, 2,4,6-trichloro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide,
4-(2-furyl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]benzenesulfonamide,
5'-fluoro-2'-methoxy-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,l'- biphenyl-4-sulfonamide,
4-(5-methylthien-2-yl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
3 '-acetyl-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl]- 1 , 1 '-biphenyl-4- sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4'-(trifluoromethoxy)-l,r- biphenyl-4-sulfonamide,
3',4'-dichloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r-biphenyl-4- sulfonamide,
4-(l,3-benzodioxol-5-yl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,-
4-(5-chlorothien-2-yl)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-pyridin-4- ylbenzenesulfonamide,
N-[4'-( { [4-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] amino} sulfonyl)- 1 , 1 '- biphenyl-3-yl]acetamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-3-ylbenzenesulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-2-ylbenzenesulfonamide,
4'-(methylthio)-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r-biphenyl-4- sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3',5,-bis(trifluoromethyl)-l,r- biphenyl-4-sulfonamide,
4'-chloro-N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl] -1,1 '-biphenyl-4- sulfonamide,
N-[4-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3'-nitro-l, -biphenyl-4- sulfonamide,
3-chloro-2-methyl-N-[4-(2-
{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3-yl]benzenesulfonamide, N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]-l-methyl-
1 H-imidazole-4-sulfonamide,
3-chloro-N-{4-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
4,5-dichloro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}thiophene-2- sulfonamide,
N- {4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl} -4- phenoxybenzenesulfonamide,
3-fluoro-N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}benzenesulfonamide,
N-{4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}-5-pyridin-2-ylthiophene-2- sulfonamide,
N- {2-chloro-4-[( {4-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl} amino)sulfonyl]phenyl} acetamide, ethyl (3 - { [(3-chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)acetate,
(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetic acid,
2-(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} thien-2-yl)-N- methylacetamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N-ethylacetamide,
2,5-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide, isopropyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate,
3 -chloro-N- [2-(2-hydroxyethyl)thien-3 -yl] -2-methylbenzenesulfonamide,
3-chloro-N-[2-(2-ethoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(3- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)-N,N- diethylacetamide, methyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate,
3-chloro-N-[2-(2-isopropoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[2-(2-methoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide,
2-(3- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)ethyl methanesulfonate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetamide,
3-chloro-N-{2-[2-(2-fluoroethoxy)ethyl]thien-3-yl}-2- methylbenzenesulfonamide, 3-chloro-2-methyl-N-{2-[2-(2,2,2-trifluoroethoxy)ethyl]thien-3- yl } benzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl acetate,
3-chloro-2-methyl-N-[2-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
N-[2-(2-bromoethyl)thien-3-yl]-3-chloro-2-methylbenzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl moφholine-4- carboxylate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl diethylcarbamate,
2-(3 - { [(3 -chloro -2-methylphenyl)sulfonyl] amino } thien-2-yl)ethyl propionate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl 2- methylpropano ate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl 2-furoate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl benzoate,
2-(3 - { [(3-chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)-N-methoxy-N- methylacetamide,
3-chloro-N-{2-[2-(diethylamino)ethyl]tlιien-3-yl}-2-methylbenzenesulfonamide,
2-(3- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)ethyl ethylcarbamate,
N- [2-(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } thien-2-yl)ethyl] -N- ethylacetamide,
3-chloro-2-methyl-N-[2-(2-oxopentyl)thien-3-yl]benzenesulfonamide,
N- {2-[2-(l , 1 -dioxidothiomoφholin-4-yl)-2-oxoethyl]thien-3-yl} -4- propylbenzenesulfonamide,
2,4,6-trichloro-N-[2-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
2,4-dichloro-N-[2-(2-moφholin-4-ylethyl)thien-3-yl]benzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
2,4-dichloro-6-methyl-N-[2-(2-moφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-moφholin-4-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yfjbenzenesulfonamide,
2,4,6-trichloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l, -biphenyl-4-sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-propylbenzenesulfonamide,
N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-l,r-biphenyl-4-sulfonamide,
N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3-yl]-4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-oxo-2-piperidin- 1 -ylethyl)thien-3-yl]- 1 , r-biphenyl-4-sulfonamide,
N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
N-(2-phenylthien-3-yl)-4-propylbenzenesulfonamide, ethyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)(oxo)acetate,
3 -chloro-2-methyl-N-(2-phenylthien-3 -yl)benzenesulfonamide,
3-chloro-N-[2-(4-fluoro-3-methylphenyl)thien-3-yl]-2- methylbenzenesulfonamide,
2,4,6-trichloro-N-(2-phenylthien-3-yl)benzenesulfonamide,
N-(2-phenylthien-3-yl)-l , r-biphenyl-4-sulfonamide,
2,4-dichloro-6-methyl-N-(2-phenylthien-3-yl)benzenesulfonamide,
2- {3-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(3 - { [(4-propylphenyl)sulfonyl] amino} thien-2-yl) acetamide,
2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2-yl)-N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2- yl)acetamide, 2,4,6-trichloro-N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
2- {3-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N-isopropyl-N- methylacetamide,
2- {3 -[(1 , 1 '-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N,N-diethylacetamide,
N,N-diethyl-2-(3-{[(4-propylphenyl)sulfonyl]amino}thien-2-yl)acetamide,
2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diethylacetamide,
N,N-diethyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2-yl)acetamide,
2- {3-[(l ,r-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N,N-diisopropylacetamide,
N,N-diisopropyl-2-(3 - { [(4-propylphenyT)sulfonyTJ amino } thien-2-yl)acetamide,
2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diisopropylacetamide,
N,N-diisopropyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2- yl)acetamide,
N- [4-(3 - { [(4-propylphenyl)sulfonyl] amino } thien-2-yl)phenyl] acetamide,
4-propyl-N-(2-pyridin-3-ylthien-3-yl)benzenesulfonamide,
N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
N-[2-(2-chlorophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
3-chloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3-chloro-N-(5'-chloro-2,2'-bithien-3-yl)-2-methylbenzenesulfonamide,
3-chloro-N-[2-(2-chlorophenyl)thien-3-yl]-2-methylbenzenesulfonamide,
N-[4-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide,
2,4,6-trichloro-N-(2-pyridin-3-ylthien-3-yl)benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]benzenesulfonamide,
2,4,6-trichloro-N-(5,-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
2,4,6-trichloro-N-[2-(2-chlorophenyl)thien-3-yl]benzenesulfonamide,
N-(4- {3-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]thien-2-yl}phenyl)acetamide3
N-(2-pyridin-3-ylthien-3 -yl)- 1 , 1 '-biphenyl-4-sulfonamide,
N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-l,l'-biphenyl-4-sulfonamide,
N- [2-(2-chlorophenyl)thien-3 -yl] -1,1 '-biphenyl-4-sulfonamide, • N-[4-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2- yl)phenyl] acetamide,
2,4-dichloro-6-methyl-N-(2-pyridin-3-ylthien-3-yl)benzenesulfonamide,
2,4-dichloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
2,4-dichloro-N-(5'-chloro-2,2'-bithien-3-yl)-6-methylbenzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- dipropylacetamide,
3-chloro-2-methyl-N-[2-(2-oxo-2-piperazin-l-ylethyl)thien-3- yl]benzenesulfonamide,
2,4-dichloro-N-[2-(2,5-dimethyl-3-furyl)thien-3-yl]-6- methylbenzenesulfonamide,
N-(3'-chloro-2,2'-bithien-3-yl)-4-propylbenzenesulfonamide,
3 -chloro-N-(3 '-chloro-2,2'-bithien-3 -yl)-2-methylbenzenesulfonamide, • 2,4,6-trichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
2,4-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)-6-methylbenzenesulfonamide,
2,4-dichloro-N-[2-(2-chlorophenyl)thien-3-yl]-6-methylbenzenesulfonamide,
4-bromo-2-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide, • N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide,
2-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-
(trifluoromethoxy)benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-phenoxybenzenesulfonamide, • 4-chloro-2,6-dimethyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2,4-dichloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide, tert-butyl 4-[(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2- yl)acetyl]piperazine- 1 -carboxylate,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- dimethylacetamide, 3 -chloro-2-methyl-N- {2- [2-(pyridin-3 -yloxy) ethyl] thien-3 - yl}benzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N-isopropyl-N- methylacetamide,
2-(3 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} thien-2-yl)-N-ethyl-N- methylacetamide,
3-chloro-2-methyl-N-[2-(2-oxo-2-thiomoφholin-4-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)-N,N- diisopropylacetamide,
3 -chloro-2-methyl-N-[2-(2-oxo-2-pyrrolidin- 1 -ylethyl)thien-3 - yl]benzenesulfonamide,
3-chloro-2-methyl-N-[2-(2-oxo-2-piperidin-l-ylethyl)thien-3- yl]benzenesulfonamide,
3-chloro-2-methyl-N-[2-(moφholin-4-ylmethyl)thien-3-yl]benzenesulfonamide,
3-chloro-N-{2-[2-(lH-imidazol-l-yl)ethyl]thien-a-yl}-2- methylbenzenesulfonamide,
2,4,5-trichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
2,3,4-trichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
2,3,4-trichloro-N-[2-(2-chlorophenyl)thien-3-yl]benzenesulfonamide,
N-[4-(3-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}thien-2- yl)phenyl] acetamide,
4-bromo-N-(3'-chloro-2,2,-bitl ien-3-yl)-2,5-difluorobenzenesulfonamide,
4,5-dichloro-N-[2-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide,
N-[4-(3-{[(2,4,5-trichlorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide,
4-bromo-5-chloro-N-(3'-chloro-2,2'-bithien-3-yl)thiophene-2-sulfonamide,
3-bromo-5-chloro-N-[2-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide,
N-[4-(3-{[(2,6-dichlorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide,
2,6-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide,
N- [2-(3 - { [(3-chloro-2-methylρhenyl)sulfonyl] amino } thien-2-yl)ethyl] acetamide, 3-chloro-2-methyl-N-(2-{2-[(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
3-chloro-2-methyl-N-{2-[2-(2-oxopyrrolidin-l-yl)ethyl]thien-3- yl}benzenesulfonamide,
2,3 ,4-trichloro-N- {2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3 - yl}benzenesulfonamide,
N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-4-propylbenzenesulfonamide,
4-bromo-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3-yl}-2,5- difluorobenzenesulfonamide,
4,5-dichloro-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]thiophene-2- sulfonamide,
4-bromo-5-chloro-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl}thiophene-2-sulfonamide,
2,4-dichloro-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-6- methylbenzenesulfonamide,
4-bromo-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-2- methylbenzenesulfonamide,
3-chloro-2-methyl-N-(2-{2-[methyl(methylsulfonyl)amino]ethyl}thien-3- yl)benzenesulfonamide,
N-[2-(3-{[(3-chloro-2-methylρhenyl)sulfonyl]amino}thien-2-yl)ethyl]-N- methylcyclopropanecarboxamide,
3-chloro-2-methyl-N- {2-[2-(4-methyl-2-oxopiperazin- 1 -yl)ethyl]thien-3- yl}benzenesulfonamide,
3-chloro-2-methyl-N-[2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3- yl]benzenesulfonamide,
N-[4-(3-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}thien-2- yl)ρhenyl] acetamide,
2,4-dichloro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
2,4-dichloro-6-methyl-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide, 2,4,6-trichloro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl } benzenesulfonamide,
4-(2-furyl)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]benzenesulfonamide,
5'-fluoro-2,-methoxy-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r- biphenyl-4-sulfonamide,
4-(5-methylthien-2-yl)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
3'-acetyl-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,l'-biphenyl-4- sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4'-(trifluoromethoxy)-l,r- biphenyl-4-sulfonamide,
3',4'-dichloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-l,r-biρhenyl-4- sulfonamide,
4-(l,3-benzodioxol-5-yl)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
4-(5-chlorothien-2-yi)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-pyridin-4- ylbenzenesulfonamide,
N-[4'-({[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]amino}sulfonyl)-l,r- biphenyl-3 -yl] acetamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-3-ylbenzenesulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-2-ylbenzenesulfonamide,
4'-(methylthio)-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3 -yl] -1,1 '-biphenyl-4- sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3,,5'-bis(trifluoromethyl)-l,r- biphenyl-4-sulfonamide,
4'-chloro-N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]- 1 , 1 '-biphenyl-4- sulfonamide,
N-[2-(2-moφholin-4-yl-2-oxoethyl)thien-3-yl]-3 '-nitro-1 , 1 '-biphenyl-4- sulfonamide,
3-chloro-2-methyl-N-[2-(2-
{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)thien-3-yl]benzenesulfonamide, N-[2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl]-l-methyl- lH-imidazole-4-sulfonamide,
3-chloro-N-{2-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]thien-3-yl}-2- methylbenzenesulfonamide,
4,5-dichloro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}thiophene-2- sulfonamide,
N- {2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl} -4- phenoxyb enzenesulfonamide,
3-fluoro-N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}benzenesulfonamide,
N-{2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3-yl}-5-pyridin-2-ylthiophene-2- sulfonamide,
N-{2-chloro-4-[({2-[2-(3-oxomoφholin-4-yl)ethyl]thien-3- yl} amino)sulfonyl]phenyl} acetamide, methyl (3-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate, methyl (3-{[(3-cyanophenyl)sulfonyl]amino}thien-2-yl)acetate, methyl (3-{[(4-butoxyphenyl)sulfonyl]amino}thien-2-yl)acetate, methyl (3 - { [(2-methylsulfanylpyrimidin-4-ylthiophene)sulfonyl] amino } thien-2- yl)acetate, methyl (3 - { [( 1 -methylimidazol-4-yl) sulfonyl] amino } thien-2-yl)acetate, and methyl (3- {[(4-methylphenyl)sulfonyl]amino}thien-2-yl)acetate.
4. The method according to any one of claims 1 to 3 for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
5. The method according to claim 4 wherein the medical condition involving delayed or impaired wound healing is diabetes.
6. The method according to claim 4 wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
7. The method according to any one of claims 1 to 3 for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
8. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for promoting wound healing, said compound being an inhibitor of 11-β- hydroxysteroid dehydrogenase type 1.
9. The use according to claim 8 in the manufacture of a medicament for the treatment of prophylaxis of a medical condition involving delayed or impaired wound healing.
10. The use according to claim 9 wherein the medical condition involving delayed or impaired wound healing is diabetes.
11. The use according to claim 9 wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
12. The use according to claim 8 in the manufacture of a medicament for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
PCT/SE2004/000994 2003-06-25 2004-06-21 New use vii WO2004112779A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0301888A SE0301888D0 (en) 2003-06-25 2003-06-25 New use VII
SE0301888-4 2003-06-25

Publications (1)

Publication Number Publication Date
WO2004112779A1 true WO2004112779A1 (en) 2004-12-29

Family

ID=27656623

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2004/000994 WO2004112779A1 (en) 2003-06-25 2004-06-21 New use vii

Country Status (2)

Country Link
SE (1) SE0301888D0 (en)
WO (1) WO2004112779A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007025892A1 (en) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag 11-beta-hydroxysteroid dehydrogenase-1-inhibitor-diabetes-type 2-1
US7253196B2 (en) 2004-05-24 2007-08-07 Amgen, Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
DE102007005045A1 (en) 2007-01-26 2008-08-07 Sanofi-Aventis New phenothiazine derivative for use in preparing medicine for blood sugar lowering and for treatment of diabetes, nicotine dependence, alcohol dependence, central nervous system disorders, schizophrenia, and Alzheimer's disease
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010007794A1 (en) 2008-07-18 2010-01-21 興和株式会社 Novel spiro compound, and pharmaceutical preparation comprising the same
WO2010023931A1 (en) 2008-08-29 2010-03-04 興和株式会社 1-adamantylazetidin-2-one derivative and pharmaceutical preparation comprising same
WO2010050191A1 (en) 2008-10-29 2010-05-06 興和株式会社 1,2-diazetidin-3-one derivative and pharmaceutical agent comprising same
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8357711B2 (en) 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US8541592B2 (en) 2005-11-22 2013-09-24 Amgen Inc. Inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US8802660B2 (en) * 2007-03-12 2014-08-12 New York University De novo synthesis of glucocorticoids in the epidermis and its uses and applications
WO2017025988A1 (en) * 2015-08-11 2017-02-16 Connexios Life Sciences Pvt. Ltd Method of wound healing
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1240545A (en) * 1967-07-17 1971-07-28 Research Corp Silver-containing therapeutic agents
WO1996031492A1 (en) * 1995-04-04 1996-10-10 Texas Biotechnology Corporation Thienyl-, furyl-, pyrrolyl- and biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin
WO1998016520A1 (en) * 1996-10-16 1998-04-23 American Cyanamid Company The preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
WO2003044009A1 (en) * 2001-11-22 2003-05-30 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1240545A (en) * 1967-07-17 1971-07-28 Research Corp Silver-containing therapeutic agents
WO1996031492A1 (en) * 1995-04-04 1996-10-10 Texas Biotechnology Corporation Thienyl-, furyl-, pyrrolyl- and biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin
WO1998016520A1 (en) * 1996-10-16 1998-04-23 American Cyanamid Company The preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
WO2003044009A1 (en) * 2001-11-22 2003-05-30 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STOZOWSKA W. ET AL.: "Urinary silver and sulfathiazole levels in thermally injured guinea pigs during treatment with silver sulfathiazole cream", S.T.P. PHARMA SCIENCES, vol. 5, no. 6, 1995, pages 452 - 455, XP002981457 *

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7253196B2 (en) 2004-05-24 2007-08-07 Amgen, Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7807700B2 (en) 2004-05-24 2010-10-05 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
WO2007025892A1 (en) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag 11-beta-hydroxysteroid dehydrogenase-1-inhibitor-diabetes-type 2-1
US8541592B2 (en) 2005-11-22 2013-09-24 Amgen Inc. Inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
DE102007005045A1 (en) 2007-01-26 2008-08-07 Sanofi-Aventis New phenothiazine derivative for use in preparing medicine for blood sugar lowering and for treatment of diabetes, nicotine dependence, alcohol dependence, central nervous system disorders, schizophrenia, and Alzheimer's disease
US8802660B2 (en) * 2007-03-12 2014-08-12 New York University De novo synthesis of glucocorticoids in the epidermis and its uses and applications
US8357711B2 (en) 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
US8741934B2 (en) 2007-03-23 2014-06-03 Pfizer Limited Inhibitors of ion channels
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010007794A1 (en) 2008-07-18 2010-01-21 興和株式会社 Novel spiro compound, and pharmaceutical preparation comprising the same
US8236789B2 (en) 2008-08-29 2012-08-07 Kowa Company, Ltd. 1-adamantyl azetidin-2-one derivatives and drugs containing same
WO2010023931A1 (en) 2008-08-29 2010-03-04 興和株式会社 1-adamantylazetidin-2-one derivative and pharmaceutical preparation comprising same
WO2010050191A1 (en) 2008-10-29 2010-05-06 興和株式会社 1,2-diazetidin-3-one derivative and pharmaceutical agent comprising same
US8252781B2 (en) 2008-10-29 2012-08-28 Kowa Company, Ltd. 1,2-diazetidin-3-one derivatives and drugs containing same
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2017025988A1 (en) * 2015-08-11 2017-02-16 Connexios Life Sciences Pvt. Ltd Method of wound healing
WO2017025989A1 (en) * 2015-08-11 2017-02-16 Connexios Life Sciences Pvt. Ltd. Method of wound healing
JP2018522917A (en) * 2015-08-11 2018-08-16 コネクシャス ライフ サイエンシス ピーヴィティー リミテッドＣｏｎｎｅｘｉｏｓ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｐｖｔ． Ｌｔｄ． How to heal wounds
US10328063B2 (en) 2015-08-11 2019-06-25 Connexios Life Sciences Pvt. Ltd Method of wound healing
AU2016305746B2 (en) * 2015-08-11 2021-10-07 Connexios Life Sciences Pvt. Ltd Method of wound healing
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives
WO2017182464A1 (en) 2016-04-19 2017-10-26 Cidqo 2012, S.L. New aza- tetracyclo derivatives

Also Published As

Publication number Publication date
SE0301888D0 (en) 2003-06-25

Similar Documents

Publication Publication Date Title
WO2004112779A1 (en) New use vii
WO2004113310A1 (en) Use of an inhibitor of 11-b-hydroxysteroid dehydrogenase type 1 compounds for promoting wound healing
WO2004112782A1 (en) New use v
EP1638553A1 (en) New use i
EP1438045B1 (en) Use of indole and indoline derivatives in the treatment of obesity or for the reduction of food intake
US6372741B1 (en) Use of CSAID™ compounds as inhibitors of angiogenesis
CA2466490A1 (en) Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
WO2004103980A1 (en) Inhibitors of 11-beta-hydroxy steroid dehydrogenase type i
JP2003534338A (en) Inhibitors of 11-β-hydroxysteroid dehydrogenase type 1
JP2001501957A (en) Aminothiophene carboxamide
JP2005504101A (en) Glycogen synthase kinase-3 (GSK-3) inhibitor for treating glaucoma
IL33918A (en) Substituted n-benzylimidazoles,their production and pharmaceutical compositions containing them
CA2536435A1 (en) Drug containing chymase inhibitor as the active ingredient
NL8000333A (en) IMIDA SOLE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH DERIVATIVES AND METHOD FOR PREPARING THESE DERIVATIVES.
JP2010248205A (en) Benzazole derivative for treating scleroderma
US6177427B1 (en) Treatment of glaucoma and ocular hypertension
EP1666469A1 (en) Plasminogen activator inhibitor-1 inhibitor
WO2004112783A1 (en) New use iv
US7173030B2 (en) Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
WO2004112781A1 (en) New use ii
US4544667A (en) 2-Sulfamoylbenzo[b]furan derivatives for the treatment of elevated intraocular pressure
WO2004112785A1 (en) New use iii
US5068239A (en) Tetrazoleacetic acid derivatives and use for aldose reductase inhibitory activity
ZA200401305B (en) Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1.
WO2005039550A2 (en) Novel medical uses of compounds showing cb1-antagonistic activity and combination treatment involving said compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase