WO2004112784A1 - New use i - Google Patents

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Publication number
WO2004112784A1
WO2004112784A1 PCT/SE2004/000996 SE2004000996W WO2004112784A1 WO 2004112784 A1 WO2004112784 A1 WO 2004112784A1 SE 2004000996 W SE2004000996 W SE 2004000996W WO 2004112784 A1 WO2004112784 A1 WO 2004112784A1
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WO
WIPO (PCT)
Prior art keywords
thiazol
ethyl
amino
sulfonyl
chloro
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Application number
PCT/SE2004/000996
Other languages
French (fr)
Inventor
Cecilia Nilsson
Catrine Dreifeldt
Original Assignee
Biovitrum Ab
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Publication date
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Priority to EP04749034A priority Critical patent/EP1638553A1/en
Priority to CA002529406A priority patent/CA2529406A1/en
Priority to JP2006517048A priority patent/JP2007521264A/en
Priority to AU2004249099A priority patent/AU2004249099A1/en
Publication of WO2004112784A1 publication Critical patent/WO2004112784A1/en
Priority to NO20060416A priority patent/NO20060416L/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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 Cushing'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).
  • 1 l ⁇ -HSD catalyzes the conversion of cortisol to cortisone, and vice versa.
  • the parallel function of 1 l ⁇ -HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5).
  • Two isoenzymes of 11 ⁇ -HSD, 1 l ⁇ - HSD 1 and 1 l ⁇ -HSD2 have been characterized, and differ from each other in function and tissue distribution (6).
  • 1 l ⁇ -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 ⁇ -HSD 1 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, angio genesis, 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 01/90090 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 1 l ⁇ -HSDl, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders.
  • Other 1 l ⁇ -HSDl inhibitors are disclosed in e.g. WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/044009; 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 1 l ⁇ -HSDl inhibitors for wound healing.
  • 1 l ⁇ -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 1 l ⁇ -hydroxysteroid dehydrogenase type 1, wherein the inhibitor of 1 l ⁇ - hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
  • T is an aryl ring or heteroaryl ring or aryl-C -alkenyl 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 can further be optionally substituted in one or more positions independently of each other by C ⁇ - 6 -acyl, C ⁇ - 6 -alkylthio, cyano,
  • R 1 is hydrogen or C ⁇ - 6 -alkyl
  • X is CH 2 or CO;
  • Y is CH 2 , CO or a single bond;
  • B is hydrogen or C ⁇ - 6 -alkyl
  • R 2 is selected from C ⁇ - 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- mo holinolinylmethylene, C ⁇ - 6 -alkoxycarbonyl, and 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, Ci- ⁇ -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl,
  • R 3 and R 4 are each independently selected from hydrogen, C ⁇ - 6 - alkyl or form together morpholinyl; R 5 O, wherein R 5 is hydrogen, optionally halogenated C ⁇ - 6 -alkyl, aryl, heteroaryl, C ⁇ - 6 - acyl, C ⁇ - 6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
  • T is selected from 5 -chloro- 1,3 -dimethyl- lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; (E)-2-phenylethenyl; 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, benzene
  • R 1 is hydrogen or methyl
  • X is CH 2 or CO
  • Y is CH 2 , CO or a single bond
  • B is hydrogen or methyl
  • 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;
  • R 3 and R 4 are each independently selected from acetyl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexylmethyl, 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, propyl, trifluoromethylsulfonyl; or
  • NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-l- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, mo ⁇ holinyl, (lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomo ⁇ holinyl, 3-oxo-l,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl;
  • R 3 and R 4 are each independently selected from ethyl, hydrogen or form together mo ⁇ holinyl;
  • R 5 is selected from acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, propionyl, 3-pyridinyl, and 2,2,2-trifluoroethyl.
  • 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
  • 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.
  • 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, 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, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
  • C ⁇ _ 6 -alkyl all subgroups thereof are contemplated such as C ⁇ - 5 -alkyl, C ⁇ - 4 -alkyl, C 2 . 6 -alkyl, C 2 - 5 -alkyl, C 2 . 4 -alkyl, C . 3 -alkyl, C 3 . 6 -alkyl, C 4 . 5 -al yl, 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 all subgroups thereof are contemplated such as C ⁇ - 5 -alkoxy, C ⁇ - 4 -alkoxy, C 2 . 6 -alkoxy, C 2 - 5 - alkoxy, C 2 .
  • 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 For parts of the range "C ⁇ - 6 -acyl" all subgroups thereof are contemplated such as C ⁇ - 5 -acyl, C ⁇ - 4 -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 2 . 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.
  • mono- or di-substituted is meant in the present description that the functionalities in question may be substituted with independently H, C ⁇ - 6 -acyl, C ⁇ _ 6 - alkenyl, C ⁇ - 6 -(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, mo ⁇ holine and thiomo ⁇ holine, which heterocyclic rings optionally may be substituted with C ⁇ - 6 -alkyl.
  • optionally mono- or disubstituted is meant in the present description that the functionalities in question may also be substituted with independently hydrogen.
  • stable referes 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 inhibition, 11 - ⁇ -HSD 1 -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 01/90090.
  • 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 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 l ⁇ - HSDl inhibitor BVT.2733 (3-Chloro-2-methyl-N- ⁇ 4-[2-oxo-2-(l-piperazinyl)ethyl]- l,3-thiazol-2-yl ⁇ benzenesulfonamide; the trifluoroacetate of this compound is disclosed as Example 172A in WO 01/90090), or vehicle started 4-6 days later and continued for 3.5 days.
  • 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.

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-b-hydroxysteroid dehydrogenase type 1, wherein the said 11b-HSD1 inhibitor has the formula (I) wherein T, B, X, Y, R1 and R2 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 I
RELATED APPLICATIONS
This application claims priority to Swedish application number 0301882-7, 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 Cushing'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).
In humans, the 1 lβ-HSD catalyzes the conversion of cortisol to cortisone, and vice versa. The parallel function of 1 lβ-HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5). Two isoenzymes of 11 β-HSD, 1 lβ- HSD 1 and 1 lβ-HSD2, have been characterized, and differ from each other in function and tissue distribution (6). Like GR, 1 lβ-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-HSD 1 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, angio genesis, 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 01/90090 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 1 lβ-HSDl, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders. Other 1 lβ-HSDl inhibitors are disclosed in e.g. WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/044009; 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 1 lβ-HSDl inhibitors for wound healing. However, the use of the 1 lβ-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 11 β-HSD 1 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 1 lβ-hydroxysteroid dehydrogenase type 1, wherein the inhibitor of 1 lβ- hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
Figure imgf000004_0001
wherein
T is an aryl ring or heteroaryl ring or aryl-C -alkenyl 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 can further be 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)-! ,3-thiazol-2-yl]amino} carbonyl);
R1 is hydrogen or Cι-6-alkyl;
X is CH2 or CO; Y is CH2, CO or a single bond;
B is hydrogen or Cι-6-alkyl;
R2 is selected from Cι-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- mo holinolinylmethylene, Cι-6-alkoxycarbonyl, and 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, Ci-ό-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl and Cι-6-alkyl substituted with one or more aryl or heteroaryl, or NR3R4 represent together heterocyclic systems which can be imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(lH)isoquinolinyl), (lS,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems can be optionally substituted by Cι-6-alkyl, Cι-6-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR3R , wherein R3 and R4 are each independently selected from hydrogen, Cι-6- alkyl or form together morpholinyl; R5O, wherein R5 is hydrogen, optionally halogenated Cι-6-alkyl, aryl, heteroaryl, Cι-6- acyl, Cι-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; and 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- 1,3 -dimethyl- lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; (E)-2-phenylethenyl; 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, benzeneamino, 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-l-piperazinyl, 4-methyl-l-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, and trifluoromethyl;
R1 is hydrogen or methyl;
X is CH2 or CO;
Y is CH2, CO or a single bond;
B is hydrogen or methyl;
R2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl;
NR3R4, wherein R3 and R4 are each independently selected from acetyl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexylmethyl, 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, propyl, trifluoromethylsulfonyl; or
NR3R4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-l- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 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, thiomorpholinyl;
1 , 1 -dioxido-thiomorpholinyl;
OCONR3R4, wherein R3 and R4 are each independently selected from ethyl, hydrogen or form together moφholinyl;
R5O, wherein R5 is selected from acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, propionyl, 3-pyridinyl, and 2,2,2-trifluoroethyl.
The following compounds are especially preferred:
ethyl (2-{[(2,4-dichloro-5-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-(2-[[(4-chlorophenyl)sulfonyl]amino]-l,3-thiazole-4-yl)acetate, ethyl 2-(2-{[(4-chloro-2,5-dimethylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, ethyl 2-(2-{[(2,4-difluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-(2-(((4-methylphenyl)sulfonyl)amino)- 1 ,3 -thiazol-4-yl)acetate, ethyl 2-(2-{[(2,5-dichloro-3-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-chlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-(2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,3-thiazol-4-yl)acetate, ethyl 2- {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl} acetate, ethyl 2-(2-{[(3-bromophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(4-nitrophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2- { [(4-methoxyphenyl)sulfonyl] mino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2-{[(3-nitrophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(3-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(3-chlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(4-fluorophenyl)sulfonyl] amino} - 1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(3-fluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[(phenylsulfonyl)amino]-l,3-thiazol-4-yl} acetate, ethyl (2-{[(4-isopropylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-({[3-({[4-(2-ethoxy-2-oxoethyl)-l,3-thiazol-2- yl]amino}carbonyl)phenyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate, ethyl [2-({[4-({[4-(2-ethoxy-2-oxoethyl)-l,3-thiazol-2- yl]amino}carbonyl)phenyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate, ethyl (2-{[(2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [2-(trifluoromethyl)phenyl] sulfonyl} amino)- 1 ,3-thiazol-4-yl] acetate, ethyl [2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate, ethyl [2-( { [4-(trifluoromethyl)phenyl] sulfonyl} amino)- 1 ,3 -thiazol-4-yl] acetate, ethyl 2-(2-{[(4-bromophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-nitrophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2,4-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(3 , 5 -dichlorophenyl)sulfonyl] amino } - 1 , 3 -thiazol-4-yl)acetate, ethyl [2-({[4-(3-chloro-2-cyanophenoxy)phenyl]sulfonyl}amino)-l,3-thiazol-4- yl] acetate, , ethyl (2- { [(3 ,4-dichlorophenyl)sulfonyl] amino } - 1 , 3 -thiazol-4-yl)acetate, ethyl (2-{[(4-butoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( {[4-(acetylamino)phenyl]sulfonyl} amino)- 1 ,3-thiazol-4-yl]acetate, ethyl {2-[(8-quinolinylsulfonyl)amino]- 1 ,3-thiazol-4-yl} acetate, ethyl (2- {[(3,4-dimethoxyphenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(4-iodophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(3 -chloro-4-methylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl) acetate, ethyl [2-({[5-(dimethylamino)-l-naphthyl]sulfonyl}amino)-l,3-thiazol-4- yl] acetate, ethyl (2-{[(l-methyl-lH-imidazol-4-yl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(5-bromo-2-methoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2,5-dimethoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[(2-naphthylsulfonyl)amino]-l,3-thiazol-4-yl}acetate, ethyl {2-[(mesitylsulfonyl)amino]- 1 ,3-thiazol-4-yl} acetate, ethyl (2-{[(3-bromo-5-chloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[({5-[(benzoylamino)methyl]-2-thienyl}sulfonyl)amino]-l,3-thiazol-4- yl} acetate, ethyl {2-[({5-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]-2- thienyl}sulfonyl)amino]-l,3-thiazol-4-yl}acetate, 5 ethyl (2-{[(4-cyanophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[({5-[2-(methylsulfanyl)-4-pyrimidinyl]-2-thienyl}sulfonyl)amino]-l,3- thiazol-4-yl} acetate, ethyl (2-{[(3-cyanophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(2,4,5-trichlorophenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, l o ethyl [2-( { [(E)-2-phenylethenyl] sulfonyl} amino)- 1 ,3-thiazol-4-yl] acetate, ethyl (2- {[(2,3,4-trichlorophenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl]acetate, ethyl [2-( { [4-(trifluoromethoxy)phenyl] sulfonyl } amino)- 1 ,3 -thiazol-4-yl] acetate, ethyl (2-{[(2,3-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, 15 ethyl (2-{[(2-bromophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4,5-dichloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [4-(phenylsulfonyl)-2-thienyl] sulfonyl} amino)- 1 ,3-thiazol-4-yl] acetate, ethyl [2-( { [5-(phenylsulfonyl)-2-thienyl] sulfonyl} amino)- 1 ,3-thiazol-4-yl] acetate, ethyl (2- { [(2,6-dichlorophenyl)sulfonyl] amino } - 1 , 3 -thiazol-4-yl) acetate, 20 ethyl (2- {[(2-cyanophenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2-( { [4-(acetylamino)-3 -chlorophenyl] sulfonyl } amino)- 1 ,3 -thiazol-4- yl] acetate, ethyl (2-{[(5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, 25 ethyl (2-{[(3-methoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2- {2-[(l -naphthylsulfonyl)amino]- 1 ,3-thiazol-4-yl} acetate, ethyl (2-{[(2,5-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-methanesulfonylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, 30 ethyl (2-{[(2-methanesulfonylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(4-bromo-2-fluorophenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)acetate, ethyl (2- { [(2-methyl-4-trifluoromethoxyphenyl)sulfonyl] amino} - 1 ,3-thiazol-4- yl)acetate, ethyl (2- { [(2,3 ,4-trifluorophenyl)sulfonyl] amino } - 1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(4-chloro-2,3,l-benzoxadiazolyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, ethyl (2- { [(2,4,6-trifluorophenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)acetate, ethyl (2- { [(5-carboxy-4-chloro-2-fluorophenyl)sulfonyl] amino } - 1 ,3-thiazol-4-
. yl)acetate, ethyl (2- { [(2-(5-chlorothienyl))sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2- { [(2-chloro-4-fluorophenyl)sulfonyl] amino } - 1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(2-(5-(3-isoxazolo)thienyl))sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-phenoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-chloro-2,6-dimethylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-methyl-4-trifluoromethoxyphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, ethyl (2- { [(2,4-bis(trifluoromethyl)phenyl)sulfonyl] amino } - 1 ,3-thiazol-4- yl)acetate, ethyl 2- {2-[[(3-chloro-2-methylphenyl)sulfonyl](methyl)amino]-l ,3-thiazol-4- yl} acetate, ethyl oxo(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3-thiazol-4- yl)(oxo)acetate, ethyl oxo(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[([ 1 , 1 '-biphenyl] -4-ylsulfonyl)amino]- 1 ,3 -thiazol-4-yl} (oxo)acetate, ethyl (2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)(oxo)acetate,
2-(2- { [(4-methylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)acetic acid, 2-(2-{[(2,5-dichloro-3-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetic acid, (2-{[(2-chlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetic acid, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetic acid, isopropyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, phenyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, methyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, methyl {2-[([ 1 , 1 -biphenyl]-4-ylsulfonyl)amino] -5 -methyl- 1 ,3-thiazol-4- yl} acetate, methyl (2-{[(4-chlorophenyl)sulfonyl]amino}-5-methyl-l,3-thiazol-4-yl)acetate, methyl (2- {[(3-chloro-2-methylphenyl)sulfonyl]amino}-5-methyl-l ,3-thiazol-4- yl)acetate, methyl [2-({[4-(3-chloro-2-cyanophenoxy)phenyl]sulfonyl}amino)-5-methyl-l,3- thiazol-4-yl] acetate, methyl (5-methyl-2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, methyl (5-methyl-2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, methyl (2- {[(2,4-dichloro-6-methylphenyl)sulfonyl]amino} -5-methyl-l ,3 -thiazol-
4-yl)acetate, N-(2-methoxyethyl)-2-(2- {[(4-methylphenyl)sulfonyl]amino} - 1 ,3-thiazol-4- yl)acetamide, 2-(2-{[(2,5-dichloro-3-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- methylacetamide, N-(l ,3-benzodioxol-5-ylmethyl)-2- {2-[(l -naphthylsulfonyl)amino]- 1 ,3-thiazol-4- yl} acetamide, N-(2-furylmethyl)-2- {2-[(l -naphthylsulfonyl)amino]- 1 ,3-thiazol-4-yl} acetamide, 2-(2- { [(2,4-difluorophenyl)sulfonyl] amino} - 1 ,3-thiazol-4-yl)-N-ethylacetamide,
N-isopropyl-2- {2-[(l -naphthylsulfonyl)amino]- 1 ,3-thiazol-4-yl} acetamide, N-[2-(lH-indol-3-yl)ethyl]-2-{2-[(l-naphthylsulfonyl)amino]-l,3-thiazol-4- yl} acetamide, N-(cyclohexylmethyl)-2-{2-[(phenylsulfonyl)amino]-l,3-thiazol-4-yl} acetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- methylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- ethylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- phenylacetamide,
2-(2-{[(4-chloroρhenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-(2- furylmethyl)acetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- diethylacetamide, 2- {2-[([ 1 , 1 ,-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl} -N,N- diethylacetamide, N,N-diethyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetamide,
2-(2-{[(2,4-dichloro-6-methylρhenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- diethylacetamide, N,N-diethyl-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2-{2-[([l,r-biphenyl]-4-ylsulfonyl)amino]-l,3-thiazol-4-yl}-N,N- diisopropylacetamide, N,N-diisopropyl-2-(2- {[(4-propylphenyl)sulfonyl]amino} -1 ,3-thiazol-4- yl)acetamide, 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- diisopropylacetamide,
N,N-diisopropyl-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2-(2- {[(3-chloro-2-methylρhenyl)sulfonyl]amino} - 1 ,3-thiazol-4-yl)-N,N- diisopropylacetamide, 2-(2-{[(3-chloro-2-methylρhenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- dipropylacetamide, N-benzyl-2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- ethylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- dimethylacetamide,
3-chloro-N-{4-[2-(3,4-dihydro-2(lH)-isoquinolinyl)-2-oxoethyl]-l,3-thiazol-2- yl} -2-methylbenzenesulfonamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-methyl-N- phenylacetamide, 2-(2- {[(3-chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3-thiazol-4-yl)-N-isopropyl-
N-methylacetamide, 2- {2-[([l , 1 '-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl}-N-isopropyl-N- methylacetamide, N-ethyl-N-methyl-2-(2- { [(2,4,6-trichlorophenyl)sulfonyl] amino } - 1 ,3-thiazol-4- yl)acetamide, 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-ethyl-
N-methylacetamide, N-ethyl-N-methyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2- {2-[([ 1 , r-biphenyl]-4-ylsulfonyl)amino j-1 ,3-thiazol-4-yl} -N-ethyl-N- methylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-ethyl-N- methylacetamide,
3 -chloro-2-methyl-N- {4-[2-oxo-2-( 1 -pyrrolidinyl)ethyl]- 1 ,3 -thiazol-2- yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-oxo-2-(l-piρeridinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N- {4- [2-oxo-2-( 1 -piperidinyl)ethyl] - 1 ,3 -thiazol-2-yl } [ 1 , 1 '-biphenyl] -4-
, sulfonamide, N- {4-[2-oxo-2-(l-piperidinyl)ethyl]-l ,3-thiazol-2-yl} -4- propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-oxo-2-(l-piperidinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
2,4,6-trichloro-N- {4-[2-oxo-2-(l -ρiρeridinyl)ethyl]-l ,3-thiazol-2- yl}benzenesulfonamide, 3 -chloro-2-methyl-N- {4- [2-(4-moφholinyl)-2-oxoethyl] - 1 ,3-thiazol-2- yl}benzenesulfonamide, 2,4,6-trichloro-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N- {4- [2-(4-moφholinyl)-2-oxoethyl] -1,3 -thiazol-2-yl} [1,1 '-biphenyl] -4- sulfonamide,
N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4- propylbenzenesulfonamide, 2,4-dichloro-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-chloro-2,6-dimethyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 5 N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4- phenoxybenzenesulfonamide, 2-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4-
(trifluoromethoxy)benzenesulfonamide, N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2-yl} -2,4- l o bis(trifluoromethyl)benzenesulfonamide,
4-bromo-2-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-(2-furyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]-l ,3-thiazol-2- yl} benzenesulfonamide, 15 4-(5-fluoro-2-methoxyphenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-
2-yl} benzenesulfonamide, 4-(5-methyl-2-thienyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, 4-(3-acetylphenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- 20 yl} benzenesulfonamide,
4-(4-trifluoromethoxyphenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, 4-(3,4-dichlorophenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl} benzenesulfonamide, 5 4-(3,4-methylenedioxyphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-
2-yl}benzenesulfonamide, 4-(5-chloro-2-thienyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 4-(4-pyridyl)-N- {4- [2-(4-moφholinyl)-2-oxoethyl] - 1 ,3 -thiazol-2- 0 yl}benzenesulfonamide,
4-(3-acetylaminophenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, -(3-thienyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(2-thienyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(4-carboxyphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(4-methylsulfanylphenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, -(3,5-bis(trifluoromethyl)phenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3- thiazol-2-yl}benzenesulfonamide, -(4-chlorophenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, -(3-nitrophenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, -(2-benzofiιryl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(l-pyrrolidino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, -(4-methyl-l-piperidino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl} benzenesulfonamide, -(benzeneamino)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, -(benzylamino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, -(2-thienylmethylamino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl} benzenesulfonamide, -(4-moφholinyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(4-methyl- 1 -piperazinyl)-N- {4-[2-(4-moφlιolinyl)-2-oxoethylj- 1 ,3-thiazol-2- yl} benzenesulfonamide, -(3-pyridylmethylamino)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, 2,4-dichloro-6-methyl-N-{5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]-l,3- thiazol-2-yl}benzenesulfonamide, N- {5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]-l ,3-thiazol-2-yl} [1,1 '-biphenyl]-
4-sulfonamide, 5 2,4,6-trichloro-N- {5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-2-methyl-N-{5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-N-(4-{2-[(2R,6S)-2,6-dimethylmoφholinyl]-2-oxoethyl}-l,3-thiazol-2- l o yl)-2-methylbenzenesulfonamide,
3-chloro-2-methyl-N-(4-{2-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2- oxoethyl} - 1 ,3 -thiazol-2-yl)benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 15 N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2-yl}[l,l'-biphenyl]-4- sulfonamide, N- {4-[2-oxo-2-(4-thiomoφholinyl)ethyl]- 1 ,3-thiazol-2-yl} -4- propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2- 20 yl}benzenesulfonamide,
2,4,6-trichloro-N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N-{4-[2-(l,l-dioxido-4-thiomoφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4- propylbenzenesulfonamide, 25 tert-butyl 4-[(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetyl]-l-piperazinecarboxylate, 4-acetyl-(4-[(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetyl])- 1 -piperazine, 4-[(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetyl]-l- 30 piperazine trifluoroacetate,
3-chloro-2-methyl-N-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, 2-methyl-N- {4-[2-(4-methyl- 1 -ρiperazinyl)-2-oxoethyl]- 1 ,3-thiazol-2-yl} -4-
(trifluoromethoxy)benzenesulfonamide, 2,4-dichloro-6-methyl-N- {4-[2-(4-methyl-l -piperazinyl)-2-oxoethyl]-l ,3-thiazol-
2-yl}benzenesulfonamide, 2,4-dichloro-N-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-N-(4-{2-[(2R)-2,4-dimethylpiperazinyl]-2-oxoethyl}-l,3-thiazol-2-yl)-2- methylbenzenesulfonamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-methoxy- N-methylacetamide,
3-chloro-2-methyl-N-[4-(2-oxopentyl)-l,3-thiazol-2-yl]benzenesulfonamide, 4-chloro-N-[4-(2-hydroxyethyl)-l,3-thiazol-2-yl]benzenesulfonamide, 3-chloro-N-[4-(2-hydroxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-chloro-N-[4-(2-ethoxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-chloro-N-[4-(2-isopropoxyethyl)-l ,3-thiazol-2-yl]-2- methylbenzenesulfonamide, N- {4-[2-(benzyloxy)ethyl]- 1 ,3-thiazol-2-yl} -3-chloro-2- methylbenzenesulfonamide, 3-chloro-N-[4-(2-methoxyethyl)-l,3-thiazol-2-yl]-2- ethylbenzenesulfonamide, 3-chloro-N- {4-[2-(2-fluoroethoxy)ethyl]- 1 ,3-thiazol-2-yl} -2- methylbenzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(2,2,2-trifluoroethoxy)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(2-pyridinylsulfanyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(3-pyridinyloxy)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-clιloro-2-methyl-N- {4- [2-methylsalicylethyl] - 1 ,3 -thiazol-2- yl}benzenesulfonamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl methanesulfonate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl acetate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl propionate, 2-(2- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)ethyl 2- methylpropanoate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl 2- furoate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl benzoate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl 4- moφholinecarboxylate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl diethylcarbamate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl ethylcarbamate, N-[4-(2-azidoethyl)-l,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide,
N-[4-(2-aminoethyl)-l,3-thiazol-2-yl]-3-chloiO-2-methylbenzenesulfonamide hydrochloride, 4-chloro-N-{4-[2-(diethylamino)ethyl]-l,3-thiazol-2-yl}benzenesulfonamide hydrochloride, 3-chloro-N-{4-[2-(diethylamino)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide hydrochloride, 3-chloro-N- {4-[2-(l -imidazolyl)ethyl]- 1 ,3-thiazol-2-yl} -2- methylbenzenesulfonamide hydrochloride, 3-chloro-2-methyl-N-{4-[2-(4-methyl-l-piperazinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide dihydrochloride,
3-chloro-2-methyl-N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, 3-chloro-2-methyl-N-{4-[(4-moφholinyl)methyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, 2,4,6-trichloro-N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, 2,4-dichloro-N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2-yl}benzenesulfonamide hydrochloride, 2,4-dichloro-6-methyl-N- {4-[2-(4-moφholinyl)ethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide hydrochloride, N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-4-propylbenzenesulfonamide hydrochloride, 3-chloro-N-{4-[2-(ethylamino)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide, 3-chloro-N-(4-{2-[(2-hydroxyethyl)amino]ethyl}-l,3-thiazol-2-yl)-2- methylbenzenesulfonamide, N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl]-N- ethylacetamide,
3-chloro-2-methyl-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-N-{4-[2-(2-hydroxy-3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide, 2,4-dichloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4-dichloro-N- {4-[2-(3-oxo-4-moφholinyl)ethyl]-l ,3-thiazol-2-yl} -6- methylbenzenesulfonamide, N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-2,4,6- trichlorobenzenesulfonamide,
4,5-dichloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-2- thienylsulfonamide, N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-4- phenoxybenzenesulfonamide, 3-fluoro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-5-(2-pyridyl)-2- thienylsulfonamide, 4-acetylamino-3-chloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
N-{4-[(3-oxo-4-moφholinyl)methyl]-l,3-thiazol-2-yl}-3-chloro-2- methylbenzenesulfonamide, N-{4-[3-(3-oxo-4-moφholinyl)ρropyl]-l,3-thiazol-2-yl}-3-chloro-2- methylbenzenesulfonamide, N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl},N-methyl-3-chloro-2- methylbenzenesulfonamide, 3-chloro-2-methyl-N- {4-[2-(2-methyl-3-oxo-4-moφholinyl)ethyl]-l ,3-thiazol-2- yl } benzenesulfonamide, N-{4-[2-(acetylamino)ethyl]-l,3-thiazol-2-yl}-3-chloro-2-methyl- benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(4-(3-oxo-l,4-oxazepinyl))ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(l-pyrrolidonyl)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(l-(2-oxoimidazolinyl))ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(l-(2-oxooxazolinyl)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-N-{4-[2-(Η-(2-furylcarbonyl),N-2-hydroxyethylamino)ethyl]-l,3- thiazol-2-yl} -2-methylbenzenesulfonamide, hydrochloride, 3-chloro-2-methyl-N-{4-[2-(4-methyl-2-oxopiperazinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(methylsulfonylamino)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(N-methyl,N-methylsulfonamino)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(trifluoromethylsulfonylamino)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(TSf-methyl,N-trifluoromethylsulfonamino)ethyl]-l,3- thiazol-2-yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(4-(l-methylimidazolyl)sulfonylamino)ethyl]-l,3- thiazol-2-yl}benzenesulfonamide,
3-chloro-N-{4-[2-(N-(3-chloro-2-methylphenylsulfonyl),N-methylamino)ethyl]-
1 ,3 -thiazol-2-yl} -2-methylbenzenesulfonamide, N-[4-(2-bromoethyl)-l,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide, 3-chloro-N-[4-(2-chloroethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-chloro-2-methyl-N-{4-[(5-methyl-l,3,4-oxadiazol-2-yl)methyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-N- {4-[2-(ethoxycarbonyl)ethyl]- 1 ,3-thiazol-2-yl} -2- methylbenzenesulfonamide.
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 general 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. 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, 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.
Cχ_6-alkyl in the compound of formula (I) according to the present application, which may be straight or branched, is preferably Cχ_4-alkyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, 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 Cι-5-alkyl, Cι-4-alkyl, C2.6-alkyl, C2-5-alkyl, C2.4-alkyl, C .3-alkyl, C3.6-alkyl, C4. 5-al yl, etc.
Cχ_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. For parts of the range "Cι-6-alkoxy" all subgroups thereof are contemplated such as Cι-5-alkoxy, Cι-4-alkoxy, C2.6-alkoxy, C2-5- alkoxy, C2.4-alkoxy, C2_3-alkoxy, C3-6-alkoxy, C4.5-alkoxy, etc. Cχ_6-acyl, in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably Cχ_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-4-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 "C2.6-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 H, Cι-6-acyl, Cι_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, referes 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 inhibition, 11 -β-HSD 1 -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 01/90090.
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- HSDl inhibitor BVT.2733 (3-Chloro-2-methyl-N-{4-[2-oxo-2-(l-piperazinyl)ethyl]- l,3-thiazol-2-yl}benzenesulfonamide; the trifluoroacetate of this compound is 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 1 lβ-HSDl inhibitors (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 WiUebrand factor to determine revascularisation. (b)
Advantageous effects of 11 β-HSD 1 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 1 lβ-HSDl inhibitor. i
(c)
Effects on wound healing after treatment with 1 lβ-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.
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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 Immun 2002;16(l):74-84.
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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, collagenase, 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 imgf000029_0001
wherein
T is an aryl ring or heteroaryl ring or aryl-C2-alkenyl 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 can further be 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;
X is CH2 or CO;
Y is CH2, CO or a single bond;
B is hydrogen or Cι.6-alkyl; R2 is selected from Cι-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- moφholinolinylmethylene, Cι-6-alkoxycarbonyl, and 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, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-fiiranylmethyl, N- carbethoxypiperidyl and Cι-6-alkyl substituted with one or more aryl or heteroaryl, or NR3R4 represent together heterocyclic systems which can be imidazole, piperidine, pyrrolidine, piperazine, moφholine, oxazepine, oxazole, thiomoφholine, 1,1- dioxidothiomoφholine, 2-(3,4-dihydro-2(lH)isoquinolinyl), (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems can be optionally substituted by Cι-6-alkyl, Cι_6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR3R4, wherein R3 and R4 are each independently selected from hydrogen, Chalky! or form together morpholinyl;
R5O, wherein R5 is hydrogen, optionally halogenated Cι-6-alkyl, aryl, heteroaryl, Cι-6- acyl, Ci-e-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; and 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-l,3-dimethyl-lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)- 1-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; (E)-2-phenylethenyl; 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, benzeneamino, l,3-benzodioxol-5-yl, 2-benzofi-ryl, 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-l -piperazinyl, 4-methyl-l-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, and trifluoromethyl;
R is hydrogen or methyl;
X is CH2 or CO;
Y is CH2, CO or a single bond;
B is hydrogen or methyl;
R2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-moφholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl;
NR3R4, wherein R3 and R4 are each independently selected from acetyl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexylmethyl, ethyl, 2-frxrylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3- yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, propyl, trifluoromethylsulfonyl; 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-oxopiperazinyl, 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 moφholinyl; R5O, wherein R5 is selected from acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, propionyl, 3-pyridinyl, and 2,2,2-trifluoroethyl.
3. The method according to any one of claims 1 or 2, wherein the compound is selected from:
ethyl (2-{[(2,4-dichloro-5-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-(2-[[(4-chlorophenyl)sulfonyl]amino]-l,3-thiazole-4-yl)acetate, ethyl 2-(2-{[(4-chloro-2,5-dimethylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl) acetate, ethyl 2-(2-{[(2,4-difluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-(2-(((4-methylphenyl)sulfonyl)amino)-l,3-thiazol-4-yl)acetate, ethyl 2-(2- {[(2,5-dichloro-3-thienyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(2-chlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2- {2-[([ 1 , 1 '-biphenyl] -4-ylsulfonyl)amino]-l ,3τthiazol-4-yl} acetate, ethyl 2-(2- { [(3 -bromophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2-{[(4-nitrophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(4-methoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(3-nitrophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(3-methylphenyl)sulfonyl]amino}-l ,3-thiazol-4-yl)acetate, ethyl (2-{[(3-chlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(4-fluorophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2- { [(3 -fluorophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl {2- [(phenylsulfonyl)amino]- 1 ,3 -thiazol-4-yl} acetate, ethyl (2- { [(4-isopropylphenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl [2-({[3-({[4-(2-ethoxy-2-oxoethyl)-l,3-thiazol-2- yl] amino} carbonyl)phenyl] sulfonyl} amino)- 1 ,3 -thiazol-4-yl] acetate, ethyl [2-({[4-({[4-(2-ethoxy-2-oxoethyl)-l,3-thiazol-2- yl]amino}carbonyl)phenyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate, ethyl (2-{[(2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [2-(trifluoromethyl)phenyl] sulfonyl} amino)- 1 ,3-thiazol-4-yl] acetate, ethyl [2-( { [3-(trifluoromethyl)phenyl] sulfonyl} amino)- 1 ,3 -thiazol-4-yl] acetate, ethyl [2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate, ethyl 2-(2- { [(4-bromophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2- {[(2-nitrophenyl)sulfonyl] amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)acetate, ethyl (2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2,4-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(4-propylphenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(3,5-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [4-(3-chloro-2-cyanophenoxy)phenyl] sulfonyl} amino)- 1 ,3 -thiazol-4- yl] acetate, ethyl (2- { [(3,4-dichlorophenyl)sulfonyl]amino} - 1 ,3-thiazol-4-yl)acetate, ethyl (2- {[(4-butoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [4-(acetylamino)phenyl] sulfonyl} amino)- 1 ,3-thiazol-4-yl] acetate, ethyl {2-[(8-quinolinylsulfonyl)amino]-l,3-thiazol-4-yl} acetate, ethyl (2- { [(3,4-dimethoxyphenyl)sulfonyl]amino} - 1 ,3 thiazol-4-yl)acetate, ethyl (2-{[(4-iodophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [5-(dimethylamino)- 1 -naphthyl] sulfonyl} amino)- 1 ,3-thiazol-4- yl] acetate, ethyl (2- { [( 1 -methyl- 1 H-imidazol-4-yl)sulfonyl] amino} - 1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(5-bromo-2-methoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(2,5-dimethoxyphenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl {2-[(2-naphthylsulfonyl)amino]-l,3-thiazol-4-yl}acetate, ethyl {2-[(mesitylsulfonyl)amino] - 1 ,3 -thiazol-4-yl} acetate, ethyl (2- { [(3 -bromo-5 -chloro-2-thienyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)acetate, ethyl {2-[({5-[(benzoylamino)methyl]-2-thienyl}sulfonyl)amino]-l,3-thiazol-4- yl} acetate, ethyl {2-[({5-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]-2- thienyl} sulfonyl)amino]- 1 ,3-thiazol-4-yl} acetate, ethyl (2-{[(4-cyanophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[( {5-[2-(methylsulfanyl)-4-pyrimidinyl]-2-thienyl} sulfonyl)amino]- 1 ,3- thiazol-4-yl} acetate, ethyl (2-{[(3-cyanophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, 5 ethyl (2-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-({[(E)-2-phenylethenyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate, ethyl (2- {[(2,3,4-trichlorophenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl]acetate, ethyl [2-( { [4-(trifluoromethoxy)phenyl] sulfonyl} amino)- 1 ,3-fhiazol-4-yl] acetate, l o ethyl (2- { [(2,3-dichlorophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetate, ethyl (2-{[(2-bromophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4,5-dichloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl [2-( { [4-(phenylsulfonyl)-2 -thienyl] sulfonyl} amino)- 1 ,3 -thiazol-4-yl] acetate, ethyl [2-({[5-(phenylsulfonyl)-2-thienyl]sulfonyl}amino)-l,3-thiazol-4-yl]acetate,
15 ethyl (2- { [(2,6-dichlorophenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)acetate, ethyl (2-{[(2-cyanophenyl)sulfonyl]amino}-l,3-thiazσl-4-yl)acetate, ethyl. (2-({[4-(acetylamino)-3-chlorophenyl]sulfonyl} amino)- 1,3 -thiazol-4- yl] acetate, ethyl (2- {[(5-chloro- 1 ,3 -dimethyl- 1 H-pyrazol-4-yl)sulfonyl] amino} - 1 ,3-thiazol-4-
20 yl)acetate, ethyl (2-{[(3-methoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl 2-{2-[(l-naphthylsulfonyl)amino]-l,3-thiazol-4-yl} acetate, ethyl (2-{[(2,5-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, 5 ethyl (2-{[(4-methanesulfonylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-methanesulfonylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-2-fluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(2-methyl-4-trifluoromethoxyphenyl)sulfonyl] amino} - 1 ,3-thiazol-4- yl)acetate, 0 ethyl (2-{[(2,3,4-trifluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- { [(4-chloro-2,3 , 1 -benzoxadiazolyl)sulfonyl] amino} - 1 ,3 -thiazol-4- yl)acetate, ethyl (2-{[(2,4,6-trifluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(5-carboxy-4-chloro-2-fluorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, ethyl (2-{[(2-(5-chlorothienyl))sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-chloro-4-fluorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(2-(5-(3-isoxazolo)thienyl))sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-bromo-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(4-phenoxyphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2- {[(4-chloro-2,6-dimethylphenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)acetate, ethyl (2-{[(2-methyl-4-trifluoromethoxyphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, ethyl (2-{[(2,4-bis(trifluoromethyl)phenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, ethyl 2-{2-[[(3-chloro-2-methylphenyl)sulfonyl](methyl)amino]-l,3-thiazol-4- yl} acetate, ethyl oxo(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,'3-thiazol-4-
. yl)(oxo)acetate, ethyl oxo(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, ethyl {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]- 1 ,3-thiazol-4-yl} (oxo)acetate, ethyl (2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)(oxo)acetate, 2-(2-{[(4-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetic acid, 2-(2-{[(2,5-dichloro-3-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetic acid, (2- { [(2-chlorophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)acetic acid, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetic acid, isopropyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, phenyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, methyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, methyl {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-5-methyl- 1 ,3-thiazol-4- yl} acetate, methyl (2- { [(4-chlorophenyl)sulfonyl] amino } -5 -methyl- 1 ,3 -thiazol-4-yl) acetate, methyl (2- { [(3-chloro-2-methylphenyl)sulfonyl] amino } -5-methyl- 1 ,3 -thiazol-4- yl)acetate, methyl [2-({[4-(3-chloro-2-cyanophenoxy)phenyl]sulfonyl}amino)-5-methyl-l,3- thiazol-4-yl] acetate, methyl (5-methyl-2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetate, methyl (5-methyl-2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetate, methyl (2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-5-methyl-l,3-thiazol-
4-yl)acetate, N-(2-methoxyethyl)-2-(2-{[(4-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2-(2-{[(2,5-dichloro-3-thienyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- methylacetamide, N-(l ,3-benzodioxol-5-ylmethyl)-2- {2-[(l-naphthylsulfonyl)amino]-l ,3-thiazol-4- yl} acetamide,
N-(2-ftιrylmethyl)-2-{2-[(l-naphthylsulfonyl)amino]-l,3-thiazol-4-yl} acetamide, 2-(2- { [(2,4-difluorophenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)-N-ethylacetamide, N-isopropyl-2- {2- [( 1 -naphthylsulfonyl)amino] - 1 ,3 -thiazol-4-yl } acetamide, N-[2-(lH-indol-3-yl)ethyl]-2-{2-[(l-naphthylsulfonyl)amino]-l,3-thiazol-4- yl} acetamide,
N-(cyclohexylmethyl)-2-{2-[(phenylsulfonyl)amino]-l,3-thiazol-4-yl} acetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- methylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- ethylacetamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- phenylacetamide, 2-(2- {[(4-chlorophenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)-N-(2- furylmethyl)acetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- diethylacetamide, 2- {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl} -N,N- diethylacetamide, N,N-diethyl-2-(2- { [(4-propylphenyl)sulfonyl]amino} - 1 ,3-thiazol-4-yl)acetamide, 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- 5 diethylacetamide,
N,N-diethyl-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2- {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl} -N,N- diisopropylacetamide, l o N,N-diisopropyl-2-(2- { [(4-propylphenyl)sulfonyl] amino} - 1 ,3 -thiazol-4- yl)acetamide, 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- diisopropylacetamide, N,N-diisopropyl-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- 15 yl)acetamide,
2r(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N-
! diisopropylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- dipropylacetamide, 0 N-benzyl-2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N- ethylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N,N- dimethylacetamide, 3-chloro-N-{4-[2-(3,4-dihydro-2(lH)-isoquinolinyl)-2-oxoethyl]-l,3-thiazol-2- 5 yl} -2-methylbenzenesulfonamide,
2-(2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3 -thiazol-4-yl)-N-methyl-N- phenylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-isopropyl-
N-methylacetamide, 0 2- {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl} -N-isopropyl-N- methylacetamide, N-ethyl-N-methyl-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2-(2- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino } - 1 ,3-thiazol-4-yl)-N-ethyl-
N-methylacetamide, N-ethyl-N-methyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetamide, 2- {2-[([l , 1 '-biρhenyl]-4-ylsulfonyl)amino]- 1 ,3-thiazol-4-yl} -N-ethyl-N- methylacetamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-ethyl-N- methylacetamide, 3-chloro-2-methyl-N-{4-[2-oxo-2-(l-pyrrolidinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-oxo-2-(l-piperidinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N- {4-[2-oxo-2-(l -piperidinyl)ethyl]-l ,3-thiazol-2-yl} [1,1 '-biphenyl] -4- sulfonamide, N-{4-[2-oxo-2-(l~piperidinyl)ethyl]-l,3-thiazol-2-yl}-4- propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-oxo-2-(l-piperidinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4,6-trichloro-N- {4- [2-oxo-2-( 1 -piperidinyl)ethyl] - 1 ,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4,6-trichloro-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-tl iazol-2- yl}benzenesulfonamide, N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2-yl} [1,1 '-biphenyl] -4- sulfonamide, N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4- propylbenzenesulfonamide,
2,4-dichloro-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-chloro-2,6-dimethyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } b enzenesulfonamide, N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2-yl} -4- phenoxybenzenesulfonamide, 2-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4-
(trifluoromethoxy)benzenesulfonamide, N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2-yl} -2,4- bis(trifluoromethyl)benzenesulfonamide, 4-bromo-2-methyl-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
4-(2-furyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-(5-fluoro-2-methoxyphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-
2-yl}benzenesulfonamide, 4-(5-methyl-2-thienyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-(3-acetylphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-(4-trifluoromethoxyphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
4-(3,4-dichlorophenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-(3,4-methylenedioxyphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-
2-yl}benzenesulfonamide, 4-(5-chloro-2-thienyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-(4-pyridyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl } benzenesulfonamide, 4-(3-acetylaminophenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
4-(3-thienyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(2-thienyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl } benzenesulfonamide, -(4-carboxyphenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, -(4-methylsulfanylphenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, -(3,5-bis(trifluoromethyl)phenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3- thiazol-2-yl}benzenesulfonamide, -(4-chlorophenyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(3-nitrophenyl)-N- {4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, -(2-benzofuryl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(l-pyrrolidino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(4-methyl-l-piperidino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } b enzenesulfonamide, -(benzeneamino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(benzylamino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, -(2-thienylmethylamino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(4-moφholinyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, -(4-methyl-l-piperazinyl)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, -(3-pyridylmethylamino)-N-{4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, ,4-dichloro-6-methyl-N- {5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]- 1 ,3- thiazol-2-yl}benzenesulfonamide, N-{5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}[l,l'-biphenyl]-
4-sulfonamide, 2,4,6-trichloro-N-{5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 5 3-chloro-2-methyl-N- {5-methyl-4-[2-(4-moφholinyl)-2-oxoethyl]-l ,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-N-(4-{2-[(2R,6S)-2,6-dimethylmoφholinyl]-2-oxoethyl}-l,3-thiazol-2- yl)-2-methylbenzenesulfonamide, 3-chloro-2-methyl-N-(4-{2-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2- l o oxoethyl} - 1 ,3 -thiazol-2-yl)benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2- yl } b enzenesulfonamide, N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2-yl}[l,l'-biphenyl]-4- sulfonamide, 15 N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2-yl}-4- propylbenzenesulfonamide, 2,4-dichloro-6-methyl-N-{4-[2-oxo-2-(4-thiomoφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4,6-trichloro-N- {4- [2-oxo-2-(4-thiomoφholinyl)ethyl] - 1 ,3 -thiazol-2- 20 yl}benzenesulfonamide,
N-{4-[2-(l,l-dioxido-4-thiomoφholinyl)-2-oxoethyl]-l,3-thiazol-2-yl}-4- propylbenzenesulfonamide, tert-butyl 4-[(2- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3-thiazol-4- yl)acetyl] - 1 -piperazinecarboxylate, 25 4-acetyl-(4-[(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)acetyl])- 1 -piperazine, 4-[(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)acetyl]-l- piperazine trifluoroacetate, 3-chloro-2-methyl-N-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethyl]-l,3-thiazol-2- 30 yl}benzenesulfonamide hydrochloride,
2-methyl-N- {4-[2-(4-methyl- 1 -piperazinyl)-2-oxoethyl] - 1 ,3 -thiazol-2-yl} -4-
(trifluoromethoxy)benzenesulfonamide, 2,4-dichloro-6-methyl-N- {4-[2-(4-methyl- 1 -piperazinyl)-2-oxoethyl] - 1 ,3-thiazol-
2-yl}benzenesulfonamide, 2,4-dichloro-N-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-N-(4-{2-[(2R)-2,4-dimethylpiperazinyl]-2-oxoethyl}-l,3-thiazol-2-yl)-2- methylbenzenesulfonamide, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)-N-methoxy-
N-methylacetamide, 3-chloro-2-methyl-N-[4-(2-oxopentyl)-l,3-thiazol-2-yl]benzenesulfonamide, 4-chloro-N-[4-(2-hydroxyethyl)-l,3-thiazol-2-yl]benzenesulfonamide,
3-chloro-N-[4-(2-hydroxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[4-(2-ethoxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide,
3-chloro-N-[4-(2-isopropoxyethyl)-l,3-thiazol-2-yl]-2- methylbenzenesulfonamide, N- {4-[2-(benzyloxy)ethyl]-l ,3-thiazol-2-yl} -3-chloro-2- methylbenzenesulfonamide, 37chloro-N-[4-(2-methoxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-chloro-N-{4-[2-(2-fluoroethoxy)ethyl]-l,3-thiazol-2-,yl}-2- methylbenzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(2,2,2-trifluoroethoxy)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(2-pyridinylsulfanyl)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(3-ρyridinyloxy)ethyl]-l,3-thiazol-2- yl} benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-methylsalicylethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2-(2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,3-thiazol-4-yl)ethyl methanesulfonate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl acetate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl propionate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl 2- methylpropanoate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl 2- furoate, 2-(2- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3-thiazol-4-yl)ethyl benzoate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl 4- moφholinecarboxylate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl diethylcarbamate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl ethylcarbamate, N-[4-(2-azidoethyl)-l,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide, N-[4-(2-aminoethyl)-l,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide hydrochloride,
4-chloro-N-{4-[2-(diethylamino)ethyl]-l,3-thiazol-2-yl}benzenesulfonamide hydrochloride, 3-chloro-N-{4-[2-(diethylamino)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide hydrochloride, 3-chloro-N- {4-[2-(l -imidazolyl)ethyl]-l ,3-thiazol-2-yl} -2- methylbenzenesulfonamide hydrochloride, 3-chloro-2-methyl-N- {4-[2-(4-methyl- 1 -piρerazinyl)ethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide dihydrochloride, 3-chloro-2-methyl-N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2- yl} benzenesulfonamide hydrochloride,
3-chloro-2-methyl-N-{4-[(4-moφholinyl)methyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, 2,4,6-trichloro-N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, 2,4-dichloro-N- {4-[2-(4-moφholinyl)ethyl]-l ,3-thiazol-2-yl}benzenesulfonamide hydrochloride, 2,4-dichloro-6-methyl-N-{4-[2-(4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide hydrochloride, N- {4-[2-(4-moφholinyl)ethyl]-l ,3-thiazol-2-yl} -4-propylbenzenesulfonamide hydrochloride, 3-chloro-N- {4-[2-(ethylamino)ethyl]- 1 ,3-thiazol-2-yl} -2- methylbenzenesulfonamide, 3-chloro-N-(4-{2-[(2-hydroxyethyl)amino]ethyl}-l,3-thiazol-2-yl)-2- methylbenzenesulfonamide, N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4-yl)ethyl]-N- ethylacetamide, 3-chloro-2-methyl-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-N-{4-[2-(2-hydroxy-3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide, 2,4-dichloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, 2,4-dichloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-6- methylbenzenesulfonamide, N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-2,4,6- trichlorobenzenesulfonamide, 4,5-dichloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-2- thienylsulfonamide,
N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl}-4- phenoxybenzenesulfonamide, 3-fluoro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N- {4-[2-(3-oxo-4-moφholinyl)ethyl]-l ,3-thiazol-2-yl} -5-(2-pyridyl)-2- thienylsulfonamide, 4-acetylamino-3-chloro-N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N-{4-[(3-oxo-4-moφholinyl)methyl]-l,3-thiazol-2-yl}-3-chloro-2- methylbenzenesulfonamide,
N-{4-[3-(3-oxo-4-moφholinyl)propyl]-l,3-thiazol-2-yl}-3-chloro-2- methylbenzenesulfonamide, N-{4-[2-(3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2-yl},N-methyl-3-chloro-2- methylbenzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(2-methyl-3-oxo-4-moφholinyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide, N-{4-[2-(acetylamino)ethyl]-l,3-thiazol-2-yl}-3-chloro-2-methyl- benzenesulfonamide, 3-chloro-2-methyl-N- {4-[2-(4-(3-oxo- 1 ,4-oxazepinyl))ethyl]- 1 ,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(l-pyrrolidonyl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-{4-[2-(l-(2-oxoimidazolinyl))ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3 -chloro-2-methyl-N- {4- [2-( 1 -(2-oxooxazolinyl)ethyl] - 1 ,3 -thiazol-2- yl}benzenesulfonamide, 3-chloro-N-{4-[2-(N-(2-furylcarbonyl),N-2-hydroxyethylamino)ethyl]-l,3-
' thiazol-2-yl} -2-methylbenzenesulfonamide, hydrochloride, 3-chloro-2-methyl-N-{4-[2-(4-methyl-2-oxopiperazinyl)ethyl]-l,3-thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(methylsulfonylamino)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-mefhyl-N- {4-[2-(N-methyl,N-methylsulfonamino)ethyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide, 3 -chloro-2-methyl-N- {4- [2-(trifluoromethylsulfonylamino)ethyl]- 1 ,3 -thiazol-2- yl } benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(N-methyl,N-trifluoromethylsulfonamino)ethyl]-l,3- thiazol-2-yl}benzenesulfonamide, 3-chloro-2-methyl-N-{4-[2-(4-(l-methylimidazolyl)sulfonylamino)ethyl]-l,3- thiazol-2-yl}benzenesulfonamide, 3-chloro-N-{4-[2-(N-(3-chloro-2-methylphenylsulfonyl),N-methylamino)ethyl]- 1 ,3-thiazol-2-yl}-2-methylbenzenesulfonamide,
N-[4-(2-bromoethyl)-l,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide, 3-chloro-N-[4-(2-chloroethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-chloro-2-methyl-N-{4-[(5-methyl-l,3,4-oxadiazol-2-yl)methyl]-l,3-thiazol-2- yl} benzenesulfonamide, and 3-chloro-N-{4-[2-(ethoxycarbonyl)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide.
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.
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