WO2004113310A1 - Use of an inhibitor of 11-b-hydroxysteroid dehydrogenase type 1 compounds for promoting wound healing - Google Patents

Use of an inhibitor of 11-b-hydroxysteroid dehydrogenase type 1 compounds for promoting wound healing Download PDF

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WO2004113310A1
WO2004113310A1 PCT/SE2004/000798 SE2004000798W WO2004113310A1 WO 2004113310 A1 WO2004113310 A1 WO 2004113310A1 SE 2004000798 W SE2004000798 W SE 2004000798W WO 2004113310 A1 WO2004113310 A1 WO 2004113310A1
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thiadiazol
chloro
amino
benzenesulfonamide
sulfonyl
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PCT/SE2004/000798
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French (fr)
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Cecilia Nilsson
Catrine Dreifeldt
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Biovitrum Ab
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Priority claimed from SE0301887A external-priority patent/SE0301887D0/en
Priority claimed from SE0301889A external-priority patent/SE0301889D0/en
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2004113310A1 publication Critical patent/WO2004113310A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • 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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/04—Amoebicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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 ll ⁇ -HSD, ll ⁇ - HSDl 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).
  • 11 ⁇ -HSDl The function of 11 ⁇ -HSDl is to fine-tune local glucocorticoid action.
  • 1 l ⁇ -HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).
  • Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, angiogenesis, wound contraction and epithelialization. It can be divided in three phases; inflammatory, proliferative and remodeling phase (reviewed in (2)).
  • glucocorticoids In surgical patients, treatment with glucocorticoids increases risk of wound infection and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF- ⁇ , EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).
  • WO 03/044000 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 1 l ⁇ -HSD 1, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders.
  • Other ll ⁇ -HSDl inhibitors are disclosed in e.g. WO 01/90090,; WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; 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 ll ⁇ -HSDl inhibitors for wound healing.
  • the use of the 1 l ⁇ -HSD 1 inhibitors according to the present invention for wound healing has not previously been disclosed.
  • this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 11 ⁇ -hydroxysteroid dehydrogenase type 1 , wherein the inhibitor of 11 ⁇ - hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
  • T is an aryl ring or heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C 1-6 -alkyl, optionally halogenated C ⁇ -6 -alkoxy, C 1-6 - 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 1-6 -alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C 1-6 - al
  • Z is selected from an aryl ring or heteroaryl ring, which can further be optionally substituted in one or more positions independently of each other by hydrogen, C 1-6 - alkyl, halogenated C 1-6 -alkyl, halogen, C 1-6 -alkoxy, nitro, C ⁇ -6 -alkoxycarbonyl, C 1-6 - alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy can further be optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R , wherein
  • R 2 is selected from - 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- mo holinolinylmethylene, C 1-6 -alkoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl; NR 3 R 4 , wherein R 3 and R 4 are each independently selected from hydrogen, C ⁇ -6 - alkyl, optionally halogenated C 1-6 -alkylsulfonyl, C ⁇ -6 -alkoxy, 2-methoxyethyl, 2- hydroxyethyl, 1-methylimidazolylsulfonyl, C 1-6 -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetra
  • R 5 O wherein R 5 is hydrogen, optionally halogenated C 1-6 -alkyl, aryl, heteroaryl, Q. 6 -acyl, C 1-6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
  • T is selected from 5-chloro-l,3-dimethyl-lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, l-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, l,3-benzo
  • R 1 is hydrogen or methyl.
  • a ⁇ and A 2 are a nitrogen atom or C-Z, provided that Aj and A have different meanings, wherein:
  • Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-
  • Y is CH , CO or a single bond
  • R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR 3 R 4 , wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, l,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, me
  • R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
  • R 5 O wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifiuoroethyl.
  • 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.
  • the various terms used, separately and in combinations, in the above definition of the compounds having the general formula (I) will be explained.
  • aryl in the present description is intended to include aromatic rings
  • phenyl (Ph) and naphthyl which optionally may be substituted by C 1-6 -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-benzotbiazole, 2,1,3- benzoselenadiazole, benzimidazole, indazole, benzodioxane, in
  • 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 ⁇ _ Q -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 For parts of the range "C ⁇ -6 -alkyl" all subgroups thereof are contemplated such as -5-alkyl, C ⁇ -alkyl, C 2-6 -alkyl, C 2-5 -alkyl, C 2-4 -alkyl, C 2-3 -alkyl, C 3-6 -alkyl, C 4- 5 -alkyl, etc.
  • C _5-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 1-6 -alkoxy For parts of the range "C 1-6 -alkoxy" all subgroups thereof are contemplated such as C s-aikoxy, C 1- -alkoxy, C 2-6 -alkoxy, C 2-5 - alkoxy, C 2-4 - alkoxy, C 2-3 -alkoxy, C 3-6 -alkoxy, C 4-5 -alkoxy, etc.
  • C ⁇ _5-acyl in the compound of formula (I) according to the present application maybe 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 1-6 -acyl For parts of the range "C 1-6 -acyl" all subgroups thereof are contemplated such as - 5 -acyl, C ⁇ -4 -acyl, C -6 -acyl, C -5 -acyl, C 2-4 -acyl, C 2- 3 -acyl, C 3-6 -acyl, C 4-5 -acyl, etc.
  • halogen in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • sulfanyl in the present description means a thio group.
  • stable 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 administraiton to a subject for the treatment of disease, 11- ⁇ -HSDl inhibition, 11- ⁇ -HSDl -mediated disease).
  • prodrug forms in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15).
  • “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
  • Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
  • the compounds of formula (I) can be prepared according to the methods described in WO 03/0044000.
  • 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 ll ⁇ - 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.

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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-ß-hydroxysteroid dehydrogenase type 1 wherein the said l lß-HSD1 inhibitor has the formula (I) wherein T, R1, A1 and A2 are as defined in the specification. These compounds may also be used in the manufacture of a medicament for promoting wound healing.

Description

_ ι _
USE OF AN INHIBITOR OF 11-B-HYDROXYSTEROID DEHYDROGENASE TYPE 1 COMPOUND FOR PROMOTING WOUND
HEALING.
RELATED APPLICATIONS
This application claims priority to Swedish application number 0301889-2, filed on June 25, 2003, U.S. provisional application 60/494,701, filed on August 12, 2003, and Swedish application number 0301887-6, filed on June 25, 2003, the contents of which is 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 llβ-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 llβ-HSD, llβ- HSDl 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-HSDl is to fine-tune local glucocorticoid action. 1 lβ-HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).
Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, angiogenesis, wound contraction and epithelialization. It can be divided in three phases; inflammatory, proliferative and remodeling phase (reviewed in (2)).
In surgical patients, treatment with glucocorticoids increases risk of wound infection and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF-β, EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).
WO 03/044000 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 1 lβ-HSD 1, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders. Other llβ-HSDl inhibitors are disclosed in e.g. WO 01/90090,; WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; 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 llβ-HSDl inhibitors for wound healing. However, the use of the 1 lβ-HSD 1 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-HSDl are useful for the promotion of wound healing. Consequently, in a first aspect this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 11 β-hydroxysteroid dehydrogenase type 1 , wherein the inhibitor of 11 β- hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
Figure imgf000004_0001
wherein
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C1-6-alkyl, optionally halogenated Cι-6-alkoxy, C1-6- 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, C1-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C1-6- alkyl, optionally halogenated Ci-6-alkoxy, amide which is optionally mono- or di- substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2- oxoethyl)- 1 ,3-thiazol-2-yl]amino} carbonyl); R1 is hydrogen or C1-6-alkyl; Ai and A2 are a nitrogen atom or C-Z, provided that Ai and A2 have different meanings, wherein:
• Z is selected from an aryl ring or heteroaryl ring, which can further be optionally substituted in one or more positions independently of each other by hydrogen, C1-6- alkyl, halogenated C1-6-alkyl, halogen, C1-6-alkoxy, nitro, Cι-6-alkoxycarbonyl, C1-6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy can further be optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R , wherein
• X is CH2 or CO; • Y is CH , CO or a single bond;
• R2 is selected from -6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- mo holinolinylmethylene, C1-6-alkoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl; NR3R4, wherein R3 and R4 are each independently selected from hydrogen, Cι-6- alkyl, optionally halogenated C1-6-alkylsulfonyl, Cι-6-alkoxy, 2-methoxyethyl, 2- hydroxyethyl, 1-methylimidazolylsulfonyl, C1-6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or C1-6-alkyl substituted with one or more aryl, heterocyclic 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), (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems can be optionally substituted by Cι-6-alkyl, C1-6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR3R4, wherein R3 and R4 are each independently selected from hydrogen, C\.
6-alkyl or form together with the N-atom to which they are attached morpholinyl; R5O, wherein R5 is hydrogen, optionally halogenated C1-6-alkyl, aryl, heteroaryl, Q. 6-acyl, C1-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
It is preferred that: T is selected from 5-chloro-l,3-dimethyl-lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, l-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- 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-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridyhnethylamino, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienyhnethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl.
R1 is hydrogen or methyl.
A\ and A2 are a nitrogen atom or C-Z, provided that Aj and A have different meanings, wherein:
• Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-
R , wherein
• X is CH2 or CO;
• Y is CH , CO or a single bond;
• R2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR3R4, wherein R3 and R4 are each independently selected from acetyl, benzhydryl, l,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (lS)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR3R4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-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-oxomorpholinyl, 3-oxo-l,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1 , 1 -dioxido-thiomorpholinyl;
OCONR3R4, wherein R3 and R4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R5O, wherein R5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifiuoroethyl.
The following compounds are especially preferred:
• ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetate
• (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)acetic acid
• 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- methylacetamide • 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- ethylacetamide
• 2,5-dichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
• isopropyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetate
• 3-chloro-N-[5-(2-hydroxyethyl)-l ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide 3-chloro-N-[5-(2-ethoxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- diethylacetamide methyl (5- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2- yl)acetate
3-chloro-N-[5-(2-isopropoxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
3-chloro-N-[5-(2-methoxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2-(5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yι)ethyl methanesulfonate
2-(5 - { [(3 -chloro-2 -methylphenyrjsulfonyl] amino } - 1 , 3 ,4-thiadiazol-2- yl)acetamide
3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-l,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonamide
3-chloro-2-methyl-N-{5-[2-(2,2,2-trifluoroethoxy)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonaniide
2-(5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} -1,3 ,4-thiadiazol-2-yl)ethyl acetate
3-chloro-2-methyl-N-[5-(2-morpholin-4-ylethyl)-l,3,4-thiadiazol-2- yl]b enzenesulfonamide
N-[5-(2-bromoethyl)-l,3,4-thiadiazol-2-yl]-3-chloro-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl morpholine-4-carboxylate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl diethylcarbamate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl propionate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl 2- methylpropanoate 2-(5- { [(3 -chloro-2 -methylphenyl)sulfonyl] amino } - 1 ,3 ,4-thiadiazol-2-yl)ethyl 2- furoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl benzoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- methoxy-N-methylacetamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl ethylcarbamate
N-[2-(5- { [(3 -chloro-2 -methylphenyl)sulfonyl] amino } - 1 ,3 ,4-thiadiazol-2- yl)ethyl] -N-ethylacetamide
3-chloro-2-methyl-N-[5-(2-oxopentyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-{5-[2-(l,l-dioxidothiomorpholin-4-yl)-2-oxoethyl]-l,3,4-thiadiazol-2-yl}-4- propylbenzenesulfonamide
2,4,6-trichloro-N-[5-(2-morpholin-4-ylethyl)-l,3,4-thiadiazol-2-. yl]benzenesulfonamide
2,4-dichloro-N-[5-(2-morpholin-4-ylethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide '
3-chloro-2-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl } benzenesulfonamide
2,4-dichloro-6-methyl-N-[5-(2-moφholin-4-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-[5-(2-morpholin-4-ylethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4,6-trichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3 ,4-thiadiazol-2-yl] -1,1 '-biphenyl-4- sulfonamide
N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3 ,4-thiadiazol-2-yl] -4- propylbenzenesulfonamide N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2-yl]-l,r-biphenyl-4- sulfonamide
N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-
2-yl]benzenesulfonamide
N-[5-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,3 ,4-thiadiazol-2-yl] -1,1 '-biphenyl-4- sulfonamide
N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4,6-trichloro-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)(oxo)acetate
2-{5-[(l,l'-biphenyl-4-ylsulfoιiyl)amino]-l,3,4-thiadiazol-2-yl}-N-ethyl-N- methylacetamide
N-ethyl-N-methyl-2-(5- { [(4-propylphenyl)sulfonyl] amino } - 1 ,3 ,4-thiadiazol-2- yl)acetamide
2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- ethyl-N-methylac etamide
N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3,4- thiadiazol-2-yl)acetamide
2,4,6-trichloro-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
2- {5-[(l ,l'-biphenyl-4-ylsulfonyl)amino]-l ,3,4-thiadiazol-2-yl} -N-isopropyl-N- methylacetamide
2-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,3,4-thiadiazol-2-yl}-N,N- diethylacetamide
N,N-diethyl-2-(5- {[(4-propylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2- yl)acetamide 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-
N,N-diethylacetamide
N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetamide
2-{5-[(l,l*-biphenyl-4-ylsulfonyl)amino]-l,3,4-thiadiazol-2-yl}-N,N- diisopropylacetamide
N,N-diisopropyl-2-(5 - { [(4-propylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2- yl)acetamide
2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-
N,N-diisopropylacetamide
N,N-diisopropyl-2-(5 - { [(2,4,6-trichlorophenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-
2-yl)acetamide
4-propyl-N-(5-pyridin-3-yl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
3-chloro-N-[5-(5-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2,4,6-trichloro-N-(5-pyridin-3-yl-l,3,4-thiadiazol-2-yl)benzenesulfonamide.
2,4,6-trichloro-N-[5-(5-chlorothien-2-yl)÷l ,3,4-thiadiazol-2- . yl]benzenesulfonamide-
N-(5-pyridin-3 -yl- 1 ,3 ,4-thiadiazol-2-yl)- 1 , 1 '-biphenyl-4-sulfonamide
2,4-dichloro-6-methyl-N-(5-pyridin-3-yl-l,3,4-thiadiazol-2- yl)benzenesulfonamide
2,4-dichloro-N-[5-(5-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylρhenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- dipropylacetamide
3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-l-ylethyl)-l,3,4-fhiadiazol-2- yijbenzenesulfonamide
2,4-dichloro-N-[5-(2,5-dimethyl-3-furyl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide
3-chloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide 2,4,6-trichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]b enzenesulfonamide
2,4-dichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
4-bromo-2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide
2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide
N- [5 -(2-moφholin-4-yl-2-oxoethyl)- 1 ,3 ,4-thiadiazol-2-yl] -4- phenoxyb enzenesulfonamide
4-chloro-2,6-dimethyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
2,4-dichloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide tert-butyl 4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetyl]piperazine- 1 -carboxylate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- dimethylacetamide
3-chloro-2-methyl-N-{5-[2-(pyridin-3-yloxy)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- isopropyl-N-methylacetamide
2-(5- { [(3 -chloro-2 -methylphenyl)sulfonyl] amino } - 1 ,3 ,4-thiadiazol-2-yl)-N- ethyl-N-methylacetamide
3-chloro-2-methyl-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
3-chloro-2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- diisopropylacetamide 3-chloro-2-methyl-N-[5-(2-oxo-2-pyrrolidin-l-ylethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
3-chloro-2-methyl-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3-chloro-2-methyl-N-[5-(moφholin-4-ylmethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
3-chloro-N-{5-[2-(lH-imidazol-l-yl)ethyl]-l,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonamide
2,4,5-trichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-
10 yl]benzenesulfonamide
2,3,4-trichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
4-bromo-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-2,5- difluorobenzenesulfonamide
•15: 4-bromo-5-chloro-N-[5-(3-chlorothien-2-.yl)-l,3,4-thiadiazol-2-yl]thiophene-2-' sulfonamide
2,6-dichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-
20 yl)ethyl] acetamide
3-chloro-2-methyl-N-(5-{2-[(methylsulfonyl)amino]ethyl}-l,3,4-thiadiazol-2- yl)benzenesulfonamide
3-chloro-2-methyl-N- {5-[2-(3-oxo-l ,4-oxazepan-4-yl)ethyl]-l ,3,4-thiadiazol-2- yl } b enzenesulfonamide
25 3-chloro-2-methyl-N-{5-[2-(2-oxopyrrolidin-l-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
3-chloro-2-methyl-N-(5- {2-[methyl(methylsulfonyl)amino]ethyl} -1 ,3,4- thiadiazol-2-yl)benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-
30 yl)ethyl]-N-methylcyclopropanecarboxamide
3-chloro-2-methyl-N-{5-[2-(4-methyl-2-oxopiperazin-l-yl)ethyl]-l,3,4- thiadiazol-2-yl}benzenesulfonamide 3-chloro-2-methyl-N-[5-(2-{[(trifiuoromethyl)sulfonyl]amino}ethyl)-l,3,4- thiadiazol-2-yl]benzenesulfonamide
2,4-dichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl } b enzenesulfonamide
2,4-dichloro-6-methyl-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
2,4,6-trichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
4-(2-furyl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
5'-fiuoro-2'-methoxy-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-
1 , 1 '-biphenyl-4-sulfonamide
4-(5-methylthien-2-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
3'-acetyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,l'- biphenyl-4-sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4 hiadiazol-2-yl]-4'-^
(trifluoromethoxy)- 1 , 1 '-biphenyl-4-sulfonamide
3',4'-dichloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,r- biphenyl-4-sulfonamide
4-(l,3-benzodioxol-5-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-
2-yl]benzenesulfonamide
4-(5-chlorothien-2-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yljbenzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-pyridin-4- ylbenzenesulfonamide
N-[4'-({[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl] amino } sulfonyl)- 1 , 1 '-biphenyl-3 -yl] acetamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-thien-3- ylbenzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-thien-2- ylbenzenesulfonamide 4'-(methylthio)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,r- biphenyl-4-sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-3',5'- bis(trifluoromethyl)- 1 , 1 '-biphenyl-4-sulfonamide
4'-chloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l ,3 ,4-thiadiazol-2-yl]- 1 , 1 '- biphenyl-4-sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-3'-nitro-l,l'- biphenyl-4-sulfonamide
3-chloro-2-methyl-N-[5-(2- {methyl[(trifluoromethyl)sulfonyl] amino} ethyl)-
1 ,3 ,4-thiadiazol-2-yl]benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)ethyl] - 1 -methyl- 1 H-imidazole-4-sulfonamide
3-chloro-N-{5-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl} -2-methylbenzenesulfonamide
4,5-dichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl].l,3,4-thiadiazol-2- yl}thiophene-2-sulfonamide , .
N- {5-[2-(3-oxomoφholin-4-yl)ethyι]--l ,-3,4-thiadiazol-2-yl} -4- phenoxyb enzenesulfonamide
3-fluoro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl } benzenesulfonamide
N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2-yl}-5-pyridin-2- ylthiophene-2-sulfonamide
N-{2-chloro-4-[({5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl} amino)sulfonyl]phenyl} acetamide ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetate
(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)acetic acid
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- methylacetamide
2-(5-{[(3-chloro-2-methylρhenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- ethylacetamide
2,5-dichloro-N-[3-(3-crιlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide isopropyl (5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 - yl)acetate
3 -chloro-N-[3-(2-hydroxyethyl)- 1 ,2,4-thiadiazol-5 -yl] -2- methylbenzenesulfonamide
3 -chloro-N-[3-(2-ethoxyethyl)- 1 ,2,4-thiadiazol-5 -yl] -2- methylb enzenesulfonamide
2-(5- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 -yl)-N,N- diethylacetamide methyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetate
3-chloro-N-[3-(2-isopropoxyethyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-N~[3-(2-methoxyethyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl methanesulfonate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l;2i4-thiadiazol-3- yl)acetamide
3-chloro-N-{3-[2-(2-fluoroethoxy)ethyl]-l,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(2,2,2-trifluoroethoxy)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl acetate
3-chloro-2-methyl-N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
N-[3-(2-bromoethyl)-l,2,4-thiadiazol-5-yl]-3-chloro-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl moφholine-4-carboxylate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl diethylcarbamate 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl propionate
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3-yl)ethyl 2- methylprop ano ate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl 2- furoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl benzoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- methoxy-N-methylacetamide
3-chloro-N- {3-[2-(diethylamino)ethyl]-l ,2,4-thiadiazol-5-yl} -2- methylbenzenesulfonamide
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3-yl)ethyl ethylcarbamate
•N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l-,2,4-thiadiazol-3- yl)ethyl]-N-ethylacetamide
3-clτloro-2--methyl-N-[3-(2-oxopentyl)-lv2,47thiadiazol-5- yljbenzenesulfonamide
N-{3-[2-(l,l-dioxidothiomoφholin-4-yl)-2-oxoethyl]-l,2,4-thiadiazol-5-yl}-4- propylbenzenesulfonamide
2,4,6-trichloro-N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]b enzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide 2,4,6-trichloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,l'-biphenyl-4- sulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
N-[3 -(2-oxo-2-thiomoφholin-4-ylethyl)- 1 ,2,4-thiadiazol-5-yl] -1,1 '-biphenyl-4- sulfonamide
N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5-yl]-4- propylb enzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-
5 -yl]b enzenesulfonamide
N-[3-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,2,4-thiadiazol-5 -yl] -1,1 '-biphenyl-4- sulfonamide
N-[3-(2-oxo-2-piperidin- 1 -ylethyl)-! ,2,4-thiadiazol-5-yl]-,4- ■ propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-oxo-2-piperidin-l-ylethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
2,4,6-trichloro-N-[3-(2-oxo-2-ρiperidin-l-ylethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
N-(3-phenyl-l,2,4-thiadiazol-5-yl)-4-propylbenzenesulfonamide ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)(oxo)acetate
3-chloro-2-methyl-N-(3-phenyl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
3-chloro-N-[3-(4-fluoro-3-methylρhenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
2,4,6-trichloro-N-(3-phenyl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
N-(3-phenyl-l ,2,4-thiadiazol-5-yl)-l, 1 '-biphenyl-4-sulfonamide
2,4-dichloro-6-methyl-N-(3-phenyl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
2-{5-[(l,r-biρhenyl-4-ylsulfonyl)amino]-l,2,4-thiadiazol-3-yl}-N-ethyl-N- methylacetamide
N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide • 2-(5 - { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 -yl)-N- ethyl-N-methylacetamide
• N-ethyl-N-methyl-2-(5- {[(2,4,6-trichlorophenyl)sulfonyl]amino} -1 ,2,4- thiadiazol-3-yl)acetamide • 2,4,6-trichloro-N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
• 2- {5-[(l ,1 '-biphenyl-4-ylsulfonyl) amino] -1 ,2,4-thiadiazol-3-yl} -N-isopropyl-N- methylacetamide
• 2-{5-[(l,l'-biphenyl-4-ylsulfonyl)amino]-l,2,4-thiadiazol-3-yl}-N,N- diethylacetamide
• N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide
• 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)- N,N-diethylacetamide • N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide .. 2- {5-[(l , 1 'Λiphenyl-4-ylsulfonyl)amino]~.l ,2,4-thiadiazol-3-yl} -N,N- diisopropylacetamide
• N,N-diisopropyl-2-(5 - { [(4-propylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 - yl)acetamide
• 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)- N,N-diisopropylacetamide
• N,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol- 3-yl)acetamide • N-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
• 4-propyl-N-(3-pyridin-3-yl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
• N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide • N-[3-(2-chlorophenyl)-l,2,4-fhiadiazol-5-yl]-4-propylbenzenesulfonamide
• 3-chloro-N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide 3-chloro-N-[3-(5-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
2,4,6-trichloro-N-(3-pyridin-3-yl-l,2,4-thiadiazol-5-yl)benzenesulfonamide 2,4,6-trichloro-N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5- yl]b enzenesulfonamide
2,4,6-trichloro-N-[3-(5-chlorothien-2-yl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
2,4,6-trichloro-N-[3-(2-chlorophenyl)-l32,4-thiadiazol-5-yl]benzenesulfonamide N-(4-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,2,4-thiadiazol-3- yl}phenyl)acetamide
N-(3 -pyridin-3 -yl- 1 ,2,4-thiadiazol-5 -yl)-l , l-'-biphenyL4-sulfonamide N-[3-(2-chloro-5-nitrόphenyl)-l,2,4-thiadiazol-5-yl]-l,l'-biphenyl-4- sulfonamide
N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]-l, -biphenyl-4-sulfonamide N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
2,4-dichloro-6-methyl-N-(3-pyridin-3-yl-l ,2,4-thiadiazol-5- yfjbenzenesulfonamide
2,4-dichloro-N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
2,4-dichloro-N-[3-(5-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-6- mefhylbenzenesulfonamide
2-(5 - { [(3 -chloro-2-methylρhenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 -yl)-N,N- dipropylacetamide
3-chloro-2-methyl-N-[3-(2-oxo-2-piperazin-l-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-(2,5-dimethyl-3-furyl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide 3 -chloro-N-[3 -(3 -chlorothien-2-yl)- 1 ,2,4-thiadiazol-5-yl] -2- methylbenzenesulfonamide
2,4,6-trichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-6- methylb enzenesulfonamide
2,4-dichloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
4-bromo-2-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-
10 yl]benzenesulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide
2-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-
(trifluoromethoxy)benzenesulfonamide
15.- N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4- phenoxybenzenesulfonamide
4-chloro-2,6-dimethyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
2,4-dichloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- 0 yl]benzenesulfonamide tert-butyl 4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetyl]piperazine- 1 -carboxylate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N,N- dimethylacetamide 5 3-chloro-2-methyl-N-{3-[2-(pyridin-3-yloxy)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-fhiadiazol-3-yl)-N- isopropyl-N-methylacetamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- 0 ethyl-N-methylacetamide
3-chloro-2-methyl-N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide 3-chloro-2-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]b enzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N,N- diisopropylacetamide
3-chloro-2-methyl-N-[3-(2-oxo-2-pyrrolidin- 1 -ylethyl)- 1 ,2,4-thiadiazol-5- yljbenzenesulfonamide
3-chloro-2-methyl-N-[3-(2-oxo-2-piperidin-l-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
3-chloro-2-methyl-N-[3-(moφholin-4-ylmethyl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
3-chloro-N-{3-[2-(lH-imidazol-l-yl)ethyl]-l,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide
2,4,5-trichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]b enzenesulfonamide
2,3,4-trichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide
2,3,4-trichloro-N-[3-(2-ehlor6phenyl)-l,2,4-thiadiazol-5-yl]benzenesulfonamide
N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amiiio}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
4-bromo-N-[3-(3-chlorotlιien-2-yl)-l,2,4-thiadiazol-5-yl]-2,5- difluorobenzenesulfonamide
4,5-dichloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide
N-[4-(5- {[(2,4,5-trichlorophenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3- yl)phenyl] acetamide
4-bromo-5-chloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide
3-bromo-5-chloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide
N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
2,6-dichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yljbenzenesulfonamide N-[2-(5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,2,4-thiadiazol-3 - yl)ethyl]acetamide
3-chloro-2-methyl-N-(3 - {2-[(methylsulfonyl)amino] ethyl} -1 ,2,4-thiadiazol-5- yl)benzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(2-oxopyrrolidin-l-yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
2,3,4-trichloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,2,4-thiadiazol-
5-yl}benzenesulfonamide
N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
4-bromo-N- {3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l ,2,4-thiadiazol-5-yl} -
2,5-difluorobenzenesulfonamide
4,5-dichloro-N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide ,-bromo-5-chloro-N-.{3>[2,6-dichloro-4r(trifluoromethyl)phenyl]-l,2,4- : thiadiazol-5-yl}thiophene-2-sulfonamide
2,4-dichloro-N- [3 -(2-chloro-6-fluorophenyl)- 1 ,2,4-thiadiazol-5-yl] -6- methylbenzenesulfonamide
4-bromo-N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-2-methyl-N-(3-{2-[methyl(methylsulfonyl)amino]ethyl} -1,2,4- thiadiazol-5-yl)benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)ethyl]-N-methylcyclopropanecarboxamide
3 -chloro-2-methyl-N- {3 -[2-(4-methyl-2-oxopiperazin- 1 -yl)ethyl] - 1 ,2,4- thiadiazol-5-yl}benzenesulfonamide
3-chloro-2-methyl-N-[3-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-l,2,4- thiadiazol-5-yl]benzenesulfonamide
N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide • 2,4-dichloro-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
• 2,4-dichloro-6-methyl-N- {3-[2-(3-oxomoφholin-4-yl)ethyl]- 1 ,2,4-thiadiazol-5- yl}benzenesulfonamide • 2,4,6-trichloro-N-{3-[2-(3-oxomoφholin-4-yl)ethyl)-l,2,4-thiadiazol-5- yijbenzenesulfonamide
• 4-(2-furyl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yijbenzenesulfonamide
• 5'-fluoro-2'-methoxy-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]- l,l'-biphenyl-4-sulfonamide
• 4-(5-methylthien-2-yl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
• 3'-acetyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl]-l , 1 '- . biphenyl-4-sulfonamide • N-[3-(2-moφholin-4-.yl-2-oxoethyl)-l,2,4-thiadiazoL5-yl]-4'-
(trifluoromethoxy)- 1 , 1 '-biphenyl-4-sulfonamide .• .3',4'-dichloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l;2,4-thiadiazol-5-yl]-l,r- , biphenyl-4-sulfonamide - • 4-(l,3-benzodioxol-5-yl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol- 5-yl]benzenesulfonamide
• 4-(5-chlorothien-2-yl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l ,2,4-thiadiazol-5- yljbenzenesulfonamide
• N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-pyridin-4- ylbenzenesulfonamide • N-[4'-({[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl] amino} sulfonyl)- 1 , 1 '-biphenyl-3 -yl] acetamide
• N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-thien-3- ylbenzenesulfonamide
• N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-thien-2- ylbenzenesulfonamide
• 4'-(methylthio)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l32,4-thiadiazol-5-yl]-l,r- biphenyl-4-sulfonamide N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-3',5'- bis(trifluoromethyl)-l , 1 '-biphenyl-4-sulfonamide
4'-chloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,l'- biphenyl-4-sulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-3'-nitro-l,r- biphenyl-4-sulfonamide
3-chloro-2-methyl-N-[3-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)- l,2,4-thiadiazol-5-yl]benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)ethyl] - 1 -methyl- 1 H-imidazole-4-sulfonamide
3-chloro-N-{3-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} -2-methylbenzenesulfonamide
4,5-dichloro-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} thiophene-2-sulfonamide
N- {3-[2-(3-oxomoφholin-4-yl)ethyl]- 1 ,2,4-thiadiazol-5-yl} -4- , phenoxyb enzenesulfonamide -fluoro-N-{3-[2-(3-oxomoφholin-4-.yl)ethyl]rl,2,4-thiadiazol-5- yl}benzenesulfonamide
N- {3-[2-(3-oxomoφholin-4-yl)ethyl]-l ,2,4-thiadiazol-5-yl} -5-pyridin-2- ylthiophene-2-sulfonamide
N-{2-chloro-4-[({3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} amino)sulfonyl]phenyl} acetamide.
3-chloro-N-{5-[2-(diethylamino)ethyl]-l,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonamide
N-(5-phenyl-l,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide
3-chloro-2-methyl-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
3-chloro-N-[5-(4-fluoro-3-methylphenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2,4,6-trichloro-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
N-(5-phenyl- 1 ,3 ,4-thiadiazol-2-yl)- 1 , 1 '-biphenyl-4-sulfonamide
2,4-dichloro-6-methyl-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
N-[4-(5- {[(4-propylphenyl)sulfonyl] amino} -1 ,3,4-thiadiazol-2- yl)phenyl] acetamide N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide
3-chloro-N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
3-chloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
N-[4-(5- {[(2,4,6-trichlorophenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2- yl)phenyl] acetamide
2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4,6-trichloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]benzenesulfonamide
N-(4- {5-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]- 1 ,3,4-fhiadiazol-2- yl } phenyl) acetamide
N-[5 -(2-chloro-5-nitrophenyl)- 1 ,3 ,4-thiadiazol-2-yl] -1,1 '-biphenyl-4- sulfonamide
N-[5-(2-chlorophenyl)-l,3,4-thi.adiazol-2-yl]-l-,l'-biphenyl-4-sulfonamide
N-[4-(5- {[(2,4-dichloro-6-methylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2- yl)phenyl] acetamide
2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
2,4-dichloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
2,3,4-trichloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]benzenesulfonamide
N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
4,5-dichloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide
N-[4-(5- {[(2,4,5-trichlorophenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2- yl)phenyl] acetamide
3-bromo-5-chloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
2,3,4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3,4-thiadiazol-
2-yl}benzenesulfonamide
N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3,4-thiadiazol-2-yl}-
2 , 5 -difluorobenzenesulfonamide
4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide
4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3,4- thiadiazol-2-yl}thiophene-2-sulfonamide
2,4-dichloro-N-[5 -(2-chloro-6-fluorophenyl)- 1 ,3 ,4-thiadiazol-2-yl] -6- methylbenzenesulfonamide
4-bromo-N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]-2- methylb enzenesulfonamide
N-[4-(5- {[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino} -1 ,3,4-thiadiazol-2- yl)phenyl] acetamide.
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 C1-6-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-benzotbiazole, 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.
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_Q-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 -5-alkyl, C^-alkyl, C2-6-alkyl, C2-5-alkyl, C2-4-alkyl, C2-3-alkyl, C3-6-alkyl, C4- 5-alkyl, etc.
C _5-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 "C1-6-alkoxy" all subgroups thereof are contemplated such as C s-aikoxy, C1- -alkoxy, C2-6-alkoxy, C2-5- alkoxy, C2-4- alkoxy, C2-3-alkoxy, C3-6-alkoxy, C4-5-alkoxy, etc.
Cχ_5-acyl, in the compound of formula (I) according to the present application maybe 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 "C1-6-acyl" all subgroups thereof are contemplated such as -5-acyl, Cι-4-acyl, C -6-acyl, C -5-acyl, C2-4-acyl, C2- 3-acyl, C3-6-acyl, C4-5-acyl, 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 C1-6-acyl, C2-6- alkenyl, C1-6-(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, moφholine and thiomoφholine, which heterocyclic rings optionally may be substituted with C1-6-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 administraiton to a subject for the treatment of disease, 11-β-HSDl inhibition, 11-β-HSDl -mediated disease).
The term "prodrug forms" in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15).
"Pharmaceutically acceptable" means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
The compounds of formula (I) can be prepared according to the methods described in WO 03/0044000.
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 llβ- 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-HSD 1 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 irnmunostaining against the von Willebrand factor to determine revascularisation. (b)
Advantageous effects of l lβ-HSDl inhibitors are confirmed in in vitro studies. Proliferation of human keratinocytes and fibroblasts, which are important cell types in the wound healing process, are studied after incubation with the 1 lβ-HSD 1 inhibitor.
(c)
Effects on wound healing after treatment with llβ-HSDl inhibitors are also studied in wounds on explants from human breast skin. The proliferative effect of the substance and the effect on re-epithelialization are determined.
REFERENCES
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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 imgf000035_0001
wherein
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C1-6-alkyl, optionally halogenated Cι-6-alkoxy, C1-6- 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 C1-6-acyl, C1-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C1-6- alkyl, optionally halogenated C1-6-alkoxy, amide which is optionally mono- or di- substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2- oxoethyl)-l,3-thiazol-2-yl]amino}carbonyl); R1 is hydrogen or C1-6-alkyl;
Ai and A2 are a nitrogen atom or C-Z, provided that Ai and A2 have different meanings, wherein: • Z is selected from an aryl ring or heteroaryl ring, which can further be optionally substituted in one or more positions independently of each other by hydrogen, C1-6- alkyl, halogenated Cι-6-alkyl, halogen, Cι-6-alkoxy, nitro, Cι-6-alkoxycarbonyl, Cι-6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy can further be optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R2, wherein
• X is CH2 or CO; • Y is CH2, CO or a single bond;
• R2 is selected from C]-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- moφholinolinylmethylene, C ι -6-alkoxycarbonyl, 5 -methyl- 1 ,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-furanylmethyl, N-carbethoxypiperidyl, or C1-6-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or
NR3R4 represent together heterocyclic systems which can be i idazole, piperidine, pyrrolidine, piperazine, moφholine, oxazepine, oxazole, thiomoφholine, 1,1- dioxidothiomoφholine, 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;
OCONR3R4, wherein R3 and R4 are each independently selected from hydrogen, C\- 6-alkyl or form together with the N-atom to which they are attached moφholinyl; . R5O, wherein R5 is hydrogen, optionally halogenated Cι-6-alkyL aryl, heteroaryl, Cι_ 6-acyl, Cι-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; 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)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, l-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- 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-mefhylsulfanylphenyl, 5-mefhyl-2- thienyl, 4-moφholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridyhnethylamino, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl;
R .1 is hydrogen or methyl;
Ai and A2 are a nitrogen atom or C-Z, provided that Ai and A2 have different meanings, wherein:
• Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-. R2, wherein
• X is CH2 or CO;
• Y is CH2, CO or a single bond; • R2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- moφholinolinylmethylene, ethoxycarbonyl, 5-methyl-l ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR3R4, wherein R3 and R4 are each independently selected from acetyl, benzhydryl, l,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (lS)-phenylethyl, n- propyl, tetrahyσ^o-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR3R4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-dimethylmoφholinyl, (2R)-2,4-dimethyl-l- piperazinyl, 2-hydroxy-3-oxomoφholinyl, imidazolyl, 2-methyl-3-oxomoφholinyl, 4- methyl-2-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 with the N-atom to which they are attached moφholinyl; R O, wherein R5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2 -triftuoroefhyl.
3. The method according to any one of claims 1 or 2, where the compound is selected from:
ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetate
(5 - { [(3 -chloro-2 -methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yl) acetic acid
2-(5- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yl)-N- methylacetamide
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2-yl)-N- ethylacetamide
2,5-dichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thιadiazόl-2- yl]benzenesulfonamide isopropyl (5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 , 3 ,4-thiadiazol-2- yl)acetate
3-chloro-N-[5-(2-hydroxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
3-chloro-N-[5-(2-ethoxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- diethylacetamide methyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetate
3-chloro-N-[5-(2-isopropoxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide 3-chloro-N-[5-(2-methoxyethyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2-(5- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yl)ethyl methanesulfonate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetamide
3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-l,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonamide
3-chloro-2-methyl-N-{5-[2-(232,2-trifluoroethoxy)ethyl]-l,3,4-thiadiazol-2- yl } benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl acetate
3-chloro-2-methyl-N-[5-(2-moφholin-4-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-[5-(2-bromoethyl)-l,3,4-thiadiazol-2-yl]-3-chloro-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]arhino}-l,3,4-thiadiazbl-2-yl)ethyl moφholine-4-carboxylate
2-(5- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yl)ethyl diethylcarbamate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl propionate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl 2- methylpropanoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl 2- furoate
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2-yl)ethyl benzoate
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2-yl)-N- methoxy-N-methylacetamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)ethyl ethylcarbamate N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)ethyl]-N-ethylacetamide
3-chloro-2-methyl-N-[5 -(2-oxoρentyl)- 1 ,3 ,4-thiadiazol-2- yl]benzenesulfonamide
N-{5-[2-(l,l-dioxidothiomoφholin-4-yl)-2-oxoethyl]-l,3,4-thiadiazol-2-yl}-4- propylbenzenesulfonamide
2,4,6-trichloro-N-[5-(2-moφholin-4-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4-dichloro-N-[5-(2-moφholin-4-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3-chloro-2-methyl-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
2,4-dichloro-6-methyl-N-[5-(2-moφholin-4-ylethyl)-l,3,4-thiadiazol-2- - yl]benzenesulfonamide N-[5-(2-moφholin-4-ylethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
2,4-.dichloro-6-methyl-N-[5-(2-moφholin--4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4,6-trichloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,l'-biphenyl-4- sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2-yl]-l,r-biphenyl-4- sulfonamide
N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol- 2-yl]benzenesulfonamide
N-[5-(2-oxo-2-piperidin- 1 -ylethyl)-l ,3,4-thiadiazol-2-yl]-l , 1 '-biphenyl-4- sulfonamide N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[5 -(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,3 ,4-thiadiazol-2- yl]benzenesulfonamide
2,4,6-trichloro-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide ethyl (5- {[(3-chloro-2-methylphenyl)sulfonyl]amino}-l ,3,4-thiadiazol-2- yl)(oxo)acetate
2-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,3,4-thiadiazol-2-yl}-N-ethyl-N- methylacetamide
N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetamide
2-(5- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yl)-N- ethyl-N-methylacetamide
N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3,4- thiadiazol-2-yl)acetamide
■, 2,4,6-trichloro-N-[5-(2-oxo-2-thiomoφholin^4-ylethyl)- 1 ,3,4-thiadiazol-2- yl]benzenesulfonamide
2- {5-[( 1 , 1 '-biphenyl-4-ylsulfonyl)amino]- 1 ,3 ,4-thiadiazol-2-yl} -N-isopropyl-N- methylacetamide
2-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,3,4-thiadiazol-2-yl}-N,N- diethylacetamide
N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yPjacetamide
2-(5- { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino} - 1 ,3 ,4-thiadiazol-2-yl)- N,N-diethylacetamide
N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetamide
2-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,3,4-thiadiazol-2-yl}-N,N- diisopropylacetamide
N,N-diisopropyl-2-(5- { [(4-propylphenyl)sulfonyl] amino } - 1 ,3 ,4-thiadiazol-2- yl)acetamide 2-(5- {[(2,4-dichloro-6-methylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2-yl)-
N,N-diisopropylacetamide
N,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-
2-yl)acetamide
4-propyl-N-(5-pyridin-3-yl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
3-chloro-N-[5-(5-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2,4,6-trichloro-N-(5-pyridin-3-yl- 1 ,3 ,4-thiadiazol-2-yl)benzenesulfonamide
2,4,6-trichloro-N-[5-(5-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-(5-pyridin-3 -yl- 1 ,3 ,4-thiadiazol-2-yl)- 1 , 1 '-biphenyl-4-sulfonamide
2,4-dichloro-6-methyl-N-(5-pyridin-3 -yl- 1 ,3 ,4-thiadiazol-2- yl)b enzenesulfonamide
2,4-dichloro-N-[5-(5-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- dipropylacetamide
3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-l-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4-dichloro-N-[5-(2,5-dimethyl-3-furyl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide
3-chloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2,4,6-trichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4-dichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-6- methylb enzenesulfonamide
4-bromo-2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]b enzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide 2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4- phenoxyb enzenesulfonamide
4-chloro-2,6-dimethyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4-dichloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide tert-butyl 4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)acetyl]piperazine-l-carboxylate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- dimethylacetamide
3 -chloro-2-methyl-N- {5- [2-(pyridin-3 -yloxy)ethyl] -1,3 ,4-thiadiazol-2- yl } benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- isopropyl-N-methylacetamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N- ethyl-N-methylacetamide
3-chloro-2-methyl-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3-chloro-2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2-yl)-N,N- diisopropylacetamide
3-chloro-2-methyl-N-[5-(2-oxo-2-pyrrolidin-l-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3-chloro-2-methyl-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3-chloro-2-methyl-N-[5-(moφholin-4-ylmethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3-chloro-N-{5-[2-(lH-imidazol-l-yl)ethyl]-l,3,4-thiadiazol-2-yl}-2- methylb enzenesulfonamide 2,4,5-trichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,3,4-trichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
4-bromo-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]-2,5- difluorobenzenesulfonamide
4-bromo-5-chloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide
2,6-dichloro-N-[5-(3-chlorothien-2-yl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)ethyl] acetamide
3-chloro-2-methyl-N-(5-{2-[(methylsulfonyl)amino]ethyl}-l,3,4-thiadiazol-2- yl)benzenesulfonamide
3-chloro-2-methyl-N-{5-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide .
3-chloro-2-methyl-N-{5-[2-(2-oxΘpyrrolidin-l-yl)ethyl]-l,3,44hiadiazol-2- yl}benzenesulfonamide
3-chloro-2-methyl-N-(5-{2-[methyl(methylsulfonyl)amino]ethyl}-l,3,4- thiadiazol-2-yl)benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)ethyl]-N-methylcyclopropanecarboxamide
3-chloro-2-methyl-N-{5-[2-(4-methyl-2-oxopiperazin-l-yl)efhyl]-l,3,4- thiadiazol-2-yl} benzenesulfonamide
3-chloro-2-methyl-N-[5-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-l,3,4- thiadiazol-2-yl]benzenesulfonamide
2,4-dichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
2,4-dichloro-6-methyl-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
2,4,6-trichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide 4-(2-furyl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
5'-fluoro-2'-methoxy-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]- 1 , 1 '-biphenyl-4-sulfonamide
4-(5-methylthien-2-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
3'-acetyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,r- biphenyl-4-sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4'- (trifluoromethoxy)- 1 , 1 '-biphenyl-4-sulfonamide
3',4'-dichloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,r- biphenyl-4-sulfonamide
4-(l,3-benzodioxol-5-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol- 2-yl]benzenesulfonamide 4-(5-chlorothien-2-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide..
N-[5-(2-moφholin-4-yl ;'2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-pyridin-4- ylbenzenesulfonamide
N-[4'-( { [5-(2-moφholin-4-yl-2-oxoethyl)- 1 ;3,4-thiadiazol-2- yl] amino} sulfonyl)- 1 , 1 '-biphenyl-3 -yl] acetamide N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-thien-3- ylbenzenesulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-4-thien-2- ylbenzenesulfonamide
4'-(methylthio)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l ,3,4-thiadiazol-2-yl]- 1 , 1 '- biphenyl-4-sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-3',5'- bis(trifluoromethyl)- 1 , 1 '-biphenyl-4-sulfonamide
4'-chloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-l,l"- biphenyl-4-sulfonamide
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3,4-thiadiazol-2-yl]-3,-nitro-l,l'- biphenyl-4-sulfonamide 3-chloro-2-methyl-N-[5-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)-
1 ,3 ,4-thiadiazol-2-yl]benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3,4-fhiadiazol-2- yl)ethyl]-l-methyl-lH-imidazole-4-sulfonamide
3-chloro-N-{5-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl} -2-methy lb enzenesulfonamide
4,5-dichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}thiophene-2-sulfonamide
N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2-yl}-4- phenoxybenzenesulfonamide
3-fluoro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2- yl}benzenesulfonamide
N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3,4-thiadiazol-2-yl}-5-pyridin-2- ylthiophene-2-sulfonamide
N-r{2-chloro-4-[({5-[2-(3-oxomoφholin-4-yl).ethyl]-l,3,4-thiadiazol-2- yl} amino)sulfonyl]phenyl} acetamide ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}÷l,2,4-thiadiazol-3- yl)acetate
(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)acetic acid
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3-yl)-N- methylacetamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- ethylacetamide
2,5-dichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide isopropyl (5- { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 - yl)acetate
3-chloro-N-[3-(2-hydroxyethyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-N-[3-(2-ethoxyethyl)-l,2,4-thiadiazol-5-yl]-2- methylb enzenesulfonamide
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3-yl)-N,N- diethylacetamide methyl (5- { [(3 -chloro-2 -methylphenyl)sulfonyl] amino } - 1 ,2,4-thiadiazol-3 - yl)acetate
3-chloro-N-[3-(2-isopropoxyethyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-N-[3-(2-methoxyethyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl methanesulfonate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide
3-chloro-N-{3-[2-(2-fluoroethoxy)ethyl]-l,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(2,2,2-trifluoroethoxy)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
2-(5- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,-4-thiadiazol-3-yI)efhyl acetate
3-chloro-2-methyl-N-[3r-(2-morpholin-4-ylethyl)-L2,4-thiadiazol-5- yl]benzenesulfonamide
N-[3-(2-bromoethyl)-l,2,4-thiadiazol-5-yl]-3-chloro-2- methylbenzenesulfonamide
2-(5 - { [(3-chloro-2-methylphenyl)sulfonyl] amino } - 1 ,2,4-thiadiazol-3-yl)ethyl moφholine-4-carboxylate
2-(5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 -yl)ethyl diethylcarbamate
2-(5 - { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,2,4-thiadiazol-3 -yl)ethyl propionate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl 2- methylpropanoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl 2- furoate
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl benzoate 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- methoxy-N-methylacetamide
3-chloro-N- {3-[2-(diethylamino)ethyl]- 1 ,2,4-fhiadiazol-5-yl} -2- methylbenzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)ethyl ethylcarbamate
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)ethyl]-N-ethylacetamide
3-chloro-2-methyl-N-[3-(2-oxopentyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
N-{3-[2-(l,l-dioxidothiomoφholin-4-yl)-2-oxoethyl]-l,2,4-thiadiazol-5-yl}-4- propylbenzenesulfonamide
2,4,6-trichloro-N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-(2-moφholin-4-ylethyl)-I,2,4.-thiadiazol-5- yl]benzenesulfonamide
3rchloro-2-methyl-NH{3-[2-(3-oxomoφholin-4^yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
N-[3-(2-moφholin-4-ylethyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4,6-trichloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,l'-biphenyl-4- sulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4- propylb enzenesulfonamide
N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5-yl]-l,r-biρhenyl-4- sulfonamide N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5-yl]-4- propylb enzenesulfonamide
2,4-dichloro-6-methyl-N-[3 -(2-oxo-2-thiomoφholin-4-ylethyl)- 1 ,2,4-thiadiazol-
5 -yl]b enzenesulfonamide
N-[3-(2-oxo-2-piperidin-l-ylethyl)-l,2,4-thiadiazol-5-yl]-l,l'-biphenyl-4- sulfonamide
N-[3-(2-oxo-2-piperidin-l-ylethyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
2,4-dichloro-6-methyl-N-[3-(2-oxo-2-piperidin-l-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4,6-trichloro-N-[3-(2-oxo-2-piperidin-l-ylethyl)-l52,4-thiadiazol-5- yl]benzenesulfonamide
N-(3-phenyl- 1 ,2,4-thiadiazol-5-yl)-4-propylbenzenesulfonamide ethyl (5 - { [(3-chloro-2-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 - yl)(oxo)acetate
3-chloro-2-methyl-N-(3-phenyl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
3^chloro-N-[3-(4-fluoro-3-methylρhenyl)-l 2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide "
2,4,6-trichloro-N-(3-phenyl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
N-(3 -phenyl- 1 ,2,4-thiadiazol-5 -yl)- 1 , 1 '-biphenyl-4-sulfonamide
2,4-dichloro-6-methyl-N-(3-phenyl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
2-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,2,4-thiadiazol-3-yl}-N-ethyl-N- methylacetamide
N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide
2-(5 - { [(2,4-dichloro-6-methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 -yl)-N- ethyl-N-methylacetamide
N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,2,4- thiadiazol-3-yl)acetamide
2,4,6-trichloro-N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2- {5-[(l , 1 '-biphenyl-4-ylsulfonyl) amino] -1 ,2,4-thiadiazol-3-yl} -N-isopropyl-N- methylacetamide 2- {5-[(l ,r-biphenyl-4-ylsulfonyl)amino]-l ,2,4-thiadiazol-3-yl} -N,N- diethylacetamide
N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl) acetamide
2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-
N,N-diethylacetamide
N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide
2-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,2,4-thiadiazol-3-yl}-N,N- diisopropylacetamide
N,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)acetamide
2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-
N,N-diisopropylacetamide
N,N-diisopropyl-2-(5 - { [(2,4,6-trichlorophenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-
3-yl)acetamide
N-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-l,2-,4-thiadiazol-3- yl)phenyl] acetamide
4-propyl-N-(3-pyridin-3-yl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
N-[3-(2-chloro-5-nitrophenyl)- 1 ,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide
3-chloro-N-[3-(2-chloro-5-nitroρhenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-N-[3-(5-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
2,4,6-trichloro-N-(3-pyridin-3-yl-l,2,4-thiadiazol-5-yl)benzenesulfonamide
2,4,6-trichloro-N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide 2,4,6-trichloro-N-[3-(5-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4,6-trichloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]benzenesulfonamide
N-(4-{5-[(l,r-biphenyl-4-ylsulfonyl)amino]-l,2,4-thiadiazol-3- yl } phenyl) acetamide
N-(3-pyridin-3-yl-l,2,4-thiadiazol-5-yl)-l,r-biphenyl-4-sulfonamide
N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5-yl]-l,l'-biρhenyl-4- sulfonamide
N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]-l,r-biphenyl-4-sulfonamide
N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfo'nyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
2,4-dichloro-6-methyl-N-(3-pyridin-3-yl-l,2,4-thiadiazol-5- yl)benzenesulfonamide
2,4-dichloro-N-[3-(2-chloro-5-nitrophenyl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
2,4-dichloro-N-[3-(5-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
2-(5-{[(3-chlofo-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N,N- dipropylacetamide
3-chloro-2-methyl-N-[3-(2-oxo-2-piperazin-l-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-(2,5-dimethyl-3-furyl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide
3-chloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
254,6-trichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
2,4-dichloro-N-[3-(2-chlorophenyl)- 1 ,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide 4-bromo-2-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide
2-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-
(trifluoromethoxy)benzenesulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4- phenoxyb enzenesulfonamide
4-chloro-2,6-dimethyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,4-dichloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide tert-butyl 4- [(5 - { [(3 -chloro-2 -methylphenyl)sulfonyl] amino} - 1 ,2,4-thiadiazol-3 - yl)acetyl]piperazine- 1 -carboxylate '
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N,N- dimethylacetamide
3-chloro-2-methyl-N-{:3τ[2.-(pyridin-3-yloxy)ethyl]-l,2,4-thiadiazol- 5- yl}b enzenesulfonamide . ,
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- isopropyl-N-methylacetamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N- ethyl-N-methylacetamide
3-chloro-2-methyl-N-[3-(2-oxo-2-thiomoφholin-4-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
3-chloro-2-methyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3-yl)-N,N- diisopropylacetamide
3 -chloro-2-methyl-N-[3 -(2-oxo-2-pyrrolidin- 1 -ylethyl)- 1 ,2,4-thiadiazol-5- yl]benzenesulfonamide
3-chloro-2-methyl-N-[3-(2-oxo-2-piperidin-l-ylethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide 3-chloro-2-methyl-N-[3-(moφholin-4-ylmethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
3-chloro-N-{3-[2-(lH-imidazol-l-yl)ethyl]-l,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide
2,4,5-trichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,3,4-trichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
2,3,4-trichloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]benzenesulfonamide
N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
4-bromo-N-[3-(3-chlorothien-2-yl)-l,2,4-thiadiazol-5-yl]-2,5- difluorobenzenesulfonamide
4,5-dichloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide .
N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
4-bromo-5-chloro-N-[3-(3-chlor thien-2-yl)-l,2,4-thiadiazol-5-yl]thiophene-2- ' sulfonamide
3-bromo-5-chloro-N-[3-(2-chlorophenyl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide
N-[4-(5- {[(2,6-dichlorophenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3- yl)phenyl] acetamide
2,6-dichloro-N-[3-(3-chlorothien-2-yl)-l,2,4-tlιiadiazol-5- yl]benzenesulfonamide
N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)ethyl] acetamide
3-chloro-2-methyl-N-(3-{2-[(methylsulfonyl)amino]ethyl}-l,2,4-thiadiazol-5- yl)benzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
3-chloro-2-methyl-N-{3-[2-(2-oxoρyrrolidin-l-yl)ethyl]-l,2,4-thiadiazol-5- . yl}benzenesulfonamide 2,3,4-trichloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,2,4-thiadiazol-
5-yl}benzenesulfonamide
N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide
4-bromo-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,2,4-thiadiazol-5-yl}-
2, 5 -difluorobenzenesulfonamide
4,5-dichloro-N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide
4-bromo-5 -chloro-N- { 3 - [2, 6-dichloro-4- (trifluoromethyl)phenyl] -1,2,4- thiadiazol-5-yl}thiophene-2-sulfonamide
2,4-dichloro-N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
4-bromo-N-[3-(2-chloro-6-fluorophenyl)-l,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide
3-chloro-2-methyl-N-(3-{2-[methyl(methylsulfonyl)amino]ethyl}-.l,2,4- thiadiazol-5-yl)benzenesulfonamide
N-[27(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}:-l,2,4-thiadiazol-3- yl)ethyl]-N-methylcyclopropanecarboxamide
3-chloro-2-methyl-N-{3-[2-(4-methyl-2-oxopiperazin-l-yl)ethyl]-l,2,4- thiadiazol-5-yl}benzenesulfonamide
3-chloro-2-methyl-N-[3-(2- { [(trifluoromethyl)sulfonyl] amino} ethyl)-l ,2,4- thiadiazol-5-yl]benzenesulfonamide
N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)phenyl] acetamide
2,4-dichloro-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl } benzenesulfonamide
2,4-dichloro-6-methyl-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} b enzenesulfonamide
2,4,6-trichloro-N- {3-[2-(3-oxomoφholin-4-yl)ethyι)- 1 ,2,4-thiadiazol-5- yl]benzenesulfonamide
4-(2-furyl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide 5'-fluoro-2'-methoxy-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]- 1 , 1 '-biphenyl-4-sulfonamide
4-(5-methylthien-2-yl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
3'-acetyl-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,r- biphenyl-4-sulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4'- (trifluoromethoxy)- 1 , 1 '-biphenyl-4-sulfonamide
3,,4'-dichloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,r- biphenyl-4-sulfonamide
4-(l,3-benzodioxol-5-yl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol- 5 -yl]b enzenesulfonamide
4-(5-chlorothien-2-yl)-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5- yl]benzenesulfonamide
N-[3-(2-moφholin-4-yl-2τ,oxoethyl)-l,2,4-thiadiazol-.5-yl]-4-pyridin-4- .ylbenzenesulfonamide ..
^N-[4'-( [3-(2-moφholin-4-yl-2.-oxoethyl)-lv2,4-thiadiazol-5- yl] amino } sulfonyl)- 1 , 1 '-bipheny 1-3 -yl] acetamide N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-thien-3- ylbenzenesulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-4-thien-2- ylbenzenesulfonamide
4'-(methylthio)-N-['3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,r- biphenyl-4-sulfonamide
N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-3',5'- bis(trifluoromethyl)- 1 , 1 '-biphenyl-4-sulfonamide 4'-chloro-N-[3-(2-moφholin-4-yl-2-oxoethyl)-l,2,4-thiadiazol-5-yl]-l,r- biphenyl-4-sulfonamide
N-[3 -(2-moφholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl] -3 '-nitro- 1,1'- biphenyl-4-sulfonamide
3-chloro-2-methyl-N-[3-(2-{methyl[(trifluoromethyl)sulfonyl]amino}ethyl)- l,2,4-thiadiazol-5-yl]benzenesulfonamide N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,2,4-thiadiazol-3- yl)ethyl] - 1 -methyl- 1 H-imidazole-4-sulfonamide
3-chloro-N-{3-[2-(2-hydroxy-3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} -2-methylbenzenesulfonamide
4,5-dichloro-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} thiophene-2-sulfonamide
N- {3-[2-(3-oxomoφholin~4-yl)ethyl]-l ,2,4-thiadiazol-5-yl} -4- phenoxybenzenesulfonamide
3-fluoro-N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl}benzenesulfonamide
N-{3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5-yl}-5-pyridin-2- ylthiophene-2-sulfonamide
N-{2-chloro-4-[({3-[2-(3-oxomoφholin-4-yl)ethyl]-l,2,4-thiadiazol-5- yl} amino)sulfonyl]phenyl} acetamide.
3-chloro-N-{5-[2-(diethylamino)ethyl]-l,3,4-thiadi.azol-2-yl}-2- methylbenzenesulfonamide
N-(5-phenyl-l,3,4-thiadiazol-2-yl)-4-pEopylhenzenesulfonamide
3-chloro-2-methyl-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
3-chloro-N-[5-(4-fluoro-3-methylphenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
2,4,6-trichloro-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
N-(5-phenyl- 1 ,3 ,4-thiadiazol-2-yl)- 1 , 1 '-biphenyl-4-sulfonamide
2,4-dichloro-6-methyl-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
N-[4-(5- {[(4-propylphenyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2- yl)phenyl] acetamide
N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide
3-chloro-N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
3-chloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2- yl]benzenesulfonamide
2,4,6-trichloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]benzenesulfonamide
N-(4- {5-[(l ,1 '-biphenyl-4-ylsulfonyl)amino]-l ,3,4-thiadiazol-2- yl } phenyl) ac etamide
N- [5-(2-chloro-5 -nitrophenyl)- 1 ,3 ,4-thiadiazol-2-yl]- 1 , 1 '-biphenyl-4- sulfonamide
N-[5-(2-chlorophenyl)- 1 ,3,4-thiadiazol-2-yl]-l , 1 '-biphenyl-4-sulfonamide
N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
2,4-dichloro-N-[5-(2-chlorophenyl)- 1 ,3,4-thiadiazol-2-yl]-6- methylb enzenesulfonamide .
2,3,4-trichloro-N-[5-(2-chlofophenyl)-l,3,4-thiadiazol-2-yl]benzenesulfonamide
N-[4-(5-{[(4-bromo-2,5-diflύorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
4,5-dichloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide
N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
3-bromo-5-chloro-N-[5-(2-chlorophenyl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide
N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-l,3,4-thiadiazol-2- yl)phenyl] acetamide
2,3,4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3,4-thiadiazol-
2-yl} benzenesulfonamide
N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide
4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3,4-thiadiazol-2-yl}-
2,5-difluorobenzenesulfonamide • 4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide
• 4-bromo-5-chloro-N- { 5 - [2,6-dichloro-4-(trifluoromethyl)phenyl]- 1 ,3 ,4- thiadiazol-2-yl}thiophene-2-sulfonamide • 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide
• 4-bromo-N-[5-(2-chloro-6-fluorophenyl)-l,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide
• N-[4-(5- { [(4-bromo-5 -chloro thien-2-yl)sulfonyl] amino } - 1 ,3 ,4-thiadiazol-2- yl)phenyl] acetamide.
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 medicaLcondition involving delayed or impaired wound healing is diabetes.
6. The method according to claim 4_wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
7. The method according to any one of claims 1 to 3 for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
8. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for promoting wound healing, said compound being an inhibitor of 11-β- hydroxysteroid dehydrogenase type 1.
9. The use according to claim 8 in the manufacture of a medicament for the treatment of prophylaxis of a medical condition involving delayed or impaired wound healing.
10. The use according to claim 9 wherein the medical condition involving delayed or impaired wound healing is diabetes.
11. The use according to claim 9 wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
12. The use according to claim 8 in the manufacture of a medicament for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
PCT/SE2004/000798 2003-06-25 2004-05-21 Use of an inhibitor of 11-b-hydroxysteroid dehydrogenase type 1 compounds for promoting wound healing WO2004113310A1 (en)

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SE0301887-6 2003-06-25
SE0301889-2 2003-06-25
US49470103P 2003-08-12 2003-08-12
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