WO2004112783A1

WO2004112783A1 - New use iv

Info

Publication number: WO2004112783A1
Application number: PCT/SE2004/000959
Authority: WO
Inventors: Cecilia Nilsson; Catrine Dreifeldt
Original assignee: Biovitrum Ab
Priority date: 2003-06-25
Filing date: 2004-06-16
Publication date: 2004-12-29
Also published as: SE0301885D0

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 (11ß-HSD1), said 11ß-HSD1 inhibitor having the formula (I) wherein T, A, and B are as defined in the specification. These compounds may also be used in the manufacture of a medicament for promoting wound healing.

Description

NEW USE IV

RELATED APPLICATIONS

This application claims priority to Swedish application number 0301885-0, filed on June 25, 2003, the contents of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to the use of chemical compounds for wound healing, said compounds acting on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (llβHSDl).

BACKGROUND ART

Cortisol performs a broad range of metabolic functions and other functions. The multitude of glucocorticoid action is exemplified in patients with prolonged increase in plasma glucocorticoids, so called "Cushing's syndrome". Patients with Gushing' s syndrome have prolonged increase in plasma glucocorticoids and exhibit impaired glucose tolerance, type 2 diabetes, central obesity, and osteoporosis. These patients also have impaired wound healing and brittle skin ( 1 ).

Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds (2). Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery (3).

The European patent application No. EP 0902288 discloses a method for diagnosing the status of wound healing in a patient, comprising detecting cortisol levels in said wound. The authors suggest that elevated levels of cortisol in wound fluid, relative to normal plasma levels in healthy individuals, correlates with large, non-healing wounds (4). In humans, the 1 lβ-HSD catalyzes the conversion of cortisol to cortisone, and vice versa. The parallel function of 1 lβ-HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5). Two isoenzymes of 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. 11 β-HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).

Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, angiogenesis, wound contraction and epithelialization. It can be divided in three phases; inflammatory, proliferative and remodeling phase (reviewed in (2)).

In surgical patients, treatment with glucocorticoids increases risk of wound infection and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF-β, EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).

WO 01/90092 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 11 β-HSDl inhibitors are disclosed in e.g. WO 01/90090; WO 01/90091 ; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/044009; WO 03/043999; and Swedish patent application No. SE 0301504-7, filed on May 21, 2003. WO 02/072084 relates to glycyrrhetinic acid derivatives, progesterone and progesterone derivatives as 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 llβ-HSDl are useful for the promotion of wound healing. Consequently, in a first aspect this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 1 lβ-hydroxysteroid dehydrogenase type 1, wherein the inhibitor of 11 β- hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):

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, halogen, Cι-6-alkyl, and aryl;

A 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_halky!, halogenated C_1-6-alkyL halogen, C_1-6-alkoxy, nitro, Cι_-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; and

B is selected from hydrogen and C_1-6-alkoxycarbonyl or is linked to A to give a 6- membered aromatic or non-aromatic ring; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.

It is preferred that:

T is selected from thienyl substituted with one or more of bromo, chloro; and phenyl optionally substituted with one or more of chloro, methyl, propyl, phenyl, bromo, fluoro;

A 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;

B is selected from hydrogen, carbethoxy or is linked to A to give a 6-membered aromatic or non-aromatic ring.

The following compounds are especially preferred:

Ethyl 2-(2- { [(4-chlorophenyl)sulfonyl] a ino} - 1 ,3-thiazol-4-yl)benzoate,

2,5-Dichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide,

4-Chloro-N-[4-(4,5-dichloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, Ethyl 2- {[(4-chlorophenyl)sulfonyl] amino} -4-phenyl- 1 ,3-thiazole-5-carboxylate, Ethyl 2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-4-phenyl-l,3-thiazole-5- carboxylate,

N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-(4-phenyl- 1 ,3-thiazol-2-yl)-4-propylbenzenesulfonamide, N-[4-(4-fluoro-3-methylphenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, 3-Chloro-2-methyl-N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 3-Chloro-2-methyl-N-(4-phenyl-l,3-thiazol-2-yl)benzenesulfonamide, 3-Chloro-N-[4-(4-fluoro-3-methylphenyl)-l,3-thiazol-2-yl]-2- methylbenzenesulfonamide, 2,4,6-Trichloro-N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-(4-phenyl-l,3-thiazol-2-yl)benzenesulfonamide,

2,4,6-Trichloro-N-[4-(4-fluoro-3-methylphenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]benzenesulfonamide, N-[4-(3-nitrophenyl)- 1 ,3-thiazol-2-yl] [1 , 1 '-biphenyl]-4-sulfonamide, N-(4-phenyl- 1 ,3-thiazol-2-yl)[ 1 , 1 '-biphenyl] -4-sulfonamide, N-[4-(4-Fluoro-3-methylphenyl)-l,3-thiazol-2-yl][l,l'-biphenyl]-4-sulfonamide, N-[4-(4-Methoxyphenyl)-l,3-thiazol-2-yl][l,r-biphenyl]-4-sulfonamide, 2,4-Dichloro-6-methyl-N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4-Dichloro-6-methyl-N-(4-phenyl-l,3-thiazol-2-yl)benzenesulfonamide, 2,4-Dichloro-N-[4-(4-fluoro-3-methylρhenyl)-l,3-thiazol-2-yl]-6- methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, N-[4-(2- { [(4-propylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-4-yl)phenyl] acetamide, 4-Propyl-N-[4-(3-pyridinyl)- 1 ,3 -thiazol-2-yl]benzenesulfonamide, N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-(7-methoxy-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2-yl)-4- propylbenzenesulfonamide,

N-[4-(5-chloro-2-thienyl)- 1 ,3-thiazol-2-yl] -4-propylbenzenesulfonamide, N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-[4-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)phenyl] acetamide,

3-Chloro-2-methyl-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, 3-Chloro-N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-Chloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)-2- methylbenzenesulfonamide, 3-Chloro-N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-Chloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, N-[4-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)phenyl]acetamide, 2,4,6-Trichloro-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2- yl)benzenesulfonamide, 2,4,6-Trichloro-N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, N-(4- {2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-l ,3-thiazol-4-yl}phenyl)acetamide, N-[4-(3-ρyridinyl)- 1 ,3-thiazol-2-yl] [1,1 '-biphenyl]-4-sulfonamide, N-[4-(2-chloro-5-nitrophenyl)-l ,3-thiazol-2-yl] [1,1 '-biphenylj-4-sulfonamide, N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)[l,l'-biphenyl]-4- sulfonamide,

N-[4-(5-chloro-2-thienyl)- 1 ,3-thiazol-2-yl] [1,1 -biρhenyl]-4-sulfonamide, N-[4-(2-chlorophenyl)- 1 ,3-thiazol-2-yl] [1,1 '-biphenyl]-4-sulfonamide, N-[4-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)phenyl]acetamide,

2,4-Dichloro-6-methyl-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4-Dichloro-N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]-6- methylbenzenesulfonamide, 2,4-Dichloro-N-(7-methoxy-4,5-dihydronaphtho[ 1 ,2-d][ 1 ,3]thiazol-2-yl)-6- methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, 2,4-Dichloro-N-[4-(2,5-dimethyl-3-furyl)-l,3-thiazol-2-yl]-6- methylbenzenesulfonamide, N-[4-(l-benzothien-3-yl)-l,3-thiazol-2-yl]-2,4-dichloro-6-methylbenzenesulfonamide, N-[4-(3-chloro-2-thienyl)- 1 ,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

3-Chloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-2 -methylbenzenesulfonamide, 2,4,6-Trichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4-Dichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, 2,4-Dichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, Ethyl 2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-4-phenyl- 1 ,3-thiazole-5-carboxylate, 3-Chloro-N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-2 -methylbenzenesulfonamide, N-[4-(2-{[(4-Bromo-2,5-difluoroρhenyl)sulfonyl]amino}-l,3-thiazol-4- yl)phenyl]acetamide,

2,3,4-Trichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]benzenesulfonamide,

2,4,5-Trichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, 5 2,3,4-Trichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide,

4-Bromo-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-2,5-difluorobenzenesulfonamide,

4,5-Dichloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)-2- thiophenesulfonamide,

4,5-Dichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-2-thiophenesulfonamide, l o N-[4-(2- { [(2,4,5-Trichlorophenyl)sulfonyl] amino} - 1 ,3-thiazol-4-yl)phenyl] acetamide,

2,3 ,4-Trichloro-N-(7-methoxy-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2- yl)benzenesulfonamide,

4-Bromo-5-chloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-2-thiophenesulfonamide,

3-Bromo-5-chloro-N-(7-methoxy-4,5-dihydronaρhtho[l,2-d][l,3]thiazol-2-yl)-2- 15 thiophenesulfonamide,

3 -Bromo-5 -chloro-N- [4-(2-chlorophenyl)- 1 ,3 -thiazol-2-yl] -2-thiophenesulfonamide,

N-[4-(2- {[(2,6-Dichlorophenyl)sulfonyl]amino} - 1 ,3-thiazol-4-yl)phenyl]acetamide,

2,6-Dichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-(7,8-dimethoxy-4,5-dihydronaρhtho[l,2-d][l,3]thiazol-2- 20 yl)benzenesulfonamide,

2,3,4-Trichloro-N- {4-[2-chloro-4-(4-chlorophenoxy)phenyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide,

2,3,4-Trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2- yl}benzenesulfonamide, 25 N-[4-(2-Chloro-6-fluorophenyl)- 1 ,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

4-Bromo-N-{4-[2-chloro-4-(4-chlorophenoxy)phenyl]-l,3-thiazol-2-yl}-2,5- difluorobenzenesulfonamide,

4-Bromo-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2,5- difluorobenzenesulfonamide, 30 4,5-Dichloro-N-[4-(2-chloro-6-fluorophenyl)-l,3-thiazol-2-yl]-2-thiophenesulfonamide,

4-Bromo-5-chloro-N-{4-[2-chloro-4-(4-chlorophenoxy)phenyl]-l,3-thiazol-2-yl}-2- thiophenesulfonamide, 4-Bromo-5-chloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2- thiophenesulfonamide,

2,4-Dichloro-N-[4-(2-chloro-6-fluoroρhenyl)-l,3-thiazol-2-yl]-6- methylbenzenesulfonamide, 2,4,6-Trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2- yl}benzenesulfonamide,

4-Bromo-N-[4-(2-chloro-6-fluorophenyl)-l,3-thiazol-2-yl]-2- methylbenzenesulfonamide,

2,4,6-Trichloro-N-{4-[2-chloro-4-(4-chloroρhenoxy)ρhenyl]-l,3-thiazol-2- yl}benzenesulfonamide,

N-[4-(2-{[(4-Bromo-5-chloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4- yl)phenyl]acetamide,

N-(4,5-Dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)benzenesulfonamide,

3,4-Dichloro-N-(4,5-dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)benzenesulfonamide, 3-Chloro-N-(4,5-dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)-2- methylbenzenesulfonamide,

2,4,6-Trichloro-N-(4,5-dihydrothieno[3,2-e] [ 1 ,3]benzothiazol-2- yl)benzenesulfonamide,

N-(4,5-Dihydrothieno[3 ,2-e] [ 1 ,3]benzothiazol-2-yl)[ 1 , 1 '-biphenyl]-4-sulfonamide, 2,4-Dichloro-N-(4,5-dihydrothieno[3,2-e] [ 1 ,3]benzothiazol-2-yl)-6- methylbenzenesulfonamide,

N-(4,5-Dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)-4-propylbenzenesulfonamide,

3-Chloro-N-[6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][l,3]benzothiazol-2- yl]-2 -methylbenzenesulfonamide, N-[6-Chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][l,3]benzothiazol-2-yl]-4- propylbenzenesulfonamide,

2,4-Dichloro-N-[6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4- e] [ 1 ,3]benzothiazol-2-yl]-6-methylbenzenesulfonamide,

N-[6-Chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e] [ 1 ,3]benzothiazol-2-yl] [1 , 1 '- biphenyl]-4-sulfonamide,

N- {2-[(Phenylsulfonyl)amino] -4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-6-yl} acetamide, N-(2- {[(3-Chloro-2-methylρhenyl)sulfonyl]amino}naphtho[ 1 ,2-d] [ 1 ,3]thiazol-6- yl)acetamide,

N-(2-{[(4-Propylphenyl)sulfonyl]amino}-4,5-dihydronaphtho[l,2-d][l,3]thiazol-6- yl)acetamide, N-(8-Nitro-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2-yl)-4-propylbenzenesulfonamide, N-(8-Nitro-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)benzenesulfonamide, and N-(8-Nitro-4,5-dihydronaρhtho[l,2-d][l,3]thiazol-2-yl)[l,r-biρhenyl]-4-sulfonamide.

In one aspect of the invention, the said method is a method for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.

Examples of such medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids. The method according to the invention is also intended for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.

The compounds referred to above may also be used in the manufacture of a medicament for promoting wound healing, e.g. for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing. Examples of such medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids. The compounds referred to above may also be used for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.

The various terms used, separately and in combinations, in the above definition of the compounds having the formula (I) will be explained.

The term "aryl" in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph) and naphthyl, which optionally may be substituted by C_1-6-alkyl. Examples of substituted aryl groups are benzyl, and 2-methylphenyl. The term "heteroaryl" means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3- benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4- tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5-naphthyridine, 1,8- naphthyridine, acridine, fenazine and xanthene. Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazme, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.

The term "heterocyclic" in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and 1,4-oxazepane.

Cι_6~alkyl in the compound of formula (I) according to the present application, which may be straight, branched or cyclic, is preferably Cχ_4-alkyl. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl. For parts of the range "C_1-6-alkyl" all subgroups thereof are contemplated such as d-s-alkyl, C_1-4-alkyl, C_2-6-alkyl, C_2-5-alkyl, C_2-4-alkyl, C_2-3- alkyl, C_3-6-alkyl, C -5-alkyl, etc. Cj.g-alkoxy, in the compound of formula (I) according to the present application may be straight or branched, is preferably Cι_4-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy. For parts of the range "C_1-6-alkoxy" all subgroups thereof are contemplated such as Cj.s-alkoxy, C_1- -alkoxy, C_2-6-alkoxy, C₂-₅- alkoxy, C_2-4-alkoxy, C_2-3-alkoxy, C _-6-alkoxy, C_4-5-alkoxy, etc.

Ci-g-acyl, in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably Cι_4-acyl. Exemplary acyl groups include foraiyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3- butenoyl), hexenoyl (e.g. 5-hexenoyl). For parts of the range "C_1-6-acyl" all subgroups thereof are contemplated such as C_1-5-acyl, C_1-4-acyl, C_2-6-acyl, C_2-5-acyl, C_2-4-acyl, C_2- ₃-acyl, C_3-6-acyl, C_4-5-acyl, etc.

C_2-6-alkenyl in the compound of formula (I) according to the present application, which may be straight, branched or cyclic, is preferably C_2-4-alkenyl. Exemplary alkenyl groups include vinyl, 1-proρenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl. For parts of the range "C_2-6-alkenyl" all subgroups thereof are contemplated such as C _-5-alkenyl, C_2-4-alkenyl, C_2-3-alkenyl, C_3- ₆-alkenyl, C -₅-alkenyl, etc.

The term "halogen" in the present description is intended to include fluorine, chlorine, bromine and iodine.

With the expression mono- or di-substituted is meant in the present description that the functionalities in question may be substituted with independently H, Cι_-6-acyl, C_1-6- alkenyl, C_1-6-(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, which heterocyclic rings optionally may be substituted with C_1-6-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 purposes detailed herein (e.g., therapeutic administration 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 Gil an'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, aleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.

The compounds of formula (I) can be prepared according to the methods described in WO 01/90092. 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 KKA^y mice underwent surgery during anesthesia whereby a catheter was inserted in the jugularis vein. Oral treatment twice daily (200 mg/kg/day) with the llβ- HSDl inhibitor BVT.2733 (disclosed as Example 172A in WO 01/90090), or vehicle started 4-6 days later and continued for 3.5 days.

Advantageous effects on wound healing of the surgical wounds were observed during treatment. In BVT.2733 treated mice, less complication were observed in and around the wound area as compared to control mice. Examples of advantageous effects were less pus in the wound, as well as better wound strength. 58 % of the vehicle treated animals showed complications during treatment period whereas complications were present in only 24 % of the BVT.2733 treated animals.

EXAMPLE 2

(a)

Advantageous effects of llβ-HSDl inhibitors (e.g. BVT.2733) on wound healing are confirmed in diabetic KKA^y 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 immxmostaining against the von Willebrand factor to determine revascularisation. (b)

Advantageous effects of llβ-HSDl inhibitors are confirmed in in vitro studies. Proliferation of human keratinocytes and fibroblasts, which are important cell types in the wound healing process, are studied after incubation with the 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

1. Ganong WF. Review of Medical Physiology. Eighteenth edition ed. Stamford, Connecticut: Appleton & Lange; 1997.

2. Anstead GM. Steroids, retinoids, and wound healing. Adv Wound Care 1998;l l(6):277-85.

3. Diethelm AG. Surgical management of complications of steroid therapy. Ann Surg l977;185(3):251-63.

4. Hutchinson TC, Swaniker HP. Wound diagnosis by quantitating cortisol in wound fluids. European patent application No. EP 0 902 288, published 17.03.1999.

5. Frey FJ, Escher G, Frey BM. Pharmacology of 11 beta-hydroxysteroid dehydrogenase. Steroids 1994;59(2):74-9.

6. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994;105(2):Rl l-7.

7. Monder C, White PC. 11 beta-hydroxysteroid dehydrogenase. Vitam Horm 1993;47:187-271.

8. Stewart PM, Krozowski ZS. 11 beta-Hydroxysteroid dehydrogenase. Vitam Horm 1999;57:249-324.

9. Stokes J, Noble J, Brett L, Phillips C, Seckl JR, O'Brien C, et al. Distribution of glucocorticoid and mineralocorticoid receptors and 1 lbeta-hydroxysteroid dehydrogenases in human and rat ocular tissues. Invest Ophthalmol Vis Sci 2000;41(7):1629-38.

10. Hammami MM, Siiteri PK. Regulation of 11 beta-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J Clin Endocrinol Metab 1991;73(2):326-34.

11. Cooper MS, Moore J, Filer A, Buckley CD, Hewison M, Stewart PM. 1 lbeta- hydroxysteroid dehydrogenase in human fibroblasts: expression and regulation depends on tissue of origin. ENDO 2003 Abstracts 2003.

12. Teelucksingh S, Mackie AD, Burt D, Mclntyre MA, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990;335(8697):1060-3.

13. Slight SH, Chilakamarri VK, Nasr S, Dhalla AK, Ramires FJ, Sun Y, et al. Inhibition of tissue repair by spironolactone: role of mineralocorticoids in fibrous tissue formation. Mol Cell Biochem 1998;189(l-2):47-54.

14. Mercado AM, Quan N, Padgett DA, Sheridan JF, Marucha PT. Restraint stress alters the expression of interleukin-1 and keratinocyte growth factor at the wound site: an in situ hybridization study. J Neuroimmunol 2002;129(l-2):74-83.

15. Rojas IG, Padgett DA, Sheridan JF, Marucha PT. Stress-induced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav Immun 2002;16(l):74-84.

16. Beer HD, Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm 2000;59:217-39.

17. Hamon GA, Hunt TK, Spencer EM. In vivo effects of systemic insulin-like growth factor-I alone and complexed with insulin-like growth factor binding protein-3 on corticosteroid suppressed wounds. Growth Regul 1993;3(l):53-6.

18. Laato M, Heino J, Kahari VM, Niinikoski J, Gerdin B. Epidermal growth factor (EGF) prevents methylprednisolone-induced inhibition of wound healing. J Surg Res 1989;47(4):354-9.

19. Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Gramates P, Deuel TF. Transforming growth factor beta reverses the glucocorticoid-induced wound-healing deficit in rats: possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci U S A 1989;86(7):2229-33. 20. Oishi Y, Fu ZW, Ohnuki Y, Kato H, Noguchi T. Molecular basis of the alteration in skin collagen metabolism in response to in vivo dexamethasone treatment: effects on the synthesis of collagen type I and III, collagenase, and tissue inhibitors of metalloproteinases. Br J Dermatol 2002;147(5):859-68.

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):

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, halogen, Cι_-6-alkyl, and aryl;

A 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-(5-alkyl, halogen, d-₆-alkoxy, nitro, C_1-6-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;

B is selected from hydrogen and Cι-6-alkoxycarbonyl or is linked to A to give a 6- membered aromatic or non-aromatic ring;

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 thienyl substituted with one or more of bromo, chloro; phenyl optionally substituted with one or more of chloro, methyl, propyl, phenyl, bromo, fluoro;

A 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-chloroρhenoxy, trifluoromethyl;

3. The method according to any one of claims 1 or 2, wherein the compound is selected from:

Ethyl 2-(2-{[(4-chlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)benzoate,

2,5-Dichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide,

4-Chloro-N-[4-(4,5-dichloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, Ethyl 2-{[(4-chlorophenyl)sulfonyl]amino}-4-phenyl-l,3-thiazole-5-carboxylate, Ethyl 2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-4-phenyl-l,3-thiazole-5- carboxylate,

N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-(4-phenyl-l,3-thiazol-2-yl)-4-propylbenzenesulfonamide, N-[4-(4-fluoro-3-methylphenyl)- 1 ,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, 3-Chloro-2-methyl-N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 3-Chloro-2-methyl-N-(4-phenyl-l,3-thiazol-2-yl)benzenesulfonamide, 3-Chloro-N-[4-(4-fluoro-3-methylphenyl)- 1 ,3-thiazol-2-yl]-2- methylbenzenesulfonamide,

2,4,6-Trichloro-N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-(4-phenyl-l,3-thiazol-2-yl)benzenesulfonamide, 2,4,6-Trichloro-N-[4-(4-fluoro-3-methylphenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]benzenesulfonamide, N-[4-(3-nitrophenyl)- 1 ,3-thiazol-2-yl] [1,1 '-biphenyl]-4-sulfonamide, N-(4-phenyl- 1 ,3-thiazol-2-yl)[ 1 , 1 '-biphenyl]-4-sulfonamide, N-[4-(4-Fluoro-3-methylρhenyl)- 1 ,3-thiazol-2-yl] [1,1 '-biρhenyl]-4-sulfonamide, N-[4-(4-Methoxyphenyl)- 1 ,3-thiazol-2-yl] [1,1 '-biphenyl]-4-sulfonamide, 2,4-Dichloro-6-methyl-N-[4-(3-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4-Dichloro-6-methyl-N-(4-phenyl- 1 ,3 -thiazol-2-yl)benzenesulfonamide, 2,4-Dichloro-N-[4-(4-fluoro-3-methylρhenyl)-l,3-thiazol-2-yl]-6- methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, N-[4-(2- {[(4-propylphenyl)sulfonyl]amino} - 1 ,3-thiazol-4-yl)phenyl]acetamide, 4-Propyl-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-(7-methoxy-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2-yl)-4- propylbenzenesulfonamide,

N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, N-[4-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)phenyl]acetamide,

3-Chloro-2-methyl-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, 3-Chloro-N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-Chloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)-2- methylbenzenesulfonamide, 3-Chloro-N-[4-(5-chloro-2-thienyl)- 1 ,3-thiazol-2-yl]-2 -methylbenzenesulfonamide, 3 -Chloro-N- [4-(2-chlorophenyl)- 1 ,3 -thiazol-2-yl] -2-methylbenzenesulfonamide, N-[4-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)phenyl]acetamide, 2,4,6-Trichloro-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2- yl)benzenesulfonamide, 2,4,6-Trichloro-N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,6-Trichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, N-(4-{2-[([l, -biphenyl]-4-ylsulfonyl)amino]-l,3-thiazol-4-yl}phenyl)acetamide, N-[4-(3-ρyridinyl)-l,3-thiazol-2-yl][l,l'-biphenyl]-4-sulfonamide, N-[4-(2-chloro-5-nitrophenyl)- 1 ,3-thiazol-2-yl] [ 1 ,l'-biphenyl]-4-sulfonamide, N-(7-methoxy-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2-yl)[ 1 , 1 '-biρhenyl]-4- sulfonamide,

N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl][l,r-biphenyl]-4-sulfonamide, N-[4-(2-chlorophenyl)- 1 ,3-thiazol-2-yl] [1,1 '-biphenyl]-4-sulfonamide, N-[4-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-4- yl)ρhenyl]acetamide,

2,4-Dichloro-6-methyl-N-[4-(3-pyridinyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4-Dichloro-N-[4-(2-chloro-5-nitrophenyl)-l,3-thiazol-2-yl]-6- methylbenzenesulfonamide, 2,4-Dichloro-N-(7-methoxy-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2-yl)-6- methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(5-chloro-2-thienyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, 2,4-Dichloro-N-[4-(2,5-dimethyl-3-furyl)- 1 ,3-thiazol-2-yl]-6- methylbenzenesulfonamide, N-[4-(l-benzothien-3-yl)-l,3-thiazol-2-yl]-2,4-dichloro-6-methylbenzenesulfonamide, N-[4-(3-chloro-2-thienyl)- 1 ,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

3-Chloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 2,4,6-Trichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4-Dichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, 2,4-Dichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-6-methylbenzenesulfonamide, Ethyl 2-[([ 1 , 1 '-biphenyl]-4-ylsulfonyl)amino]-4-phenyl- 1 ,3 -thiazole-5-carboxylate, 3-Chloro-N-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-2 -methylbenzenesulfonamide, N-[4-(2- {[(4-Bromo-2,5-difluorophenyl)sulfonyl] amino} - 1 ,3-thiazol-4- yl)phenyl]acetamide, 2,3,4-Trichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]benzenesulfonamide, 2,4,5-Trichloro-N-[4-(3-chloro-2-thienyl)- 1 ,3 -thiazol-2-yl]benzenesulfonamide, 2,3,4-Trichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide, 4-Bromo-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]-2,5-difluorobenzenesulfonamide, 4,5-Dichloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)-2- thiophenesulfonamide,

4,5-Dichloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-2-thiophenesulfonamide,

N-[4-(2-{[(2,4,5-Trichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)phenyl]acetamide, 2,3,4-Trichloro-N-(7-methoxy-4,5-dihydronaρhtho[l,2-d][l,3]thiazol-2- yl)benzenesulfonamide,

3-Bromo-5-chloro-N-(7-methoxy-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)-2- thiophenesulfonamide, 3-Bromo-5-chloro-N-[4-(2-chlorophenyl)-l,3-thiazol-2-yl]-2-thiophenesulfonamide,

N-[4-(2-{[(2,6-Dichlorophenyl)sulfonyl]amino}-l,3-thiazol-4-yl)phenyl]acetamide,

2,6-Dichloro-N-[4-(3-chloro-2-thienyl)-l,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-(7, 8-dimethoxy-4,5 -dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2- yl)benzenesulfonamide, 2,3,4-Trichloro-N-{4-[2-chloro-4-(4-chlorophenoxy)phenyl]-l,3-thiazol-2- yl} benzenesulfonamide,

2,3,4-Trichloro-N- {4-[2,6-dichloro-4-(trifluoromethyl)ρhenyl]- 1 ,3-thiazol-2- yl}benzenesulfonamide,

N-[4-(2-Chloro-6-fluorophenyl)-l,3-thiazol-2-yl]-4-propylbenzenesulfonamide, 4-Bromo-N- {4-[2-chloro-4-(4-chlorophenoxy)phenyl]- 1 ,3-thiazol-2-yl} -2,5- difluorobenzenesulfonamide,

4-Bromo-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2,5- difluorobenzenesulfonamide,

4,5-Dichloro-N-[4-(2-chloro-6-fluorophenyl)-l,3-thiazol-2-yl]-2-thiophenesulfonamide, 4-Bromo-5-chloro-N- {4-[2-chloro-4-(4-chlorophenoxy)phenyl]- 1 ,3-thiazol-2-yl} -2- thiophenesulfonamide,

4-Bromo-5-chloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2- thiophenesulfonamide,

2,4-Dichloro-N-[4-(2-chloro-6-fluoroρhenyl)-l,3-tluazol-2-yl]-6- methylbenzenesulfonamide,

2,4,6-Trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)ρhenyl]-l,3-thiazol-2- yl}benzenesulfonamide, 4-Bromo-N-[4-(2-chloro-6-fluorophenyl)-l,3-thiazol-2-yl]-2- methylbenzenesulfonamide,

2,4,6-Trichloro-N-{4-[2-chloro-4-(4-chlorophenoxy)phenyl]-l,3-thiazol-2- yl}benzenesulfonamide, N-[4-(2-{[(4-Bromo-5-chloro-2-thienyl)sulfonyl]amino}-l,3-thiazol-4- yl)phenyl] acetamide,

N-(4,5-Dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)benzenesulfonamide,

3,4-Dichloro-N-(4,5-dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)benzenesulfonamide,

3-Chloro-N-(4,5-dihydrothieno[3,2-e] [ 1 ,3]benzothiazol-2-yl)-2- methylbenzenesulfonamide,

2,4,6-Trichloro-N-(4,5-dihydrothieno[3,2-e][l,3]benzothiazol-2- yl)benzenesulfonamide,

N-(4,5-Dihydrothieno[3,2-e] [ 1 ,3]benzothiazol-2-yl)[ 1 , 1 '-biphenyl]-4-sulfonamide,

2,4-Dichloro-N-(4,5-dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)-6- methylbenzenesulfonamide,

N-(4,5-Dihydrothieno[3,2-e][l,3]benzothiazol-2-yl)-4-propylbenzenesulfonamide,

3-Chloro-N-[6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][l,3]benzothiazol-2- yl]-2 -methylbenzenesulfonamide,

N-[6-Chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][l,3]benzothiazol-2-yl]-4- propylbenzenesulfonamide,

2,4-Dichloro-N-[6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4- e][l,3]benzothiazol-2-yl]-6-methylbenzenesulfonamide,

N-[6-Chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e] [ 1 ,3]benzothiazol-2-yl] [1,1'- biphenyl] -4-suIfonamide, N- {2-[(Phenylsulfonyl)amino]-4,5-dihydronaphtho[ 1 ,2-d][ 1 ,3]thiazol-6-yl} acetamide,

N-(2-{[(3-Chloro-2-methylphenyl)sulfonyl]amino}naphtho[l,2-d][l,3]thiazol-6- yl)acetamide,

N-(2-{[(4-Propylphenyl)sulfonyl]amino}-4,5-dihydronaphtho[l,2-d][l,3]thiazol-6- yl)acetamide, N-(8-Nitro-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thiazol-2-yl)-4-propylbenzenesulfonamide,

N-(8-Nitro-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)benzenesulfonamide, and

N-(8-Nitro-4,5-dihydronaphtho[l,2-d][l,3]thiazol-2-yl)[l,l'-biρhenyl]-4-sulfonamide.

4. The method according to any one of claims 1 to 3 for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.

5. The method according to claim 4 wherein the medical condition involving delayed or impaired wound healing is diabetes.

6. The method according to claim 4 wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.

7. The method according to any one of claims 1 to 3 for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.

8. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for promoting wound healing, said compound being an inhibitor of 11-β- hydroxysteroid dehydrogenase type 1.

9. The use according to claim 8 in the manufacture of a medicament for the treatment of prophylaxis of a medical condition involving delayed or impaired wound healing.

10. The use according to claim 9 wherein the medical condition involving delayed or impaired wound healing is diabetes.

11. The use according to claim 9 wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.

12. The use according to claim 8 in the manufacture of a medicament for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.