NEW USE V
RELATED APPLICATIONS
This application claims priority to Swedish application number 0301886-8, filed on June 25, 2003, the contents of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to the use of chemical compounds for wound healing, said compounds acting on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (llβHSDl).
BACKGROUND ART
Cortisol performs a broad range of metabolic functions and other functions. The multitude of glucocorticoid action is exemplified in patients with prolonged increase in plasma glucocorticoids, so called "Cushing's syndrome". Patients with Cushing's syndrome have prolonged increase in plasma glucocorticoids and exhibit impaired glucose tolerance, type 2 diabetes, central obesity, and osteoporosis. These patients also have impaired wound healing and brittle skin (1).
Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds (2). Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery (3).
The European patent application No. EP 0902288 discloses a method for diagnosing the status of wound healing in a patient, comprising detecting cortisol levels in said wound. The authors suggest that elevated levels of cortisol in wound fluid, relative to normal plasma levels in healthy individuals, correlates with large, non-healing wounds (4).
fri humans, the 11 β-HSD catalyzes the conversion of cortisol to cortisone, and vice versa. The parallel function of 11 β-HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5). Two isoenzymes of 11 β-HSD, l lβ- HSD1 and 1 lβ-HSD2, have been characterized, and differ from each other in function and tissue distribution (6). Like GR, 11 β-HSD 1 is expressed in numerous tissues like liver, adipose tissue, adrenal cortex, gonads, lung, pituitary, brain, eye etc (7-9). The function of 11 β-HSD 1 is to fine-tune local glucocorticoid action. 11 β-HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).
Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, 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 03/043999 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 11 β-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
01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/044009; 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 11 β-HSDl inhibitors for wound healing. However, the use of the 11 β-HSDl inhibitors according to the present invention for wound healing has not previously been disclosed.
DISCLOSURE OF THE INVENTION
It has surprisingly been found that the present inhibitors of 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 1 lβ- 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, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Cι-6-alkyl, optionally halogenated C1-6-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)- 1 ,3-thiazol-2-yl]amino} carbonyl);
R1 is hydrogen or -6-alkyl;
X is CH2 or CO;
Y is CH2, CO or a single bond; B is hydrogen, C1-6-alkyl or dimethylaminomethyl; R is selected from C1-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C1-6-alkoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl;
NR3R4, wherein R3 and R4 are each independently selected from hydrogen, C1-6-alkyl, optionally halogenated C1-6-alkylsulfonyl, C1-6-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C1-6-acyl, C3-10-cycloalkyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tefrahydro-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- dioxidothiomo holine, 2-(3,4-dihydro-2(lH)isoquinolinyl), (1 S,4S)-2-oxa-5- azabicyclo[2.2. l]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, C1-6- 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, C1-6- acyl, Cι-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides an 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- pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R1 is hydrogen or methyl; B is hydrogen, methyl or dimethylaminomethyl; 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-dimethylmorρholinyl, (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-trifluoroethyl.
The following compounds are especially preferred:
• ethyl (2-{[(2,4-dichloro-5-methylphenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate, ethyl (2-{[(4-chlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2- { [(2,4-difluorophenyl)sulfonyl] amino} - 1 ,3-thiazol-5-yl)acetate, ethyl (2-{[(2,5-dichlorothien-3-yl)sulfonyl]amino}-l,3-thiazol-5-yl)acetat.e, ethyl (2- {[(2-chlorophenyl)sulfonyl]amino} - 1 ,3-thiazol-5-yl)acetate, ethyl {2-[(l-naphthylsulfonyl)amino]-l,3-thiazol-5-yl} acetate, ethyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, 2-(2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-5 -yl)-N- methylacetamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N- ethylacetamide, ethyl {2-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]- 1 ,3-thiazol-5-yl} acetate, ethyl (2-{[(4-nitrophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2- { [(4-methoxyphenyl)sulfonyl] amino} - 1 ,3 -thiazol-5-yl)acetate, ethyl (2-{[(2,5-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, 3-chloro-N-[5-(2-hydroxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, 3-chloro-N-[5-(2-ethoxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide, ethyl (2-{[(3-chlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(4-fluorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(4-isopropylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl [2-({[4-({[4-(2-ethoxy-2-oxoethyl)-l,3-thiazol-2- yl] amino } carbonyl)phenyl] sulfonyl} amino)- 1 ,3 -thiazol-5 -yl] acetate, 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N,N- diethylacetamide, ethyl [2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)-l,3-thiazol-5-yl]acetate,
ethyl [2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)-l,3-thiazol-5-yl]acetate, ethyl [2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)-l,3-thiazol-5-yl]acetate, methyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate,
3-chloro-N-[5-(2-isopropoxyethyl)-l,3-thiazol-2-yl]-2- methylbenzenesulfonamide,
3-chloro-N-[5-(2-methoxyethyl)-l,3-thiazol-2-yl]-2-methylbenzenesulfonamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl methanesulfonate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetamide,
3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide,
3-chloro-2-methyl-N-{5-[2-(2,2,2-trifluoroethoxy)ethyl]-l,3-thiazol-2- yljbenzenesulfonamide,
2-(2- {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,3-thiazol-5-yl)ethyl acetate,
3-chloro-2-methyl-N-[5-(2-moφholin-4-ylethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
N-[5-(2-bromoethyl)-l,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl moφholine-4-carboxylate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl diethylcarbamate,
2-(2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-5 -yl)ethyl propionate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl 2- methylpropanoate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl 2- furoate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl benzoate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N-methoxy-
N-methylacetamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl ethylcarbamate,
N-[2-(2-{[(3-chloro-2-methylρhenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl]-N- ethylacetamide,
3-chloro-2-methyl-N-[5-(2-oxopentyl)-l,3-thiazol-2-yl]benzenesulfonamide,
N- {5-[2-(l , 1 -dioxidothiomoφholin-4-yl)-2-oxoethyl]-l ,3-thiazol-2-yl} -4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N- {5-[2-(4-methylpiperazin- 1 -yl)-2-oxoethyl] -1,3- thiazol-2-yl}benzenesulfonamide,
3-chloro-2-methyl-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3-thiazol-2- yljbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yljbenzenesulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l ,3-thiazol-2-yl]- 1 , 1 '-biphenyl-4- sulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4- propylbenzenesulfonamide,
N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)- 1 ,3-thiazol-2-yl]- 1 , 1 '-biphenyl-4- sulfonamide,
N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3-thiazol-2-yl]-4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3-thiazol-2- yljbenzenesulfonamide,
N-[5-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,3-thiazol-2-yl] -1,1 '-biρhenyl-4- sulfonamide,
N-[5-(2-oxo-2-ρiperidin-l-ylethyl)-l,3-thiazol-2-yl]-4- propylbenzenesulfonamide,
2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3-thiazol-2- yljbenzenesulfonamide, ethyl oxo(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5- yl)(oxo)acetate,
ethyl oxo(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl {2-[(l , 1 '-biphenyl-4-ylsulfonyl)arnino]-l ,3-thiazol-5-yl} (oxo)acetate,
3-chloro-2-methyl-N-[4-methyl-5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
2,4,6-trichloro-N-[4-methyl-5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
2- {2-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]-l ,3-thiazol-5-yl} -N-ethyl-N- methylacetamide,
N-ethyl-N-methyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetamide,
2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N-ethyl-
N-methylacetamide,
N-[4-methyl-5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-l,r-biρhenyl-4- sulfonamide,
2- {2-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]-l ,3-thiazol-5-yl} -N-isopropyl-N- methylacetamide,
2- {2-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]-l ,3-thiazol-5-yl} -N,N- diethylacetamide,
N,N-diethyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetamide,
2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N,N- diethylacetamide, ethyl (2-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate, ethyl (2-{[(3-bromo-5-chlorothien-2-yl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate, ethyl {2-[({5-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]thien-2- yl}sulfonyl)amino]-l,3-thiazol-5-yl}acetate, ethyl {2-[({5-[2-(methylthio)pyrimidin-4-yl]thien-2-yl}sulfonyl)amino]-l,3- thiazol-5-yl} acetate,
2- {2-[(l , 1 '-biphenyl-4-ylsulfonyl)amino]-l ,3-thiazol-5-yl} -N,N- diisopropylacetamide,
N,N-diisopropyl-2-(2- { [(4-propylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-5 - yl)acetamide,
2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N,N- diisopropylacetamide, methyl (4-methyl-2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N,N- dipropylacetamide,
3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-l-ylethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
4-bromo-2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l ,3-thiazol-2-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide,
2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4-
(trifluoromethoxy)benzenesulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4- phenoxybenzenesulfonamide, ethyl (2- { [(2,3 ,4-trichlorophenyl)sulfonyl] amino } - 1 ,3 -thiazol-5 -yl)acetate, ethyl (2-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate, ethyl [2-( { [4-(trifluoromethoxy)phenyl] sulfonyl} amino)- 1 ,3 -thiazol-5 - yl] acetate, ethyl [2-({[4-(phenylsulfonyl)thien-2-yl]sulfonyl}amino)-l,3-thiazol-5- yl] acetate, ethyl [2-({[5-(phenylsulfonyl)thien-2-yl]sulfonyl}amino)-l,3-thiazol-5- yl] acetate, ethyl (2-{[(2,6-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(2,4-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, tert-butyl 4- [(2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-5- yl)acetyl]piperazine- 1 -carboxylate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N,N- dimethylacetamide,
3-chloro-2-methyl-N-{5-[2-(ρyridin-3-yloxy)ethyl]-l,3-thiazol-2- yljbenzenesulfonamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N- isopropyl-N-methylacetamide,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N-ethyl-N- methylacetamide,
3-chloro-2-methyl-N-[5-(2-oxo-2-thiomoφholin-4-ylethyl)-l,3-thiazol-2- yljbenzenesulfonamide, ethyl (2-{[(4-bromo-2-fluorophenyl)sulfonyl]amino}-l,3-tl iazol-5-yl)acetate,
3-chloro-2-methyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yl]benzenesulfonamide, methyl (2-{[(4-chlorophenyl)sulfonyl]amino}-4-methyl-l,3-thiazol-5-yl)acetate, methyl (2- { [(3 -chloro-2-methylphenyl)sulfonyl] amino } -4-methyl- 1 ,3 -thiazol-5 - yl)acetate,
2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)-N,N- diisopropylacetamide,
3 -chloro-2-methyl-N- [5 -(2-oxo-2-pyrrolidin- 1 -ylethyl)- 1 ,3 -thiazol-2- yl]benzenesulfonamide, ethyl (2-{[(3-methoxyphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2- { [(4-propylphenyl)sulfonyl] amino } - 1 ,3 -thiazol-5 -yl)acetate,
3-chloro-2-methyl-N-[5-(2-oxo-2-piperidin-l-ylethyl)-l,3-thiazol-2- yl]benzenesulfonamide, ethyl (2-{[(3,5-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(3,4-dichlorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate
3 -chloro-2-methyl-N- [5 -(moφholin-4-ylmethyl)- 1 ,3 -thiazol-2- yl]benzenesulfonamide,
3-chloro-N-{5-[2-(lH-imidazol-l-yl)ethyl]-l,3-thiazol-2-yl}-2- methylbenzenesulfonamide,
N-[2-(2- { [(3-chloro-2-methylρhenyl)sulfonyl] amino) - 1 ,3-thiazol-5- yl)ethyl]acetamide, ethyl [2-({[2-methyl-4-(trifluoromethoxy)phenyl]sulfonyl}amino)-l,3-thiazol-5- yl] acetate, ethyl (2-{[(2,3,4-trifluorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(2,4,6-trifluorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate,
3-chloro-2-methyl-N-(5- {2-[(methylsulfonyl)amino]ethyl} -1 ,3-thiazol-2- yl)benzenesulfonamide, ethyl (2- {[(5-chlorothien-2-yl)sulfonyl]amino} - 1 ,3-thiazol-5-yl)acetate, ethyl (2-{[(2-chloro-4-fluorophenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(5-isoxazol-3-ylthien-2-yl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl (2-{[(4-phenoxyphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetate, ethyl [2-({[2,4-bis(trifluoromethyl)phenyl]sulfonyl}amino)-l,3-thiazol-5- yl] acetate,
3-chloro-2-methyl-N-{5-[2-(3-oxo-l,4-oxazepan-4-yl)ethyl]-l,3-thiazol-2- yljbenzenesulfonamide,
3-chloro-2-methyl-N- {5-[2-(2-oxopyrrolidin- 1 -yl)ethyl]-l ,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-(5-{2-[methyl(methylsulfonyl)amino]ethyl}-l,3-thiazol-2- yl)benzenesulfonamide,
N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)ethyl]-N- methylcyclopropanecarboxamide,
3-chloro-2-methyl-N-{5-[2-(4-methyl-2-oxopiperazin-l-yl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
3-chloro-2-methyl-N-[5-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-l,3- thiazol-2-yl]benzenesulfonamide,
2,4-dichloro-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
2,4-dichloro-6-methyl-N-{5-[2-(3-oxomoφholin-4-yl)ethyl]-l,3-thiazol-2- yl}benzenesulfonamide,
4-(2-furyl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
5'-fluoro-2'-methoxy-N-[5-(2-moφholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]-l , 1 '- biphenyl-4-sulfonamide,
4-(5-methylthien-2-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2- yl]benzenesulfonamide,
3'-acetyl-N-[5-(2-moφholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]- 1 , l'-biρhenyl-4- sulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4'-(trifluoromethoxy)-l, - biphenyl-4-sulfonamide,
3',4'-dichloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-l,r- biphenyl-4-sulfonamide,
4-(l ,3-benzodioxol-5-yl)-N-[5-(2-moφholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2- yl]benzenesulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4-pyridin-4- ylbenzenesulfonamide,
N-[4'-( { [5-(2-moφholin-4-yl-2-oxoethyl)- 1 ,3 -thiazol-2-yl] amino} sulfonyl)- 1 , 1 '- biphenyl-3 -yl] acetamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4-thien-3- ylbenzenesulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-4-thien-2- ylbenzenesulfonamide,
4'-( {[5-(2-moφholin-4-yl-2-oxoethyl)-l ,3-thiazol-2-yl] amino} sulfonyl)- 1,1'- biphenyl-4-carboxylic acid,
4'-(methylthio)-N-[5-(2-moφholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]- 1 , 1 '- biphenyl-4-sulfonamide,
N-[5-(2-mθφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-3',5'-bis(trifluoromethyl)-
1 , 1 '-biphenyl-4-sulfonamide,
4'-chloro-N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-l,l'-biphenyl-4- sulfonamide,
N-[5-(2-moφholin-4-yl-2-oxoethyl)-l,3-thiazol-2-yl]-3'-nitro-l,l'-biphenyl-4- sulfonamide,
• isopropyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5- yl)acetate, and • (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-l,3-thiazol-5-yl)acetic acid.
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 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-benzothiazole, 2,1,3- benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4- tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5-naphthyridine, 1,8- naphthyridine, acridine, fenazine and xanthene. Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
The term "heterocyclic" in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, moφholine, thiomoφholine and 1,4-oxazepane.
C1-6-alkyl in the compound of formula (I) according to the present application, which may be straight, branched or cyclic, is preferably C1-4-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 "C1-6-alkyl" all subgroups thereof are contemplated such as .s-alkyl, C1-4-alkyl, C1-3-alkyl, C1-2-alkyl, C -6-alkyl, C2-5- alkyl, C2-4-alkyl, C2-3-alkyl, C3-6-alkyl, C4-5-alkyl, etc.
C3-ιo-cycloalkyl, in the compound of formula (I) according to the present application may be straight or branched, is preferably C3-8-cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. For parts of the range "C3-1o-cycloalkyl" all subgroups thereof are contemplated such as C3- -cycloalkyl, C3-8-cycloalkyl, C3-7-cycloalkyl, C3-6-
cycloalkyl, C3-5-cycloalkyl, C4-1o-cycloalkyl, C5-10-cycloalkyl, Cδ-io-cycloalkyl, C7-10- cycloalkyl, C8-9-cycloalkyl, etc.
C1-6-alkoxy, in the compound of formula (I) according to the present application may be straight or branched, is preferably C1-4-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 C1-5-alkoxy, C1-4-alkoxy, C1-3-alkoxy, C1-2- alkoxy, C2-6-alkoxy, C2-5-alkoxy, C2- -alkoxy, C2-3-alkoxy, C3-6-alkoxy, C4-5-alkoxy, etc.
C1-6-acyl, in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably C1-4-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 " -6-acyl" all subgroups thereof are contemplated such as C1-5-acyl, C1-4-acyl, C1-3-acyl, C1-2-acyl, C2-6-acyl, C2- 5-acyl, C2- -acyl, C2-3-acyl, C3-6-acyl, C4-5-acyl, etc.
C2-6-alkenyl in the compound of formula (I) according to the present application, which may be straight, branched or cyclic, is preferably C2-4-alkenyl. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl. For parts of the range "C2-6-alkenyl" all subgroups thereof are contemplated such as C2-5-alkenyl, C2-4-alkenyl, C2-3-alkenyl, C3, 6-alkenyl, C4-5-alkenyl, etc.
The term "halogen" in the present description is intended to include fluorine, chlorine, bromine and iodine.
The term "sulfanyl" in the present description means a thio group.
With the expression mono- or di-substituted is meant in the present description that the functionalities in question may be substituted with independently H, C1-6-acyl, C2-6- alkenyl, Cι-6-(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine,
pyrrolidine, piperidine, piperazine, moφholine and thiomoφholine, which heterocyclic rings optionally may be substituted with 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 pmposes 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 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 03/43999.
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 11 β- HSD1 inhibitor BVT.2733 (disclosed as Example 172A in WO 01/90090), or vehicle started 4-6 days later and continued for 3.5 days.
Advantageous effects on wound healing of the surgical wounds were observed during treatment. In BVT.2733 treated mice, less complication were observed in and around the wound area as compared to control mice. Examples of advantageous effects were less pus in the wound, as well as better wound strength. 58 % of the vehicle treated animals showed complications during treatment period whereas complications were present in only 24 % of the BVT.2733 treated animals.
EXAMPLE 2
(a) Advantageous effects of 11 β-HSDl inhibitors (e.g. BVT.2733) on wound healing are confirmed in diabetic KKAy mice employing the excisional wound-healing model. 1 cm full-thickness wounds, including the panniculus carnosus muscle, are cut with a scalpel
on the back of the mice. Mice are treated with BVT.2733 for 5 days. On day 2 and 9 of treatment wounds are harvested, embedded and sectioned. Histological staining of the sections with hematoxylin/eosin are made to determine degree of re-epithelialization and immunostaining against the von Willebrand factor to determine revascularisation.
(b)
Advantageous effects of 11 β-HSDl inhibitors are confirmed in in vitro studies. Proliferation of human keratinocytes and fibroblasts, which are important cell types in the wound healing process, are studied after incubation with the 11 β-HSDl inhibitor.
(c)
Effects on wound healing after treatment with 11 β-HSDl inhibitors are also studied in wounds on explants from human breast skin. The proliferative effect of the substance and the effect on re-epithelialization are determined.
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