WO2004112781A1 - Nouvelle utilisation ii - Google Patents

Nouvelle utilisation ii Download PDF

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Publication number
WO2004112781A1
WO2004112781A1 PCT/SE2004/000956 SE2004000956W WO2004112781A1 WO 2004112781 A1 WO2004112781 A1 WO 2004112781A1 SE 2004000956 W SE2004000956 W SE 2004000956W WO 2004112781 A1 WO2004112781 A1 WO 2004112781A1
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WO
WIPO (PCT)
Prior art keywords
thiazol
methyl
chloro
acetyl
wound healing
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Application number
PCT/SE2004/000956
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English (en)
Inventor
Cecilia Nilsson
Catrine Dreifeldt
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Biovitrum Ab
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Publication date
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Publication of WO2004112781A1 publication Critical patent/WO2004112781A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

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).
  • 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).
  • the ll ⁇ -HSD catalyzes the conversion of cortisol to cortisone, and vies versa.
  • the parallel function of 1 l ⁇ -HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5).
  • 1 l ⁇ -HSD 1 Two isoenzymes of ll ⁇ -HSD, 1 l ⁇ - HSD 1 and 1 l ⁇ -HSD2, have been characterized, and differ from each other in function and tissue distribution (6). Like GR, 1 l ⁇ -HSD 1 is expressed in numerous tissues like liver, adipose tissue, adrenal cortex, gonads, lung, pituitary, brain, eye etc (7-9). The function of 1 l ⁇ -HSD 1 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 infect ' on and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF- ⁇ , EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).
  • WO 01/90091 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 11 ⁇ -HSDl inhibitors are disclosed in e.g. WO 01/90090; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/044009; WO 03/043999; and Swedish patent application No. SE 0301504-7, filed on May 21, 2003.
  • WO 02/072084 relates to glycyrrhetinic acid derivatives, progesterone and progesterone derivatives as 11 ⁇ -HSDl inhibitors for wound healing.
  • 11 ⁇ -HSDl inhibitors according to the present invention for wound healing has not previously been disclosed.
  • this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 1 l ⁇ -hydroxysteroid dehydrogenase type 1, wherein the inhibitor of 1 l ⁇ - hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
  • T is an aryl ring or heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, C ⁇ - 6 -alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue is optionally substituted in one or more positions independently of each other by cyano and halogen;
  • A is C ⁇ - 6 -alkyl, vinyl or 3 -(ethyl 3-methylbutanoate);
  • B is hydrogen, halogen, C ⁇ . 6 -alkyl, halogenated C ⁇ - 6 -alkyl, C ⁇ - 6 -acyl or C ⁇ - 6 - alkoxycarbonyl; pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof. It is preferred that:
  • T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl, phenyl, and n-propyl;
  • A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, vinyl and 3-(ethyl 3-methylbutanoate);
  • B is selected from hydrogen, bromo, methyl, ethyl, n-propyl, n-butyl, 2,2,2- trichloroethyl, acetyl and carbethoxy.
  • the said method is a method for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids.
  • the method according to the invention is also intended for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • the compounds referred to above may also be used in the manufacture of a medicament for promoting wound healing, e.g. for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • a medical condition involving delayed or impaired wound healing.
  • medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids.
  • the compounds referred to above may also be used for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • aryl in the present description is intended to include aromatic rings
  • phenyl (Ph) and naphthyl which optionally may be substituted by C ⁇ - 6 -alkyl.
  • substituted aryl groups are benzyl and 2-methylphenyl.
  • heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, s ⁇ .fur, oxygen and selenium.
  • heteroaryl rings examples include pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3- benzoselenadiazole, benzimidazole, indazole, benzodioxane, indan
  • Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
  • heterocyclic in the present description is intended to include unsaturatsd 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.
  • Ci _6-alkyl in the compound of formula (I) according to the present application is preferably C ⁇ _4-alkyl.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
  • C ⁇ - 6 -alkyl all subgroups thereof are contemplated such as d- 5 -alkyl, C ⁇ . 4 -alkyl, C . 6 -alkyl, C 2 - 5 -alkyl, C 2 . 4 -alkyl, C 2 - -alkyl, C 3 . 6 -alkyl, C 4 . 5 -alkyl, etc.
  • Cj.g-alkoxy in the compound of formula (I) according to the present application may be straight or branched, is preferably C ⁇ _4-alkoxy.
  • Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
  • C ⁇ . 6 -alkoxy all subgroups thereof are contemplated such as C ⁇ . 5 -alkoxy, C ⁇ - 4 -alkoxy, C 2 . 6 -alkoxy, C 2 . 5 - alkoxy, C 2 . 4 -alkoxy, C 2 . 3 -alkoxy, C 3 . 6 -alkoxy, C 4 - 5 -alkoxy, etc.
  • Ci. ⁇ -acyl in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably C ⁇ _4-acyl.
  • exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3- butenoyl), hexenoyl (e.g. 5-hexenoyl).
  • C ⁇ . 6 -acyl all subgroups thereof are contemplated such as Ci-s-acyl, C ⁇ - 4 -acyl, C 2 . 6 -acyl, C 2 -5-acyl, C 2 - 4 -acyl, C 2 .
  • C 2 . 6 -alkenyl in the compound of formula (I) according to the present application is preferably C 2 . 4 -alkenyl.
  • Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl.
  • C 2 - 6 -alkenyl all subgroups thereof are contemplated such as C 2 -5-alkenyl, C 2 . 4 -alkenyl, C 2 . 3 -alkenyl, C . 6 -alkenyl, C 4 . 5 -alkenyl, etc.
  • halogen in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • 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 purposes detailed herein (e.g., therapeutic administration 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 01/90091.
  • the compounds of formula (I) can preferably be topically administered.
  • the compounds could also be administered by other routes, for instance orally, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
  • Diabetic KKA y mice underwent surgery during anesthesia whereby a catheter was inserted in the jugularis vein.
  • Oral treatment twice daily (200 mg/kg/day) with the 11 ⁇ - 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.
  • BNT.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 BNT.2733 treated animals.
  • 11 ⁇ -HSDl inhibitors e.g. BNT.2733
  • BNT.2733 11 ⁇ -HSDl inhibitors
  • 1 cm full-thickness wounds, including the panniculus carnosus muscle, are cut with a scalpel on the back of the mice.
  • Mice are treated with BVT.2733 for 5 days.
  • On day 2 and 9 of treatment wounds are harvested, embedded and sectioned. Histological staining of the sections with hematoxylin eosin are made to determine degree of re-epithelialization and immunostaining against the von Willebrand factor to determine revascularisation.
  • Hutchinson TC Swaniker HP. Wound diagnosis by quantitating cortisol in wound fluids.
  • Beer HD Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Nitam Horm 2000;59:217-39.

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

Abstract

La présente invention a trait à un procédé pour favoriser la cicatrisation, comprenant l'administration à un mammifère, y compris l'homme, nécessitant un tel traitement d'une quantité efficace d'un inhibiteur de 11-β-hydrostéroïde déshydrogénase de type 1 (11β-HSD1), ledit inhibiteur étant de formule (I), dans laquelle : A, B et T sont tels que définis dans la description. Ces composés peuvent également être utilisés dans la fabrication d'un médicament pour favoriser la cicatrisation.
PCT/SE2004/000956 2003-06-25 2004-06-16 Nouvelle utilisation ii WO2004112781A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007025892A1 (fr) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag Inhibiteur de la 11-bêta-hydroxystéroïde déhydrogénase-1 des diabètes de type 2-1
US7253196B2 (en) 2004-05-24 2007-08-07 Amgen, Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7345058B2 (en) 2005-04-05 2008-03-18 Hoffmann-La Roche Inc. Pyrazoles
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US8541592B2 (en) 2005-11-22 2013-09-24 Amgen Inc. Inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US9067922B2 (en) 2013-04-19 2015-06-30 Pfizer Limited Chemical compounds
EP3235813A1 (fr) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Dérivés aza-tétra-cycliques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031492A1 (fr) * 1995-04-04 1996-10-10 Texas Biotechnology Corporation Thienyl-, furyl-, pyrrolyl- et biphenyl sulfonamides et leurs derives modulant l'activite de l'endotheline
WO1998016520A1 (fr) * 1996-10-16 1998-04-23 American Cyanamid Company Preparation d'acides ortho-sulfonamido heteraryl-hydroxamiques et leur utilisation en tant qu'inhibiteurs des metalloproteinases matricielles et de tace
WO2001090091A1 (fr) * 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031492A1 (fr) * 1995-04-04 1996-10-10 Texas Biotechnology Corporation Thienyl-, furyl-, pyrrolyl- et biphenyl sulfonamides et leurs derives modulant l'activite de l'endotheline
WO1998016520A1 (fr) * 1996-10-16 1998-04-23 American Cyanamid Company Preparation d'acides ortho-sulfonamido heteraryl-hydroxamiques et leur utilisation en tant qu'inhibiteurs des metalloproteinases matricielles et de tace
WO2001090091A1 (fr) * 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1

Non-Patent Citations (1)

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

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7253196B2 (en) 2004-05-24 2007-08-07 Amgen, Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7807700B2 (en) 2004-05-24 2010-10-05 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US7345058B2 (en) 2005-04-05 2008-03-18 Hoffmann-La Roche Inc. Pyrazoles
WO2007025892A1 (fr) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag Inhibiteur de la 11-bêta-hydroxystéroïde déhydrogénase-1 des diabètes de type 2-1
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
US8541592B2 (en) 2005-11-22 2013-09-24 Amgen Inc. Inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US9067922B2 (en) 2013-04-19 2015-06-30 Pfizer Limited Chemical compounds
EP3235813A1 (fr) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Dérivés aza-tétra-cycliques
WO2017182464A1 (fr) 2016-04-19 2017-10-26 Cidqo 2012, S.L. Nouveaux dérivés d'aza-tétracyclo

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