US20070281938A1 - Inhibitors of 11-Beta-Hydroxy Steroid Dehydrogenase Type 1 - Google Patents

Inhibitors of 11-Beta-Hydroxy Steroid Dehydrogenase Type 1 Download PDF

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US20070281938A1
US20070281938A1 US11/596,982 US59698205A US2007281938A1 US 20070281938 A1 US20070281938 A1 US 20070281938A1 US 59698205 A US59698205 A US 59698205A US 2007281938 A1 US2007281938 A1 US 2007281938A1
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Prior art keywords
alkyl
thiazol
aryl
methyl
heterocyclyl
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Inventor
Martin Henriksson
Evert Homan
Lars Johansson
Jerk Vallagarda
Meredith Williams
Christopher Fostsch
Eric Bercot
Aiwen Li
Guolin Cai
Randall Hungate
Chester Yuan
Christopher Tegley
David St. Jean
Nianhe Han
Qi Huang
Qingyian Liu
Michael Bartberger
George Moniz
Matthew Frizzle
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Swedish Orphan Biovitrum AB
Amgen Inc
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Biovitrum AB
Amgen Inc
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Priority claimed from SE0401324A external-priority patent/SE0401324D0/xx
Priority claimed from SE0402509A external-priority patent/SE0402509D0/xx
Application filed by Biovitrum AB, Amgen Inc filed Critical Biovitrum AB
Priority to US11/596,982 priority Critical patent/US20070281938A1/en
Assigned to BIOVITRUM AB, AMGEN INC. reassignment BIOVITRUM AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HENRIKSSON, MARTIN, JOHANSSON, LARS, VALLGARDA, JERK, CAI, GUOLIN, FRIZZLE, MATTHEW J., BARTBERGER, MICHAEL D., BERCOT, ERIC A., FOTSCH, CHRISTOPHER H., HAN, NIANHE, HUANG, QI, LI, AIWEN, LIU, QINGYIAN, MONIZ, GEORGE A., ST. JEAN, DAVID J., JR., TEGLEY, CHRISTOPHER, YUAN, CHESTER CHENGUANG, HUNGATE, RANDALL W., HOMAN, EVERT, WILLIAMS, MEREDITH
Publication of US20070281938A1 publication Critical patent/US20070281938A1/en
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Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11 ⁇ HSD1).
  • 11 ⁇ HSD1 human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme
  • HSDs Hydroxysteroid dehydrogenases
  • the 11-beta-hydroxysteroid dehydrogenases catalyze the interconversion of active glucocorticoids (such as cortisol and corticosterone), and their inertiforms (such as cortisone and 11-dehydrocorticosterone).
  • the isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11 ⁇ -HSD1) is expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissue and is a potential target for therapy directed at numerous disorders that may be ameliorated by reduction of glucocorticoid action, such as diabetes, obesity and age-related cognitive dysfunction. Seckl, et al., Endocrinology, 2001, 142:1371-1376.
  • the various isozymes of the 17-beta-hydroxysteroid dehydrogenases (17 ⁇ -HSDs) bind to androgen receptors or estrogen receptors and catalyze the interconversion of various sex hormones including estradiol/estrone and testosterone/androstenedione.
  • 17-beta-Hydroxysteroid dehydrogenase type 2 (170-HSD2) is expressed in human endometrium and its activity has been reported to be linked to cervical cancer. Kitawaki et al., J. Clin. Endocrin.
  • 17-beta-Hydroxysteroid dehydrogenase type 3 (17 ⁇ -HSD3) is expressed in the testes and its modulation may be useful for the treatment of androgen-related disorders.
  • Androgens and estrogens are active in their 17 ⁇ -hydroxy configurations, whereas their 17-keto derivatives do not bind to androgen and estrogen receptors and are thus inactive.
  • the conversion between the active and inactive forms (estradiol/estrone and testosterone/androstenedione) of sex hormones is catalyzed by members of the 17 ⁇ -HSD family.
  • 17 ⁇ -HSD1 catalyzes the formation of estradiol in breast tissue, which is important for the growth of malignant breast tumors. Labrie et al., Mol. Cell. Endocrinol. 1991, 78:C113-C118.
  • a similar role has been suggested for 17 ⁇ -HSD4 in colon cancer. English et al., J. Clin.
  • 17 ⁇ -HSD3 is almost exclusively expressed in the testes and converts androstenedione into testosterone. Deficiency of this enzyme during fetal development leads to male pseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39. Both 17 ⁇ -HSD3 and various 3 ⁇ -HSD isozymes are involved in complex metabolic pathways which lead to androgen shuffles between inactive and active forms. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation of certain HSDs can have potentially beneficial effects in the treatment of androgen- and estrogen-related disorders.
  • the 20-alpha-hydroxysteroid dehydrogenases (20 ⁇ -HSDs) catalyze the interconversion of progestins (such as between progesterone and 20 ⁇ -hydroxy progesterone).
  • Other substrates for 20 ⁇ -HSDs include 17 ⁇ -hydroxypregnenolone or 17 ⁇ -hydroxyprogesterone, leading to 20 ⁇ -OH steroids.
  • 20 ⁇ -HSD isoforms have been identified and 20 ⁇ -HSDs are expressed in various tissues, including the placenta, ovaries, testes and adrenals. Peltoketo, et al., J. Mol. Endocrinol. 1999, 23:1-11.
  • the 3-alpha-hydroxysteroid dehydrogenases (3 ⁇ -HSDs) catalyze the interconversion of the androgens dihydrotestosterone (DHT) and 5 ⁇ -androstane-3 ⁇ ,17 ⁇ -diol and the interconversion of the androgens DHEA and androstenedione and therefore play an important role in androgen metabolism.
  • DHT dihydrotestosterone
  • DHEA dihydrotestosterone
  • androstenedione and therefore play an important role in androgen metabolism.
  • glucocorticoids have a central role in diabetes. For example, the removal of the pituitary gland or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and Leukins, F. D. W. (1936) J. Exp. Med. 63: 465-490; Houssay, B. A. (1942) Endocrinology 30: 884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.
  • 11 ⁇ HSD1 as an important regulator of local glucocorticoid effect and thus of hepatic glucose production is well substantiated (see, e.g., Jamieson et al. (2000) J. Endocrinol. 165: 685-692). Hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11 ⁇ HSD1 inhibitor carbenoxolone (Walker, B. R. et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats.
  • FR 2,384,498 discloses compounds having a high hypoglycemic effect. Therefore, treatment of hyperglycemia with these compounds may lead to hypoglycemia.
  • Obesity is an important factor in syndrome X as well as in the majority (>80%) of type 2 diabetes, and omental fat appears to be of central importance.
  • Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X (e.g. increased blood pressure, decreased levels of HDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes 49: 883-888, 2000).
  • Inhibition of the 11 ⁇ HSD1 enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes.
  • Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 ⁇ HSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S. C. et al. (1998) Science, 280: 1378-1383).
  • glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W. (1999) Baillièr's Clin. Endocrinol. Metab. 13: 576-581).
  • HPA hypothalamo-pituitary-adrenal
  • the balance between the cell-mediated response and humoral responses is modulated by glucocorticoids.
  • a high glucocorticoid activity such as at a state of stress, is associated with a humoral response.
  • inhibition of the enzyme 11 ⁇ HSD1 has been suggested as a means of shifting the response towards a cell-based reaction.
  • 11 ⁇ HSD1 In the eye, expression of 11 ⁇ HSD1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris.
  • the distant isoenzyme 11 ⁇ HSD2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage.
  • 11 ⁇ HSD1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
  • Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess.
  • Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, C. H., Cheng, S. L. and Kim, G. S. (1999) J. Endocrinol. 162: 371-379).
  • the negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11 ⁇ HSD1 in the glucocorticoid effect (Bellows, C. G., Ciaccia, A. and Heersche, J. N. M. (1998) Bone 23: 119-125).
  • WO 99/65884 discloses carbon substituted aminothiazole inhibitors of cyclin dependent kinases. These compounds may, e.g., be used against cancer, inflammation and arthritis.
  • U.S. Pat. No. 5,856,347 discloses an antibacterial preparation or bactericide comprising 2-aminothiazole derivative and/or salt thereof.
  • U.S. Pat. No. 5,403,857 discloses benzenesulfonamide derivatives having 5-lipoxygenase inhibitory activity.
  • tetrahydrothiazolo[5,4-c]pyridines are disclosed in: Analgesic tetrahydrothiazolo[5,4-c]pyridines. Fr. Addn. (1969), 18 pp, Addn. to Fr.
  • WO 98/16520 discloses compounds inhibiting matrix metalloproteinases (MMPs) and TNF- ⁇ converting enzyme (TACE).
  • MMPs matrix metalloproteinases
  • TACE TNF- ⁇ converting enzyme
  • EP 0 749 964 A1 and U.S. Pat. No. 5,962,490 disclose compounds having an endothelin receptor antagonist activity.
  • WO 00/02851 discloses compounds associated with a disturbed cGMP balance. None of these compounds fall within formula (I) according to the present invention. Furthermore, nothing is said about the activity on 11 ⁇ HSD1.
  • U.S. Pat. No. 5,783,697 discloses thiophene derivatives as inhibitors of PGE2 and LTB4. None is said about the activity on 11 ⁇ HSD1.
  • EP 0 558 258, EP 0 569 193, and EP 1 069 114 disclose isoxazole derivatives as endothelin agonists and antagonists. None is said about the activity on 11 ⁇ HSD1.
  • 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 (Ganong, W. F. Review of Medical Physiology. Eighteenth edition ed. Stamford, Conn.: Appleton & Lange; 1997).
  • Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds (Anstead, G. M. Steroids, retinoids, and wound healing. Adv Wound Care 1998;11(6):277-85). Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery (Diethelm, A. G. Surgical management of complications of steroid therapy. Ann Surg 1977;185(3):251-63).
  • 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 (Hutchinson, T. C., Swaniker, H. P., Wound diagnosis by quantitating cortisol in wound fluids.
  • the 11 ⁇ -HSD catalyzes the conversion of cortisol to cortisone, and vice versa.
  • the parallel function of 11 ⁇ -HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (Frey, F. J., Escher, G., Frey, B. M. Pharmacology of 11 beta-hydroxysteroid dehydrogenase. Steroids 1994;59(2):74-9).
  • Two isoenzymes of 11 ⁇ -HSD, 11 ⁇ -HSD1 and 11 ⁇ -HSD2 have been characterized, and differ from each other in function and tissue distribution (Albiston, A. L., Obeyesekere, V. R., Smith, R.
  • 11 ⁇ -HSD1 is expressed in numerous tissues like liver, adipose tissue, adrenal cortex, gonads, lung, pituitary, brain, eye etc (Monder C, White P C. 11 beta-hydroxysteroid dehydrogenase. Vitam Horm 1993;47:187-271; Stewart, P. M., Krozowski, Z. S. 11 beta-Hydroxysteroid dehydrogenase.
  • 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 Anstead et al., supra).
  • glucocorticoid receptor antagonist RU486 Mercado, A. M., Quan, N., Padgett, D. A., Sheridan, J. F., Marucha, P. T. 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(1-2):74-83; Rojas, I. G., Padgett, D.
  • Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (Anstead et al., supra). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF- ⁇ , EGF, KGF and PDGF (Beer, H. D., Fassler, R., Werner, S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horn 2000;59:217-39; Hamon, G.
  • 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 USA 1989;86(7):2229-33). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (Oishi, Y., Fu, Z. W., 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 Dennatol 2002; 147(5):859-68).
  • WO 01/90090 discloses thiazole compounds, which compounds inhibit the human 11 ⁇ -HSD1, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders.
  • Other 11 ⁇ -HSD1 inhibitors are disclosed in e.g. WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/043999; WO 03/044000; WO 03/044009; U.S. Patent Publication No.
  • the compounds according to the present invention solves the above problems and embraces a novel class of compounds which has been developed and which inhibit the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11- ⁇ -HSD1), and may therefore be of use in treating disorders related to 11- ⁇ -HSD1 activity, such as, but not limited to diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, hypertension, and wound healing.
  • 11- ⁇ -HSD1 human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme
  • One object of the present invention is a compound of the general formula (I)
  • Z is sulfur, R 1 is hydrogen, R 2 is selected from hydrogen; C 3-10 -cycloalkyl optionally independently substituted by one or more of C 1-8 -alkyl and aryl; C 3-10 -cycloalkyl-C 1-8 -alkyl; aryl; aryl-C 1-8 -alkyl; heterocyclyl; heterocyclyl-C 1-8 -alkyl; wherein any aryl or heterocyclyl residue is optionally independently substituted by one or more C 1-8 -alkyl and halogen; or R 1 and R 2 form together with the nitrogen atom bonded thereto a monocyclic heterocyclyl optionally independently substituted by one or more of aryl-C 1-8 -alkyl, C 1-8 -alkyl and halogen; R 3 and R 4 are each independently selected from hydrogen; C 1-8 -alkyl; C 3-10 -cycloalkyl-C 1-8 -alkyl; cyano-C 1-8 -
  • Z is oxygen, R 1 is hydrogen, R 2 is selected from hydrogen; C 5-10 -cycloalkyl optionally independently substituted by one or more of C 1-8 -alkyl and aryl; C 3-10 -cycloalkyl-C 1-8 -alkyl; aryl, but not an unsubstituted phenyl group; aryl-C 1-8 -alkyl; heterocyclyl; heterocyclyl-C 3-8 -alkyl; wherein any aryl or heterocyclyl residue is optionally independently substituted by one or more of C 1-8 -alkyl and halogen; R 3 and R 4 are each independently selected from hydrogen; C 1-8 -alkyl; C 3-10 -cycloalkyl-C 1-8 -alkyl; cyano-C 1-8 -alkyl; aryl, but not an unsubstituted phenyl group; aryl-C 1-8 -alkyl; heterocyclyl-C 1-8 --al
  • Z is oxygen and R 3 ⁇ H, then R 4 is not methyl.
  • R 1 and R 2 are each independently selected from hydrogen, cyclohexyl, cycloheptyl, cyclooctyl, 2,2,3,3-tetramethylcyclopropyl, 1-(4-chlorophenyl)cyclobutyl, bicyclo[2.2.1]hept-2-yl, tricyclo[3.3.1.0-3,7-]non-3-yl, cyclohexylmethyl, phenyl, 2-methylphenyl, 3-methylphenyl, 2-isopropylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-phenylpropyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-(2,2,6,6-tetramethyl)piperidyl, 2-morpholinyl-4-ylethyl, or R 1 and R 2 form together with the nitrogen atom bonded thereto morpholinyl, azocane, or 4-benzylpiperidyl;
  • R 3 and R 4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclohexylmethyl, cyanomethyl, phenyl, 2-hydroxyphenyl, benzyl, 2-hydroxybenzyl, 4-hydroxybenzyl, 3,4-dihydroxybenzyl, 1H-imidazol-4-ylmethyl, indol-3-ylmethyl, 3-pyridylmethyl, or R 3 and R 4 form together with the carbon atom bonded thereto cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
  • R 2 as an aryl group is selected from 2-methylphenyl, 3-methylphenyl, 2-isopropylphenyl, 2-fluorophenyl, and 2-chlorophenyl.
  • Z sulfur
  • R 3 is ethyl and R 4 is hydrogen
  • R 2 as an aryl group is selected from 2-methylphenyl, 2-isopropylphenyl, 2-fluorophenyl, and 2-chlorophenyl.
  • each of R 2 , R 3 , and R 4 as an aryl group is selected from 2-methylphenyl, 3-methylphenyl, 2-isopropylphenyl, 2-fluorophenyl, and 2-chlorophenyl.
  • R 4 as a C 1-8 -alkyl group is selected from C 2-8 -alkyl.
  • Preferred compounds are Examples 1-38, 40-66, 68, and 73-79.
  • Another object of the present invention is a process for the preparation of a compound above comprising at least one of the following steps:
  • X is S or O
  • R 5 is selected from hydrogen, C 1 -C 8 alkyl, C 3-10 -cycloalkyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl, heterocyclyl-C 1-8 -alkyl and haloalkyl;
  • R 6 is selected from C 1-8 -alkyl, C 1-8 -alkoxy, C 3-10 -cycloalkyl, heterocyclyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, CN—C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl and haloalkyl;
  • R 7 is selected from —NR 8 R 9 , halo, C 1-8 -alkyl, —(CR 8 R 9 ) n —OR 8 , —S—C 1 -C 8 -alkyl, C 3-10 -cycloalkyl, heterocyclyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, cyano-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl, heterocyclyl-C(O)—C 1-8 -alkyl, heterocyclyl-SO 2 —C 1-8 -alkyl, C 1-8 -haloalkyl, R 8 R 9 N—C 1-8 -alkyl, HO—C 1-8 -alkyl, —C(O)—C 3 -C 10 -cycloalkyl, —C(O)—C 1 -C 8 -haloalky
  • R 8 and R 9 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —NR 10 R 10 , —S—(C 1 -C 8 )alkyl, aryl and heterocyclyl;
  • R 10 is independently selected from hydrogen, C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —S—(C 1 -C 8 )alkyl, heterocyclyl and aryl;
  • R 6 and R 7 form, together with the carbon atom bonded thereto, a saturated, partially unsaturated or unsaturated C 3-10 -cycloalkyl or a saturated, partially unsaturated or unsaturated C 4 -C 14 heterocyclyl;
  • X is S, R 6 and R 7 combine to form a cyclopropyl ring, then R 5 is not n-butyl, cyclohexyl, benzyl, phenyl or naphthyl.
  • R 5 is selected from hydrogen, C 1 -C 8 alkyl, C 3-10 -cycloalkyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl, heterocyclyl-C 1-8 -alkyl and haloalkyl;
  • R 6 is selected from C 1-8 -alkyl, C 1-8 -alkoxy, C 3-10 -cycloalkyl, heterocyclyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, CN—C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl and haloalkyl;
  • R 7 is selected from —NR 8 R 9 , halo, C 1-8 -alkyl, —(CR 8 R 9 ) n —OR 8 , —S—C 1 -C 8 -alkyl, C 3-10 -cycloalkyl, heterocyclyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, cyano-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl, heterocyclyl-C(O)—C 1-8 -alkyl, heterocyclyl-SO 2 —C 1-8 -alkyl, C 1-8 -haloalkyl, R 8 R 9 N—C 1-8 -alkyl, HO—C 1-8 -alkyl, —C(O)—C 3 -C 10 -cycloalkyl, —C(O)—C 1 -C 8 -haloalky
  • R 8 and R 9 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —NR 10 R 10 , —S—(C 1 -C 8 )alkyl, aryl and heterocyclyl;
  • R 10 is independently selected from hydrogen, C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —S—(C 1 -C 8 )alkyl, heterocyclyl and aryl;
  • R 6 and R 7 form, together with the carbon atom bonded thereto, a saturated, partially unsaturated or unsaturated C 3-10 -cycloalkyl or a saturated, partially unsaturated or unsaturated C 4 -C 14 heterocyclyl;
  • R 6 ⁇ R 7 -Methyl, then R 5 is not phenyl or 4-iodophenyl,
  • R 6 ⁇ R 7 phenyl, then R 5 is not phenyl,
  • R 6 and R 7 combine to form a cyclopropyl ring, then R 5 is not n-butyl, cyclohexyl, benzyl, phenyl or naphthyl.
  • R 5 is selected from hydrogen, C 1 -C 8 alkyl, C 3-10 -cycloalkyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl, heterocyclyl-C 1-8 -alkyl and haloalkyl;
  • R 6 is selected from C 1-8 -alkyl, C 1-8 -alkoxy, C 3-10 -cycloalkyl, heterocyclyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, CN—C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl and haloalkyl;
  • R 7 is selected from —NR 8 R 9 , halo, C 1-8 -alkyl, —(CR 8 R 9 ) n —OR 8 , —S—C 1 -C 8 -alkyl, C 3-10 -cycloalkyl, heterocyclyl, C 3-10 -cycloalkyl-C 1-8 -alkyl, cyano-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl, heterocyclyl-C(O)-C 1-8 -alkyl, heterocyclyl-SO 2 —C 1-8 -alkyl, C 1-8 -haloalkyl, R 8 R 9 N—C 1-8 -alkyl, HO—C 1-8 -alkyl, —C(O)—C 3 -C 10 -cycloalkyl, —C(O)—C 1 -C 8 -haloalky
  • R 8 and R 9 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —NR 10 R 10 , —S—(C 1 -C 8 )alkyl, aryl and heterocyclyl;
  • R 10 is independently selected from hydrogen, C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, C 1 -C 8 alkoxy, —S—(C 1 -C 8 )alkyl, heterocyclyl and aryl;
  • R 6 and R 7 form, together with the carbon atom bonded thereto, a saturated, partially unsaturated or unsaturated C 3-10 -cycloalkyl or a saturated, partially unsaturated or unsaturated C 4 -C 14 heterocyclyl;
  • One embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein:
  • R 5 is selected from cyclohexyl, cycloheptyl, cyclooctyl, 2,2,3,3-tetramethylcyclopropyl, 1-(4-chlorophenyl)cyclobutyl, bicyclo[2.2.1]hept-2-yl, tricyclo[3.3.1.0-3,7-]non-3-yl, cyclohexylmethyl, phenyl, 2-methylphenyl, 3-methylphenyl, 2-isopropylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-phenylpropyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-(2,2,6,6-tetramethyl)piperidyl, 2-morpholinyl-4-ylethyl and tetrahydropyran-4-yl-methyl; and
  • R 6 and R 7 are each independently selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclohexylmethyl, cyanomethyl, phenyl, 2-hydroxyphenyl, benzyl, 2-hydroxybenzyl, 4-hydroxybenzyl, 3,4-dihydroxybenzyl, 1H-imidazol-4-ylmethyl, indol-3-ylmethyl, 3-pyridylmethyl;
  • R 6 and R 7 form together with the carbon atom bonded thereto cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 6 is methyl and R 7 is isopropyl.
  • R 5 is selected from optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl and optionally substituted aryl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 5 is C 3 -C 8 alkyl.
  • R 5 is optionally substituted phenyl-(CR 10a R 10a ) 1-3 —; and wherein R 10a is independently selected from H, methyl, fluoro or R 10a and R 10a may combine together to form a C 3 -C 6 -cycloalkyl ring.
  • R 5 is (optionally substituted phenyl)-(C(CH 3 ) 2 )— (optionally substituted phenyl)-(CHCH 3 ) or benzyl.
  • R 5 is C 3 -C 10 cycloalkyl.
  • R 5 is selected from cyclohexyl, norbornyl and adamantyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 5 is norbornyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 5 is aryl.
  • R 5 is selected from optionally substituted phenyl.
  • R 6 is selected from C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, saturated or partially unsaturated heterocyclyl, heteroaryl and aryl.
  • R 6 is C 1 -C 8 alkyl.
  • the alkyl is selected from methyl, ethyl, n-propyl and iso-propyl.
  • Another embodiment relates to compounds of Formula (1), (II), (III) or (IV) wherein: R 6 is C 3 -C 10 cycloalkyl.
  • R 6 is selected from cyclohexyl, norbornyl and adamantyl.
  • R 6 is saturated or partially unsaturated 5 or 6-membered heterocyclyl.
  • R 6 is selected from tetrahydrofuryl, piperidinyl and tetrahydropyranyl.
  • R 6 is a 5 or 6 membered heteroaryl ring.
  • R 6 is selected from pyridyl, furyl and pyrrolyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 6 is C 6 -C 10 aryl.
  • R 6 is selected from optionally substituted phenyl and optionally substituted benzyl.
  • R 7 is selected from —NR 8 R 9 , C 1 -C 8 alkoxy, heterocyclyl and heterocyclyl-C 1 -C 8 -alkyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 7 is —NR 8 R 9 .
  • R 8 is methyl, ethyl, isopropyl or butyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 5 is isopropyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 9 is methyl or H.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 7 is C 1 -C 8 alkoxy.
  • R 7 is methoxy, ethoxy, propoxy or butoxy.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 7 is n-butoxy.
  • R 7 is saturated or partially unsaturated 5 or 6-membered heterocyclyl.
  • R 7 is pyrroldinyl, morpholinyl or piperidinyl.
  • R 7 is piperidinyl
  • R 7 is heterocycyl-C 1 -C 8 -alkyl.
  • R 7 is heterocycyl-C 1 -C 3 -alkyl.
  • R 7 is optionally substituted piperidin-4-yl-CH 2 —.
  • R 7 is R 8 -piperidin-4-yl-CH 2 —.
  • R 6 and R 7 form, together with the carbon atom bonded thereto, an optionally unsaturated C 3-10 -cycloalkyl or an optionally unsaturated C 4 -C 14 heterocyclyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 6 and R 7 form an optionally unsaturated C 3 -C 10 cycloalkyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 6 and R 7 form a six-membered spiro ring.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 6 and R 7 form a five-membered spiro ring.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: R 6 and R 7 form an optionally unsaturated C 4 -C 14 heterocyclyl.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: the optionally unsaturated C 4 -C 14 heterocyclyl is a six-membered heterocyclic Spiro ring.
  • Another embodiment relates to compounds of Formula (I), (II), (III) or (IV) wherein: the C 4 -C 14 heterocyclyl is a cyclic amide Spiro ring.
  • One embodiment relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising a compound according to Formula (I), (II), (III), or (IV) as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical formulation is formulated for oral delivery.
  • the oral delivery form is a tablet.
  • One embodiment relates to a method for the prophylaxis or treatment of a 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder or achieving immuno-modulation comprising administering the compound of Formula (I), (II), (III), or (IV) to an individual.
  • the disorder is selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, and inflammatory diseases.
  • Another embodiment relates to the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • Another embodiment relates to methods of treatment wherein the medical condition involving delayed or impaired wound healing is diabetes.
  • Another embodiment relates to methods of treatment wherein the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
  • Another embodiment relates to methods of treatment for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • Another embodiment relates to methods of treatment wherein immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
  • Another embodiment relates to a method for inhibiting a 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, which comprises administering to a subject in need of such treatment an effective amount of a compound according to Formula (I), (II), (III) or (IV).
  • Another object of the present invention is a compound according to general formula (I) for use in therapy:
  • R 1 and R 2 are each independently selected from hydrogen; C 3-10 -cycloalkyl optionally independently substituted by one or more of C 1-8 -alkyl and aryl; C 3-10 -cycloalkyl-C 1-8 -alkyl; aryl; aryl-C 1-8 -alkyl; heterocyclyl; heterocyclyl-C 1-8 -alkyl; or R 1 and R 2 form together with the nitrogen atom bonded thereto heterocyclyl optionally independently substituted by one or more of aryl-C 1-8 -alkyl, wherein any aryl or heterocyclyl residue is optionally independently substituted by one or more of C 1-8 -alkyl and halogen;
  • R 3 and R 4 are each independently selected from hydrogen; C 1-8 -alkyl; C 3-10 -cycloalkyl-C 1-8 -alkyl; cyano-C 1-8 -alkyl; aryl; aryl-C 1-8 -alkyl; heterocyclyl-C 1-8 -alkyl; heteroaryl-C 1-8 -alkyl; or R 3 and R 4 form together with the carbon atom bonded thereto C 3-10 -cycloalkyl, wherein any aryl residue is optionally independently substituted by one or more of hydroxy;
  • Z is sulfur or oxygen
  • R 1 and R 2 are each independently selected from hydrogen, cyclohexyl, cycloheptyl, cyclooctyl, 2,2,3,3-tetramethylcyclopropyl, 1-(4-chlorophenyl)cyclobutyl, bicyclo[2.2.1]hept-2-yl, tricyclo[3.3.1.0 ⁇ 3,7 ⁇ ]non-3-yl, cyclohexylmethyl, phenyl, 2-methylphenyl, 3-methylphenyl, 2-isopropylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-phenylpropyl, 2-chlorobenzyl, 4-chlorobenzyl, 4-(2,2,6,6-tetramethyl)piperidyl, 2-morpholinyl-4-ylethyl, or R 1 and R 2 form together with the nitrogen atom bonded thereto morpholinyl, azocane, or 4-benzylpiperidyl;
  • R 3 and R 4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclohexylmethyl, cyanomethyl, phenyl, 2-hydroxyphenyl, benzyl, 2-hydroxybenzyl, 4-hydroxybenzyl, 3,4-dihydroxybenzyl, 1H-imidazol-4-ylmethyl, indol-3-ylmethyl, 3-pyridylmethyl, or R 3 and R 4 form together with the carbon atom bonded thereto cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the compounds of Formula (I) when using the compounds of Formula (I) in therapy (e.g., Examples 39, 67, and 69-72), they may advantageously be used in the prophylaxis or treatment of an 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder or achieving immuno-modulation.
  • the disorder may be selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, and inflammatory diseases.
  • the treatment or prophylaxis is of the medical condition involves delayed or impaired wound healing.
  • the medical condition involving delayed or impaired wound healing may be associated with diabetes and may have been caused by treatment with glucocorticoids.
  • the compounds of Formula (I) for use in therapy may be for promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • Immuno-modulation may encompass tuberculosis, lepra, and psoriasis.
  • Another object of the present invention is a pharmaceutical formulation comprising a compound according to Formula (I) for use in therapy as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier, especially for use in the prophylaxis or treatment of a 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder or achieving immuno-modulation.
  • the pharmaceutical formulation can include a second active ingredient.
  • the second active ingredient can be an inhibitor of 11- ⁇ -hydroxysteroid dehydrogenase type 1 or it can have some other activity.
  • Another object of the present invention is a method for the prophylaxis or treatment of a 11- ⁇ -hydroxysteroid dehydrogenase type I enzyme-mediated disorder or achieving immuno-modulation, which comprises administering to a subject in need of such treatment an effective amount of a compound according to Formula (I), (II), (III) and (IV).
  • Another object of the present invention is a method for inhibiting a 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, which comprises administering to a subject in need of such treatment an effective amount of a compound according to Formula (I), (II), (III) and (IV).
  • Another object of the present invention is the use of a compound according to Formula (I), (II), (III) and (IV) for the manufacture of a medicament for use in the prophylaxis or treatment of a 11- ⁇ -hydroxysteroid dehydrogenase type I enzyme-mediated disorder or achieving immuno-modulation.
  • 11- ⁇ -hydroxysteroid dehydrogenase type I enzyme-mediated disorders include: diabetes, syndrome X, obesity, glaucoma, osteoporosis, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, cognitive disorders, dementia, depression, immune disorders, virus diseases, wound healing and inflammatory diseases.
  • the medical condition involving delayed or impaired wound healing is diabetes.
  • the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
  • the compound according to Formula (I), (II), (III) and (IV) may be used for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
  • a method for making a compound of formula (I) includes taking any intermediate compound delineated herein, reacting it with one or more reagents to form a compound of Formula (I), (II), (III) and (IV) including any processes specifically delineated herein.
  • the disorder is selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, and inflammatory diseases.
  • the medical condition involving delayed or impaired wound healing is diabetes.
  • the medical condition involving delayed or impaired wound healing is caused by treatment with glucocorticoids.
  • the use is for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
  • the compounds according to the present invention may be used in several indications which involve 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme.
  • the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis, E.
  • 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), naphthyl, and indanyl (i.e., 2,3-dihydroindenyl), which optionally may be substituted by C 1-6 -alkyl.
  • substituted aryl groups are benzyl, and 2-methylphenyl.
  • heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system.
  • 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, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzopyrazole; benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,5-na
  • heterocyclic and “heterocyclyl” 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 having one or more heteroatoms (e.g., oxygen, sulfur, or nitrogen) as part of the ring system and the reminder being carbon, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings.
  • heteroatoms e.g., oxygen, sulfur, or nitrogen
  • Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,4-oxazepane, azepane, phthalimide, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-1,4-benzoxazine, hexahydroazepine, 3,4-dihydro-2(1H)isoquinoline, 2,3-dihydro-1H-indole, 1,3-dihydro-2H-isoindole, azocane, 1-oxa-4-azaspiro[4.5]dec-4-ene, decahydroisoquinoline, and 1,4-diazepane.
  • the heterocyclyl or heterocyclic moiety may optionally be substituted with one or more oxo groups.
  • C 1-8 -alkyl in the compound of formula (I) according to the present application may be a straight or branched alkyl group containing 1-8 carbon atoms.
  • exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, n-heptyl, and n-octyl.
  • C 1-8 -alkyl For parts of the range “C 1-8 -alkyl” all subgroups thereof are contemplated such as C 1-7 -alkyl, C 1-6 -alkyl, C 1-5 -alkyl, C 1-4 -alkyl, C 2-8 -alkyl, C 2-7 -alkyl, C 2-6 -alkyl, C 2-5 -alkyl, C 3-7 -alkyl, C 4-6 -alkyl, etc.
  • C 1-8 -alkoxy in the compound of formula (I) according to the present application may be a straight or branched alkoxy group containing 1-8 carbon atoms.
  • exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, n-heptyloxy, and n-octyloxy.
  • C 1-6 -alkoxy For parts of the range “C 1-6 -alkoxy” all subgroups thereof are contemplated such as C 1-7 -alkoxy, C 1-6 -alkoxy, C 1-5 -alkoxy, C 1-4 -alkoxy, C 2-8 -alkoxy, C 2-7 -alkoxy, C 2-6 alkoxy, C 2-5 -alkoxy, C 3-7 -alkoxy, C 4-6 -alkoxy, etc.
  • C 1-8 -acyl in the compound of formula (I) according to the present application may be a straight or branched acyl group containing 1-8 carbon atoms.
  • exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, n-hexanoyl, n-heptanoyl, and n-octanoyl.
  • C 1-8 -acyl For parts of the range “C 1-8 -acyl” all subgroups thereof are contemplated such as C 1-7 -acyl, C 1-6 -acyl, C 1-5 -acyl, C 1-4 -acyl, C 2-8 -acyl, C 2-7 -acyl, C 2-6 acyl, C 2-5 -acyl, C 3-7 -acyl, C 4-6 -acyl, etc.
  • C 2-8 -alkenyl in the compound of formula (I) according to the present application may be a straight or branched acyl group containing 2-8 carbon atoms.
  • exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, and 1-octenyl.
  • C 2-8 -alkenyl For parts of the range “C 2-8 -alkenyl” all subgroups thereof are contemplated such as C 2-7 -alkenyl, C 2-6 -alkenyl, C 2-5 -alkenyl, C 2-4 -alkenyl, C 3-8 -alkenyl, C 3-7 -alkenyl, C 3-6 -alkenyl, C 3-5 -alkenyl, C 4-7 alkenyl, C 5-6 -alkenyl, etc.
  • C 3-10 -cycloalkyl in the compound of formula (I) according to the present application may be an optionally substituted monocyclic, bicyclic or tricyclic alkyl group containing between 3-10 carbon atoms.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2.1]hept-2-yl, tricyclo[3.3.1.0 ⁇ 3,7 ⁇ ]non-3-yl, (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl, (1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl, 1-adamantyl, noradamantyl, and 2,2,3,3-tetramethylcycl
  • C 3-10 -cycloalkyl For parts of the range “C 3-10 -cycloalkyl” all subgroups thereof are contemplated such as C 3-9 -cycloalkyl, C 3-8 -cycloalkyl, C 3-7 -cycloalkyl, C 3-6 -cycloalkyl, C 3-5 -cycloalkyl, C 4-10 -cycloalkyl, C 5-10 -cycloalkyl, C 6-10 -cycloalkyl, C 7-10 -cycloalkyl, C 8-9 -cycloalkyl, etc.
  • the cycloalkyl moiety may optionally be substituted with one or more oxo groups.
  • C 3-10 -cycloalkenyl in the compound of formula (I) according to the present application may be an optionally alkyl substituted cyclic, bicyclic or tricyclic alkenyl group containing totally 3-10 carbon atoms.
  • exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, and bicyclo[2.2.1]hept-5-en-2-yl.
  • C 3-10 -cycloalkenyl For parts of the range “C 3-10 -cycloalkenyl” all subgroups thereof are contemplated such as C 3-9 -cycloalkenyl, C 3-8 -cycloalkenyl, C 3-7 -cycloalkenyl, C 3-6 -cycloalkenyl, C 3-5 -cycloalkenyl, C 4-10 -cycloalkenyl, C 5-10 -cycloalkenyl, C 6-10 -cycloalkenyl, C 7-10 -cycloalkenyl, C 8-9 -cycloalkenyl, etc.
  • the cycloalkenyl moiety may optionally be substituted with one or more oxo groups.
  • halogen or “halo” in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • sulfanyl in the present description means a thio group.
  • hetero(C 1 -C 8 )alkyl refers to a moiety wherein a hetero atom, selected from optionally substituted nitrogen, sulfur and oxygen, is the point of attachment to the core molecule and is attached to a C 1 -C 8 alkyl chain.
  • cyclic amide spiro ring refers to compounds where the substituents at the 5-position of the thiazolinone or the oxazolone ring combine together to form a cyclic ring having a —NR 10 C(O)— therein.
  • An example of such a moiety is shown in the example below:
  • the functionalities in question may be substituted with independently C 1-8 -acyl, C 2-8 -alkenyl, C 1-8 -(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 1-8 -alkyl.
  • the expression “optionally mono- or disubstituted” is meant in the present description that the functionalities in question may also be substituted with independently hydrogen.
  • C 3-10 -cycloalkyl-C 1-8 -alkyl means a C 1-8 -alkyl group that is substituted by a C 3-10 -cycloalkyl group.
  • a C 1-8 -haloalkyl means a C 1-8 -alkyl group that is substituted by a halogen atom.
  • Metabolites of the compounds of Formula (I), (II), (III) and (IV) can take on many forms and the present invention encompasses the metabolites of the compounds as well as the parent compound.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a benzamide derivative.
  • prodrugs include, but are not limited to, derivatives and metabolites of a benzamide derivative that include biohydrolyzable groups such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues (e.g., monophosphate, diphosphate or triphosphate).
  • prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
  • the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
  • Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6 th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).
  • Tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another, in the present case, tautomers of the structures below are encompassed by the present invention.
  • hydrate is a form of a compound of Formula (I), (II), (III), or (IV) where water molecules are combined in a definite ratio as an integral part of the crystal structure of the compound.
  • solvate is a form of of a compound of Formula (I), (II), (III), or (IV) where solvent molecules are combined in a definite ratio as an integral part of the crystal structure of the compound.
  • the phrase “pharmaceutically acceptable salt,” as used herein, refers to a pharmaceutically acceptable organic or inorganic acid or base salt of a benzamide derivative.
  • Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hex
  • geometrical isomers refers compounds that have the same molecular formula but the atoms are in different non-equivalent positions to one another.
  • optical isomers refers to compounds with chiral atoms which have the ability to rotate plane polarized light, RIS configuration.
  • optical isomer include enantiomers and diastereomers as well as compounds which can be distinguished one from the other by the designations of (D) and (L),
  • DCM dichloromethane
  • DEAD means diethyl azocarboxylate
  • DMF means dimethylformamide
  • EDCI means 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • Ether means diethyl ether
  • HOBt means 1-hydroxybenzotriazole
  • HPLC means high-performance liquid chromatography
  • MeCN means acetonitrile
  • DPPA means diphenylphosphoryl azide
  • TEA means triethylamine
  • THF means tetrahydrofuran
  • stable refers 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- ⁇ -HSD1 inhibition, 11- ⁇ -HSD1-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.
  • 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
  • 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. Included in the invention are pharmaceutically acceptable salts or compounds of any of the formulae herein.
  • compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula (I) as described herein above, dissolved or dispersed therein as an active, antimicrobial, ingredient.
  • the therapeutic composition is not immunogenic when administered to a human patient for therapeutic purposes, unless that purpose is to induce an immune response.
  • compositions that contains active ingredients dissolved or dispersed therein are well understood in the art.
  • compositions are prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non-aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared.
  • the preparation can also be emulsified.
  • the active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
  • the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient.
  • Adjuvants may also be present in the composition.
  • aqueous carriers are well known in the art.
  • exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline.
  • aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes.
  • Liquid compositions can also contain liquid phases in addition to and to the exclusion of water.
  • additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
  • compositions comprising compounds comprising the formula (I), may include pharmaceutically acceptable salts of that component therein as set out above.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and the like.
  • the preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
  • Other routes are known to those of ordinary skill in the art.
  • compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, calcium hydrogen phosphate, sodium starch glycolate, sorbitol or glycine; tabletting lubricant e.g.
  • Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose (optionally microcrystalline), glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g.
  • non-aqueous vehicles which may include edible oils, e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • edible oils e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol
  • preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • a pharmaceutical composition according to the present invention may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula (I) per weight of total therapeutic composition.
  • a weight percent is a ratio by weight of total composition.
  • 0.1 weight percent is 0.1 grams of compound comprising the formula (I) per 100 grams of total composition.
  • a suitable daily oral dose for a mammal, preferably a human being may vary widely depending on the condition of the patient. However a dose of compound comprising the formula (I) of about 0.1 to 300 mg/kg body weight may be appropriate.
  • compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier.
  • the compounds and compositions may be thus administered to animals, e.g., cats, dogs, or horses, in treatment methods.
  • the compounds of the present invention in labelled form may be used as a diagnostic agent.
  • This invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein.
  • the compounds of formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in-vitro was studied using the following reagents and methods.
  • the chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds.
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M.
  • [1,2(n)— 3 H]-cortisone was purchased from Amersham Pharmacia Biotech.
  • Anti-cortisol monoclonal mouse antibody, clone 6D6.7 was obtained from Immunotech and Scintillation proximity assay (SPA) beads coated with monoclonal antimouse antibodies were from Amersham Pharmacia Biotech.
  • NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate (G-6-P) was supplied by Sigma.
  • the human 11- ⁇ -hydroxysteroid dehydrogenase type-1 enzyme (11- ⁇ -HSD 1 ) was expressed in Pichiapastoris.
  • 18- ⁇ -glycyrrhetinic acid (GA) was obtained from Sigma.
  • the 11- ⁇ -HSD 1 enzyme assay was carried out in 96 well microtiter plates (Packard, Optiplate) in a total well volume of 220 ⁇ L and contained 30 mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiated Cortisone/NADPH (175 nM/181 ⁇ M), G-6-P (1 mM) and inhibitors in serial dilutions (9 to 0.15 ⁇ M). Reactions were initiated by the addition of human 11- ⁇ -HSD 1 , either as Pichia pastoris cell homogenate or microsomes prepared from Pichia pastoris (the final amount of enzyme used was varied between 0.057 to 0.11 mg/mL).
  • the plates were covered with plastic film and incubated on a shaker for 30 minutes, at room temperature, before counting.
  • the amount of [ 3 H]-cortisol, bound to the beads was determined in a microplate liquid scintillation counter.
  • the calculation of the K i values for the inhibitors was performed by use of Activity Base.
  • the IC 50 is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance.
  • the Ki values of the compounds of the present invention for the 11- ⁇ -HSD1 enzyme lie typically between about 10 nM and about 10 ⁇ M. Below follow some Ki examples according to the present invention.
  • the expression and purification of the murine enzyme is described by J. Zhang, et al. Biochemistry, 44, 2005, pp 6948-57.
  • the expression and purification of the human enzyme is similar to that of the murine sequence.
  • the IC50 and Ki of the compounds are determined by the following method:
  • NADPH (Sigma, 200 ⁇ M)
  • Compound Stock Solution (10 mM in DMSO), serially diluted in assay buffer. Each compound is tested at six different concentrations usually (10 ⁇ M to 0.1 nM). All of the solutions and dilutions are made in the Assay Buffer.
  • Assay is run using white/white, 96-well assay plates (Corning) in a total volume of 100 ⁇ L.
  • the plate is covered with tape and incubated on an orbital shaker for 1 h at RT.
  • the plate is incubated (30 min) on an orbital shaker at RT.
  • the counts are read on a TopCount NXT reader.
  • a dose-response curve is first plotted using the Graphpad Prism software, to generate the IC50 values.
  • the compounds of the present invention all show 11 ⁇ -HSD1 enzyme activity (IC 50 ) in the assays ranging, from 10 nM and 10 ⁇ M.
  • Analytical HPLC were performed on Agilent 1100 system equipped with System A: ACE 3 (C8, 50 ⁇ 3.0 mm) or System B: YMC ODS-AQ, (33 ⁇ 3.0 mm) using the eluent system: water/0.1% TFA and CH 3 CN, 1 mL/min, with a gradient time of 3 min.
  • System A ACE 3 (C8, 50 ⁇ 3.0 mm) or System B: YMC ODS-AQ, (33 ⁇ 3.0 mm) using the eluent system: water/0.1% TFA and CH 3 CN, 1 mL/min, with a gradient time of 3 min.
  • Preparative HPLC was performed on a Gilson system equipped with System A: ACE 5 C8 column (50x20mm) gradient time 5 min, system B: YMC ODS-AQ (150 ⁇ 30 mm) gradient time 8.5 min or system C: YMC ODS-AQ (50 ⁇ 20 mm) gradient time 5 min using the eluent system: water/0.1% TFA and CH 3 CN.
  • Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh).
  • Method A or B was used depending if the isothiocyanate or of the corresponding amine was used.
  • the amine or the isothiocyanate was purchased from either Maybridge Plc. or from Sigma-Aldrich Co.
  • the thiourea (1.0 eq.) and the ⁇ -bromoester/ ⁇ -bromoacid (1.0 eq.) was dissolved in acetone and heated to 60° C. in a sealed tube for 15-72 hours. The solvent was removed. And the product purified by crystallization from MeOH/preparative reverse-phase HPLC.
  • the thiourea (1.0 eq.) and the ⁇ -bromoester/ ⁇ -bromoacid (1.0 eq.) was mixed in water and heated in the microwave at 140° C. for 1 hour.
  • the aqueous phase was extracted twice with DCM.
  • the combined organic phases were evaporated and the obtained crude product was purified by preparative reverse-phase HPLC.
  • the thiourea (1.0 eq.) and the ⁇ -bromoester (1.0 eq.) was dissolved in 1,4-dioxane and heated to 100° C. in a sealed tube for 1-11 days. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC.
  • the thiourea (1.0 eq.) and the ⁇ -bromoester (1.0 eq.) was dissolved in THF and heated to 70° C. in a sealed tube for 1 day. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC.
  • the thiourea (1.0 eq.) and the ⁇ -bromoester (1.0 eq.) was dissolved in 2-propanol and heated to 95° C. in a sealed tube for 3 days. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC.
  • the thiourea (1.0 eq.) and the ⁇ -bromoester/ ⁇ -bromoacid (1.0 eq.) was dissolved in MeCN and heated to 60° C. in a sealed tube for 2 days. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC.
  • the amino acid (1 eq.) was suspended in 2.0 M H 2 SO 4 , KBr (8 eq.) was added and the mixture was cooled in an ice-bath. NaNO 2 (1.3 eq.) dissolved in water was slowly added. The reaction mixture was stirred for 4 h while cooling was continued. The reaction mixture was then extracted with EtOAc, washed with brine and brine containing Na 2 S 2 O 3 . The organic phase was concentrated in vacuum. The product was used in the next step without further purification.
  • the thiourea (1 eq.) and 3-bromo-2-coumarone (1 eq.) was dissolved in acetone and heated to 60° C. for 3 hours. Water was added. The obtained solid was collected. Recrystallised from water/MeCN. The solid was collected. The mother liquor was concentrated and the obtained solid was dried in vacuum to give the product.
  • Examples 60-63 were prepared using one of the methodologies described above.
  • the thioisocyante intermediates can be prepared by the method K. Formation of the acid chloride, such as by treatment with oxalyl chloride and DMF, or thionyl chloride, followed by treatment with KNCS provides the thioisocyantes. Alternatively, treatment of the carboxylic acid with thionyl chloride, then bromination, such as with Br 2 and PBr 3 , followed by treatment with KNCS also provides the thioisocyantes.
  • bromination of the carboxylic acid such as with Br 2 , PCl 3 (cat.), followed by formation of the acid chloride, such as by treatment with oxalyl chloride or thionyl chloride, and treatment with alcohols, TMSCHN 2 or CH 2 N 2 , yields the desired compounds.
  • the acid chloride can be formed first, followed by bromination step.
  • Starting from esters treatment with strong base, e.g. LDA, and a leaving group supplier such as TMSCl, followed by bromination provides the desired esters.
  • TMSCl a leaving group supplier
  • bromination such as by reaction with HBr in the presence of NaNO 2 , yields the desired bromo acids.
  • Method O Formation of the desired thioureas is detailed in Method O.
  • the thiourea is formed through treatment with 1,1-thiocarbonyldiimidazole in the presence of base, e.g. NEt 3 , followed by treatment with ammonia.
  • the thiourea is formed as described in Method P. Treatment of a substituted thioisocyanate with ammonia yields the desired thioureas.
  • Bicyclo[2.2.1]heptanyl thioureas are provided via Method S. Bromination of carboxylic acids, such as with Br 2 , PCl 3 , and the resulting rearrangement provides the 2-bromo-1-carboxylic acids. Dehalogenation, such as with Zn in AcOH, yields the 1-carboxylic acids. The Curtius rearrangement such as by treatment with DPPA and a base, e.g. NEt 3 , and an alcohol provides the protected amine. Deprotection, such as with acid, followed by formation of the thiourea and deprotection, as described above, provides the desired thioureas.
  • Base mediated substitution of a nitrophenol with a alkyl halide provides the nitophenyl ether.
  • Cs 2 CO 3 can be used in the presence of NaI.
  • Method U describes the formation of cyclopropanamines from benzonitriles is accomplished by treatment with EtMgBr in the presence of Ti(Oi-Pr) 4 , followed by treatment with BF 3 .OEt 2 .
  • Thiazolones can be prepared by many methods, including that described in Method X. Treatment of a bromo-substituted carboxylic acid or ester with thiourea in the presence of base, such as DIEA provides the condensation/ring closure to the desired 2-amino-thiazolones.
  • Thiazolones also can be prepared from amines by the method described in Method Z. Coupling of an amine with an isothiocyante, e.g. in the presence of base, such as NEt 3 , provides the condensation/ring closure to the desired 2-amino-thiazolones.
  • 5,5-Disubstituted thiazolones can be prepared from thiazolones via the method described in Method AA. Treatment first with strong base, e.g. LDA or NaHMDS, then with a compound comprising an appropriate leaving group, such as R B -LG, provides the desired compounds.
  • strong base e.g. LDA or NaHMDS
  • R B -LG a compound comprising an appropriate leaving group
  • 5-fluoro-thiazolones can be prepared as described in Method BB. Treatment first with strong base, e.g. LDA or NaHMDS, and TMSCl, followed by fluorination, e.g. with Selectfluor, provides the desired compounds.
  • strong base e.g. LDA or NaHMDS
  • TMSCl e.g. TMSCl
  • fluorination e.g. with Selectfluor
  • 5-trifluoromethyl-thiazolones can be prepared as described in Method CC. Treatment first with strong base, e.g. LDA or NaHMDS, and TMSCl, followed by trifluoromethylation, e.g. with S-(trifluoromethyl)dibenzothiophenium salt, provides the desired compounds.
  • strong base e.g. LDA or NaHMDS
  • TMSCl trifluoromethylation
  • Formation of 5-spiro-thiazolones can be prepared as described in Method EE. Coupling of the thiazolone in the presence of strong base, e.g. LDA or NaHMDS, provides the desired compounds. Alternatively, the cyclization can be achieved in two steps, alkylation first with base, e.g. HMDS, in the presence of TMSCl; followed by further treatment with base, e.g. LDA, in the presence of a bis-electrophile.
  • strong base e.g. LDA or NaHMDS
  • Formation of 5-hydroxymethyl-thiazolones can be prepared as described in Method FF.
  • the compounds of the invention can be prepared by the method described in this scheme.
  • Alkylation of the racemic thiazalone with a chiral base such as where R m and R n are independently selected from alkyl, aryl, and heterocyclyl, where R o and R p are independently selected from aryl, where J is alkyl, O, NH or S, and where M 1 and M 2 are independently selected from Li, Na, K, Cs, Cu, Zn, and Mg, e.g. a chiral lithium base, more specifically and an appropriate alkylating agent, such as a alkyl halide (e.g.
  • an alkyl iodide) or sulfonate e.g., mesylate, triflate
  • [LG is halide, tosylate, mesylate, triflate, or the like] provides the desired chiral di-substituted thiazolone.
  • the alkylation is performed in the presence of amine base, such as TMEDA.
  • Treatment with the R,R form of the base provides the stereochemistry shown when R 3 is methyl.
  • Treatment with the S,S form provides the opposite stereochemistry to that shown when R 3 is methyl.
  • the reaction is maintained at a temperature below about RT, preferably below about 0° C., more preferably at or below about ⁇ 15° C.
  • An aprotic solvent e.g. toluene is acceptable.
  • thiazolone amines and ethers can be prepared as described in Method II. Bromination of thiazolones e.g. with NBS or other techniques known to one skilled in the art, followed by treatment with an amine or alcohol, provides the desired compounds.
  • thiazolone amines can be prepared from the alcohols as described in Method JJ. Following the procedure for the Dess-Martin Periodinane or Swern reactions, followed reductive amidation, such as with reacting with an amine together with NaBH(OAc) 3 or NaBH 3 CN, provides the desired compounds.
  • 5-spiro-thiazolones can be prepared from the furanone as described in Method KK.
  • Treatment of the furanone with a thiourea provides thiazolone alcohol. Protection of the alcohol, such as with dihydropyran in the presence of acid, followed by treatment with strong base, e.g. LDA, and 3-bromo-2-methylprop-1-ene, and deprotection, e.g. with PTSA, and cyclization, such as with acid, provides the desired compounds.
  • 5-spiro-thiazolones can be prepared from the thiazolone as described in Method LL.
  • Treatment of the thiazolone with strong base, e.g. LDA or NaHMDS and alkylation, such as with (2-bromoethoxy)(tert-butyl)dimethylsilane provides the protected thiazolone alcohol.
  • a subsequent round of base and silane provides the disubstituted thiazolone.
  • Deprotection e.g. with acid, followed with addition of a compound containing an appropriate leaving group, e.g. MsCl, in the presence of base, e.g. DIEA, and cyclization, such as with a substituted amine, provides the desired spiro piperidine compounds.
  • 1-Substituted piperidinemethylthiazolones can be prepared by method MM.
  • deprotection such as by treatment with acid, treatment with sulfonyl chlorides (R 12 SO 2 Cl) in the presence of base, e.g. NEt 3 , provides compounds where R Q ⁇ SO 2 R S .
  • treatment with carboxylic acid (R R CO 2 H) with standard coupling chemistry, e.g. EDCI, and HOBt provides compounds where R Q ⁇ COR R .
  • treatment with active carbonyl compounds e.g. acid anhydrides (R R CO—O—COR R ) in the presence of base, e.g. DIEA, provides compounds where R Q ⁇ COR R .
  • Formation of 5-spiro-thiazolones can be prepared from the thiazolone as described in Method NN.
  • Treatment of the thiazolone with strong base, e.g. LDA and alkylation, such as with BrCH 2 CH 2 Br provides the thiazolone bromoethyl compound.
  • Further treatment with strong base, e.g. LDA, and dimethylketone provides the desired spiro tetrahydrofuryl compounds.
  • Substituted amidomethylthiazolones can be prepared by method OO.
  • Treatment of the acid with an amine, such as in the presence of a coupling reagent, e.g. HATU and base such as DIEA provides the desired amides.
  • Substituted thiazolone esters can be prepared from the alcohol by method PP.
  • active carbonyl compounds e.g. an acid chloride
  • base e.g. DIEA
  • NPLC normal phase liquid chromatography
  • SFC supercritical fluid chromatography
  • the mobile phased was comprised of liquid carbon dioxide and an organic modifier such as methanol (with or without 0.2% DEA), ethanol (with or without 0.2% DEA), isopropanol (with or without 0.2% DEA), or acetonitrile (with or without 0.2% DEA).
  • Organic modifiers were used individually with liquid carbon dioxide or in combinations with each other and the liquid carbon dioxide.
  • Column/oven temperature was between 35 and 40° C., and the outlet pressure was either 100 or 120 bar.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110150825A1 (en) * 2006-11-14 2011-06-23 Pharmacyclics, Inc. Uses of selective inhibitors of hdac8 for treatment of inflammatory conditions
US10183938B2 (en) 2014-12-16 2019-01-22 Axovant Sciences Gmbh Geminal substituted quinuclidine amide compounds as agonists of α-7 nicotonic acetylcholine receptors
US10370370B2 (en) 2015-06-10 2019-08-06 Axovant Sciences Gmbh Aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
US10428062B2 (en) 2015-08-12 2019-10-01 Axovant Sciences Gmbh Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors

Families Citing this family (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7754709B2 (en) * 2003-06-10 2010-07-13 Solvay Pharmaceuticals Bv Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20100222316A1 (en) 2004-04-29 2010-09-02 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
WO2005116002A2 (en) * 2004-05-24 2005-12-08 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
US8686011B2 (en) 2004-05-24 2014-04-01 Amgen Inc. Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
CN101142172A (zh) 2005-01-05 2008-03-12 艾博特公司 11-β-羟甾类脱氢酶1型酶的抑制剂
US20090192198A1 (en) 2005-01-05 2009-07-30 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
EP1866298A2 (en) 2005-03-31 2007-12-19 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US7563813B2 (en) 2005-05-13 2009-07-21 Wyeth Iminothiazolidinone derivatives as SFRP-1 antagonists
WO2006130986A1 (en) * 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
JP5204662B2 (ja) * 2005-11-22 2013-06-05 アムジエン・インコーポレーテツド １１−β−ヒドロキシステロイドデヒドロゲナーゼ１型の阻害剤
AU2006317070B2 (en) 2005-11-22 2011-06-23 Amgen, Inc. Catalyzed process of making C-5-substituted heterocyclic inhibitors of 11beta-hydroxy steroid dehydrogenase type 1
BRPI0710479A2 (pt) 2006-01-18 2012-08-14 Hoffmann La Roche composto, processo para sua preparaÇço, composiÇço farmacÊutica, uso de um composto e mÉtodo de tratamento de doenÇa ou desosrdem metabàlica.
PE20110235A1 (es) 2006-05-04 2011-04-14 Boehringer Ingelheim Int Combinaciones farmaceuticas que comprenden linagliptina y metmorfina
US9090604B2 (en) 2006-07-27 2015-07-28 E I Du Pont De Nemours And Company Fungicidal azocyclic amides
WO2008013622A2 (en) 2006-07-27 2008-01-31 E. I. Du Pont De Nemours And Company Fungicidal azocyclic amides
US8927715B2 (en) 2006-08-25 2015-01-06 Vitae Pharmaceuticals, Inc. Inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8314119B2 (en) * 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
WO2008090356A1 (en) * 2007-01-25 2008-07-31 Betagenon Ab Thiazolidinone derivatives useful in the treatment of cancer and disorders caused by excess adiposity
NZ581127A (en) * 2007-05-25 2012-06-29 Abbott Gmbh & Co Kg Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mglu2 receptor)
AU2008267017A1 (en) * 2007-06-14 2008-12-24 Amgen Inc. Tricyclic inhibitors of hydroxysteroid dehydrogenases
US8541593B2 (en) * 2007-06-21 2013-09-24 Amgen Inc. Process for making substituted 2-amino-thiazolones
AR067673A1 (es) 2007-07-26 2009-10-21 Vitae Pharmaceuticals Inc Derivados de 1,3 oxazinan - 2 - ona como inhibidores ciclicos de la 11 beta -hidroxiesteroide deshidrogenasa 1. composiciones farmaceuticas.
JP5736098B2 (ja) 2007-08-21 2015-06-17 アッヴィ・インコーポレイテッド 中枢神経系障害を治療するための医薬組成物
US20100234363A1 (en) * 2007-09-19 2010-09-16 Institute Of Medicinal Molecular Design, Inc. Heterocyclic derivative having inhibitory activity on type-i 11 data-hydroxysteroid dehydrogenase
AR069207A1 (es) 2007-11-07 2010-01-06 Vitae Pharmaceuticals Inc Ureas ciclicas como inhibidores de la 11 beta - hidroxi-esteroide deshidrogenasa 1
CA2708303A1 (en) 2007-12-11 2009-06-18 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1
TW200934490A (en) 2008-01-07 2009-08-16 Vitae Pharmaceuticals Inc Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1
JP5490020B2 (ja) 2008-01-24 2014-05-14 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状カルバゼート及びセミカルバジドインヒビター
CA2715290A1 (en) 2008-02-15 2009-08-20 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
NZ588954A (en) 2008-05-01 2012-08-31 Vitae Pharmaceuticals Inc Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2723034A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2303854A2 (en) 2008-06-20 2011-04-06 Amgen, Inc Process for making substituted 2-amino-thiazolones
JP5777030B2 (ja) 2008-07-25 2015-09-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング １１β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤
JP5390610B2 (ja) 2008-07-25 2014-01-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング １１β−ヒドロキシステロイドデヒドロゲナーゼ１型の阻害剤の合成
CN102119160B (zh) 2008-07-25 2014-11-05 贝林格尔·英格海姆国际有限公司 11β-羟基类固醇脱氢酶1的环状抑制剂
JP2011529896A (ja) * 2008-07-29 2011-12-15 アムジェン インコーポレイテッド 置換２−アミノ−チアゾロンの合成のための不斉プロセス
WO2010086613A1 (en) 2009-01-30 2010-08-05 Betagenon Ab Compounds useful as inhibitors as ampk
EP2393807B1 (en) 2009-02-04 2013-08-14 Boehringer Ingelheim International GmbH Cyclic inhibitors of 11 -hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
ES2350077B1 (es) 2009-06-04 2011-11-04 Laboratorios Salvat, S.A. Compuestos inhibidores de 11beta-hidroxiesteroide deshidrogenasa de tipo 1.
JP5656986B2 (ja) 2009-06-11 2015-01-21 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １，３−オキサジナン−２−オン構造に基づく１１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状阻害剤
WO2011056737A1 (en) 2009-11-05 2011-05-12 Boehringer Ingelheim International Gmbh Novel chiral phosphorus ligands
EP2576570A1 (en) 2010-05-26 2013-04-10 Boehringer Ingelheim International GmbH 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
EP2582698B1 (en) 2010-06-16 2016-09-14 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
EP2585444B1 (en) 2010-06-25 2014-10-22 Boehringer Ingelheim International GmbH Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders
EP2619205B1 (en) 2010-09-23 2017-05-17 AbbVie Bahamas Ltd. Monohydrate of an azaadamantane derivative
US20130310431A1 (en) * 2010-10-15 2013-11-21 Amgen Inc Uses for substituted 2-amino-thiazolones in treating alzheimer's disease
CA2813671A1 (en) 2010-11-02 2012-05-10 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
CN102408392A (zh) * 2011-11-10 2012-04-11 浙江大学 水相中2-(n, n-二取代氨基)-4-噻唑啉酮的绿色制备方法
RU2483722C1 (ru) * 2012-05-22 2013-06-10 Автономная Некоммерческая Организация "Научно-Исследовательский Центр Биотехнологии Антибиотиков И Других Биологически Активных Веществ "Биоан" Аминотиазольные производные усниновой кислоты как новые противотуберкулезные агенты
JP7493835B2 (ja) * 2019-11-06 2024-06-03 アルベルト・アインシュタイン・カレッジ・オブ・メディシン 小分子プロスタグラジン輸送阻害剤
CN115322208B (zh) * 2021-05-10 2023-04-11 中国药科大学 2-氨基噻唑类衍生物及其制备方法和医药用途
CN115010616B (zh) * 2022-07-01 2024-03-26 常州锐博生物科技有限公司 一种1-氨基环丙烷羧酸盐酸盐的合成方法

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2786838A (en) * 1957-03-26 Cshy b
US2701248A (en) * 1950-12-30 1955-02-01 Monsanto Chemicals Esters of pseudothiohydantoin-5-acetic acid and method for their preparation
DE929549C (de) 1951-11-29 1955-08-01 Hoechst Ag Verfahren zur Herstellung substituierter Pseudothiohydantoine und ihrer Hydrohalogenide
FR6278M (pt) * 1966-12-14 1968-09-02
US4428948A (en) * 1977-02-03 1984-01-31 Rohm And Haas Company Novel heterocyclic compounds
JPS58183603A (ja) * 1982-04-19 1983-10-26 Mitsubishi Chem Ind Ltd 土壌病害用殺菌剤
ZA844557B (en) * 1983-06-23 1985-02-27 Hoffmann La Roche Novel thiazolidine derivatives
DK277484A (da) * 1983-06-23 1984-12-24 Hoffmann La Roche Thiazolidinderivater
JPH08277266A (ja) * 1983-09-14 1996-10-22 Alcon Lab スピロ三環式芳香族スクシンイミド誘導体、並びにヒト及び動物の糖尿病合併症治療剤
JPS6360987A (ja) * 1986-08-29 1988-03-17 Tanabe Seiyaku Co Ltd キナゾリノン誘導体の製法
MY116093A (en) * 1996-02-26 2003-11-28 Upjohn Co Azolyl piperazinyl phenyl oxazolidinone antimicrobials
US6169102B1 (en) * 1996-06-25 2001-01-02 Takeda Chemical Industries, Ltd. Oxazolone derivatives and their use as anti-Helicobacter pylori agent
SE0001899D0 (sv) 2000-05-22 2000-05-22 Pharmacia & Upjohn Ab New compounds
WO2003044009A1 (en) 2001-11-22 2003-05-30 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
IL160630A0 (en) 2001-11-22 2004-07-25 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
PL370111A1 (en) * 2001-11-22 2005-05-16 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
AR037714A1 (es) * 2001-12-06 2004-12-01 Maxia Pharmaceuticals Inc Derivados de tiazolidinona y oxazolidinona 2-sustituidos para la inhibicion de fosfatasas y el tratamiento de cancer
US7173030B2 (en) 2003-05-21 2007-02-06 Biovitrum Ab Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1
EP1631558A1 (en) 2003-05-21 2006-03-08 Biovitrum Ab Inhibitors of 11-beta-hydroxy steroid dehydrogenase type i
SE0301882D0 (sv) 2003-06-25 2003-06-25 Biovitrum Ab New use I
SE0301888D0 (sv) 2003-06-25 2003-06-25 Biovitrum Ab New use VII
SE0301885D0 (sv) 2003-06-25 2003-06-25 Biovitrum Ab New use IV
SE0301886D0 (sv) 2003-06-25 2003-06-25 Biovitrum Ab New use V
SE0301883D0 (sv) 2003-06-25 2003-06-25 Biovitrum Ab New use II
WO2004113310A1 (en) 2003-06-25 2004-12-29 Biovitrum Ab Use of an inhibitor of 11-b-hydroxysteroid dehydrogenase type 1 compounds for promoting wound healing
SE0301884D0 (sv) 2003-06-25 2003-06-25 Biovitrum Ab New use III
US20050239853A1 (en) * 2004-02-04 2005-10-27 Tjeerd Barf New compounds
WO2005116002A2 (en) * 2004-05-24 2005-12-08 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110150825A1 (en) * 2006-11-14 2011-06-23 Pharmacyclics, Inc. Uses of selective inhibitors of hdac8 for treatment of inflammatory conditions
US10183938B2 (en) 2014-12-16 2019-01-22 Axovant Sciences Gmbh Geminal substituted quinuclidine amide compounds as agonists of α-7 nicotonic acetylcholine receptors
US10370370B2 (en) 2015-06-10 2019-08-06 Axovant Sciences Gmbh Aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
US10428062B2 (en) 2015-08-12 2019-10-01 Axovant Sciences Gmbh Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors

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