WO2004037251A1 - Inhibiteurs de 11-beta-hydroxy steroide dehydrogenase de type 1 et de type 2 - Google Patents

Inhibiteurs de 11-beta-hydroxy steroide dehydrogenase de type 1 et de type 2 Download PDF

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Publication number
WO2004037251A1
WO2004037251A1 PCT/GB2003/004590 GB0304590W WO2004037251A1 WO 2004037251 A1 WO2004037251 A1 WO 2004037251A1 GB 0304590 W GB0304590 W GB 0304590W WO 2004037251 A1 WO2004037251 A1 WO 2004037251A1
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Prior art keywords
arh
compound according
formula
hsd
group
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PCT/GB2003/004590
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Inventor
Nigel Vicker
Xiangdong Su
Dharshini Ganeshapillai
Atul Purohit
Michael John Reed
Barry Victor Lloyd Potter
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Sterix Limited
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Priority claimed from GBGB0224830.0A external-priority patent/GB0224830D0/en
Application filed by Sterix Limited filed Critical Sterix Limited
Priority to MXPA05004434A priority Critical patent/MXPA05004434A/es
Priority to CA002501228A priority patent/CA2501228A1/fr
Priority to JP2004546183A priority patent/JP2006514614A/ja
Priority to EP03758357A priority patent/EP1556040A1/fr
Priority to AU2003274373A priority patent/AU2003274373A1/en
Priority to BR0315605-2A priority patent/BR0315605A/pt
Publication of WO2004037251A1 publication Critical patent/WO2004037251A1/fr
Priority to NO20052469A priority patent/NO20052469L/no

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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D277/62—Benzothiazoles
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention relates to a compound.
  • the present invention provides compounds capable of inhibiting 11 ⁇ -hydroxysteroid dehydrogenase (11 ⁇ - HSD).
  • Glucocorticoids are synthesised in the adrenal cortex from cholesterol.
  • the principle glucocorticoid in the human body is cortisol, this hormone is synthesised and secreted in response to the adrenocortictrophic hormone (ACTH) from the pituitary gland in a circadian, episodic manner, but the secretion of this hormone can also be stimulated by stress, exercise and infection.
  • Cortisol circulates mainly bound to transcortin (cortisol binding protein) or albumin and only a small fraction is free (5-10%) for biological processes [1].
  • Cortisol has a wide range of physiological effects, including regulation of carbohydrate, protein and lipid metabolism, regulation of normal growth and development, influence on cognitive function, resistance to stress and mineralocorticoid activity. Cortisol works in the opposite direction compared to insulin meaning a stimulation of hepatic gluconeogenesis, inhibition of peripheral glucose uptake and increased blood glucose concentration. Glucocorticoids are also essential in the regulation of the immune response. When circulating at higher concentrations glucocorticoids are immunosuppressive and are used pharmacologically as anti-inflammatory agents.
  • Glucocorticoids like other steroid hormones are lipophilic and penetrate the cell membrane freely. Cortisol binds, primarily, to the intracellular glucocorticoid receptor (GR) that then acts as a transcription factor to induce the expression of glucocorticoid responsive genes, and as a result of that protein synthesis.
  • GR glucocorticoid receptor
  • 11 ⁇ -HSD Localisation of the 11 ⁇ -HSD showed that the enzyme and its activity is highly present in the MR dependent tissues, kidney and parotid. However in tissues where the MR is not mineralocorticoid specific and is normally occupied by glucocorticoids, 11 ⁇ -HSD is not present in these tissues, for example in the heart and hippocampus [5]. This research also showed that inhibition of 11 ⁇ -HSD caused a loss of the aldosterone specificity of the MR in these mineralocorticoid dependent tissues.
  • 11 ⁇ -HSD type 2 acts as a dehydrogenase to convert the secondary alcohol group at the C-11 position of cortisol to a secondary ketone, so producing the less active metabolite cortisone.
  • 11 ⁇ -HSD type 1 is thought to act mainly in vivo as a reductase, that is in the opposite direction to type 2 [6] [see below].
  • 11 ⁇ - HSD type 1 and type 2 have only a 30% amino acid homology.
  • cortisol The intracellular activity of cortisol is dependent on the concentration of glucocorticoids and can be modified and independently controlled without involving the overall secretion and synthesis of the hormone.
  • 11 ⁇ -HSD type 1 The direction of 11 ⁇ -HSD type 1 reaction in vivo is generally accepted to be opposite to the dehydrogenation of type 2. In vivo homozygous mice with a disrupted type 1 gene are unable to convert cortisone to cortisol, giving further evidence for the reductive activity of the enzyme [7]. 11 ⁇ -HSD type 1 is expressed in many key glucocorticoid regulated tissues like the liver, pituitary, gonad, brain, adipose and adrenals .however, the function of the enzyme in many of these tissues is poorly understood [8].
  • cortisone in the body is higher than that of cortisol , cortisone also binds poorly to binding globulins, making cortisone many times more biologically available.
  • cortisol is secreted by the adrenal cortex, there is a growing amount of evidence that the intracellular conversion of E to F may be an important mechanism in regulating the action of glucocorticoids [9].
  • 11 ⁇ -HSD type 1 allows certain tissues to convert cortisone to cortisol to increase local glucocorticoid activity and potentiate adaptive response and counteracting the type 2 activity that could result in a fall in active glucocorticoids [10]. Potentiation of the stress response would be especially important in the brain and high levels of 11 ⁇ - HSD type 1 are found around the hippocampus, further proving the role of the enzyme. 11 ⁇ -HSD type 1 also seems to play an important role in hepatocyte maturation [8].
  • the 11 ⁇ -HSD type 1 enzyme is in the detoxification process of many non-steroidal carbonyl compounds, reduction of the carbonyl group of many toxic compounds is a common way to increase solubility and therefore increase their excretion.
  • the 11 ⁇ -HSD typel enzyme has recently been shown to be active in lung tissue [11]. Type 1 activity is not seen until after birth, therefore mothers who smoke during pregnancy expose their children to the harmful effects of tobacco before the child is able to metabolically detoxify this compound.
  • the 11 ⁇ -HSD type 2 converts cortisol to cortisone, thus protecting the MR in many key regulatory tissues of the body.
  • the importance of protecting the MR from occupation by glucocorticoids is seen in patients with AME or liquorice intoxification.
  • Defects or inactivity of the type 2 enzyme results in hypertensive syndromes and research has shown that patients with an hypertensive syndrome have an increased urinary excretion ratio of cortisol : cortisone. This along with a reported increase in the half life of radiolabelled cortisol suggests a reduction of 11 ⁇ -HSD type 2 activity [12].
  • cortisol opposes the action of insulin meaning a stimulation of hepatic gluconeogenesis, inhibition of peripheral glucose uptake and increased blood glucose concentration.
  • the effects of cortisol appear to be enhanced in patients suffering from glucose intolerance or diabetes mellitus.
  • Inhibition of the enzyme 11 ⁇ -HSD type 1 would increase glucose uptake and inhibit hepatic gluconeogenesis, giving a reduction in circulatory glucose levels.
  • the development of a potent 11 ⁇ -HSD type 1 inhibitor could therefore have considerable therapeutic potential for conditions associated with elevated blood glucose levels.
  • a specific 11 ⁇ -HSD type 1 inhibitor might be of some importance by reducing neuronal dysfunctions and the loss of cognitive functions associated with ageing, by blocking the conversion of cortisone to cortisol.
  • Glucocorticoids also have an important role in regulating part of the immune response [13]. Glucocorticoids can suppress the production of cytokines and regulate the receptor levels. They are also involved in determining whether T-helper (Th) lymphocytes progress into either Th1 or Th2 phenotype. These two different types of Th cells secrete a different profile of cytokines, Th2 is predominant in a glucocorticoid environment. By inhibiting 11 ⁇ -HSD type 1 , Th1 cytokine response would be favoured. It is also possible to inhibit 11 ⁇ -HSD type 2 , thus by inhibiting the inactivation of cortisol, it may be possible to potentiate the anti-inflammatory effects of glucocorticoids.
  • the present invention provides a compound having Formula Formula I
  • R 4 is selected from H and hydrocarbyl
  • R 5 is a hydrocarbyl group and L is an optional linker group, or R-, and R 2 together form a ring substituted with the group
  • R 3 is H or a substituent, and wherein X is selected from S, O, NR 6 and C(R 7 )(R 8 ). wherein R 6 is selected from H and hydrocarbyl groups, wherein each of R 7 and R 8 are independently selected from H and hydrocarbyl groups.
  • the present invention provides a pharmaceutical composition comprising
  • R 4 is selected from H and hydrocarbyl
  • R 5 is a hydrocarbyl group and L is an optional linker group, or R.
  • R 2 together form a ring substituted with the group
  • R 3 is H or a substituent, and wherein X is selected from S, O, NR 6 and C(R 7 )(R 8 ), wherein R 6 is selected from H and hydrocarbyl groups, wherein each of R 7 and R 8 are independently selected from H and hydrocarbyl groups.
  • the present invention provides a compound having Formula I Formula
  • R., and R 2 are a group of the formula wherein R 4 is selected from H and hydrocarbyl, R 5 is a hydrocarbyl group and L is an optional linker group, or R., and R 2 together form a ring substituted with the group
  • R 3 is H or a substituent, and wherein X is selected from S, O, NR 6 and C(R 7 )(R 8 ), wherein R 6 is selected from H and hydrocarbyl groups, wherein each of R 7 and R 8 are independently selected from H and hydrocarbyl groups, for use in medicine.
  • the present invention provides a use of a compound in the manufacture of a medicament for use in the therapy of a condition or disease associated with 11 ⁇ -HSD, wherein the compound has Formula I Formula
  • R 4 is selected from H and hydrocarbyl
  • R 5 is a hydrocarbyl group and L is an optional linker group, or R.
  • R 2 together form a ring substituted with the group wherein R 3 is H or a substituent
  • X is selected from S, O, NR 6 and C(R 7 )(R 8 ), wherein R 6 is selected from H and hydrocarbyl groups, wherein each of R 7 and R 8 are independently selected from H and hydrocarbyl groups.
  • the compounds of the present invention can act as 11 ⁇ -HSD inhibitors.
  • the compounds may inhibit the interconversion of inactive 11-keto steroids with their active hydroxy equivalents.
  • present invention provides methods by which the conversion of the inactive to the active form may be controlled, and to useful therapeutic effects which may be obtained as a result of such control. More specifically, but not exclusively, the invention is concerned with interconversion between cortisone and cortisol in humans.
  • Another advantage of the compounds of the present invention is that they may be potent 11 ⁇ -HSD inhibitors in vivo.
  • Some of the compounds of the present invention are also advantageous in that they may be orally active.
  • the present invention may provide for a medicament for one or more of (i) regulation of carbohydrate metabolism, (ii) regulation of protein metabolism, (iii) regulation of lipid metabolism, (iv) regulation of normal growth and/or development, (v) influence on cognitive function, (vi) resistance to stress and mineralocorticoid activity.
  • Some of the compounds of the present invention may also be useful for inhibiting hepatic gluconeogenesis.
  • the present invention may also provide a medicament to relieve the effects of endogenous glucocorticoids in diabetes mellitus, obesity (including centripetal obesity), neuronal loss and/or the cognitive impairment of old age.
  • the invention provides the use of an inhibitor of 11 ⁇ -HSD in the manufacture of a medicament for producing one or more therapeutic effects in a patient to whom the medicament is administered, said therapeutic effects selected from inhibition of hepatic gluconeogenesis, an increase in insulin sensitivity in adipose tissue and muscle, and the prevention of or reduction in neuronal loss/cognitive impairment due to glucocorticoid- potentiated neurotoxicity or neural dysfunction or damage.
  • the invention provides a method of treatment of a human or animal patient suffering from a condition selected from the group consisting of: hepatic insulin resistance, adipose tissue insulin resistance, muscle insulin resistance, neuronal loss or dysfunction due to glucocorticoid potentiated neurotoxicity, and any combination of the aforementioned conditions, the method comprising the step of administering to said patient a medicament comprising a pharmaceutically active amount of a compound in accordance with the present invention.
  • Some of the compounds of the present invention may be useful for the treatment of cancer, such as breast cancer, as well as (or in the alternative) non-malignant conditions, such as the prevention of auto-immune diseases, particularly when pharmaceuticals may need to be administered from an early age.
  • cancer such as breast cancer
  • non-malignant conditions such as the prevention of auto-immune diseases, particularly when pharmaceuticals may need to be administered from an early age.
  • the present invention provides a compound having Formula Formula I
  • R 4 is selected from H and hydrocarbyl
  • R 5 is a hydrocarbyl group and L is an optional linker group, or R.
  • R 2 together form a ring substituted with the group wherein R 3 is H or a substituent
  • X is selected from S, O, NR 6 and C(R 7 )(R 8 ), wherein R 6 is selected from H and hydrocarbyl groups, wherein each of R 7 and R 8 are independently selected from H and hydrocarbyl groups.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • the present invention provides a compound having Formula I defined above, for use in medicine.
  • the present invention provides a use of a compound having Formula I defined above in the manufacture of a medicament for use in the therapy of a condition or disease associated with 11 ⁇ -HSD.
  • the present invention provides a use of a compound having Formula I defined above in the manufacture of a medicament for use in the therapy of a condition or disease associated with adverse 11 ⁇ -HSD levels.
  • the present invention provides a use of a compound having Formula I defined above in the manufacture of a pharmaceutical for inhibiting 11 ⁇ -HSD activity.
  • the present invention provides a use of a compound having Formula I defined above in the manufacture of a pharmaceutical for inhibiting 11 ⁇ -HSD activity.
  • the present invention provides a method comprising (a) performing a 11 ⁇ - HSD assay with one or more candidate compounds having Formula I defined above; (b) determining whether one or more of said candidate compounds is/are capable of modulating 11 ⁇ -HSD activity; and (c) selecting one or more of said candidate compounds that is/are capable of modulating 11 ⁇ -HSD activity.
  • the present invention provides a method comprising (a) performing a 11 ⁇ - HSD assay with one or more candidate compounds having Formula I defined above; (b) determining whether one or more of said candidate compounds is/are capable of inhibiting 11 ⁇ -HSD activity; and (c) selecting one or more of said candidate compounds that is/are capable of inhibiting 11 ⁇ -HSD activity.
  • the present invention provides
  • composition comprising the said compound, optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant,
  • the compound of the present invention has Formula II Formula II
  • R 4 is selected from H and hydrocarbyl, and R 5 is a hydrocarbyl group; or R and R 2 together form a ring substituted with the group
  • R- is H or a substituent
  • R 1 and R 2 together form a ring substituted with the group
  • R-, and R 2 together form a carbocyclic ring.
  • R-, and R 2 together form a six membered ring.
  • R-i and R 2 together form a six membered carbocyclic ring. In one preferred aspect the compound of the present invention wherein R., and R 2 together form an aryl ring.
  • Preferred compounds of the present invention are those having one of the following formulae.
  • R 3 is selected from H, hydrocarbyl, -S- hydrocarbyl, -S-H, halogen and N(R 9 )(R 10 ), wherein each of R 9 and R 10 are independently selected from H and hydrocarbyl groups.
  • R 3 is selected from H, hydroxy, alkyl especially C,-C 10 alkyl groups, C,-C 6 alkyl, e.g. C.,-C 3 alkyl group, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and other pentyl isomers, and n-hexyl and other hexyl isomers, alkoxy especially C r C 10 alkoxy groups, C r C 6 alkoxy, e.g. C 1 -C 3 alkoxy group, methoxy, ethoxy, propoxy etc., alkinyl, e.g. ethinyl, or halogen, e.g. fluoro substituents.
  • R3 is -S-hydrocarbyl, preferably R3 is selected from -S-alkyl, -S-carboxylic acid, - S-ether, and -S-amide, preferably selected from -S-C ⁇ alkyl, -S- CnoCarboxcylic acid, -S- C-noether, and -S- C ⁇ amide.
  • R 3 is -CH 3 .
  • R 3 is selected from O, hydrocarbyl, and N(R 9 ) wherein R 9 is selected from H and hydrocarbyl groups. More preferably R 3 is selected from O, 0,-0, 0 alkenyl groups, such as C,-C 6 alkenyl group, and C,-C 3 alkenyl group, NH and N-C-,-C 10 alkyl groups, such as N-C,-C 6 alkyl group, and N-C,-C 3 alkyl groups.
  • R 4 is selected from H and 0,-0, 0 alkyl groups, such as C,-C 6 alkyl group, and C,-C 3 alkyl group.
  • R 4 is H.
  • R 4 is a group of the formula.
  • each R 5 is independently selected from hydrocarbyl groups.
  • Each R 5 may be the same of different to the other R 5 .
  • the two R 5 groups are the same.
  • R 5 is a cyclic hydrocarbyl group.
  • R 5 is a cyclic hydrocarbyl group comprising a hydrocarbon ring.
  • R 5 may be a substituted ring or an unsubstituted ring. In some preferred aspects of the invention R 5 is substituted ring. Preferably R 5 is a carbocyclic ring.
  • R 5 is a six membered ring.
  • R 5 is a six membered carbocyclic ring. More preferably R 5 is a substituted six membered carbocyclic ring.
  • R 5 is an aryl ring.
  • R 5 is a substituted aryl ring.
  • R 5 is a group having the formula
  • R ⁇ , R 12 , R 13 , R 14 and R 15 are independently selected from H, halogen, and hydrocarbyl groups.
  • each of R ⁇ , R 12 , R 13 , R 14 and R 15 are independently selected from H, halogen, alkyl, such as C 1-6 alkyl, phenyl, O-alkyl, O-phenyl, nitrile, haloalkyl, such as CF 3 , CCI 3 and CBr 3 , carboxyalkyl, -CO 2 H, CO 2 alkyl, and NH-acetyl groups.
  • R 11; R 12 , R 13 , R-, 4 and R 15 may join to form a ring.
  • R 1 4 and Ri5 ma Y °r a y not be adjacent.
  • the ring may be carbocyclic or heterocyclic ring.
  • the ring may be optionally substituted by any of the R ⁇ , R 12 , R 13 , R 14 and R 15 substituents listed above.
  • quinolyl may provide a naphthyl, quinolyl, tetrahydroquinolyl, or benzothtrahydropyranyl, each of which may be substituted or unsubstituted.
  • the compound of the present invention may have substituents other than those of the ring systems show herein.
  • the ring systems herein are given as general formulae and should be interpreted as such.
  • the absence of any specifically shown substituents on a given ring member indicates that the ring member may substituted with any moiety of which H is only one example.
  • the ring system may contain one or more degrees of unsaturation, for example is some aspects one or more rings of the ring system is aromatic.
  • the ring system may be carbocyclic or may contain one or more hetero atoms.
  • the compound of the invention in particular the ring system compound of the invention of the present invention may contain substituents other than those show herein.
  • substituents may be one or more of: one or more halo groups, one or more O groups, one or more hydroxy groups, one or more amino groups, one or more sulphur containing group(s), one or more hydrocarbyl group(s) - such as an oxyhydrocarbyl group.
  • the ring system of the present compounds may contain a variety of non- interfering substituents.
  • the ring system may contain one or more hydroxy, alkyl especially lower (C,-C 6 ) alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, n-pentyl and other pentyl isomers, and n-hexyl and other hexyl isomers, alkoxy especially lower (C r C 6 ) alkoxy, e.g. methoxy, ethoxy, propoxy etc., alkinyl, e.g.
  • hydrocarbylsulphanyl means a group that comprises at least hydrocarbyl group (as herein defined) and sulphur, preferably -S- hydrocarbyl, more preferably -S-hydrocarbon. That sulphur group may be optionally oxidised.
  • the hydrocarbylsulphanyl group is -S-C 1-10 alkyl, more preferably -S-C 1-5 alkyl, more preferably -S-C 1-3 alkyl, more preferably -S-CH 2 CH 2 CH 3 , -S-CH 2 CH 3 or -SCH 3
  • the compounds have a reversible action.
  • the compounds have an irreversible action.
  • the compounds of the present invention are useful for the treatment of breast cancer.
  • the compounds of the present invention may be in the form of a salt.
  • the present invention also covers novel intermediates that are useful to prepare the compounds of the present invention.
  • the present invention covers novel alcohol precursors for the compounds.
  • the present invention covers bis protected precursors for the compounds. Examples of each of these precursors are presented herein.
  • the present invention also encompasses a process comprising each or both of those precursors for the synthesis of the compounds of the present invention.
  • 11 ⁇ Steroid dehydrogenase may be referred to as “11 ⁇ -HSD” or “HD” for short
  • 11 ⁇ -HSD is preferably 11 ⁇ -HSD Type 1.
  • 11 ⁇ -HSD is preferably 11 ⁇ -HSD Type 2.
  • the term “inhibit” includes reduce and/or eliminate and/or mask and/or prevent the detrimental action of HD.
  • the compound of the present invention is capable of acting as an HD inhibitor.
  • the term "inhibitor” as used herein with respect to the compound of the present invention means a compound that can inhibit HD activity - such as reduce and/or eliminate and/or mask and/or prevent the detrimental action of HD.
  • the HD inhibitor may act as an antagonist.
  • the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit HD activity.
  • hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo, alkoxy, nitro, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen. A non- limiting example of a hydrocarbyl group is an acyl group.
  • a typical hydrocarbyl group is a hydrocarbon group.
  • hydrocarbon means any one of an alkyl group, an alkenyl group, an alkynyl group, which groups may be linear, branched or cyclic, or an aryl group.
  • the term hydrocarbon also includes those groups but wherein they have been optionally substituted. If the hydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
  • one or more hydrocarbyl groups is independently selected from optionally substituted alkyl group, optionally substituted haloalkyl group, aryl group, alkylaryl group, alkylarylakyl group, and an alkene group.
  • one or more hydrocarbyl groups is independently selected from C r C 10 alkyl group, such as C,-C 6 alkyl group, and C,-C 3 alkyl group.
  • Typical alkyl groups include C, alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 7 alkyl, and C 8 alkyl.
  • one or more hydrocarbyl groups is independently selected from 0,-0, 0 haloalkyl group, C C 6 haloalkyl group, C r C 3 haloalkyl group, C,-C 10 bromoalkyl group, C,-C 6 bromoalkyl group, and C,-C 3 bromoalkyl group.
  • Typical haloalkyl groups include C, haloalkyl, C 2 haloalkyl, C 3 haloalkyl, C 4 haloalkyl, C 5 haloalkyl, C 7 haloalkyl, C 8 haloalkyl, C, bromoalkyl, C 2 bromoalkyl, C 3 bromoalkyl, C 4 bromoalkyl, C 5 bromoalkyl, C 7 bromoalkyl, and C 8 bromoalkyl.
  • one or more hydrocarbyl groups is independently selected from aryl groups, alkylaryl groups, alkylarylakyl groups, -(CH 2 ).,. 10 -aryl, -(CH 2 ) 1-10 -Ph, (CH 2 ) 1-10 -Ph-C 1-10 alkyl, -(CH 2 ) 1-5 -Ph, (CH 2 ) 1 . 5 -Ph-C 1-5 alkyl, -(CH 2 ) 1-3 - Ph, (CH 2 ) 1-3 -Ph-C 1-3 alkyl, -CH 2 -Ph, and -CH 2 -Ph-C(CH 3 ) 3 .
  • the aryl groups may contain a hetero atom.
  • the aryl group or one or more of the aryl groups may be carbocyclic or more may heterocyclic. Typical hetero atoms include O, N and S, in particular N.
  • one or more hydrocarbyl groups is independently selected from -(CH 2 ) 1-10 -cycloalkyl, -(CH 2 ) 1-10 -C 3-1 ocycloalkyl, -(CH 2 ) 1 . 7 -C 3- 7 cycloalkyl, -(CH 2 ) 1 . 5 -C 3 . 5 cycloalkyl, -(CH 2 ) 1 . 3 -C 3-5 cycloalkyl, and -CH 2 - C 3 cycloalkyl.
  • one or more hydrocarbyl groups is independently selected from alkene groups.
  • Typical alkene groups include 0,-0, 0 alkene group, C,-C 6 alkene group, C,-C 3 alkene group, such as C,, C 2 , C 3 , C 4 , C 5 , C 6 , or C 7 alkene group.
  • one or more hydrocarbyl groups is independently selected from oxyhydrocarbyl groups.
  • oxyhydrocarbyl group as used herein means a group comprising at least C, H and O and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the oxyhydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the oxyhydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur and nitrogen.
  • the oxyhydrocarbyl group is a oxyhydrocarbon group.
  • oxyhydrocarbon means any one of an alkoxy group, an oxyalkenyl group, an oxyalkynyl group, which groups may be linear, branched or cyclic, or an oxyaryl group.
  • the term oxyhydrocarbon also includes those groups but wherein they have been optionally substituted. If the oxyhydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
  • the oxyhydrocarbyl group is of the formula C ⁇ O (such as a C 1-3 O).
  • the compounds of the present invention may be studied using an animal model, in particular in ovariectomised rats.
  • an animal model in particular in ovariectomised rats.
  • compounds which are oestrogenic stimulate uterine growth.
  • the compound (10 mg/Kg/day for five days) was administered orally to rats with another group of animals receiving vehicle only (propylene glycol).
  • a further group received the estrogenic compound EMATE subcutaneously in an amount of 10 ⁇ g/day for five days.
  • uteri were obtained and weighed with the results being expressed as uterine weight/whole body weight x 100.
  • reporter gene may encode an enzyme which catalyses a reaction which alters light absorption properties.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • FACS fluorescent activated cell sorting
  • reporter molecules include but are not limited to ( ⁇ -galactosidase, invertase, green fluorescent protein, luciferase, chloramphenicol, acetyltransferase, (- glucuronidase, exo-glucanase and glucoamylase.
  • radiolabelled or fluorescent tag-labelled nucleotides can be incorporated into nascent transcripts which are then identified when bound to oligonucleotide probes.
  • reporter molecules or labels include those radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents as well as substrates, cofactors, inhibitors, magnetic particles and the like. Patents teaching the use of such labels include US-A-3817837; US-A-3850752; US-A-3939350; US-A-3996345; US-A-4277437; US-A-4275149 and US-A-4366241.
  • host cell in relation to the present invention includes any cell that could comprise the target for the agent of the present invention.
  • a further embodiment of the present invention provides host cells transformed or transfected with a polynucleotide that is or expresses the target of the present invention.
  • said polynucleotide is carried in a vector for the replication and expression of polynucleotides that are to be the target or are to express the target.
  • the cells will be chosen to be compatible with the said vector and may for example be prokaryotic (for example bacterial), fungal, yeast or plant cells.
  • the gram negative bacterium E. coli is widely used as a host for heterologous gene expression.
  • large amounts of heterologous protein tend to accumulate inside the cell.
  • Subsequent purification of the desired protein from the bulk of E.coli intracellular proteins can sometimes be difficult.
  • bacteria from the genus Bacillus are very suitable as heterologous hosts because of their capability to secrete proteins into the culture medium.
  • Other bacteria suitable as hosts are those from the genera Streptomyces and Pseudomonas.
  • eukaryotic hosts such as yeasts or other fungi may be preferred.
  • yeast cells are preferred over fungal cells because they are easier to manipulate.
  • some proteins are either poorly secreted from the yeast cell, or in some cases are not processed properly (e.g. hyperglycosylation in yeast). In these instances, a different fungal host organism should be selected.
  • suitable expression hosts within the scope of the present invention are fungi such as Aspergillus species (such as those described in EP-A-0184438 and EP-A- 0284603) and Trichoderma species; bacteria such as Bacillus species (such as those described in EP-A-0134048 and EP-A-0253455), Streptomyces species and Pseudomonas species; and yeasts such as Kluyveromyces species (such as those described in EP-A-0096430 and EP-A-0301670) and Saccharomyces species.
  • typical expression hosts may be selected from Aspergillus niger, Aspergillus niger var. tubigenis, Aspergillus niger var.
  • suitable host cells - such as yeast, fungal and plant host cells - may provide for post-translational modifications (e.g. myristoylation, glycosylation, truncation, lapidation and tyrosine, serine or threonine phosphorylation) as may be needed to confer optimal biological activity on recombinant expression products of the present invention.
  • post-translational modifications e.g. myristoylation, glycosylation, truncation, lapidation and tyrosine, serine or threonine phosphorylation
  • organism in relation to the present invention includes any organism that could comprise the target according to the present invention and/or products obtained therefrom. Examples of organisms may include a fungus, yeast or a plant.
  • transgenic organism in relation to the present invention includes any organism that comprises the target according to the present invention and/or products obtained.
  • the host organism can be a prokaryotic or a eukaryotic organism.
  • suitable prokaryotic hosts include E. coli and Bacillus subtilis. Teachings on the transformation of prokaryotic hosts is well documented in the art, for example see Sambrook et al (Molecular Cloning: A Laboratory Manual, 2nd edition, 1989, Cold Spring Harbor Laboratory Press) and Ausubel et al., Current Protocols in Molecular Biology (1995), John Wiley & Sons, Inc.
  • nucleotide sequence may need to be suitably modified before transformation - such as by removal of introns.
  • the transgenic organism can be a yeast.
  • yeast have also been widely used as a vehicle for heterologous gene expression.
  • the species Saccharomyces cerevisiae has a long history of industrial use, including its use for heterologous gene expression.
  • Expression of heterologous genes in Saccharomyces cerevisiae has been reviewed by Goodey et al (1987, Yeast Biotechnology, D R Berry et al, eds, pp 401-429, Allen and Unwin, London) and by King et al (1989, Molecular and Cell Biology of Yeasts, E F Walton and G T Yarronton, eds, pp 107-133, Blackie, Glasgow).
  • Saccharomyces cerevisiae is well suited for heterologous gene expression. First, it is non-pathogenic to humans and it is incapable of producing certain endotoxins. Second, it has a long history of safe use following centuries of commercial exploitation for various purposes. This has led to wide public acceptability. Third, the extensive commercial use and research devoted to the organism has resulted in a wealth of knowledge about the genetics and physiology as well as large-scale fermentation characteristics of Saccharomyces cerevisiae.
  • yeast vectors include integrative vectors, which require recombination with the host genome for their maintenance, and autonomously replicating plasmid vectors.
  • expression constructs are prepared by inserting the nucleotide sequence into a construct designed for expression in yeast.
  • constructs used for heterologous expression have been developed.
  • the constructs contain a promoter active in yeast fused to the nucleotide sequence, usually a promoter of yeast origin, such as the GAL1 promoter, is used.
  • a promoter of yeast origin such as the GAL1 promoter
  • a signal sequence of yeast origin such as the sequence encoding the SUC2 signal peptide, is used.
  • a terminator active in yeast ends the expression system.
  • transgenic Saccharomyces can be prepared by following the teachings of Hinnen et al (1978, Proceedings of the National Academy of Sciences of the USA 75, 1929); Beggs, J D (1978, Nature, London, 275, 104); and Ito, H et al (1983, J Bacteriology 153, 163-168).
  • the transformed yeast cells are selected using various selective markers.
  • markers used for transformation are a number of auxotrophic markers such as LEU2, HIS4 and TRP1 , and dominant antibiotic resistance markers such as aminoglycoside antibiotic markers, e.g. G418.
  • Another host organism is a plant.
  • the basic principle in the construction of genetically modified plants is to insert genetic information in the plant genome so as to obtain a stable maintenance of the inserted genetic material.
  • Several techniques exist for inserting the genetic information the two main principles being direct introduction of the genetic information and introduction of the genetic information by use of a vector system.
  • a review of the general techniques may be found in articles by Potrykus (Annu Rev Plant Physiol Plant Mol Biol [1991] 42:205-225) and Christou (Agro-Food-Industry Hi-Tech March/April 1994 17-27). Further teachings on plant transformation may be found in EP- A-0449375.
  • the present invention also provides a method of transforming a host cell with a nucleotide sequence that is to be the target or is to express the target.
  • Host cells transformed with the nucleotide sequence may be cultured under conditions suitable for the expression of the encoded protein.
  • the protein produced by a recombinant cell may be displayed on the surface of the cell.
  • expression vectors containing coding sequences can be designed with signal sequences which direct secretion of the coding sequences through a particular prokaryotic or eukaryotic cell membrane.
  • the present invention also encompasses the use of variants, homologue and derivatives thereof.
  • the term “homology” can be equated with “identity”.
  • an homologous sequence is taken to include an amino acid sequence which may be at least 75, 85 or 90% identical, preferably at least 95 or 98% identical.
  • homology can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties/functions), in the context of the present invention it is preferred to express homology in terms of sequence identity.
  • Homology comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate % homology between two or more sequences.
  • % homology may be calculated over contiguous sequences, i.e. one sequence is aligned with the other sequence and each amino acid in one sequence is directly compared with the corresponding amino acid in the other sequence, one residue at a time. This is called an "ungapped" alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues.
  • a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance.
  • An example of such a matrix commonly used is the BLOSUM62 matrix - the default matrix for the BLAST suite of programs.
  • GCG Wisconsin programs generally use either the public default values or a custom symbol comparison table if supplied (see user manual for further details). It is preferred to use the public default values for the GCG package, or in the case of other software, the default matrix, such as BLOSUM62.
  • % homology preferably % sequence identity.
  • the software typically does this as part of the sequence comparison and generates a numerical result.
  • the sequences may also have deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent substance. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues as long as the secondary binding activity of the substance is retained.
  • negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.
  • the nucleotide sequence for use as the target or for expressing the target can be incorporated into a recombinant replicable vector.
  • the vector may be used to replicate and express the nucleotide sequence in and/or from a compatible host cell. Expression may be controlled using control sequences which include promoters/enhancers and other expression regulation signals. Prokaryotic promoters and promoters functional in eukaryotic cells may be used. Tissue specific or stimuli specific promoters may be used. Chimeric promoters may also be used comprising sequence elements from two or more different promoters described above.
  • the protein produced by a host recombinant cell by expression of the nucleotide sequence may be secreted or may be contained intracellularly depending on the sequence and/or the vector used.
  • the coding sequences can be designed with signal sequences which direct secretion of the substance coding sequences through a particular prokaryotic or eukaryotic cell membrane.
  • the target amino acid sequence may be produced as a fusion protein, for example to aid in extraction and purification.
  • fusion protein partners include glutathione-S- transferase (GST), 6xHis, GAL4 (DNA binding and/or transcriptional activation domains) and (-galactosidase. It may also be convenient to include a proteolytic cleavage site between the fusion protein partner and the protein sequence of interest to allow removal of fusion protein sequences. Preferably the fusion protein will not hinder the activity of the target.
  • the fusion protein may comprise an antigen or an antigenic determinant fused to the substance of the present invention.
  • the fusion protein may be a non-naturally occurring fusion protein comprising a substance which may act as an adjuvant in the sense of providing a generalised stimulation of the immune system.
  • the antigen or antigenic determinant may be attached to either the amino or carboxy terminus of the substance.
  • the amino acid sequence may be ligated to a heterologous sequence to encode a fusion protein.
  • a heterologous sequence for example, for screening of peptide libraries for agents capable of affecting the substance activity, it may be useful to encode a c imeric substance expressing a heterologous epitope that is recognised by a commercially available antibody.
  • the compounds of the present invention may be used as therapeutic agents - i.e. in therapy applications.
  • the term "therapy” includes curative effects, alleviation effects, and prophylactic effects.
  • the therapy may be on humans or animals, preferably female animals.
  • the present invention provides a pharmaceutical composition, which comprises a compound according to the present invention and optionally a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Preservatives may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the formulation may be designed to be delivered by both routes.
  • the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
  • compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • the compound of the present invention may be used in combination with one or more other active agents, such as one or more other pharmaceutically active agents.
  • the compounds of the present invention may be used in combination with other 11 ⁇ -HSD inhibitors and/or other inhibitors such as an aromatase inhibitor (such as for example, 4hydroxyandrostenedione (4-OHA)), and/or a steroid sulphatase inhibitors such as EMATE and/or steroids - such as the naturally occurring stemeursteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and/or other structurally similar organic compounds.
  • an aromatase inhibitor such as for example, 4hydroxyandrostenedione (4-OHA)
  • a steroid sulphatase inhibitors such as EMATE and/or steroids - such as the naturally occurring stemeurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and/or other structurally similar organic compounds.
  • DHEAS dehydroepian
  • the compound of the present invention may be used in combination with a biological response modifier.
  • biological response modifier includes cytokines, immune modulators, growth factors, haematopoiesis regulating factors, colony stimulating factors, chemotactic, haemolytic and thrombolytic factors, cell surface receptors, ligands, leukocyte adhesion molecules, monoclonal antibodies, preventative and therapeutic vaccines, hormones, extracellular matrix components, fibronectin, etc.
  • the biological response modifier is a cytokine.
  • cytokines examples include: interleukins (IL) - such as IL-1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL- 9, IL-10, IL-11 , IL-12, IL-19; Tumour Necrosis Factor (TNF) - such as TNF- ⁇ ; Interferon alpha, beta and gamma; TGF- ⁇ .
  • TNF Tumour Necrosis Factor
  • the cytokine is tumour necrosis factor (TNF).
  • the TNF may be any type of TNF - such as TNF- ⁇ , TNF- ⁇ , including derivatives or mixtures thereof. More preferably the cytokine is TNF- ⁇ . Teachings on TNF may be found in the art - such as WO-A-98/08870 and WO-A-98/13348.
  • a physician will determine the actual dosage which will be most suitable for an individual subject and it will vary with the age, weight and response of the particular patient.
  • the dosages below are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.
  • compositions of the present invention may be administered by direct injection.
  • the composition may be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular or transdermal administration.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • the agents of the present invention may be administered in accordance with a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • administered also includes delivery by techniques such as lipid mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof.
  • routes for such delivery mechanisms include but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.
  • administered includes but is not limited to delivery by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution; a parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.
  • the compounds of the present invention can be formulated in any suitable manner utilising conventional pharmaceutical formulating techniques and pharmaceutical carriers, adjuvants, excipients, diluents etc. and usually for parenteral administration.
  • Approximate effective dose rates may be in the range from 1 to 1000 mg/day, such as from 10 to 900 mg/day or even from 100 to 800 mg/day depending on the individual activities of the compounds in question and for a patient of average (70Kg) bodyweight. More usual dosage rates for the preferred and more active compounds will be in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day, most preferably from 200 to 250 mg/day.
  • the compounds may be given in single dose regimes, split dose regimes and/or in multiple dose regimes lasting over several days.
  • oral administration they may be formulated in tablets, capsules, solution or suspension containing from 100 to 500 mg of compound per unit dose.
  • the compounds will be formulated for parenteral administration in a suitable parenterally administrable carrier and providing single daily dosage rates in the range 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250 mg.
  • Such effective daily doses will, however, vary depending on inherent activity of the active ingredient and on the bodyweight of the patient, such variations being within the skill and judgement of the physician.
  • the compounds of the present invention may be useful in the method of treatment of a cell cycling disorder.
  • Yeast cells can divide every 120 min., and the first divisions of fertilised eggs in the embryonic cells of sea urchins and insects take only 1530 min. because one large pre-existing cell is subdivided. However, most growing plant and animal cells take 10-20 hours to double in number, and some duplicate at a much slower rate. Many cells in adults, such as nerve cells and striated muscle cells, do not divide at all; others, like the fibroblasts that assist in healing wounds, grow on demand but are otherwise quiescent. Still, every eukaryotic cell that divides must be ready to donate equal genetic material to two daughter cells. DNA synthesis in eukaryotes does not occur throughout the cell division cycle but is restricted to a part of it before cell division.
  • FACS fluorescence-activated cell sorter
  • the stages of mitosis and cytokinesis in an animal cell are as follows
  • Each contains a centromere that is linked by a spindle fibre to one pole, to which it moves. Thus one copy of each chromosome is donated to each daughter cell.
  • Cytokinesis begins as the cleavage furrow starts to form.
  • cell cycling is an extremely important cell process. Deviations from normal cell cycling can result in a number of medical disorders. Increased and/or unrestricted cell cycling may result in cancer. Reduced cell cycling may result in degenerative conditions. Use of the compound of the present invention may provide a means to treat such disorders and conditions. Thus, the compound of the present invention may be suitable for use in the treatment of cell cycling disorders such as cancers, including hormone dependent and hormone independent cancers.
  • the compound of the present invention may be suitable for the treatment of cancers such as breast cancer, ovarian cancer, endometrial cancer, sarcomas, melanomas, prostate cancer, pancreatic cancer etc. and other solid tumours.
  • cancers such as breast cancer, ovarian cancer, endometrial cancer, sarcomas, melanomas, prostate cancer, pancreatic cancer etc. and other solid tumours.
  • cell cycling is inhibited and/or prevented and/or arrested, preferably wherein cell cycling is prevented and/or arrested.
  • cell cycling may be inhibited and/or prevented and/or arrested in the G 2 /M phase.
  • cell cycling may be irreversibly prevented and/or inhibited and/or arrested, preferably wherein cell cycling is irreversibly prevented and/or arrested.
  • irreversibly prevented and/or inhibited and/or arrested it is meant after application of a compound of the present invention, on removal of the compound the effects of the compound, namely prevention and/or inhibition and/or arrest of cell cycling, are still observable. More particularly by the term “irreversibly prevented and/or inhibited and/or arrested” it is meant that when assayed in accordance with the cell cycling assay protocol presented herein, cells treated with a compound of interest show less growth after Stage 2 of the protocol 1 than control cells. Details on this protocol are presented below.
  • the present invention provides compounds which: cause inhibition of growth of oestrogen receptor positive (ER+) and ER negative (ER-) breast cancer cells in vitro by preventing and/or inhibiting and/or arresting cell cycling; and/or cause regression of nitroso-methyl urea (NMU)-induced mammary tumours in intact animals (i.e. not ovariectomised), and/or prevent and/or inhibit and/or arrest cell cycling in cancer cells; and/or act in vivo by preventing and/or inhibiting and/or arresting cell cycling and/or act as a cell cycling agonist.
  • NMU nitroso-methyl urea
  • CELL CYCLING ASSAY PROTOCOL 2 Procedure Stage 1 MCF-7 breast cancer cells are seeded into multi-well culture plates at a density of 105 cells/well. Cells were allowed to attach and grown until about 30% confluent when they are treated as follows:
  • Cells are grown for 6 days in growth medium containing the COI with changes of medium/COI every 3 days. At the end of this period cell numbers were counted using a Coulter cell counter.
  • the compounds of the present invention may be useful in the treatment of a cell cycling disorder.
  • a particular cell cycling disorder is cancer.
  • Cancer remains a major cause of mortality in most Western countries. Cancer therapies developed so far have included blocking the action or synthesis of hormones to inhibit the growth of hormone-dependent tumours. However, more aggressive chemotherapy is currently employed for the treatment of hormone-independent tumours.
  • the compound of the present invention provides a means for the treatment of cancers and, especially, breast cancer.
  • the compound of the present invention may be useful in the blocking the growth of cancers including leukaemias and solid tumours such as breast, endometrium, prostate, ovary and pancreatic tumours.
  • the compound or composition of the present invention may be useful in the treatment of the disorders listed in WO-A-99/52890 - viz:
  • the compound or composition of the present invention may be useful in the treatment of the disorders listed in WO-A-98/05635.
  • diabetes including Type II diabetes, obesity, cancer, inflammation or inflammatory disease, dermatological disorders, fever, cardiovascular effects, haemorrhage, coagulation and acute phase response, cachexia, anorexia, acute infection, HIV infection, shock states, graft-versus-host reactions, autoimmune disease, reperfusion injury, meningitis, migraine and aspirin-dependent anti-thrombosis; tumour growth, invasion and spread, angiogenesis, metastases, malignant, ascites and malignant pleural effusion; cerebral ischaemia, ischaemic heart disease, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer's disease, atherosclerosis, stroke, vasculitis, Crohn's disease and ulcerative colitis; periodontitis, gingivitis
  • the compound or composition of the present invention may be useful in the treatment of disorders listed in WO-A-98/07859.
  • cytokine and cell proliferation/differentiation activity e.g. for treating immune deficiency, including infection with human immune deficiency virus; regulation of lymphocyte growth; treating cancer and many autoimmune diseases, and to prevent transplant rejection or induce tumour immunity
  • regulation of haematopoiesis e.g. treatment of myeloid or lymphoid diseases
  • promoting growth of bone, cartilage, tendon, ligament and nerve tissue e.g.
  • follicle-stimulating hormone for healing wounds, treatment of burns, ulcers and periodontal disease and neurodegeneration; inhibition or activation of follicle-stimulating hormone (modulation of fertility); chemotactic/chemokinetic activity (e.g. for mobilising specific cell types to sites of injury or infection); haemostatic and thrombolytic activity (e.g. for treating haemophilia and stroke); antiinflammatory activity (for treating e.g. septic shock or Crohn's disease); as antimicrobials; modulators of e.g. metabolism or behaviour; as analgesics; treating specific deficiency disorders; in treatment of e.g. psoriasis, in human or veterinary medicine.
  • composition of the present invention may be useful in the treatment of disorders listed in WO-A-98/09985.
  • macrophage inhibitory and/or T cell inhibitory activity and thus, anti-inflammatory activity i.e.
  • inhibitory effects against a cellular and/or humoral immune response including a response not associated with inflammation; inhibit the ability of macrophages and T cells to adhere to extracellular matrix components and fibronectin, as well as up-regulated fas receptor expression in T cells; inhibit unwanted immune reaction and inflammation including arthritis, including rheumatoid arthritis, inflammation associated with hypersensitivity, allergic reactions, asthma, systemic lupus erythematosus, collagen diseases and other autoimmune diseases, inflammation associated with atherosclerosis, arteriosclerosis, atherosclerotic heart disease, reperfusion injury, cardiac arrest, myocardial infarction, vascular inflammatory disorders, respiratory distress syndrome or other cardiopulmonary diseases, inflammation associated with peptic ulcer, ulcerative colitis and other diseases of the gastrointestinal tract, hepatic fibrosis, liver cirrhosis or other hepatic diseases, thyroiditis or other glandular diseases, glomerulonephritis or other renal and urologic diseases, otitis or other oto-rhino-
  • retinitis or cystoid macular oedema retinitis or cystoid macular oedema, sympathetic ophthalmia, scleritis, retinitis pigmentosa, immune and inflammatory components of degenerative fondus disease, inflammatory components of ocular trauma, ocular inflammation caused by infection, proliferative vitreo-retinopathies, acute ischaemic optic neuropathy, excessive scarring, e.g.
  • monocyte or leukocyte proliferative diseases e.g. leukaemia
  • monocytes or lymphocytes for the prevention and/or treatment of graft rejection in cases of transplantation of natural or artificial cells, tissue and organs such as cornea, bone marrow, organs, lenses, pacemakers, natural or artificial skin tissue.
  • the present invention provides use of a compound as described herein in the manufacture of a medicament for use in the therapy of a condition or disease associated with 11 ⁇ -HSD.
  • condition or disease is selected from the list consisting of:
  • glaucoma inflammatory disorders such as arthritis or asthma immune disorders bone disorders, such as osteoporosis cancer intra-uterine growth retardation apparent mineralocorticoid excess syndrome (AME) polycystic ovary syndrome (PCOS) hirsutism acne oligo- or amenorrhea adrenal cortical adenoma and carcinoma
  • AME osteoporosis cancer intra-uterine growth retardation apparent mineralocorticoid excess syndrome
  • PCOS polycystic ovary syndrome
  • Cushing's syndrome pituitary tumours invasive carcinomas breast cancer; and endometrial cancer.
  • the present invention provides compounds for use as steroid dehydrogenase inhibitors, and pharmaceutical compositions for the same.
  • Figure 1 is of graph 1 which shows the amount of protein per ⁇ L of rat liver and rat kidney.
  • Figure 2 is of graph 2 which shows the enzyme concentration and time-dependency course, E to F, in rat liver, 11 ⁇ -HSD type 1 activity.
  • Figure 3 is of graph 3 which shows the enzyme concentration and time-dependency course, F to E, in rat kidney, 11 ⁇ -HSD type 2 activity.
  • Figure 4 is a graph showing extraction efficiencies obtained with four extraction methods.
  • Figure 5 is a graph showing a comparison of 11 ⁇ -HSD1 activity in rat and human hepatic microsomes.
  • Figure 6 is a series of graphs showing the effect of incubation time on human microsomal 11 ⁇ -HSD1 activity.
  • Figure 7 is a series of graphs showing the effect of microsomal protein concentration on human microsomal 11 ⁇ -HSD1 activity.
  • Figure 8 is a graph showing the substrate (cortisone) saturation curve for human hepatic microsomal 11 ⁇ HSD1.
  • Figure 9 is a Lineweaver-Burke plot of substrate saturation data for human hepatic microsomal 11 ⁇ HSD1.
  • Figure 10 is a graph showing the IC 50 determination for glycyrrhetinic acid.
  • Figure 11 is a graph showing the IC 50 determination for carbenoxolone.
  • Figures 12(A), 12(B) and 12(C) are graphs showing the 11 ⁇ -HSD1 activity measured by Immunoassay.
  • Figure 12(A) shows the effect of protein
  • Figure 12(B) shows the effect of cortisone
  • Figure 12(C) shows the effect of Tween-80.
  • Figure 13 is a graph showing the evaluation of the Assay Designs Cortisol
  • Figure 14 is a graph showing the effect of increasing microsomal protein on measurement of 11 ⁇ HSD1 activity detected by Assay Designs Immunoassay.
  • Figure 15 is a graph showing the detection of 11 ⁇ HSD1 activity by RIA using the
  • Figure 16 is a graph showing the effect of lowering the Immunotech antibody concentration on the signal to noise (microsome group compared to GA blank group).
  • Figure 17 is a graph showing the Immunotech antibody saturation curve for detection of 11 ⁇ HSD1 activity by RIA.
  • Figure 18 is a graph showing the linearity of human hepatic microsomal 11 ⁇ HSD1 activity detected by RIA.
  • Figure 19 is a graph showing the effect of Tween 80 on detection of human hepatic microsomal 11 ⁇ HSD1 activity by RIA.
  • Figure 20 is a graph showing the effect of buffer systems on detection of human hepatic microsomal 11 ⁇ HDS1 activity by RIA.
  • Figure 21 is a graph showing the linearity of human hepatic microsomal 11 ⁇ HSD1 activity with incubation time detected by RIA.
  • Figure 22 is a graph showing the substrate saturation curve for human hepatic microsomal 11 ⁇ HDS1 activity detected by RIA.
  • Figure 23 is a Lineweaver-Burke plot of substrate saturation data for human hepatic microsomal 11 ⁇ HDS1 activity detected by RIA.
  • Figure 24 is a graph showing the DMSO tolerance of human hepatic microsomal 11 ⁇ HSD1 activity.
  • Figure 25 is an IC 50 curve for inhibition of human hepatic microsomal 11 ⁇ HSD1 activity by glycyrrhetinic acid.
  • TLC aluminium sheets 20 x 20 cm silica gel 60 F 254 , Merck, Germany.
  • Scintillation vials 20 ml polypropylene vials with caps, SARSTEDT, Germany.
  • Scintillation counter Beckman LS 6000 SC, Beckman Instruments Inc., USA.
  • Assay medium PBS-sucrose buffer, Dulbecco's Phosphate Buffered Saline, 1 tablet/100 ml with 0,25 M sucrose, pH 7,4 BDH Laboratory supplies, UK.
  • Extraction fluid Di-ethylether, Fischer Chemicals, UK.
  • Inhibitors compounds were synthesised in accordance with the synthetic routes below .
  • Labelled cortisol (F) ( 3 H-F and C-F) was oxidised at the C-11 position with CrO 3 in order to synthesize to the corresponding labelled cortisone ( 3 H-E and 1 C-E).
  • the experiment was done according to the Bradford method [14]. The following method was used: first a BSA (protein) solution was prepared (1 mg/ml). Protein solutions containing 10 to 100 ⁇ g protein were pipetted into tubes and volumes adjusted with distilled water. Then 5 ml of protein reagent was added to the tubes and vortex mixed. The absorbance was measured at 595 nm after 15 minutes and before 1 hour in 3 ml cuvettes against a reagent blank. The weight of the protein was plotted against the corresponding absorbance resulting in a standard curve used to determine the protein concentration in rat liver and rat kidney cytosols.
  • 11 ⁇ -HSD type 1 is the enzyme responsible for the conversion E to F and this type of enzyme is present in rat liver.
  • the substrate solution used in this assay contained 70,000 cpm/ml 3 H-E in PBS-sucrose and 0.5 ⁇ M of unlabelled E and co-factor NADPH (9 mg/10 ml of substrate solution). 1 ml of the substrate solution and the different amounts of rat liver homogenate was added to all tubes.
  • the amount of rat liver homogenate needed for an assay was determined by incubating the substrate solution with 25, 50, 100 and 150 ⁇ l for 30, 60, 90 and 120 minutes at 37°C in a water bath with the tubes being mechanically shaken. After the incubation 50 ⁇ L of recovery solution was added, containing about 8,000 cpm/ 50 ⁇ L of 14 C-F and 50 ⁇ g/50 ⁇ L of unlabelled F for visualising the spot on the TLC-plate, to correct for the losses made in the next two steps. F was then extracted from the aqueous phase with 4 ml of ether (2 x 30 sec cycle, vortex mix). The aqueous phase was then frozen using dry-ice and the organic layer was decanted and poured into smaller tubes and evaporated.
  • TLC-plate aluminium thin layer chromatography plate
  • the TLC-plate was developed in a TLC tank under saturated conditions.
  • the solvent system used was chloroform : methanol 9:1 (v/v).
  • the spots from the TLC- plate were then put into scintillation vials and 0.5 ml of methanol was added to all vials to elute the radioactivity from the TLC-plate for 5 minutes.
  • the substrate solution contained about 50,000 cpm/ml 3 H-F in PBS-sucrose and 0.5 ⁇ M F. 1ml of the substrate solution was added to each tube, the inhibitors were also added, at a 10 ⁇ M concentration, to each tube except to the "control" and "blank” tubes. 150 ⁇ L was added to all tubes except to the blanks, this was done to correct for the amount of 3 H-F spontaneously formed. The tubes were incubated for 60 minutes in a mechanically shaken water bath at 37°C. The amount of kidney liver homogenate and incubation time used resulted from the enzyme- and time-dependency assay.
  • the TLC-plate was developed in chloroform : methanol (9:1 v/v) solvent system, the TLC-plate ran for about 90 minutes until the solvent front had moved about 18 cm.
  • the position of the product E was visualised under UV-light and cut out from the TLC-plate and put into scintillation vials. Radioactivity was eluted over 5 minutes with 0.5 ml methanol.
  • 0.5 ml of PBS- sucrose and 10 ml of Ecoscint were then added and vortex mixed before counting in the scintillation counter. Before counting the samples, two total activity vials were prepared.
  • Buffer 1 from Barf [15]: 30 mM Tris-HCL, pH 7.2, containing 1 mM EDTA Buffer 2, from the Sterix protocol: PBS (pH 7.4) containing 0.25M sucrose Buffer 3, from the Sigma RIA protocol: 50 mM Tris-HCL, pH 8, containing 0.1 M NaCL and 0.1 % gelatin Stop solution, from Barf [15]: 1 mM glycyrrhetinic acid in 100 % DMSO
  • Enzyme assays were carried out in the presence of 181 ⁇ M NADPH, 1 mM Glucose-6- Phosphate and cortisone concentrations indicated for each experiment.
  • Enzyme assay buffer 30 mM Tris-HCL, pH 7.2 containing 1 mM EDTA
  • Antibody binding buffer 50 mM Tris-HCL, pH 8, containing 0.1 M NaCl and 0.1 % gelatin
  • Compound preparation Prepare 10 mM stock solutions in 100% DMSO at 100 times the required assay concentration. Dilute into assay buffer 1 in 25. Also dilute neat DMSO 1 in 25 into assay buffer for controls.
  • Substrate preparation Prepare a solution of cortisone in ethanol 600 times the required assay concentration (175 nM). Dilute this 1 in 50 into assay buffer. Prepare NADPH as a 1.8 mg/ml solution in assay buffer. Prepare G-6-P as a 3.65 mg/ml solution in assay buffer.
  • Microsome preparation Dilute stock 20 mg/ml solution 1 in 100 with assay buffer.
  • Antibody preparation Dilute stock antibody solution to 17 ⁇ g/ml in antibody binding buffer.
  • Dextran coated charcoal preparation Make a 20 mg/ml solution in antibody binding buffer and chill on ice.
  • Enzyme assay To a u-bottom polypropylene 96 well plate add:
  • the 11 ⁇ HSD1 enzyme assay was carried out following the standard operating procedure described above in u-bottom polypropylene 96 well plates or 1.5 ml Eppendorf tubes as indicated for each experiment. Subsequent to stopping the enzyme reaction, 100 ⁇ l antibody prepared in buffer 3 unless otherwise indicated was added to test samples and 100 ⁇ l buffer 3 was added to the NSB samples. The samples were incubated for 1 hour at 37°C and the chilled on ice for 15 mins. Dextran coated charcoal (50 ⁇ l / sample) prepared to the indicated concentration in buffer 3 was added and the samples were mixed (vortex for tubes and aspiration 5 times with an 8-channel pipette for 96 well plates) and chilled for a further 10 min.
  • [ 1 C]-labelled cortisol was obtained from NEN.
  • a stock was prepared in phosphate buffered saline (PBS) containing 4000 DPM in 50 ⁇ l with cold cortisol (1 ⁇ g) added as a carrier.
  • the final ethanol concentration was 0.4%.
  • Aliquots of this solution were added to glass tubes (100 ⁇ l) and the following extractions were carried out: 1. 1 ml CH 2 CI 2t vortex and pass through phase separating filter paper (Whatman, IPS) 2. 1ml ethyl acetate, vortex and pass through phase separating filter paper 3.
  • the 11 ⁇ -HSD1 activities in rat and human microsomes were similar, 0.7pmol/mg/min and 0.5pmol/mg/min for rat and human microsomes respectively.
  • the activity in human microsomes is apparently not related to microsomal protein concentration, which may suggest that that the protein concentration range examined is too high.
  • the standard compounds glycyrrhetinic acid and carbenoxolone were examined in this assay system, as part of the validation process.
  • the assay was performed using 175nM cortisone substrate, with 10 ⁇ g microsomal protein and a 30 minute incubation at 37°C, as described by Barf [15]. Although the data in figures 8 and 9 above suggest that this substrate concentration is not saturating under these assay conditions.
  • Glycyrrhetinic acid and carbenoxolone were tested at concentrations from 0.012 ⁇ M to 3 ⁇ M , the DMSO concentration was 1% in all samples. The results are shown in figures 10 and 11.
  • Glycyrrhetinic acid and carbenoxolone give IC 50 values of 40nM and 119nM respectively.
  • the IC 50 reported for carbenoxolone by Barf et al. using the SPA format and recombinant 11 ⁇ -HSD is 330nM [15], approximately three-fold less potent.
  • the difference in potency in the two assay systems is probably due to the different assay conditions, SPA compared to tic end point, and also the enzyme source, native hepatic enzyme compared to recombinant enzyme.
  • the assay conditions described above support good enzyme activity however, which should be transferable to a 96 well plate format.
  • An Assay Designs enzyme immunoassay system was evaluated as a potential assay format.
  • the basis of the assay is competition for antibody binding between sample cortisol, generated by 11 ⁇ -HSD1 , and labelled cortisol binding.
  • the anti-cortisol detection antibody provided in the kit is a mouse monoclonal, reported to cross react less than 0.1% with cortisone.
  • the kit is designed for the analysis of cortisol levels in saliva, urine, serum and plasma and also in tissue culture media, rather than for determining enzyme activity however.
  • Figure 12(A) shows the effect of protein. Data taken from the 700 ⁇ M cortisone group tested in the presence of Tween-80.
  • Figure 12(B) shows the effect of cortisone. Data taken from the 25 ⁇ g microsomal protein group tested in the presence of Tween-80.
  • Figure 12(C) shows the effect of Tween-80.
  • the assay detected cortisol in the standard curve (313 pg/ml to 10,000 pg/ml) as expected but the signal obtained from the enzyme assay samples decreased with increasing microsomal protein concentration, suggesting that the microsomal protein may interfere with the immunoassay, figure 12(A).
  • Addition of exogenous cortisone had no effect on levels of cortisol detected in the enzyme assay samples, suggesting the antibody does not cross react with cortisone, figure 12(B).
  • Inclusion of detergent in the enzyme assay buffer had little effect, figure 12(C).
  • the assay conditions were varied to determine if it was feasible to use the immunoassay system to detect 11 ⁇ -HSD1 activity; 24 ⁇ g microsomal protein per sample and 2 ⁇ M cortisone substrate in Buffer 2. Enzyme activity was also measured in samples following the addition of steroid displacement reagent; a kit component which releases cortisol from cortisol binding protein, if present in the sample. The assay detected the cortisol in the standard curve (313pg/ml to 10,000pg/ml). Figure 13 shows the absorbance at 405m obtained for the different groups:
  • Glycyrrhetinic acid (GA) in the presence of the top concentration of cortisol standard has no effect on the ability of the kit to measure cortisol concentrations.
  • the 11 ⁇ HSD1 assay was carried out using 10 ⁇ g/well human hepatic microsomal protein.
  • the Immunotech antibody was used in the RIA at concentrations from 6.25 ⁇ g/well to 25 ⁇ g/well, the results are shown in figure 15.
  • the Immunotech antibody worked well in the assay and gave good signal to background at all the concentrations tested.
  • the signal to noise with 12.5 and 6.1 ⁇ g antibody per well was similar suggesting it may be possible to reduce the antibody concentration.
  • the antibody titre at concentrations from 0.67 ⁇ g/well to 6.7 ⁇ g/well, was examined.
  • the 11 ⁇ HSD1 assay was carried out using human microsomal protein at 20 ⁇ g/well, to generate the optimum signal to background.
  • Each antibody concentration was tested against a "no enzyme" blank (buffer substituted for microsomes), a "GA blank” (10 ⁇ l stop solution added prior to microsomes) and a control group. The results are shown in figures 16 and 17.
  • the saturation curve indicates that there is no difference in the detection of enzyme activity above 1.68 ⁇ g/well.
  • the signal to background ratio with this antibody concentration is good, (6 fold).Consequently the antibody will be used at 1.7 ⁇ g/well in future assays.
  • the 11 ⁇ HSD1 assay was carried with microsomal protein concentrations varying from 1 ⁇ g/well to 40 ⁇ g/well. 11 ⁇ HSD1 activity was linear with protein up to concentrations of 20 ⁇ g/well, figure 18, confirming the results obtained with the classical enzyme assay (figure 7).
  • the optimal concentration of human microsomal protein to use in the assay appears to be 10 ⁇ g/well.
  • Tween 80 in the enzyme assay buffer was also investigated. This assay was carried out in parallel with the assay above and under the same conditions except that the enzyme assay buffer (Buffer 2) contained 0.05 % Tween 80. Microsomal protein was tested at four concentrations. Tween 80 was found to increase the blank CPM, reducing the signal to noise of the assay. Representative data, from the group tested 10 ⁇ g/well microsomal protein, are shown in figure 19. Similar results were obtained with all the microsome protein concentrations examined, consequently Tween will not be used in future studies..
  • both phases were carried out in either enzyme assay buffer (Buffer 2) or Buffer 3 (RIA buffer).
  • Buffer 2 enzyme assay buffer
  • RIA buffer Buffer 3
  • the microsomal protein concentration used was 10 ⁇ g/well and the cortisone concentration was 175 nM. Performing both enzyme assay and RIA in Buffer 3 appears to improve the data slightly, figure 20.
  • IC 50 value was generated for the standard inhibitor glycyrrhetinic acid, the compound was tested at concentrations between 0.012 ⁇ M and 3 ⁇ M, with a final DMSO concentration of 1 %, figure 25.
  • An IC 50 value of 30nM has been reported for glycyrrhetinic acid inhibition of 11 ⁇ HSD1 in human hepatic microsomes, using dehydro-dexamethasone as the substrate [19]. However, these values are lower than the value reported by Barf et al. [15].
  • DGS03062B (STX469) To a stirred solution of DGS03022A (50 mg, 0.14 mmol, 1 eq.) in anhy. DMF (5 ml) and NaH (7 mg, 0.16 mmol, 1.1 eq.) was added Mel (3 ml, 0.21 mmol, 1.5 eq.) and the mixture was stirred for 1h. The resulting mixture was poured into water and the organic layer was extracted with ethyl acetate, dried (MgSO 4 ), filtered and concentrated under reduced pressure to give a yellow suspension.
  • 2,4-Dichloro benzoic acid (10 g, 0.0523 mol, 1 eq.) was heated to 115 °C with excess chlorosulphonic acid (10.5 mL, 0.1571 mol, 3 eq.) under N 2 for 18 h. The resulting mixture was cooled and consciously poured into ice-water. The resulted white precipitate was filtered out, washed with plenty of water and dried under vacuum over night.
  • DGS03116A (STX580) Synthesised by method B. Pale yellow crystals of DGS03116A (151 mg; 44%). mp 153 °C; TLC R f : 0.55 CH 2 CI 2 /EtOAc (4:1 ); 1 H NMR (DMSO-d 6 ) ⁇ 10.96 (s, 1 H, NH, Ex.
  • DGS03122B (STX583) Yellow crystals of DGS03122B (47 mg; 16%). mp 204-206 °C; TLC R f : 0.48 CH 2 CI 2 /EtOAc (4:1 ); 1 H NMR (DMSO-d 6 ) ⁇ 10.95 (s, 1H, NH, Ex.
  • DGS03130B (STX701) Pale yellow crystals of DGS03130A (45 mg; 14%). mp 169 °C; TLC R f : 0.42 CH 2 CI 2 /EtOAc (4:1 ); 1 H NMR (DMSO-d 6 ) ⁇ 10.63 (s, 1H, NH, Ex.
  • R -CH 2 COOC 2 H 5
  • R -CH 2 COOC 2 H 5
  • R -H
  • R -CH 3
  • Ar 3-CI-2-CH 3 -phenyl
  • R -H
  • R -CH 2 COOC 2 H 5 a) RX, NaH, THF r.t. b) ArS0 3 CI, DC .Pyridine or ArS0 3 CI, DCM.Pyridine/DMAP c) Diethylamine, DCM, AICI 3 d) RX, K 2 C0 3 , Acetone, reflux
  • R -NHCH 3
  • R -NHCH 3
  • R -N(C 2 H 5 ) 2
  • R -N(C 2 H 5 ) 2
  • Ar 3-CI-2-CH 3 -phenyl
  • Ar 2,5-dichlorophenyl a) HNO3, H 2 S0 4 -5 - 0°C b) H 2 , 5% Pd/C, C 2 H 5 OH, c) ArS0 3 CI, DCM.Pyridine or ArS0 3 CI, DCM,Pyridine/DMAP d) amine, THF, reflux
  • STX987 5-(3-Chloro-2-methyl-benzenesulfonylamino)-1-ethyl-2,3-dihydro-1H-indolium chloride (STX987, XDS02031)
  • STX987 The free base of STX987 was synthesized as above.
  • 1 -Acetyl-5-aminoindoline The solution of 1 -acetyl-5-nitroindoline (1.0 g, 4.85 mmol) in ethanol-THF (100 mL : 30 mL) was hydrogenated over 5% Pd/C (600 mg) at atmosphere pressure for 2h, filtered through Celite and concentrated in vacuo to give a white solid which was recrystalllized from ethanol. White crystalline solid (580 mg, 68%) was obtained.
  • 5-amino-1H-indole-3-carboxylic acid methyl ester (KRB01131): To a solution of 5- nitro-1W-indole-3-carboxylic acid methyl ester (206 mg, 0.940 mmol) in methanol (40 mL) was added 5% palladium on carbon (40 mg) and the mixture was stirred under 1 atm H 2 for 5h. The mixture was filtered through celite and the filtrate evaporated to yield a brown solid that was used without further purification (173 mg, 97%), single spot at R f 0.64 (ethyl acetate).
  • Ar 2-Me-3-CI-phenyl
  • R -CH 2 C 6 H 5
  • R -CH 2 C00C 2 H 5
  • Ar 4-n-propylphenyl
  • R -CH 3
  • R -Cri ⁇ CgHs
  • N 1 -Phenyl-benzene-1 ,2,4-triamine 800 mg, 4 mmol was dissolved in acetic acid (10 mL), acetic anhydride (1.0 mL) was added to the solution. The mixture was stirred at
  • the compound was prepared with general method of benzenesulphonamide formation.

Abstract

L'invention concerne un composé de formule (I). Dans cette formule R1 et R2 désignent un groupe de formule (a). Dans cette formule R4 est sélectionné parmi H et hydrocarbyle, R5 désigne un groupe hydrocarbyle et L désigne un groupe de liaison optionnel, ou R1 et R2 forment ensemble un anneau substitué avec le groupe (a), R3 désignant H ou un substituant, et X étant sélectionné dans S, O, NR6 et C(R7)(R8), R6 étant sélectionné parmi H et des groupes hydrocarbyle, R7 et R8 étant indépendamment sélectionnés parmi H et des groupes hydrocarbyle.
PCT/GB2003/004590 2002-10-24 2003-10-23 Inhibiteurs de 11-beta-hydroxy steroide dehydrogenase de type 1 et de type 2 WO2004037251A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
MXPA05004434A MXPA05004434A (es) 2002-10-24 2003-10-23 Inhibidores de 11-beta-hidroxi esteroide deshidrogenasa tipo 1 y tipo 2.
CA002501228A CA2501228A1 (fr) 2002-10-24 2003-10-23 Inhibiteurs de 11-beta-hydroxy steroide dehydrogenase de type 1 et de type 2
JP2004546183A JP2006514614A (ja) 2002-10-24 2003-10-23 １１β−ヒドロキシステロイドデヒドロゲナーゼ１型および２型のインヒビター
EP03758357A EP1556040A1 (fr) 2002-10-24 2003-10-23 Inhibiteurs de 11-beta-hydroxy steroide dehydrogenase de type 1 et de type 2
AU2003274373A AU2003274373A1 (en) 2002-10-24 2003-10-23 Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 and type 2
BR0315605-2A BR0315605A (pt) 2002-10-24 2003-10-23 Inibidores da 11-beta-hidroxi esteróide desidrogenase tipo 1 e tipo 2
NO20052469A NO20052469L (no) 2002-10-24 2005-05-23 Inhibitorer av II-beta-hydroksysteroid-dehydrogenase type 1 og type 2.

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GB0224830.0 2002-10-24
GBGB0224830.0A GB0224830D0 (en) 2002-10-24 2002-10-24 Compound
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US60/436,635 2002-12-30

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CA (1) CA2501228A1 (fr)
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Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005103023A1 (fr) * 2004-04-20 2005-11-03 Sterix Limited Derives de phenylsulfonamide utiles en tant qu'inhibiteurs de 11-beta-hydroxysteroide deshydrogenase
DE102004047272A1 (de) * 2004-09-24 2006-04-06 Schering Ag Inhibitoren der löslichen Adenylatzyklase
WO2006097337A2 (fr) * 2005-03-18 2006-09-21 Onepharm Gmbh Inhibiteurs de la 11$g(b)-hydroxysteroide deshydrogenases
WO2006105127A2 (fr) * 2005-03-31 2006-10-05 Takeda San Diego, Inc. Inhibiteurs de l'hydroxysteroide deshydrogenase
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
JP2007506724A (ja) * 2003-09-26 2007-03-22 アストラゼネカ・アクチエボラーグ ベンゾイミダゾール誘導体、それを含む組成物、その製造およびその使用
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AU2003274373A1 (en) 2004-05-13
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