WO2005042513A1 - Derives de carboxamide de phenyle et de sulfonamide utilisables comme 11-beta-hydroxysteroide deshydrogenase - Google Patents

Derives de carboxamide de phenyle et de sulfonamide utilisables comme 11-beta-hydroxysteroide deshydrogenase Download PDF

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WO2005042513A1
WO2005042513A1 PCT/GB2004/004498 GB2004004498W WO2005042513A1 WO 2005042513 A1 WO2005042513 A1 WO 2005042513A1 GB 2004004498 W GB2004004498 W GB 2004004498W WO 2005042513 A1 WO2005042513 A1 WO 2005042513A1
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arh
compound according
mmol
ethyl acetate
hsd
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PCT/GB2004/004498
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English (en)
Inventor
Nigel Vicker
Su Xiangdong
Dharshini Ganeshapillai
Atul Purohit
Michael John Reed
Barry Victor Lloyd Potter
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Sterix Limited
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Priority claimed from GBGB0324792.1A external-priority patent/GB0324792D0/en
Application filed by Sterix Limited filed Critical Sterix Limited
Priority to CA002540843A priority Critical patent/CA2540843A1/fr
Priority to EP04791576A priority patent/EP1675844A1/fr
Publication of WO2005042513A1 publication Critical patent/WO2005042513A1/fr

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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
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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 15 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 25 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.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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 I defined above.
  • 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 modulating 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
  • a pharmaceutical composition comprising the said compound, optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, • use of the said compound in the manufacture of a medicament for use in the therapy of a condition or disease associated with 11 ⁇ -HSD, and
  • Q is an atom selected from the group consisting of S, O, N and C, include the following structural moieties
  • the structural moiety may be saturated or may include unsaturation, such as one or more double bonds.
  • the structural moiety may be substituted.
  • the structural moiety may be part of a polycyclic system such as , for example
  • R ⁇ is an optionally substituted phenyl ring and R 2 is or comprises an optionally substituted aromatic ring.
  • R-j and R 2 are referred to collectively as the ring systems.
  • Ri is an optionally substituted phenyl ring.
  • Ri may be substituted or unsubstituted.
  • Ri is substituted.
  • Ri may be substituted with one or more hydrocarbyl substituents.
  • the substituents are selected from hydrocarbon groups, oxyhydrocarbon groups, halogens, amines and amides. More preferably the substituents are selected from aromatic hydrocarbon groups, alkyl groups, oxyalkyl groups, halogens, amines and amides, such as from aromatic hydrocarbon groups, alkyl groups, oxyalkyl groups and halogens.
  • the substituents are selected from phenyl groups, C 1-5 alkyl groups, oxy-C 1-5 -alkyl groups, chloro, bromo and iodo. More preferably the substituents are selected from phenyl, methyl, ethyl, propyl, O-methyl, O-ethyl, O-propyl and chloro.
  • Ri is selected from the following:
  • Ri is or comprises a group selected from the following wherein indicates the point of attachment to Z.
  • Ri is selected from the following:
  • R 2 is or comprises an optionally substituted aromatic ring.
  • the optionally substituted aromatic ring is a five or six membered ring.
  • R 2 is an optionally substituted five membered aromatic ring.
  • R 2 is an optionally substituted six membered aromatic ring.
  • the optionally substituted aromatic ring is a heterocyclic ring.
  • R 2 is an optionally substituted five or six membered aromatic heterocyclic ring.
  • the optionally substituted aromatic ring is a heterocyclic ring comprising a carbon and a hetero atom selected from O, S and N. More preferably the optionally substituted aromatic ring is a heterocyclic ring comprising a carbon and a hetero atom selected from O and N.
  • R 2 is or comprises:
  • R 2 is
  • R 2 is or comprises a group selected from the following wherein indicates the point of attachment to Z.
  • R 2 is an optionally substituted five membered heterocyclic aromatic ring. In this aspect preferably R 2 is or comprises:
  • R 2 is or comprises:
  • the optionally substituted aromatic ring is a carbocyclic ring.
  • R 2 may be substituted or unsubstituted.
  • R 2 is substituted, more preferably R 2 is a substituted aromatic carbocyclic ring.
  • the substituents are selected from hydrocarbon groups, oxyhydrocarbon groups, halogens, amines and amides. More preferably the substituents are selected from aromatic hydrocarbon groups, alkyl groups, oxyalkyl groups, halogens, amines and amides, such as from aromatic hydrocarbon groups, alkyl groups, oxyalkyl groups and halogens.
  • R 2 is substituted with two or more substituents.
  • R 2 is substituted with two or more substituents and the two or more substituents together form a ring which is fused to the carbocyclic ring of R 2 .
  • the carbocyclic ring is a five or six membered aromatic carbocyclic ring. More preferably the carbocyclic ring is a phenyl ring.
  • R 2 is a substituted phenyl ring.
  • R 2 is substituted with two or more substituents and the two or more substituents together form a ring which is fused to the phenyl ring of R 2 .
  • R 2 comprises the following structure:
  • R 2 comprises the following structure:
  • R 2 is or comprises a group selected from the following:
  • R 2 is or comprises a group selected from the following:
  • R 2 comprises the following structure:
  • R 2 is or comprises a group selected from the following:
  • R 2 is or comprises a group selected from the following:
  • R 2 is or comprises a group selected from the following:
  • R 2 is or comprises a group selected from the following:
  • R 2 is or comprises a group selected from the following wherein — indicates the point of attachment to Z.
  • 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.
  • Each ring system may contain one or more degrees of unsaturation, for example is some aspects one or more rings of a ring system is aromatic.
  • Each ring system may be carbocyclic or may contain one or more hetero atoms.
  • the compound of the invention in particular the ring systems of the compound of the 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 oxy hydrocarbyl group.
  • the ring systems of the present compounds may contain a variety of non- interfering substituents.
  • the ring systems 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 C 6 ) alkoxy, e.g. methoxy, ethoxy, propoxy etc., alkinyl, e.g. ethinyl, or halogen, e.g. fluoro substituents.
  • alkyl especially lower (C C 6 ) alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl
  • X is -S-.
  • Z is selected from -S- C(R 4 )(R 5 )-, -S-C(R 4 )(R 5 )-L-, -C(R 4 )(R 5 )-S- and -C(R 4 )(R 5 )-S-L-.
  • Y is -NR 3 -.
  • Y is -C(R 4 )(R 5 )-.
  • X is -S- and Y is -C(R )(R 5 ) ⁇ .
  • Z is - SC(R 4 )(R 5 )- or -C(R 4 )(R 5 )S-, such as -SCH 2 - or -CH 2 S-
  • L is an optional linker.
  • L may be any suitable group, for example L may a hydrocarbyl group or a hetero atom, in particular L may be a hydrocarbon group such a C ⁇ o alkyl group.
  • 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 1 -C 1 0 alkyl group, such as C ⁇ -C 6 alkyl group, and C 1 -C 3 alkyl group.
  • Typical alkyl groups include Ci 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 C C 10 haloalkyl group, C C 6 haloalkyl group, C 1 -C 3 haloalkyl group, CrC bromoalkyl group, C ⁇ -C 6 bromoalkyl group, and C C 3 bromoalkyl group.
  • Typical haloalkyl groups include Ci haloalkyl, C 2 haloalkyl, C 3 haloalkyl, C haloalkyl, C 5 haloalkyl, C 7 haloalkyl, C 8 haloalkyl, Ci 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 ) ⁇ -5 -Ph-C ⁇ -5 alkyl, -(CHs 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 ) ⁇ - ⁇ o-C 3-1 ocycloalkyl, -(CH 2 ) 1-7 -C 3- 7 cycloalkyl, -(CH 2 ) 1-5 -C 3 . 5 cycloalkyl, -(CH 2 ) ⁇ - 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 C C 10 alkene group, C C 6 alkene group, C 1 -C 3 alkene group, such as C-i, 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 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 1-6 0 (such as a C-i -3 0).
  • R 3 is selected from H and hydrocarbon groups.
  • R 3 is selected from H and alkyl groups, preferably from H and C ⁇ oalkyl groups, preferably from H and C ⁇ _ 5 alkyl groups.
  • R 3 is H.
  • R 3 may be equivalent to -L-R 2 wherein L and R 2 are independently selected from the possibilities defined herein.
  • the present compound contains two groups of the formula -L-R 2 wherein each L and R 2 are selected independently of each other.
  • each of L and R 2 may be the same as the other of L and R 2 present in the compound. Examples of compounds meeting such requirements are shown below.
  • R 4 and R 5 are independently selected from H and hydrocarbon groups.
  • R and R 5 are independently selected from H and alkyl groups, preferably independently selected from H and C -10 alkyl groups, preferably independently selected from H and C 1-5 alkyl groups.
  • at least one of R and R 5 is H.
  • R and R 5 are both H.
  • 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 also encompasses a process comprising 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. Therapy
  • 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 sterneursteroids 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 sterneurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and/or other structurally similar organic compounds.
  • DHEAS dehydro
  • biological response modifier includes cytokines, immune modulators, growth factors, haematopoiesis regulating factors, colony stimulating factors, chernotactic, 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, lL-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.
  • 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.
  • Telophase New membranes form around the daughter nuclei; the chromosomes uncoil and become less distinct, the nucleolus becomes visible again, and the nuclear membrane forms around each daughter nucleus. Cytokinesis is nearly complete, and the spindle disappears as the microtubules and other fibres depolymerise. Throughout mitosis the "daughter" centriole at each pole grows until it is full-length. At telophase the duplication of each of the original centrioles is completed, and new daughter centrioles will be generated during the next interphase.
  • 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.
  • 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 I 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
  • 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 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 group consisting of:
  • cardiovascular disorders such as hypertension
  • 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 Cushing's syndrome pituitary tumours invasive carcinomas breast cancer; and • endometrial cancer.
  • AME apparent mineralocorticoid excess syndrome
  • PCOS polycystic ovary syndrome
  • 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 compounds for use as steroid dehydrogenase inhibitors, and pharmaceutical compositions for the same.
  • the present invention provides a pharmaceutical composition
  • Ri is an aromatic ring.
  • Ri is a five or six membered aromatic ring, more preferably a six membered aromatic ring.
  • Ri is a carbocyclic ring.
  • Ri is an optionally substituted phenyl ring.
  • R 2 is or comprises a ring, preferably an aromatic ring, more preferably an optionally substituted aromatic ring.
  • R 2 comprises the following structure:
  • A represents a heterocyclic ring, preferably a five or six membered heterocyclic ring.
  • Figure 1 is a graph showing extraction efficiencies obtained with four extraction methods.
  • Figure 2 is a graph showing a comparison of 11 ⁇ -HSD1 activity in rat and human hepatic microsomes.
  • Figure 3 is a series of graphs showing the effect of incubation time on human microsomal 11 ⁇ -HSD1 activity
  • Figure 4 is a series of graphs showing the effect of microsomal protein concentration on human microsomal 11 ⁇ -HSD1 activity.
  • Figure 5 is a graph showing the substrate (cortisone) saturation curve for human hepatic microsomal 11 ⁇ HSD1.
  • Figure 6 is a Lineweaver-Burke plot.
  • Figure 7 is a graph showing the IC 50 determination for Glycyrrhetinic acid.
  • Figure 8 is a graph showing the IC 50 determination for Carbenoxolone.
  • Figures 9(A), 9(B) and 9(C) are graphs showing the 11 ⁇ -HSD1 activity measured by
  • Figure 9(A) shows the effect of protein
  • Figure 9(B) shows the effect of cortisone
  • Figure 9(C) shows the effect of Tween-80.
  • Figure 10 is a graph showing the performance of the cortisol immunoassay: various experimental designs.
  • Figure 11 is a graph showing the effect of increasing microsomal protein on measurement of 11 ⁇ HSD1 activity detected by Assay Designs Immunoassay.
  • Figure 12 is a graph showing the detection of 11 ⁇ HSD1 activity by RIA using the Immunotech anti-cortisol antibody.
  • Figure 13 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 14 is a graph showing the Immunotech antibody saturation curve for detection of
  • Figure 15 is a graph showing the linearity of human hepatic microsomal 11 ⁇ HSD1 activity detected by RIA.
  • Figure 16 is a graph showing the effect of Tween 80 on detection of human hepatic microsomal 11 ⁇ HSD1 activity by RIA.
  • Figure 17 is a graph showing the effect of buffer systems on detection of human hepatic microsomal 11 ⁇ HDS1 activity by RIA.
  • Figure 18 is a graph showing the linearity of human hepatic microsomal 11 ⁇ HSD1 activity with incubation time detected by RIA.
  • Figure 19 is a graph showing the substrate saturation curve for human hepatic microsomal 11 ⁇ HDS1 activity detected by RIA.
  • Figure 20 is a Lineweaver-Burke plot
  • Figure 21 is an IC 50 curve for inhibition of human hepatic microsomal 11 ⁇ HSD1 activity by Glycyrrhetinic acid.
  • Figure 22 is an IC 5 o curve for inhibition of human hepatic microsomal 11 ⁇ HSD1 activity by Glycyrrhetinic acid in the presence of 350 nM cortisone.
  • Figure 23 is an IC 50 curve for inhibition of human hepatic microsomal 11 ⁇ HSD1 activity by Carbenoxolone in the presence of 350 nM cortisone.
  • Cortisone, Cortisol (Hydrocortisone), NADPH, Glucose-6-phosphate, Glycyrrhetinic acid (GA), Dextran coated charcoal (C6197) and DMSO were obtained from Sigma Aldrich, Carbenoxolone was obtained from ICN Biomedicals, Product 215493001 , 3 H-cortisone was obtained from American Radiolabelled Compounds Inc, Product ART-743, 3 H- cortisol was obtained from NEN, Product NET 396, 14 C-cortisol was obtained from NEN, Product NEC 163, human hepatic microsomes were obtained from XenoTech, product H0610 / Lot 0210078, rat hepatic microsomes were obtained from XenoTech, SPA beads were obtained from Amersham, Product RPNQ0017, the Immunoassay kit was obtained from Assay Designs, Product 900-071 , the Immunologicals Direct anti-cortisol antibody was Product OBT 0646
  • Buffer 1 from Barf et al., (2002) [14]: 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 et al., (2002) [14]: 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.
  • 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.
  • Thin layer chromatography was performed on precoated plates (Merck TLC aluminium sheets silica gel 60 F 254 , Art. No. 5554). Compounds were visualised by either viewing under UV light or treating with an ethanolic solution of phosphomolybdic acid (PMA) followed by heating. Flash chromatography was carried out using Sorbsil C60 silica gel or Isolute ® pre-packed Flash Si columns from Argonaut Technologies. Parallel synthesis was performed on either Radleys Carousel reaction stations or Radleys GreenHouse parallel synthesisers. Solvent removal from parallel syntheses was performed on a GeneVac DD4 evaporation system.
  • PMA ethanolic solution of phosphomolybdic acid
  • NMR spectra were recorded with a JEOL GX-270 or Varian-Mercury-400 spectrometer, and chemical shifts are reported in parts per million (ppm, ⁇ relative to tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded at the Mass Spectrometry Service Centre, University of Bath. FAB-MS were carried out using m-nitrobenzyl alcohol (NBA) as the matrix. High performance liquid chromatography (HPLC) analysis was performed with a Waters Delta 600 liquid chromatograph with a Waters 996 photodiode Array Detector using a Waters Radialpack C18, 8x100 mm column. Melting points (Mp) were measured with a Reichert-Jung ThermoGalen Kofler block or a Sanyo Gallenkamp melting point apparatus and are uncorrected.
  • HPLC high performance liquid chromatography
  • 5-amino-benzo[b]thiophene-2-carboxylic acid methyl ester KRB01094: To a solution of 5-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester [15] (130 mg, 0.548 mmol) in methanol (30 mL) was added 5% palladium on carbon (20 mg) and the mixture was stirred under 1 atm H 2 for 2 h. The mixture was filtered through celite and the filtrate evaporated.
  • 5-amino-benzofuran-2-carboxylic acid methyl ester KRB01099: To a solution of 5- nitrobenzofuran-2-carboxylic acid methyl ester (100 mg, 0.452 mmol) in methanol (20 mL) was added 5% palladium on carbon (20 mg) and the mixture was stirred under 1 atm H 2 for 4h. The mixture was filtered through celite and the filtrate evaporated.
  • 6-amino-2-methylquinoxaline KRB01078: To a solution of 2-methyl-6-nitroquinoxaline [23] (500 mg, 2.64 mmol) in methanol (22 mL) was added 10% palladium on carbon (50 mg) and the mixture was stirred under 1 atm H 2 for 4 h. The mixture was filtered through celite and the filtrate evaporated. The residue was passed through a silica plug and evaporated to afford 6-amino-2-methylquinoxaline as a yellow solid (376 mg, 89%), single spot at R f 0.33 (ethyl acetate), mp 163-164°C ([23] 164-165°C).
  • 6-aminoquinoxaline KRB01083: To a solution of 6-nitroquinoxaline [24] (500 mg, 2.86 mmol) in methanol (20 mL) was added 10% palladium on carbon (50 mg) and the mixture was stirred under 1 atm H 2 for 4 h. The mixture was filtered through celite and the filtrate evaporated. The residue was passed through a silica plug and evaporated to afford 6-aminoquinoxaline as a yellow solid (342 mg, 82%), single spot at R f 0.32 (ethyl acetate).
  • Method B A solution of the acid (3n mmol) in thionyl chloride is refluxed 3 hours. Thionyl chloride is then removed under reduced pressure. The crude product is diluted in dry THF and added to a solution of the amine (n mmol) and triethylamine in THF. After completion, ethyl acetate and water are added . The aqueous layer is extracted by EtOAc. The combined organic layers are then washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is purified to give the amide. Biphenyl-4-carboxylic acid (2-thiophen-2-yl-ethyl -amide (STX1377.
  • Method A to a stirred solution of the amine (n mmol) in THF are added triethylamine (1.2n mmol) and the acyl chloride (1.2n mrr ⁇ ol) at room temperature. After completion, ethyl acetate and water are added. The aqueous layer is extracted by ethyl acetate. The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is then purified to give the amide.
  • Method B A solution of the acid (3n mmol) in thionyl chloride is refluxed 3 hours. Thionyl chloride is then removed under reduced pressure.
  • the crude product is diluted in dry THF and added to a solution of the amine (n mmol) and triethylamine in THF. After completion, ethyl acetate and water are added . The aqueous layer is extracted by EtOAc. The combined organic layers are then washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is purified to give the amide.
  • Method A to a stirred solution of the amine (n mmol) in THF are added triethylamine (1.2n mmol) and the acyl chloride (1.2n mmol) at room temperature. After completion, ethyl acetate and water are added. The aqueous layer is extracted by ethyl acetate. The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is then purified to give the amide.
  • Method B A solution of the acid (3n mmol) in thionyl chloride is refluxed 3 hours. Thionyl chloride is then removed under reduced pressure.
  • the crude product is diluted in dry THF and added to a solution of the amine (n mmol) and triethylamine in THF. After completion, ethyl acetate and water are added . The aqueous layer is extracted by EtOAc. The combined organic layers are then washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is purified to give the amide.
  • N-(4-Benzoyl-phenyl -3.5-dichloro-benzamide STX1431.
  • CCM0103n Reaction of 4-aminobenzophenone (100 mg, 0.51 mmol) in THF (6 mL) with 3,5- dicchlorobenzoyl chloride (136 mg, 0.65 mmol) in presence of triethylamine (90 ⁇ L, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-3,5-dichloro-benzamide (160 mg, 0.33 mmol, 63% yield) as a white powder after purification by crystallisation in
  • N-(4-Benzoyl-phenyl -3-methoxy-benzamide (STX1432. CCM01032 ⁇ ) Reaction of 4-aminobenzophenone (100 mg, 0.51 mmol) in THF (6 mL) with m-anisoyl chloride (136 mg, 0.65 mmol) in presence of triethylamine (90 ⁇ L, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-3-methoxy-benzamide (160 mg, 0.48 mmol, 94% yield) as a white powder after purification by cliromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95.
  • N-(4-Benzoyl-phenyl -2.5-dichloro-benzamide (STX1433.
  • CCM01034 Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 4-aminobenzophenone (100 mg, 0.51 mmol) in presence of triethylamine (90 ⁇ L) in THF (6 mL) according to method B gave N-(4-benzoyl-phenyl)-2,5-dichloro- benzamide (160 mg, 0.43 mmol, 84% yield) as a off-white powder after purification by cliromatography on silica gel (eluent : EtOAc/exane 1/9 to 3/7).
  • N-f4-Benzoyl-phenylV4-propyl-benzamide (STX1434.
  • CCM01036 Reaction of 4-aminobenzophenone (99 mg, 0.51 mmol) in THF (6 mL) with 4- propylbenzoyl chloride (100 ⁇ L, 0.65 mmol) in presence of triethylamine (90 ⁇ L, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-propyl-benzamide (136 mg, 0.40 mmol, 78% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95).
  • N-(4-Benzoyl-phenyl -4-methoxy-benzamide STX1435.
  • CCM01037 Reaction of 4-aminobenzophenone (98 mg, 0.51 mmol) in THF (6 mL) with -anisoyl chloride (90 ⁇ L, 0.65 mmol) in presence of triethylamine (90 ⁇ L, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-methoxy-benzamide (165 mg, 0.50 mmol, 98% yield) as a white powder after purification by washing the crude product with ethyl acetate and hexane.
  • Method A to a stirred solution of the amine (n mmol) in THF are added triethylamine (1.2n mmol) and the acyl chloride (1.2n mmol) at room temperature. After completion, ethyl acetate and water are added. The aqueous layer is extracted by ethyl acetate. The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is then purified to give the amide.
  • Method B A solution of the acid (3n mmol) in thionyl chloride is refluxed 3 hours. Thionyl chloride is then removed under reduced pressure.
  • the crude product is diluted in dry THF and added to a solution of the amine (n mmol) and triethylamine in THF. After completion, ethyl acetate and water are added . The aqueous layer is extracted by EtOAc. The combined organic layers are then washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is purified to give the amide.
  • Biphenyl-4-carboxylic acid (4-chloro-2-methyl-benzothiazol-5-yl)-amide (STX1364, CCM01009) Reaction of 4-biphenylacetic acid (160 mg, 0.76 mmol) in thionyl chloride (1 mL) then with 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in presence of triethylamine (0.5 mL) in THF (2 mL) according to method B gave biphenyl-4-carboxylic acid (4-chloro-2-methyl-benzothiazol-5-yl)-amide (60 mg, 0.15 mmol, 60% yield) as a pink powder after purification by chromatography on silica gel (eluent : DCM).
  • Method A to a stirred solution of the amine (n mmol) in THF are added triethylamine (1.2n mmol) and the acyl chloride (1.2n mmol) at room temperature. After completion, ethyl acetate and water are added. The aqueous layer is extracted by ethyl acetate. The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is then purified to give the amide.
  • Method B A solution of the acid (3n mmol) in thionyl chloride is refluxed 3 hours. Thionyl chloride is then removed under reduced pressure.
  • the crude product is diluted in dry THF and added to a solution of the amine (n mmol) and triethylamine in THF. After completion, ethyl acetate and water are added . The aqueous layer is extracted by EtOAc. The combined organic layers are then washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is purified to give the amide.
  • 2,5-Dichloro-W-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (CCM01044, STX1465) Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 6-Amino-3,4-dihydro-2H-naphthalen-l-one (80 mg, 0.50 mmol) in presence of triethylamine (90 ⁇ L, 0.65 mmol) in T ⁇ F (6 mL) according to method B gave 2,5- dichloro-N-(5-oxo-5,6,7,8-tetraliydro-naphthalen-2-yl)-benzamide (150 mg, 0.48 mmol, 76% yield) as a grey powder after purification by crystallisation in DCM.
  • Method A to a stirred solution of the amine (n mmol) in THF are added triethylamine (1.2n mmol) and the acyl chloride (1.2n mmol) at room temperature. After completion, ethyl acetate and water are added. The aqueous layer is extracted by ethyl acetate. The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated under reduce pressure. The crude product is then purified to give the amide.
  • Method B A solution of the acid (3n mmol) in thionyl chloride is refluxed 3 hours. Thionyl chloride is then removed under reduced pressure.
  • the crude product is diluted in dry THF and added to a solution of the amine (n mmol) and triethylamine in THF. After completion, ethyl acetate and water are added . The aqueous layer is extracted by EtOAc. The combined organic layers are then washed with brine, dried (MgS04), filtered and evaporated under reduce pressure. The crude product is purified to give the amide.
  • This experiment was carried out to compare the enzyme activity in hepatic microsomes from human and rat and to assess minimum microsomal protein concentrations necessary for reasonable measurement of enzyme activity.
  • the assay was carried out in Buffer 2 and the cortisone concentration used was 2 ⁇ M containing 0.5 ⁇ Ci per incubation 3 H-cortisone.
  • Rat and human hepatic microsomes were tested at concentrations ranging from 400 ⁇ g to 50 ⁇ g microsomal protein per incubation in a final incubation volume of 100 ⁇ l in glass tubes. Buffer was substituted for microsomal protein for blanks.
  • Enzyme activity is linear with microsomal protein concentrations below 30 ⁇ g per sample
  • An enzyme immunoassay kit was obtained from Assay Designs, Inc.
  • the antibody provided in the kit is a mouse monoclonal reported to cross react 100% with cortisol (the enzyme product) and ⁇ 0.1 % with cortisone (the enzyme substrate).
  • the kit is designed for the analysis of cortisol levels in saliva, urine, serum and plasma and also in tissue culture media, not for microsomal enzyme activity.
  • Figure 9 (11 B-HSD1 activity measured by Immunoassay)
  • Figure 9(A) shows the effect of protein. Data taken from 700 ⁇ M cortisone group tested in the presence of Tween-80
  • Figure 9(B) shows the effect of cortisone. Data taken from the 25 ⁇ g microsomal protein group tested in the presence of Tween-80
  • Figure 9(C) shows the effect of Tween-80. Data taken from the 25 ⁇ g microsomal protein group tested in the presence of 700 ⁇ M cortisone
  • the enzyme assay was carried out in Buffer 2.
  • the substrate (cortisone) concentration of 175 nM was chosen from the SPA method described by Barf et al. [14] with 0.5 ⁇ Ci / well 3 H- cortisone.
  • the enzyme assay was carried out in a polypropylene plate in a final incubation volume of 100 ⁇ l containing 10 ⁇ g / well human hepatic microsomal protein. Blanks had either buffer substituted for microsomal protein or had 10 ⁇ l stop solution added prior to the microsomes.
  • the assay was incubated at 37°C for 30 mins and the reaction was terminated by the addition of the stop solution to all remaining wells.
  • the Immunotech antibody was diluted in Buffer 3 to give 25 ⁇ g / 100 ⁇ l down to 6.25 ⁇ g / 100 ⁇ l.
  • the antibody (100 ⁇ l) was added to test wells, 100 ⁇ l Buffer 3 was added to the antibody blank wells. The remainder of the procedures followed the 96 well plate RIA protocol exactly. Results demonstrating 11 ⁇ HSD1 activity using the Immunotech are shown in Figure 12.
  • the antibody titre was examined in the next test, investigating concentrations per well from 6.7 ⁇ g down to 0.67 ⁇ g.
  • the usual 11 ⁇ HSD1 assay was carried out except that the microsomal protein concentration was doubled to 20 ⁇ g / well in order to get the best signal to noise.
  • the cortisone concentration was 175 nM and the enzyme assay buffer was Buffer 2.
  • Each antibody concentration was tested against a "no enzyme" blank (buffer substituted for microsomes) and a "GA blank” (10 ⁇ l stop solution added prior to microsomes) and a control group.
  • the RIA was carried out exactly as indicated in the methods for assay in 96 wells. These results are shown in Figure 13 and Figure 14.
  • the antibody will be used at 1.7 ⁇ 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. The data in Figure 16 are taken from the group tested with 10 ⁇ g / well microsomal protein, but the same effect was seen with all protein concentrations examined.
  • both enzyme assay and RIA stages were carried out in the same buffer, both phases were carried out in either enzyme assay buffer (buffer 2) or buffer 3 (RIA buffer).
  • the microsomal protein concentration used was 10 ⁇ g / well and the cortisone concentration was 175 nM.
  • Performing both enzyme assay and RIA in enzyme assay buffer gave similar data to the two buffers system but performing both enzyme assay and RIA in Buffer 3 appeared to improve the data slightly.
  • Figure 18 Linearity of human hepatic microsomal 11 ⁇ HSD1 activity with incubation time detected by RIA
  • the substrate saturation effects were examined in the next assay.
  • the enzyme assay was carried out exactly as indicated in the methods section in buffer 3 with 10 ⁇ g / well microsomal protein and with [cold cortisone] as indicated. 3H-cortisone was 0.5 ⁇ Ci / sample throughout. The reaction was stopped after 30 min by the addition of 10 ⁇ l stop solution. The RIA was carried out exactly as indicated in the methods section. Results are shown in Figure 19.
  • an IC 50 for Glycyrrhetinic acid was determined in the next test.
  • a 10 mM stock solution of Glycyrrhetinic acid was prepared in 100 % DMSO and was further diluted in 100 %
  • GA blanks (addition of 10 ⁇ l stop solution prior to the addition of microsomes) were included with and without the addition of 1 % DMSO.
  • Human hepatic microsomal protein was tested at 10 ⁇ g / well and the substrate concentration (cortisone) was 175 nM, 0.5 ⁇ Ci / well. All other procedures were as indicated in the methods section.
  • GA inhibition data are shown in Figure 21.
  • Figure 22 (ICm curve for inhibition of human hepatic microsomal 11 ⁇ HSD1 activity by Glycyrrhetinic acid in the presence of 350 nM cortisone) and Figure 23 (ICgn curve for inhibition of human hepatic microsomal 11 ⁇ HSD1 activity by Carbenoxolone in the presence of 350 nM cortisone)

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Abstract

L'invention concerne un composé de formule (I), dans laquelle R1 est un cycle phénylique éventuellement substitué; R2 est ou comprend un noyau aromatique éventuellement substitué; et Z est -X-Y-L- ou -Y-X-L- (dont X est sélectionné dans le groupe constitué par -S(=O)(=O)- et -C(=O)-, et Y est -NR3-; ou X est sélectionné dans le groupe constitué par -S(=O)(=O)- et -S-, et Y est -C(R4)(R5)-; L est un lieur facultatif; et R4 et R5 sont sélectionnés chacun indépendamment dans le groupe constitué par H et hydrocarbyle); R2 comprend le fragment de structure de formule (II), dans laquelle Q est un atome sélectionné dans le groupe constitué par S, O, N et C; ledit composé étant choisi parmi des composés des formules R1-C(=O)-NR3-L-R2; R1-S(=O)(=O)-C(R4)(R5)-L-R2; R1-S-C(R4)(R5)-L-R2; R1-NR3-S(=O)(=O)-L-R2; R1-NR3-C(=O)-L-R2; R1-C(R4)(R5)-S(=O)(=O)-L-R2; et R1-C(R4)(R5)-S-L-R2. Les composés de l'invention sont utiles comme inhibiteurs de 11-bêta-hydroxystéroïde déshydrogénase dans le traitement du diabète.
PCT/GB2004/004498 2003-10-23 2004-10-22 Derives de carboxamide de phenyle et de sulfonamide utilisables comme 11-beta-hydroxysteroide deshydrogenase WO2005042513A1 (fr)

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WO2005103023A1 (fr) * 2004-04-20 2005-11-03 Sterix Limited Derives de phenylsulfonamide utiles en tant qu'inhibiteurs de 11-beta-hydroxysteroide deshydrogenase
WO2005108370A1 (fr) * 2004-04-16 2005-11-17 Ajinomoto Co., Inc. Composés du benzène
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
US7217838B2 (en) 2005-01-05 2007-05-15 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
WO2007129019A1 (fr) * 2006-04-21 2007-11-15 Astrazeneca Ab Dérivés de sulfonamide pouvant être employés en tant que modulateurs de récepteurs edg
US7511175B2 (en) 2005-01-05 2009-03-31 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
WO2011156610A3 (fr) * 2010-06-09 2012-01-26 Gilead Sciences, Inc. Inhibiteurs du virus de l'hépatite c
WO2012071414A2 (fr) * 2010-11-22 2012-05-31 Board Of Regents Of The University Of Nebraska Composés de quinoxaline et leurs utilisations
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8372841B2 (en) 2004-04-29 2013-02-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8524894B2 (en) 2009-06-04 2013-09-03 Laboratorios Salvat, S.A. Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
US8716345B2 (en) 2005-01-05 2014-05-06 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
JPWO2013058258A1 (ja) * 2011-10-18 2015-04-02 アステラス製薬株式会社 二環式ヘテロ環化合物
CN105085427A (zh) * 2015-08-21 2015-11-25 中国科学院广州生物医药与健康研究院 一类苯并[d]异恶唑类化合物及其应用
WO2023023310A1 (fr) * 2021-08-20 2023-02-23 Enanta Pharmaceuticals, Inc. Inhibiteurs de la 17-bêta-hydroxystéroïde déshydrogénase de type 13 et leurs procédés d'utilisation
WO2023236920A1 (fr) * 2022-06-07 2023-12-14 Sironax Ltd. Modulateurs de sarm1, leurs préparations et leurs utilisations

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US8372841B2 (en) 2004-04-29 2013-02-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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US9290444B2 (en) 2005-01-05 2016-03-22 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
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
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US9464072B2 (en) 2006-04-07 2016-10-11 Abbvie Inc. Treatment of central nervous system disorders
US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
WO2007129019A1 (fr) * 2006-04-21 2007-11-15 Astrazeneca Ab Dérivés de sulfonamide pouvant être employés en tant que modulateurs de récepteurs edg
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
US8524894B2 (en) 2009-06-04 2013-09-03 Laboratorios Salvat, S.A. Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
US8822452B2 (en) 2009-06-04 2014-09-02 Laboratorios Salvat, S.A. Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
WO2011156610A3 (fr) * 2010-06-09 2012-01-26 Gilead Sciences, Inc. Inhibiteurs du virus de l'hépatite c
US8993758B2 (en) 2010-11-22 2015-03-31 Board Of Regents Of The University Of Nebraska Substituted quinoxalines and uses thereof
WO2012071414A3 (fr) * 2010-11-22 2012-08-16 Board Of Regents Of The University Of Nebraska Composés de quinoxaline et leurs utilisations
US9353094B2 (en) 2010-11-22 2016-05-31 Board Of Regents Of The University Of Nebraska Substituted quinoxalines as kinase inhibitors
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JPWO2013058258A1 (ja) * 2011-10-18 2015-04-02 アステラス製薬株式会社 二環式ヘテロ環化合物
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