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    • 专利摘要:
    ADRENAL HORMONE MODIFICATION COMPOUND, ITS USE AND PHARMACEUTICAL COMPOSITION The present invention relates to a method of treating a disease or disorder characterized by increased levels of stress hormone and / or decreased levels of androgen hormone in an individual, comprising administering to the individual a therapeutically effective amount of a compound represented by formula (I): where n is 1 or 3; R is hydrogen or - C (O) N (Ra) (Rb) where Ra and Rb are independently - (C1-C4) alkyl, or - (C1-C4) alkyl- (C5-C7) aryl, where each one of Ra and Rb is optionally substituted by - (C1-C4) alkoxy; Rl, R2 and R3 are independently hydrogen, halogen, cyano or - (C6-C10) aryl, in which referred - (C6-C10) aryl is optionally substituted by halogen, with the condition that no more than one of Rl, R2 and R3 is hydrogen; and R4 and R5 are hydrogen; or a pharmaceutically acceptable salt thereof.
    公开号:BR112012017458B1
    申请号:R112012017458-4
    申请日:2011-01-13
    公开日:2020-10-20
    发明作者:Qi-Ying Hu；Gary Ksander；Erik Meredith；Lauren G. Monovich；Julien Papillon；Christoph Schumacher
    申请人:Recordati Ag；
    IPC主号:
    专利说明:

    Field of the Invention
    [001] The invention relates to the use of a compound with adrenal hormone modifying properties in disease states characterized by increased levels of stress hormone and / or decreased levels of androgen hormone. Background of the Invention
    [002] Steroidogenesis in the adrenal gland occurs via highly related and controlled cytochrome P450 enzymes. Inhibition of Aldosterone Synthase or the enzyme cytochrome P450 11B2 (CYP11B2) represents a new pharmacological strategy to reduce excessive levels of aldosterone. Aldosterone is a mineralocorticoid that is mainly synthesized in the adrenal gland and released into the circulation for control in the renal epithelium of the sodium / potassium balance and, thus, water and blood pressure homeostasis, as well as in the non-epithelial tissue of the heart and kidney. , the formation of extracellular matrix and organ re-modeling. Aldosterone synthase is the mediator in the adrenal gland of the terminal conversion and rate limiting conversion of 11-deoxycorticosterone to corticosterone, via 11-beta-hydroxylation, the conversion of corticosterone to 18-hydroxy-corticosterone, via 18-methylhydroxylation and, finally , the conversion of 18-hydroxy-corticosterone to aldosterone, via 18-methyloxidation. The activity and expression of the enzyme is mainly regulated by angiotensin II, potassium and adrenocorticotropin. These aldosterone synthase regulators are sensitive to the actions of aldosterone and the daily physiological rhythm and, as such, create a closed loop of endocrine feedback. Angiotensin II is produced under the stimulation of renin activity, which is triggered, via sodium loss and decreased blood pressure due to hypoaldosteronemic states. Potassium is retained in exchange for sodium loss in hypoaldosteronemic conditions. Finally, adrenocorticotropin is produced from the pituitary gland in response to low levels of glucocorticoid and the daily rhythm. Consequently, a selective inhibition of aldosterone synthase and a reduction in aldosterone secretion is countered with the stimulation of renin and the generation of angiotensin II, as well as with a potassium retention; both increased levels of angiotensin II and potassium being potent stimulators of aldosterone synthase activity and thus aldosterone secretion. The daily rhythm under aldosterone synthase inhibition is weakened for aldosterone; yet adrenocorticotropin levels are not significantly changed as glucocorticoids are the main regulators of adrenocorticotropin secretion. The cortisol secretion rate limiting enzyme is the adrenal 11-beta-hydroxylase or cytochrome P450 11B1 (CYP11B1) enzyme that converts 11-deoxicortisol to cortisol. Cortisol levels are controlled via the hypothalamic-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-pituitary-adrenal feedback loop by controlling the release adrenocorticotropin (ACTH). Adrenocorti-coptropine stimulates the adrenal gland in anterior and posterior steroidogenic reactions, which lead to the synthesis of cortisol, but also dehydroepiandrosterone and androstendione (see figure 1, a diagram for adrenal steroidogenesis). The cortisol producing enzyme CYP11B1 shows a high sequence homology of 95% at the amino acid level for the aldosterone producing enzyme CYP11B2. Therefore, a target compound in aldosterone synthase to reduce excessive aldosterone secretion needs to be tested for its enzyme activity. Summary of the Invention
    [003] In one aspect, the present invention provides a method of treating a disease or disorder characterized by increased levels of stress hormone and / or decreased levels of androgen hormone in an individual, comprising administering to the individual a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
    [004] In another aspect, a method of treating heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, cushing syndrome or metabolic syndrome is provided, comprising administering to the individual a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
    [005] In a further aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the preparation of a pharmaceutical composition for the treatment of a disorder or disease characterized by increased levels of hormone of stress and / or decreased levels of androgen hormone in an individual.
    [006] In an additional aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided in the treatment of a disorder or disease characterized by increased levels of stress hormone and / or decreased levels of hormone androgen in an individual.
    [007] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a selected heart failure disorder or disease , cachexia, acute coronary syndrome, chronic stress syndrome, cushing syndrome, or metabolic syndrome.
    [008] In an additional aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided in the treatment of a disorder or disease selected from heart failure, cachexia, acute coronary syndrome, stress syndrome chronic, cushing's syndrome, or metabolic syndrome. Detailed description of the invention
    [009] The compounds that can be used in the present invention are described using the following formula (I)

    [0010] where n is 1 or 3;
    [0011] R is hydrogen or --C (O) N (Ra) (Rb), in which Ra and Rb are independently - (C1-C4) alkyl, or - (C1-C4) alkyl- ( C5-C ) Aryl, in which each of Ra and Rb is optionally substituted by - (C1-C4) alkoxy;
    [0012] Ri, R2, θ R3, are independently hydrogen, halogen, cyan or - (C6-C10) aryl, in which referred - (Ce-Cw) aryl is optionally substituted by halogen, with the condition that no more than one from Ri, R2, and R3 is hydrogen; and
    [0013] R4 θ Rs are hydrogen; or a pharmaceutically acceptable salt thereof.
    [0014] In one embodiment, the compound of Formula (I) is 4- [(5R) -6 7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-flurorbenzonitrile having formula (II).

    [0015] As used herein, the term "alkyl" refers to a portion of fully saturated branched or unbranched hydrocarbon. Preferably, the alkyl comprises 1 to 6 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
    [0016] As used herein, the term "alkoxy" refers to alkyl-O-, in which alkyl is defined here above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. As used herein, the term "lower alkoxy" refers to alkoxy groups having about 1-7, preferably about 1-4 carbons.
    [0017] The term "aryl" refers to aromatic monocyclic or bicyclic hydrocarbon groups having 6-20 carbon atoms in the ring portion. Preferably, the aryl is a (C6-C10) aryl. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which can optionally be substituted by 1-4 substitutes, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl- C (O) -O--, aryl-O--, heteroaryl-O--, amino, HS--, S-alkyl—, aryl-S—, nitro, cyano, carboxy, OC-O (O) - -, carbamoyl, S-alkyl (O) -, sulfonyl, sulfonamido, heterocyclyl, and the like, in which R is independently hydrogen, alkyl, aryl, heteroaryl, aryl-alkyl—, heteroaryl-alkyl--, and the like.
    [0018] Additionally, the term "aryl", as used herein, refers to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, covertly articulated, or articulated to a common group such as a portion of methylene or ethylene. The common joint group can also be a carbonyl as in benzophenone or oxygen as in diphenylether or nitrogen as in diphenylamine.
    [0019] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.
    [0020] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the efficiency and biological properties of the compounds of this invention, and that are not biologically, or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or bases by virtue of the presence of amino and / or carboxyl groups, or groups similar to these. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonia, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonia, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, die - tilamine, triethylamine, tripropylamine, and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or aseptic portion, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting forms free base of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media similar to ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, are preferred, where practicable. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.
    [0021] In another embodiment, the compound of Formula (I) is a salt of 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3 -flurorbenzonitrile dihydrogen phosphate.
    [0022] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion medium, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, agents absorption delay, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, dyes, such similar materials and combinations thereof, as would be known to a person skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except that since any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
    [0023] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will induce an individual's biological or medical response, or symptoms of improvement, decrease or delay in disease progression, or preventing a disease, etc. In a non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to an individual, is effective to (1) at least partially alleviate, inhibit, prevent and / or improve a condition, or a disorder, or a disease (i) characterized by excessive levels of stress hormone and / or insufficient levels of androgen hormone, or (ii) associated with activities of excessive levels of stress hormone and / or insufficient levels of androgen hormone, or (iii) characterized by abnormal activities of excessive levels of stress hormone and / or insufficient levels of androgen hormone; or (2) reducing or inhibiting the activity of excessive levels of stress hormone and / or reducing or inhibiting the activity of steroidal enzymes that indirectly lead to insufficient levels of androgen hormone, or
    [0024] (3) reduction or inhibition of the synthesis of excessively produced levels of stress hormone and / or increased levels of androgen hormone.
    [0025] In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, tissue, or non-cellular biological material, or in a medium, it is effective to at least partially reduce or inhibit the activities of excessive levels of stress hormone and / or increased levels of androgen hormone; or at least partially reduce or inhibit the synthesis of excessively produced stress hormone levels and / or increased levels of androgen hormone.
    [0026] As used herein, the term "individual" refers to an animal. In one embodiment, the animal is a mammal. An individual also refers to, for example, primates (for example, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In one embodiment, the individual is a human.
    [0027] As used throughout this patent application, the levels of hormones as measured in an individual can be in any sample taken from that individual. In one embodiment, the levels are measured in a blood sample. In another embodiment, the levels are determined from a plasma sample.
    [0028] As used herein, the term "a disorder" or "a disease" refers to any breakdown or abnormality of function; a morbid physical or mental state. See Dorland's Illustrated Medical Dictionary, (W.B. Saunders Co. 27th ed. 1988).
    [0029] As used herein, the term "treating" or "treating" any disease or disorder refers, in one embodiment, to partial or total improvement of the disease or disorder (i.e., cessation or reduction in the development of the disease, or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to partially or totally improving at least one physical parameter, which cannot be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to the modulation of the disease or disorder, either physically (for example, stabilization of a discernible symptom), physiologically, (for example, stabilization of a physical parameter), or both . In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
    [0030] As used herein, the term "um", "uma", "o", and similar terms used in the context of the present invention (especially in the context of the claims), are to be constructed to cover both the singular and plural, unless otherwise indicated here, or clearly contradicted by the context. The determination of ranges of values here is merely intended to serve as a reference method individually for each separate value that falls within the range. Unless otherwise indicated here, each individual value is incorporated into the specification as if it were individually determined here. All of the methods described herein may be performed in any suitable order, unless otherwise indicated herein, or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (for example, "as is") provided herein, is intended merely to better clarify the invention and not to impose a limitation on the scope of the otherwise claimed invention. No language in the specification should be constructed as indicating any unclaimed elements essential to the practice of the invention.
    [0031] Any asymmetric carbon atom in the compounds of the present invention can be present in the (R) -, (S) - or (R, S) - configuration, preferably in the (R) - or (S) - configuration. Substituents in atoms with unsaturated bonds may, if possible, be present in cis- (Z) - or trans (E) - form. Therefore, the compounds of the present invention can be in the form of one of the possible isomers, or mixtures thereof, for example, as substantially pure geometric isomers (cis or trans), diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
    [0032] Any mixtures resulting from isomers can be separated on the basis of physicochemical differences of the constituents, in the pure or optical geometric isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.
    [0033] Any racemates resulting from final or intermediate products can be decomposed into optical antipodes by known methods, for example, by separating the diastereomeric salts thereof, obtained with an optically active acid or base, and releasing the acidic or basic compound optically active. In particular, the imidazolyl moiety can therefore be used to decompose the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyl tartaric acid - co, diacetyl tartaric acid, di-O, O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-1 O-sulfonic acid. The racemic products can also be decomposed by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using a chiral adsorbent.
    [0034] In addition, the present invention contemplates compounds of Formula (I) to include the free form, a salt form, or prodrug derivatives thereof. The compounds can be obtained in the form of hydrates, or include solvents used for their crystallization.
    [0035] The compounds of the present invention can be synthesized or produced and characterized by the methods as described in W02007 / 024945, the contents of which are incorporated herein by reference.
    [0036] In another embodiment, the methods include using the compounds according to Formula (I) to treat diseases or disorders described above, in which the compounds, including isomers, optical isomers, or pharmaceutically acceptable salts thereof, preferably including isomers, optical isomers, are selected from
    [0037] 4'-fluoro-6- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) biphenyl-3-carbonitrile;
    [0038] 3-bromo-4- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) benzonitrile;
    [0039] 5- (2-chloro-4-cyanophenyl) -N- (4-methoxybenzyl) -N-methyl-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxamide ;
    [0040] 5- (4-Cyano-2-methoxyphenyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxylic acid (4-fluorobenzyl) methylamide;
    [0041] 4- (6,7-Dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl) -3-fluorobenzonitrile;
    [0042] 5- (3-fluoro-4-methoxyphenyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole;
    [0043] 5- (2-Chloro-4-cyanophenyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxylic acid 4-fluorobenzyl ester;
    [0044] 5- (2-Bromo-4-fluorophenyl) -6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepine;
    [0045] 2-Bromo-4- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) benzonitrile;
    [0046] 3-Pyridin-3-yl-4- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) benzonitrile; and
    [0047] 3-Chloro-4- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) benzonitrile;
    [0048] in particular selected from
    [0049] 4'-fluoro-6- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) biphenyl-3-carbonitrile;
    [0050] 3-bromo-4- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) benzonitrile;
    [0051] 5- (2-chloro-4-cyanophenyl) -N- (4-methoxybenzyl) -N-methyl-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxamide ; and
    [0052] 4- (6,7-Dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl) -3-fluorobenzonitrile.
    [0053] Preferably, a compound of formula (I), as described herein, is of formula (4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5- yl] -3-flurorbenzonitrile, or a pharmaceutically acceptable salt thereof, in particular (4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3 - flurorbenzo-nitrile dihydrogen phosphate A salt of a compound of formula (I), as defined herein, preferably a phosphate salt, such as dihydrogen phosphate, can be prepared according to standard methods known to the person skilled in the art, for example, as described in Chem. Commun., 2007, 419-421 (2007); in Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid Alex M. Chen, Martha E. Ellison, Andrey Peresypkin, Robert M. Wenslow , Narayan Variankaval, Cecile G. Savarin, Theresa K. Natishan, David J. Mathre, Peter G. Dormer, Danielle H. Euler, b Richard G. Ball, Zhixiong Ye, Yaling Wanga and Ivan Santos; Handbook of Pharmaceutical Salts: Properties, Sel ection, and Use Edited by P. Heinrich Stahl and Camile G. Wermuth. VHCA, Verlag Helvetica Chimica Acta, Zürich, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002; in Organic Process Research & Development 2000, 4, 427-435 Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities Richard J. Bastin, Michael J. Bowker, and Bryan J. Slater; in Advanced Drug Delivery Reviews 56 (2004) 275- 300, High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids Sherry L. Morissettea, *, O "rn Al-marssona, Matthew L. Petersona, Julius F. Remenara, Michael J. Reada, Anthony V. Lemmoa, Steve Ellisa, Michael J. Cimab, Colin R. Gardner; and in Journal of Pharmaceutical Sciences, VOL. 96, NO.5, MAY 2007, Structure, Solubility , Screening, and Synthesis of Molecular Salts, Black, SN, Collier, EA, Davey, RJ and Roberts, RJ
    [0054] According to the invention, a compound of formula (I), and / or a pharmaceutically acceptable salt thereof, represents a pleiotropic modifier of adrenal steroidogenesis when administered to an individual. A compound of formula (I) maintains or lowers cortisol levels when administered to an individual. A compound of formula (I) increases levels of 11-deoxicortisol when administered to an individual. A compound of formula (I) increases levels of adrenocorticotropin when administered to an individual. A compound of formula (I) increases levels of 11-deoxycorticosterone. A compound of formula (I) increases adrenal androgens when administered to an individual.
    [0055] In example 1, it was shown that a compound of formula (I), namely, (4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5 -il] -3- flurorbenzonitrile dihydrogen phosphate represents a pleiotropic modifier of adrenal steroidogenesis when administered to the individual. It is shown in Figure 1 that 4 - [(5R) -6,7-dihydro-5H-pyrrole [1, 2- c] imidazol-5-yl] -3-flurorbenzo-nitrile dihydrogen phosphate maintains or lowers cortisol levels when administered to an individual, and 4 - [(5R) -6,7-di- hydro-5H-pyrrolo [1,2-c] imidazol-5-yl] - 3-flurorbenzonitrile dihydrogen phosphate increases levels of 11-deoxicortisol when administered to an individual. 4 - [(5R) -6,7- dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-flurorbenzonitrile dihydrogen phosphate increases levels of adreonocorticotropin when administered to an individual. 4 - [(5R) -6,7- dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile dihydrogen phosphate increases levels of 11-deoxycorticosterone. 4 - [(5R) -6,7-di -hydr o-5H-pyrrolo [1,2-c] imidazol-5-yl] - 3-fluorobenzonitrile dihydro-geno phosphate increases adrenal androgens when administered to an individual.
    [0056] The clinical relevance of increased levels of stress hormone and / or decreased levels of androgen hormone has been shown for the following conditions. (i) chronic heart failure (ii) chronic heart failure with impaired exercise tolerance (iii) chronic heart failure with muscle weakness (iv) cardiac cachexia (v) COPD-induced cachexia (vi) cirrhosis-induced cachexia (vii ) tumor-induced cachexia (viii) virus-induced cachexia (HIV) (ix) acute heart failure (x) acute decompensated heart failure (xi) acute coronary syndrome (xii) chronic stress syndrome (xiii) Cushing's syndrome ( xiv) metabolic syndrome (xv) hypercortisolemia (i) Chronic heart failure, as well as chronic heart failure conditions with impaired exercise tolerance (ii) and muscle weakness (iv) show elevated levels of aldosterone plasma as shown by Bolger et al . Circulation 2002; 106: 92-99, a plasma elevated to dihydroepiandrosterone ratio, as shown by Anker et al. European Heart Journal 1999; 20: 683-693, and decreased androgen levels, as shown by Jankowaska et al., Circulation 2006; 114: 1829-1837. (iv) Cardiac cachexia is a serious complication of chronic heart failure as patients suffer from a general loss of fat tissue, non-fat tissue and bone tissue. Patients with cardiac cachexia show elevated plasma levels of aldosterone and cortisol, as well as reduced levels of dehydroepiandrosterone, as described by Anker et al., Circulation 1997; 96: 526- 534, and illustrated in WO 2000/21509 and US 2009/0023639. (v) COPD-induced cachexia, cirrhosis-induced cachexia (vi), tumor-induced cachexia (vii) and virus-induced cachexia (HIV) (viii) are characterized by increased levels of aldosterone plasma, as documented in WO 2000 / 21509 or US 2009/0023639, and were treated with anabolic androgen, or androgen derivatives, as reported by Yeh et al., Chest 2002; 122: 421-428 and by Cuerda et al., Nutrition Clinical Practice 2005 20; 93 -97. (ix-x) Cardiac events predicted by plasma cortisol, such as death and hospitalization in patients with heart failure, according to Yamaji et al. Circulation Heart Failure 2009; 2: 608-613. (xi) Myocardial infarction raises cortisol levels that affect cardiac remodeling as indicated by Mihailidu et al., Hypertension 2009 in the press. The magnitude of the cortisol response is related to the size of the infarction, as shown by Bain et al., International Journal of Cardiology 1992; 27: 145-150. (xii) Chronic stress disorders with their physical and psychological ramifications were associated with excessive levels of aldosterone and cortisol according to Kubzansky and Adler, Neuroscience and Biobehavioral Reviews, 2009; 5: 1-7. In particular, persistent excessive secretion of cortisol can lead to depression, hyperglycemia and suppression of the immune system. (xiii) Cushing's syndrome describes a chronically excessive cortisol release condition. Excess cortisol may originate directly from an adrenocortical tumor or secondarily from a pituitary tumor (Cushing’s disease) or an ectopic that releases adrenocorticotropin, as illustrated by Boscaro and Arnaldi, Journal of Clinical Endocrinology and Metabolism 2009; 94: 3121-3131. (xiv) Metabolic syndrome defines a state of metabolic dysregulation characterized by insulin resistance and a predisposition to type 2 diabetes, central and visceral obesity, hypertension and dyslipidemia. Metabolic dysregulation can be caused by an underlying endocrine imbalance mediated by adrenal steroids aldosterone and cortisol, as reported by Kidamby et al. Hypertension 2007; 49: 704-711. (xv) Hypercortisolemia refers to conditions that are characterized by high levels of cortisol circulation. High levels of plasma cortisol can directly contribute to a pathological condition, represent a sign of a pathological condition or be non-pathological in nature.
    [0057] The invention relates to the use of a compound of formula (I), and / or a pharmaceutically acceptable salt thereof, or any other form thereof, as discussed above, with adrenal hormone modifying properties as a treatment for conditions that are characterized by excessive levels of stress hormone, and / or insufficient levels of androgen hormone, such as heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, hypercortisolemia, cushing syndrome, or metabolic syndrome, in particular, failure of the heart, cachexia, acute coronary syndrome, chronic stress syndrome, cushing syndrome, or metabolic syndrome. Heart failure can be both acute heart failure and chronic heart failure. Acute heart failure can be acute decompensated heart failure. Chronic heart failure can be associated with impaired exercise tolerance, and or with muscle weakness. Cachexia can be cardiac cachexia, COPD-induced cachexia, cirrhosis-induced cachexia, tumor-induced cachexia, or virus-induced cachexia (HIV). Chronic stress syndrome can include depression, hyperglycemia and immune suppression. Cushing's syndrome can include hypercortisolism due to adrenocortical, pituitary or ectopic tumors. Metabolic syndrome can include obesity, diabetes, hypertension, dyslipidemia and atherosclerosis. The Formula (I) compounds have adrenal hormone-modifying properties in diseases or conditions characterized by increased levels of stress hormone, and / or decreased levels of androgen hormone, as shown in the experimental section.
    The present invention provides a method of lowering or maintaining cortisol levels in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0059] The present invention provides a method of treating a disorder, disease or condition, characterized by decreased or insufficient levels of androgen hormone in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0060] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder, disease or condition, characterized by decreased or insufficient levels of androgen hormone.
    [0061] The present invention provides a method of treating a disorder, disease or condition, characterized by excessive levels of stress hormone, such as aldesterone, and cortisol levels in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0062] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder, disease or condition, characterized by excessive levels of stress hormone, such as aldesterone, and cortisol levels.
    [0063] The present invention provides a method of increasing or maintaining 11-deoxicortisol levels in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0064] The present invention provides a method of increasing or maintaining levels of adreonocorticotropin in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0065] The present invention provides a method of increasing or maintaining 11-deoxycorticosterone levels in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0066] The present invention provides a method of increasing or maintaining levels of adrenal androgens in an individual by administering a therapeutically efficient dose of a compound of formula (I).
    [0067] The present invention provides the use of a compound of Formula (I) as a pleiotropic modifier of adrenal steroidogenesis in an individual.
    [0068] It additionally provides for the use of a compound according to Formula (I) for the preparation of a pharmaceutical composition for the treatment of a disorder, disease or condition, characterized by excessive levels of stress hormone, and / or insufficient levels of androgen hormone.
    [0069] It additionally provides a pharmaceutical composition comprising a compound according to formula (I) for use in the treatment of a disorder, disease or condition, characterized by excessive levels of stress hormone, and / or insufficient levels of androgen hormone. Such diseases or disorders can be heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, hypercortisolemia, cushing's syndrome, or metabolic syndrome.
    [0070] It additionally provides for the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of a disorder or disease or condition, characterized by excessive levels of stress hormone, and or insufficient levels of androgen hormone , such as heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, cushing syndrome, or metabolic syndrome.
    [0071] In another aspect, the present invention provides methods of treating diseases or disorders, characterized by excessive levels of stress hormone, and / or insufficient levels of androgen hormone, by administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to Formula (I) and a pharmaceutically acceptable carrier. In another aspect, such diseases or disorders can be heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, cushing's syndrome, or metabolic syndrome.
    [0072] In one embodiment, the present invention provides methods of administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound according to Formula (I), and a pharmaceutically acceptable carrier, to treat diseases or disorders, characterized by excessive levels of stress hormone, and / or insufficient levels of androgen hormone. In another aspect, such diseases or disorders may be heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, hypercortisolemia, cushing's syndrome, or metabolic syndrome; in particular, heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, cushing syndrome, or metabolic syndrome.
    [0073] Whatever is used above, heart failure can be both acute heart failure and chronic heart failure. Acute heart failure can be acute decompensated heart failure. Chronic heart failure can be associated with impaired exercise tolerance, and or with muscle weakness. Cachexia can be cardiac cachexia, COPD-induced cachexia, cirrhosis-induced cachexia, tumor-induced cachexia, or virus-induced cachexia (HIV). Chronic stress syndrome can include depression, hyperglycemia and immune suppression. Cushing's syndrome can include hypercortisolism due to adrenocortical, pituitary or ectopic tumors. Metabolic syndrome can include obesity, diabetes, hypertension, dyslipidemia and atherosclerosis. The compounds of Formula (I) have adrenal hormone-modifying properties in diseases or conditions, characterized by increased levels of stress hormone, and / or decreased levels of androgen hormone, as shown in the experimental section.
    [0074] A pharmaceutical composition comprising a compound of the present invention can be prepared according to methods known in the art. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be presented in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations, such as sterilization and / or may contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, earplugs, etc.
    [0075] The pharmaceutical composition according to the present invention can be in unit dosage of at least 0.05 or 1 mg or greater, of the compounds described herein as the active ingredient, such as from 0.01 mg at 1000 mg, from from 0.01 mg to 500 mg, from from 0.01 to 50 mg, from from 0.01 mg to 5 mg, from from 0.01 to 2 mg or , from 0.1 mg to 2 mg of active ingredient, as in unit dosage of at least 0.05 or 1 mg or from 4 mg to 100 mg, for example, from 2 mg at 50 mg, of the compounds described herein as the active ingredient of an individual of about 50-70 kg. For example, the unit dosage may contain 1- 1000 mg of active ingredient for an individual of about 50-70 kg, about 1-500 mg, about 1-50 mg, about 0.5-5 mg, 0 , 1-1 mg or about 0.05-0.5 mg of active ingredient. The dosage regimen using the compounds described herein can be selected according to a variety of factors, including type, species, age, weight, sex, the type of disease or disorder to be treated, the severity of the disease or disorder to be treated. treated, the route of administration, and the particular compound or salt employed. A physician, clinician or technical veterinarian in the field can readily determine the effective amount of each of the active ingredients needed to prevent, treat or inhibit the progress of the disorder or disease.
    [0076] The dosing properties are demonstrable in vitro (See PCT Orders PCT / US2007 / 018660 & W02007 / 065942A2) and in vivo tests (See Example 1 below) using advantageously mammals, for example, mice, rats, dogs, monkeys or isolated organs, tissues, and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, for example, preferably aqueous solutions, and in vivo or enterally, parenterally, advantageously intravenously, for example, as a suspension, or in aqueous solution. The in vitro dosage can vary between about 10-3 and 10-9 molar concentrations. A therapeutically effective amount in vivo can vary depending on the route of administration, between 0.001-15 mg / kg, preferably between 0.003-0.05 mg / kg.
    [0077] Listed below are definitions of various terms used throughout the specification:
    [0078] The term "stress hormone", as used here, refers to a hormone that is secreted in response to unusual exposure to life. The stress response involves the activation of both the sympathetic adrenomedullary system with the secretion of epinephrine and norepinephrine, and the hypothalamic pituitary acrenocortical system (HPA) with the secretion of cortisol. Examples of stress hormones are, for example, described in Table 1 in W02007 / 105203, which is incorporated here by reference. In a preferred embodiment, a stress hormone is aldosterone or cortisol, preferably cortisol.
    [0079] The term "increased levels of stress hormone", or "excessive levels of stress hormone" is used to indicate that the level of hormone levels is statistically significantly higher than those of other parameters, such as aldosterone, for plasma renin activity, or is statistically significantly elevated from normal clinical reference values. For example, stress hormone levels are increased if the aldosterone level is above 277 pM in the remainder, or if the cortisol level is above 552 nM in the morning, as described, for example, in Endocrinology 9th eidtions (Editors JD Wilson, DW Foster, HM Kronenberg, PR Larsen) WB Saunders Co., Philadelphia, 1988.
    [0080] The term "reduction or inhibition of activities of excessive levels of stress hormone", as used herein, means any improvement in the prevention, control, delay, abatement or increased relative and / or absolute or excessive stress hormone imbalances that lead to pathophysiology. Although the term "inhibition" is not intended to be restricted to normalizing stress hormone levels, it also includes the possibility that stress hormone levels are fully normalized to clinical reference values.
    [0081] The term "reduction or inhibition of the synthesis of excessively produced stress hormone levels", as used herein, means any improvement in prevention, control, delay, abatement or increased relative and / or absolute increased, or excessive imbalances stress hormone that lead to pathophysiology. Although the term "inhibition" is not intended to be restricted to normalizing stress hormone levels, it also includes the possibility that stress hormone levels are fully normalized to clinical reference values.
    [0082] The term "androgen hormone" as used herein refers to male hormones and includes, for example, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T) and dihydrotestosterone (DHT).
    [0083] The terms "decreased levels of androgen hormone", or "insufficient levels of androgen hormone", are used here to indicate that the level of androgen levels is statistically significantly lowered in relation to those of other parameters, or is statistically significantly lowered in relation to normal clinical reference values. For example, androgen hormone levels are decreased or insufficient if the level of androstendione is, for example, below 2619 pM, or if the level of dehydroandrosterone is, for example, below 6.94 nM, as described, for example, in Endocrinology 9th eidtions (Editors JD Wilson, DW Foster, HM Kronenberg, PR Larsen) WB Saunders Co., Philadelphia, 1988.
    [0084] The term "reduction or inhibition of the activity of steroidal enzymes that indirectly lead to insufficient levels of androgen hormone", as used herein, means any improvement in the relative, and / or absolute, increased prevention, control, delay, abatement or mitigation , or excessive stress hormone imbalances that lead to pathophysiology. Although the term "inhibition" is not intended to be restricted to normalizing androgen hormone levels, it also includes the possibility that androgen hormone levels are fully normalized to clinical reference values.
    [0085] The term "maintain" or "maintenance" when referring to hormone levels is used here to mean an improvement in the prevention, control or delay of relative and / or absolute decreases / insufficient levels of androgen hormone and / or relative and / or absolute increases / excessive levels of stress hormone.
    [0086] The term "lower" or "lower" when referring to levels of stress hormone is used here to mean any improvement in the reduction of relative and / or absolute decreases / excessive levels of stress hormone.
    [0087] The term "increase" or "increasing", when referring to androgen hormone levels, is used here to mean any improvement in mitigating relative and / or absolute decreases / insufficient androgen hormone levels.
    [0088] As used herein, the term "abnormal" refers to an activity or characteristic that differs from a normal activity or characteristic.
    [0089] The term "abnormal activity", as used herein, refers to any breakdown of normal function. Normal activity can be stronger or weaker than normal activity. In one embodiment, "abnormal activity" refers to either over- or under-activity of, for example, and hormone, as defined herein.
    [0090] The term "activity", as used here, refers to any specific activity that a molecule is capable of carrying out or coding. For example, the activity may be that a molecule is able to associate with a specific binding co-participant with a specific affinity, capable of catalyzing a specific reaction, capable of inhibiting a specific reaction, or capable of effecting a particular cellular response .
    [0091] The term "expression", as used herein, is to be understood as defined, for example, in Maniatis et al "Molecular Cloning: A Laboratory Manual" Cold Spring Harbor Laboratory Press: 2nd Edition, 1989, for example, it refers to the accumulation of a molecule, such as a hormone, as defined herein.
    [0092] The term "pleotropic adrenal hormone modifying agent", as used herein, is to be understood as a molecule, such as a compound of formula (I), as defined herein, which inhibits the synthesis of both, aldosterone and cortisol, while increasing the levels of ACTH, 11-deoxycorticosterone and the synthesis of adrenal androgens, androstendione and dehydroepiandrosterone.
    [0093] The term "substituted", as used herein, refers to one or more substituents, for example, one or two substituents, for example, substituents, as defined herein, for a compound of formula (I).
    [0094] The term "cushing's syndrome" is also referred to as hyperadrenocorticism or hypercorticism. Cushing's syndrome can include hypercortisolism due to adrenocortical, pituitary or ectopic tumors.
    [0095] For the purpose of this invention, the compound of formula (I), as defined herein, refers to both the free form, as well as any acceptable pharmaceutical salt thereof. Experimental section
    [0096] The following examples illustrate the invention described above. However, it is not intended to restrict the scope of this invention in any way.
    [0097] Other embodiments will be apparent to a person skilled in the art while reading the previous detailed description. The scope of the present invention is not limited to the examples above, but is involved by the claims that follow. Example 1 In vitro assay of rat CYP11B1
    [0098] Complete EDTA-free protease inhibitor tablets were obtained from Roche Applied Science (Indianapolis, IN). Dulbecco’s modified Eagle medium (DMEM), antibiotic, geneticin, hygromycin, and fetal bovine serum (FBS) were products of Invitrogen (Carlsbad, CA). Solution A and Solution B of NADPH Regeneration were purchased from BD Biosciences Clontech (Palo Alto, CA). Drops of Anti-ram PVT SPA and [1,2,6,7-3H (N)] corticosterone were purchased from Amersham (Piscataway, NJ) and PerkinElmer (Boston, MA), respectively.
    [0099] Cell line V79-4 CYP11B1-adrenodoxin-adrenodoxin reductase # 259 was maintained in DMEM supplemented with 10% FBS, 0.5x antibiotic, 800 pg / ml geneticin, and 250 pg / ml hygromycin (double selection medium). For enzyme preparation, cells # 259 were seeded in 150 mm dishes in double selection medium. After 2 days of growth, the cells were washed once with PBS, scraped and collected in PBS, and centrifuged at 1,300 rpm for 6 minutes. Each pellet (representing 10 cell dishes) was resuspended in 3 ml of ice-cooled homogenization buffer (8.5 mM MgCl2, 3.13 mM KCI, 7.59 mM NaCI, 50 mM Tris / HCI, pH 7.4, and a complete EDTA-free protease inhibitor tablet per 100 mL of buffer), sonified using a Branson 450 Sounder with 6 pulses, and then placed on ice for 5 minutes. The sonification procedure was repeated 3 more times, with a reagent of minutes on ice between sonifications. The sonicated material was then spun at 500 x g for 4 minutes to remove unbroken cells. The supernatant was brought to a final glycerol concentration of 5%, frozen instantly in liquid nitrogen, and stored at -80 oC.
    [00100] Material from frozen CYP11B1 preparations was thawed on ice on the day of the experiment and then diluted in an ice-cooled assay buffer containing 8.5 mM MgCI2, 3.13 mM KCI, 7.59 mM NaCI, and 50 mM Tris / HCI, pH 7.4, at a protein concentration of 0.5 - 6 mg / ml. The CYP11B1 assays were performed on 96-well U-bottom treated non-woven culture plates. Depending on the experiment, 50 to 300 pg of protein in 35 pl was incubated with 75 pl of assay buffer, or a compound at the desired concentration, and 20 pl of substrate mixture (1.08x NADPH Regeneration Solution A, 6 , 5x NADPH Regeneration Solution B, 811 pM NADPH, and 3.25 pM 11-deoxycorticosterone in assay buffer) for up to 4 hours at 25oC in an oscillating incubator. The reaction was stopped by adding 10 µl of 1.4% Triton X-100, and briefly shaking the plates. The plates were then centrifuged at 2,400 rpm for 6 minutes, and 50 µl of supernatant was removed for measurement of corticosterone content by a scintillation proximity test (SPA).
    [00101] Corticosterone measurement was performed using a 96-well plate format. Each test sample (50 pl) was incubated with 0.02 pCi of [1,2,6,7-3H (N)] corticosterone and 0.3 pg of anti-corticosterone antibody in PBS containing 0.1% Triton X-100, 0.1% bovine serum albumin, and 12% glycerol in a total volume of 200 pl at room temperature for 1 hour. Drops of Anti-ram PVT SPA (50 pl) were then added to each well and incubated overnight at room temperature before counting in a Microbeta plate counter. The amount of corticosterone in each sample was calculated by comparison with a standard curve generated using known amounts of the hormone.
    [00102] Total concentration response curves of an inhibitor were performed at least 3 times. The IC50 values were derived using a non-linear least squares curve fitting program from IDBS XLfit. Compounds within the scope of the present invention, particularly the specific compounds disclosed herein, have been found to be active inhibitors of CYP11B1 having IC 50s ranging from 0.3 nM to 600 nM. Example 2: In vitro assay of rat CYP11B2
    [00103] Cell line V79-4 rCYP11 B2-adrenodoxin-adrenodoxin reductase # 305 is maintained in DMEM supplemented with 10% FBS, 0.5x antibiotic, 800 pg / ml geneticin, and 250 pg / ml hygromycin cina (double selection medium). For enzyme preparation, # 305 cells are seeded in 150 mm dishes (double selection medium) with an approximate 1:15 divided surface area of T-185 culture flasks growing at 75-85% confluence. After 2 days of growth, the cells are washed once with PBS, scraped and collected in PBS, and centrifuged at 1,300 rpm for 6 minutes. Each pellet (representing 10 cell dishes) is resuspended in 3 mL of ice-cooled homogenization buffer (8.5 mM MgCI2, 3.13 mM KCI, 7.59 mM NaCI, 50 mM Tris / HCI, pH 7.4, and a complete EDTA-free protease inhibitor tablet per 100 mL of buffer), sonified using a 6 pulse Branson 450 Sounder, and then placed on ice for 5 minutes. The sonification procedure is repeated 3 more times, with a 5 minute incubation on ice between sonifications. The sonicated material is then spun at 500 x g for 4 minutes to remove unbroken cells. The supernatant is brought to a final 5% glycerol concentration, frozen instantly in liquid nitrogen, and stored at -80 oC
    [00104] The material from frozen CYP11B2 preparations is thawed on ice on the day of the experiment and then diluted in an ice-cooled assay buffer containing 8.5 mM MgCI2, 3.13 mM KCI, 7.59 mM NaCI, and 50 mM Tris / HCI, pH 7.4, at a protein concentration of 0.25 - 1.5 mg / ml. The CYP11B2 assay is performed on 96-well U-bottom treated non-woven culture plates. Depending on the experiment, 14 to 84 pg of protein in 55 pl is incubated with 75 pl of assay buffer or a compound in the desired concentration, and 20 pl of substrate mix (1.25x NADPH Regeneration Solution A, 7, 5x NADPH Regeneration Solution B, 935.75 pM NADPH, and 15 pM 11-deoxycorticosterone in assay buffer) for up to 5 hours at 25oC in an oscillating incubator. The reaction is stopped by adding 10 µl of 1.6% Triton X-100 and briefly shaking the plates. The plates are then centrifuged at 2,400 rpm for 6 minutes, and 100 pl of supernatant is removed for measurement of aldosterone content by scintillation proximity test (SPA).
    [00105] Aldosterone measurement is performed using a 96-well plate format. Each test sample (2 - 10 pl of cell culture medium or 100 pl of cell homogenate) is incubated with 0.02 pCi of [1,2,6,7-3H (N)] aldosterone and 0.3 pg of anti-aldosterone antibody in PBS containing 0.1% Triton X-100, 0.1% bovine serum albumin, and 12% glycerol in a total volume of 200 pl at room temperature for 1 hour. Drops of Anti-mouse PVT SPA (50 pl) are then added to each well, and incubated for 4 hours at room temperature before counting in a Microbeta plate counter. The amount of aldosterone in each sample is calculated by comparison with a standard curve generated using known amounts of the hormone.
    [00106] Total concentration response curves of an inhibitor are performed at least 3 times. IC50 values are derived using a DBS XLfit non-linear least squares curve fitting program. Example 3 In vitro assay of human CYP11B1
    [00107] Complete EDTA-free protease inhibitor tablets were obtained from Roche Applied Science (Indianapolis, IN). Dulbecco’s modified Eagle medium (DMEM), antibiotic, geneticinq, hygromycin, and fetal bovine serum (FBS) were products of Invitrogen (Carlsbad, CA). NADPH Regeneration Solution A and Solution B were purchased from Biosciences Clontech (Palo Alto, CA). Drops of Anti-mouse PVT SPA and [1,2,6,7-3H (N)] hydrocortisone were purchased from Amersham (Piscataway, NJ) and PerkinElmer (Boston, MA), respectively.
    [00108] V79-4 cell lines CYP11B1-adrenodoxin-adrenodoxin reductase # 618 was maintained in DMEM supplemented with 10% FBS, 0.5x antibiotic, 800 pg / ml geneticin, and 250 pg / ml hygromycin (double selection medium). For enzyme preparation, # 618 cells were seeded in 150 mm dishes at 6.75 x 105 cells per dish in double selection medium. After 4 days of growth, cells were washed once with PBS, scraped and collected in PBS, and centrifuged at 1,300 rpm for 6 minutes. Each pellet (representing 10 dishes of cells) was resuspended in 3 ml of ice-cooled homogenization buffer (8.5 mM MgCI2, 3.13 mM KCI, 7.59 mM NaCI, 50 mM Tris / HCI, pH 7.4, and a complete EDTA-free protease inhibitor tablet per 100 mL buffer), sonicated using a Branson 450 Sonifier with 6 pulses, and then placed on ice for 5 minutes. The sonification procedure was repeated 3 more times, with the remaining 5 minutes on ice between sonications. The sonicated material was then centrifuged at 500 x g for 4 minutes to remove unbroken cells. The supernatant was brought to a final glycerol concentration of 5%, frozen instantly in liquid nitrogen, and stored at -80 oC.
    [00109] Material from frozen CYP11B1 preparations was thawed on ice on the day of the experiment and then diluted in an ice-cooled assay buffer containing 8.5 mM MgCI2, 3.13 mM KCI, 7.59 mM NaCI, and 50 mM Tris / HCI, pH 7.4, at a protein concentration of 0.5 - 6 mg / mL. The CYP11B1 Assays were performed on 96-well U-bottom treated non-woven culture plates. Depending on the experiment, 50 to 300 pg of protein in 35 pl was incubated with 75 pl of assay buffer or a compound in the desired concentration and 20 pl of substrate mixture (1.08x NADPH Regeneration Solution A, 6.5x NADPH Regeneration Solution B, 811 pM NADPH, and 3.25 pM 11-deoxychortisol in assay buffer) for up to 4 hours at 25 oC in an oscillating incubator. The reaction was stopped by adding 10 µl of 1.4% Triton X-100 and shaking the plates briefly. The plates were then centrifuged at 2,400 rpm for 6 minutes, and 50 µl of supernatant was removed for measurement of cortisol content by a scintillation proximity test (SPA). Cortisol measurement was performed using a 96-well plate format. Each test sample (50 pl) was incubated with 0.02 pCi of [1,2,6,7-3H (N)] hydrocortisone and 0.3 pg of anti-cortisol antibody in PBS containing 0.1% Triton X-100, 0.1% bovine serum albumin, and 12% glycerol in a total volume of 200 pl at room temperature for 1 hour. Drops of anti-mouse PVT SPA (50 pl) were then added to each well and incubated overnight at room temperature before counting in a Microbeta Plate Counter. The amount of cortisol in each sample was calculated by comparison with the standard curve generated using known amounts of the hormone. The total concentration response curves of an inhibitor were performed at least 3 times. The IC50 values were derived using a non-linear least squares curve fitting program from IDBS XLfit. It has been found that compounds within the scope of the present invention, particularly the specific compounds disclosed herein, are active inhibitors of CYP11B1 having IC 50s ranging from 0.2 nM to 200nM. Example 4 In vitro assay of human CYP11B2 (aldesterone)
    [00110] NCI-H295R human adrenocortical carcinoma cell line was obtained from American Type Culture Collection (Manassas, VA). Insulin / transferrin / selenium (ITS) -A (100x), DMEM / F-12, antibiotic / antimycotic supplement (100x), and fetal bovine serum (FBS) were purchased from Invitrogen (Carlsbad, CA). Drops of anti-mouse scintillation proximity PVT (SPA) and NBS 96-well plates were obtained from GE Health Sciences (Piscataway, NJ) and Corning (Acton, MA), respectively. Flat bottom plates of 96 solid black cavities were purchased from Costar (Corning, NY). Aldosterone and angiotensin (Ang II) were purchased from Sigma (St. Louis, MO). D- [1,2,6,7-3H (N)] aldosterone was purchased from PerkinElmer (Boston, MA). Nu-serum was a product of BD Biosciences (Franklin Lakes, NJ).
    [00111] For in vitrode measurement of aldosterone activity, human cells of NCI-H295R adrenocortical carcinoma are seeded in 96 well plates of NBS at a density of 25,000 cells / well in 100 pl of a growth medium containing DMEM / F12 supplemented with 10% FCS, 2.5% Nu-serum, 1 pg ITS / mL, and 1x antibiotic / antimycotic. The medium is changed after cultivation for 3 days at 37 ° C under an atmosphere of 5% CO2 / 95% air. The next day, the cells are rinsed with 100 pl of phosphate-buffered saline (PBS) and incubated with 100 pl of treatment medium containing 1 pM Ang II and a compound at different concentrations in quadruplicate wells at 37 ° C for 24 hours. At the end of the incubation, 50 µl of medium is removed from each well for measurement of aldosterone production by a SPA using mouse anti-aldosterone monoclonal antibodies.
    [00112] The measurement of aldosterone activity can also be performed using a 96-well plate format. Each test sample is incubated with 0.02 pCi of D- [1,2,6,7-3H (N)] aldosterone and 0.3 pg of anti-aldosterone antibodies in PBS containing 0.1% Triton X- 100, 0.1% bovine serum albumin, and 12% glycerol in a total volume of 200 pl at room temperature for 1 hour. Drops of anti-mouse PVT SPA (50 pl) are then added to each well and incubated overnight at room temperature before counting in a Microbeta Plate Counter. The amounts of aldosterone in each sample are calculated by comparison with a standard curve generated using known amounts of the hormone. Example 5 Determination of IC50 values for CYP11B1 and CYP11B2
    [00113] The excretion of aldosterone, cortisol, corticosterone and stradiol / estrone in the culture medium can be detected and quantified by specific monoclonal antibodies commercially available in radioimmunoassays according to the manufacturer's instructions. Inhibition of the release of certain steroids can be used as a measure of the respective enzyme inhibition by additional test compounds. The dose-dependent inhibition of enzyme activity by a compound is calculated using an inhibition graph that is characterized by an IC50. The IC50 values for active test compounds are determined by simple linear regression analysis in order to construct inhibition plots without weighing data. The inhibition graph is calculated by adjusting a 4-parameter logistic function for the raw data points using the least square method. The 4-parameter logistic function equation is calculated as follows: Y = (da) / ((1 + (x / c) b)) + a, where a = minimum data level, b = gradient, I c = ICED, d = maximum data level, x = inhibitor concentration.
    [00114] The activity of inhibiting aldosterone production can also be expressed as a percentage of inhibition (% inhibition) at a given concentration (for example,% inhibition at 1 pM), which is the level of aldosterone when the cell is treated with the given concentration of a compound of this invention (for example, 1 pM concentration), versus aldosterone excretion when the cell is free of the compound of the invention:% inhibition of aldosterone production = [(YX) / Y] x 100
    [00115] where X is the level of aldosterone when the cell is treated with a compound according to any of Formulas I to IVB; or pharmaceutically acceptable salt thereof, and Y is the level of aldosterone when the cell is free of the compound according to any of Formulas I to IVB, or pharmaceutically acceptable salt thereof.
    [00116] CYP11B1 production inhibiting activity can also be expressed as a percentage of inhibition (% inhibition) at a given concentration (e.g., 1 pM% inhibition), which is the level of cortisol when the cell is treated with the given concentration of a compound of the invention (e.g., 1 pM concentration) versus the excretion of cortisol when the cell is free of the compound of the invention. % inhibition of cortisol production = [(Y’-X ’) ZY’] x 100
    [00117] where X 'is the level of cortisol when the cell is treated with a compound of Formulas I to IVB; and Y 'is the cortisol level when the cell is free of the compound of Formulas I to IVB.
    [00118] Using test assays for measuring CYP11B1 (cortisol) and CYP11B2 (aldosterone), as described above, the compounds of the invention exhibited inhibitory efficacy as shown in Table 1. Table 1 Data from Example 1, 2, 3 and 4
    **: Please refer to WO2007 / 024945 for details. Example 6 CYP11B1 assay in vivo
    [00119] The in vivo effects of compounds on plasma aldosterone concentration (PAC) and glucocorticoid plasma (corticosterone) concentration (PCC) were evaluated in conscious rats.
    [00120] Male Sprague-Dawley rats (-400-600 g body weight) were surgically instrumented with an arterial and venous femoral catheter. The catheters were externalized from the lower back using a stainless steel spring and swivel system that enabled the rats to move freely at all times. The rats were allowed at least one week to recover from the surgery before starting the experiments.
    [00121] On the morning of the experiment, a pre-treated blood sample was collected in heparin from the arterial catheter. Blood samples were centrifuged in a refrigerated centrifuge to generate plasma. The plasma was stored frozen at -70 ° C until later measurement of PAC and PCC (by radioimmunoassay). Adrenocorticotropic hormone (ACTH (1-24), referred to here as ACTH) was then administered as an intravenous (iv) mass (100 ng / kg), followed by a continuous iv infusion (30 ng / kg / minutes ) for 9 hours. After an hour of infusion, a baseline blood sample (time 0) was removed from the arterial catheter and processed and stored as described above. The rats were then dosed (typically 0.01 to 100 mg / kg) with the test compound p.o. by oral or parenteral ingestion, via the arterial catheter (a.i.). The compounds were formulated in an appropriate vehicle (for example, water (p.o.) or saline (i.a.)) at a physiologically compatible volume (typically 1-2 ml / kg). Additional blood samples were taken at 0.083 (ia only), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, and 24 hours after compounding and processed and stored as above for later determination of PAC, PCC, and plasma compound concentration (by LC / MS / MS). Oral bioavailability and traditional pharmacokinetic parameters (PK) were estimated from plasma compound concentrations.
    [00122] In control rats, ACTH administration resulted in a sustained increase in CAP by ~ 10-fold (from ~ 0.26 nM to ~ 2.5 nM) and PCC by ~ 4- to 5-fold (from ~ 300 nM to ~ 1340 nM) for the duration of the 9-hour experiment. In contrast, administration of a test compound time - and PAC and PCC lowered regardless of dose by 0 to 97%, depending on the compound's inherent CYP11B2 and inhibitory potencies of CYP11B1 and its ADME properties (absorption, distribution, metabolism, excretion). Based on the plasma compound concentration in each dose, the PK / PD (pharmacodynamic) profiles (PAC and PCC reduction) of each compound were determined. Table 2 below summarizes the inhibitory activities of CYP11B1 and CYP11B2 of representative compounds. Table 2

    **: Please refer to W02007 / 024945 for details. Example 7
    [00123] A pilot study of forced titration was carried out to evaluate the hormonal effects of a compound of formula (I), 4 - [(5R) -6,7-dihydro-5H-pyrrole [1,2-c] imidazol-5-yl] -3-flurorbenzonitrile dihydrogen phosphate, in patients with diagnosed primary hyperaldosteronism. The clinical study was designed, implemented and reported in accordance with the harmonized ICH tripartite guidelines for good clinical practice with applicable local regulations. Each patient participated in a classification / washout period, a 2 week placebo operation period, a 4 week treatment period, and a 1 week placebo wash period. The treatment period consisted of the oral administration of the compound of formula (I) twice daily at a dose of 0.5 mg for two weeks, followed by an increase in dose to 1.0 mg twice daily for another 2 weeks. Blood samples were taken at a baseline, from 1 and 2, day 8, day 15, day 22, day 29 and 30 (all at the pre-dose, ie, 12 hours after the last dose), and in the study end day 36. Each sample was evaluated for aldosterone and active renin immunoreactive, 11-deoxychorticosterone, cortisol, 11-deoxicortisol and adrenocorticotropin (ACTH) after subjects were at rest for at least 60 minutes to avoid any changes in postural value or induced by stress. Aldosterone plasma was measured using a commercially available radioimmunoassay kit (DPC, France). Renin Active Plasma was measured using the two monoclonal antibodies 3E8 and 125I-4G1 in a commercially available immunoradiometric kit (CisBio, France). Plasma 11-deoxycorticosterone, cortisol and 11-deoxycortisol were measured using a standardized LC-MS / MS method. ACTH plasma was measured using a commercially available immunoradiometric kit (CisBio, France).
    [00124] The statistical analysis of the pharmacodynamic biomarker was summarized using descriptive statistics as well as graphical and / or regression methods. Administration of a compound of formula (I), 4- [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-flurorbenzonitrile dihydrogen phosphate to patients with primary hyperaldosteronism over a period of 2 times 2 weeks is shown in Figure 2 and induced as anticipated potent aldosterone suppression that was reflected by an increased active renin level, but also by an unexpectedly high composition of the steroid precursor 11-deoxychorticosterone . The accumulation of 11-deoxycorticosterone (P11DOCS) was stimulated by increased ACTH levels. The increased levels of adrenocorticotropin resulted from inhibition of cortisol synthesis via 11-beta-hydroxylase as reflected by decreased levels of cortisol and an accumulation of the 11-deoxycortisol enzyme substrate (P11DOC). Increased levels of 11-deoxycorticosterone in the presence of inhibited stress hormone synthesis are altered to increased synthesis of adrenal androgens androstendione and dehydroepiandrosterone (see Figure 1, a diagram for adrenal steroidogenesis). Thus, the compound of formula (I), exhibited the pharmacological profile of a pleiotropic adrenal hormone modifying agent as it inhibits the synthesis of both aldosterone and cortisol, while increasing the levels of ACTH, 11-deoxychorticosterone and finally the synthesis of adrenal androgens, androstendione and dehydroepiandrosterone. Example 8
    [00125] A multi-center, single-dose, open-label sequential dose escalation study in patients with Cushing's disease is performed as described here below.
    [00126] The study consists of a 10-14-day baseline period, a 10-week treatment period consisting of bi-weekly treatment with dose escalation and a 14-day washout period, followed by a Completion assessment of the Study in 14 days after the administration of the last drug. The study drug is applied on dose scales of 2 mg, 5 mg, 10 mg, 20 mg and 50 mg twice daily (bid) each for a period of two weeks (see study timeline below). The optimal therapeutic dose is dependent on the severity and responsiveness of the underlying pathological conditions.

    [00127] Population: The study population is comprised of male and female patients with endogenous hypercortisolism due to increased production of ACTH [Adrenocorticotropic HGormone] from the pituitary (Cushing’s disease).
    [00128] Male and female patients 18-75 years old
    [00129] Patients confirmed Cushing's Disease as evidenced by: • UFC [Cortidol Linear Urinary]> 1.5XULN [Upper Limit of Normal] (Average value of three urine samples collected 24 hours within 14 days) • Plasma ACTH above 10 pg / mL
    [00130] Individuals are allowed to try current drug therapy to meet these entry criteria if they have a known diagnosis of Cushing's disease.
    [00131] Therapy: Individuals start at a dose of 2 mg b.i.d. 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-flurorbenzonitrile dihydrogen phosphate and increases your dose every 2 weeks. The optimal therapeutic dose is determined by the treatment effect and tolerability of the intervention. Efficacy / Pharmacodynamic Assessments: Efficacy assessments include urinary free cortisol, ACTH asthma, cortisol and renin, urine plasma and aldosterone, plasma and urine potassium, salivary cortisol and aldosterone and plasma insulin.
    [00132] Safety Assessments: Safety assessments include physical exams, ECGs (Electrocardiograms), vital signs, standard clinical laboratory assessments (hematology, blood chemistry, urinalysis,) adverse event and monitoring of serious adverse event.
    [00133] Data analysis: The primary efficacy variable is defined as the proportion of responders to 4- (5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3flurorbenzonitrile dihydrogen phosphate. A patient is considered to be a responder if the average UFC level from Week 10 24-hour urine samples is <1 x ULN. Patients who discontinue a treatment-related illness or reason (for example, death, adverse event, progression of clinical illness, etc.), or whose average levels of mean week 10 24-hour CFU are higher than the normal limit are classified as non-responders. Patients who have only a baseline or post-baseline 24-hour UFC measurement will not be included in the primary efficacy analysis.
    权利要求:
    Claims (7)
    [0001]
    1. Use of 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] - 3-flurorbenzonitrile, presenting the formula
    [0002]
    2. Use, according to claim 1, characterized by the fact that the disease or disorder is Cushing's syndrome.
    [0003]
    3. Use, according to claim 1, characterized by the fact that the disease or disorder is Cushing's disease.
    [0004]
    4. Use according to claim 1 or 2, characterized by the fact that Cushing's syndrome includes hypercortisolism due to adrenocortical, pituitary or ectopic tumors.
    [0005]
    5. Use, according to claim 1, characterized by the fact that the compound is in the form of its dihydrogen phosphate salt.
    [0006]
    6. Use of 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] - 3-flurorbenzonitrile, presenting the formula
    [0007]
    7. Use, according to claim 6, characterized by the fact that the compound is in the form of its dihydrogen phosphate salt.
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-04-17| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2019-08-20| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-01-28| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-06-02| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-08-11| B25A| Requested transfer of rights approved|Owner name: RECORDATI AG (CH) |
    2020-10-20| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 13/01/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US29498010P| true| 2010-01-14|2010-01-14|
    US61/294,980|2010-01-14|
    PCT/US2011/021100|WO2011088188A1|2010-01-14|2011-01-13|Use of an adrenal hormone-modifying agent|
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