CYCLOHEXYL PYRIMIDINE AS A GLUCOCORTICOID RECEPTOR MODULATOR

专利摘要:
cyclohexyl pyrimidines as glucocorticoid receptor modulators. The present invention provides a class of cyclohexyl pyrimidinedione compounds and methods of using such compounds as modulators of glucocorticoid receptors.
公开号:BR112013023689B1
申请号:R112013023689-2
申请日:2012-03-16
公开日:2022-01-11
发明作者:Clark Robin；Hynd George；Ray Nicholas；Sajad Mohammad
申请人:Corcept Therapeutics, Inc；
IPC主号:

专利说明:

CROSS-REFERENCE TO PATENT AND RELATED PATENT APPLICATIONS
This patent application claims priority to US Provisional Patent Application No. 61/454,289, filed March 18, 2011, which is incorporated in its tonality in this patent application for all purposes. BACKGROUND OF THE INVENTION
In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which shows both: variation due to circadian rhythm, and increases in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a steroid and acts by binding to the intracellular glucocorticoid receptor (GR). In man, glucocorticoid receptors are present in two forms: GR-alpha binding ligand of 777 amino acids; and GR-beta isoform that differs only in the last fifteen amino acids. Both types of GR have high affinity for their specific ligands, and are thought to function by the same transduction pathways.
The biological effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level by the use of receptor modulators, such as agonists, partial agonists, and antagonists. Several classes of agents are capable of blocking the physiological effects of GR-agonist binding. These antagonists include compositions that, upon binding to the GR, block the ability of the agonist to effectively bind to and/or activate the GR. A known GR antagonist, mifepristone, has been determined to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, its dissociation constant (Kd) is 10 s M (Cadepond (1997) Annu. Rev. Med. 48:129).
In addition to cortisol, the biological effects of other steroids can be modulated at the GR level by the use of receptor modulators, such as agonists, partial agonists and antagonists. When administered to individuals in need thereof, steroids can provide both the desired therapeutic effects, for example, by stimulating glucocorticoid receptor transrepression, and negative side effects, for example, chronic glucocorticoid receptor transactivation. What is needed in the art are new compositions and methods for modulating GR receptors. Surprisingly, the present invention satisfies these and other needs. BRIEF SUMMARY OF THE INVENTION
Embodiment of the present invention provides compound of formula I:
in which the dashed line is absent or is a link. X is O or S. R1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted by 1 to 3 Rla groups. Each Rla is independently H, C2-g alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkyl-ORlb, halogen, Cg-g haloalkyl, Cg-g haloaloxy, -ORlb, -NRlbRlc -C(O)Rlb, -C(O)ORlb, -OC(O)Rlb, -C(O)NRlbRlc, -NRlbC(O)Rlc, -SO2Rlb, -SO2NRlbRiC, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Rlb and Rlc are each H or Cg-g alkyl. R2 is H, C1-g alkyl, Cg-g alkyl-ORlb, Cg-g alkyl-NRlbRlc or Cg-g alkylene-heterocycloalkyl. R3 is H or C6 -g alkyl. Ar is aryl, optionally substituted by 1-4 R4 groups; Each R4 is H, Cg-g alkyl, Cg-g alkoxy, halogen, Cg-g haloalkyl or Cg-g haloalkoxy. L1 is bond or C1-6 alkylene; the subscript n is an integer from 0 to 3. Salts and isomers of the compounds recited in this patent application are also included.
In a second embodiment, the present invention provides a pharmaceutical composition that includes a pharmaceutically acceptable excipient and a compound of formula I.
In a third embodiment, the present invention provides a method of treating a disease or condition by means of a glucocorticoid receptor modulator, the method includes administering to the individual in need of such treatment a therapeutically effective amount of a compound of formula I to in this way carry out the treatment of the illness or condition.
In a fourth embodiment, the present invention provides a method of treating a disease or condition by antagonizing glucocorticoid receptors, the method includes administering to the individual in need of such treatment an effective amount of a compound of formula 1. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows method for preparing compounds of the present invention.
Figure 2 shows an additional method for preparing the compounds of the present invention. DETAILED DESCRIPTION OF THE INVENTION I. General
The present invention provides compounds capable of modulating a glucocorticoid receptor (GR pa) and thus providing beneficial therapeutic effects. The compounds include benzyl pyrimidinedione-cyclohexyl-phenyls. The present invention also provides methods of treating diseases and disorders by modulating GR with the compounds of the present invention. II. Definitions
The abbreviations used in this patent application have their conventional meaning in the chemical and biological arts.
When substituent groups are specified by their conventional chemical formula, written from left to right, they also encompass the chemically identical substituents that would result from writing the structure from right to left, for example, -CH2O- is equivalent to -OCH2- .
As used in this patent application, the term "alkyl" refers to a saturated, straight- or branched-chain aliphatic radical having the indicated number of carbon atoms. For example, C2 -C12 alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
As used in this patent application, the term "alkylene" refers to either straight or branched chain of 1 to 7 carbon atoms, i.e. divalent hydrocarbon radical of 1 to 7 carbon atoms, e.g. straight chain alkylene the bivalent radical of the general formula being (Cfpln-, where n is 1, 2, 3, 4, 5, 6 or 7. Preferably, alkylene represents straight chain alkylene of 1 to 4 carbon atoms, for example, methylene chain , ethylene, propylene or butylene, or methylene, ethylene, propylene or butylene monosubstituted by a C1-Cβ-alkyl chain (preferably methyl) or disubstituted on the same or different carbon atoms by C1-C3-alkyl (preferably methyl), the number total carbon atoms equal to or less than 7. One skilled in the art will appreciate that a single carbon of the alkylene can be bivalent, such as in -CH((CH 2 )nCfp) -, where n = 0-5.
As used in this patent application, the term "alkenyl" refers to hydrocarbons having 2 to 6 carbon atoms, both straight chain and branched with at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4- pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatrienyl. Alkenyl groups may also have 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbon atoms. Alkenyl groups are normally monovalent, but can be bivalent, for example when the alkenyl group links two moieties.
As used in this patent application, the term "alkynyl" refers to hydrocarbons having 2 to 6 carbon atoms, both straight chain and branched with at least one triple bond. Examples of 5-alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butad-1-ynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1, 3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 31-hexynyl, 1,3-hexadiinyl, 1,4-hexadiinyl, 1,5-hexadiynyl, 2 ,4-hexadiinyl, or 1,3,5-hexatriinyl. Alkynyl groups may also have 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbon atoms. Alkynyl groups are normally monovalent, but can be bivalent, for example when the alkynyl group links two moieties.
As used in this patent application, the term "alkoxy" refers to an alkyl radical as described above, which also bears an oxygen substituent capable of covalently bonding to another hydrocarbon, for example, the methoxy, ethoxy or t- butoxy.
As used in this patent application, the term "halogen" by itself or as part of another substituent, means, unless otherwise indicated, fluorine, chlorine, bromine, or iodine atom.
As used in this patent application, the term "haloalkyl" refers to alkyl as defined above, in which some or all of the hydrogen atoms are replaced with halogen atoms. Halogen (halo) preferably represents chlorine or fluorine, but may also represent bromine or iodine. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 1,2,3,4,5 pentafluorophenyl, etc. The term "perfluoro" defines a compound or radical that has at least two available hydrogen atoms replaced by fluorine. For example, perfluoromethane refers to 1,1,1-trifluoromethyl.
As used in the present application, the term "haloalkoxy" refers to alkoxy, as defined above, in which some or all of the hydrogen atoms are replaced by halogen atoms. "Haloalkoxy" is intended to include monohaloalkyl(oxy), and polyhaloalkyl(oxy).
As used in this patent application, the term "alkylamine" refers to an alkyl group, as defined herein, having one or more amine groups. Amine groups can be primary, secondary or tertiary. The alkylamine may further be substituted with a hydroxy group. Alkylamines useful in the present invention include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine and ethanolamine. The amine group can link alkylamines at the point of coupling with the rest of the compound, be in the omega position of the alkyl group, or join at least two carbon atoms of the alkyl group. Those of skill in the art will understand that other alkylamines are useful in the present invention.
As used in this patent application, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic or bridged polycyclic ring set having 3 to 12 ring atoms, or the indicated number of atoms. For example, C3-C8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl also includes norbornyl and adamantyl.
As used in this patent application, the term "heterocycloalkyl" refers to a ring system having from 3 ring members to about 20 ring members and from 1 to about 5 heteroatoms, such as N, O and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si, and P. Heteroatoms can also be oxidized, such as, but not limited to, S(O) - and S(O) 2 . For example, the heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholine, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and 1,4-dioxa- 8-azaspiro[4.5]dec-8-yl.
As used in this patent application, the term "alkylene-heterocycloalkyl" refers to a heterocycloalkyl group, as defined above, which is linked to another group by an alkylene. The heterocycloalkyl and the group to which the heterocycloalkyl is bonded by the alkylene may be bonded to the same or different atoms of the alkylene.
As used in this patent application, the term "aryl" means, unless otherwise indicated, a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) that are fused together. together or covalently linked. Examples include, but are not limited to, phenyl, biphenyl, naphthyl and benzyl.
As used in this patent application, the term "heteroaryl" refers to aryl groups (or rings) that contain one to four heteroatoms selected from N, O and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2 - oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl , 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl , 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above-noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
For brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings above as defined. Thus, the term "arylalkyl" is intended to include radicals in which an aryl group is bonded to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including alkyl groups in which a carbon atom (e.g., a methylene) has been replaced by, for example, an oxygen atom (for example, phenoxymethyl, 2-pyridyloxyethyl, 3-(1-naphthyloxy)propyl, and the like). Likewise, the term "heteroarylalkyl" is intended to include radicals in which a heteroaryl group is bonded to an alkyl group.
Each of the above terms (e.g., "alkyl", "aryl", and "heteroaryl") are intended to include both substituted and unsubstituted forms of the indicated radical. Examples of substituents for each type of radical are given below.
The substituents for alkyl and heteroalkyl radicals (including the groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to a: -OR', =0, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', - C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'C(O)NR"R"', - NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NRC(NR'R")=NR"' , - S(O)R', - S(O)2R', -S(O)2NR'R", -NR(SO2)R', -CN and -NO2 in numbers ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such a radical. R', R", R"' and R"" each independently preferably refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (for example, aryl substituted by 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When the compound of the present invention includes more than one R group, for example, each of the R groups is independently selected as are each of the R', R", R'" and R"" groups when more than one of these groups is gift. When R' and R" are bonded to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4, 5-, 6-, or 7-membered ring. For example, -NR'R" is intended to include , but not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one skilled in the art will understand that the term "alkyl" implies the inclusion of groups that include carbon atoms attached to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups are varied and are selected from, for example: halogen, OR', -NR'R", SR', -halogen, -SiR'R"R , OC(O)R', -C(O)R', CO3R', -CONR'R", -OC(O)NR'R", NR"C(O)R', 15 NR'C(0 )NR"R"', -NR"C(O)2R', NR-C(NR'R"R'")=NR"",NRC (NR'R") =NR' ", -S(O )R', -S(O)2R', -S(O)2NR'R", NR(SO2)R', -CN and -NO2, -R', -N3, CH(Ph)2, fluoro ( C1-C4)alkoxy,fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valencies in the aromatic ring system; and wherein R', R", R"' and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
When the compound of the present invention includes more than one R group, for example, each of the R groups is independently selected as are each of the 30 R', R", R'" and R"" groups when more than one such group is is present.
When two substituents are "optionally joined to form a ring", the two substituents are covalently bonded together with the atom or atoms to which the two substituents are joined to form rings substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted cycloalkyl or unsubstituted, or substituted or unsubstituted heterocycloalkyl.
"Salt" refers to acid or base salts of compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), organic acid salts (acetic acid, propionic acid, glutamic acid, citric acid and the like), quaternary ammonium salts (methyl iodide, ethyl iodide, and the like). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated into this patent application by reference.
"Hydrate" refers to a compound that is complexed with at least one water molecule. The compounds of the present invention can be complexed with 1 to 10 molecules of á CJ Uâ .
"Isomers" refers to compounds with the same chemical formula, but which are structurally distinguishable.
"Tautomer" refers to one of two or more structural isomers that exist in equilibrium and that are readily converted from one form to another.
As used in this patent application, the phrases "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of the active agent and absorption by the individual and which can be included in the compositions of the present invention without causing an effect. significant adverse toxicology in the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, and so on. One skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.
As used in this patent application, the terms "treat", "treating" and "treatment" refer to any evidence of successful treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission, lessening of symptoms or making the injury, pathology or condition more tolerable for the patient; reduce the rate of degeneration or decline; make the end point of degeneration less debilitating; improve the physical or mental well-being of the patient. Treatment or improvement of symptoms may be based on objective or subjective parameters, which include the results of physical examination, neuropsychiatric examinations, and/or psychiatric evaluation.
As used in this patent application, the terms "illness" or "condition" refer to the physical condition or health status of the patient or individual amenable to treatment by the glucocorticoid receptor modulators of the present invention. Examples of illnesses or conditions include, but are not limited to, obesity, hypertension, depression, anxiety, and Cushing's syndrome.
As used in this patent application, the term "glucocorticoid receptor", ("GR") refers to the family of intracellular receptors that specifically bind cortisol and/or cortisol analogues (e.g., dexamethasone). The glucocorticoid receptor is c-pmo is also referred to as the cortisol receptor. The term includes the GR isoforms, recombinant GR and mutant GR.
As used in this patent application, the term "glucocorticoid receptor modulation" refers to methods for regulating the glucocorticoid receptor response to glucocorticoids, glucocorticoid antagonists, agonists and partial agonists. Methods include contacting the glucocorticoid receptor with an effective amount of antagonist, agonist, or partial agonist and detecting the change in GR activity.
As used in this patent application, the term "glucocorticoid receptor modulator" refers to any composition or compound that modulates the binding of a glucocorticoid receptor (GR) agonist, such as cortisol, or cortisol analogues, synthetic or natural, to a GR. Modulation can include partial or complete inhibition (antagonism) of the binding of a GR agonist to a GR. "Specific glucocorticoid receptor antagonist" refers to any composition or compound that inhibits any biological response associated with the binding of the GR to the agonist. By "specific", it is intended that the drug preferentially binds to the GR rather than to other nuclear receptors, such as the mineralocorticoid receptor (MR) or progesterone receptor (PR). GR modulators of the present invention include compounds of Formula I below.
As used in the present application, the term "antagonist" refers to blocking the binding of an agonist to a receptor molecule or inhibiting the signal produced by a receptor agonist. A receptor antagonist blocks or dampens agonist-mediated responses.
As used in this patent application, the terms "patient" or "subject" refer to the living organism suffering from or prone to the condition which can be treated by administering a pharmaceutical composition as provided by this patent application. Non-limiting examples include humans, other mammals and other non-mammalian animals.
As used in this patent application, the phrase "therapeutically effective amount" refers to that amount of the conjugated functional agent or pharmaceutical composition useful for treating or ameliorating the identified disease or condition, or which exhibits detectable therapeutic or inhibitory effect. The effect can be detected by any test method known in the art.
As used in this patent application, the terms "a", "an" or "an(a)", when used in reference to a substituent group, or "substituent group" in the present application, means at least one. For example, when a compound is substituted with "an" alkyl or aryl group, the compound is optionally substituted with at least one alkyl and/or at least one aryl, wherein each alkyl and/or aryl is optionally different. In another example, where a compound is substituted with "a" substituent group, the compound is substituted with at least one substituent group, where each substituent group is optionally different.
Descriptions of the compounds of the present invention are limited by chemical bonding principles known to those skilled in the art. Consequently, whenever a group can be substituted by one or more of a series of substituents, such substitutions are selected so as to comply with the principles of chemical bonding and to result in compounds that are not inherently unstable and/or known to a person with normal skill in the art as likely to be unstable under environmental conditions, such as aqueous, neutral or physiological conditions. III. compounds
In some embodiments, the present invention provides a compound of Formula I:
in which the dashed line is absent or is a link. X is 0 or S. R1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted by 1 to 3 R1'1 groups. Each Rla is independently H, C1-g alkyl, C2-and alkenyl, C-- alchemy, C1-6 alkoxy, C1-6 alkyl-ORlb, halogen, C1-g haloalkyl, Ime haloaloxy, -ORlb, -NRlbRlc, -C(O)Ric, -C(O)ORlfc, -OC(O) RIb, -C(O)NRlbRlc, -NRibC(O)Rlc, -SO2Rlb, -SO2NRlbRiv, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Rlb and Rb" are each H or C1-6 alkyl. R2 is H, Cg-g alkyl, Cg-g alkyl-ORlb, Cg-g alkylNRlbRlc or Cg-g alkylene-heterocycloalkyl. R is H or Cg-g alkyl Ar is aryl, optionally substituted with 1-4 R4 groups, each R4 is H, C1-6 alkyl, C1-6 alkoxy, halogen, C6-6 haloalkyl or C6-6 haloalkoxy, L1 is bond or C1-6 alkylene; the subscript n is an integer from 0 to 3. Salts and isomers of the compounds recited in this patent application are also included.
In other embodiments, it provides compound of Formula Ia:

In some embodiments, L1 embodiments, Ar is phenyl.
In some embodiments, it provides compound of Formula Ib:

In other embodiments, it provides compound of Formula Ic:

In some embodiments, the present invention provides a compound wherein R1 is aryl or heteroaryl. In other embodiments, R1 is selected from the group consisting of phenyl, pyridyl, pyrimidine, and thiazole. In other embodiments, each R'd is independently H, C6-6 alkyl, C1-6 alkoxy, halogen, C6-6 haloalkyl, -NRlbR1c, or -SCcR113 . In still other embodiments, each Ria is Cp-g haloalkyl. In other embodiments, each Rla is independently H, Me, Et, -OMe, F, CP, -CF3, -NMe2, or -SO Me. In other embodiments, each Rla is -CF3. In some other embodiments, R' is H or C6-g alkyl. In other embodiments, R~ is H.
In some embodiments, the present invention provides a compound selected from the following:



In some other embodiments, the present invention provides a compound having the formula:

The compounds of the present invention may exist in the form of salts. The present invention includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. Such salts can be prepared by methods known to those skilled in the art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulphuric, hydroiodic or phosphorous acids. and the like, as well as salts derived from organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and others similar. Also included are salts of amino acids such as arginate and the like and salts of organic acids such as glucuronic or galacturonic acids and the like. Some specific compounds of the present invention contain basic and acidic functionalities that allow the compounds to be converted to either base or acid addition salts.
Other salts include acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), organic acid salts (acetic acid, propionic acid, glutamic acid, citric acid and the like), quaternary ammonium salts (methyl iodide, ethyl iodide, and the like). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated into this patent application by reference.
Pharmaceutically acceptable salts include salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulphuric, hydroiodic or phosphorous and the like, as well as salts derived from organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and others similar. Also included are salts of amino acids such as arginate and the like and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Some specific compounds of the present invention contain basic and acidic functionalities that allow the compounds to be converted to either base or acid addition salts.
Neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The original form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention which means they fall within the scope of the present invention.
Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; and the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms which can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)- for amino acids , and the individual isomers are encompassed within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and/or isolate. The present invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or decomposed using conventional techniques.
Isomers include compounds that have the same number and type of atoms, and therefore the same molecular weight, but that differ with respect to the arrangement or structural configuration of the atoms.
It will be apparent to one skilled in the art that certain compounds of the present invention may exist in tautomeric forms, all tautomeric forms of the compounds fall within the scope of the invention. Tautomer refers to one of two or more structural isomers that exist in equilibrium and that are readily converted from one form to another. 1
Unless otherwise indicated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
Unless otherwise indicated, compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of their constituent atoms. For example, compounds of the present invention may be radiolabeled with radioactive isotopes such as, for example, deuterium RH), tritium (JH), iodine-125 ('■''I), carbon-13 or carbon-14 (''" 'C) All isotopic variations of the compounds of the present invention, whether radioactive or not, fall within the scope of the present invention.
In addition to the salt forms, the present invention provides compounds, which are in prodrug form. Prodrugs of the compounds described herein are compounds that, under physiological conditions, experience immediate chemical changes in order to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
The compounds of the present invention can be prepared by a variety of methods known in the art. For example, compounds can be prepared as shown in Figure 1. In Figure 1, the chloropyrimidinediones 1 (described in WO06/014394 and incorporated in this patent application) are coupled with a boronate ester of 4-phenylcyclohex-1 -enyl, in the presence of a Pd catalyst to obtain cyclohexenyl pyrimidinediones 2. Catalytic hydrogenation then provides cis/trans mixture from which the desired transisomer 3 can be obtained by conventional separation techniques, eg chromatography in column.
Compounds 3 can be prepared by stereospecific synthesis described in Figure 2. Commercially available trans-4-(4-chlorophenyl)-cyclohexanecarboxylic acid (4) is hydrogenated in the presence of a palladium-on-carbon catalyst in alcohol, preferably ethanol, to obtain trans-4-phenyl cyclohexanecarboxylic acid (5). Acid 5 is converted to ketoescer 7 by treatment with Meldrum's acid (6) in the presence of 4-dimethylaminopyridine and dicyclohexylcarbodiimide, followed by heating in ethanol. The alkylation of the ketoester 7 can be carried out by treatment with a base, such. as NaH, and a benzyl halide 8 in solvent such as tetrahydrofuran to provide the benzylated ketoester 11. Alternatively, the ketoester 7 can be condensed with a benzaldehyde 9 by heating in toluene in the presence of acetic acid and piperidine to produce the olefin 10. Catalytic hydrogenation of 10 provides the benzylated ketoester 11. Treatment of 11 with thiourea in ethanol in the presence of sodium ethoxide results in 2-thioxo-2,3-dihydro-1H-pyrimidin-4-ones which are 12 subsequently converted to the subject compounds 3 by acid hydrolysis, preferably with aqueous chloroacetic acid solution in dioxane.
Compounds where R" is heteroaryl group are similarly prepared using methyl heteroaryl halide or heteroaryl aldehyde in place of benzyl halide (8) or benzaldehyde (9) in Figure 2.
Compounds wherein R 1 are alkyls or substituted alkyl groups can be prepared by treating 3 with a base, such as sodium hydride, and the necessary alkylating agent, preferably alkyl halide or substituted alkyl halide. IV. Pharmaceutical Compositions
In some embodiments, the present invention provides a pharmaceutical composition that includes a pharmaceutically acceptable excipient and the compound of Formula I.
The compounds of the present invention can be prepared and administered in widely varied oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, pills, capsules, liquids, lozenges, gels, syrups, pastes, suspensions, etc., suitable for patient ingestion. The compounds of the present invention may also be administered by injection, i.e., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Furthermore, the compounds described in this patent application can be administered by inhalation, for example, intranasally. Additionally, compounds of the present invention can be administered transdermally. The GR modulators of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflations, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193 , 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present invention also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and any of the compounds of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I).
For the preparation of pharmaceutical compositions with compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, lozenges, suppositories, and dispersible granules. The solid carrier may comprise one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Haack Publishing Co, Easton PA ("Remington's").
In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size.
Powders and tablets preferably contain from 5% or 10% to 30% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulating the active compound with encapsulating material as a carrier by providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Likewise, lozenges and tablets are included. Tablets, powders, capsules, pills, lozenges and tablets can be used as solid dosage forms suitable for oral administration.
Suitable solid excipients are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol, corn, wheat, rice, potato, or other plant starch; cellulose such as methyl cellulose, hydroxypropyl methyl cellulose, or sodium carboxymethyl cellulose, and gums, including arabic and tragacanth, as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
The tablet cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablet or dragee coatings for product identification or to characterize the amount of active compound (ie dosage). The pharmaceutical preparations of the present invention may also be administered orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Snap-on capsules may contain GR modulator mixed with filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the GR modulating compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
For the preparation of suppositories, low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is initially melted and the active component is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool, and thereby solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example water, or water/propylene glycol solutions. For parenteral injection, liquid preparations may be formulated in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g. lecithin), the condensation product of alkylene oxide with fatty acid (e.g. polyoxyethylene stearate), the condensation product of ethylene with long-chain aliphatic alcohol (e.g. oxycetanol heptadecaethylene), the condensation product of ethylene oxide with a partial ester derived from fatty acid and hexitol (e.g., polyoxyethylene sorbitol monooleate), or the condensation product of the oxide of ethylene with a partial ester derived from fatty acid and hexitol anhydride (e.g. sorbitan monooleate year polyoxyethylene). The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
Oily suspensions can be formulated by suspending GR modulator in vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oil such as liquid paraffin, or mixtures thereof. Oily suspensions may contain a thickening agent, such as hard paraffin beeswax or cetyl alcohol. Sweetening agents, such as glycerol, sorbitol, or sucrose, may be added to provide a palatable oral preparation. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oily vehicle, see Minto, J.Pharmacol. Exp. Ther. 281:93-102, 1997. Pharmaceutical formulations of the invention may also be in an oil-in-water form. The oil phase may be vegetable oil or mineral oil, described above, or mixtures thereof. Suitable emulsifying agents include naturally occurring gums such as acacia gum and gum tragacanth, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, a preservative, or a coloring agent.
The GR modulators of the invention can be delivered transdermally, pipr topically, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.
The GR modulators and compositions of the invention can also be delivered as microspheres for slow release into the body. For example, microspheres can be administered by intradermal injection of drug-containing microspheres, which slowly release the drug subcutaneously (see Rao, J. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12:857-863, 1995), or, as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). transdermal and intradermal patches allow for constant delivery over weeks or months.
The GR modulator pharmaceutical formulations of the invention may be provided as a salt and may be formed from many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic acid, etc. The salts tend to be more soluble in aqueous solvents or other protonic solvents that correspond to the free base forms. In other cases, the preparation may be a powder lyophilized in 1 mM-50 mM histidine, 0.1-2% sucrose, 2-7% mannitol in the pH region of 4.5 to 5.5, which is combined with buffer before use.
In another embodiment, the GR modulator formulations of the invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by using ligands linked to the liposomemap or linked directly to the oligonucleotide, which binds to the cell membrane. membrane surface of the cell's protein receptors, resulting in endocytosis. By using liposomes, particularly when the surface of the liposome carries ligands specific to the target cells, or is otherwise preferentially targeted to a specific organ, one can focus on the delivery of the GR modulator to the target cells in vivo. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989).
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation, such as packets of tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form can be a capsule, tablet, lozenge, or tablet itself, or it can be the appropriate amount of any of these in packaged form.
The amount of active ingredient in a unit dose preparation can be varied or adjusted from 0.1 mg to 10,000 mg, more typically 1.0 mg to 1,000 mg, even more typically from 10 mg to 500 mg, according to the particular application. and the power of the active component. The composition may, if desired, also contain other compatible therapeutic agents.
The dosage regimen also takes into account pharmacokinetic parameters well known in the art, i.e., rate of absorption, metabolism, bioavailability, clearance, and the like (see, for example, Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi ( 1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; the most recent from Remington, cited above). The state of the art allows the clinician to determine the dosage regimen for each individual patient, GR modulator and disease or condition treated.
Single or multiple administrations of GR modulators formulations can be performed depending on the dosage and frequency required and tolerated by the patient. The formulations should provide a sufficient amount of active agent to effectively treat the disease state. Thus, in one embodiment, pharmaceutical formulations for oral administration of GR modulator is a daily amount of between about 0.5 to about 20 mg per kilogram of body weight per day. In an alternative embodiment, dosages of about 1 mg to about 4 mg per kg of body weight per patient per day are used.
Lower dosages can be used, in particular, when the drug is administered in an anatomically isolated location, such as the cerebrospinal fluid space (CSF), in contrast to oral administration, into the bloodstream, into a cavity. body or in the lumen of an organ. Substantially higher dosages can be used for topical administration. Effective methods for preparing parenterally administrable formulations of GR modulator are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, in "Receptor Mediated Antisteroid Action", Agarwal, et al., Eds., De Gruyter, New York (1987).
The compounds described in this patent application can be used in combination with one another, with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjuvant agents that may not be effective on their own, but may contribute to the effectiveness of the active agent substance.
In some embodiments, co-administration includes administration of the active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administration of two active agents at the same time, at approximately the same time (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration may be accomplished by co-formulation, i.e., the preparation of a single pharmaceutical composition, including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and/or adjuvants may be linked or conjugated to each other.
After the pharmaceutical composition including GR modulator of the invention has been formulated in an acceptable vehicle, it can be placed in an appropriate container and labeled for the treatment of the indicated condition. For the administration of GR modulators, such labeling should include, for example, instructions regarding the amount, frequency and method of administration.
The pharmaceutical compositions of the present invention can be provided as a salt and can be formed from many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic acid, etc. The salts tend to be more soluble in aqueous solvents or other protonic solvents, which are the corresponding free base forms. In other cases, the preparation may be a powder lyophilized in 1 mM-50 mM histidine, 0.1-21 sucrose, 2-7% mannitol in the pH region of 4.5 to 5.5, which is combined with buffer before use.
In another embodiment, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Formulations for administration will generally include solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be used are water and Ringer's solution, isotonic sodium chloride. In addition, sterile, fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of unwanted material. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as needed to approximate physiological conditions such as by pH adjustment and buffering agents, toxicity adjusting agents, e.g. sodium acetate, sodium chloride, potassium chloride, calcium chloride, lactate sodium and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily on the basis of fluid volumes, viscosities, body weight and the like, in accordance with the particular mode of administration selected and the needs of the patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile aqueous or oleaginous injectable suspension. This suspension may be formulated in accordance with the known technique using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol solution.
In another embodiment, the formulations use liposomes that fuse with the cell membrane or are endocytosed, that is, by the use of ligands coupled to the liposome, or directly coupled to the oligonucleotide, which binds to surface membrane protein receptors. cell, resulting in endocytosis. When using liposomes, particularly when the surface of the liposome carries ligands specific to the target cells, or is otherwise preferentially targeted to a specific organ, one can focus on delivering the compositions of the present invention to the target cells in vivo. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989). V. Treatment Method by Glucocorticoid Modulation
In some embodiments, the present invention provides a method of treating a disease or condition by means of a glucocorticoid receptor modulator, which method includes administering to the subject in need of such treatment a therapeutically effective amount of a compound of formula I.
In certain other embodiments, the present invention provides a method of treating a disease or condition by antagonizing a glucocorticoid receptor, which method includes administering to a subject in need of such treatment an effective amount of the compound of formula I.
In another embodiment, the present invention provides methods of modulating glucocorticoid receptor activity using the techniques described herein. In an exemplary embodiment, the method includes contacting the GR with an effective amount of a compound of the present invention, such as the compound of formula I, and detecting the change in GR activity.
In an exemplary embodiment, the GR modulator is an antagonist of GR activity (also referred to herein as a "glucocorticoid receptor antagonist"). Glucocorticoid Receptor Antagonist, as used in this application, refers to any composition or compound that partially or completely inhibits (antagonizes) glucocorticoid receptor (GR) agonist binding (e.g., cortisol and synthetic or natural analogue). of cortisol) to the GR, thus inhibiting any biological response associated with the binding of the GR to the agonist.
In a related embodiment, the GR modulator is a specific glucocorticoid receptor antagonist. As used in this patent application, a specific glucocorticoid receptor antagonist refers to a composition or compound that inhibits any biological response associated with binding of the GR to the agonist by preferentially binding to the GR rather than another nuclear receptor (NR acronym in English). In some embodiments, the specific glucocorticoid receptor antagonist binds preferentially to the GR rather than the mineralocorticoid receptor (MR) or progesterone receptor (PR). In an exemplary embodiment, the specific glucocorticoid receptor antagonist binds preferentially to the GR rather than the mineralocorticoid receptor (MR). In another exemplary embodiment, the specific glucocorticoid receptor antagonist binds preferentially to the GR rather than the progesterone receptor (PR).
In a related embodiment, the specific glucocorticoid receptor antagonist binds to the GR with association constant (Kd) that is at least 10-fold lower than the Kd for NR. In another embodiment, the specific glucocorticoid receptor antagonist binds to the GR with an association constant (kd) that is at least 100-fold smaller than the Kd for NR. jIn another embodiment, the specific glucocorticoid receptor antagonist binds to the GR with association constant (kd) that is at least 1000-fold lower than the Kd for NR.
Examples of diseases or conditions suitable for use in the present invention include, but are not limited to, obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome ( AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease, increased cognition, Cushing's syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, inflammatory diseases, osteoarthritis, rheumatoid arthritis, asthma and rhinitis, diseases related to adrenal function, viral infection, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing, compulsive behavior, multidrug resistance, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, medical catabolism, psychotic depression , mild cognitive disorder, psychosis, dementia, hyperglycemia, stress disorders, weight gain antipsychotic-induced delirium, cognitive impairment in depressed patients, cognitive impairment in individuals with Down syndrome, psychosis associated with interferon-alpha therapy, chronic pain, pain associated with gastroesophageal reflux disease, postpartum psychosis, postpartum depression , neurological diseases in premature newborns, and migraine. In some embodiments, the illness or condition is psychotic depression, stress disorders, or antipsychotic-induced weight gain. SAW. Assays and Methods to Modulate Glucocorticoid Receptor Activity
Compounds of the present invention can be tested for their antiglucocorticoid properties. Methods of testing compounds capable of modulating glucocorticoid receptor activity are disclosed in this patent application. Typically, compounds of the present invention are capable of modulating glucocorticoid receptor activity by selectively binding to the GR or by preventing GR ligands from binding to the GR. In some embodiments, the compounds show little or no cytotoxic effect. A. Connection Tests
In some embodiments, GR modulators are identified by screening for molecules that compete with a GR ligand, such as dexamethasone. Those of skill in the art will recognize that there are several ways to perform competitive binding assays. In some embodiments, the GR is pre-incubated with labeled GR ligand and then contacted with the test compound. This type of competitive binding assay may also be referred to in this application as a binding displacement assay. The change (eg, decrease) in the amount of ligands bound to the GR indicates that the molecule is GR modulating potential. Alternatively, binding of the test compound to the GR can be measured directly with a labeled test compound. This last type of assay is called a direct link assay.
Both direct binding assays and competitive binding assays can be used in a variety of different formats. The formats may be similar to those used in immunoassays and receptor binding assays. For a description of the different formats of binding assays, which include competitive binding assays and direct binding assays, see Basic and Clinical Immunology 7th Edition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E.T. Maggio, ed., CRC Press, Boca Raton, Florida (1980); and "Practice and Theory of Enzyme Immunoassays," P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers B.V. Amsterdam (1985), each of which is incorporated into this patent application by reference.
In solid phase competitive binding assays, for example, the sample compound may compete with a labeled analyte for specific binding sites on solid surface bound binding agent. In this type of format, the labeled analyte can be a GR ligand and the binding agent can be GR bound to a solid phase. Alternatively, the labeled analyte can be labeled GR and the binding agent can be a solid phase GR ligand. The concentration of labeled analyte bound to the capture agent is inversely proportional to the ability of the test compound to compete in the binding assay.
Alternatively, the competitive binding assay can be performed in the liquid phase, and any of a variety of techniques known in the art can be used to separate bound labeled protein from unbound labeled protein. For example, several procedures have been developed to distinguish between bound ligand and excess bound ligand or between bound test compound and excess unbound test compound. These include identification of the bound complex by sedimentation on sucrose gradients, gel electrophoresis, or isoelectric gel concentration, precipitation of the receptor-ligand complex with protamine sulfate or adsorption on hydroxylapatite; and removing unbound compounds or ligands by adsorption onto dextran-coated charcoal (DCC) or by binding to the immobilized antibody. After separation, the amount of bound ligand or test compound is determined.
Alternatively, a homogeneous binding assay can be performed where the separation step is not required. For example, the label on the GR can be altered by binding the GR to its ligand or test compound. This change in labeled GR results in a decrease or increase in the signal emitted by the label, so measuring the label at the end of the binding assay allows detection or quantification of GR in the bound state. Wide variety of markers can be used. The component can be marked by any of several methods. Useful radioactive labels include those incorporating :H, kI, 'r'S, 14C, or '5'P. Useful non-radioactive labels include those that incorporate fluorophores, chemiluminescent agents, phosphorescent agents, electrochemiluminescent agents, and the like. Fluorescent agents are especially useful in analysis techniques that are used to detect changes in protein structure, such as fluorescence anisotropy and/or fluorescence polarization. The choice of label depends on the sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation. For a review of various marking systems or signal producers that may be used, see Patent No. 4,391,904, which is incorporated in this patent application by reference in its entirety for all purposes. The label can be coupled directly or indirectly to the desired component of the assay according to methods well known in the art.
High throughput screening methods can be used to screen for a large number of potential modulatory compounds. Such "compound libraries" are then screened in one or more assays, as described in the present application, to identify those library members (particular chemical species or subclasses) that exhibit the desired characteristic activity. Preparation and screening of chemical libraries is well known to those skilled in the art. Devices for preparing chemical libraries are commercially available (see, for example, 357 MPS, 390 MPS, Advanced Chem Tech, LouisvilJe KY, Symphony, Rainin, Woburn, MA, 433A Applied Biosystems, Foster City, CA, 9050 Plus, Millipore, Bedford, MA). B. Cell-Based Assays
Cell-based assays involve whole cells or GR-containing cell fractions to assay for binding or modulation of GR activity by the compound of the present invention. Examples of cell types that can be used in accordance with the methods of the present invention include, for example, any mammalian cells, including leukocytes, such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes, such as T cells and B cells, leukemia cells, Burkitt's lymphomas, tumor cells (including mouse mammary tumor virus -4 cells), endothelial cells, fibroblasts, heart cells, muscle cells, breast tumor cells, breast cancer carcinomas ovary, cervical carcinoma, glioblastomas, liver cells, kidney cells, and neuronal cells, as well as fungal cells, including yeast. The cells can be primary cells or tumor cells or other types of immortal cell lines. Naturally, GR can be expressed in cells that do not express an endogenous version of GR.
In some cases, GR fragments as well as fusion proteins can be used for screening. When molecules that compete for binding with GR ligands are desired, the GR fragments used are those fragments capable of binding the ligands (eg, dexamethasone). Alternatively, any GR fragment can be used as a target to identify molecules that bind to GR. GR fragments can include any fragment of, for example, at least 20, 30, 40, 50 anuno acids a up to protein that contains all but one GR amino acid. Typically, ligand-binding fragments will comprise transmembrane regions and/or most or all of the extracellular domains of GR.
In some embodiments, activation of GR-triggered signaling is used to identify GR modulators. GR signaling activity can be determined in many ways. For example, downstream molecular events can be monitored to determine signaling activity. Downstream events include those activities or manifestations that occur as a result of GR receptor stimulation. Examples of downstream events useful in the functional assessment of transcriptional activation and antagonism in intact cells include upregulation of a number of gene-dependent glucocorticoid response element (GRE) (PEPCK, tyrosine amino transferase, aromatase). In addition, specific cell types susceptible to GR activation can be used, such as osteocalcin expression in osteoblasts that is downregulated by glucocorticoids; primary hepatocytes that show glucocorticoid-mediated upregulation of PEPCK and glucose-6-phospahte (G-6-Pase)). GRE-mediated gene expression has also been demonstrated in cell lines transfected using well-known GRE-regulated sequences (e.g., mouse mammary tumor promoter virus (MMTV) transfected upstream by reporter gene construct). Examples of useful gene constructs include luciferase reporter (luc), alkaline phosphates-e (ALP), and chloramphenicol acetyl transferase (CAT). Functional assessment of transcriptional repression can be performed on cell lines, such as human skin monocytes or fibroblasts. Useful functional assays include those that measure IL-1beta-stimulated IL-6 expression; downregulation of collagenase, cyclooxygenase-2 and various chemokines (MCP-1, RANTES); or gene expression regulated by NFkB or AP-1 transcription factors in transfected cell lines.
Typically, compounds that are tested in whole cell assays are also tested in cytotoxicity assays. Cytotoxicity assays are used to determine the extent to which a perceived modulatory effect is due to non-GR binding cellular effects. In an exemplary embodiment, the cytotoxicity assay includes contacting a constitutively active cell with the test compound. Any decrease in cellular activity indicates a cytotoxic effect. C. Specificity
Compounds of the present invention may be subjected to a specificity assay (also referred to herein as a selectivity assay). Typically, specificity assays include testing a compound that binds to GR in vitro or in a cell-based assay for the degree of binding to non-GR proteins. Selectivity assays can be performed in vitro or in cell-based systems as described above. GR binding can be tested against any appropriate non-GR protein, including antibodies, receptors, enzymes, and the like. In an exemplary embodiment, the non-GR binding protein is cell surface receptor or nuclear receptor. In another exemplary embodiment, the non-GR protein is steroid receptor, such as estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor.
The terms and expressions that have been used in the present patent application are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude equivalents of the characteristics shown and described, or parts thereof, being It is recognized that various modifications are possible within the scope of the claimed invention. Furthermore, any one or more features of any embodiment of the invention may be combined with any one or more other features of any other embodiment of the invention, without departing from the scope of the invention. For example, the characteristics of GR modulating compounds are equally applicable to methods of treating disease states and/or pharmaceutical compositions described in this patent application. All publications, patents and patent applications cited in the present application are hereby incorporated by reference in their entirety for all purposes. VII. Examples LCMS Methods:
Method A: Experiments were performed using Waters Platform LC positive and negative ion electrospray quadrupole mass spectrometer and ELS/diode array detection using Phenomenex Luna 3 micron C18(2) 30 x 4.6 mm column and flow rate of 2 ml/minute. The solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 50 seconds, followed by a gradient up to 5% of the solvent A and 95% of solvent B over the next 4 minutes. The final solvent system was held constant for an additional 1 minute.
Method B: Experiments were performed using a Waters Micromass ZQ2000 quadrupole mass spectrometer with positive and negative ion electrospray and ELS/diode array detection using a 5 micron C18 100 x 3.0 mm Higgins Clipeus column and a flow rate of 1 ml/minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5 % solvent A and 95% solvent B over the next 8 minutes. The final solvent system was held constant for an additional 5 minutes.
Method C: Experiments were performed using a Waters ZMD quadrupole mass spectrometer with electrospray of positive and negative ions and ELS/diode array detection using Luna 3 micron C18 (2) 30 x 4.6 mm column and flow rate of 2 mL/minute. The solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 50 seconds, followed by gradient up to 5% of solvent A and 95% of solvent B over the next 4 minutes. The final solvent system was held constant for an additional 1 minute.
Method D: Experiments were performed using a Waters Micromass ZQ2000 quadrupole mass spectrometer connected to an Acquity Waters UPLC system with a PDA UV detector using an Acquity UPLC BEH C18 1.7 micron 100 x 2.1 mm, held at 40°C. °C The spectrometer has an electrospray source that operates in positive and negative ion mode. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for 0.4 minutes followed by a gradient of up to 5% solvent A and 95% solvent B over the next 6.4 minutes.0
Method E: The experiments were performed using a quadrupole Waters Quattro 10 Micro triple mass spectrometer connected to a Hewlett-Packard HP1100 LC system with positive and negative ion electrospray and ELS/Diode Array detection using a 5 micron C18 Higgins Clipeus column. 100 x 3.0 mm and flow rate of 1 mL/minute. The starting solvent system was 95% water containing 0.1%; of formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 13 minutes . The solvent system was held constant for 20 plus 7 minutes before returning to the initial solvent conditions. Example 1: Preparation of 5-Benzyl-6-(4-phenylcyclohex-1-enyl)-1H-pyrimic:line-2 -!J-dione (2a)

Trifluoromethanesulfonic acid 4-phenyl-cyclohex-1-enyl ester. Solution of diisopropylamine (4.46 mL) in tetrahydrofuran (25 mL) under nitrogen at -20 °C was treated with a 2.5 M solution of n-butyl lithium (12.6 mL) and stirred for 15 minutes. The resulting mixture was cooled to -78°C before a solution of 4-phenylcyclohexanone (5.0g) in tetrahydrofuran (20ml) was added over 20 minutes. The resulting solution was stirred at -78°C for 3 hours, then treated with a solution of N-phenyl-bis(trifluoromethanesulfonimide) (10.76g) in tetrahydrofuran (25ml). The mixture was stirred at -78°C for 1.5 hours and then warmed to room temperature and stirred for a further 18 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue partitioned between ethyl acetate and water. The organic layer was washed with 2M sodium hydroxide solution and brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to provide the title compound as an oil (7.3g). 1 H NMR (CDCl3 ): δ 7.32-7.31 (2H, m), 7.24-7.22 (3H, m), 5.87-5.84 (1H, m), 2.85-2.84 (1H, m), 2.55-2.54 (1H, m), 2.44-2.43 (2H, m), 2.35-2.34 ( 1H, m), 2.09-2.07 (1H, m), 1.96-1.95 (1H, m).
4,4,5,5-tetramethyl-2-(4-phenylcyclohex-1-enyl)-1,3,2]dioxaborolane. Mixture of 4-phenyl-cyclohex-1-enyl ester trifluoromethanesulfonic acid (5.8 g), bis(pinacolate) diboron (5.3 g), potassium acetate (5.58 g) and [1, 1'-Bis(diphenylphosphine)ferrocene]dichloropalladium (11) (0.77g) in 1,4-dioxane (150ml) was degassed then heated to 80°C for 2 hours. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with a mixture of diethyl ether and hexane (0:01 to 1:20 by volume) to provide the title compound (4.0 g). 1H NMR (CDCl3 ): δ 7.30-7.28 (2H, m), 7.24-7.15 (3H, m), 6.656.64 (1H, m), 2.82-2 .71 (1H, m), 2.40-2.36 (2H, m), 2.23-2.22 (2H, m), 1.95-1.94 (1H, m) , 1.70-1.68 (1H, m), 1.43 (3H, s), 1.28 (9H, s).
5-Benzyl-6-(4-phenylcyclohex-1-enyl)-1H-pyrimidine-2,4-dione (2a). Mixture of 5-Benzyl-6-chloro-1H-pyrimidine-2,4-dione (W006014394) (1.0 g), 4,4,5,5-tetramethyl-2-(4-phenylcyclohex-1- enyl)-[1,3,2]dioxaborolane (1.4 g), bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (0.06 g) and cesium fluoride (1. 92 g) in 1,4-dioxane (18 ml) and water (2 ml) was heated to 140 °C in microwave reactor for 20 minutes. The resulting mixture was diluted with saturated aqueous ammonium chloride and filtered to remove the precipitate. The filtrate was extracted with dichloromethane and the combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with a mixture of methanol and dichloromethane (0:01 - 1:20 by volume) to give the title compound 2a as an off-white solid (0.48 g). LCMS (Method A): Rt = 3.56 min. (M+H)' = 359. NMR (DMSO-D6): δ 11.06 (1H, s), 10.69 (1H, s), 7.23-7.21 (10H, m) , 5.84-5.79 (1H, m), 3.61 (2H, s), 3.57 (1H, s), 2.77-2.67 (1H, m), 2 .19-2.16 (3H, m), 1.84-1.81 (1H, m), 1.68-1.67 (1H, m). Examples 2-4: Preparation of 5-substituted 6-(4-phenylcyclohex-1-enyl)-1H-5-pyrimidine-2,4-diones
The intermediates shown in Table 1 were prepared following the procedures described in WO06014394, the contents of which are incorporated in this patent application by reference in their entirety. Table 1: Previously described chlorpyrimidinedione intermediates.

The examples shown in Table 2 were prepared using similar methods as described for Example 1, using intermediates 1a-lc in Table 1 in the final cross-coupling. Table 2: 5-substituted 6-(4-phenylcyclohex-1-enyl)-1H-pyrimidine-2,4-diones prepared via palladium-catalyzed cross-coupling.

Example 5: Preparation of (E)-5-Benzyl-6-(4-phenylcyclohexyl)-1H-pyrimidine-2,4-dione (3a)

(E)-5-Benzyl-6-(4-phenylcyclohexyl)-1H-pyrimidine-2,4-dione (3a). Solution of 5-benzyl-6-(4-phenylcyclohex-1-enyl)-1H-pyrimidine-2,4-dione (2a) (380 mg) in [5:2] mixture of IMS/DCM, was hydrogenated over Pd(OH) 2 (150 mg) and 10% Pd/C (100 mg) at 310 kPa at 50°C for 18 hours. The crude reaction mixture was degassed with argon, filtered through a pad of Celite and concentrated in vacuo to give a cream solid. 1H NMR showed a mixture of cis/trans isomers, part of which was separated into individual isomers, using a Synergy C18 elution column with 70-80% MeOH/water (+0.1% formic acid) for 20 minutes in then isocratic (80%) for another 5 minutes. LH NMR (cyclohexane bridgehead proton coupling constants), allowed the assignment of the first elution isomer as the trans isomer 3a and the second as the cis isomer 3bb. First elution 3a isomer: Rf = 10.86 min, (M+H)+ = 361. Second elution cis 3bb isomer: Rt = 11.01 min, (M+H) + - 3 61.
Example 6: Preparation of (E)-6-(4-phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione (3b)

(E)-4-Phenylcyclohexanecarboxylic acid (5).Mixture of (E)-4-(4-chlorophenyl)-cyclohexanecarboxylic acid (4) (15g) and 10% palladium on carbon (4g) in ethanol (400 ml) was stirred under a hydrogen atmosphere for 4 days. The reaction mixture was diluted with dichloromethane, filtered through Celite® and the filtrate concentrated under reduced pressure. The resulting residue was dissolved in ethanol (150 mL) and treated with 5M aqueous sodium hydroxide (25 mL). The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was treated with 1M aqueous hydrochloric acid (200 mL) and stirred for 15 minutes, then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to provide the title compound as a white solid (11g). 1 H NMR (CDClj): δ 7.27-7.25 (5 H, m), 2.52 (1 H, tt, J = 11.90, 3.44 Hz), 2.48-2.29 (1H, m), 2.17-2.14 (2H, m), 2.02-1.98 (2H, m), 1.56-1.55 (4H, m).

(E)-3-Oxo-3-(4-phenylcyclohexyl)-propionic acid ethyl ester (7). Mixture of (E)-4-phenylcyclohexanecarboxylic acid (5) (11 g), dimethylpyridin-4-yl-amine (7.3 g), 2,2-dimethyl-[1,3]dioxane-4,6 -dione (8.5 g) and 4 Å molecular sieve (2.0 g) in dichloromethane (200 mL) was stirred at room temperature for 10 minutes and then treated with dicyclohexylcarbodiimide solution (12.4 g) in dichloromethane (40 ml). The resulting mixture was stirred at room temperature for 1.5 hours and then filtered and the filtrate was washed with 1M aqueous hydrochloric acid solution and water, then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid was dissolved in ethanol (100 mL) and heated at reflux for 1.5 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with a mixture of ethyl acetate and cyclohexane (0:11 to 3:7 by volume) to provide the title compound as a white solid (11g) . NMR (CDCl3 ): δ 7.23-7.22 (5H, m), 4.25-4.17 (2H, m), 3.52 (2H, s), 2.54-2, 53 (2H, m), 2.09-1.99 (4H, m), 1.54-1.51 (4H, m), 1.32-1.25 (3H, m).

(Z)-2-(4-Phenylcyclohexanecarbonyl)-3-(3-trifluoromethylphenyl)-acrylic acid ethyl ester (10). 3-Oxo-3-(4-phenyl-cyclohexyl)-propionic acid ethyl ester (7) (11.56 g, 42.1 mmol), 3-trifluoromethylbenzaldehyde (11 g, 63.15 mmol), acetic acid glacial (7.16 mmol, 0.41 ml) and piperidine (2.1 mmol, 0.21 ml) were dissolved in toluene (250 ml) and heated under Dean and Stark conditions at reflux for 48 hours. The cooled reaction mixture was diluted with an equal volume of ethyl acetate and washed with IM aqueous HCl and brine. The organics were dried over sodium sulfate, filtered and evaporated to give a clear, brown oil. The residue was purified by silica gel column chromatography (gradient: 0 to 101 tert-butyl methyl ether in cyclohexane) to provide 12.3 g (68%) of (Z)-2-( 4-phenyl-cyclohexanecarbonyl)-3-(3-trifluoromethyl-phenyl)-acrylic. 1 H NMR (400 MHz, 192191), LCMS (method C) Rt = 4.77 min, (M+H)+ = 431.2.

3-Oxo-3-(4-phenylcyclohexyl)-2-(3-trifluoromethylbenzyl)-propionic acid ethyl ester (11). Mixture of (Z)-2-(4-phenylcyclohexanecarbonyl)-3-(3-trifluoromethylphenyl)-acrylic acid ethyl ester (10) (12.3 g, 28.6 mmol) and 10% Pd on carbon (2.5 g, 20% by weight) in denatured ethanol (250 mL) was stirred under a hydrogen atmosphere for 2 hours. The solids were removed by filtration through Celite and washed with ethanol. The filtrate was evaporated in vacuo to yield a clear oil. The residue was purified by silica gel column chromatography (gradient: 0 to 10% methyl tert-butyl ether in cyclohexane) to provide 8.6 g (70%) of 3-oxo-3-acid ethyl ester. -(4-phenylcyclohexyl)-2-(3-trifluoromethylbenzyl)-propionic (22). 'h NMR (400 MHz, 192227). LCMS (Method A), RL = 4.76 min, (M+Hf = 4 33.2 (94%), Rt = 5.22 mm, (M+H)" = 262.9 (6.5%) .

(E)-6-(4-phenylcyclohexyl)-2-thioxo-5-(3-trifluoromethylbenzyl)-2,3-dihydro-1H-pyrimidin-4-one (12a). Sodium (5 g, 217.8 mmol) and thiourea (18 g, 236 mmol) were dissolved in absolute ethanol (300 mL) and heated at reflux under nitrogen for 1 hour. The reaction mixture was cooled to 0 °C and 3-oxo-3-(4-phenylcyclohexyl)-2-(3-trifluoromethylbenzyl)-propionic acid ethyl ester (11) (15.7 g, 36.3 mmol) in absolute ethanol (150 ml) was added slowly (reaction mixture temperature <10°C). The reaction mixture was heated at reflux for 1.5 h. The reaction mixture was cooled, then evaporated in vacuo to a peach colored solid. The solid was suspended in water (500 mL) and adjusted to pH = 5 with glacial acetic acid. The resulting precipitate was isolated by filtration, redissolved in DCM and passed through a phase separation cartridge to remove water. The filtrate was evaporated to give an off-white solid which was triturated in hot methanol. The solid was recovered by filtration and dried under vacuum at 50°C to provide 4.8 g (30%) of the title compound. 1H NMR (400 MHz, 192268). LCMS (method C): R-. = 4.10 min, (M+H)+ = 444.9.

(E)-6-(4-phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione (3b). (E)-6-(4-phenylcyclohexyl)-2-thioxo-5-(3-trifluoromethylbenzyl)-2,3-dihydro-1H-pyrimidine-4-one (12a) (4.8 g, 10, 8 mmol) was suspended in dioxane (150 mL), and 10% (w/v) aqueous chloroacetic acid (100 mL) was added. The reaction mixture was heated to 100 °C, and more dioxane (25 mL) was added to effect complete dissolution. Heating was continued for 64 hours. The cooled reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, filtered and evaporated to give an off-white solid which was triturated in hot methanol. The solid was recovered by filtration and dried under vacuum at 50°C to obtain 3.7 g (80%) of the title compound. LH NMR (DMSO-d6): δ 11.12 (1H, s), 10.52 (1H, s), 7.61 (1H, s), 7.51 (3H, m), 7.30 -7.13 (5H, m), 3.83 (2H, s), 2.90 (1H, m), 1.83-1.80 (4H, m), 1.50-1 .40 (4H, m). LCMS (method B): R. = 5.26 min, (M+H)' = 429.01. Example 7: Preparation of (E)-5-(3-methylbenzyl)-6-(4-phenylcyclohexyl)-1H-pyrimidine-2,4-dione (3h)

(E)-2-(2-Ethylbenzyl)-3-oxo-3-(4-phenylcyclohexyl)-propionic acid ethyl ester (11a). Sodium hydride suspension (0.07 g) in tetrahydrofuran (10 mL) was treated with (E)-3-oxo-3-(4-phenylcyclohexyl)-propionic acid ethyl ester solution (7) (0.50 g) in tetrahydrofuran (8 ml), and the resulting mixture was stirred for 1 hour at room temperature. 1-Bromomethyl-2-ethylbenzene (0.38 g) was added and the resulting mixture was refluxed for 2 hours, cooled to room temperature and quenched by the addition of 1M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluted with a mixture of dichloromethane and cyclohexane (0:1 to 4:6 by volume) to provide the title compound (0.86 g). 1 NMR (CDCl 3 ) : δ 7.31-7.27 (1H, m), 7.17-7.16 (6H, m), 10 7.09-7.08 (2H, m), 4.16-4 .16 (2 H, m), 3.97 (1 H, t, J = 7.47 Hz), 3.22-3.21 (2 H, m), 2.68 (2 H, q, J = 7.55 Hz), 2.41-2.41 (2H, m), 1.94-1.92 (3H, m), 1.75-1.68 (1H, m), 1 .54 (1H, s), 1.40-1.39 (3H, m), 1.27-1.18 (6H, m).

(E)-2-(3-Methylbenzyl)-3-oxo-3-(4-phenylcyclohexyl)-propionic acid ethyl ester (IIh). The title compound was prepared as described for compound 11a above. :H NMR (CDCl3 ): 7.29 (2H, m), 7.17-7.12 (4H, m), 7.02-6.95 (3H, m), 4.16 (2 H, qd, J = 7.13, 2.38 Hz), 3.95 (1 H, t, J = 7.51 Hz), 3.13 (2 H, dd, J = 7.52, 2, 32 Hz), 2.45 (2H, m), 2.31 (3H, s), 1.97-1.94 (3H, m), 1.80-1.73 (1H, m ), 1.53-1.27 (4H, m), 1.22 (3H, t, J = 7.13 Hz).

(E)-6-(4-phenylcyclohexyl)-2-thioxo-5-(3-methylbenzyl)-2,3-dihydro-1H-pyrimidin-4-one (12 g). The title compound was prepared from compounds 11h as described for compound 12a above. LCMS (method A): Rt = 4.07 min, (M+H)+ = 391.

(E)-5-(3-methylbenzyl)-6-(4-phenylcyclohexyl)-1H-pyrimidin-2,4-dione (3h). The title compound was prepared from compound 12g as described for compound 3B above. NMR (DMSO-dJ: 11.06 (1H, s), 10.46 (1H, s), 7.32-7.24 (2H, m), 7.18-7.16 (4H , m), 7.00-6.98 (3H, m), 3.68 (2H, s), 2.90-2.79 (1H, m), 2.48-2.44 ( 1H, m), 2.25 (3H, s), 1.91-1.73 (4H, m), 1.46-1.43 (4H, m).LCMS (method B), Rt = 5.17 min, (M+H)+ = 375. Examples 8-34: Preparation of 5-substituted (E)-6-(4-cyclohexyl)-1H-pyrimidine-2,4-diones
Intermediates 11 in Table 3 below were prepared from 7B as described for compound 11 in Example 7. Table 3: 2-Substituted (E)-3-oxo-3-(4-phenylcyclohexyl)-propionic acid ethyl esters .












Intermediates 11 were converted to intermediates 12 in Table 4 below, as described for the preparation of 12a in Example 6.Example 6: Preparation of (E)-6-(4-phenylcyclohexyl)-5-(3-trifluoromethylbenzyl) -1H-pyrimidine-2,4-dione (3b) Table 4: Substituted 2-Thioxo-2,3-dihydro-pyrimidine-4-ones.






Intermediates 12 were converted to compounds 3 of Table 5 below, as for the preparation of compounds 3b in Example 6.Example 6: Preparation of (E)—6—(4-phenylcyclohexyl)-5-(3-trifluoromethylbenzyl) ) - 1H-pyrirvidin-2,4-dione (3b) Table 5: 5-substituted (E)-6-(4-cyclohexyl)-1H-pyrimidine-2,4-diones.



















Example 35: (E)-3-Methyl-5-(3-methylbenzyl)-6-(4-phenylcyclohexyl)-1H-pyrimidine-2,4-dione (13a)

(E)-3-methyl-5-(3-methylbenzyl)-6-(4-phenylcyclohexyl)-1H-pyrimidine-2,4-dione (13a). Sodium hydride (2.1mg, 0.053mmol) was added to a solution of compound 3h (20mg, 0.053mmol) in dry DMF (2ml), followed by the addition of 3.3µl (0.053mmol) Mel. The mixture was stirred at room temperature for 16h. more leg. of NaH and Honey was added over the next 24h. The contents were diluted with water (0.5 mL) and concentrated in vacuo, and the resulting residue was purified by preparative liquid chromatography (C18 column eluted with 30-95% CH3CN/H2O + 0.1% formic acid) to provide the title product (13mg) after lyophilization. 1 H NMR δ (ppm) (DMSO-dg/: 10.76 (1H, s), 7.28 (2H, m), 7.18-7.17 (4H, m), 7.05 -6.92 (3 H, m), 3.74 (2 H, s), 3.16 (3 H, s), 2.90 (1 H, s), 2.25 (3 H, s) , 1.90-1.78 (4H, m), 1.48 (4H, m) LCMS (Method B): Rt = 5.56 minutes, (M+H)' = 389. Examples 36-42: Preparation of (E)-3-Alky1-6-(4-cyclohexyl)-1H-pyrimidine-2,4-diones 5-substituted
Examples of compounds in Table 6 below were prepared from the appropriate compounds of 3 with the necessary alkylating agents, such as those described below for Examples 38-41. For related reactions describing alkylation of amines, see pages 397-408 of Larock, R.C. Comprehensive Organic Transformations.
New York: VCH Publishers, Inc., 1989, the contents of which are incorporated in this patent application by reference in its entirety.Table 6: (E)-3-alkyl-6-(4-cyclohexyl)-1H-pyrimidine- 2,4-5 5-substituted diones.







Example 38. Preparation of (E)-3-Methyl-6-(4-phenyl-cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2,4-dione (13d)

Sodium hydride (6 mg, 0.14 mmol) was added to a solution of (E)-6-(4-phenyl-cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2, 4-dione (3b) (50 mg, 0.117 mmol) in dry DMF (3 mL), followed by the addition of 9 pL of 1 methyl odide (0.14 mmol) after 30 minutes. The reaction mixture 10 was stirred at room temperature for 18 hours. Additional 0.2 equivalents of NaH and Mel was added and stirring continued for 2 hours and 25 minutes. Then the contents were diluted with water (10 ml). The mixture was extracted with ethyl acetate (2 x 20 ml) and the organic phases were dried (Na2SO4), filtered and evaporated. The residue was recrystallized from boiling methanol to provide 10.2 mg of product. Rt = 5.63 minutes.Example 39. Preparation of (E)-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-6-(4-phenyl-cyclohexyl)-5-(3 - i trifluoromethyl-benzyl)-1H-pyrimidine-2,4-dione (13e)

Sodium hydride (18mg, 0.46mmol) was added to a solution of (E)-6-(4-phenyl-cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2.4 -dione (3b) (150 mg, 0.35 mmol) in dry DMF (5 mL), followed by the addition of 9L (0.14 mmol) of (2-bromo-ethoxy)-tert-butyl-dimethyl-silane then for 25 minutes at 80°C. The reaction mixture was stirred at 80°C for 18 h. Supplement of 2.5 equivalents of NaH and Mel was. triggered over 24 hours. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (4 x 10 ml), then the organic phase was dried (Na2SO4), filtered and evaporated. The material was purified by column chromatography eluted with a mixture of ethyl acetate and cyclohexane (0:1 - 1:0 by volume) to yield 57mg of the title compound. Rt = 5.09 minutes. Example 40. Preparation of (E)-3-(2-hydroxy-ethyl)-6-(4-phenyl-cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2,4-dione (13f)

Tetrabutylammonium fluoride (1M in THE, 141 pL.0.141 mmol) was added to a stirred solution of (E)-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-6-(4-phenyl - cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2,4-dione (13f) (55 mg, 0.094 mmol) in THE (5 mL). The reaction mixture was stirred for 1 hour and then allowed to stand for 5 days. Water (10 ml) was added and the mixture was extracted with diethyl ether (2 x 10 ml). The organics were dried (Na2SO4), filtered and evaporated. The material was purified by column chromatography eluted with a mixture of ethyl acetate and cyclohexane (0:1 - 1:0 by volume) to yield 20 mg of the title compound. Rf = 5.28 minutes. Example 4L Preparation of (E)-3-(2-methoxy-ethyl)-6-(4-phenyl-cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2,4 - 20 dione (13 g)

Sodium hydride (13 mg, 0.316 mmol) was added to a solution of (E)-6-(4-phenyl-cyclohexyl)-5-(3-trifluoromethyl-benzyl)-1H-pyrimidine-2,4- dione (3b) (104 mg, 0.243 mmol) in dry DMF (4 mL), followed by the addition of 30 µL (0.316 mmol) of 1-bromo-2-methoxyethane after 30 minutes. The reaction mixture was stirred at 80°C for 42 hours. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3 x 10 ml), then the organic phases were dried (Na 2 SO 4 ), filtered and evaporated. The material was purified by column chromatography eluted with a mixture of ethyl acetate and cyclohexane (0:1 - 1:0 by volume), then further purified by preparative LC (C18 column eluted with 10-98% CH3CN/ H2O + 0.1% formic acid, to produce 7 mg of the product, after lyophilization. Rt = 5.70 minutes. "1 Example 43: Glucocorticoid Receptor Binding Assay
The following is a description of an assay to determine the inhibition of dexamethasone binding to the Human Recombinant Glucocorticoid Receptor.
Binding Protocol: Compounds were tested in a binding displacement assay using recombinant human glucocorticoid receptor with 3 H-dexamethasone as the ligand. The source of the receptor was recombinant baculovirus-infected insect cells. This GR was a full-length steroid hormone receptor likely associated with heat shock protein and other endogenous proteins.
The assay was performed in 96-well polypropylene V-bottom plates with a final volume of 100 μL of solution containing 0.5 nM GR, 2.5 nM 3H-dexamethasone (Perkin Elmer NET119200) in the presence of test compounds, vehicle of test compound (for total binding) or excess dexamethasone (20 µM, to determine non-specific binding) in appropriate volume of assay buffer.
For IC50 determinations, test compounds were tested at 6 concentrations in duplicate. Test compounds were diluted from 10 mM starting material in 100% DMSO. Tested solutions were prepared with 2x the final assay concentration in 2% DMSO/assay buffer.
All reagents and the assay plate were kept on ice during reagent addition. Reagents were added to the wells of a V-bottom polypropylene plate in the following order: 25 μL of 10 nM 3H-dexamethasone solution, 50 μL of TB/NSB/Compound solution, and 25 μL of 2 nM solution of GR After the additions, the incubation mixture was mixed and incubated for 2.5 hours at 4°C. °
After 2.5 hours of incubation, unbound counts were removed with dextran-coated charcoal (DCC) as follows: 15 μL of DCC solution (DCC at 10°6 in assay buffer) was added to all wells and mixed (total volume 115 μL). The plate was centrifuged at 4000 rpm for 10 minutes at 4°C. 7 5μL of the supernatants is carefully pipetted into an OptiPlate. 150 µL of scintillation cocktail (Microscint-40, Perkin Elmer) was added. The plate was shaken vigorously for approx. 10 minutes and counted to obtain IC50 values (compound concentration that shifts 50% of bound counts). IC50 values were converted to Ki (inhibition constant) using the Cheng-Prusoff equation. The test results are shown in Table 7.
Reagents: Assay buffer: 10 mM potassium phosphate buffer pH 7.6, containing 5 mM DTT, 10 mM sodium molybdate, 100 µM EDTA and 0.1% BSA. Example 44: GR Functional Assay using > SW1353/MMTV-5 cells
SW1353/MMTV-5 is an adherent human chondrosarcoma cell line that contains endogenous glucocorticoid receptors. She was transfected with a plasmid (pMAMneo-Luc) encoding firefly luciferase located behind a glucocorticoid response element (GRE) derived from a viral promoter (mouse mammary tumor virus long terminal repeat). A stable cell line SW1353/MMTV-5 was selected with geneticin, which was required to maintain this plasmid. This cell line was therefore sensitive to glucocorticoids (dexamethasone) which directs luciferase expression (EC5ndex 10 nM). This dexamethasone-induced response was gradually lost over time, and a new culture from a previous subculture was started (from a cryo-stored aliquot) every three months and s.
In order to test for GR antagonist, SW1353/MMTV-5 cells were incubated with various dilutions of compounds in the presence of 5xECiOdex (50nM), and inhibition of induced luciferase expression was measured using luminescence detected on a Topcount (Britelite Plus kit , Perkin Elmer). For each assay, a dose-response curve for dexamethasone was prepared in order to determine the EC50dex required to calculate the Ki of the IC50's of each tested compound.
SW1353/MMTV-5 cells were distributed in 96-well plates and incubated in medium (geneticin-free) for 24 hours. Dilutions of compounds in medium + 50 nM dexamethasone were added and the plates were again incubated for a further 24 hours, after which 10 luciferase expression was measured.Table 7: Activity data for selected compounds.










In Table 7, GR binding compounds with Ki value of less than 5.0 nM are flagged with + + + ; compounds with nm Ki value from 5.0 nM to 10.0 nM are flagged with + + , and compounds with a Ki value greater than 10 nM are flagged with +. GR functional compounds with a Ki value of less than 50 nM are designated as + + + , compounds with a Ki value of 50 nM to 100 nM are designated as i +4-, and compounds with a Ki value of greater than 100 nM are designated as designated with +.
While the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided is incorporated into the present patent application 5 by reference in its entirety to the same extent as if each reference were incorporated by reference individually. Where there is a conflict between the patent application under consideration and a reference in this patent application, the patent application under consideration must 10 overlap.

权利要求:
Claims (13)
[0001]
1. Compound of formula I:
[0002]
The compound of claim 1, characterized in that it has formula Ia, Ib or Ic:
[0003]
The compound of claims 1 to 2, characterized in that R 1 is selected from the group consisting of aryl and heteroaryl.
[0004]
The compound of any of claims 1 to 3, characterized in that R 1 is selected from the group consisting of phenyl, pyridyl, pyrimidine, and thiazole.
[0005]
The compound of any one of claims 1 to 4, wherein each R1a is independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkyl, -NR1bR1c, and -SO2R1b.
[0006]
The compound of any one of claims 1 to 5, characterized in that each R1a is C1-6 haloalkyl.
[0007]
The compound of any of claims 1 to 5, wherein each R1a is independently selected from the group consisting of H, Me, Et, -OMe, F, Cl, -CF3, -NMe2, and -SO2Me.
[0008]
The compound of any one of claims 1 to 5, characterized in that each R1a is -CF3.
[0009]
The compound of any of claims 1 to 8, characterized in that R 2 is selected from the group consisting of H and C 1-6 alkyl.
[0010]
10. Compound of claim 1, characterized in that it is selected from the group consisting of:
[0011]
11. Compound of claim 1, characterized in that it has the formula:
[0012]
12. Pharmaceutical composition characterized by: comprising pharmaceutically acceptable excipient and compound of any of claims 1 to 11.
[0013]
13. Use of the compound of any of claims 1 to 11, characterized in that it is for the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease, increased cognition, Cushing's syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, diseases inflammation, osteoarthritis, rheumatoid arthritis, asthma and rhinitis, diseases related to adrenal function, viral infection, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing, compulsive behavior, multidrug resistance, addiction, psychosis, anorexia, cachexia, syndrome post-traumatic stress disorder, post-surgical bone fracture, medical catabolism, psychotic depression, mild cognitive impairment, psychosis, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in depressed patients, cognitive impairment in individuals with Down syndrome, psychosis associated with interferon-alpha therapy, chronic pain, pain associated with gastroesophageal reflux disease, postpartum psychosis, postpartum depression, neurological disorders of premature newborns, and migraine.

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法律状态:
2016-08-09| B15I| Others concerning applications: loss of priority|Free format text: PERDA DA PRIORIDADE US61/454,289 DE 18/03/2011 REIVINDICADA NO PCT/US2012/029376 , CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 167O, ITEM 28 DO ATO NORMATIVO 128/97 E NO ART. 29 DA RESOLUCAO INPI-PR 77/2013. ESTA PERDA SE DEU PELO FATO DE O DEPOSITANTE CONSTANTE DA PETICAO DE REQUERIMENTO DO PEDIDO SER DISTINTO DAQUELE QUE DEPOSITOU A PRIORIDADE REIVINDICADA E NAO APRESENTOU DOCUMENTO COMPROBATORIO DE CESSAO, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 166O, ITEM 27 DO ATO NORMATIVO 128/97 E NO ART. 28 DA RESOLUCAO INPI-PR 77/2013. |

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2016-12-27| B12F| Other appeals [chapter 12.6 patent gazette]|

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2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-07-02| 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 |

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2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-07-20| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-08-24| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A01N 43/54 , A61K 31/505 , A61K 31/497 , C07D 401/00 Ipc: A61K 31/505 (2006.01), A61K 31/497 (2006.01), C07D |

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2021-10-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-01-11| 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 16/03/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161454289P| true| 2011-03-18|2011-03-18|

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US61/454,289|2011-03-18|

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PCT/US2012/029376|WO2012129074A1|2011-03-18|2012-03-16|Pyrimidine cyclohexyl glucocorticoid receptor modulators|

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