WO2006134481A1 - Inhibiteurs de la 11-beta hydroxysteroide deshydrogenase de type 1 - Google Patents

Inhibiteurs de la 11-beta hydroxysteroide deshydrogenase de type 1 Download PDF

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Publication number
WO2006134481A1
WO2006134481A1 PCT/IB2006/001607 IB2006001607W WO2006134481A1 WO 2006134481 A1 WO2006134481 A1 WO 2006134481A1 IB 2006001607 W IB2006001607 W IB 2006001607W WO 2006134481 A1 WO2006134481 A1 WO 2006134481A1
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compound
aryl
alkyl
groups
substituted
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PCT/IB2006/001607
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English (en)
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Hengmiao Cheng
Klaus Ruprecht Dress
Buwen Huang
Stanley William Kupchinsky
Phuong Thi Quy Le
Christopher Ronald Smith
Yong Wang
Yi Yang
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Pfizer Inc.
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Publication of WO2006134481A1 publication Critical patent/WO2006134481A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds and compositions for the treatment of conditions mediated by 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11 ⁇ HSD1).
  • 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme 11 ⁇ HSD1
  • Type 2 diabetes is a major health concern with an estimated 150 million people affected worldwide. Characteristics of Type 2 diabetes are insulin resistance, hyperglycemia and hyperinsulinaemia. Although there are several marketed drugs that partially lower plasma glucose levels and improved insulin sensitivity, there is still a need for more effective therapies with fewer side effects. Many research labs are studying novel biological mechanisms that influence this disease. One biological target that has gained a lot of attention is 11 ⁇ HSD1 because of the role it plays in gluconeogenesis and insulin sensitivity.
  • Gluconeogenesis the de novo synthesis of glucose from non-carbohydrate precursors, primarily occurs in the liver and is abnormally high in Type 2 diabetes. Hepatic glucose output is poorly regulated by insulin in the late stages of the disease, which results in higher serum glucose levels. Hepatic glucose output attributed to gluconeogenesis in Type 2 diabetic patients may reach as high as 90%, whereas in healthy patients only 25% of glucose output is a result of gluconeogenesis.
  • GR glucocorticoid receptor
  • 11 ⁇ HSD1 plays a role in ligand-induced activation of GR by raising the tissue specific concentration of Cortisol. It does this by catalyzing the reduction of the 11-keto group found on inactive cortisone using NAD(P)H as the cofactor. Increased activity of 11 ⁇ HSD1 therefore leads to an increase In GR activation.
  • 11 ⁇ HSD1 activity affects adipocytes where, for example, it decreases insulin-dependent glucose uptake and increases lipolysis. Expression of 1 1 ⁇ HSD1 in visceral fat is higher than in subcutaneous fat. Visceral obesity is strongly correlated with insulin resistance and the metabolic syndrome.
  • 11 ⁇ HSD1 11 ⁇ HSD1 and therefore, are useful in the treatment of type 2 diabetes, obesity, ophthalmic diseases, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and metabolic diseases.
  • the present invention provides compounds having formula (I):
  • R 1 is pyridine substituted with 1 to 3 R 7 groups; or R 1 is
  • W is C or N, and R 1 is substituted with O to 3 R 7 groups;
  • R 2 and R 3 form a 5, 6 or 7-membered saturated ring containing 1 or 2 heteroatoms each independently selected from N, O or S 1 and the 5, 6 or 7 membered saturated ring is substituted with O to 4 R 7 groups;
  • R 4 is selected from hydrogen, hydroxyl, halogen, (C 1 -C 6 JaIkOXy and and R 4 is optionally substituted with O to 4 R 7 groups;
  • each R 7 is substituted with O to 4 R 10 groups; each j, k and m are independently O, 1 , 2 or 3; and each R 8 and R 9 are independently selected from hydrogen, (C r C 6 )alkyl, (CR 5 R 6 ) p (C 6 -C 10 )aryl or (CR 5 R 6 )p(5-10)-membered heterocyclyl; each R 10 is independently selected from hydroxyl, halogen, cyano, amino, azido, nitro, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (C r C 6 )alkoxy, (C ⁇ CeJalkyl, (C 2 -C 6
  • the present invention provides compounds of formula I, wherein R 1 is pyridine
  • the present invention provides compounds of formula I, wherein R 1 is benzo[b]th ⁇ ophene
  • the present invention provides compounds of formula I, wherein R 2 and R 3 form a pyrrolidine, pipe ⁇ dine or morpholine ring
  • the present invention provides compounds of formula I, wherein the compound is selected from
  • the present invention provides compounds of formula I, wherein the compound is selected from - A -
  • the present invention provides compounds of formula I 1 wherein the compound is selected-from:
  • R 1 is naphthyl or is wherein Q and Z are each independently C or N, but are not both N, and wherein R 1 is substituted with O to 4 R 10 groups;
  • R 4 is selected from hydrogen, hydroxyl, halogen, (C 1 -C 6 )BIkOXy and (C ⁇ CeJalkyl, and R 4 is optionally substituted with O to 4 R 10 groups;
  • R 5 and R 6 are each independently selected from hydrogen and (C 1 -C 6 )alkyl;
  • the present invention provides compounds of formula II, wherein R 1 is
  • R 7 is either benzyl or pyridine.
  • Q is C and Z is N.
  • Q is N and Z is C.
  • R 1 is naphthyl substituted with 1 to 4 R 10 groups.
  • the present invention provides pharmaceutical compositions comprising an effective amount of the compound of formula 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides methods for treating conditions that are mediated by the modulation of 11 ⁇ HSD1 , comprising administering to a mammal an effective amount of the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides methods for treating conditions that are mediated by the modulation of 11 ⁇ HSD1 , wherein the condition is diabetes, metabolic syndrome, insulin resistance syndrome, obesity, ophthalmic diseases, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.
  • the condition is diabetes, metabolic syndrome, insulin resistance syndrome, obesity, ophthalmic diseases, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.
  • the present invention provides methods for treating glaucoma comprising administering to a mammal an effective amount of an inventive compound in combination with a prostanoid receptor agonist, wherein said agonist is latanoprost.
  • alkyl refers to a linear, branched, or cyclic saturated hydrocarbon group containing 1 to about 24 carbon atoms, preferably 1 to about 12 carbon atoms, including groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.
  • lower alkyl means an alkyl group of 1 to 6 carbon - Q -
  • substituted alkyl refers to an alkyl group which is substituted with one or more substituent groups
  • heteroatom containing alkyl refers to an alkyl group which is substituted with one or more heteroatoms.
  • alkyl and lower alkyl include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively.
  • alkenyl refers to a linear, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyi, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • Preferred alkenyl groups herein contain 2 to about 12 carbon atoms.
  • lower alkenyl intends an alkenyl group of 2 to 6 carbon atoms
  • cycloalkenyl intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom- containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.
  • alkenyl and lower alkenyl include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to about 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Preferred alkynyl groups herein contain 2 to about 12 carbon atoms.
  • lower alkynyl intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups
  • heteroatom-containing alkynyl and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.
  • alkynyl and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • cycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms.
  • cycloalkyls include monocyclic rings having from 3-10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; fused rings having from 6 to 10 carbon atoms such tetrahydrodecalin and tetrahydronaphthalene; and bicyclic rings having from 6 to 10 carbon atoms such as norbornane, norbornene and adamantane.
  • Illustrative examples of cycloalkyls include but not limited to:
  • aryl or "(C 6 -C 10 )aryl
  • aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Preferred aryl groups contain 6 to 10 carbon atoms.
  • Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, and the like.
  • “Substituted aryl” refers to an aryl moiety substituted with one or more substituent groups.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • heteroaryl or “(5-10)-membered heteroaryl”, unless otherwise indicated, includes aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heteroaryl group has from 5 to 10 atoms in its ring system.
  • heteroaryl groups include but are not limited to pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1 ,2,4-triazolyl, tetrazolyl, and the like.
  • heterocyclic includes aromatic and non- aromatic heterocyclic groups containing 3 to 10 atoms in their ring systems.
  • Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, whereas aromatic heterocyclic groups have at least 5 atoms in their ring system.
  • the heterocyclic groups also include benzo-fused ring systems.
  • An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolin
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • the 4-7 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1 ,1-dioxo-thiomorpholinyl.
  • the terms “optional” or “optionally”, unless otherwise indicated means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • solvate refers to pharmaceutically acceptable solvate forms of a specified compound that retains the biological effectiveness of such compound.
  • examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.
  • the phrase "pharmaceutically acceptable salt(s)”, unless otherwise indicated, refers to salts of acidic or basic groups which may be present in the compounds of formula (I).
  • the compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edeta.te, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate ' , malate, maleate, mandelate, me
  • Certain compounds of formula (I) may have asymmetric centers and therefore exist in different diastereomeric and/or enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention.
  • the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof.
  • the compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
  • chiral refers to a structure that does not have an improper rotation axis (S n ), i.e., it belongs to point group C n or D n . Such molecules are thus chiral with respect to an axis, plane or center of asymmetry.
  • Preferred "chiral" molecules herein are in enantiomerically pure form, such that a particular chiral molecule represents at least about 95 wt. % of the composition in which it is contained, more preferably at least about 99 wt. % of that composition.
  • the desired enantiomer represents at least about 80 wt. % of the product, more preferably at least about 85 wt. % of the product, optimally at least about 95 wt. % of the product.
  • protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene et al., Protective Groups in Organic Synthesis (New York: Wiley, 1991).
  • Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labeled compounds of formula (I) of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
  • the term "diseases in which the liver is a target organ" means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria.
  • the term "metabolic syndrome" means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxy butyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
  • modulate refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/ m 2 , and for females, as individuals whose body mass index is greater than 27.3 kg/m 2 .
  • the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
  • inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
  • the phrase "therapeutically effective amount”, unless otherwise indicated, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • insulin resistance refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
  • insulin resistance syndrome refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
  • NIDDM non insulin dependent diabetes mellitus
  • ophthalmic diseases refers to diseases of the eye including but not limited to glaucoma, age related macular degeneration including exudative (wet AMD) and non-exudative (dry AMD), choroidal neovascularization, retinopathies such as diabetic retinopathy, retinitis pigmentosa and retinopathy of prematurity, diabetic macular edema, retinitis, uveitis, cystoid macular edema, glaucoma, and other diseases or conditions of the eye.
  • inventive compositions may be used to form a drug depot behind the eye and may include one or more pharmaceutically active agents, in addition to one or more non-active excipients as described herein.
  • pharmaceutically active agents useful in the inventive compositions includes anti-infectives, including, without limitation, antibiotics, antivirals, and antifungals; antiallergenic agents and mast cell stabilizers; steroidal and nonsteroidal anti-inflammatory agents (such as nepafenac); cyclooxygenase inhibitors, including, without limitation, Cox I and Cox Il inhibitors; combinations of anti- infective and anti-inflammatory agents; decongestants; anti-glaucoma agents, including, without limitation, adrenergics, beta-adrenergic blocking agents, alpha-adrenergic agonists, parasypathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and prostaglandins; combinations of anti- glaucoma agents; antioxidants;
  • a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
  • a compound of the invention may also be injected directly into the vitreous humor or aqueous humor.
  • a compound of the present invention may be also be administered by well known, acceptable methods, such as sub-Tenon and/or subconjunctival injections.
  • the macula is comprised primarily of retinal cones and is the region of maximum visual acuity in the retina.
  • a Tenon's capsule or Tenon's membrane is disposed on the sclera.
  • a conjunctiva covers a short area of the globe of the eyeposterior to the limbus (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of the upper eyelid and lower eyelid, respectively.
  • the conjunctiva is disposed on top of Tenon's capsule.
  • the sclera and Tenon's capsule define the exterior surface of the globe of the eye.
  • ocular diseases such as age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD), choroidal neovascularization, retinopathies (such as diabetic retinopathy, retinopathy of prematurity), diabetic macular edema, retinitis, uveitis, cystoid macular edema (CME), glaucoma, and other diseases or conditions of the posterior segment of the eye, it is preferable to dispose a depot of a specific quantity of an ophthalmically acceptable pharmaceutically active agent directly on the outer surface of the sclera and below Tenon's capsule.
  • the compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned sub-Tenon or intravitreal injection.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eye-drop form.
  • the solution or suspension may be prepared in its pure form and administered several times daily.
  • the present compositions, prepared as described above, may also be administered directly to the cornea.
  • the composition is prepared with a muco-adhesive polymer that binds to cornea.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) contains VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used i ⁇ stead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes' and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained- release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid- or gel-phase carriers or excipients.
  • suitable solid- or gel-phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • the preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention.
  • non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
  • This coupling step is accomplished using a suitable solvent such as CH 2 CI 2 or DMF, and advantageously, in the presence of a suitable base such as pyridine or triethyla ⁇ nine, and at temperatures ranging from about -78 0 C to about 10O 0 C.
  • a suitable solvent such as CH 2 CI 2 or DMF
  • a suitable base such as pyridine or triethyla ⁇ nine
  • the R 1 and pyrrolidine amino group may be functionalized by first coupling the sulfonyl chloride compound of formula D with the amino protected pyrrolidine compound of formula E (the use of amino protecting groups (PG) and their subsequent removal are well known to those skilled in the art), using suitable reaction conditions such as those described above, to provide the pyrrolidine sulfonyl compound of formula F:
  • the R 1 group may be functionalized using Suzuki or Heck reaction conditions.
  • reaction of the compound of formula F under Suzuki conditions using the boronic acid R 7 B(OH) 2 and catalyzed by metal catalysts such as [1 ,1-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex or bis(triphenylphosphine)dichloropalladium, in a suitable solvent such as DMF or DMCA and water, in the presence of a base such as potassium carbonate or cesium carbonate and at a temperature ranging from about room temperature to about 140 0 C under conventional conditions or microwave conditions, provides the R 7 substituted compound of formula G:
  • Functionalization of the secondary amino group is accomplished by exposure of the compound of formula H to R 3 X, wherein X is a leaving group as described above, in a suitable solvent such as CH 2 Cl 2 or DMF, and advantageously, in the presence of a base such as potassium carbonate, sodium bicarbonate or triethylamine, ranging from about room temperature to about the boiling point of the solvent, typically from about 20 degrees 0 C to about 100 0 C, to provide the compound of formula I.
  • a suitable solvent such as CH 2 Cl 2 or DMF
  • a base such as potassium carbonate, sodium bicarbonate or triethylamine
  • the compounds described herein may be prepared through use of the hydroxy pyrrolidine compound of formula J. Coupling of the sulfonyl chloride compound of formula D with the hydroxyl pyrrolidine compound of formula J, using suitable reaction conditions as described above, provides the pyrrolidine sulfonyl compound of formula K
  • hydroxy protecting groups may be used in these steps as the use of such groups are well known to those skilled in the art.
  • R 1 aryl or heteroaryl group may be functionalized using Heck or Suzuki reaction conditions to provide the compound of formula L
  • a suitable solvent e.g. dichloromethane or N 1 N- dimethyl formamide
  • a base e.g. potassium carbonate, sodium bicarbonate or triethylamine
  • the compound of formula Q may be prepared by oxidation of the compound of formula O using methods well known to those skilled in the art to provide the keto compound of formula P.
  • Reductive amination of the compound of formula P with an amine of formula R 2 R 3 NH in a suitable solvent such as CH 2 CI 2 , methanol (MeOH) or tetrahydrofuran (THF) in the presence of an acid such as acetic acid and a reducing agent such as NaBCNH 3 or NaB(OAc) 3 H at a temperature ranging from about room temperature to about 60 0 C, provides the tertiary amino compound of formula Q
  • the compounds of formula (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline- earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I).
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the compounds of the present invention may be modulators of 11 ⁇ HSD1.
  • the compounds of the present invention may modulate processes mediated by 1 1 ⁇ HSD1 , which refer to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the 11 (3HSD1 inhibitors described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g.
  • ischemic heart disease and the like cell injury (e.g.) brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
  • inflammatory diseases e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, e
  • the compounds according to the present invention may be used in several indications which involve modulations of 11 ⁇ HSD1 enzyme.
  • the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical
  • Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 ⁇ HSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S. C, et al. 1998) Science, 280: 1378-1383).
  • Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B. C. J. Sutter (1979) Horm. Metab. Res. 11 : 555-560). Thus, inhibition of 11 ⁇ HSD1 is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat.
  • the enzyme 11 ⁇ HSD1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., C. R. W. Edwards, and J. R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl, J. R., Front. (2000) Neuroendocrine/. 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11 ⁇ HSD1 inhibitor.
  • glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W. (1999) Baillier's Clin. Endocrinol. Metab. 13: 576-581).
  • HPA hypothalamo-pituitary-adrenal
  • the balance between the cell- mediated response and humoral responses is modulated by glucocorticoids.
  • a high glucocorticoid activity such as at a state of stress, is associated with a humoral response.
  • inhibition of the enzyme 11 ⁇ HSD1 has been suggested as a means of shifting the response towards a cell-based reaction.
  • 11 ⁇ HSD1 In the eye, expression of 11 ⁇ HSD1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris.
  • the distant isoenzyme 11 beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage.
  • 11 ⁇ HSD1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
  • Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess.
  • Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, C. H., S. L. Cheng, and G. S. Kim (1999) J. Endocrinol. 162: 371-379).
  • the negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11 ⁇ HSD1 in the glucocorticoid effect (Bellows, C. G., A. Ciaccia, and J. N. M. Heersche, (1998) Bone 23: 119-125).
  • the compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension.
  • the reaction mixture for the assay includes 500 ⁇ M NADPH, about 6nM 11 ⁇ HSD1 (based on active site titration with potent reversible inhibitor), 1 % DMSO (inhibitor), 2mM G6P, 1 U/ml G6P dehydrogenase, and 6mM MgCI 2 .
  • G6P, G6P dehydrogenase and MgCI 2 act as a regeneration system to amplify 11 ⁇ HSD1 activity.
  • NADPH and 11 ⁇ HSD1 were incubated in buffer for 30 minutes in the presence of inhibitor at 25 celcius prior to the addition of the regeneration system and initiation with 3 H-cortisone.
  • Initial reaction velocities were measured by stopping the reaction at various time points between 0 and 60 minutes by mixing 60 ⁇ l of sample with 60 ⁇ l of DMSO.
  • These samples were then analyzed by reversed phase liquid chromatography by injecting 15 ⁇ l of sample into a Jupiter C18, 150 x 4.6mm, 5 micron, 300 A 0 Phenomenex column, while running an isocratic method of 34:66 methanol to water at 1.25ml/min.
  • the ⁇ -Ram model 3 pumps at a 3:1 liquid scintillation cocktail to eluate ratio, and a 3 H signal is subsequently measured by the area of the peak observed.
  • 3 H-cortisone comes off at approximately 7 minutes, while the 3 H-cortisol product of the 11 ⁇ HSD1 reaction comes off at approximately 9 minutes.
  • the area of 3 H-cortisol is then plotted versus time to determine a linear velocity and this rate can then be plotted to inhibitor concentration to determine a Ki and IC 50 .
  • [1 ,2-3H]-cortisone was purchased from American Radiolabeled Chemicals Inc. NADPH, Glucose- 6-Phosphate (G6P), and Glucose-6-Phosphate dehydrogenase were purchased from Sigma.
  • the K] values of the compounds of the present invention for the 11 ⁇ HSD1 enzyme may lie typically between about 10 nM and about 10 ⁇ M.
  • the compounds of the present invention that were tested all have Kj's in at least one of the above SPA assays of less than 1 ⁇ M, preferably less than 100 nM.
  • Certain preferred groups of compounds possess differential selectivity toward the various H ⁇ HSD's.
  • One group of preferred compounds possesses selective activity towards 11 ⁇ HSD1 over 11 ⁇ HSD2.
  • Another preferred group of compounds possesses selective activity towards 11 ⁇ HSD2 over 11 ⁇ HSD1.
  • the amino heterocyclyl compounds of formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of 11 ⁇ HSD1 mediated diseases.
  • the compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs.
  • the compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets.
  • these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
  • a pharmaceutically acceptable enteric coating such as glyceryl monostearate or glyceryl distearate
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension.
  • Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a • long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate.
  • a suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the amino heterocyclyl compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and other glycerides.
  • the amino heterocyclyl compounds of formula (I) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles.
  • Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight.
  • a preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the column used is an Alltech Platinum EPS 100A 1.5 micron C18 column; 33mm x 7mm.
  • the samples are run on a Hewlett Packard- 1100 system.
  • a gradient solvent method is used running 5% acetonitrile in water (0.1 % trifluoroacetic acid) to 95% acetonitrile in water (0.1 % trifluoroacetic acid) over 5.5 minutes.
  • the system then proceeds on a wash cycle with 95 percent acetonitrile in water (0.1 % trifluoroacetic acid) for 1.5 minutes.
  • the flow rate over this period is a constant 1.5 mL / minute.
  • Et means ethyl
  • AC means acetyl
  • Me means methyl
  • ETOAC or "ETOAc” means ethyl acetate
  • THF means tetrahydrofuran
  • Bu means butyl
  • DMSO means dimethylsulfoxide.
  • Example A1 (3R)-1-[(4'-chloro-3-fluorobiphenyl-4-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine
  • AKi 375 mg, 1.06 mmol
  • (4-chlorophenylboronic acid, 1.2 eq, 200 mg, 1.28 mmol) and cesium carbonate (3eq, 1.03 g, 3.12 mmol) in 1,4-dioxane (6 mL) was added(2-[D- ⁇ N)methyl]phenyl- ⁇ C](tricyclohexylphosphine)trifluoroacetato- ⁇ O-(sp-4-3)-palladium (5mg, 0.5 mol%), (Bedford, R.
  • the title compound was prepared from A2 using the method described for Example A1 above, except substituting A2(i) for AKi) and substituting 4-O-methylphenylboronic acid for 4-chloro-phenylboronic acid.
  • Example A4 4'- ⁇ [(3R)-3-(dimethylamino)pyrroiidin-1-yl]sulfonyl ⁇ -2',5'-difluorobiphenyl-4-carbonitrile
  • the title compound was prepared by the procedure described for A3 above, except substituting A4(i) for Aim. See Table 1 for NMR data.
  • A1(D and 4-fluorophenylboronic acid for 4-chlorophenylboronic acid See Table 1 for NMR data.
  • Example A6 4-(5- ⁇ [3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl ⁇ pyridin-2-yl)benzonitrile
  • the title compound was prepared by the procedure described for Al above, except substituting A6(iv) for AKi) and 4-cyanophenylboronic acid for 4-chlorophenylboronic acid. See Table 1 for NMR data.
  • Example B1 (3R)- ⁇ /,N-dimethyl-1-(1-naphthylsulfonyl)pyrrolidin-3-amine
  • the reaction mixture was passed through a pre-packed silica column (0.5 g), washed with CH 2 CI 2 (4 mL) and methanol (4 mL). The filtrate was concentrated and then diluted with CH 2 CI 2 (40 mL) and saturated NaHCO 3 (10 mL), and extracted twice with CH 2 CI 2 . The combined organic layer was washed with H 2 O and brine, and then dried with magnesium sulfate. The desired product Bl was obtained as a white solid (0.1O g, yield 40%) without further purification. See Table 1 for NMR data.
  • Example B4 2-[ ⁇ (3R)-1-[(5-chloro-2-naphthyl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino]ethanol
  • the title compound was prepared using the method described in Example B1 above, except substituting B4(iv) for (R)- ⁇ /, ⁇ /-dimethylpyrrolidin-3-amine and 5-chloro-2-naphthylsulfonyl chloride for naphthalene-1- sulfonyl chloride. See Table 1 for NMR data.
  • the title compound was prepared in a manner similar to methods B1 to B4 above, except using 5-bromo- 3-methyl-1-benzothiophene-2-sulfonyl chloride and for B4(iv). See Table 1 for NMR data.
  • the title compound was prepared in a manner similar to methods B5 to B6 above, except using 5-bromo- 3-methyl-1-benzothiophene-2-sulfonyl chloride and (3R)- ⁇ /, ⁇ /-dimethylpyrrolidin-3-amine. See Table 1 for NMR data.
  • the title compound was prepared in a manner similar to methods B5 to B6 above, except using 5-bromo- 3-methyl-1-benzothiophene-2-sulfonyl chloride and (3'R)-1 ,3'-bipyrrolidine. See Table 1 for NMR data.
  • Example C1 4'- ⁇ [(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl ⁇ -2'-(trifluoromethyl)biphenyl-4-carbonitrile
  • Example D1 4'-(1 ,3'-bipyrrolidin-1'-ylsulfonyl)biphenyl-4-carbonitrile
  • the total weight of the desired product D1 (ii) was 470 mg (80%).
  • Example E1 4-(5- ⁇ [(3R)-3-piperidin-1-ylpyrrolidin-1-yl]sulfonyl ⁇ pyridin-2-yl)benzonitrile
  • Example E1 4-(5- ⁇ [(3R)-3-piperidin-1-ylpyrrolidin-1-yl]sulfonyl ⁇ pyridin-2-yl)benzonitrile
  • a solution of E1 (iii) (20 mg, 0.05 mmol) and piperidine (0.1 mL) in acetonitrile (2 mL) was heated in a microwave oven at 170 0 C for 30 minutes.
  • the mixture was then concentrated and the residue purified by silica gel chromatography eluting with 60% ethyl acetate/hexane to obtain the desired product EJ. (11 mg, 50%) as a white solid. See Table 1 for NMR data.
  • Example F1 2-[ ⁇ (3R)-1-[(4'-chlorobiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino] ethanol
  • reaction mixture was stirred for 10 minutes at room temperature under nitrogen for 1.5 hours, diluted with CH 2 CI 2 (120 ml.) and washed with saturated aqueous NaHCO 3 (20 mL). The organic layer was dried over K 2 CO 3 , filtered and concentrated in vacuo to return the desired product FM as a white solid (1.5g, 95%).
  • Example F2 2-[ ⁇ (3R)-1-[(4'-chlorobiphenyI-4-yl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino] ethanol
  • a solution of FKiii) (240 mg, 0.53 mmol) and trifluoroacetic acid (2.0 mL) in CH 2 CI 2 (4 mL) was stirred at ambient temperature for 16 hours.
  • the reaction mixture was diluted with CH 2 CI 2 (150 mL), washed with saturated NaHCO 3 (15 mL), dried with K 2 CO 3 and filtered. The filtrate was concentrated in vacuo to obtain FKiv).
  • (3R)-1-[(4'-chlorobiphenyl-4-yl)sulfonyl]- ⁇ /-methylpyrrolidin-3-amine trifluoroacetic acid salt 150 mg.
  • Step B A solution of FKiv) (100 mg, 0.285 mmol) ), iodoethanol (245 mg, 1.425 mmol) and triethylamine (0.196 mL) in anhydrous dimethylformamide (1.0 mL) was stirred at 6O 0 C for 3.5 days, cooled to ambient temperature, diluted with 2:1 ethyl acetate:benzene (100 mL) and washed with saturated aqueous NaHCO 3 (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic extracts were dried with K 2 CO 3 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified via flash column chromatography eluting with 0-6% methanol in CH 2 CI 2 to return the title compound FJ. (41.5 mg, 37%). See Table 1 for NMR data.
  • Example F3 2-[ ⁇ (3R)-1 - ⁇ '-isocyano-S'-methylbiphenyl ⁇ -yOsulfonyljpyrrolidin-S-ylXmethyOaminolethanol
  • Example F3 2-[ ⁇ (3R)-1-[(4'-isocyano ⁇ 3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino]ethanoi
  • the title compound was prepared using the method described for preparing F1 above, except substituting F3(i) for FKiii). See Table 1 for NMR data.
  • Example F4 2 ⁇ (3R)-1-[(4'-chloro-3'-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino]ethanol
  • the title compound was prepared using the method described for preparing F1 above, except substituting
  • Example F5 2-[ ⁇ (3R)-1-[(4'-isocyano-3-meihylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino]ethanol
  • Example F6 2-[ ⁇ (3R)-1-[(4'-chloro-3-methylbiphenyl-4-yl)sulfonyl]pyrrolidin-3-yl ⁇ (methyl)amino]ethanol
  • the title compound was prepared using the method described for preparing F1 above, except substituting F6(i) for F1 (iii). See Table 1 for NMR data.
  • Example F7 4-[5-( ⁇ (3R)-3-[(2-hydroxyethyl)(methyl)amino]pyrrolidin-1-yl ⁇ sulfonyl)pyridin-2-yl]-2- methylbenzonitrile
  • the compounds G2 through G5 were prepared using the method described in Example G1 above, except using compounds B6 through B8 as starting reagents. See Table 1 for NMR data.
  • Example J1 (3R)-1-[(5-chloro-1H-indol-2-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine lntermediate JKi) (449mg, 1.04 mmol) was taken up in dichloromethane (4 mL) to which trifluoroacetic acid (2 mL) was added. The mixture was stirred at ambient temperature for 18 hours. After such time the mixture was concentrated in vacuo, the residue taken up in water (20 mL) and washed with diethyl ether (20 mL), neutralized via addition of sodium hydrogen carbonate and extracted with dichloromethane (3 x 20 mL).
  • Example K1 4'- ⁇ [(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl ⁇ -3'-hydroxybiphenyl-4-carbonitrile
  • sodium hydride 60% suspension in oil, 37 mg, 1.55mmol
  • 2-mercaptoethanol 0.052 mL, 0.778 mmol
  • dimethylformamide 0.8 mL
  • KKii 150 mg, 0.39 mmol
  • dimethylformamide 0.2 mL
  • Examples L1 and L2 4'- ⁇ K3f?)-3-(4-fluoropiperidin-1-vl)pyrrolidin-1-yi1sulfonvl ⁇ biphenvl-4-carbonitrile and 4'- ⁇ [(3S)-3-(4-fluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl ⁇ biphenyl-4-carbonitrile
  • the resulting reaction mixture was stirred at room temperature for 16 h, and then quenched with 1.0 M aqueous K 2 CO 3 (20 mL) diluted with additional 200 mL water.
  • the aqueous solution was extracted with ethyl acetate (2 x 30OmL).
  • the combined organic phases were dried over sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography eluting with 40% ethyl acetate in petroleum ether -> 80% ethyl acetate in petroleum ether to afford a racemic mixture.
  • the racemates were resolved by super critical fluid chromatography (Chiralpak IA, 20% 1 :1 methanol:acetonitrile @ 140 bar, 2.5 mL/min.
  • Examples L3 and L4 4'- ⁇ [(3/ : ?)-3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]sulfonyl ⁇ biphenyl-4-carbonitrile and 4'- ⁇ [(3S)-3-(4,4-difluoropiperidin-1-yl)pyrrolidin-1-yl]suifonyl ⁇ biphenyl-4-carbonitrile
  • Examples L3 and L4 were prepared according to method L substituting 4-fiuoropiperidine for 4,4'- difluoropiperidine. The racemates were resolved by supercritical , fluid chromatography to afford first peak at 2.981 min. designated as S enantiomer, example L4 (209 mg, 100%EE, 51% yield).
  • a sulfonyl chloride reagent 200 uL, 0.08 mmol, 0.4 M solution in anhydrous 1 ,2-d ⁇ chloroethane
  • an amine reagent 400 uL, 0.08 mmol, 0.2 M solution in anhydrous dimethoxy ethane
  • t ⁇ ethylamine 80 uL, 0.08 mmol, 1.0 M in anhydrous dimethoxy ethane
  • the solvent was evaporated and the residue dissolved in DMSO (containing 0.01 % BHT) to give 0.05 M solution.
  • the solution was injected into an automated HPLC system and the product containing fraction was collected.
  • the solvent was evaporated and the residue dissolved in the appropriate volume of DMSO to give an either 30 mM or 10 mM solution.
  • the product containing solutions were analyzed by LCMS and submitted for screening.
  • a ketone reagent 200 uL, 0.08 mmol, 0.4 M in a mixture of anhydrous THF and anhydrous DMSO (1 :1 ' v:v)
  • an amine reagent 200 uL, 0.08 mmol, 0.4 M in a mixture of anhydrous THF and anhydrous DMSO (1 :1 v:v)
  • sodium triacetoxyborohydride 330 uL, 0.20 mmol, 0.6 M dispersion in a mixture of anhydrous THF and anhydrous DMSO (1 :1 v:v)
  • glacial (pure) acetic acid 10 uL
  • the plate was sealed with a Teflon-lined aluminum plate vice and agitated on a vortexer for 16-24 h at ambient temperature.
  • K2CO3 200 uL. 3 M solution in water
  • ethanol 550 uL
  • the plate was sealed.vortexted for 30 min, and then centrifuged for phase separation.
  • the liquid phase was transferred into a test tube and the solvent was evaporated.
  • the solvent was evaporated and the residue dissolved in DMSO (containing 0.01% BHT) to give 0.0572 M solution.
  • the solution was injected into an automated HPLC system and the product containing fraction was collected.
  • the solvent was evaporated and the residue dissolved in the appropriate volume of DMSO to give an either 30 mM or 10 mM solution.
  • the product containing solutions were analyzed by LCMS and submitted for screening.
  • a sulfonyl chloride reagent (104 ⁇ mol, 1.3 eq, 400 uL of a 0.26 M solution in anhydrous pyridine) and an amine reagent (80 ⁇ mol, 1.0 eq, 400 uL of a 0.2 M solution in anhydrous pyridine) were placed into a test tube (75x10 mm, dried by heating at 110 0 C for 16 h) equipped with a stir bar.
  • the test tube was covered with Parafilm and the reaction was stirred for 24 h at ambient temperature.
  • the solvent was evaporated and the residue was dissolved in EtOAc (1 mL). After dissolution was completed or a fine suspension had formed, NaHCO 3 (0.5 mL of a sat. aq.

Abstract

L'invention concerne des composés représentés par la formule (I), ou des sels ou solvates pharmaceutiquement acceptables de ceux-ci, n, X, Y, R1, R2, R3 et R4 étant décrits dans le descriptif. L'invention concerne aussi des compositions pharmaceutiques comprenant les composés représentés par la formule (I), et des méthodes de traitement d'états pathologiques dans lesquels intervient une modulation de la 11ßHSD1, et qui consistent à administrer à un mammifère une quantité efficace d'un composé représenté par la formule (I).
PCT/IB2006/001607 2005-06-16 2006-06-06 Inhibiteurs de la 11-beta hydroxysteroide deshydrogenase de type 1 WO2006134481A1 (fr)

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US60/691,373 2005-06-16
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WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
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JP2011506438A (ja) * 2007-12-11 2011-03-03 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１型の環状尿素阻害剤
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
US20110098281A9 (en) * 2007-04-09 2011-04-28 Purdue Pharma L.P. Benzenesulfonyl Compounds and the Use Thereof
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WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
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US8791264B2 (en) 2006-04-13 2014-07-29 Purdue Pharma L.P. Benzenesulfonamide compounds and their use as blockers of calcium channels
US8937181B2 (en) 2006-04-13 2015-01-20 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
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