HK1117509A - N-(pyridin-2-yl)-sulfonamide derivatives - Google Patents

Description

N- (pyridin-2-yl) -sulfonamide derivatives

This application claims benefit of U.S. provisional application No.60/691,350 filed on 16/6/2005 and U.S. provisional application No.60/748,778 filed on 9/2005, the contents of which are incorporated herein by reference in their entireties.

The present invention relates to novel compounds, pharmaceutical compositions comprising the compounds and the use of the compounds in medicine and for the preparation of a medicament for acting on human 11-beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD 1).

Background

Over half a century, we have known that glucocorticoids play an important role in diabetes. For example, removal of pituitary or adrenal glands from diabetic animals can alleviate the most severe symptoms of diabetes and lower blood glucose concentrations (Long, C.D. and F.D.W.Leukins (1936) J.Exp.Med.63: 465-. In addition, it is well established that glucocorticoids enable glucagon action in the liver. The role of 11. beta. HSD1 as an important modulator of the local glucocorticoid effect, and thus the regulation of hepatic glucose production, is well established (see e.g. Jamieson et al (2000) J. Endocrinol.165: p.685-692). Hepatic insulin sensitivity was increased in healthy human volunteers treated with the nonspecific 11 β HSD1 inhibitor carbenoxolone (Walker, B.R. et al (1995) J.Clin Endocrinol.Metab.80: 3155-3159). In addition, the predicted mechanism has been established by different mouse and rat experiments. These studies show that the mRNA levels and activities of two key enzymes in hepatic glucose production are reduced, namely, the rate-limiting enzymes in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), which catalyze the last common step in gluconeogenesis and glycogenolysis. Finally, blood glucose levels and hepatic glucose production were reduced in mice with 11 β HSD1 gene knockout. The data obtained from this model also demonstrate that inhibition of 11 β HSD1 does not lead to hypoglycemia, as expected, since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, y, et al, (1997) proc. natl. acad. sci. usa 94: 14924-.

Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia and other factors known as metabolic syndrome, such as elevated blood pressure, reduced HDL levels and elevated VLDL levels (Montague & O' Rahilly, Diabetes 49: 883-888, 2000). Obesity is an important factor in metabolic syndrome and most (> 80%) of type 2 diabetes, and omental fat appears to be of critical importance. Inhibition of this enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in a reduction in omental fat storage expansion (possibly shrinkage), i.e. a reduction in central obesity (Bujalska, I.J., Kumar, S. and Stewart, P.M (1997) Lancet 349: 1210-.

Summary of The Invention

The compounds of the present invention are useful as 11 β HSD1 inhibitors.

In one aspect, the invention provides a compound of formula (I):

wherein

R¹Is H or (C)₁-C₄) An alkyl group;

R²is H or (C)₁-C₄) An alkyl group;

R³is H, halogen, (C)₁-C₆) Alkyl or (C)₁-C₆) An alkoxy group;

and when the compound is a chiral compound, the compound is the (+) enantiomer,

and pharmaceutically acceptable salts, hydrates or solvates thereof.

In one embodiment, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is¹Is H. In another embodiment, the invention relates to compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is³Is H or CH₃. In another embodiment, the invention relates to compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein R is²is-CH₂CH₃。

In another aspect, the present invention provides a compound of formula I selected from the group consisting of:

and

wherein when the compound is a chiral compound, the compound is the (+) enantiomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another aspect, the present invention provides compounds having formula II

Or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of any of the compounds of formula I or II above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of treating a disease, condition or disorder (such as type 2 diabetes) that would benefit from treatment with an inhibitor of 11 β HSD1, comprising administering to a mammal an effective amount of any of the compounds of formula I or II above, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another aspect, the present invention provides a method of treating metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, atherosclerosis, dementia, depression, or a disease in which the liver is a target organ, wherein the method comprises administering to a mammal an effective amount of any of the compounds of formula I or II described above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In another aspect, the present invention provides a method of treating glaucoma, comprising administering to a mammal an effective amount of a compound of any of formulas I or II above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with a prostanoid receptor agonist, wherein the agonist is latanoprost.

In another aspect, the present invention provides a compound of formula I or II, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as a medicament.

In another aspect, the present invention provides the use of a compound of formula I or II, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease, condition or disorder that would benefit from treatment with an 11 β HSD1 inhibitor, such as type 2 diabetes.

Definition of

The terms "comprising" and "including" as used herein are used in their open, non-limiting sense.

The term "alkyl" as used herein, unless otherwise indicated, means a saturated monovalent hydrocarbon group, having straight or branched moieties.

The term "alkenyl", as used herein, unless otherwise indicated, means an alkyl moiety having at least one carbon-carbon double bond, wherein alkyl is as defined above, and includes both E and Z isomers of the alkenyl moiety.

The term "alkynyl", as used herein, unless otherwise indicated, means an alkyl moiety having at least one carbon-carbon triple bond, wherein alkyl is as defined above.

The term "alkoxy" as used herein, unless otherwise indicated, means O-alkyl, wherein alkyl is as defined above.

The term "amino", as used herein, unless otherwise indicated, means-NH₂Groups and any substitution of the N atom.

The terms "halogen" and "halo" as used herein, unless otherwise indicated, mean fluorine, chlorine, bromine and/or iodine.

The term "trifluoromethyl" as used herein, unless otherwise indicated, means-CF₃A group.

The term "trifluoromethoxy" as used herein, unless otherwise indicated, means-OCF₃A group.

The term "cyano" as used herein, unless otherwise indicated, means a-CN group.

The term "Ms" as used herein, unless otherwise indicated, means mesylate (-SO) groups₂CH₃)。

The term "Me" as used herein, unless otherwise indicated, means methyl.

The term "MeOH" as used herein, unless otherwise indicated, means methanol.

The term "Et", as used herein, unless otherwise indicated, means ethyl.

The term "Et" as used herein₂O ", unless otherwise indicated, means diethyl ether.

The term "EtOH" as used herein, unless otherwise indicated, means ethanol.

The term "Et" as used herein₃N ", unless otherwise indicated, it means triethylamine.

The term "TEA" as used herein, unless otherwise indicated, means triethylamine.

The term "EtOAc" as used herein, unless otherwise indicated, means ethyl acetate.

The term "AlMe" as used herein₂Cl ", unless otherwise indicated, means dimethylaluminum chloride.

The term "Ac", as used herein, unless otherwise indicated, means acetyl.

The term "TFA" as used herein, unless otherwise indicated, means trifluoroacetic acid.

The term "HATU" as used herein, unless otherwise indicated, means N, N' -tetramethyluronium hexafluorophosphate.

The term "THF" as used herein, unless otherwise indicated, means tetrahydrofuran.

The term "T1 OH" as used herein, unless otherwise indicated, means thallium (I) hydroxide.

The term "T1 OEt" as used herein, unless otherwise indicated, means thallium (I) ethoxide.

The term "PCy" as used herein₃", unless otherwise indicated, it means tricyclohexylphosphine.

The term "Pd" as used herein₂(dba)₃", unless otherwise indicated, it means tris (dibenzylideneacetone) dipalladium (O).

The term "Pd (OAc)₂", unless otherwise indicated, it means palladium (II) acetate.

The term "Pd (PPh) as used herein₃)₂Cl₂", unless otherwise indicated, it means bis (triphenylphosphine) palladium (II) dichloride.

The term "Pd (PPh) as used herein₃)₄", unless otherwise indicated, it means tetrakis (triphenylphosphine) palladium (O).

The term "Pd (dppf) Cl" as used herein₂", unless otherwise indicated, it means dichloro (1, 1' -bis (diphenylphosphino) -ferrocene) palladium (II), complexed with dichloromethane (1: 1).

The term "G6P" as used herein, unless otherwise indicated, means glucose-6-phosphate.

The term "NIDDM" as used herein, unless otherwise indicated, means non-insulin dependent diabetes mellitus.

The term "NADPH" as used herein, unless otherwise indicated, means reduced nicotinamide adenine dinucleotide phosphate.

The term "CDCl" as used herein₃Or CHLORFORM-D ", unless otherwise indicated, which meansDeuterium chloroform.

The term "CD" as used herein₃OD ", unless otherwise indicated, means deuterated methanol.

The term "CD" as used herein₃CN ", unless otherwise indicated, means deuterium acetonitrile.

The term "DEAD" as used herein, unless otherwise indicated, means diethyl azodicarboxylate.

The term "TsCH" as used herein₂NC ", unless otherwise indicated, means tosylmethylisonitrile.

The term "ClSO" as used herein₃H ", unless otherwise indicated, means chlorosulfonic acid.

The term "DMSO-d" as used herein₆Or DMSO-D₆", unless otherwise indicated, it means deuterium dimethyl sulfoxide.

The term "DME" as used herein, unless otherwise indicated, means 1, 2-dimethoxyethane.

The term "DMF" as used herein, unless otherwise indicated, means N, N-dimethylformamide.

The term "DMSO", as used herein, unless otherwise indicated, means dimethylsulfoxide.

The term "DIPEA" as used herein, unless otherwise indicated, means diisopropylethylamine.

The term "DI" as used herein, unless otherwise indicated, means deionized.

The term "KOAc" as used herein, unless otherwise indicated, means potassium acetate.

The term "neat" as used herein, unless otherwise indicated, means that no solvent is present.

The term "mmol" as used herein means millimolar unless otherwise indicated.

The term "equiv" as used herein means equivalent weight unless otherwise indicated.

The term "mL" as used herein, unless otherwise indicated, means mL.

The term "U" as used herein, unless otherwise indicated, means a unit.

The term "mm" as used herein means millimeters, unless otherwise indicated.

The term "g" as used herein, unless otherwise indicated, means grams.

The term "kg", as used herein, means kilograms (kilograms) unless otherwise indicated.

The term "h", as used herein, means hours, unless otherwise indicated.

The term "min" as used herein means minutes, unless otherwise indicated.

The term "μ L" as used herein, unless otherwise indicated, means μ L.

The term "μ M" as used herein, unless otherwise indicated, means micromolar concentration.

The term "μm" as used herein, unless otherwise indicated, means microns.

The term "M", as used herein, means molar concentration, unless otherwise indicated.

The term "N" as used herein, unless otherwise indicated, means equivalent concentration.

The term "nm" as used herein, unless otherwise indicated, means nanometer.

The term "nM" as used herein, unless otherwise indicated, means nanomolar.

The term "amu" as used herein, unless otherwise indicated, means atomic mass units.

The term "C" as used herein means degrees Celsius unless otherwise indicated.

The term "m/z" as used herein, unless otherwise indicated, means the mass/charge ratio.

The term "wt/wt" as used herein means weight/weight unless otherwise indicated.

The term "v/v" as used herein means volume/volume unless otherwise indicated.

The term "mL/min" as used herein means mL/min, unless otherwise indicated.

The term "UV" as used herein, unless otherwise indicated, means ultraviolet.

The term "APCI-MS" as used herein, unless otherwise indicated, means atmospheric pressure chemical ionization mass spectrometry.

The term "HPLC" as used herein, unless otherwise indicated, means high performance liquid chromatography.

The term "LC" as used herein, unless otherwise indicated, means liquid chromatography.

The term "LCMS" as used herein, unless otherwise indicated, means liquid chromatography mass spectrometry.

The term "SFC," as used herein, means supercritical fluid chromatography, unless otherwise indicated.

The term "sat" as used herein means saturated unless otherwise indicated.

The term "aq" as used herein, unless otherwise indicated, is intended to be aqueous.

The term "ELSD" as used herein, unless otherwise indicated, means evaporative light scattering detection.

The term "MS" as used herein, unless otherwise indicated, means mass spectrometry.

The term "hrms (esi)", as used herein, unless otherwise indicated, means high resolution mass spectrometry (electrospray ionization).

The term "anal", as used herein, is intended to be analytical unless otherwise indicated.

The term "Calcd" as used herein means calculated, unless otherwise indicated.

The term "NT", as used herein, means not tested unless otherwise indicated.

The term "NA" as used herein means not tested unless otherwise indicated.

The term "RT" as used herein, unless otherwise indicated, means room temperature.

The term "mth." as used herein means a method unless otherwise indicated.

The term "Celite" as used herein^®", unless otherwise indicated, it means a white solid diatomaceous earth filter, commercially available from World Minerals located in Los Angeles, California USA.

The term "K" as used herein_i", unless otherwise indicated, means enzyme inhibition constant values.

The term "K" as used herein_iapp ", unless otherwise indicated, means apparent K_i。

The term IC as used herein₅₀", unless otherwise indicated, means the concentration required for at least 50% enzyme inhibition.

The term "substituted" as used herein, unless otherwise indicated, means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents.

The term "optionally substituted" as used herein, unless otherwise indicated, means that the specified group is unsubstituted or substituted with one or more substituents.

By convention, in some structural formulae herein, the carbon atoms and their bound hydrogen atoms are not explicitly depicted, for example,represents a methyl group, and a salt thereof,represents an ethyl group, and the like,represents cyclopentyl, etc.

The term "cycloalkyl" as used herein, unless otherwise indicated, means a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon compound, as described herein, containing a total of 3 to 10 carbon atoms, suitably 5 to 8 ring carbon atoms. Exemplary cycloalkyl groups include rings having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

The term "aryl" or "(C) as used herein₆-C₁₀) Aryl ", unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, for example phenyl or naphthyl.

The term "heteroaryl" or "(5-10) membered heteroaryl", as used herein, unless otherwise indicated, means an aromatic group containing 1 to 4 heteroatoms each selected from O, S and N, wherein each heterocyclic ring has 5 to 10 atoms per ring system, respectively, provided that the ring of the group does not contain two adjacent O or S atoms. Heteroaryl groups include benzo-fused ring systems. An example of a 5-membered heterocyclic group is thiazolyl, an example of a 7-membered ring is aza *, and an example of a 10-membered heterocyclic group is quinolinyl. Further examples of heteroaryl groups are pyridyl, 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, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

Unless otherwise indicated, the term "oxo" means ═ O.

The compounds of the present invention, as used herein, are meant to include solvates, hydrates and pharmaceutically acceptable salts of the compounds of formulas I and II, as well as specific embodiments thereof.

The term "solvate" as used herein means a pharmaceutically acceptable solvate form of a particular compound which retains the biological utility of that compound. Examples of solvates include the compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethyl sulfoxide), ethyl acetate, acetic acid or ethanolamine.

The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the claimed compounds. The claimed compounds, which are basic in nature, are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. The salts of the present invention are further described below.

The term "disease in which the liver is a target organ" as used herein means, unless otherwise indicated, diabetes, hepatitis, liver cancer, liver fibrosis and malaria.

The term "metabolic syndrome" as used herein, unless otherwise indicated, means psoriasis, diabetes, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine-uracil, sulfinuria, isovaleric acid blood disease, saccharonine urine disease, 4-hydroxybutyric acid urine disease, glucose-6-phosphate dehydrogenase deficiency and pyruvate dehydrogenase deficiency.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing the disease or disorder or one or more symptoms of the disease or disorder to which the term applies. The term "treatment" as used herein, unless otherwise indicated, means the act of treating, "treatment" as defined above.

The term "modulation" as used herein, refers to the ability of a modulator to a member of the steroid/thyroid superfamily to induce expression of or inhibit expression of genes maintained under the control of hormone expression, either directly (by binding to a receptor as a ligand) or indirectly (as a precursor to a ligand or an inducer which promotes production of a ligand from a precursor).

The term "ophthalmic disease" as used herein, unless otherwise indicated, means an ocular disease including, but not limited to, glaucoma, age-related macular degeneration including both 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 ocular diseases or disorders.

The term "obese" or "obese" as used herein, generally means that the individual is at least about 20-30% above its average weight for age, sex, and height. Technically, "obesity" is defined as a body mass index greater than 27.8kg/m for men²For women, the body mass index of the individual is more than 27.3kg/m². One skilled in the art will readily recognize that the methods of the present invention are not limited to individuals falling within the above-described ranges. Indeed, the methods of the present invention may also be advantageously practiced by individuals outside of these conventional standards, e.g., there may beThose prone to obesity.

The term "inflammatory disorder" as used herein, unless otherwise indicated, means disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrococalcinosis, gout, inflammatory bowel disease, ulcerative colitis, crohn's disease, fibromyalgia, and cachexia.

The term "therapeutically effective amount" as used herein, unless otherwise indicated, means an amount of a pharmaceutical or pharmaceutically active agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, or medical doctor.

The term "amount effective to lower blood glucose levels" as used herein, unless otherwise indicated, means that the level of the compound is sufficient to provide a circulating concentration high enough to achieve the desired effect. Generally, the concentration falls within the range of about 10nM to 2 μ M; and preferred concentrations range from about 100nM up to 500 nM. As previously mentioned, since the activity of the various compounds described above may vary significantly, and since individual subjects may exhibit wide variation in symptom severity, individual subject response to treatment is determined by the practitioner and the dosage is varied accordingly.

The term "insulin resistance" as used herein, unless otherwise indicated, means reduced sensitivity to the action of insulin in the whole body or in individual tissues such as skeletal muscle tissue, cardiac muscle tissue, adipose tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes.

The term "insulin resistance syndrome" as used herein, unless otherwise indicated, means a group of manifestations including insulin resistance, hyperinsulinemia, NIDDM, arterial hypertension, central (visceral) obesity, and dyslipidemia.

Certain functional groups comprised in the compounds of the invention may be replaced by bioisosteric groups, i.e. having similar steric or electronic requirements as the parent group, but exhibiting compatible or improved physicochemical properties, or combinations thereofGroups of its nature. Suitable examples are well known to those skilled in the art and include, but are not limited to, those described in Patini et al,Chem.Rev1996, 96, 3147-3176 and the references cited therein.

Isotopically labeled compounds of the present 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 labeled reagent for a non-isotopically labeled reagent.

Other aspects, advantages and features of the present invention will become more apparent from the following detailed description of the invention.

Detailed Description

The following scheme illustrates the preparation of the compounds of the present invention.

Scheme 1

Referring to scheme 1 above, the compound of formula A can be prepared by reacting a compound of formula B with Ar-sulfonyl halide, Ar-sulfinyl halide, or Ar^-Sulfinates are prepared by reaction in a suitable solvent in the presence of a suitable base, such as an amine. Suitable bases include pyridine, triethylamine and diisopropylethylamine. Suitable solvents include pyridine, dichloromethane or THF. The foregoing reaction may be carried out at about room temperature (about 20 ℃) or heated for a suitable period of time, such as 2 to 16 hours, depending on the solvent system used. After the reaction is substantially complete, the base can be removed in vacuo and the resulting residue can be purified using conventional purification techniques.

Any of the above compounds of formula I can be converted to other similar compounds by standard chemical manipulations. All starting materials, reagents and solvents are commercially available and well known to those skilled in the art unless otherwise indicated. These chemical manipulations are well known to those skilled in the art and include (a) removal of protecting Groups as described in t.w.greene and p.g.m.wuts, "Protective Groups in Organic Synthesis", Second Edition, john wiley and Sons, New York, 1991; (b) displacement of the leaving group (halogen, methanesulfonyl, toluenesulfonyl, etc.) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; (c) treating the primary and secondary amines with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding urea, amide, carbamate or sulfonamide; (d) reductive amination of primary or secondary amines using aldehydes is carried out.

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 physicochemical differences, by methods known to those skilled in the art, for example, chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Unless otherwise indicated, all such isomers, including diastereomeric mixtures and pure enantiomers, are considered as part of the invention.

The compounds of the present invention, which are basic in nature, are capable of forming a wide variety of salts with a wide variety of 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 compounds of the invention from the reaction mixture as pharmaceutically unacceptable salts and then simply convert the latter back to the free base compound by treatment with a basic agent, followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention can be readily prepared by treating the base compound with substantial equivalents of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt may also be precipitated from a solution of the free base in an organic solvent by adding a suitable mineral or organic acid to the solution.

Those compounds that are acidic in nature are capable of forming base salts with a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially sodium and potassium salts. These salts are prepared by conventional techniques. Chemical bases useful as reagents for preparing the pharmaceutically acceptable base salts of the present invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmaceutically acceptable cations as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In either case, it is preferred to use stoichiometric amounts of reagents to ensure complete reaction and maximum yield of the desired end product.

The compounds of the invention are useful as modulators of 11 β HSD 1. The compounds of the invention may modulate processes mediated by 11 β HSD1, i.e., biological, physiological, endocrine, and other bodily processes mediated via a receptor or combination of receptors responsive to 11 β HSD1 inhibitors as described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g., retinopathy, nephropathy, psychofunctional disorders, cataracts, and coronary artery disease and the like), arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g., ischemic heart disease and the like), cellular damage induced by atherosclerosis or ischemic heart disease (e.g., brain damage resulting from stroke and the like), gout, inflammatory diseases (e.g., arthritis, pain, fever, rheumatoid arthritis, inflammatory bowel inflammation, acne, sunburn, wound, injury, inflammatory bowel disease, Psoriasis, eczema, allergies, asthma, GI ulcers, cachexia, autoimmune diseases, pancreatitis and similar conditions), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo. In vivo regulation may be performed in a variety of subjects, such as humans, rodents, sheep, pigs, cows, etc.

The compounds of the invention are useful in several indications involving 11 β HSD1 enzyme modulation. Thus, The compounds of The present invention are useful against dementia (see WO97/07789), Osteoporosis (see cancer E1996, "Mechanisms of Staphylococcus Action in bone: abnormalities to Staphylococcus-Induced Osteoporosis", Journal of Clinical Endocrinology and Metabolism, 81, 3441-Induced Osteoporosis 3447), and also for disorders of The Immune system (see Franchimont, et al, "Inhibition of Th1 Immune Response by Staphylococcus infection IL-12-Induced Station 4Phosphorylation in T Lymphocytes", Immunol Journal of physiology 2000, Feb 15, 164, 1768-1768), and indications thereof.

Inhibition of 11 β HSD1 in isolated murine pancreatic β -cells enhanced glucose-stimulated insulin secretion (Davani, B., et al (2000) J.biol.chem.Nov.10, 2000; 275 (45): 34841-4). Glucocorticoids have previously been known to reduce pancreatic insulin release in vivo (Billuudel, B.and B.C.J.Sutter (1979) Horm.Metab.Res.11: 555-560). Thus, in addition to effects on liver and fat, inhibition of 11 β HSD1 is predicted to produce other beneficial effects for the treatment of diabetes.

Recent data suggest that the levels of glucocorticoid target receptor and 11 β HSD1 enzyme determine susceptibility to glaucoma (Stokes, J. et al, (2000) invest. Ophthalmol.41: 1629-1638). Furthermore, inhibition of 11 β HSD1 has recently emerged as a novel method of lowering intraocular pressure (Walker e.a., et al, poster P3-698 at the endocrine meeting jun.12-15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific 11 β HSD1 inhibitor, was shown to reduce intraocular pressure by 20% in normal individuals. In the eye, expression of 11 β HSD1 was restricted to basal cells of the corneal epithelium, as well as to the non-pigmented epithelium of the cornea (site of aqueous humor production), ciliary muscle, and sphincter and dilator muscles of the iris. In contrast, the teleisozyme 11 β -hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and the corneal endothelium. None of the enzymes is present in the trabecular meshwork (drainage site). Thus, 11 β HSD1 is proposed to play a role in aqueous humor production (rather than excretion), but it is not currently known that this is by interfering with the activation of the glucocorticoid or mineralocorticoid receptors, or both.

Bile acids inhibit 11-beta-hydroxysteroid dehydrogenase type 2. This results in a shift in overall body balance towards hydrogenated vs. as shown by the study on urine metabolite ratios (Quattropani C, Vogt B, Odermat A, Dick B, Frey B M, Frey F J.2001. J.Clin invest. Nov; 108 (9): 1299) -. By reducing the activity of 11 β HSD1 in the liver by selective inhibitors, it is expected that this imbalance can be reversed, rapidly fighting symptoms such as hypertension, while awaiting surgical treatment to remove biliary obstruction.

The compounds of the present invention are also useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance, including the major late complications of NIDDM such as diabetic vasculopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic eye complications such as retinopathy, cataract formation, and glaucoma, as well as many other conditions associated with NIDDM, including dyslipidemia glucocorticoid-induced insulin resistance, dyslipidemia, polycystic ovary syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, and hypertension. A brief definition of these conditions can be obtained in any Medical Dictionary, for example, Stedman's Medical Dictionary (10)^th Ed.)。

Inhibition of 11 β HSD1 activity

11 β HSD1 enzyme assay

The 11. beta. HSD1 enzyme was assayed at 0, containing 200mM NaCl.02% n-dodecyl-beta-D-maltoside, 5% glycerol, 5mM beta-mercaptoethanol in 100mM triethanolamine buffer, pH 8.0. Determination of K_iappTypical reaction of values Corning at room temperature^®u-bottom 96 well plates and are described below: 11 β HSD1 enzyme (5nM, final concentration) was preincubated in assay buffer for at least 30 min in the presence of inhibitor and NADPH (500 μ M, final concentration). When the pre-incubation was complete, regeneration system (2mM glucose-6-phosphate, 1U/mL glucose-6-phosphate dehydrogenase, and 6mM MgCl) was added₂All concentrations were final concentrations in assay buffer), and 3H-codiexon (200nM, final concentration). After 60 minutes, 60 μ L of the assay mixture was transferred to a second 96-well plate and mixed with an equal volume of dimethyl sulfoxide to stop the reaction. A15 μ L aliquot of the reaction mixture was loaded onto a C-18 column (Polaris C18-A, 50x4.6mm, 5 μ 180 Angstrom from Varian) connected to an automated high performance liquid chromatograph developed by Cohesive Technologies, commercially available from Franklin, Massachusetts USA, equipped with a β -RAM model 3 Radio-HPLC detector from IN/US, commercially available from Tampa, Florida USA. The substrate and product peaks were separated by using an isocratic mixture of 43: 57 methanol: water (v/v) at a flow rate of 1.0 mL/min.

The initial reaction rate was measured as follows: the reaction was stopped at 60 minutes and the area of product formed in the absence and presence of each concentration of inhibitor was measured. K_iappValues were determined using the equation for the tight binding inhibitor developed by Morrison, JF. (Morrison JF. BiochimBiophys acta.1969; 185: 269-86):

wherein v is_iAnd v_oThe rate of hydrocortisone formation in the presence and absence of inhibitor, I the inhibitor concentration, and E the concentration of 11 β HSD1 in the assay buffer, respectively. All concentrations reported are final concentrations in assay buffer.

See also Morrison, J.F., "Kinetics of the conversion of enzyme-catalyzed reactions by light-binding inhibitors," Biochim Biophys acta., 1969; 185: 269-86.

K of the inventive Compounds for 11. beta. HSD1 enzyme_iappValues are generally between about 10nM and about 10. mu.M. The tested compounds of the invention all had a K of less than 1 μ M in at least one of the SPA assays described above_iappValues, preferably less than 100 nM. Certain preferred groups of compounds have differential selectivity for various 11- β -HSDs. A preferred group of compounds have selective activity for 11 β HSD1 over 11 β -HSD-2. Another group of preferred compounds have selective activity for 11. beta. HSD-2 over 11. beta. HSD 1. (Morrison JF. BiochimBiophys acta.1969; 185：269-86)。

The percent inhibition was determined in 100mM triethanolamine buffer, pH8.0, 200mM NaCl, 0.02% n-dodecyl-D-maltoside and 5mM β -ME. Typical reaction in Corning^®u-bottom 96 well plates and are described below: 11 β HSD1 enzyme (5nM, final concentration) was preincubated in assay buffer for at least 30 min in the presence of inhibitor and NADPH (500 μ M, final concentration). When the pre-incubation was complete, regeneration system (2mM glucose-6-phosphate, 1U/mL glucose-6-phosphate dehydrogenase, and 6mM MgCl) was added₂All reported concentrations are final concentrations in assay buffer), and 3H-codiexon (200nM, final concentration). After 60 minutes, 60 μ L of the assay mixture was transferred to a second 96-well plate and mixed with an equal volume of dimethyl sulfoxide to stop the reaction. A15 μ L aliquot of the reaction mixture was loaded onto a C-18 column (Polaris C18-A, 50x4.6mm, 5 μ 180 Angstrom from Varian) connected to an automated high performance liquid chromatograph developed by Cohesive Technologies, commercially available from Franklin, Massachusetts, equipped with a β -RAM model 3 Radio-HPLC detector from IN/US, commercially available from Tampa, Florida. The substrate and product peaks were separated by using an isocratic mixture of 43: 57 methanol: water (v/v) at a flow rate of 1.0 mL/min.

Percent inhibition was calculated based on the following equation: (100- (peak area of 3H-hydrocortisone with inhibitor/peak area of 3H hydrocortisone without inhibitor) × 100). Certain groups of compounds have differential selectivity for various 11- β -HSD enzymes. One group of compounds has selective activity for 11 β HSD1 over 11 β HSD 1-2. While another group of compounds has selective activity for 11 β HSD-2 over 11 β HSD 1.

[1，2-3H]Cordinopine is commercially available from American Radiolabel Chemicals Inc., St.Louis, Missouri USA. NADPH, glucose-6-phosphate and glucose-6-phosphate dehydrogenase were purchased from Sigma^®。

HEK 293-11. beta. HSD 1/GRE-luciferase cell typeMeasurement of

Inhibition of 11 β HSD1 enzyme activity was also measured using Human kidney HEK293 stably transfected cells, which overexpress Human 11 β HSD1, and a reporter plasmid containing a DNA sequence that specifically recognizes glucocorticoid-activated Glucocorticoid Receptor (GRE), using a DNA sequence similar to that of Bujalska et al, Human 11 β -hydrosteroid dehydrogenase: studies on the stable transformed microorganisms and localization of the type 2 isozyme with the same biological tissue,Steroids62(1), 1991, 77-82. These sequences were fused to a luciferase reporter gene (Luc) to quantify 11 β HSD1 enzyme regulation. 11 β HSD1 is responsible for converting inactive glucocorticoids into active glucocorticoids (in humans, cotrione to hydrocortisone). Hydrocortisone (but not coniferone) binds to and activates the Glucocorticoid Receptor (GR), which leads to activation of the luciferase enzyme and luminescence (readout of the assay). Compounds with the ability to inhibit 11 β HSD1 reduced luciferase signal compared to the cotazone control (enzyme substrate).

Cells were seeded in 384-well flat-bottom white polystyrene TC-treated microplates at 20,000 cells/well in a volume of 40. mu.l/well in serum-free DME medium. Plates at 37 ℃ with 5% CO₂Incubate overnight and then add inhibitor compounds. Various concentrations of inhibitor compound were added to 10% (v/v) dimethyl sulfoxide (5. mu.L/well) followed by 3. mu.M Cortisol (5. mu.L/well) and cells at 37 ℃ (5% CO)₂) Incubate for six hours. At the end of the incubation, 25. mu.L/well of SteadyLite HTS was added and the plates were incubated for 10 minutes in a room temperature shaker. The plates were then read on a Top Count using 384HSD1 program. The inhibitor compound concentration that resulted in 50% inhibition of the optical signal was determined via a custom Excel Macro. All results were compared to 100% activated controls-i.e. cells treated with just comberson (no inhibitor added).

Human Fa2N-4 immortalized cell-based assays

Fa2N-4 is a cell derived from human hepatocytesDeveloped by multicell technologies, inc. (U.S. patent No.6,107,043), commercialized by xeno tech LLC via exclusive licensing. These cells are uniquely morphologically and functionally similar to primary cultures, and thus exhibit many of the characteristics of normal human hepatocytes, thereby providing a virtually unlimited and renewable cellular supply to support drug discovery. Inhibition of 11 β HSD1 enzyme activity was assessed in this cell model by measuring the reduction in accumulation of hydrocortisone (enzyme product) in cultures co-treated with hydrocortisone (enzyme substrate) and a potential enzyme inhibitor. Hydrocortisone signal was quantitatively determined in the supernatant of treated cells using a corelate-Enzymeimmunoassay (EIA)^TMHydrocortisone kit (Assay Designs, Inc.).

Cells were seeded in 96-well flat-bottom collagen-coated microplate at 20,000 cells/well in 200. mu.l/well MFE^TM(Multi-functional Enhancing-XenoTech, LLC) medium containing antibiotic (penicillin-streptomycin) supplemented with 10% heat-inactivated fetal bovine serum. Plates were incubated at 37 ℃ with 5% CO₂Incubate overnight. The next day, the medium was changed to hepatocyte basal medium containing only antibiotics (HBM-Cambrex Bio sciences Walkers Ville, Inc) before adding the cortisol and inhibitor compounds. Thirty minutes after preincubation with various concentrations of inhibitor compounds (20. mu.L/well), 5. mu.M Cortisol (20. mu.L/well) was added and the cells were incubated at 37 ℃ with 5% CO₂Incubate overnight. At the end of the incubation, 100 μ L of each supernatant was analyzed for hydrocodone content using a hydrocodone pine-EIA kit, purchased from Assay signatures, according to the manual. The plate was read on a plate reader (Spectra MAXPLUS-Molecular Devices Corporation) at 405nm and corrected at 580 nm. All results were compared to 100% activation control, i.e. cells treated with just comberson (no inhibitor added).

Pharmaceutical compositions/formulations, dosages and modes of administration

Pharmaceutically acceptable salts of the claimed compounds include acid addition salts and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples thereof include: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoylphthalate, hydrochloric acid/chloride, bromic acid/bromide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, pyroglutamate, gluconate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and 1-hydroxy-2-naphthoate (xinofoate).

Suitable base salts are formed from bases which form non-toxic salts. Examples thereof include: aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, hydramine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

For a review of suitable Salts, please see Handbook of Pharmaceutical Salts: properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of the claimed compounds can be prepared by one or more of three methods:

(i) by reacting the claimed compounds with the desired acid or base;

(ii) removal of acid-or base-labile protecting groups from appropriate precursors of the claimed compounds by use of the desired acid or base, or by ring-opening of appropriate cyclic precursors such as lactones or lactams; or

(iii) By converting one salt of the claimed compounds to another, by reaction with an appropriate acid or base, or by means of a suitable ion exchange column.

All three reactions are generally carried out in solution. The resulting salts can be precipitated, or collected by filtration, or recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to nearly non-ionized.

The compounds of the present invention may exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of a solid or a liquid. Generally, such materials do not give a characteristic X-ray diffraction pattern and, although exhibiting solid properties, are more often described as liquids. Upon heating, a transition from solid to liquid properties occurs, characterized by a change of state, typically of the second order ('glass transition'). The term "crystalline" refers to a solid phase in which the substance has a regular ordered internal structure at the molecular level and gives a characteristic X-ray diffraction pattern having defined peaks. Such materials, when heated sufficiently, will also exhibit liquid properties, but the change from solid to liquid is characterized by a phase change, typically first order ("melting point").

The compounds of the present invention may also exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water.

The currently accepted system of classification of organic hydrates is that of defining separation sites, channels or metal-ion coordinated hydrates-please see Polymorphism in Pharmaceutical Solids, k.r.morris (ed.h.g.brittain, Marcel dekker, 1995). An isolated site hydrate is a hydrate in which water molecules are separated by intervening organic molecules without directly contacting each other. In channel hydrates, water molecules are located in lattice channels where they are adjacent to other water molecules. In the metal-ion complex hydrate, water molecules are bonded to metal ions.

When the solvent or water is intimately bound, the complex will have a well-defined stoichiometry, independent of humidity. However, when the solvent or water is weakly bound, such as channel solvates and hygroscopic compounds, the water/solvent content will depend on the humidity and drying conditions. In this case, the non-stoichiometry would be the standard specification.

Also included within the scope of the invention are multicomponent complexes (in addition to salts and solvates) wherein the drug is present in stoichiometric or non-stoichiometric amounts with at least one other component. This type of complex includes clathrates (drug-host inclusion complexes), as well as co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components that are held together via non-covalent interactions, but may also be a complex of a neutral molecule and a salt. The co-crystals may be prepared by melt crystallization, recrystallization from solvents, or co-physical milling of the components-see Chem Commun, 17, 1889-. For a general review of multicomponent complexes, please see j.pharm. sci, 64(8), 1269-.

The compounds according to the invention may also be present in the mesomorphic state (mesomorphic phase or liquid crystal) when appropriate. Mesomorphic states are intermediate stages between a truly crystalline state and a truly liquid state (whether molten or solution). The mesogenic phenomena occurring as a result of a temperature change are described as "thermotropic", while those occurring due to the addition of a second component, such as water or another solvent, are described as "lyotropic". Compounds having the potential to form lyotropic mesomorphic phases are described as "amphiphilic" and consist of compounds having ionic character (e.g., -COO)^-Na⁺、-COO^-K⁺or-SO 3^-Na⁺) Or non-ionic (e.g. -N)^-N⁺(CH₃)₃) Molecular composition of polar head group. For more information see Crystal and the polarizing Microscope, N.H. Hartshrone and A.S tuner, 4 th^thVersion (Edward Arnold, 1970).

Hereinafter, all references to the claimed compounds include references to their salts, solvates, multi-component complexes and liquid crystals, as well as to solvates of their salts, multi-component complexes and liquid crystals.

The compounds of the present invention include the claimed compounds as defined above, including all polymorphs and crystal habit thereof, prodrugs and isomers thereof (including optical, stereo and tautomeric isomers) as defined below, and isotopically labeled claimed compounds.

Also within the scope of the invention are so-called "prodrugs" of the claimed compounds. Thus, certain derivatives of the claimed compounds, which may themselves have little or no pharmacological activity, may be converted to the claimed compounds having the desired activity when administered in or on the body, for example by hydrolytic cleavage. These derivatives are referred to as "prodrugs". For further information on the use of prodrugs see "Pro-Drugs as Novel Delivery Systems, Vol.14, ACSSymposium Series (T Higuchi and W Stella)" and "BiorevebleCarriers in Drug designs", Pergamon Press, 1987(ed.E B Roche, American Pharmaceutical Association).

Prodrugs according to the invention may be prepared, for example, by replacing the appropriate functional group present in the claimed compounds with certain moieties known to those skilled in the art, such as, for example, the 'pro-moiety' described in "Design of produgs" (Elsevier, 1985) by h.

Some examples of prodrugs according to the invention include:

(i) in the case where the claimed compounds contain a carboxylic acid function (-COOH), esters thereof, for example, wherein the hydrogen of the carboxylic acid function of the claimed compounds is replaced by (C)₁-C₈) An alkyl-substituted compound;

(ii) in the case where the claimed compounds contain an alcohol function (-OH), ethers thereof, for example, wherein the hydrogen of the alcohol function of the claimed compounds is replaced by (C)₁-C₆) Alkanoyloxymethyl-substituted compounds; and

(iii) the compounds claimed contain primary or secondary amino functions (-NH)₂or-NHR, where R.noteq.H), amides thereof, for example, where, as the case may be, one or two hydrogens of the amino function of the claimed compounds are replaced by (C)₁-C₁₀) Alkanoyl substituted compounds.

Further examples of substituent groups according to the preceding examples and examples of other prodrug types can be found in the above references.

Furthermore, certain claimed compounds may themselves be useful as prodrugs of other claimed compounds. Also included within the scope of the invention are metabolites of the claimed compounds, i.e., compounds that are formed in vivo following administration of the drug. Some examples of metabolites according to the invention include

(i) In case the claimed compounds contain methyl groups, the hydroxymethyl derivative thereof (-CH)₃→-CH₂OH)：

(ii) In case the claimed compound comprises an alkoxy group, its hydroxyl derivative (-OR → -OH);

(iii) in the case where the claimed compounds contain a tertiary amino group, the secondary amino derivative thereof (-NR)¹R²→-NHR¹or-NHR²)；

(iv) In case the claimed compounds comprise secondary amino groups, their primary amino derivatives (-NHR)¹→-NH₂)；

(v) In the case where the claimed compounds contain a phenyl moiety, the phenolic derivative thereof (-Ph → -PhOH); and

(vi) in the case where the claimed compounds contain an amido group, the carboxylic acid derivative thereof (-CONH)₂→COOH)。

The claimed compounds containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where the claimed compounds contain alkenyl or alkenylene groups, geometric cis/trans (or Z/E) isomers are possible. In the case of structural isomers that are interconvertible via a low energy barrier, tautomerism ('tautomerism') may occur. This may take the form of proton tautomerism in the claimed compounds containing, for example, imino, keto, or nitrile groups, or so-called valence tautomerism in compounds containing aromatic moieties. It follows from this that: a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the claimed compounds, including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition or base salts in which the counterion is optically active, e.g., d-lactate or 1-lysine, or racemic, e.g., d 1-tartrate or d 1-arginine.

The cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) may be reacted with an appropriate optically active compound (e.g., an alcohol) or, in the case of the claimed compounds containing an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization and one or both of the diastereomers can be converted to the corresponding pure enantiomers by methods well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) on an asymmetric resin comprising from 0 to 50% by volume isopropanol, typically from 2 to 20%, and from 0 to 5% by volume alkylamine, typically 0.1% diethylamine. Concentrating the eluate provides an enriched mixture.

When any racemate crystallizes, two different types of crystals may appear. The first type is the so-called racemate (true racemate) in which a homogeneous form of crystals is produced containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or an aggregate, in which the crystals of the two forms are produced in equimolar amounts, each containing a single enantiomer.

When two crystal forms present in a racemic mixture have equivalent physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be isolated by conventional techniques known to those skilled in the art-see, e.g., Stereochemistry of Organic Compounds by E.L.Eliel and S.H.Wilen (Wiley, 1994).

The invention includes all pharmaceutically acceptable isotopically-labeled compounds claimed in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the predominant one in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include: isotopes of hydrogen, e.g.²H and³h; isotopes of carbon, e.g.¹¹C，¹³C and¹⁴c; isotopes of chlorine, e.g.³⁶Cl; isotopes of fluorine, e.g.¹⁸F; isotopes of iodine, e.g.¹²³I and¹²⁵i; isotopes of nitrogen, e.g.¹³N and¹⁵n; isotopes of oxygen, e.g.¹⁵O、¹⁷O and¹⁸o; isotopes of phosphorus, e.g.³²Isotopes of P and sulfur, e.g.³⁵S。

Certain isotopically-labeled claimed compounds, for example those into which a radioisotope is incorporated, are useful for drug and/or substrate tissue distribution. With radioactive isotopes of tritium³H and carbon-14 i.e¹⁴C, is particularly useful for this purpose because of its ease of incorporation and ease of detection.

With heavier isotopes such as deuterium (i.e. deuterium²H) Instead, certain therapeutic benefits may be provided by greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements, and thus may be preferred in certain circumstances.

With positron-emitting isotopes, e.g.¹¹C、¹⁸F、¹⁵O and¹³n substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy.

Isotopically-labeled compounds of the claimed invention can generally be prepared by conventional techniques known to those skilled in the art or by analogous procedures to those described in the accompanying examples and preparations, using an appropriate isotopically-labeled reagent in place of the previously used unlabeled reagent.

Pharmaceutically acceptable solvates of the invention include those in which the solvent of the crystals is isotopically substituted, e.g. D₂O、d₆-acetone, d₆-DMSO。

Also within the scope of the present invention are intermediate compounds of the claimed compounds as defined above, all salts, solvates and complexes thereof, and all solvates and complexes of the salts thereof, as defined above for the claimed compounds. The present invention includes all polymorphs and crystal habit of the aforementioned substances.

When preparing the claimed compounds according to the invention, the person skilled in the art can routinely select the compound form, providing the best combination of features for this purpose. Such characteristics include melting point, solubility, processability and yield of intermediate form, and ease of isolation and purification of the product.

Pharmaceutical product

The claimed compounds should be evaluated for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., to select the most appropriate dosage form and route of administration to treat the proposed indication.

The compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained, for example, by precipitation, crystallization, freeze drying, spray drying or evaporation drying, for example as solid plugs, powders or films. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Examples of pharmaceutically active agents that may be used in combination include anti-infective agents, including, but not limited to, antibiotics, antivirals, and antifungals; anti-allergic agents and mast cell stabilizers; steroidal and non-steroidal anti-inflammatory drugs (such as nepafenac); cyclooxygenase inhibitors, including, but not limited to, Cox I and Cox II inhibitors; combinations of anti-infective agents with anti-inflammatory agents; a decongestant; anti-glaucoma agents including, but not limited to, adrenergic agents, beta-adrenergic blockers, alpha-adrenergic agonists, parasympathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and prostaglandins; combinations of anti-glaucoma agents; an antioxidant; a nutritional supplement; drugs for the treatment of cystoid macular edema, including, but not limited to, non-steroidal anti-inflammatory drugs; drugs for the treatment of age-related macular degeneration, including non-exudative (dry AMD) and exudative (wet AMD), including, but not limited to, angiogenesis inhibitors, including angiogenesis inhibitors that inhibit protein kinase receptors, including as VEGF receptor protein kinase receptors; and a nutritional supplement; medicaments for the treatment of herpes infections and CMV ocular infections; agents for the treatment of proliferative vitreoretinopathy including, but not limited to, antimetabolites and fibrinolytics; wound modulators, including but not limited to, growth factors; an antimetabolite; neuroprotective drugs including, but not limited to, eliprodil; and angiostatic steroids for treating diseases or conditions of the posterior segment 26 including, but not limited to, age-related macular degeneration (including non-exudative (dry AMD) and exudative (wet AMD)), choroidal neovascularization, retinopathy, retinitis, uveitis, macular edema, and glaucoma. Such angiostatic steroids are more fully disclosed in U.S. patent nos. 5,679,666 and 5,770,592. The non-steroidal anti-inflammatory drug used to treat cystoid macular edema is nepafenac.

In general, the pharmaceutical compositions of the present invention will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" as used herein refers to any ingredient other than the compound of the present invention. The choice of excipient will depend in large part on such factors as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the invention, as well as methods for their preparation, will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example,Remington’s Pharmaceutical Sciences，19^thversion (Mack publishing company, 1995).

Oral administration

The compounds of the invention may be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound may pass directly from the oral cavity into the bloodstream.

Suitable formulations for oral administration include solid formulations such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid filled), chewable tablets, multiple and nano-particles, gels, solid solutions, liposomes, films (including mucoadhesives), ovules, sprays and liquid formulations.

The liquid preparation comprises: suspensions, solutions, syrups and elixirs. These formulations may be presented as a filler for soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by reconstituting the solid, for example from a sachet.

The compounds of the present invention may also be used in fast dissolving, rapidly disintegrating dosage forms, such as those described in Liang and Chen (2001), Expert Opinion in therapeutic Patents, 11(6), 981-.

In tablet dosage forms, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form, depending on the dosage. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include: sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium (croscarmellose sodium), crospovidone (crospovidone), polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. The content of the disintegrant is generally 1 to 25% by weight, preferably 5 to 20% by weight of the dosage form.

Binders are typically used to provide the setting qualities of the tablet formulation. Suitable binders include: microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic colloids, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrate, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surfactant may be present in an amount of 0.2% to 5% by weight of the tablet and the glidant may be present in an amount of 0.2% to 1% by weight of the tablet.

Tablets also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant content is generally from 0.25 to 10% by weight, preferably from 0.5 to 3% by weight, of the tablet.

Other possible ingredients include: antioxidants, pigments, fragrances, preservatives and flavour masking agents.

Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant.

The tablet mixture can be compressed into tablets either directly or by means of a roller. The tablet mixture or mixture portion may be subjected to wet, dry or melt granulation, melt congealing or extrusion prior to tableting. The final formulation may comprise one or more layers and may or may not be coated; and may even be encapsulated.

Tablet formulations are discussed in "Pharmaceutical Dosage Forms" by h.lieberman and l.lachman, Marcel Dekker, N, y: tablets, Vol.1 ", 1980.

Consumable oral films for human or veterinary use can generally be in the form of soft, water-soluble or water-swellable films which dissolve rapidly or are mucoadhesive and generally comprise the claimed compounds, film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Certain components of the formulation may perform more than one function.

The claimed compounds may be water soluble or water insoluble. The water soluble compound typically comprises from 1 wt% to 80 wt%, more typically from 20 wt% to 50 wt% of the solute. The less soluble compounds may constitute a greater proportion of the composition, typically up to 88% by weight of the solute. Furthermore, the claimed compounds may be in the form of multiparticulate microbeads.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is generally present in an amount of from 0.01% to 99% by weight, more usually from 30% to 80% by weight.

Other possible ingredients include antioxidants, colour enhancers, flavour and flavour enhancers, preservatives, salivary gland stimulants, coolants, co-solvents (including oils), softeners, caking agents, anti-foaming agents, surfactants and taste masking agents.

The films of the present invention are generally prepared by evaporating and drying an aqueous film of the film applied to a releasable backing or paper. This can be done in a drying oven or tower, typically a combination coater dryer, or by freeze drying or vacuum preparation.

Solid formulations for oral administration may be formulated for immediate and/or modified controlled release. Modified release formulations include: delayed, sustained, pulsatile, controlled, targeted and programmed release.

Suitable modified release formulations for use in the present invention are described in U.S. Pat. No.6,106,864. Other suitable delivery techniques, such as high energy dispersions and details of osmotic and coated particles, are described in Verma et al, pharmaceutical technology On-line, 25(2), 1-14 (2001). The use of chewing gum for controlled release is described in WO 00/35298.

Parenteral administration

The compounds of the invention may also be administered directly into the blood, muscle or internal organs. Suitable parenteral administration forms include: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular/ventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include: needle (including micro-needle) syringes, needleless injectors, and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but in some applications may be suitably formulated as sterile nonaqueous solutions or as powdered dry forms for use in conjunction with a suitable carrier, e.g. sterile, pyrogen-free water.

Manufacture of parenteral formulations under sterile conditions, for example by lyophilization, may be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (I) for use in the preparation of parenteral solutions may be enhanced by appropriate formulation techniques, for example the addition of solubility enhancers.

Formulations for parenteral administration may be formulated for immediate and/or modified controlled release, the modified release formulation comprising: delayed, sustained, pulsatile, controlled, targeted and programmed release. Thus, the compounds of the present invention may be formulated for administration as a solid, semi-solid or thixotropic liquid as an implantable reservoir that provides modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

Topical administration of drugs

The compounds of the invention may also be applied topically to the skin or mucosa, i.e.: transdermal or penetrating the skin. Typical formulations for this use include: gels, hydrogels, emulsions, solutions, creams, ointments, powders for application, poultices, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical vectors include: alcohol, water, mineral oil, liquid mineral oil, white mineral oil, glycerol, polyethylene glycol and propylene glycol. Penetration enhancers may be added-see, for example, J Pharm Sci, 88(10), 955-958, Finnin and Morgan (1999, 10 months).

For topical administrationOther means include by electroporation, iontophoresis, sonophoresis and micro-or needleless (e.g. Powderject)^TM、Bioject^TMEtc.) injection method.

Formulations for topical administration may be formulated for immediate and/or modified controlled release. Modified release formulations include: delayed, sustained, pulsatile, controlled, targeted and programmed release.

Inhalation/intranasal administration

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone or in admixture, e.g. with a dry blend of lactose or with particles of a component, e.g. with a phospholipid such as phosphatidylcholine), or as an aerosol spray from a pressurised container, pump, spray, nebuliser (preferably one that uses electrohydrodynamic generation of a fine mist) or nebuliser, without or with the use of a suitable propellant, e.g. 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin.

Solutions or suspensions of the compounds of the invention in a pressurised container, pump, spray, atomiser or nebuliser, for example with ethanol, aqueous ethanol or other suitable agent for dispersing, dissolving or providing prolonged release of the active ingredient, a propellant as the solvent and, optionally, a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

The drug product is first micronised to a suitable size (typically less than 5 microns) for delivery by inhalation, before use in a dry powder or suspension formulation. This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (e.g. made from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention in a suitable powder base such as lactose or starch and a performance modifying agent such as 1-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or of the monohydrate type, the latter being preferred. Other suitable excipients include: dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable solution formulations for use in nebulizers which generate fine mist using electrohydrodynamics contain from 1. mu.g to 20mg of a compound of the invention per spray and the volume per spray may be from 1. mu.l to 100. mu.l. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that may be substituted for propylene glycol include: glycerol and polyethylene glycols.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium may be added to the inhaled/intranasal formulations of the invention.

Formulations for inhalation/intranasal administration may be formulated for immediate and/or modified controlled release, for example, with poly (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include: delayed, sustained, pulsatile, controlled, targeted and programmed release.

Rectal/intravaginal administration

The compounds of the invention may be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a conventional suppository base, but various suitable alternatives may be used.

Formulations for rectal/vaginal administration may be formulated for immediate and/or modified controlled release. Modified release formulations include: delayed, sustained, pulsed, controlled, targeted and programmed release.

Ocular/otic administration

For ophthalmic administration, the compounds of the invention may be delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound remains in contact with the ocular surface for a sufficient time 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, aqueous humor, vitreous humor, cornea, iris/ciliary body, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic carrier may be an ointment, vegetable oil or encapsulating material. The compounds of the invention may also be injected directly into the vitreous humor or aqueous humor.

In addition, the compounds may be administered by known, acceptable methods, such as sub-tenon and/or subconjunctival injection. The cornea and tenon's capsule define the outer surface of the eyeball. For the treatment of ARMD, CNV, retinopathy, retinitis, uveitis, Cystoid Macular Edema (CME), glaucoma, and other diseases or conditions of the posterior segment of the eye, it is preferred to directly place a specific amount of an ophthalmically acceptable pharmaceutically active agent depot on the outer surface of the sclera, beneath the tenon's capsule. In addition, in the case of ARMD and CME, it is most preferred to place the depot directly on the outer surface of the sclera, under the tenon's capsule, and generally over the macula.

In addition to the formulations described above, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly), by intramuscular injection, or by sub-tenon or intravitreal injection as described above.

In a particular embodiment of the invention, the compounds may be prepared for topical administration, in physiological saline (in combination with any preservatives and antimicrobial agents commonly used in ophthalmic formulations), and in eye drops. Solutions or suspensions may be prepared in pure form and administered several times daily. In addition, the composition of the present invention prepared as described above can also be administered directly to the cornea.

In addition, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

In other alternative embodiments, the composition is prepared with a muco-adhesive polymer that can bind to the cornea. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives such as a sparingly soluble salt.

In other embodiments, the compositions of the present invention may be used as an adjunct to conventional steroid therapy.

The pharmaceutical carrier for the hydrophobic compound is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD was a 3% w/v benzyl alcohol, 8% w/v non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300 to make up the volume of the solution in absolute ethanol. The VPD cosolvent system (VPD: 5w) contained VPD diluted 1: 1 with 5% aqueous glucose solution. This co-solvent system will dissolve hydrophobic compounds well, which itself results in low toxicity after systemic administration. The ratio of the co-solvent system can be varied widely without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent component may vary: for example, other low toxicity non-polar surfactants may be used in place of polysorbate 80; the size of the polyethylene glycol fraction may vary; other biocompatible polymers may be substituted for polyethylene glycol, such as polyvinylpyrrolidone; and other saccharides or polysaccharides may be substituted for glucose.

In addition, other delivery systems for hydrophobic drug compounds may be used. Liposomes and emulsions are examples of known hydrophobic drug delivery vehicles or carriers. Certain organic solvents such as dimethyl sulfoxide can also be used, although usually at the expense of greater toxicity. In addition, the compounds may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained release materials are established and known to those skilled in the art. Sustained release capsules, depending on their chemical nature, can release the compound for weeks to over 100 days. Other protein stabilization strategies may also be used depending on the chemical nature and biological stability of the therapeutic agent.

The pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Other techniques

The compounds of the invention may be combined with soluble macromolecular substances, such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are known to be universally useful in most dosage forms and routes of administration. Both inclusion and non-inclusion type complexes can be used. As a substitute for compounding with drugs, cyclodextrin can be used as an auxiliary additive, namely: as a carrier, diluent or dissolving agent. The most common of these uses are alpha-, beta-and gamma-cyclodextrins, examples of which are described in international patent applications WO 91/11172, WO 94/02518 and W098/55148.

Kit of parts

It may sometimes be desirable to administer a combination of active compounds, for example in order to treat a particular disease or condition, and the scope of the present invention includes two or more pharmaceutical compositions, at least one of which contains a compound according to the present invention, which may conveniently be combined in a kit of parts of the type suitable for co-administration of the compositions.

The kit of the present invention thus comprises two or more separate pharmaceutical compositions, at least one of which contains a compound as claimed in the present invention, and means for separately holding the compositions, such as a container, a separate bottle or a separate packet of aluminium foil. Examples of such kits are the familiar blister packs used for packaging tablets, capsules and the like.

The kits of the present invention are particularly suitable for administering different dosage forms, e.g. orally and parenterally, administering separate compositions at different dosage intervals, or titrating separate compositions against each other. To aid compliance, the kit will typically contain directions for administration and may provide a so-called memory aid.

Dosage form

For administration to human patients, the total daily dosage of the compounds of the invention will typically range from 0.5mg/kg body weight to about 100mg/kg, depending, of course, on the mode of administration. Preferred dosage rates are from 30mg/kg body weight to about 100mg/kg body weight. The total daily dose may be administered in single or divided doses and may fall outside the typical ranges given herein at the discretion of the physician.

These doses are based on an average human subject weighing about 60kg to 70 kg. The physician may determine dosages for individuals with weights outside this range, such as infants and the elderly.

For the avoidance of doubt, reference herein to "treatment" includes reference to curative, palliative and prophylactic treatment.

Examples

The examples, methods and preparations provided below further explain and exemplify the compounds of the invention and their methods of preparation. It is to be understood that the scope of the present invention is not limited to the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise noted, are present as racemic mixtures. Molecules with two or more chiral centers, unless otherwise noted, exist as racemic mixtures of diastereomers. The single enantiomers/diastereomers may be obtained via methods known to those skilled in the art.

The structure of the compound was confirmed by elemental analysis or NMR, giving peaks designated for the characteristic protons in the title compound as appropriate.¹H NMR Shift (. delta.)_H) Expressed in parts per million (ppm) low field with internal reference standards.

The invention will now be described with reference to the following examples. These examples should not be construed as limiting the scope of the invention but merely as illustrative thereof.

Method A

Example 1: n- (6-amino-4-methylpyridin-2-yl) -2- (4-cyanophenyl) -4-methyl 1, 3-thiazole-5-yl-sulfonamides

i. Preparation of tert-butyl (6-amino-4-methylpyridin-2-yl) carbamate

Lithium bis (trimethylsilyl) amide (34.6mL, 1M) was added to a solution of 4-methyl-pyridine-2, 6-diamine (2.13g, 17.3mmol, 1 equiv) in tetrahydrofuran (18mL) at 0 deg.C. After 30 min di-tert-butyl dicarbonate (3.78g, 17.3mmol) was added to the reaction mixture. After completion, the reaction was warmed to 24 ℃ and concentrated in vacuo (. about.25 mm Hg). To the resulting solid was added 1: 1 saturated ammonium chloride and brine solution (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). Purification by high performance flash chromatography (0 → 30% ethyl acetate in hexanes) afforded the carbamate intermediate (1.94g, 50%).¹H NMR(CDCl₃，400MHz)，δ：7.12(s，1H)，7.09(brs，1H)，6.02(br s，2H)，2.23(s，3H)，1.51(s，9H)；LRMS(ESI) m/z：224.2。

Preparation of tert-butyl [6- ({ [2- (acetylamino) -4-methyl-1, 3-thiazol-5-yl ] sulfonyl } amino) -4-methylpyridin-2-yl ] carbamate

To a solution of tert-butyl (6-amino-4-methylpyridin-2-yl) carbamate (1.2g, 6.0mmol) in pyridine (30mL) was added 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (1.5g, 6.0 mmol). The resulting mixture was stirred at 24 ℃ for 16 hours. The reaction was concentrated in vacuo (-25 mmHg). Purification by high performance flash chromatography (0 → 5% methanol in dichloromethane) afforded intermediate (2.1g, 80%).¹H NMR(400 MHz，CDCl₃)，δ：7.43(brs，1H)，6.99(s，1H)，5.31(s，1H)，2.34(s，3H)，2.31(s，3H)，2.22(s，3H)，1.54(s，9H)；LRMS(ESI)m/z：342[M-CO₂C(CH₃)₃]⁺。

Preparation of tert-butyl (6- { [ (2-amino-4-methyl-1, 3-thiazol-5-yl) sulfonyl ] amino } -4-methylpyridin-2-yl) carbamate

Tert-butyl [6- ({ [2- (acetylamino) -4-methyl-1, 3-thiazol-5-yl)]Sulfonyl } amino) -4-methylpyridin-2-yl]A solution of carbamate (2.1g, 4.8mmol, 1 equiv) and 1N aqueous sodium hydroxide (7.2mL) in methanol (30mL) was heated to 50 ℃ for 48 hours. After cooling to 24 ℃, the reaction mixture was concentrated in vacuo (-25 mmHg). The resulting solid was dissolved in water (20 mL). The solution was neutralized with concentrated hydrochloric acid until pH 7. The resulting solid was collected by filtration and washed with water (30mL) and ether (2 × 30mL) (1.59g, 83%).¹H NMR(400 MHz，CDCl₃)，δ：8.29(br s，1H)，7.48(s，1H)，6.91(s，1H)，2.40(s，3H)，2.33(s，3H)，1.52(s，9H)；LCMS(ESI)m/z：400.2。

Preparation of tert-butyl (6- { [ (2-bromo-4-methyl-1, 3-thiazol-5-yl) sulfonyl ] amino } -4-methylpyridin-2-yl) carbamate

To a solution of tert-butyl (6- { [ (2-amino-4-methyl-1, 3-thiazol-5-yl) sulfonyl ] amino } -4-methylpyridin-2-yl) carbamate (1.59g, 3.98mmol, 1 equiv) and copper (II) bromide (0.55g, 2.47mmol, 0.62 equiv) in acetonitrile (30mL) was added tert-butyl nitrite (0.71mL, 5.97mmol, 1.5equiv) at 65 ℃. The reaction mixture was observed to turn from green to red and gas evolution occurred. After 10 minutes, when evolution of gas ceased, the reaction mixture was cooled to 24 ℃ and concentrated in vacuo (-25 mmHg). The resulting solid was dissolved in ethyl acetate (30mL) and the resulting solution was washed with water (30mL) acidified with sulfuric acid (0.5 mL). The collected organics were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by high performance flash chromatography (0 → 1.5% methanol in dichloromethane) afforded the above intermediate (0.96g, 52%). LRMS (ESI) m/z: 463.

v. preparation of tert-butyl [6- ({ [2- (4-cyanophenyl) -4-methyl-1, 3-thiazol-5-yl ] sulfonyl } -amino) -4-methylpyridin-2-yl ] carbamate

Reacting tert-butyl (6- { [ (2-bromo-4-methyl-1, 3-thiazol-5-yl) sulfonyl]A solution of amino } -4-methylpyridin-2-yl) carbamate (0.96g, 2.08mmol, 1 equiv), 4-cyanophenylboronic acid (0.336g, 2.29mmol, 1.1 equiv) and cesium carbonate (2.03g, 6.24mmol, 3 equiv) in 2: 1 dimethoxyethane/water (30mL) was purged with nitrogen for 15 minutes. Then dichloro [1, 1' -bis (diphenylphosphino) ferrocene is added]Palladium (II) chloride (0.068g, 0.08mmol, 0.04 equiv), and the resulting mixture was purged with nitrogen for an additional 15 minutes. The reaction was heated to 80 ℃ for 1 hour. After cooling to 24 deg.C, the solution was concentrated in vacuo (. about.25 mmHg). The resulting aqueous mixture was extracted with ethyl acetate (60 mL). The collected organics were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by high performance flash chromatography (0 → 10% ethyl acetate in hexanes) afforded intermediate (0.334g, 33%).¹H NMR(400MHz，CDCl₃)，δ：7.97(d，J＝8.3Hz，2H)，7.73(d，J＝8.3Hz，2H)，7.63 (brs，1H)，7.43(s，1H)，6.90(s，1H)，2.65(s，3H)，2.32(s，3H)，1.50(s，9H)；LRMS(ESI)m/z486.1。

Preparation of N- (6-amino-4-methylpyridin-2-yl) -2- (4-cyanophenyl) -4-methyl-1, 3-thiazole-5-sulfonamide

Tert-butyl [6- ({ [2- (4-cyanophenyl) -4-methyl-1, 3-thiazol-5-yl)]Sulfonyl } amino) -4-methylpyridin-2-yl]To a solution of carbamate (0.334g, 0.68mmol, 1 equiv) in dichloromethane (3mL) was added trifluoroacetic acid (0.21mL, 4 equiv). The reaction mixture was stirred at 24 ℃ for 48 hours. The solution was neutralized with saturated aqueous sodium bicarbonate and the resulting solution was extracted with dichloromethane (3 × 20 mL). The collected organics were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by high performance flash chromatography (0 → 1% methanol in dichloromethane) afforded the title product N- (6-amino-4-methylpyridin-2-yl) -2- (4-cyanophenyl) -4-methyl-1, 3-thiazole-5-sulfonamide (0.22g, 81%).¹H NMR(400 MHz，DMSO-d₆) δ: 12.08(brs, 1H), 8.09(d, J ═ 8.3Hz, 2H), 7.95(d, J ═ 8.3Hz, 2H), 6.62(brs, 2H), 6.12(s, 1H), 5.79(s, 1H), 2.59(s, 3H), 2.08(s, 3H); hrms (esi): calculated value C₁₇H₁₆N₅O₂S₂m/z 386.0740; measured value: 386.0745, respectively; analytical calculation C₁₇H₁₅N₅O₂S₂: c, 52.97; h, 3.92; n, 18.17; measured value: c, 52.75; h, 3.76; and N, 18.03.

Method B

Example 2:

(+) -4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl]Biphenyl-4-sulfonamides and (-) -4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl]Biphenyl-4-sulfonamides

i. Preparation of N- [6- (1-hydroxyethyl) pyridin-2-yl ] -2, 2-dimethylpropionamide

To an ice-cooled solution of N- (6-formylpyridin-2-yl) -2, 2-dimethylpropionamide (4.0g, 19.4mmol) in tetrahydrofuran (30mL) was added dropwise methylmagnesium chloride (13.6mL, 40.7mmol, 3M in THF). After 2 hours, the reaction was quenched with saturated aqueous ammonium chloride (10mL) and diluted with ethyl acetate (50 mL). The mixture was saturated NaHCO₃Aqueous (2x50mL) rinse. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (2: 1 hexanes/EtOAc) to afford intermediate (0.56g, 49%) as a clear oil.¹H NMR(400MHz，CDCl₃)，δ：8.14(d，J＝8.1Hz，1H)，8.00(brs，1H)，7.70(t，J＝7.8Hz，1H)，7.00(d，J＝7.5Hz，1H)，4.82(m，1H)，3.81(d，J＝5.0Hz，1H)，1.49(d，J＝6.5Hz，3H)，1.35(s，9H)；LRMS(ESI)：m/z：223.2。

Preparation of 1- (6-aminopyridin-2-yl) ethanol

In the presence of N- [6- (1-hydroxyethyl) pyridin-2-yl]-2, 2-Dimethylpropionamide (2.0g, 9.6mmol) in dioxane (20mL) 9N HCl in water was addedSolution (10 mL). The reaction mixture was warmed to 100 ℃ for 24 hours. After cooling to 25 ℃, the solution was neutralized to pH 9 with solid NaOH and diluted with EtOAc (50 mL). The resulting mixture was saturated NaHCO₃Aqueous (2 × 30mL) rinse. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was dissolved in dichloromethane (10: 1, 5 mL). Ether (10mL) was added and the solution was allowed to stand for 24 hours. The resulting crystals were filtered and washed with diethyl ether (2 × 10mL) to afford the title intermediate (0.65g, 49%) as a white solid.¹H NMR(400 MHz，CDCl₃)，δ：7.43(t，J＝7.5Hz，1H)，6.59(d，J＝7.3Hz，1H)，6.39(d，J＝8.1Hz，1H)，4.72(q，J＝6.3Hz，1H)，4.43(bs，2H)，4.21(bs，1H)，1.45(d，J＝6.3Hz，3H)；LRMS(ESI)：m/z：139.1。

(+) -4 '-cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl ] biphenyl-4-sulfonamide and (-) -4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl ] biphenyl-4-sulfonamide

To a solution of 1- (6-aminopyridin-2-yl) ethanol (0.20g, 1.4mmol) and diisopropylethylamine (0.22mL, 1.8mmol) in dichloromethane (5mL) was added (trimethyl) chlorosilane (0.48mL, 2.9 mmol). After 1 hour, the reaction mixture was concentrated and the resulting residue was dissolved in dichloromethane (2mL) and pyridine (2 mL). 4' -Cyanobiphenyl-4-sulfonyl chloride (0.43g, 1.53mmol) was then added to the reaction mixture. After 3 hours, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with acetic acid (1mL) and methanol (1mL) and stirred for 0.5 h. The reaction mixture was then diluted with ethyl acetate (50mL) and washed with saturated aqueous sodium bicarbonate (2 × 30 mL). After concentrating the organic layer, the resulting residue was purified by flash column chromatography (1: 1 hexane/ethyl acetate). The resulting racemic product was prepared by dissolving in diethyl ether (5mL) and adding HCl (1N in Et)₂O) to provide the racemic product of the title as a white solid (0.21g, 37%).¹H NMR(400MHz，CD₃OD)，δ：8.01(d，J＝8.3，2H)，7.96(t，J＝8.1，1H)，7.81(d，J＝8.6Hz，2H)，7.78-7.73(m，4H)，7.21-7.16(m, 2H), 4.86(q, J ═ 6.6Hz, 1H), 1.38(d, J ═ 6.6Hz, 3H). Hrms (esi): calculated value C₂₀H₁₈N₃O₃S m/z: 380.1069, respectively; measured value: 380.1061, respectively; analytical calculation C₂₀H₁₇N₃O₃S HCl: c, 57.76; h, 4.36; n, 10.10; measured value: c, 57.87; h, 4.58; and N, 9.88.

The racemic free base is separated via preparative enantiomeric separation, developed using Supercritical Fluid Chromatography (SFC) technology, in which supercritical carbon dioxide constitutes the majority of the mobile phase. Resolution and separation of chiral enantiomers in Berger SFC Multiram^TMOn a purification system (Mettler Toledo AutoChem, Inc). Conditions for preparative chromatography to separate enantiomers included Chiralpak AD-H (amylose tris- (3, 5-dimethylphenylcarbamate)) 250x21mm, 5 μ half preparative column as Chiral stationary phase (Chiral Technologies, Inc.). The column temperature was maintained at 35 ℃. The mobile phase is supercritical CO₂40% methanol was used as modifier, maintained isocratically at a flow rate of 50mL/min and a constant pressure of 100 bar.

Enantiomer 1[ alpha ]]_D(MeOH)＝-66.67°。

Enantiomer 2[ alpha ]]_D(MeOH)＝+100°。

Example 3: (-) -4' -cyano-N- [6- (1-hydroxypropyl) pyridin-2-yl]Biphenyl radical -4-sulfonamides and (+) -4' -cyano-N- [6- (1-hydroxypropyl) pyridin-2-yl]Biphenyl-4- Sulfonamides

The title racemic mixture was prepared using the procedure described in preparative example 2 above, except that ethylmagnesium bromide was used instead of methylmagnesium chloride. The racemic mixture is maintained as the free base without further treatmentAnd converted into salt. Purification by high performance flash chromatography (15 → 60% EtOAc in hexanes) afforded the product (0.267g, 83%).¹H NMR(400MHz，CDCl₃)，δ：8.05(d，J＝8.3Hz，2H)，7.76(m，2H)，7.58-7.71(m，6H)，7.15(d，J＝8.3Hz，1H)，6.81(d，J＝7.6Hz，1H)，4.62(dd，J＝7.2，4.9Hz，1H)，1.60-1.87(m，2H)，0.89(t，J＝7.5Hz，3H)；LRMS(ESI)：m/z：394.0。

Preparative enantiomeric separations were similar to those used in example 2 above. Conditions for preparative chromatography to separate enantiomers included Chiralpak AD-H (amylose tris- (3, 5-dimethylphenylcarbamate)) 250x21mm, 5 μ half preparative column as Chiral stationary phase (Chiral Technologies, Inc.). The column temperature was maintained at 35 ℃. The mobile phase is supercritical CO₂The flow rate was maintained isocratically at 55mL/min and a constant pressure of 140 bar using 45% methanol as modifier. The sample was dissolved in methanol to 100mg/mL and the column loading capacity was 50mg per 1mL injection. The total run time for each injection was 6.1 minutes. The retention time of the first enantiomer (-) was 4.0 min and the second eluted enantiomer (+) was eluted from the column at 5.0 min. Specific optical rotation, [ alpha ]]_DThe temperatures were measured at-17.34 ℃ and +22.29 ℃ for (-) and (+) respectively.

Enantiomer 1: (-) -4' -cyano-N- [6- (1-hydroxypropyl) pyridin-2-yl]Biphenyl-4-sulfonamide. [ alpha ] to]_D(MeOH) — 19.77 °; analytical calculation C₂₁H₁₉N₃O₅S 0.17H₂O: c, 63.61; h, 4.92; and N, 10.60. Measured value: c, 63.59; h, 4.93; and N, 10.60.

Enantiomer 2: (+) -4' -cyano-N- [6- (1-hydroxypropyl) pyridin-2-yl]Biphenyl-4-sulfonamide. [ alpha ] to]_D(MeOH) +18.92 °; analytical calculation C₂₁H₁₉N₃O₅S 0.14H₂O: c, 63.70; h, 4.91; n, 10.61. Measured value: c, 63.68; h, 4.92; n, 10.45.

Example 4: (+) -4' -cyano-N- [6- (1-hydroxy)Ethyl) pyridin-2-yl]-3-methyl Biphenyl-4-sulfonamides and (-) -4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl]-3- Methylbiphenyl-4-sulfonamides

Reagent 4-bromo-2-methyl-N- (6- {1- [ (trimethylsilyl) oxy]Ethyl } pyridin-2-yl) benzenesulfonamide was prepared following example 2 above to prepare 4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl]Biphenyl-4-sulfonamide. To the sulfonamide reagent (0.11g, 0.3mmol) was added 4-cyanophenylboronic acid (0.087g, 0.59mmol), Pd (PPh)₃)₄(0.034, 0.03mmol), sodium carbonate (0.1g, 1.18mmol), DMF (2mL) and water (1mL) and the mixture was placed in a microwave tube and heated with a microwave at 200 ℃ for 30 minutes. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by high performance flash chromatography (15 → 70% EtOAc in hexanes) provided the title product above (0.081g, 74%).¹H NMR(400MHz，CDCl₃) δ: 8.19(d, J ═ 8.1Hz, 1H), 7.70-7.77(m, 2H), 7.63-7.69(m, 2H), 7.57(t, J ═ 8.0Hz, 1H), 7.46-7.53(m, 2H), 7.00(m, 1H), 6.81(m, 1H), 4.78(m, 1H), 2.78(s, 3H), 1.44(d, J ═ 6.6Hz, 3H); HRMS (ESI) m/z calculated value C₂₁H₂₀N₃O₅S394.1220, found 394.1215;

preparative enantiomeric separations were similar to those used in example 2 above. Conditions for preparative chromatography for separation of enantiomers include Chiralcel OJ-H (cellulose tris- (4-methylbenzoate) 250x21mm, 5 μ half preparative column as Chiral stationary phase (chiraltechnologies, Inc.) the column temperature is maintained at 35 ℃₂With 25% isopropanol as modifier, isocratically maintained at a flow rate of 50mL/min and a constant pressure of 140 bar.

Enantiomer 1: (-) -4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl]-3-methylbiphenyl-4-sulfonamide. [ alpha ] to]_D(MeOH) — 12.12 °; analytical calculation C₂₁H₁₉N₃O₅S0.21 H₂O: c, 63.49; h, 4.93; n, 10.58. Measured value: c, 63.45; h, 4.73; n, 10.54.

Enantiomer 2: (+) -4' -cyano-N- [6- (1-hydroxyethyl) pyridin-2-yl]-3-methylbiphenyl-4-sulfonamide. [ alpha ] to]_D(MeOH) +11.43 °; analytical calculation C₂₁H₁₉N₃O₅S0.20 H₂O: c, 63.52; h, 4.92; n, 10.58. Measured value: c, 63.55; h, 4.85; n, 10.51.

Example 5:

n- (6-aminopyridin-2-yl) -4-chloro-2-fluoro-5-methylbenzenesulfonamide

To a solution of 2, 6-diaminopyridine (178mg, 1.6mmol, 2.2 equiv) in pyridine (7mL) was added 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (188mg, 0.735mmol, 1 equiv) at 24 ℃. After 18 hours, the reaction mixture was concentrated in vacuo. The resulting residue was partitioned between saturated aqueous ammonium chloride (20mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The collected organics were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the product (69mg, 27%).¹H NMR(400MHz，CDCl₃) δ: 7.80(d, J ═ 7.6Hz, 1H), 7.42(t, J ═ 8.3Hz, 1H), 7.08(d, J ═ 9.4Hz, 1H), 6.83(d, J ═ 8.3Hz, 1H), 6.00(d, J ═ 8.3Hz, 1H), 5.91(s, 2H), 2.38(s, 3H); calculated value C₁₂H₁₂N₃O₂ClFS m/z 316.0318; measured value: 316.0322, respectively; analysis ofCalculating C₁₂H₁₁N₃O₂ClFS 0.27 CH₃CO₂H: c, 45.37; h, 3.67; n, 12.66; measured value: c, 45.08; h, 3.67; and N, 12.65.

Example 9: 4' -cyano-N- [6- (hydroxymethyl) pyridin-2-yl]Biphenyl-4-sulfonyl group Amines as pesticides

i. Preparation of N- [6- (1-hydroxyethyl) pyridin-2-yl ] -2, 2-dimethylpropionamide

To a solution of N- (6-formylpyridin-2-yl) -2, 2-dimethylpropionamide (3.0g, 14.9mmol) in methanol (10mL) was added sodium borohydride (1.37g, 37.1mmol) and stirred for 3 hours. The mixture was diluted with ethyl acetate (50 mL). The mixture was washed with aqueous hydrochloric acid (2x30mL, 0.1N) and saturated sodium bicarbonate (2x50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide the title intermediate above as a white solid (2.49g, 80%).¹H NMR(400MHz，CDCl₃)，δ：8.16(d，J＝8.3Hz，1H)，8.00(brs，1H)，7.71(t，J＝7.8Hz，1H)，7.12(d，J＝7.5Hz，1H)，4.05-3.96(m，2H)，1.35(s，9H)；LRMS(ESI)：m/z209.2。

Preparation of (6-aminopyridin-2-yl) methanol

To a solution of dioxane (15mL) was added N- [6- (1-hydroxy)Ethyl) pyridin-2-yl]2, 2-Dimethylpropionamide (1.5g, 7.2mmol) and aqueous hydrochloric acid (6N, 15mL), and the mixture was stirred at 90 ℃ for 14 hours. The solution was cooled to 0 ℃, triturated with ether (2 × 30mL) and the aqueous layer was neutralized to about pH8 with sodium hydroxide. The mixture was diluted with chloroform/IPA (10: 1, 50 mL). The mixture was washed with saturated brine solution (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide the title intermediate as a white solid (0.86g, 96%). HPLC: r_t0.628 minutes. (99.5% area).¹HNMR(400MHz，CDCl₃)，δ：7.48(t，J＝7.4Hz，1H)，6.66(d，J＝7.3Hz，1H)，6.50(d，J＝8.4Hz，1H)，4.58(s，2H)，4.23(bs，2H)。LCMS(ESI)：m/z：125.2。

Preparation of 6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) pyridin-2-amine

To a solution of dichloromethane (15mL) was added (6-aminopyridin-2-yl) methanol (0.72g, 5.8mmol), tert-butyl (chloro) dimethylsilane (1.05g, 6.95mmol) and triethylamine (1.05mL, 7.53 mmol). The mixture was stirred for 24 hours and washed with saturated sodium bicarbonate (2x30mL) and aqueous hydrochloric acid (2x30mL, 0.1N). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography eluting with hexane: ethyl acetate (1: 1), the fractions were combined and concentrated to provide the title product as a white solid (1.06g, 70%). HPLC: r_t2.58 minutes (96.5% area).¹H NMR(400MHz，CDCl₃)，δ：7.34(t，J＝7.6Hz，1H)，6.75(d，J＝7.6Hz，1H)，6.25(d，J＝8.1Hz，1H)，4.54(s，2H)，4.27(bs，2H)，0.84(s，9H)，0.11(s，6H)；LRMS(ESI)：m/z：239.2。

Preparation of N- [6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) pyridin-2-yl ] -4' -cyanobiphenyl-4-sulfonamide

To a solution of dichloromethane (3mL) was added 6- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) pyridin-2-amine (0.15g, 0.63mmol), 4' -cyanobiphenyl-4-sulfonyl chloride (0.18g, 0.63mmol), and pyridine (1.0 mL). The mixture was stirred for 3 hours and then washed with saturated sodium bicarbonate (2x30mL) and aqueous hydrochloric acid (2x30mL, 0.1N). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification was accomplished by silica gel chromatography eluting with hexane: ethyl acetate (1: 1) and the combined fractions were concentrated to provide the title intermediate as a white solid (0.21g, 76%) as described above. HPLC: r_t4.236 minutes (81% area).¹H NMR(400MHz，CDCl₃)，δ：7.89(d，J＝8.3Hz，2H)，7.60(d，J＝8.3Hz，2H)，7.52-7.49(m，4H)，7.43(t，J＝7.6Hz，1H)，6.87(d，J＝8.6Hz，1H)，6.59(d，J＝7.3Hz，1H)，6.22(d，J＝8.0Hz，1H)，4.55(s，2H)，0.82(s，9H)，0.05(s，6H)；LRMS(ESI)：m/z：480.1。

v. preparation of 4' -cyano-N- [6- (hydroxymethyl) pyridin-2-yl ] biphenyl-4-sulfonamide

To a solution of ethanol (5mL) was added N- [6- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) pyridin-2-yl]-4' -cyanobiphenyl-4-sulfonamide (0.21g, 0.44mmol) and aqueous hydrochloric acid (1.0mL, 1N). The mixture was stirred for 2 hours and then diluted with ethyl acetate (40 mL). The mixture was washed with saturated sodium bicarbonate (2x30mL) and aqueous hydrochloric acid (2x30mL, 0.1N). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography eluting with hexane to ethyl acetate (1: 1) and the purified fractions were combined and concentrated. The residue was recrystallized from ethyl acetate and dried in vacuo to afford the title product as an off-white crystalline solid (0.13g, 79%) above. HPLC: r_t2.450 min (99.5% area).¹H NMR(400 MHz，CD₃OD), δ: 7.92(d, J ═ 8.6Hz, 2H), 7.71-7.66(m, 6H), 7.53(t, J ═ 8.1Hz, 1H), 6.94(d, J ═ 8.6Hz, 1H), 6.83(d, J ═ 8.1Hz, 1H), 4.39(s, 2H); hrms (esi): m/z: calculated value (C)₁₉H₁₆N₃O₃S): 366.0912, respectively; measured value: 366.0914.

method C

Example 6: n- (6-amino-4-methylpyridin-2-yl) -4-chloro-2-fluoro-5-methylbenzenesulfone Amides of carboxylic acids

To a solution of tert-butyl (6-amino-4-methylpyridin-2-yl) carbamate (146mg, 0.652mmol, 1 equiv) in pyridine (3mL) was added 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (200mg, 0.782mmol, 1.2 equiv) at 24 ℃. After 24 hours, the reaction mixture was concentrated in vacuo (. about.25 mmHg). The residue was diluted with saturated aqueous ammonium chloride (10mL) and the resulting solution was extracted with ethyl acetate (3 × 5 mL). The collected organics were dried over anhydrous sodium sulfate, filtered and concentrated.

Trifluoroacetic acid (1mL) was added to a solution of the crude product in dichloromethane (3mL) at 24 ℃. After 16 hours, the reaction mixture was concentrated in vacuo (-25 mmHg). Purification by high performance flash chromatography (0.5 → 3% methanol/dichloromethane) afforded the named compound (212mg, 98%).¹H NMR(400 MHz，DMSO-d₆) δ: 12.00(brs, 1H), 7.82(d, J ═ 7.8Hz, 1H), 7.49(d, J ═ 9.6Hz, 1H), 6.51(brs, 2H), 6.03(s, 1H), 5.74(s, 1H), 2.34(s, 3H), 2.05(s, 3H); calculated value C₁₃H₁₄N₃O₂ClFS m/z: 330.0474, respectively; measured value: 330.0470.

example 7: n- (6-aminopyridin-2-yl) -4-butoxybenzenesulfonamide

4-Butoxybenzenesulfonyl chloride (160. mu. mol, 2.0eq, 400. mu.L, 0.40M in anhydrous pyridine) and tert-butyl (6-aminopyridin-2-yl) carbamate (80. mu. mol, 1.0eq, 400. mu.L, 0.20M in anhydrous pyridine) were added to a test tube (75X10mm, heat dried at 110 ℃ for 16 hours before use) equipped with a stir bar. The tube was covered with Parafilm and stirred at room temperature for 24 hours. The solvent (pyridine) was evaporated under vacuum. Trifluoroacetic acid (320 μ L, 52.0eq, excess, neat) was added to the tube. The tube was capped and vortexed at room temperature for 5 hours. Excess TFA was removed in vacuo, and the residue was dissolved in DMSO (1.340mL) and purified by HPLC.¹H NMR(500MHz，DMSO-d₆)δ：7.73(d，J＝7.7Hz，2H)，7.21(t，J＝7.2Hz，1H)，6.96(d，J＝6.9Hz，1H)，6.10(d，J＝6.1Hz，1H)，5.92(d，J＝5.9Hz，1H)，3.96(t，J＝6.6Hz，1H)，1.64(m，2H)，1.37(m，2H)，0.87(t，J＝7.4Hz，3H)。LRMSm/z：322.0。

Method D

Example 8: 4' -cyano-N- [6- (ethylamino) pyridin-2-yl]Biphenyl-4-sulfonyl group Amines as pesticides

To a suspension of N- (6-aminopyridin-2-yl) -4' -cyanobiphenyl-4-sulfonamide (0.08g, 0.23mmol) in methanol (1mL) was added acetaldehyde (0.02mL, 0.34mmol) and molecular sieves (4 Å). After stirring the resulting suspension for 30 minutes, sodium cyanoborohydride (0.043g, 0.70mmol) was then added. After 6 hours, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and the aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic layers were washed with brine and with sodium sulfateAnd (5) drying. Purification by high performance flash chromatography (25% EtOAc in hexanes) afforded the product (0.055g, 63%).¹H NMR(400MHz，CDCl₃) δ: 8.03(d, J ═ 8.6Hz, 2H), 7.73(d, J ═ 8.6Hz, 2H), 7.65(d, J ═ 8.6Hz, 2H), 7.62(d, J ═ 8.6Hz, 2H), 7.40(t, J ═ 8.3Hz, 1H), 6.64(d, J ═ 8.1Hz, 1H), 5.88(d, J ═ 8.3Hz, 1H), 3.10-3.21(m, 2H)1.23(t, J ═ 7.2Hz, 3H); LRMS (ESI) m/z: 379.12, respectively; analytical calculation C₂₀H₁₈N₄O₂S: c, 63.47; h, 4.79; n, 14.80. Measured value: c, 63.11; h, 4.82; n, 14.63.

Furthermore, the remaining examples shown in table 1 can be prepared by one skilled in the art following the procedures described in the above examples using appropriate starting materials.

TABLE 1

In table 1, "min" means minutes; the term "MS" means mass spectrometry; the term m/z means mass to charge ratio; the term "HPLC" means high performance liquid chromatography; the term "Ki" means activity against 11 β HSD1, as measured by the assay described above; N/A means not tested.

TABLE 2

Comparative example a is example 117 from WO2005-0148631a 1.

While various embodiments of the invention have been described above, those skilled in the art will recognize other minor variations that would fall within the scope of the invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims (14)

1. A compound of formula (I):

wherein

R¹Is H or (C)₁-C₄) An alkyl group;

R²is H or (C)₁-C₄) An alkyl group;

R³is H, halogen, (C)₁-C₆) Alkyl or (C)₁-C₆) An alkoxy group;

and when the compound is a chiral compound, the compound is the (+) enantiomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

2. The compound, pharmaceutically acceptable salt, hydrate or solvate thereof according to claim 1, wherein R is¹Is H.

3. A compound, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 or 2, wherein R is³Is H or CH₃。

4. A compound, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1, 2 or 3, wherein R is²is-CH₂CH₃。

5. A compound selected from:

and

wherein when the compound is a chiral compound, the compound is the (+) enantiomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

6. A compound having the formula II

Or a pharmaceutically acceptable salt, hydrate or solvate thereof.

7. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

8. A method of treating a disease, condition, or disorder that would benefit from treatment with an inhibitor of 11 β HSD1, comprising administering to a mammal an effective amount of a compound, pharmaceutically acceptable salt, hydrate, or solvate thereof, as claimed in any one of claims 1, 2, 3, 4, 5, or 6.

9. The method of claim 8, wherein the disease, condition or disorder is type 2 diabetes.

10. The method of claim 8, wherein the disease, condition or disorder is selected from the group consisting of: metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, atherosclerosis, dementia, depression, or a disease in which the liver is a target organ.

11. The method of claim 10 wherein the disease, condition or disorder is glaucoma and the method comprises administering to the mammal an effective amount of a compound, pharmaceutically acceptable salt, hydrate or solvate thereof, as claimed in any one of claims 1, 2, 3, 4, 5 or 6, in combination with a prostanoid agonist, wherein the agonist is latanoprost.

12. A compound, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1, 2, 3, 4, 5 or 6 for use as a medicament.

13. Use of a compound, pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1, 2, 3, 4, 5 or 6, in the manufacture of a medicament for the treatment of a disease, condition or disorder that would benefit from treatment with an 11 β HSD1 inhibitor, such as type 2 diabetes.

14. A novel compound, salt, hydrate, solvate, intermediate, method of treatment, pharmaceutical composition or use substantially as described herein with reference to the examples.