WO2006008644A1 - Composes anti-diabetiques - Google Patents

Composes anti-diabetiques Download PDF

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Publication number
WO2006008644A1
WO2006008644A1 PCT/IB2005/002159 IB2005002159W WO2006008644A1 WO 2006008644 A1 WO2006008644 A1 WO 2006008644A1 IB 2005002159 W IB2005002159 W IB 2005002159W WO 2006008644 A1 WO2006008644 A1 WO 2006008644A1
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Prior art keywords
alkyl
compound
cyano
prodrug
hydrogen
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PCT/IB2005/002159
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English (en)
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Shawn Cabral
Bernard Hulin
David Walter Piotrowski
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Pfizer Products Inc.
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Publication of WO2006008644A1 publication Critical patent/WO2006008644A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to selective inhibitors of the enzyme dipeptidyl peptidase-IV (DPP-IV), pharmaceutical compositions thereof, and uses thereof for treating diseases associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes, metabolic syndrome (Syndrome X or insulin resistance syndrome), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, inflammatory bowel syndrome, and preventing disease progression in Type 2 diabetes.
  • DPP-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2-position.
  • the physiological roles of DPP-IV have not been fully elucidated, but it is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T-cell activation, among others.
  • DPP-IV has been implicated in the control of glucose homeostasis because its substrates include the incretin peptides glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Cleavage of the N-terminal amino acids from these peptides renders them functionally inactive.
  • GLP-1 has been shown to be an effective anti-diabetic therapy in Type 2 diabetic patients and to reduce the meal-related insulin requirement in Type 1 diabetic patients.
  • GLP-1 and/or GIP are believed to regulate satiety, lipidemia and osteogenesis.
  • Exogenous GLP-1 has been proposed as a treatment for patients suffering from acute coronary syndrome, angina, and ischemic heart disease.
  • DPP-IV inhibitors in vivo prevents N-terminal degradation of GLP-1 and GIP, resulting in higher circulating concentrations of these peptides, increased insulin secretion and improved glucose tolerance.
  • DPP-IV inhibitors are regarded as agents for the treatment of Type 2 diabetes, a disease in which glucose tolerance is impaired.
  • treatment with DPP-IV inhibitors prevents degradation of Neuropeptide Y (NPY), a peptide associated with a variety of central nervous system disorders, and Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease, and inflammatory bowel disease.
  • NPY Neuropeptide Y
  • Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease, and inflammatory bowel disease.
  • Treatment of Type 2 diabetes usually comprises a combination of diet, exercise, oral agents, and in more severe cases, insulin.
  • the clinically available hypoglycemics can have side effects that limit their use.
  • Type 2 diabetes is a direct cause of the multiplicity of complications (cataracts, neuropathy, nephropathy, retinopathy, cardiomyopathy) that characterize advanced Type 2 diabetes.
  • Type 2 diabetes is a comorbid disease that frequently confounds hyperlipidemia, atherosclerosis and hypertension, adding significantly to the overall morbidity and mortality attributable to those diseases.
  • CVD cardiovascular disease
  • Such "essential" hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia and it is known that hypertension is positively associated with heart failure, renal failure, and stroke. Hypertension can also contribute to the development of atherosclerosis and coronary disease. Hypertension, together with insulin resistance and hyperlipidemia, comprise the constellation of symptoms that characterize metabolic syndrome, also known as insulin resistance syndrome (IRS) and Syndrome X.
  • IRS insulin resistance syndrome
  • Obesity is a well-known and common risk factor for the development of atherosclerosis, hypertension, and diabetes. The incidence of obesity and its related sequelae is increasing worldwide.
  • Osteoporosis is a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis and the consequences of compromised bone strength are a significant cause of frailty, and of increased morbidity and mortality.
  • Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease. Acute coronary syndrome denotes patients who have or are at high risk of developing an acute myocardial infarction (Ml). Though there are therapies available for the treatment of diabetes, hyperglycemia, hyperlipidemia, hypertension, obesity, and osteoporosis there is a continuing need for alternative and improved therapies. Various indications for DPP-IV inhibitors are discussed in Augustyns, et al., Curr. Medicinal
  • prodrugs and stereoisomers thereof and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein R 1 , R 2 , R 3 , R 4 , HET, n, Q, X, and Y are as described hereinbelow; compositions thereof; and uses thereof.
  • R 1 is hydrogen, -(CrC 6 )aIkyl, -(CrC 6 )alkoxy, -(C r C 6 )arylalkyl, -NR a R b , hydroxy, cyano, aryl, or heteroaryl, wherein said -(Ci-C 6 )alkyl, said aryl, or said heteroaryl is optionally substituted independently with one to three -COOH, -C(O)(C r C 6 )alkoxy, -C(O)(Ci-C 6 )alkyl, -C(O)NR a R b , cyano, halogen, nitro, trifluoromethyl, -(Ci-C 6 )alkyl, -(d-C 6 )alkoxy, -(C 3 -C 6 )cycloalkyl, or phenyl, wherein: R a and R b are, independently, hydrogen, -(Ci
  • R a and R b taken together with the nitrogen atom to which they are attached, form a four- to six- membered heterocyclic ring, wherein said ring optionally incorporates an additional one or two nitrogen, oxygen, or sulfur ring heteroatoms;
  • R 2 and R 3 are, independently, hydrogen, halogen, -(C r C 6 )alkyl, or -(C 3 -C 8 )cycloalkyl;
  • R 4 is (i) hydrogen, (ii) -COOH, (iii) -C(O) (C 1 -C 6 )alkoxy, (iv) -C(O)(C r C 6 )alkyl, (v) -C(O)NR a R b , (vi) cyano, or (vii) -(Ci-C 6 )alkyl, optionally substituted with one to six halogen atoms, -(Ci-C 6 )alkoxy, cyano, hydroxy, or -NR a R b , (viii) -(C 3 -C 6 )cycloalkyl, (ix) -(Ci-C 6 )arylalkyl, (x) aryl, or (xi) hetero
  • Q is a covalent bond, -C(O)-, or -SO 2 -;
  • HET is a heterocycloalkyl ring moiety, optionally substituted independently with: (A) one to four -(Gr C 6 )alkyl, optionally substituted with one to six halogen atoms, -(CrC 6 )alkoxy, cyano, halogen, hydroxy, or -NR a R b , or (B) -(C r C 6 )arylalkyl, optionally substituted with one to six halogen atoms, -(CrC 6 )alkoxy, cyano, halogen, hydroxy, or -NR a R b ; - A -
  • n zero or one
  • X is hydrogen or cyano
  • Y is -CH 2 -, -S-, -S(O)-, or -SO 2 -; provided that R 2 , R 3 and R 4 are not all hydrogen.
  • stereoisomeric configurations of the compounds of formula (I), the prodrugs thereof, and the pharmaceutically acceptable salts of the compounds and prodrugs comprise the (2S) and (2S.4S) configurations, depicted in formulae (Ia) and (Ib) respectively, hereinbelow.
  • a generally preferred subgroup of formula (Ib) compounds comprises those compounds wherein: R 1 is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted independently with one to three cyano, halogen, nitro, trifluoromethyl, -(CrC 6 )alkyl, -(CrC 6 )alkoxy, -(C 3 -C 6 )cycloalkyl, or phenyl;
  • R 2 , R 3 and R 4 are, independently, hydrogen or -(Ci-C 6 )alkyl
  • Q is a covalent bond, -C(O)-, or -SO 2 -;
  • HET is azetidinyl, piperazinyl, piperidinyl, or pyrrolidinyl; n is zero or one;
  • X is hydrogen or cyano
  • Y is -CH 2 - or -S-.
  • An especially preferred subgroup of the compounds of formula (Ib) comprises those compounds wherein: R 1 is pyrazinyl, pyridyl, pyrimidyl, or quinolyl, wherein said pyrazinyl, pyridyl, pyrimidyl, or quinoyl is optionally substituted independently with one to three cyano, halogen, nitro, trifluoromethyl, -(C ⁇ C 6 )aIkyl,
  • R 2 is -(C r C 6 )alkyI
  • R 3 and R 4 are hydrogen; Q is a covalent bond;
  • HET is piperazinyl; n is one;
  • X is hydrogen or cyano
  • Y is -CH 2 - or -S-. Even more preferably, for compounds of formula (Ib), R 2 is methyl; and
  • Y is -CH 2 - .
  • the compounds and intermediates of the present invention may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems.
  • the carbon atom content of the various hydrocarbon-containing moieties may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix "- (C a -C b )alkyl” indicates an alkyl moiety of the integer "a” to "b” carbon atoms, inclusive.
  • alkoxy denotes a straight or branched, monovalent, saturated chains of carbon atoms bonded to an oxygen atom, wherein the alkoxy group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds.
  • alkoxy groups include methoxy, ethoxy, propoxy, /so-butoxy, terf-butoxy, and the like.
  • alkyl denotes a straight or branched chain of carbon atoms, wherein the alkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, allyl, 2- methylpropenyl, 2-butenyl, 1 ,3-butadienyl, ethynyl, propargyl, and the like.
  • aryl denotes a monocyclic or polycyclic aromatic hydrocarbon group, for example, anthracenyl, fluorenyl, naphthyl, phenanthrenyl, phenyl, and the like.
  • arylalkyl means an alkyl group, as defined hereinabove, wherein at least one of the hydrogen atoms thereof has been substituted with an aryl group, also as defined hereinabove.
  • arylalkyl groups include, inter alia, benzyl groups.
  • halogen means chloro, bromo, fluoro, or iodo.
  • heterocycloalkyl refers to a saturated four- to eight-membered heterocyclic ring system, optionally fused to a five- or six-membered aromatic or heteroaromatic ring system.
  • non-limiting heterocycloalkyl groups comprise homopiperazinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, 2-aza-bicyclo[2.2.1]heptanyl, 3-aza- bicyclo[3.1.0]hexanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 5,6,7,8-tetrahydro-2H-imidazo[1 ,2-a]pyrazinyl, 5,6,7,8-tetrahydro[1 ,2,4]triazolo[4,3-a]pyrazinyl, 3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, 4,5,6,7- tetrahydropyrazolo[1 ,5-a]pyrazinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, 5,6,7,8-
  • heteroaryl denotes a monocyclic or polycyclic aromatic heterocyclic ring system.
  • heteroaryl groups comprise benzoisothiazolyl, benzisoxazolyl, benzooxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxadiazolyl, isoxazolyl, oxazolopyridyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, quinoxalinyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, 1 ,1- dioxo-1 H-1 ,2-benzoisothiazolyI, oxazolo[4,5-c]pyridyl, and the like.
  • mammal means animals including, for example, dogs, cats, cows, sheep, horses, and humans. Preferred mammals include humans of either gender.
  • prodrug refers to a compound that is a drug precursor which, following administration, releases the drug in vivo via a chemical or physiological process (e.g., upon being brought to physiological pH or through enzymatic activity).
  • salts refers to both organic and inorganic salts of a compound, prodrug, or stereoisomer of formula (I). Such salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a compound, prodrug, or stereoisomer of formula (I) with a suitable organic or inorganic acid or base and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like For additional examples see, for example, Berge, et al., J. Pharm. ScL, 66, 1-19 (1977).
  • substituted means that a hydrogen atom on a molecule has been replaced with a different atom or functional group.
  • the atom or functional group replacing the hydrogen atom is denoted as a "substituent.”
  • reaction-inert solvent or “inert solvent” refers to a solvent, or mixture of solvents, that does not interact with starting materials, reagents, intermediates, or products in a manner that adversely affects their desired properties.
  • treating includes preventative (e.g., prophylactic), palliative, or curative use or result.
  • the compounds and prodrugs of formula (I) may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds and prodrugs of formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound or prodrug of formula (I) incorporates a double bond, both the cis- and trans- forms, as well as mixtures thereof, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those of ordinary skill in the art, such as by chromatography and/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., alcohol), separating the diastereomers and converting (e.g., hydroiyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., alcohol
  • converting e.g., hydroiyzing
  • some of the compounds of formula (I) may be atropisomers (e.g., substituted biaryls) and are also considered as part of the invention.
  • the compounds, prodrugs, and stereoisomers of formula (I) may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the compounds, prodrugs, and stereoisomers of formula (I) may exist as tautomeric isomers in equilibrium, and all such forms are embraced within the scope of the invention.
  • the present invention also embraces isotopically-labeled compounds of formula (I), which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • the compounds of formula (I), the prodrugs, and stereoisomers thereof, and the pharmaceutically acceptable salts thereof, that contain the aforementioned isotopes and/or other isotopes of the other atoms are intended to be within the scope of the instant invention.
  • isotopically-labeled compounds of formula (I) for example those compounds into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in compound and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their relative ease of preparation and facile detection. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • the isotopically-labeled compounds of formula (I) can generally be prepared by carrying out procedures analogous to those disclosed in the Schemes and/or Examples set forth hereinbelow, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • the invention is directed to pharmaceutical compositions comprising an amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug, or stereoisomer, and a pharmaceutically acceptable carrier, vehicle, or diluent.
  • the invention is directed to pharmaceutical compositions comprising amounts of: a) a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug, or stereoisomer; b) a second compound selected from an antidiabetic agent, a prodrug or pharmaceutically acceptable salt thereof, insulin or an analog thereof, insulinotropin, a biguanide, an ⁇ 2 -antagonist, an imidazoline, a glitazone, an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a fatty acid oxidation inhibitor, an ⁇ -glucosidase inhibitor, a ⁇ -agonist, a phosphodiesterase inhibitor, a lipid-lowering agent, an antiobesity agent, a vanadate, a vanadium complex, a peroxovanadium complex, an amylin antagonist, a glucagon
  • the invention is directed to methods of inhibiting DPP-IV which methods comprise administering to a mammal in need of such inhibition a DPP-IV inhibiting amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug or stereoisomer; a DPP-IV inhibiting amount of a pharmaceutical composition comprising a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer; and a pharmaceutically acceptable vehicle, carrier, or diluent; or a DPP-IV inhibiting amount of the pharmaceutical composition described above comprising a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer, the second compound, and a pharmaceutically acceptable carrier, vehicle, or diluent.
  • the invention is directed to methods of treating conditions mediated by DPP- IV in mammals in need of such treatment which methods comprise administering to the mammal a therapeutically effective amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug or stereoisomer; a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer; and a pharmaceutically acceptable vehicle, carrier, or diluent; or a therapeutically effective amount of the pharmaceutical composition described above comprising a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer, the second compound, and a pharmaceutically acceptable carrier, vehicle, or diluent.
  • Conditions treatable according to the instant methods are Type 2 diabetes, progression of disease in Type 2 diabetes, metabolic syndrome (Syndrome X and/or IRS), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, short stature due to bone growth deficiency, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, or inflammatory bowel syndrome.
  • the condition is Type 2 diabetes.
  • the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers may be administered to mammals at dosage levels in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 1 mg/kg/day, in single or divided doses. Some variations in dosage will necessarily occur, however, depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject. Preferably, a single dose is administered orally.
  • the compounds of formula (I) may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, ⁇ e.g., intravenously, subcutaneously or intramedullary). Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
  • the appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula (I), or the prodrug or stereoisomer being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated, and/or the severity of the conditions being treated.
  • Administration may be in single (e.g., once daily) or multiple doses or via constant infusion.
  • the compounds may also be administered alone or, preferably, in combination with pharmaceutically acceptable carriers, vehicles, or diluents, in either single or multiple doses.
  • Suitable pharmaceutical carriers, vehicles, and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and/or calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and/or certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia.
  • disintegrants such as starch, alginic acid and/or certain complex silicates
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules.
  • preferred materials for oral include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
  • diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
  • solutions in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the compounds of formula (I) are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of a compound of this invention.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
  • a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
  • the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers may be prepared according to the exemplary routes disclosed in the Schemes and Examples below, as well as by other conventional preparative procedures known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • the methods disclosed in the instant Schemes and Examples are intended for purposes of exemplifying the instant invention, and are not to be construed in any manner as limitations thereon. In the discussions below, the following abbreviations are used: BOC (te/t-butoxycarbonyl), Cbz
  • the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers may be prepared according to the exemplary synthetic routes set forth in the Schemes and Examples hereinbelow, as well as by other conventional organic preparative methods known, or apparent in light of the instant disclosure, to one of ordinary skill in the relevant art. It is to be understood that the methods disclosed in the instant Schemes are intended for purposes of exemplifying the instant invention, and are not to be construed in any manner as limitations thereon. A generalized method for preparing the compounds of formula (I) is depicted in Scheme 1 hereinbelow.
  • the reaction mixture is stirred about 15 minutes, allowed to reach room temperature, then stirred an additional 30 minutes.
  • (II) is dissolved in TFA and, after a suitable time (e.g., about 30 min to about 24 hours), excess TFA is removed in vacuo, and the residual product is triturated with a solvent such as ether.
  • deprotection may be performed by hydrogenolysis in the presence of catalyst, such as 10% palladium or palladium hydroxide, in a suitable solvent such as ethanol (EtOH) or EtOAc, at a pressure of about 30 psi to about 60 psi, for a sufficient period of time, usually overnight, at a temperature of between about 20° C and about 80° C.
  • hydrogenolysis is effected at a pressure of about 45 psi at RT.
  • the compounds of formula (II) may be prepared by coupling an appropriately-substituted carboxylic acid derivative (III) with an appropriately-substituted amine derivative (IV) as depicted hereinbelow in Scheme 2.
  • the coupling is typically accomplished by combining (III) and (IV) in a reaction-inert solvent, preferably an aprotic solvent such as acetonitrile, dichloromethane, DMF, or chloroform.
  • a coupling agent such as EDC, HATU, DCC, EEDQ, CDI, or diethylphosphorylcyanide is then added, optionally in the presence of a base, such as TEA or pyridine, and an optional adjuvant, such as HOBT or HOAT.
  • the coupling is typically effected at a temperature of between about 0° C and about 50° C, for a suitable time, such as from about one hour and about 24 hours, for example about 16 hours.
  • (Vl) amines are well-known in the relevant art and may be obtained commercially or prepared by known methods. See, for example, D.A. Horton, et al., Chem. Rev., 103, 893-930 (2003).
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxyborohydride, or hydrogen in the presence of a catalyst (10% Pd/C, platinum oxide, etc.), optionally in the presence of an acid (e.g. acetic acid (AcOH), hydrochloric acid, etc.).
  • the coupling is normally effected in a reaction-inert solvent, such as 1 ,2-dichloroethane, THF, DMF, EtOH, or methanol (MeOH).
  • a reaction-inert solvent such as 1 ,2-dichloroethane, THF, DMF, EtOH, or methanol (MeOH).
  • the reaction is performed at a suitable temperature, such as 0 to 50 0 C, for a suitable period of time, such as between about one to about 24 hours, for example, about 16 hours.
  • the compounds of formula (II), where R 4 is other than hydrogen may be generally prepared by treating (V) and (Vl) first with a cyanide source, followed by an organometallic reagent.
  • the reaction is effected by first forming an enamine or iminium species by reacting ketone (V) with an amine (Vl) in the presence of a dehydrating agent, such as titanium (IV) isopropoxide or molecular sieves, followed by treatment with the cyanide source.
  • a dehydrating agent such as titanium (IV) isopropoxide or molecular sieves
  • suitable cyanide sources include (C 2 H 5 ) 2 AICN, acetone cyanohydrin, and trimethylsilylcyanide (TMSCN).
  • the intermediate ⁇ -aminonitrile can be converted into (II), where R 4 is other than hydrogen, by subsequent hydrolysis to a carboxylic acid and conversion thereof to an ester, amide, or ketone by known methods or by treatment with an organometallic reagent.
  • organometallic reagents include Grignard reagents such as methyl magnesium bromide or methyl magnesium chloride.
  • Such transformations are well known to one skilled in the art. See, for example, E. Coderc, et al., Eur. J. Med. Chem., 30, 463 (1995) and A. Palani, et al., J. Med. Chem., 45, 3143 (2002).
  • the compounds of formula (V) may be prepared as described hereinbelow in Scheme 4, beginning with, as appropriate, commercially available carboxylic acid (VII), ketocarboxylic acid (IX), or ketoester (X).
  • alcohol (VIII) is oxidized to ketone (Va) by treating (VIII) with an oxidizing agent in a reaction-inert solvent.
  • oxidizing agents comprise pyridine/sulfur trioxide in DMSO; aqueous sodium hypochlorite in the presence of sodium bromide and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) free radical catalyst; chromium-based reagents, such as chromium trioxide, pyridinium dichromate, or pyridinium chlorochromate; and oxalyl chloride in DMSO in the presence of a tertiary amine.
  • reaction-inert solvents comprise dichloromethane, EtOAc, toluene, or pyridine.
  • the oxidation is typically conducted at a temperature of between about -78 0 C and about 5O 0 C, for between about one and about 24 hours, for example, about 16 hours.
  • Such oxidations are well known to one skilled in the art. See, for example, M. Tamaki, et al., J. Org. Chem., 66, 3593 (2001) and X-I. Qiu, et al., J. Org. Chem., 67, 7162 (2002).
  • Step 3 protected ketocarboxylic acid (IX) is first coupled with amine (IV), as described hereinabove in Scheme 2, to afford (Va), which is then alkylated (Step 4) to afford ketone (V).
  • the alkylation is typically effected by first forming an enamine by reacting ketone (Va) with a secondary amine, for example, pyrrolidine, piperidine or morpholine, followed by treatment with an alkylating agent, optionally in the presence of a base, such as potassium carbonate.
  • a secondary amine for example, pyrrolidine, piperidine or morpholine
  • an alkylating agent optionally in the presence of a base, such as potassium carbonate.
  • the reaction is effected in a solvent such as benzene, toluene, acetonitrile, or dioxane.
  • solvent such as benzene, toluene, acetonitrile, or dioxane.
  • Step 5 protected ketoester (X), wherein R represents an alkyl or arylaikyl moiety, is alkylated under the conditions previously described in Step 4 to afford ketoester (Xl).
  • Step 6 ketoester (Xl) is saponified to yield the corresponding carboxylic acid which, in Step 7, is coupled with an appropriately-substituted amine (IV), as previously described hereinabove in Scheme 2.
  • the saponification step is typically accomplished by dissolving (Xl) in a water- miscible solvent, such as MeOH or EtOH, and water in the presence of a base, such as lithium hydroxide or sodium hydroxide.
  • the saponification is effected at suitable temperature, such as between about 0 °C and about 100 0 C, preferably RT, for a suitable time, such as between about one and about 24 hours, for example, about 16 hours.
  • the compounds of formula (I), the stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds and stereoisomers may be prepared as described in the following Examples.
  • Example 1 r(2S,4S)-4-Methyl-4-(4-phenyl-piperazin-1-yl)-pyrro]idin-2-yl1-pyrrolidin-1 -yl-methanone dihvdrochloride
  • Step i ferf-butyl (2S.4S)-4-Methyl-4-(4-phenylpiperazin-1 -yl)-2-(pyrrolidin-1 -ylcarbonyl)pyrrolidine-1 -carboxylate
  • Methyl magnesium bromide (0.5 ml_, 1.5 mmol., 1.4 M in THF/toluene) was added to a solution of the title compound of Preparation 2 (227 mg, 0.5 mmol) in 2 ml_ of toluene.
  • Step 4 To a mixture of the product of Step 2 (74 mg, 0.25 mmol), AcOH (16 ⁇ l_), and sodium acetate (23 mg, 0.28 mmol) in MeOH (1 ml.) was added sodium cyanoborohydride (21 mg, 028 mmol). The mixture was stirred at RT for 65 hrs and then concentrated. The residue was taken up in EtOAc (20 ml.) and the solution was washed with 1 N sodium hydroxide (2 x 3ml_) and brine (5 ml_), dried over magnesium sulfate, and concentrated to dryness. The residue was purified by chromatography (Biotage ® Flash 4OM; 1% followed by 2% MeOH/dichloromethane) and the product was isolated as a yellow solid (13.5 mg, 11 % yield). Step 4
  • the utility of the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, in the treatment or prevention of the conditions enumerated hereinabove in mammals may be demonstrated in conventional assays known to one of ordinary skill in the relevant art, including the in vivo and in vitro assays described below. Such assays also provide a means by which the activities of the compounds of formula (I), the prodrugs, and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, may be compared with the activities of other compounds.
  • DPP-IV inhibition may be demonstrated in vitro by the following assay, which is adapted from methods of Scharpe, et al., A. Clin. Chem., 2299 (1988) and Lodja, Z. Czechoslovak Medicine, 181
  • an enzyme-substrate solution is pipetted into microtiter wells of a polystyrene 96-well plate, and maintained at 4°C.
  • the enzyme-substrate solution comprises 50 ⁇ M Gly-Pro-4-methoxy- ⁇ - naphthylamide hydrochloride in 5OmM Tris assay buffer pH 7.3 containing 0.1 M sodium chloride, 0.1% (v/v) Triton and 50 ⁇ U/mL DPP-IV (MP Biomedicals, Livermore, CA; DPP-IV 5 mU/mL stock).
  • Five ⁇ L per well of the compound of formula (I) is added, bringing the final concentrations of the formula (I) compound to between three ⁇ M and 10 nM per well.
  • Enzyme is omitted from four wells, as a reagent blank. Five ⁇ L of 3 mM Diprotin A
  • the entire assay is incubated overnight (between 14 and 18 hours) at 37 0 C.
  • the reaction is quenched by adding 10 ⁇ L of Fast Blue B solution (0.5 mg/mL Fast Blue B in a buffer comprising 0.1 M sodium acetate pH 4.2 and 10% (v/v) Triton X-100 to each well, followed by shaking for approximately 5 min at room temperature.
  • the plates may be analyzed on a Spectramax spectrophotometer (Molecular
  • IC 50 data for compounds may be obtained by measuring the activity of DPP-IV over a range of compound concentrations from 1 OnM to 3 ⁇ M.
  • the glucose lowering effects of DPP-IV inhibitors may be exemplified in 4-6 week old KK/H1 J mice (Jackson Labs; Bar Harbor, ME) in the context of an oral glucose tolerance test.
  • Oral glucose tolerance tests have been in use in humans since, at least, the 1930s, as described by Pincus, et al., Am. J. Med. Sci., 782 (1934), and are routinely used in the diagnosis of human diabetes, though not to evaluate the efficacy of therapeutic agents in patients.
  • KK mice have been used to evaluate (i) glitazones (Fujita etal. Diabetes, 804 (1983); Fujiwara, et al., Diabetes, 1549 (1988); and Izumi, et al., Biopharm Drug. Dispos., 247 (1997)); (ii) metformin (Reddi, et al., Diabet. Metabol., 44 (1993)); (iii) glucosidase inhibitors (Hamada, et al., Jap. Pharmacol.
  • KK mice are derived from an inbred line first established and described by Kondo, et al., Bull. Exp. Anim., 107 (1957). These mice spontaneously develop a hereditary form of polygenic diabetes that progresses to cause renal, retinal, and neurological complications analogous to those seen in human diabetic subjects, however, they do not require insulin or other medication for survival.
  • Another aspect of the invention is directed to the use of KK mice to evaluate the effects of insulin secretagogue agents in the context of an oral glucose tolerance test.
  • the mice (10 per group) are then orally dosed with a solution of a compound of formula (I) in 0.5% methylcellulose (0.2 mL/mouse). Two controls groups receive only 0.5% methylcellulose.
  • mice are bled, as described above, and then dosed with 1 mg/kg glucose in distilled water (0.2 mL/mouse).
  • the first control group is dosed with glucose.
  • the second control group is dosed with water.
  • the mice are again bled, as described above.
  • the blood samples are centrifuged, the plasma collected and analyzed for glucose content on a Roche-Hitachi 912 glucose analyzer (Roche Diagnostics Corp.; Indianapolis, IN).
  • the data may be expressed as percent (%) inhibition of glucose excursion relative to the two control groups (i.e., the glucose level in the animals receiving glucose but no test compound representing 0% inhibition and the glucose concentration in the animals receiving only water representing 100% inhibition).
  • the compounds of formula (I) generally exhibit inhibitory activity, expressed as IC 50 1 S, against DPP-IV that are less than 3,000 nM. More specifically, the compounds of Examples 1-5, herein, were generally found to have IC 50 values of less than 3000 nM with the exception of the compound of Example 2 which exhibited an IC 50 value of more than 3000 nM.
  • the compound [(2S,4S)-4- cyano-4-(4-phenyl-piperazin-1-yl)-pyrrolidin-2-yl]-pyrroIidin-1-yl-methanone dihydrochloride which has a structure similar to those of the compounds of Examples 1 -5, was also prepared. This compound also exhibited an IC 50 value of more than 3000 nM.
  • Generally preferred compounds have IC 50 1 S of less thanlOO nM.
  • the compound of Example 15 ⁇ (2S,3R,4S)-4-[4-(3,5-dichloro-pyridin-4-yl)-piperazin-1 -yl]-3-methyl-pyrrolidin-2-yl ⁇ - pyrrolidin-1 -yl-methanone has an IC 50 of 6.13 nM.

Abstract

L'invention concerne des composés représentés par la formule (I), des promédicaments et des stéréo-isomères de ces composés ainsi que des sels pharmaceutiquement acceptables desdits composés, promédicaments et stéréo-isomères. Dans cette formule: R1 est hydrogène, -(C1-C6)alkyle, -(C1-C6)alkoxy, -(C1-C6)arylalkyle, -NRaRb, hydroxy, cyano, aryle ou hétéroaryle, lesdits -(C1-C6)alkyle, aryle, ou hétéroaryle étant éventuellement substitué indépendamment avec l'un de trois -COOH, -C(O)(C1-C6)alkyle, -C(O)NRaRb cyano, halogène, nitro, trifluorométhyle, -(C1-C6)alkyle, --(C1-C6)alkoxy, -(C3-C6)cycloalkyle ou phényle; Ra et Rb sont, indépendamment, hydrogène, -(C1-C6)alkyle, aryl ou hétéroaryle; Ra et Rb, pris ensemble avec l'atome d'azote auquel ils sont fixés, forment un noyau hétérocyclique de quatre à six éléments, où ledit noyau comporte éventuellement un ou deux atomes d'azote, d'oxygène ou de soufre supplémentaires; R2 et R3 sont, indépendamment, hydrogène, halogène, -(C1-C6)alkyle, ou -(C3-C8)cycloalkyle; R4 est (i) hydrogène, (ii) - COOH, (iii) -C(O)(C1-C6)alkoxy, (iv) -C(O)(C1-C6)alkyle, (v) -C(O)NRaRb, (vi) cyano ou (vii) -(C1-C6)alkyle, éventuellement substitué avec de un à six atomes halogène, -(C1-C6)alkoxy, cyano, hydroxy, ou -NRaRb, (viii) -(C3-C6)cycloalkyle, (ix) -(C1-C6)arylalkyle, (x) aryle, ou (xi) hétéroaryle; Q est une liaison covalente, -C(O)-, ou -SO2-; HET est un noyau hétérocycloalkyle, éventuellement substitué indépendamment avec: (A) un à quatre -(C1-C6)alkyle éventuellement substitués avec de un à six atomes halogène, -(C1-C6)alkoxy, cyano, halogène, hydroxy, ou -NRaRb, ou (B) -(C1-C6)aralkyle, éventuellement substitué avec de un à six atomes halogène, -(C1-C6)alkoxy, cyano, halogène, hydroxy, ou -NRaRb; n vaut zéro ou un; X est hydrogène ou cyano; et Y est -CH2-, -S-, -S(O)-, ou -SO2; à condition que R2, R3 et R4 ne soient pas tous hydrogène. L'invention concerne des compositions obtenues à partir de ces composés et leurs utilisations pour le traitement de complications liées au diabète telles que neuropathie diabétique, néphropathie diabétique ou microangiopathie diabétique, notamment.
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US7635698B2 (en) 2004-12-29 2009-12-22 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US7880002B2 (en) 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
WO2012099915A1 (fr) * 2011-01-19 2012-07-26 Hongwen Zhu Dérivés de thiazolidine et leur utilisation thérapeutique
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7635698B2 (en) 2004-12-29 2009-12-22 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US7880002B2 (en) 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US8168788B2 (en) 2004-12-29 2012-05-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US8399455B2 (en) 2004-12-29 2013-03-19 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US8648197B2 (en) 2004-12-29 2014-02-11 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
WO2007148185A2 (fr) * 2006-06-21 2007-12-27 Pfizer Products Inc. 3-amino-pyrrolidino-4-lactames substitués
WO2007148185A3 (fr) * 2006-06-21 2008-03-13 Pfizer Prod Inc 3-amino-pyrrolidino-4-lactames substitués
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
WO2012099915A1 (fr) * 2011-01-19 2012-07-26 Hongwen Zhu Dérivés de thiazolidine et leur utilisation thérapeutique
US11884647B2 (en) 2019-10-18 2024-01-30 The Regents Of The University Of California Compounds and methods for targeting pathogenic blood vessels

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