WO2003002530A2 - Pyrrolidines as dipeptidyl peptidase inhibitors - Google Patents

Pyrrolidines as dipeptidyl peptidase inhibitors Download PDF

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Publication number
WO2003002530A2
WO2003002530A2 PCT/US2002/020466 US0220466W WO03002530A2 WO 2003002530 A2 WO2003002530 A2 WO 2003002530A2 US 0220466 W US0220466 W US 0220466W WO 03002530 A2 WO03002530 A2 WO 03002530A2
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Prior art keywords
compound
disorders
alkyl
amino
dpp
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PCT/US2002/020466
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English (en)
French (fr)
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WO2003002530A3 (en
Inventor
Curt Dale Haffner
Darryl Lynn Mcdougald
Amarjit Sab Randhawa
Steven Michael Reister
David N. Deaton
James Martin Lenhard
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to US10/481,288 priority Critical patent/US7196201B2/en
Priority to DE60223920T priority patent/DE60223920T2/de
Priority to EP02746739A priority patent/EP1399420B1/en
Priority to AU2002316437A priority patent/AU2002316437A1/en
Priority to JP2003508713A priority patent/JP4300108B2/ja
Publication of WO2003002530A2 publication Critical patent/WO2003002530A2/en
Publication of WO2003002530A3 publication Critical patent/WO2003002530A3/en
Anticipated expiration legal-status Critical
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Definitions

  • the present invention relates to compounds inhibiting dipeptidyl peptidases
  • DPP-II II
  • IV IV
  • Dipeptidyl peptidase IV is a post-proline/alanine cleaving serine
  • DPP-IV is thought to regulate the activity of multiple physiogically important
  • peptides including, but not limited to, GLP1 , GIP, GLP2, GRP, vasoactive intestinal
  • PACAP38 prolactin, chorionic gonadotropin, aprotinin, corticotropin-like intermediate
  • LD78beta(3-70) RANTES, eotaxin procolipase, enterostatin, vasostatin 1, endomorphin,
  • DPP-IV DPP-IV is believed to be involved in a variety of metabolic
  • gastrointestinal, viral, and inflammatory diseases including, but not limited to,
  • diabetes obesity, hyperlipidemia, dermatological or mucous membrane disorders,
  • Iipodystrophy and tissue damage, psychosomatic, depressive, and neuropsychiatric
  • cytokine-mediated murine abortions examples include DPP-IV, also known as
  • T-cells mediates T-cell activation and HIV infection (Ohtsuki et al., 2000).
  • DPP-IV/CD26 are preferentially infected and depleted in HIV-infected
  • DPP-IV is thought to regulate metabolism by cleaving the penultimate proline/alanine
  • GLP GLP
  • NPY neuropeptide Y
  • GLPs help metabolize glucose and, thus, regulation of GLPs
  • Diabetes for example type 2 (also called noninsulin-dependent diabetes mellitus).
  • Type 2 diabetes is the more common
  • Insulin attaches to
  • glucose does not get inside, a condition known as insulin
  • GLP-1 overcome insulin resistance.
  • GLP-1 enhances insulin secretion.
  • GLP-1 correlates to a regulation of insulin secretion. Moreover, GLP-1 decreases hepatic glucose production, gastric emptying, and food intake (Deacon et al., 1995).
  • GLP-2 maintains the integrity of the intestinal mucosal epithelium via effects
  • DPP-IV inhibitors preserve GLP-1 function for a longer time (Balka, 1999).
  • DPP-IV inhibitors may promote satiety, weight loss, and the antidiabetic effects
  • Diabetologia 42: 1324-1331 Both subcutaneously and intravenously administered
  • GLP-1 is rapidly degraded from the NH 2 -terminus in type II diabetic patients and in
  • DPP-IV inhibitors preserve GLP-2 for longer periods of time and,
  • DPP-IV is the predominate protease regulating GLP turnover, similar
  • proteases include, but are not limited to, dipeptidyl peptidase-ll (DPP-II), dipeptidyl
  • fibroblast activating protein alpha seprase
  • prolyl tripeptidyl peptidase prolyl
  • oligopeptidase endoproteinase Pro-C
  • attractin soluble dipeptidyl-aminopeptidase
  • acylaminoacyl-peptidase N-acylpeptide hydrolase; fMet aminopeptidase
  • lysosomal Pro-X carboxypeptidase angiotensinase C, prolyl carboxypeptidase.
  • Proline-cleaving metallopeptidases that may share similar substrate or inhibitor specificity to DPP-IV include membrane Pro-X carboxypeptidase (carboxypeptidase P),
  • elastase metaloelastase; matrix metalloproteinase 12; MMP-12], Matrilysin (matrix
  • metallopeptidases other non-mammalian proteases may share similar substrate or
  • proteases include prolyl aminopeptidase (prolyl iminopeptidase), lgA1 -specific serine
  • aminopeptidase A (STE13) [Saccharomyces cerevisiae), dipeptidyl aminopeptidase B
  • non-mammalian proline-cleaving metallopeptidases include
  • penicillolysin fungal acid metalloendopeptidase
  • Dipeptidyl peptidase II (DPP II) is a serine protease localized to lysosomes in
  • DPP-II has significant sequence
  • the present invention includes novel DPP-II and/or DPP-IV inhibitors, as well as
  • diabetes including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or
  • neuropsychiatric disease such as anxiety, depression, insomnia, schizophrenia, epilepsy,
  • the present invention includes compounds of formula (I):
  • X is -S(0)b- or -CH2-; b is 0-2; R 1 and R 2 each are either H; alkyl; optionally substituted
  • aryl or heteroaryl or combine to form a 3 to 14 membered ring sytem, optionally
  • R 1 and R 2 are optionally substitued aryl or heteroaryl, then R 3 is
  • R 4 is R 5 when Y is S, 0, alkylene, alkenylene, alkynylene, or a bond, where R 5 is
  • R 4 is R 6 when Y
  • R 6 is alkyl, aryl, cycloalkyl, heteroaryl, amino, alkylamino,
  • arylamino arylamino, heteroarylamino, or cycloalkylamino.
  • R 1 and R 2 are each alkyl and R 3 is
  • each alkyl is G-Cs alkyl. More preferably, each of alkyl is methyl. lii a particular compound included within the present invention X is -S(0)b-, b
  • R 5 is optionally substituted aryl.
  • R 5 is phenyl substituted with alkoxy.
  • X is -CH2-, n is
  • m is 1
  • Y is -S(0) P -
  • p is 1
  • R 4 is R 5
  • R 5 is optionally substituted aryl.
  • R 5 is phenyl substituted with alkoxy.
  • X is -CH2-, n is
  • R 6 is optionally substituted aryl.
  • X is S(0)b
  • b is
  • n 0, m is 1 , Y is S(0) P , p is 2, R 4 is R 6 , and R 6 is optionally substituted aryl.
  • the depicted NH2 group is cis to the
  • depicted nitrile warhead preferably the depicted NH2 group is
  • Particularly preferred compounds of the present invention include:
  • the present invention also includes pharmaceutical formulation comprising a
  • pharmaceutical formulation further includes a pharmaceutically acceptable carrier.
  • the present invention also includes a method of inhibiting a post
  • proline/analine cleaving protease comprising administering a compound of the
  • the dipeptidyl peptidase is DPP-II. In another aspect
  • the dipeptidyl peptidase is DPP-IV.
  • the present invention also includes a method for the treatment or prophylaxis
  • diabetes preferably Type II diabetes.
  • the present invention also includes the use of a compound of the present
  • proline/analine cleaving protease is a serine protease. More preferably, the serine protease is a dipeptidyl peptidase. In one aspect preferably the dipeptidyl peptidase is
  • DPP-II In another aspect preferably the dipeptidyl peptidase is DPP-IV.
  • the present invention also includes the use of a compound of the present
  • the present invention also includes a compound the present invention as
  • present invention inlcudes a compound the present invention as herein described for
  • diabetes obesity, hyperlipidemia, dermatological or mucous membrane disorders,
  • alkyl refers to a straight or branched chain saturated aliphatic
  • hydrocarbon that may be optionally substituted, with multiple degrees of substitution
  • alkyl examples include, but are not limited to methyl, ethyl, n-
  • propyl isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl, and the like.
  • alkylene refers to a divalent straight or branched chain aliphatic
  • hydrocarbon radical that may be optionally substituted, with multiple degrees of
  • alkylene includes, without limitation,
  • alkenyl refers to a straight or branched chain aliphatic
  • hydrocarbon containing one or more carbon-to-carbon double bonds that may be
  • alkenylene refers to a divalent straight or branched
  • alkenylene includes, without limitation, vinylene,
  • alkynyl refers to a straight or branched aliphatic
  • hydrocarbon containing one or more triple bond which may optionally be substituted, with multuiple degrees of substitution being allowed.
  • alkynyl as used
  • alkynylene refers to a divalent straight or branched
  • substituted benzene ring system such as phenyl.
  • substituted benzene ring system such as phenyl.
  • the term encompasses fused systems
  • alkylene linker such as C ⁇ -Cs alkylene
  • aryl groups include, but are not limited to
  • heteroaryl refers to a monocyclic aromatic ring system, or to a
  • heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N-
  • rings may be optionally substituted, with multiple degrees of substitution being
  • the term includes ring(s) optionally substituted, with multiple degrees of
  • substitution being allowed, and also includes an optional alkylene linker, such as G-Ce
  • heteroaryl groups used herein include furan, thiophene, pyrrole, imidazole, pyrazole,
  • cycloalkyl refers to a mono- or bi-cyclic
  • hydrocarbon ring system which may be further substituted with multiple degrees of
  • cycloalkyl examples include, but are
  • cycloalkyl includes bridged or fused ring systems, as well, such as
  • cycloalkyl/aryl fused systems where, for example, a cycloalkyl, such as
  • cyclohexyl is fused with an aromatic ring, such as a benzene ring, to form groups such
  • heterocyclic or the term “heterocyclyl” refers to a
  • heterocyclic ring preferably three to twelve-membered, that is either saturated or has
  • heterocyclic rings contain one or more
  • heteroatom such as nitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur
  • heterocyclic groups optionally may be substituted, with multiple degrees of
  • substitution being allowed, and also includes an optional alkylene linker, such as G-Cs
  • cycloalkyl ring(s) examples include, but are not limited to,
  • alkoxy refers to the group -ORa, where Ra is alkyl as
  • amino refers to the group -NH2.
  • alkylamino refers to the group -N(Ra)2, where one Ra
  • Ra is alkyl and the other Ra independently is H or alkyl, as herein defined.
  • cycloalkylamino refers to the group -N(Ra)2, where
  • Ra is cycloalkyl and the other Ra independently is H or cycloalkyl, as herein
  • heteroarylamino refers to the group -N(Ra) 2 , where
  • one Ra is heteroaryl and the other Ra independently is H or heteroaryl, as herein defined.
  • acyl alkyl; alkenyl; alkynyl; alkylsulfonyl; alkoxy; cyano; halogen; haloalkyl; hydroxy;
  • aryl which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl,
  • alkylsulfonyl cyano, halogen, haloalkyl, hydroxy, or nitro; heteroaryl, which may be
  • aryloxy which may be further substituted with acyl, alkoxy, alkyl, alkenyl,
  • alkynyl alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; heteroaryloxy,
  • alkylsulfonyl cyano, halogen, haloalkyl, hydroxy, or nitro; -R'OR'R 4 ; or -NR 4 R 5 ;
  • heteroaryl alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, where each occurrence of
  • Such aryl or heteroaryl may be substituted with one or more acyl, alkoxy, alkyl,
  • the compounds of the present invention may have the ability to crystallize in
  • polymorphism a characteristic known as polymorphism. All polymorphic forms
  • Polymorphs are within the scope of the present invention. Polymorphism generally
  • present invention includes pure stereoisomers as well as mixtures of stereoisomers
  • the present invention covers the individual isomers of the
  • the present invention includes salts, solvates, and
  • Salts include addition salts, metal salts, or optionally alkylated ammonium salts.
  • salts examples include hydrochloric, hydrobromic, hydroiodic, phosphoric,
  • salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
  • borate bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate,
  • phosphate/diphosphate polygalacturonate
  • potassium salicylate
  • sodium sodium, stearate
  • solvate refers to a complex of variable stoichiometry
  • solvents include, but are not limited to
  • the solvent used is a
  • solvents include water, ethanol, and acetic acid.
  • an ester or an amide which upon administration to a mammal is capable of
  • the present invention further includes a pharmaceutical formulation
  • insulin one or more of the following agents: insulin, ⁇ -glucosidase inhibitors, biguanides,
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • insulin secretagogue or insulin sensitizers.
  • inhibitors include acarbose, emiglitate, miglitol, and voglibose.
  • biguanides include metformin, buformin, and phenformin.
  • metformin metformin
  • buformin metformin
  • phenformin phenformin
  • insulin secretagogues include sulphonylureas.
  • sensitizers include peroxisome proliferator activated receptor (PPAR) ligands, such as
  • PPAR- ⁇ agonists for example ActosTM and AvandiaTM.
  • Formulations of the present invention include those especially formulated for
  • capsules, and caplets may contain conventional excipients such as binding agents, fillers, lubricants,
  • binding agents are disintegrants, and/or wetting agents.
  • binding agents include disintegrants, and/or wetting agents.
  • syrup examples include syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, or
  • PVP polyvinylpyrrolidone
  • lactose sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol.
  • Non-limiting examples of lubricants include, for example, magnesium sterate, stearic
  • the compounds of the present invention may be incorporated
  • oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions,
  • compositions containing these compounds may be
  • Liquid preparations may contain conventional additives.
  • Non-limiting examples are examples of
  • suspending agents such as sorbitol syrup, methyl cellulose,
  • glucose/sugar syrup gelatin, hydroxyethylcellulose, carboxymethyl cellulose,
  • non-aqueous vehicles such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may
  • edible oils such as almond oil, fractionated coconut oil, oily esters, propylene
  • glycol or ethyl alcohol my be included.
  • preservatives such as methyl or propyl
  • p-hydroxybenzoates or sorbic acid may be incorporated into the preparation.
  • preparations may also be formulated as suppositories, for example, containing
  • formulations of the present invention may be formulated for any convenient suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any convenient suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any convenient suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any convenient suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any suitable suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any suitable suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any suitable suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for any suitable suppository bases such as cocoa butter
  • injection may take such forms as suspensions, solutions, or emulsions in oily or
  • aqueous vehicles may contain formulatory agents such as suspending, stabilizing
  • the active ingredient may be in powder form
  • a suitable vehicle for example, sterile, pyrogen-free water, before use.
  • formulations according to the invention may also be formulated as a
  • depot preparation Such long acting formulations may be administered by:
  • the compounds of the invention may be formulated with
  • suitable polymeric or hydrophobic materials such as an emulsion in an acceptable oil
  • compositions may be presented in unit dose forms containing a
  • Such a unit may contain
  • Such amounts include the formulation containing about 0.1 to
  • a predetermined dose such as a daily dose, or an appropriate fraction
  • Such pharmaceutical formulations may be prepared
  • the term "effective amount” means that amount of a drug or
  • terapéuticaally effective amount means any one of
  • DPP-IV for purposes of treatment or prophylaxis of a variety of metabolic
  • gastrointestinal, viral, and inflammatory diseases including, but not limited to,
  • diabetes obesity, hyperlipidemia, dermatological or mucous membrane disorders,
  • Iipodystrophy and tissue damage, HIV infection, allergies, inflammation, arthritis,
  • transplant rejection high blood pressure, congestive heart failure, tumors, and stress-induced
  • induced abortions for example cytokine-mediated murine abortions. No toxicological effects are indicated/expected when a compound of the
  • present invention is administered in the above mentioned dosage range.
  • IUPAC names are included to further identify particular compounds of the present invention.
  • the IUPAC names stated herein should in no way limit the scope of the present invention.
  • one embodiment of the compounds of the present invention can be prepared by reacting a compound of
  • aminocarboxylates both designated herein generally as aminocarboxylates, under standard coupling conditions, for example, with HATU, DMF, Hunigs base.
  • amino carboxylate where the amino carboxylate is suitably protected, for example on the ⁇ - nitrogen, with an appropriate protecting group such as, for example, a t-butyl carboxy protecting group.
  • a compound of formula II may be reacted with an
  • amino activated carboxylate such as, for example, N-hydroxysuccinimide ester or acid
  • reaction mixture was stirred for 30 minutes at 0°C and then for 14 hours
  • reaction mixture was stirred at RT for 5 minutes. A white solid precipitated during
  • reaction mixture was stirred at RT for 5 minutes. A white solid precipitated during
  • triisopropylbenzenesulfonyl azide (trisyl azide) (1.84 g, 5.94 mmol) in THF (10 mL, anhydrous) was added in one portion. After 3 minutes acetic acid was added (1.31 g,
  • H-Ala-Pro-pNA «HCI was purchased from BACHEM Bioscience Inc. (product no.
  • Gly-Pro-AMC was purchased from Enzyme System Products (product no.
  • the purified human DPP-IV The material was isolated from human prostasomes using
  • DPP-IV (20 ng/mL) was
  • test compounds mixed in microtiter plates with test compounds, substrate and assay buffer to yield
  • the enzymatic activity was determined by estimating
  • Vmax was the best fit estimate of the maximal enzymatic activity.
  • Ki values were calculated from ICso values using equation
  • the intermediate plate contained 5.3 ⁇ L of test compound in 2-fold serial
  • assay were 100 nM enzyme and 1000 ⁇ M substrate in 100 mM NaOAc, pH 5.5, 2.5%
  • Vmax was the best fit estimate of the maximal enzymatic activity.
  • Ki values were calculated from ICso values using equation
  • Certain compounds of the present invention showed activity for DPP-II, for
  • the filters set at 360 nm excitation and 460 nm emission.

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DE60223920T DE60223920T2 (de) 2001-06-27 2002-06-26 Pyrrolidine als dipeptidyl-peptidase-inhibitoren
EP02746739A EP1399420B1 (en) 2001-06-27 2002-06-26 Pyrrolidines as dipeptidyl peptidase inhibitors
AU2002316437A AU2002316437A1 (en) 2001-06-27 2002-06-26 Pyrrolidines as dipeptidyl peptidase inhibitors
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US7196201B2 (en) 2007-03-27
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