HK1178155B

HK1178155B - Novel synthesis for thiazolidinedione compounds

Info

Publication number: HK1178155B
Application number: HK13105164.4A
Authority: HK
Inventors: James R. Zeller; Steven P. Tanis; Scott D. Larsen; Timothy Parker
Original assignee: Cirius Therapeutics, Inc.
Priority date: 2010-04-19
Filing date: 2011-04-18
Publication date: 2016-06-03

Description

Novel synthesis of thiazolidinedione compounds

cross Reference to Related Applications

This PCT application claims priority from us patent application 61/325,502 filed on day 4/19 2010 and us patent application 61/327,498 filed on day 4/23 2010. The foregoing application is incorporated by reference herein in its entirety.

Technical Field

The present invention provides novel methods of synthesizing PPAR γ sparing compounds, such as thiazolidinediones, for preventing and/or treating metabolic diseases such as diabetes, obesity, hypertension and inflammatory diseases.

Background

Over the past several decades, scientists have assumed that PPAR γ is the site of action of the generally accepted insulin-sensitizing thiazolidinedione compound.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-activated transcription factors that regulate gene expression. PPARs are implicated in autoimmune and other diseases, i.e. diabetes, cardiovascular and gastrointestinal diseases, and alzheimer's disease.

PPAR γ is a key regulator of adipocyte differentiation and lipid metabolism. PPAR γ is also present in other cell types, including fibroblasts, muscle cells, breast cells, human bone marrow precursors and macrophages/monocytes. In addition, PPAR γ has been shown in macrophage foam cells of atherosclerotic plaques.

Thiazolidinediones, such as pioglitazone, originally developed for the treatment of type II diabetes, often show high affinity as PPAR γ ligands. The discovery that thiazolidinediones can modulate their therapeutic effects through direct interaction with PPAR γ helps establish the concept that PPAR γ is a key regulator of glucose and lipid homeostasis. However, compounds such as pioglitazone that are involved in the activation of PPAR γ also cause sodium reabsorption and other unsatisfactory side effects.

Disclosure of Invention

The present invention relates generally to methods of synthesizing compounds with reduced binding and activation of the nuclear transcription factor PPAR γ (when compared to high affinity PPAR γ ligands such as pioglitazone). These novel processes are useful for industrial production and employ safer, more stable and/or less expensive starting materials and production conditions.

Compounds exhibiting PPAR γ activity induce transcription of genes that favor sodium reabsorption. Advantageously, the synthetically produced compounds of the present invention have reduced binding and activation of the nuclear transcription factor PPAR γ (when compared to conventional high affinity PPAR γ ligands (e.g., pioglitazone or rosiglitazone)) and, therefore, produce fewer or reduced side effects associated with conventional high affinity PPAR γ ligands (e.g., reduced increase in sodium reabsorption) and, therefore, are more effective for the treatment of hypertension, diabetes and inflammatory diseases. Most particularly, the reduced PPAR γ binding and activity exhibited by these compounds (when compared to conventional high affinity PPAR γ ligands such as pioglitazone or rosiglitazone) is of particular use in the treatment of hypertension, diabetes and inflammatory diseases, both as a sole agent and in combination with other types of antihypertensive agents. Since hypertension and inflammatory diseases are major risk factors for diabetes and pre-diabetes, these compounds are also useful in the treatment and prevention of diabetes and other inflammatory diseases. In fact, the compounds synthesized by the present invention can induce a reduction in the symptoms of diabetes in human patients.

One aspect of the present invention provides a novel synthetic method for the production of thiazolidinedione compounds that are useful for treating metabolic disorders. This synthesis is useful for preparing compounds of formula I:

wherein R is₁And R₃Each independently selected from H, halogen, aliphatic group and alkoxy group, wherein the aliphatic group or alkoxy group is optionally substituted with 1-3 halogens; r'₂And R₂Each independently selected from-H, halogen, hydroxy or optionally substituted aliphatic, alkoxy, -O-acyl, -O-aroyl, -O-heteroaroyl, -O (SO)₂)NH₂、-O-CH(R_m)OC(O)R_n、-O-CH(R_m)OP(O)(OR_n)₂、-O-P(O)(OR_n)₂OrWherein each R_mIndependently is C_1-6Alkyl radical, each R_nIndependently is C_1-12Alkyl radical, C_3-8Cycloalkyl or phenyl, each of which is optionally substituted; or R₂And R'₂Together form an oxo group, R₂And R'₂Together form-O (CH)₂)_nO-, wherein n is 2 or 3, or R₂And R'₂Together form-S (CH)₂)_mS-, wherein m is 2 or 3; and ring a is phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is optionally substituted; the method comprises the following steps:

reacting a compound of formula 2A with a compound of formula 3A to form a compound of formula 4A,

the compound of formula 2A is:

wherein X is a leaving group,

the compound of formula 3A is:

wherein ring B is selected from:

wherein Y is₁Is hydrogen or PG_NAnd Y₂Is PG_OWherein PG is_NIs a nitrogen protecting group and PG_OIs an oxygen protecting group, and is,

the compound of formula 4A is:

and when Y is₁Not being hydrogen or when Y₂When present, deprotecting the compound of formula 4A to form the compound of formula I.

Detailed Description

The present invention provides a novel method for preparing thiazolidinedione compounds having reduced PPAR γ activity.

As used herein, the following definitions shall be used unless otherwise stated.

I. Definition of

For the purposes of the present invention, chemical elements are identified according to the periodic table of the elements, CAS version, handbook of chemistry and physics, 75 th edition. In addition, the general principles of organic chemistry are described in "organic chemistry", ThomasSorrell, university science Books, Sausaltito: 1999 and "March's sAdvanceorganics chemistry", 5th ed: Smith, M.B. and March, J., John Wiley & Sons, NewYork:2001, the entire contents of which are incorporated herein by reference.

"protecting group" as used herein refers to a moiety or functional group that is introduced into a molecule by chemical modification of the functional group to achieve chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Wutsand Greene, "Greene's Protective Groups in organic Synthesis"4th ed, Wuts, P.G.M.and Greene, T.W., Wiley-Interscience, New York: 2006.

As described herein, the compounds of the present invention may be optionally substituted with one or more moieties, such as those described generally above or exemplified by particular types, subclasses, and classes of the invention.

The term "hydroxy" or "hydroxyl" as used herein refers to the-OH moiety.

The term "aliphatic group" as used herein includes the terms alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or1 to 4) carbon atoms. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. The alkyl group may be substituted (i.e., optionally substituted) with one or more substituents such as halogen, phosphonyl, cycloaliphatic [ e.g., cycloalkyl or cycloalkenyl group]Heterocycloaliphatic radicals [ e.g. heterocycloalkyl or heterocycloalkenyl]Aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [ e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl]Nitro, cyano, acylamino [ e.g., (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl]Amino [ e.g. aliphatic amino, cycloaliphatic amino or heterocycloaliphatic amino]Sulfonyl [ e.g. aliphatic-SO₂-]Sulfinyl, sulfanyl, sulfinyloxy, ureido, thioureido, sulfamoyl, sulfonamido, oxo,carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxy. Some examples of substituted alkyl groups include, without limitation, carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, arylalkyl, (alkoxyaryl) alkyl, (sulfonylamino) alkyl (such as (alkyl-SO)₂-amino) alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic) alkyl or haloalkyl.

As used herein, "alkenyl" refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and at least one double bond. Like alkyl groups, alkenyl groups may be straight or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. The alkenyl group may be optionally substituted with one or more substituents such as halogen, phosphono, cycloaliphatic [ e.g., cycloalkyl or cycloalkenyl)]Heterocycloaliphatic radicals [ e.g. heterocycloalkyl or heterocycloalkenyl]Aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [ e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl]Nitro, cyano, acylamino [ e.g., (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl]Amino [ e.g. aliphatic amino, cycloaliphatic amino, heterocycloaliphatic amino or aliphatic sulfonylamino]Sulfonyl [ e.g. alkyl-SO)₂-, cycloaliphatic radical-SO₂-or aryl-SO₂-]Sulfinyl, sulfanyl, sulfinyloxy, ureido, thioureido, sulfamoyl, sulfonamido, oxo, carboxyl, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxyAralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxy. Some examples of substituted alkenyl groups include, without limitation, cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl) alkenyl, (sulfonylamino) alkenyl (such as (alkyl-SO)₂-amino) alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic) alkenyl or haloalkenyl.

As used herein, "alkynyl" refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and having at least one triple bond. The alkynyl group may be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups may be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halogen, hydroxy, sulfo, mercapto, thio [ e.g., aliphatic thio or cycloaliphatic thio]Sulfinyl [ e.g. aliphatic sulfinyl or cycloaliphatic sulfinyl]Sulfonyl [ e.g. aliphatic-SO₂-, aliphatic radical amino-SO₂Or a cycloaliphatic radical-SO₂-]Acylamino [ e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl]Ureido, thioureido, sulfamoyl, sulfonamido, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [ e.g., (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl]Amino [ e.g. aliphatic amino]Sulfinyloxy, oxo, carboxy, carbamoyl, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy or (heteroaryl) alkoxy.

As used herein, "amido" includes "aminocarbonyl"and" carbonylamino ". These terms, when used alone or in combination with another group, refer to an amido group, such as-N (R) when used terminally^X)-C(O)-R^Yor-C (O) -N (R)^X)₂And when used intermediately is-C (O) -N (R)^X) -or-N (R)^X) -C (O) -, wherein R^XAnd R^YCan be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroarylaliphatic. Examples of acylamino groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) acylamino, (heteroaralkyl) acylamino, (heteroaryl) acylamino, (heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido or cycloalkylamido.

As used herein, "amino" refers to-NR^XR^YWherein R is^XAnd R^YEach independently is hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, heteroaryl, carboxy, thio, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl, or (heteroarylaliphatic) carbonyl, each as defined herein and optionally substituted. Examples of the amino group include an alkylamino group, a dialkylamino group, or an arylamino group. When the term "amino" is not terminal (e.g., alkylcarbonylamino), it is substituted with-NR^X-represents wherein R^XHave the same meaning as defined above.

As used herein, "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to a monocyclic ring (e.g., phenyl); bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g. fluorenyl, tetrahydrofluorenyl or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or bicyclicOr at least one ring in a tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2-3 membered carbocyclic rings. For example, the benzo-fused group includes two or more C' s_4-8Phenyl fused to a carbocyclic moiety. Aryl groups are optionally substituted with one or more substituents including aliphatic groups [ e.g. alkyl, alkenyl or alkynyl](ii) a A cycloaliphatic group; (cycloaliphatic) aliphatic groups; a heterocycloaliphatic group; (heterocycloaliphatic) aliphatic; an aryl group; a heteroaryl group; an alkoxy group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; an aryloxy group; a heteroaryloxy group; (araliphatic group) oxy; (heteroarylaliphatic) oxy; aroyl; a heteroaroyl group; an amino group; oxo (on a non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); a nitro group; a carboxyl group; an amido group; acyl [ e.g. (aliphatic) carbonyl; (cycloaliphatic) carbonyl; ((cycloaliphatic) aliphatic group) carbonyl; (araliphatic) carbonyl; (heterocycloaliphatic) carbonyl; a ((heterocycloaliphatic) aliphatic) carbonyl group; or a (heteroaraliphatic) carbonyl group](ii) a Sulfonyl [ e.g. aliphatic-SO₂-or amino-SO₂-](ii) a Sulfinyl [ e.g. aliphatic-S (O) -or cycloaliphatic-S (O) - -](ii) a Sulfanyl [ e.g. aliphatic radical-S-](ii) a A cyano group; halogen; a hydroxyl group; a mercapto group; a sulfinato group; urea; thiourea; a sulfamoyl group; a sulfonamido group; or a carbamoyl group. Alternatively, the aryl group may be unsubstituted.

Non-limiting examples of substituted aryl groups include halogenated aryl groups [ e.g., mono-, di (such as para, meta-dihaloaryl) and (trihalo) aryl ]; (carboxy) aryl [ e.g., (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl, and (alkoxycarbonyl) aryl ]; (amido) aryl [ e.g., (aminocarbonyl) aryl, ((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl, and (((heteroaryl) amino) carbonyl) aryl ]; aminoaryl [ e.g., ((alkylsulfonyl) amino) aryl or ((dialkyl) amino) aryl ]; (cyanoalkyl) aryl; (alkoxy) aryl; (sulfamoyl) aryl [ e.g., (sulfamoyl) aryl ]; (alkylsulfonyl) aryl; (cyano) aryl; (hydroxyalkyl) aryl; ((alkoxy) alkyl) aryl; (hydroxy) aryl, ((carboxy) alkyl) aryl; ((dialkyl) amino) alkyl) aryl; (nitroalkyl) aryl; ((alkylsulfonyl) amino) alkyl) aryl; ((heterocycloaliphatic) carbonyl) aryl; ((alkylsulfonyl) alkyl) aryl; (cyanoalkyl) aryl; (hydroxyalkyl) aryl; (alkylcarbonyl) aryl; an alkylaryl group; (trihaloalkyl) aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; para-halo-meta-aminoaryl; or (meta (heterocycloaliphatic) -ortho (alkyl)) aryl.

As used herein, "araliphatic radical" such as "aralkyl" refers to an aliphatic radical (e.g., C) substituted with an aryl group_1-4Alkyl groups). "aliphatic group", "alkyl group" and "aryl group" are defined herein. An example of an araliphatic group such as aralkyl is benzyl.

As used herein, "aralkyl" refers to an alkyl group substituted with an aryl group (e.g., C)_1-4Alkyl groups). "alkyl" and "aryl" are as defined above. An example of an aralkyl group is benzyl. The aralkyl group is optionally substituted with one or more substituents such as aliphatic groups [ e.g., alkyl, alkenyl, or alkynyl groups, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl]Cycloaliphatic radicals [ e.g. cycloalkyl or cycloalkenyl](cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, acylamino [ e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino or heteroaralkylcarbonylamino]Cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfinyloxy, ureido, thioureido, sulfamoyl, sulfonamido, oxo, or carbamoyl.

As used herein, a "bicyclic ring system" includes an 8-12 (e.g., 9, 10, or 11) membered structure forming two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicyclic aliphatic groups (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic groups, bicyclic aryl, and bicyclic heteroaryl groups.

As used herein, "cycloaliphatic radical" includes "cycloalkyl" and "cycloalkenyl", each of which is optionally substituted as described below.

"cycloalkyl" as used herein refers to a saturated mono-or bicyclic (fused or bridged) carbocyclic ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubic alkyl (cubyl), octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.3.2] decyl, bicyclo [2.2.2] octyl, adamantyl or ((aminocarbonyl) cycloalkyl.

"cycloalkenyl" as used herein refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl include cyclopentenyl, 1, 4-cyclohex-di-alkenyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl.

The cycloalkyl or cycloalkenyl groups can be optionally substituted with one or more substituents such as phosphono, aliphatic [ e.g., alkyl, alkenyl, or alkynyl groups]Cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroarylaliphatic) oxy, aroyl, heteroaroyl, amino, amido [ e.g., (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylaminoA (heterocycloaliphatic) aliphatic group) carbonylamino group, a (heteroaryl) carbonylamino group, or a (heteroarylaliphatic) carbonylamino group]Nitro, carboxyl [ e.g. HOOC-, alkoxycarbonyl or alkylcarbonyloxy ]]Acyl [ e.g., (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl]Cyano, halogen, hydroxy, mercapto, sulfonyl [ e.g. alkyl-SO₂And aryl-SO₂-]Sulfinyl [ e.g. alkyl-S (O) -]Thioalkyl [ e.g. alkyl-S-]Sulfinyloxy, ureido, thioureido, sulfamoyl, sulfonamide, oxo, or carbamoyl.

As used herein, the term "heterocycloaliphatic" includes heterocycloalkyl and heterocycloalkenyl, each of which is optionally substituted as described below.

As used herein, "heterocycloalkyl" refers to a 3-10 membered mono-or bicyclic (fused or bridged) (e.g., 5-to 10-membered mono-or bicyclic) saturated ring structure in which one or more of the ring atoms is a heteroatom (e.g., N, O, S or a combination thereof). Examples of heterocycloalkyl include piperidinyl, piperazinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 4-dioxolanyl, 1, 4-dithianyl, 1, 3-dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridinyl, decahydroquinolinyl, octahydrobenzo [ b ] b]Thienyl, 2-oxa-bicyclo [2.2.2]Octyl, 1-aza-bicyclo [2.2.2]Octyl, 3-aza-bicyclo [3.2.1]Octyl and 2, 6-dioxa-tricyclo [3.3.1.0^3,7]Nonyl radical. Monocyclic heterocycloalkyl groups can be fused with a phenyl moiety to form a structure, such as tetrahydroisoquinoline, which can be classified as heteroaryl.

As used herein, "heterocycloalkenyl" refers to a mono-or bicyclic (e.g., 5-to 10-membered mono-or bicyclic) non-aromatic ring structure having one or more double bonds and wherein one or more of the ring atoms is a heteroatom (e.g., N, O or S). Monocyclic and bicyclic heterocycloaliphatic groups are numbered according to standard chemical nomenclature.

The heterocycloalkyl or heterocycloalkenyl can be optionally substituted with one or more substituents such as phosphono, aliphatic [ e.g., alkyl, alkenyl, or alkynyl ], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroarylaliphatic) oxy, aroyl, heteroaroyl, amino, amido [ e.g., (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) carbonylamino, and the like, (heteroaryl) carbonylamino or (heteroaraliphatic) carbonylamino ], nitro, carboxy [ e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy ], acyl [ e.g., (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl ], nitro, cyano, halogen, hydroxy, mercapto, sulfonyl [ e.g., alkylsulfonyl or arylsulfonyl ], sulfinyl [ e.g., alkylsulfinyl ], sulfanyl [ e.g., alkylsulfanyl ], sulfinoyloxy, ureido, thioureido, sulfamoyl, sulfonamide, oxo, or carbamoyl.

As used herein, "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and wherein the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. Heteroaryl includes benzo-fused ring systems having 2-3 rings. For example, benzo-fused groups include benzo-fused groups fused to one or two 4-8 membered heterocycloaliphatic moieties (e.g., indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl groups are pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolyl, benzothiazolyl, xanthyl, thioxanthyl, phenothiazine, indoline, benzo [1,3] dioxole, benzo [ b ] furyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, quinolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, 4H-quinolizinyl, benzo-1, 2, 5-thiadiazolyl or1, 8-naphthyridinyl.

Monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, 2H-pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3, 4-thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl or1, 3, 5-triazinyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

Bicyclic heteroaryls include, but are not limited to, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo [ b ] furanyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, or pteridinyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

Heteroaryl is optionally substituted with one or more substituents such as aliphatic groups [ e.g., alkyl, alkenyl, or alkynyl ]; a cycloaliphatic group; (cycloaliphatic) aliphatic groups; a heterocycloaliphatic group; (heterocycloaliphatic) aliphatic; an aryl group; a heteroaryl group; an alkoxy group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; an aryloxy group; a heteroaryloxy group; (araliphatic group) oxy; (heteroarylaliphatic) oxy; aroyl; a heteroaroyl group; an amino group; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); a carboxyl group; an amido group; acyl [ e.g., aliphatic carbonyl; (cycloaliphatic) carbonyl; ((cycloaliphatic) aliphatic group) carbonyl; (araliphatic) carbonyl; (heterocycloaliphatic) carbonyl; a ((heterocycloaliphatic) aliphatic) carbonyl group; or (heteroaraliphatic) carbonyl ]; sulfonyl [ e.g., the aliphatic group sulfonyl or aminosulfonyl ]; sulfinyl [ e.g., the aliphatic group sulfinyl ]; thio [ e.g., aliphatic thio ]; a nitro group; a cyano group; halogen; a hydroxyl group; a mercapto group; a sulfinato group; urea; thiourea; a sulfamoyl group; a sulfonamido group; or a carbamoyl group. Alternatively, the heteroaryl group may be unsubstituted.

Non-limiting examples of substituted heteroaryl groups include (halo) heteroaryl [ e.g., mono-and di- (halo) heteroaryl ]; (carboxy) heteroaryl [ e.g., (alkoxycarbonyl) heteroaryl ]; a cyanoheteroaryl group; aminoheteroaryl [ e.g., ((alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl ]; (amido) heteroaryl [ e.g., aminocarbonylheteroaryl, ((alkylcarbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarbonyl) heteroaryl, (((heteroaryl) amino) carbonyl) heteroaryl, ((heterocycloaliphatic) carbonyl) heteroaryl, and ((alkylcarbonyl) amino) heteroaryl ]; (cyanoalkyl) heteroaryl; (alkoxy) heteroaryl; (sulfamoyl) heteroaryl [ e.g., (sulfamoyl) heteroaryl ]; (sulfonyl) heteroaryl [ e.g., (alkylsulfonyl) heteroaryl ]; (hydroxyalkyl) heteroaryl; (alkoxyalkyl) heteroaryl; (hydroxy) heteroaryl; ((carboxy) alkyl) heteroaryl; ((dialkyl) amino) alkyl) heteroaryl; (heterocycloaliphatic) heteroaryl; (cycloaliphatic) heteroaryl; (nitroalkyl) heteroaryl; ((alkylsulfonyl) amino) alkyl) heteroaryl; ((alkylsulfonyl) alkyl) heteroaryl; (cyanoalkyl) heteroaryl; (acyl) heteroaryl [ e.g., (alkylcarbonyl) heteroaryl ]; (alkyl) heteroaryl, or (haloalkyl) heteroaryl [ e.g., trihaloalkylheteroaryl ].

As used herein, "heteroarylaliphatic group (such as heteroarylalkyl) refers to an ester substituted with a heteroaryl groupGroup (e.g. C)_1-4Alkyl groups). "aliphatic group", "alkyl group" and "heteroaryl group" are as defined above.

As used herein, "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group (e.g., C)_1-4Alkyl groups). "alkyl" and "heteroaryl" are as defined above. Heteroarylalkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfinyloxy, ureido, thioureido, sulfamoyl, sulfonamido, oxo, or carbamoyl.

As used herein, "cyclic moiety" and "cyclic group" refer to mono-, di-and tri-cyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl groups, each as defined above.

As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system, wherein the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, bicyclo [3.2.1]Octyl, bicyclo [2.2.2]Octyl, bicyclo [3.3.1]Nonyl, bicyclo [3.3.2]Decyl, 2-oxabicyclo [2.2.2]Octyl, l-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl and 2, 6-dioxa-tricyclo [3.3.1.0^3,7]Nonyl radical. The bridged bicyclic ring system may be optionally substituted with one or more substituents, such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkylSuch as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfinyloxy, ureido, thioureido, sulfamoyl, sulfonamido, oxo or carbamoyl.

As used herein, "acyl" refers to formyl or R^X-C (O) - (such as alkyl-C (O) -, also known as "alkylcarbonyl"), wherein R^XAnd "alkyl" is as defined above. Acetyl and pivaloyl are examples of acyl groups.

As used herein, "aroyl" or "heteroaroyl" refers to aryl-C (O) -or heteroaryl-C (O) -. The aryl and heteroaryl portions of the aroyl or heteroaroyl groups are optionally substituted as described above.

As used herein, "alkoxy" refers to alkyl-O-, wherein "alkyl" is as defined above.

As used herein, "carbamoyl" refers to a compound having the structure-O-CO-NR^XR^Yor-NR^X-CO-O-R^ZWherein R is^XAnd R^YAs defined above and R^ZMay be an aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroarylaliphatic group.

As used herein, "carboxy" when used as a terminal group means-COOH, -COOR^X、-OC(O)H、-OC(O)R^X(ii) a or-OC (O) -or-C (O) O-when used as a mid-group.

As used herein, "halogenated estersAn aliphatic group "refers to an aliphatic group substituted with 1-3 halogens. For example, the term haloalkyl includes the group-CF₃。

As used herein, "mercapto" refers to-SH.

As used herein, "sulfo", when used terminally, means-SO₃H or-SO₃R^XOr when used intermediately-S (O)₃-。

As used herein, a "sulfonamide" group, when used terminally, refers to the structure-NR^X-S(O)₂-NR^YR^ZAnd when used intermediately refers to-NR^X-S(O)₂-NR^Y-, wherein R^X、R^YAnd R^ZAs defined above.

As used herein, "sulfamoyloxy" refers to the structure-O-S (O)₂-NR^YR^ZWherein R is^YAnd R^ZAs defined above.

As used herein, the "sulfonamide" group, when used terminally, refers to the structure-S (O)₂-NR^XR^Yor-NR^X-S(O)₂-R^Z(ii) a Or when used intermediately-S (O)₂-NR^X-or-NR^X-S(O)₂-, wherein R^X、R^YAnd R^ZAs defined above.

As used herein, "sulfanyl" refers to-S-R when used terminally^XWhen used intermediately, means-S-, wherein R^XAs defined above. Examples of sulfur radicals include aliphatic-S-, cycloaliphatic-S-, aryl-S-, and the like.

As used herein, "sulfinyl" when used terminally means-S (O) -R^XAnd when used intermediately refers to-S (O) -, wherein R^XAs defined above. Examples of sulfinyl groups include aliphatic-S (O) -, aryl-S (O) -, (cycloaliphatic (aliphatic)) -S (O) -, cycloalkyl-S (O) -, heterocycloaliphatic-S (O) -, heteroaryl-S (O) -, and the like.

As used herein, "sulfonyl" when used terminally means-S (O)₂-R^XAnd when used intermediately means-S (O)₂-, wherein R^XAs defined above. Exemplary sulfonyl groups include aliphatic groups-S (O)₂-, aryl-S (O)₂-, (cycloaliphatic (aliphatic)) -S (O)₂-, cycloaliphatic radical-S (O)₂-, heterocycloaliphatic-S (O)₂-, heteroaryl-S (O)₂-, (cycloaliphatic (amido (aliphatic))) -S (O)₂-and the like.

As used herein, "sulfinyloxy" (sulfoxy) "when used terminally means-O-SO-R^Xor-SO-O-R^XAnd when used intermediately means-O-S (O) -or-S (O) -O-, wherein R^XAs defined above.

As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

The term "alkoxycarbonyl" encompassed by carboxy as used herein, alone or in combination with another group, refers to a group such as alkyl-O-C (O) -.

As used herein, "alkoxyalkyl" refers to an alkyl group, such as alkyl-O-alkyl-, wherein alkyl is as defined above.

As used herein, "carbonyl" refers to-C (O) -.

As used herein, "oxo" means = O.

The term "phosphono" as used herein refers to phosphinic acid groups (phosphonates) and phosphonic acid groups (phosphonates). Examples of phosphinic and phosphonic acid groups include-P (O) (R)^P)₂Wherein R is^PIs an aliphatic group, alkoxy group, aryloxy group, heteroaryloxy group, a (cycloaliphatic) oxy group, a (heterocycloaliphatic) oxyaryl group, heteroaryl group, cycloaliphatic group or amino group.

As used herein, "aminoalkyl" refers to the structure (R)^X)₂N-alkyl-.

As used herein, "cyanoalkyl" refers to the structure (NC) -alkyl-.

As used herein, the term "urea" group, when used terminally, refers to the structure-NT^X-CO-NR^YT^ZAnd the "thiourea" group refers to the structure-NT^X-CS-NR^YR^ZAnd when used intermediately refers to the structure-NR^X-CO-NR^Y-or-NR^X-CS-NR^Y-, wherein R^X、R^YAnd R^ZAs defined above.

As used herein, a "guanidino" group refers to the structure-N = C (N (R)^XR^Y))N(R^XR^Y) or-NR^X-C(=NR^X)NR^XR^YWherein R is^XAnd R^YAs defined above.

As used herein, an "amidine" group refers to the structure-C = (NR)^X)N(R^XR^Y) Wherein R is^XAnd R^YAs defined above.

Generally, the term "ortho" refers to a substituent position on a group comprising two or more carbon atoms, wherein the substituent is attached to an adjacent carbon atom.

Generally, the term "geminal" refers to a substituent position on a group comprising two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

The terms "at the end" and "in the middle" refer to the position of the group in a substituent. When a group is present at the end of a substituent that is not further bonded to the remainder of the chemical structure, the group is a terminal group. Carboxyalkyl, i.e. R^XO (O) C-alkyl is an example of a carboxyl group used at the terminal. When a group is present in the middle of a substituent of a chemical structure, the group is a group. Alkylcarboxy (e.g., alkyl-C (O) O-or alkyl-OC (O) -) and alkylcarboxylaryl (e.g., alkyl-C (O) O-aryl-or alkyl-O (CO) -aryl-) are examples of carboxyl groups used in the middle.

As used herein, "aliphatic radical chain" refers to a branched or straight chain aliphatic radical (e.g., alkyl)Alkenyl or alkynyl). The linear aliphatic radical chain having the structure- [ CH ]₂]_v-, where v is 1 to 12. A branched aliphatic radical chain is a straight chain aliphatic radical chain substituted with one or more aliphatic groups. The branched aliphatic radical chain has the structure- [ CQQ]_v-, wherein Q is independently hydrogen or an aliphatic group; however, Q should in at least one instance be an aliphatic group. The term aliphatic radical chain includes alkyl chains, alkenyl chains and alkynyl chains, wherein alkyl, alkenyl and alkynyl are as defined above.

The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". The compounds of the invention described herein may be optionally substituted with one or more substituents, such as those generally described above or exemplified by specific types, subclasses, and classes of the invention. Variable R as used herein₁、R₂、R'₂、R₃、R₄And other variables contained in the formulae described herein include specific groups such as alkyl and aryl groups. Unless otherwise stated, for variable R₁、R₂、R'₂、R₃、R₄And other variables contained herein, may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is further optionally substituted with 1-3 of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For example, alkyl may be substituted with alkylthio and alkylthio may be optionally substituted with 1-3 of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, the cycloalkyl portion of a (cycloalkyl) carbonylamino group is optionally substituted with 1-3 of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bonded to the same or adjacent atoms, the two alkoxy groups may form a ring together with the atoms to which they are bonded.

In general, the term "substituted", whether preceded by the term "optionally" or not, means that a hydrogen atom on the specified structure is replaced with a particular substituent. Specific substituents are as defined above and illustrated in the description of the following compounds and examples thereof. Unless otherwise specified, an optionally substituted group may bear a substituent at each substitutable position of the group, and when more than one position on any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. A ring substituent, such as heterocycloalkyl, may be bonded to another ring, such as cycloalkyl, to form a spiro-bicyclic ring system, e.g., the two rings share a common atom. One skilled in the art will recognize that the combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds.

The phrase "stable or chemically feasible" as used herein refers to compounds that do not substantially change when subjected to conditions for their preparation, detection, and use, preferably for their recovery, purification, and one or more of the purposes disclosed herein. In certain embodiments, a stable compound or chemically feasible compound is one that does not substantially change when held at 40 ℃ or below 40 ℃ for at least 1 week in the absence of moisture or other chemical reaction conditions.

As used herein, an "effective amount" is defined as the amount required to confer a therapeutic effect on a treated patient and is generally determined based on the age, body surface area, weight and health of the patient. Animal and human dose correlations (in milligrams per square meter of body surface area) are described by Freirich et al, cancer Chemother Rep., 50:219 (1966). Body surface area can be determined approximately from the height and weight of the patient. See, for example, scientific tables, Geigy pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

Unless otherwise stated, structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of the structure; for example, the R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers of each asymmetric center. Thus, a single compound of the inventionStereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) isomer mixtures are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention but with hydrogen replaced by deuterium or tritium or with carbon enriched¹³C-or¹⁴Carbon-substituted compounds of C are within the scope of the present invention. For example, such compounds are useful as analytical tools or probes in bioassays or as therapeutic agents.

Chemical structures and nomenclature were generated by ChemDraw, 11.0.1 th edition, Cambridge, MA.

General abbreviations II

The following abbreviations are used:

PG protecting group

LG leaving group

DCM dichloromethane

Ac acetyl group

DMF dimethyl formamide

EtOAc ethyl acetate

DMSO dimethyl sulfoxide

MeCN acetonitrile

TCA trifluoroacetic acid

ATP adenosine triphosphate

EtOH ethanol

Ph phenyl

Me methyl group

Et Ethyl group

Bu butyl

DEAD azodicarboxylic acid diethyl ester

HEPES4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

BSA bovine serum albumin

DTT dithiothreitol

MOPS 4-Morpholinylpropanesulfonic acid

NMR nuclear magnetic resonance

HPLC high performance liquid chromatography

LCMS liquid chromatography-mass spectrometry

TLC thin layer chromatography

Rt Retention time

HOBt hydroxybenzotriazole

Ms methanesulfonyl

Ts tosyl group

Tf trifluoromethanesulfonyl (triflyl)

Bs benzenesulfonyl (besyl)

Ns nitrobenzenesulfonyl (nosyl)

Cbz carboxybenzyl radical

Moz para-methoxybenzylcarbonyl

Boc tert-butyloxycarbonyl

Fmoc 9-fluorenylmethyloxycarbonyl

Bz benzoyl

Bn benzyl group

PMB p-methoxybenzyl

DMPM3, 4-dimethoxybenzyl

PMP p-methoxyphenyl

Method for synthesizing a compound of formula I

One aspect of the present invention provides a novel synthetic method for the production of thiazolidine compounds for the treatment of metabolic diseases. One aspect of the present invention provides a novel synthetic method for the production of thiazolidine compounds for the treatment of metabolic diseases. The process is useful for preparing a compound of formula I:

wherein R is₁And R₃Each independently selected from H, halogen, aliphatic group and alkoxy group, wherein the aliphatic group or alkoxy group is optionally substituted with 1-3 halogens; r'₂And R₂Each independently selected from-H, halogen, hydroxy or optionally substituted aliphatic, alkoxy, -O-acyl, -O-aroyl, -O-heteroaroyl, -O (SO)₂)NH₂、-O-CH(R_m)OC(O)R_n、-O-CH(R_m)OP(O)(OR_n)₂、-O-P(O)(OR_n)₂OrWherein each R_mIndependently is C_1-6Alkyl radical, each R_nIndependently is C_1-12Alkyl radical, C_3-8Cycloalkyl or phenyl, each of which is optionally substituted; r₂And R'₂Together form an oxo group, R₂And R'₂Together form-O (CH)₂)_nO-, wherein n is 2 or 3, or R₂And R'₂Together form-S (CH)₂)_mS-, wherein m is 2 or 3; and ring a is phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is optionally substituted; the method comprises the following steps:

the compound of formula 2A is:

wherein X is a leaving group,

the compound of formula 3A is:

wherein ring B is selected from:

wherein Y is₁Is hydrogen or PG_NWherein PG is_NIs a nitrogen protecting group, and Y₂Is PG_OWherein PG is_OIs an oxygen protecting group, and is,

the compound of formula 4A is:

It should be noted that when ring B isAnd Y is₁When not hydrogen, the nitrogen atom is considered to be protected, i.e. notIn the form of (1). Similarly, when ring B isAnd Y is₂When present, the oxygen atom is considered protected. In any case where the nitrogen atom or oxygen atom is protectedThe compound of formula 4A must undergo an additional deprotection step (e.g., treatment with a reagent such as aqueous acid or aqueous base) to form the compound of formula I. However, when Y is₁When hydrogen is present on ring B, then the compound of formula 4A is a compound of formula I.

In several embodiments, X is a leaving group selected from: -Br, -Cl, -I, -OMs, -OTs, -OTf, -OBs, -ONs, -O-trifluoroethylsulfonyl OR-OPO (OR)₄)₂Wherein each R is₄Independently is C_1-4Alkyl or two R₄Together with the oxygen and phosphorus atoms to which they are attached form a 5-7 membered ring. For example, X is halogen. In other examples, X is-Br, -Cl, or-I.

Certain embodiments further include converting a compound of formula 2B to a compound of formula 2A, the compound of formula 2B being:

certain embodiments include reacting a compound of formula 5A with a compound of formula 6A to produce a compound of formula 2B,

the compound of formula 5A is:

wherein X₁Is a halogen, and the halogen is a halogen,

the compound of formula 6A is:

wherein R is₅And R'₅Each independently selected from optionally substituted C_1-6Alkyl, or R₅And R'₅Nitrogen bound to themThe atoms together form an optionally substituted 3-7 membered monocyclic heterocycle, optionally containing 1-2 additional heteroatoms selected from N, O or S.

Other embodiments include halogenating a compound of formula 7A to form a compound of formula 5A, the compound of formula 7A being:

in many embodiments, the compound of formula 6A includes standard Weinreb amides or NCH₃OCH₃. In some embodiments, R₅And R'₅Together with the nitrogen atom to which they are attached form a ring selected from:

in other examples, R₅And R'₅Together with the nitrogen atom to which they are attached form a radical selected fromOf (2) a ring of (a). And in some examples, R₅And R'₅Together with the nitrogen atom to which they are attached form

In some embodiments, the compound of formula 7A comprisesWherein R is₁And R₃Each independently selected from H, halogen, aliphatic group and alkoxy group, wherein the aliphatic group or alkoxy group is optionally substituted with 1-3 halogens; and the compound of formula 5A comprisesWherein X₁Is halogen. For example, compounds of formula 7A includeAnd the compound of formula 5A comprisesWherein X₁Is halogen.

In some embodiments, the compound of formula 5A is treated with a grignard reagent and reacted with the compound of formula 6A to form the compound of formula 2B. And in some examples, the Grignard reagent comprises i-PrMgBr (isopropyl magnesium bromide) or i-PrMgCl (isopropyl magnesium chloride).

In other embodiments, the compound of formula 7A is reacted with the compound of formula 6A under direct acylation conditions to form the compound of formula 2B. For example, the compounds of formula 7A are substituted with n-butyllithium and Me₂NCH₂CH₂OLi treatment followed by treatment with a compound of formula 6A forms a compound of formula 2B.

In some embodiments, X and X₁Independently selected from-Br and-Cl.

Other embodiments include halogenating a compound of formula 8A to form a compound of formula 2A, the compound of formula 8A being:

in some embodiments, the compound of formula 8A comprisesWherein R is₁And R₃Each independently selected from H, halogen, aliphatic group and alkoxy group, wherein the aliphatic group or alkoxy group is optionally substituted with 1-3 halogens; r'₂And R₂Each independently selected from-H, halogen, hydroxy or optionally substituted aliphatic, alkoxy, -O-acyl, -O-aroyl, -O-heteroaroylRadical, -O (SO)₂)NH₂、-O-CH(R_m)OC(O)R_n、-O-CH(R_m)OP(O)(OR_n)₂、-O-P(O)(OR_n)₂OrWherein each R_mIndependently is C_1-6Alkyl radical, each R_nIndependently is C_1-12Alkyl radical, C_3-8Cycloalkyl or phenyl, each of which is optionally substituted; or R₂And R'₂Together form an oxo group, R₂And R'₂Together form-O (CH)₂)_nO-, wherein n is 2 or 3, or R₂And R'₂Together form-S (CH)₂)_mS-, wherein m is 2 or 3.

In some embodiments, R₂And R'₂Each independently selected from-H, -OH or optionally substituted alkoxy; or R₂And R'₂Together form an oxo group, R₂And R'₂Together form-O (CH)₂)_nO-, wherein n is 2 or 3, or R₂And R'₂Together form-S (CH)₂)_mS-, wherein m is 2 or 3. For example, in some instances, R₂And R'₂Together form an oxo group.

In some embodiments, the compound of formula 8A comprisesWherein R is₁Is selected from C_1-6Alkyl or C_1-6Alkoxy, each of which is optionally substituted with 1-3 halogens, and R₃is-H or halogen. In some examples of this embodiment, R₁Is C optionally substituted by 1-3 halogen_1-6An alkoxy group. For example, R₁Selected from methoxy, ethoxy or propoxy, any of which is optionally substituted with 1-3 halogens.

Certain embodiments include reacting a compoundReacting with a compound of formula 9A under condensation conditions to form a compound of formula 10A, said compound of formula 9A being:

wherein ring B is

The compound of formula 10A is:

hydrogenating the compound of formula 10A to form the compound of formula 3A.

In some embodiments, ring B of formula 9A isY₁Is PG_NAnd PG is_NTo select the following nitrogen protecting groups: cbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, PMP, or trityl. In other embodiments, ring B of formula 9A isAnd Y is₁Is hydrogen.

In some embodiments, ring B of formula 9A isY₂Is PG_OAnd PG is_OTo select the following oxygen protecting groups: -Si (R)₆)₃Optionally substituted alkyl or optionally substituted alkylcarbonyl, wherein each R is₆Independently is a straight or branched chain C_1-4Alkyl orA phenyl group. For example, ring B of formula 9A isY₂Is PG_OAnd PG is_Ois-Si (R)₆)₃Wherein each R is₆Independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl or phenyl. In other examples, ring B of formula 9A isY₂Is PG_OAnd PG is_OIs C_1-6Alkyl or C_1-6An alkylcarbonyl group.

In several embodiments, R'₂And R₂Independently selected from-OMe, -OEt or other optionally substituted O-C in any of the formulae_1-6An alkyl group. In other embodiments, R'₂And R₂A group which can be easily converted into an oxo group without undergoing an oxidation reaction.

In some embodiments, X is a leaving group that allows nucleophilic displacement of 1, 3-thiazolidine-2, 4-dione or protected 1, 3-thiazolidine-2, 4-dione. For example, X is-Br, -Cl, -I, -OMs, -OTs, -ONs OR-OPO (OR)₄)₂Wherein each R is₄Independently is C_1-12Alkyl radical, C_3-8Cycloalkyl or phenyl, each of which is optionally substituted.

In certain embodiments, wherein in any of the above formulas, Y is₁Is PG_N，PG_NAc, methoxymethyl, ethoxyethyl, ethoxymethyl, p-methoxybenzyl, methoxycarbonyl, ethoxycarbonyl or triphenylmethyl.

Another aspect of the present invention provides a process for preparing a compound of formula I:

reacting a compound of formula 2A with a compound of formula 10A to form a compound of formula 4B,

the compound of formula 2A is:

wherein X is a leaving group,

the compound of formula 10A is:

wherein ring B is selected from

the compound of formula 4B is:

hydrogenating the compound of formula 4B to produce a compound of formula 4A:

when Y is₁Not being hydrogen or when Y₂When present, deprotecting the compound of formula 4A to form the compound of I.

In several embodiments, X is a leaving group selected from: -Br, -Cl, -I, -OMs, -OTs, -OTf, -OBs, -ONs, -O-tresylsulfonyl (tresylate), OR-OPO (OR)₄)₂Wherein each R is₄Independently is C_1-4Alkyl or two R₄Together with the oxygen and phosphorus atoms to which they are attached form a 5-7 membered ring.

Certain embodiments include converting a compound of formula 2B to a compound of formula 2A, the compound of formula 2B being:

other embodiments include reacting a compound of formula 5A with a compound of formula 6A to form a compound of formula 2B, the compound of formula 5A being:

wherein X₁Is a halogen, and the halogen is a halogen,

the compound of formula 6A is:

wherein R is₅And R'₅Each independently selected from optionally substituted C_1-6Alkyl, or R₅And R'₅Together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered monocyclic heterocyclic ring, optionally containing 1-2 additional heteroatoms selected from N, O or S.

Certain embodiments include halogenating a compound of formula 7A to form a compound of formula 5A, the compound of formula 7A being:

in some embodiments, R₅And R'₅Together with the nitrogen atom to which they are attached form a ring selected from:

for example, R₅And R'₅Together with the nitrogen atom to which they are attached form

In other embodiments, the compound of formula 5A is treated with a grignard reagent and reacted with the compound of formula 6A to form the compound of formula 2B. And in some examples, the grignard reagent comprises i-PrMgBr.

In some embodiments, X and X₁Independently selected from-Br and-Cl.

Other embodiments include reacting a compound of formula 7A with a compound of formula 6A under direct acylation conditions to produce a compound of formula 2B,

the compound of formula 7A is:

the compound of formula 6A is:

Certain embodiments include halogenating a compound of formula 8A to form a compound of formula 2A, the compound of formula 8A being:

and in some embodiments, the compound of formula 8A includesWherein R is₁And R₃Each independently selected from H, halogen, aliphatic group and alkoxy group, wherein the aliphatic group or alkoxy group is optionally substituted with 1-3 halogens; r'₂And R₂Each independently selected from-H, halogen, hydroxy or optionally substituted aliphatic, alkoxy, -O-acyl, -O-aroyl, -O-heteroaroyl, -O (SO)₂)NH₂、-O-CH(R_m)OC(O)R_n、-O-CH(R_m)OP(O)(OR_n)₂、-O-P(O)(OR_n)₂OrWherein each R_mIndependently is C_1-6Alkyl radical, each R_nIndependently is C_1-12Alkyl radical, C_3-8Cycloalkyl or phenyl, each of which is optionally substituted;

R₂and R'₂Together form an oxo group which,

R₂and R'₂Together form-O (CH)₂)_nO-, wherein n is 2 or 3, or

R₂And R'₂Together form-S (CH)₂)_mS-, wherein m is 2 or 3.

In some embodiments, R₂And R'₂Each independently selected from-H, -OH or optionally substituted alkoxy; or R₂And R'₂Together form an oxo group, R₂And R'₂Together form-O (CH)₂)_nO-, wherein n is 2 or 3, or R₂And R'₂Together form-S (CH)₂)_mS-, wherein m is 2 or 3. For example, R₂And R'₂Together form an oxo group.

In some embodiments, the compound of formula 8A comprisesWherein R is₁Is selected from C_1-6Alkyl or C_1-6Alkoxy, each of which is optionally substituted with 1-3 halogens, and R₃is-H or halogen. In some examples, R₁Is C optionally substituted by 1-3 halogen_1-6An alkoxy group. In other examples, R₁Selected from methoxy, ethoxy or propoxy, any of which is optionally substituted with 1-3 halogens.

wherein ring B isIn some examples, ring B of formula 9A isY₁Is PG_NAnd PG is_NIs a nitrogen protecting group selected from: cbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, trityl, or PMP. In other examples, ring B of formula 9A isAnd Y is₁Is hydrogen. In other examples, ring B of formula 9A isY₂Is PG_OAnd PG is_OIs an oxygen protecting group selected from: -Si (R)₆)₃Optionally substituted alkyl or optionally substituted alkylcarbonyl, wherein each R is₆Independently is a straight or branched chain C_1-4Alkyl or phenyl. Or, ring B of formula 9A isY₂Is PG_OAnd PG is_Ois-Si (R)₆)₃Wherein each R is₆Independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl or phenyl. Alternatively, ring B of formula 9A isY₂Is PG_OAnd PG is_OIs C_1-6Alkyl or C_1-6An alkylcarbonyl group.

Exemplary Synthesis

The following synthetic schemes represent exemplary embodiments of the present invention:

scheme 1:

wherein X and Y₁As defined above in formula I.

In several embodiments, the starting material ia is produced according to scheme 1A as follows:

scheme 1A:

wherein X is a leaving group as defined above in formula I.

In several embodiments, the starting material ia is produced according to scheme 1B as follows:

scheme 1B:

wherein X is-Cl.

In several embodiments, the starting material ib is produced according to scheme 1C below:

scheme 1C:

wherein Y is₁Is hydrogen.

Scheme 2:

wherein X and Y₁As aboveIs defined in formula I.

In some embodiments, the starting material iia is produced according to scheme 2A as follows:

scheme 2A:

wherein X is-Cl.

Scheme 3

Novel compounds

Another aspect of the invention provides novel compounds useful in the synthesis of compounds of formula I. For example, one aspect of the invention provides a compound of formula 11A, 12A or 13A:

wherein R is₇Is C optionally substituted by 1-3 halogen_1-6An alkyl group.

For example, in some embodiments, the compound is selected from:

another aspect of the present invention provides compounds of formula ib

Wherein Y is¹As defined above in formula I.

Another aspect of the invention provides a compound selected from

V. examples

EXAMPLE 1 preparation of 5- {4- [2- (3-methoxyphenyl) -2-oxoethoxy ] benzyl } -1, 3-thiazolidine-2, 4-dione

To a stirred solution of 5- (4-hydroxybenzyl) thiazolidine-2, 4-dione (100mg,0.4mmol) in DMSO (2ml) was added potassium tert-butoxide (106mg,0.941 mmol). Stirring was continued at room temperature for about 1 hour. 2-bromo-3' -methoxyacetophenone (100mg,0.5mmol) was then added to the mixture. After 2 hours LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine and dried (Na)₂SO₄) Filtered and evaporated in vacuo. The residue was analyzed on a small RediSep column (eluting with 0-10% acetone/DCM). The fractions containing the product were combined and evaporated in vacuo to give 70mg of 5- {4- [2- (3-methoxyphenyl) -2-oxoethoxy group]Benzyl } -1, 3-thiazolidine-2, 4-dione as a light yellow solid.

Example 2 preparation of 2- (4- (hydroxymethyl) phenoxy) -1- (3-methoxyphenyl) ethanone

To a stirred solution of 2-bromo-3' -methoxyacetophenone (3.00g,13.1 mmol; supplier = Kalexsyn; batch =803-TTP-145) in acetone (30ml) was added 4-hydroxybenzyl alcohol (1.69g,13.6mmol) and potassium carbonate (1.88g,13.6 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine and dried (Na)₂SO₄) Filtered and evaporated in vacuo. The product was analyzed on a large Biotage column (eluting with 50% EtOAc/hexanes). The fractions containing the product were combined and evaporated in vacuo to give 2.98g of the title compound as a white solid.

Example 3 measurement

Assays for measuring reduced PPAR gamma receptor activation

Although activation of the PPAR γ receptor is generally considered a selection criterion for selecting molecules with anti-diabetic and insulin-sensitizing pharmacology, it has been found in the present invention that activation of this receptor should be a negative selection criterion. Molecules are selected from this chemical space because they have reduced properties of PPAR γ activation (not just selectivity). The optimal compounds have at least a 10-fold reduction in potency compared to pioglitazone and are less than 50% of the full activation produced by rosiglitazone in a PPAR γ receptor transactivation assay performed in vitro. The assay was performed by first evaluating the interaction of the molecule with the ligand binding domain of PPAR γ. This can be done with a commercially available interaction kit that directly interacts by fluorometry, using rosiglitazone as a positive control. Further assays may be performed in a manner similar to that described by Lehmann et al [ Lehmann JM, MooreLB, Smith-Oliver TA: Antidiadinotic ThiazolidinediationeisaHighafatingie ligand for peroxisome Prolierator-activitedReceptor (PPAR) J.biol.chem. (1995)270:12953], but using a luciferase as a reporter, as described by Vosper et al [ Vosper, H.J., Khouduloli, GA, Palmer, CN (2003) the peroxisome proliferactatric tissue analyzer requirement for the luciferase of the family of microorganisms of the family of 1. Compound stocks were dissolved in DMSO and added to cell cultures at final concentrations of 0.1-100 μ M, relative activation was calculated as induction of the reporter gene (luciferase) and corrected for by expression of a control plasmid (encoding galactosidase). Pioglitazone and rosiglitazone will be used as reference compounds as described above.

In addition to showing a reduction in PPAR γ receptor activation in vitro, the compounds do not produce significant receptor activation in animals. According to the results determined by the expression of P2 (a biomarker of ectopic adipogenesis in the Liver), in contrast to pioglitazone and rosiglitazone, which increase P2 expression under these conditions, compounds administered at doses that are fully effective in insulin sensitization in vivo (see below) do not increase PPAR γ activation in the Liver [ MatsuseK, HaluzikM, LambertG, Yims-H, Oksana Gavrilo, WardJM, Brewer B, ReitmanmL, GonzezFJ. (2003) Liver-specific discription of Linleuptin-defibrotide nanoparticles, Invitrorbuttatgratevate nanoparticles, J. Clin. 737.; 111: PPA. ].

Insulin sensitizing and antidiabetic pharmacological properties were determined in KKAY mice as previously reported [ Hofmann, C., Lornez, K., and Colca, J.R. (1991.) glucose electrotransport cytotoxic-cytotoxic peptide methylation with the enzymatic-hypercritical, 129:1915-1925 ]. The compounds were formulated in 1% sodium carboxymethylcellulose and 0.01% tween 20 and administered daily by oral gavage. After 4 days of once daily treatment, blood samples were collected from the retro-orbital (retro-orbital) and analyzed for glucose, triglycerides and insulin as described by Hofmann et al. The compound dose that produced at least 80% of the maximal decrease in glucose, triglycerides and insulin did not significantly increase the expression of P2 in the liver of these mice.

Measurement of PPAR gamma receptor activation

The ability of several exemplary compounds of the invention to bind PPAR γ was measured using a commercially available binding assay (invitrogen corporation, Carlsbad, CA) that measures the ability of the test compound to bind the PPAR-LBD/fluoromoneppred complex. These assays were performed using 4 separate wells (in quadruplicate) for each concentration of test compound, with each assay performed in triplicate. Data are mean and SEM of values from three experiments. Rosiglitazone was used as a positive control in each experiment. The compounds were added at the indicated concentrations, ranging from 0.1 to 100 micromolar.

Glucose, insulin and triglycerides in diabetic KKAy mice treated with exemplary compounds of the invention

Insulin sensitizing and antidiabetic pharmacological effects were measured in KKAY mice as previously reported [ Hofmann, C., Lornez, K., and Colca, J.R. (1991.) glucose electrotransport cytotoxic beta-peroxisomally catalytic kinase. Endocrinology,129:1915-1925 ]. The compounds were formulated in 1% sodium carboxymethylcellulose and 0.01% tween 20 and administered daily by oral gavage. After 4 days of once daily treatment, treatment blood samples were collected from the retro-orbit and analyzed for glucose, triglycerides and insulin as described by Hofmann et al. The compound dose that produced at least 80% of the maximal decrease in glucose, triglycerides and insulin did not significantly increase the expression of P2 in the liver of these mice.

The compounds were formulated by suspension and administered at 93mg/kg orally to KKA^YMice were 4 days. Compounds were first dissolved in DMSO and then placed in an aqueous suspension containing 7-10% DMSO, 1% sodium methylcarboxyl cellulose, and 0.01% tween 20. On the fifth day, mice were fasted and were onBlood samples were obtained about 18 hours after the last dose. The parameters were measured by standard assay methods. Data are mean and SEM, N =6-12 mice.

TABLE A measurement results

Compound nos. 1-5 show plasma insulin levels less than about 5ng/ml and compound No. 6 shows plasma insulin levels between about 15 and 20 ng/ml; compound numbers 1,2, 3,4 and 5 showed plasma triglyceride levels between about 100 and 200mg/dl, and compound number 6 showed plasma triglyceride levels between about 300 and 400 mg/dl; compound numbers 1,2, 3,4 and 5 showed plasma glucose levels between about 350 and 425mg/dl and compound number 6 showed plasma glucose levels between about 450 and 525 mg/dl.

The PPAR γ sparing compounds of the present invention can be more effectively used for treating diseases caused by metabolic inflammation, such as diabetes and metabolic syndrome, by limiting side effects caused by direct and partial activation of nuclear transcription factors.

Because the compounds of the present invention exhibit reduced PPAR γ activation, it is expected that these compounds will be suitable for use in combination with other compounds having anti-diabetic activity (such as metformin, DDP-4 inhibitors) or other anti-diabetic agents (which act by different mechanisms) to increase the action or secretion of GLP1 or insulin. These compounds may also be particularly well combined with lipid lowering statins such as atorvastatin and the like for the treatment of dyslipidemia associated with metabolic inflammatory diseases, especially because of reduced PPAR γ interaction. It is also expected that the combination of a compound of formula I and other antidiabetic compounds may be more effective in treating diabetes than the combination with a PPAR activating compound because they will avoid the side effects associated with PPAR γ activation, which may include volume expansion (volumeexpansion), edema, and bone loss.

Other embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the claims.

Claims

1. A compound having the structure: