JP2021501180A - Serenogalactoside compounds and their use for the treatment of systemic insulin resistance disorders - Google Patents

Abstract

Aspects of the invention relate to novel synthetic compounds having binding affinities with galectin proteins for the treatment of systemic insulin resistance disorders.

Description

Inventors Peter Jim Traber, Eliza Zomer, Diadora Slate, Joseph M Johnson, Rian George, Sharon Schecter and Rafael Neil
Related Applications This application claims the benefit and priority to US Provisional Application No. 62 / 579,343 filed October 31, 2017. The entire disclosure of the above application is incorporated herein by reference.
Technical Fields Aspects of the present invention relate to compounds, pharmaceutical compositions, methods of producing compounds, and methods of treating metabolic disorders in which one or more galactose-binding proteins, also referred to as galectin, are at least partially mediated.

Galectin is a family of S-type lectins that bind to glycoproteins, including beta-galactose glycans. To date, 15 mammalian galectins have been isolated.

Galectin regulates a variety of biological processes such as diabetes, inflammation, fibrosis, metabolic disorders, cancer progression, metastasis, apoptosis, and immune evasion.

Aspect of the outline of the Invention The present invention for use in therapeutic formulation relates to a composition comprising a compound to compound and parenteral or acceptable pharmaceutical carrier for enteral administration. In some embodiments, the composition can be administered orally, locally or parenterally via an intravenous or subcutaneous route.

Aspects of the invention relate to compounds, compositions and methods for treating various disorders in which the lectin protein plays a role in the etiology, including but not limited to the treatment of systemic insulin resistance. In some embodiments, the compound is capable of reversing the binding of galectin-3 to the insulin receptor and / or enhancing the sensitivity of various tissues to insulin activity.

Aspects of the invention relate to, but are not limited to, compounds, compositions and methods for treating systemic insulin resistance. In some embodiments, systemic insulin resistance is associated with obesity in which elevated galectin-3 interacts with the insulin receptor. In some embodiments, treatment with the compounds of the invention can restore the sensitivity of various tissues to insulin activity.

Aspects of the invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 1 diabetes. Aspects of the invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 2 diabetes (T2DM). Aspects of the invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores the cell's sensitivity to insulin activity. In some embodiments, the compound inhibits the interaction of galectin-3 with the insulin receptor, interfering with insulin binding and cellular glucose uptake mechanisms. Aspects of the invention are compounds for treating mild inflammation due to elevated levels of free fatty acids and triglycerides that cause insulin resistance in skeletal muscle and liver, which contribute to the development of atherosclerotic vascular disease and NAFLD. Regarding compositions and methods. Aspects of the invention relate to compounds, compositions and methods for the treatment of polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance, and compensatory hyperinsulinemia. Aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis by weakening the integrin and TGFβ receptor pathways in chronic renal disease. In some embodiments, the compound inhibits the overexpression of the TGFβ receptor signaling system caused by insulin resistance in diabetes, causes a decline in renal function, and reverses the established lesions of diabetic glomerulopathy. Can be made to.

In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or a combination thereof. In some embodiments, the compound is administered with an activator and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, the compound is administered with one or more antidiabetic agents. In some embodiments, administration of the compounds and activators of the invention produces a synergistic effect.

Aspects of the invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity in which elevated galectin-3 interacts with the insulin receptor. In some embodiments, treatment with the compounds of the invention can restore the sensitivity of various tissues to insulin activity.

In some embodiments, the compounds or compositions of the invention that bind to the insulin receptor (also referred to as IR, INSR, CD220, HHF5).

Aspects of the invention relate to compounds, compositions and methods for treating diseases caused by disruption of TGFb1 (transforming growth factor beta 1) activity.

Aspects of the invention relate to compounds, compositions and methods for treating diseases associated with the transforming growth factor beta signaling pathway.

Aspects of the invention relate to compounds or compositions for treating a variety of chronic inflammatory diseases, fibrotic diseases, and cancers. In some embodiments, the compound is a glycoprotein with a lectin or galectin protein that is known to regulate pathophysiological pathways leading to immune recognition, inflammation, fibrosis, angiogenesis, cancer progression and metastasis. The interaction can be mimicked.

In some embodiments, the compound comprises a pyranosyl and / or furanosyl structure attached to a selenium atom on the anomeric carbon of pyranosyl and / or furanosyl.

In some embodiments, specific aromatic substitutions can be added to the galactose score or heteroglycoside core to further enhance the affinity of the selenium-bound pyranosyl and / or furanosyl structure. Such aromatic substitutions enhance the interaction of the compound with the amino acid residues that make up the carbohydrate recognition domain (CRD) of the lectin (eg, arginine, tryptophan, histidine, glutamic acid, etc.) and enhance binding and binding specificity. Can be strengthened.

In some embodiments, the compound can comprise a galactose monosaccharide, disaccharide, oligosaccharide, or heteroglycoside core attached to a selenium atom (Se) on the anomeric carbon of galactose or heteroglycoside.

In some embodiments, the compound is a symmetric digalactoside in which two galactoside are attached by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside, where two galactosides are attached by one or more selenium bonds, and selenium is attached to the anomeric carbon of galactose. In some embodiments, the compound is a symmetric digalactoside, where two galactosides are attached by one or more selenium and one or more sulfur bonds, with selenium being attached to the anomeric carbon of galactose. In yet other embodiments, the compound can be an asymmetric digalactoside. For example, a compound can have different aromatic or aliphatic substitutions on the galactose score.

In some embodiments, the compound is a symmetric galactoside having one or more seleniums on the anomeric carbon of galactose. In some embodiments, the galactoside has one or more selenium attached to the anomeric carbon of galactose and one or more sulfur attached to the selenium. In some embodiments, the compound can have different aromatic or aliphatic substitutions on the galactose score.

Without being bound by theory, compounds containing selenium-containing molecules maintain the chemical, physical and allosteric properties of certain interactions with lectins or galectins known to recognize carbohydrates. Is believed to be metabolically stable.

In some embodiments, the monogalactoside, digalactoside or oligosaccharide of the galactose of the present invention is more metabolically stable than a compound having an O-glycoside or S-glycoside bond.

式1

式2
[式中、
Xは、セレンである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、S、SO₃、PO₂、アミノ酸、分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式疎水性炭化水素誘導体およびそれらの組み合わせからなる群から選択される；
Zは、O、S、N、CH、Se、S、P、および3つ以上の原子の複素環置換を含む疎水性炭化水素誘導体からなる群から選択される；
R₁、R₂、およびR₃は独立して、CO、O₂、SO₂、PO₂、PO、CH、水素、またはこれらの組み合わせ、ならびに、a)少なくとも3つの炭素からなるアルキル基、少なくとも3つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基で置換された少なくとも3つの炭素からなるアルキル基、アミノ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基、b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基、c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基、d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基、ならびにe)サッカリド、置換サッカリド、D-ガラクトース、置換D-ガラクトース、C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース、水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体、アミノ基、置換アミノ基、イミノ基、および置換イミノ基からなる群から選択される]
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物である。 In some embodiments, the compound is of formula (1) or formula (2):

Equation 1

Equation 2
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic open chain and cyclic containing O, S, C, NH, CH ₂ , Se, S, SO ₃ , PO ₂ , amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrophobic hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , and R ₃ are independently CO, O ₂ , SO ₂ , PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least three carbons, at least. It consists of an alkenyl group consisting of 3 carbons, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and at least 3 carbons substituted with an amino group. Alkyl group, alkenyl group consisting of at least 3 carbons substituted with amino group, alkyl group consisting of at least 3 carbons substituted with both amino group and carboxy group, at least substituted with both amino group and carboxy group An alkenyl group consisting of three carbons and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy Phenyl group substituted with a group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least one alkylamino group Phenyl group substituted with, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and at least one substituted carbonyl group Phenyl group substituted with, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one Phenyl group substituted with nitro group, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkyl Amino group substituted naphthyl group, at least one hydroxy group substituted naphthyl group, at least one carbonyl group substituted naphthyl group and at least one substituted carbonyl group substituted naphthyl group, d) heteroaryl Group, heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, few Heteroaryl groups substituted with at least one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heterozygous substituted with at least one amino group Aryl groups, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, with at least one carbonyl group Heteroaryl groups substituted with substituted heteroaryl groups and at least one substituted carbonyl group, as well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazole- Selected from the group consisting of 1-yl-substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocycles and derivatives, amino groups, substituted amino groups, imino groups, and substituted imino groups. Ru]
A compound represented by (1) or a pharmaceutically acceptable salt or solvate thereof.

式(4)

[式中、
Xは、セレンである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、S、SO₃、PO₂、アミノ酸、分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式疎水性炭化水素誘導体およびそれらの組み合わせからなる群から選択される；
Zは、O、S、N、CH、Se、S、SO₂、PO₂、および3つ以上の原子の複素環置換を含む疎水性炭化水素誘導体からなる群から選択される；
nは、≦24である；
R₁およびR₂は独立して、CO、O₂、SO₂、SO、PO₂、PO、CH、水素、またはこれらの組み合わせ、ならびに、a)少なくとも3つの炭素からなるアルキル基、少なくとも3つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基で置換された少なくとも3つの炭素からなるアルキル基、アミノ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基、b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基、c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基、d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基、ならびにe)サッカリド、置換サッカリド、D-ガラクトース、置換D-ガラクトース、C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース、水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体、アミノ基、置換アミノ基、イミノ基、および置換イミノ基からなる群から選択される]
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物である。いくつかの実施態様では、n=1である。他の実施態様では、n=3である。 In some embodiments, the compound is of formula (3) or formula (4):
Equation (3)

Equation (4)

[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic open chain and cyclic containing O, S, C, NH, CH ₂ , Se, S, SO ₃ , PO ₂ , amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrophobic hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, SO ₂ , PO ₂ , and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
n is ≤24;
R ₁ and R ₂ are independently CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least 3 carbons, at least 3 An alkenyl group consisting of carbon, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and an alkyl group consisting of at least 3 carbons substituted with an amino group. , An alkenyl group consisting of at least 3 carbons substituted with an amino group, an alkyl group consisting of at least 3 carbons substituted with both an amino group and a carboxy group, and at least 3 substituted with both an amino group and a carboxy group. An alkenyl group consisting of carbon and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy group Substituted phenyl group, substituted phenyl group with at least one nitro group, substituted phenyl group substituted with at least one sulfo group, substituted phenyl group substituted with at least one amino group, substituted with at least one alkylamino group Phenyl group substituted, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and substituted with at least one substituted carbonyl group Phenyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one nitro group Phenyl group substituted with, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkylamino group Phenyl group substituted with, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one carbonyl group and naphthyl group substituted with at least one substituted carbonyl group, d) heteroaryl group, Heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, at least 1 Heteroaryl groups substituted with one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heteroaryl groups substituted with at least one amino group, Heteroaryl group substituted with at least one alkylamino group, heteroaryl group substituted with at least one dialkylamino group, heteroaryl group substituted with at least one hydroxy group, substituted with at least one carbonyl group Heteroaryl groups substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl. -Selected from the group consisting of substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocycles and derivatives, amino groups, substituted amino groups, imino groups, and substituted imino groups]
A compound represented by (1) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, n = 1. In another embodiment, n = 3.

式(6)

[式中、
Xは、Se、Se-Se、Se-S；S-Se、Se-SO₂、またはSO₂-Seである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、アミノ酸およびそれらの組み合わせからなる群から選択される；
Zは、O、S、N、CH、Se、S、P、および3つ以上の原子の複素環置換を含む疎水性炭化水素誘導体からなる群から選択される；
R₁、R₂、R₃およびR₄は独立して、CO、O₂、SO₂、SO、PO₂、PO、CH、水素、またはこれらの組み合わせ、ならびに、a)少なくとも3つの炭素からなるアルキル基、少なくとも3つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基で置換された少なくとも3つの炭素からなるアルキル基、アミノ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基、b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基、c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基、d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基、ならびにe)サッカリド、置換サッカリド、D-ガラクトース、置換D-ガラクトース、C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース、水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体、アミノ基、置換アミノ基、イミノ基、および置換イミノ基からなる群から選択される]
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物である。 In some embodiments, the compound is of formula (5) or formula (6):
Equation (5)

Equation (6)

[During the ceremony,
X is Se, Se-Se, Se-S; S-Se, Se-SO ₂ , or SO ₂ -Se;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is selected from the group consisting of O, S, C, NH, CH ₂ , Se, amino acids and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , R ₃ and R ₄ independently consist of CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) at least 3 carbons. Alkyl group, alkenyl group consisting of at least 3 carbons, alkyl group consisting of at least 3 carbons substituted with carboxy group, alkenyl group consisting of at least 3 carbons substituted with carboxy group, at least 3 substituted with amino group An alkyl group consisting of one carbon, an alkenyl group consisting of at least three carbons substituted with an amino group, an alkyl group consisting of at least three carbons substituted with both an amino group and a carboxy group, and both an amino group and a carboxy group. An alkenyl group consisting of at least three carbons substituted, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, Phenyl group substituted with at least one alkoxy group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least 1 A phenyl group substituted with one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and at least one Phenyl group substituted with one substituted carbonyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group , A naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, A naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) Heteroaryl group, heteroaryl group substituted with at least one carboxy group, heteroary substituted with at least one halogen Aryl group, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, substituted with at least one amino group. Heteroaryl groups substituted, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, at least one Heteroaryl groups substituted with carbonyl groups and heteroaryl groups substituted with at least one substituted carbonyl group, as well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -Triazole-1-yl-substituted D-galactose, hydrogen, alkyl group, alkenyl group, aryl group, heteroaryl group, and heterocycle and derivative, amino group, substituted amino group, imino group, and substituted imino group. Selected from]
A compound represented by (1) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the halogen is a fluoro, chloro, bromo or iodo group.

In some embodiments, the compound is a 3-derivatized diselenogalactoside with fluorophenyltriazole.

式7
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物に関する。 In one aspect, the present invention relates to equation (7):

Equation 7
With respect to the compound represented by, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound is in free form. In some embodiments, the free form is anhydrous. In some embodiments, the free form is a solvate, such as a hydrate.

In some embodiments, the compound is in crystalline form.

Some aspects of the invention relate to pharmaceutical compositions comprising the compounds of the invention and optionally pharmaceutically acceptable additives such as adjuvants, carriers, excipients or combinations thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (1), (2), (3), (4), (5), (6) or (7), and optionally an adjuvant. Includes pharmaceutically acceptable additives such as carriers, excipients or combinations thereof.

In some embodiments, the compounds of the invention bind to one or more galectins. In some embodiments, the compound binds to galectin-3, galectin-1, galectin-8, and / or galectin-9.

In some embodiments, the compounds of the invention have selectivity and affinity for galectin-3. In some embodiments, the compounds of the invention have an affinity for galectin-3 from about 1 nM to about 50 μM.

Aspects of the invention relate to compositions or compounds that can be used in the treatment of diseases. Aspects of the invention relate to compositions or compounds in which galectin can be used in the treatment of diseases that are at least partially associated with the etiology. Another aspect of the invention relates to a method of treating a disease in a subject in need thereof.

Some embodiments of the present invention are methods of treating insulin resistance in therapeutically effective amounts of formulas (1), (2), (3), (4), (5), (6) or (7). ), Or a pharmaceutically acceptable salt or solvate thereof, comprising administering to a subject in need thereof.

Some embodiments of the present invention are methods of treating insulin resistance in therapeutically effective amounts of formulas (1), (2), (3), (4), (5), (6) or (7). ), Or a composition comprising a pharmaceutically acceptable salt or solvate thereof, comprising administering to a subject in need thereof.

In some embodiments of the invention, the compound can be used with an activator. In some embodiments of the invention, the activator is an immunomodulator, an anti-inflammatory agent, a vitamin, a dietary supplement, a supplement, or a combination thereof. In some embodiments, administration of the compounds and activators of the invention produces a synergistic effect.

Some aspects of the invention are TGFβ1 (transforming growth factor beta) by reversing the interaction of galectin-3 with its receptor (TGFβ1 receptor) in order to restore normal tissue regeneration activity. Regarding the treatment method of the disease caused by the confusion in the activity of 1).

Some aspects of the invention involve transforming proliferation involving many cell and pathological processes in both adult and embryonic development, such as cell proliferation, cell differentiation, apoptosis, cell homeostasis and other cellular functions. It relates to a method of treating a disease associated with a factor beta signaling pathway.

Some aspects of the invention are methods of treating diseases associated with the binding of galectin-3, such as galectin-3, which binds to the insulin receptor or TGFβ1 receptor in humans, with therapeutically effective amounts of formulas (1), (1), ( Administer the compound represented by 2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof. Regarding methods including that.

Some aspects of the invention have formulas (1), (2), (3), (4), (for use in methods of treating disorders associated with galectin binding in subjects in need thereof. 5), (6) or (7), or a pharmaceutically acceptable salt or solvate thereof. Some aspects of the invention have formulas (1), (2), (3), for use in methods of treating disorders associated with binding of galectin-3 to a ligand in a subject in need thereof. It relates to the compound represented by (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the subject in need of it is a mammal. In some embodiments, the subject in need of it is a human.

Some aspects of the invention are methods of treating disorders associated with binding of galectin such as calectin-3 to a ligand in humans, wherein at least one of the therapeutically effective amounts of formulas (1), (2), (3). ), (4), (5), (6) or (7), the method comprising administering a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treatment is for systemic insulin resistance.

The patent or application file contains at least one drawing created in color. A copy of this patent or patent application publication, including color drawings, will be provided by the Office by paying the required fee upon request.

The present invention is further described with reference to the accompanying drawings, through which similar structures are referred to by similar numbers. The drawings shown are not necessarily on scale and instead the emphasis is on explaining the principles of the invention.

Interactions Shows a high-resolution 3D structure of a galectin-3 carbohydrate recognition domain (CRD) binding pocket with three potential sites. The location of the CRD pocket at the Galectin-3 C-terminus with bound lactose units is shown. Galectin-3 CRD site neighborhood map-shows potential co-amino acids for strengthening binding. The synthesis of selenium galactoside compounds according to some embodiments is shown. A fluorescence polarization assay format for detecting compounds that specifically bind to CRD, according to some embodiments, is shown. A fluorescence resonance energy transfer assay (FRET format) for screening compounds that inhibit the interaction of galectin-3 with its glycoprotein ligand (eg, TGFb1 receptor FRET format) according to some embodiments is shown. Inhibition of galectin-binding moieties using a particular anti-galectin-3 monoclonal antibody binding assay (ELISA format) by several embodiments is shown. A functional assay for screening compounds that inhibit the interaction of galectin-3 with its glycoprotein ligand, according to some embodiments (eg, insulin receptor ELISA format). Examples of Compound IC50s with Fluorescent Polarization-CRD-specific assays for compounds according to several embodiments are provided. Examples of compound IC50 by insulin receptor-galectin-3 ELISA format assay according to several embodiments are provided. Examples of compound IC50 by TGFb1-receptor-galectin-3 ELISA format assay according to some embodiments are provided.

Detailed Description of the Invention Detailed embodiments of the invention are disclosed herein; however, it is understood that the disclosed embodiments are merely embodiments of the invention that can be embodied in various forms. It should be. Moreover, each of the examples given in connection with the various embodiments of the present invention is intended to be exemplary and not limiting. Moreover, the figures are not always on scale and some features may be exaggerated to show details of a particular component. Furthermore, the measured values, specifications, etc. shown in the figure are for the purpose of exemplification and are not limited. Therefore, the particular structural and functional details disclosed herein should not be construed as limiting and serve as a representative basis for teaching one of ordinary skill in the art to use the invention in various ways. It is a thing.

Citation of a document herein acknowledges that any of the documents cited herein are related prior art, or the cited document is important to the patentability of the claims of the present application. Not intended as an approval to be considered.

Throughout the specification and claims, the following terms have the meanings expressly associated with the present specification, unless otherwise apparent from the context. The terms "in one embodiment" and "in some embodiments" as used herein may indicate the same embodiment, but are not always the case. Moreover, the terms "in another embodiment" and "in some other embodiments" used herein do not necessarily indicate different embodiments. Therefore, various embodiments of the invention can be easily combined without departing from the scope or true spirit of the invention, as described below.

Moreover, as used herein, the term "or" is a comprehensive "or" operator and is equivalent to the term "and / or" unless the context clearly dictates otherwise. is there. The term "based on" is not exclusive and allows for additional elements that are not explained unless explicitly stated in the context. In addition, throughout the specification, the meanings of "a," "an," and "the" include multiple references.

Unless otherwise specified, all percentages expressed herein are weight / weight.

Aspects of the invention relate to the composition of monosaccharides, disaccharides and oligosaccharides of a galactose (or heteroglycoside) core attached to a selenium atom (Se) on the anomeric carbon of galactose (or heteroglycoside). In some embodiments, Se-containing molecules make them metabolically stable while maintaining the chemical, physical and allosteric properties of certain interactions with lectins known to recognize carbohydrates. To do. In some embodiments, the particular aromatic substitution added to the galactose score has an affinity for the selenium-binding pyranosyl and / or furanosyl structure, amino acid residues that make up the carbohydrate recognition domain (CRD) of the lectin (eg, for example. It is further enhanced by enhancing its interaction with arginine, tryptophan, histidine, glutamic acid, etc.) and thus enhances binding and binding specificity.

In some embodiments, the composition or compound can be used to treat non-alcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic disease or cancer. ..

In some embodiments, the composition can be used in the treatment of liver fibrosis, renal fibrosis, pulmonary fibrosis, or cardiac fibrosis.

In some embodiments, the composition or compound can enhance antifibrotic activity in organs, including but not limited to liver, kidney, lung, and heart.

In some embodiments, the composition or compound can be used to treat inflammatory disorders of the vascular system, including atherosclerosis and pulmonary hypertension.

In some embodiments, the composition or compound can be used in the treatment of heart disorders, including heart failure, arrhythmias, and uremic cardiomyopathy.

In some embodiments, the composition or compound can be used in the treatment of kidney disease, including glomerulopathy and interstitial nephritis.

In some embodiments, the composition or compound can be used in the treatment of inflammatory, proliferative and fibrous skin disorders, including but not limited to psoriasis and scleroderma.

Aspects of the invention relate to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.

Aspects of the invention include, but are not limited to, liver, kidney, lung, and heart inflammatory and fibrotic fibers in which galectin is at least partially involved in the etiology by enhancing antifibrotic activity in organs. On how to treat sexual disorders.

Aspects of the present invention relate to compositions or compounds having therapeutic activity for treating nonalcoholic steatohepatitis (NASH). In another aspect, the invention relates to a method of reducing pathological and disease activity associated with nonalcoholic steatohepatitis (NASH).

Aspects of the invention are methods of treating or treating inflammatory and autoimmune disorders in which galectin is at least partially involved in the etiology including, but not limited to, arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease. With respect to the composition or compound used in.

Aspects of the invention are for treating neoplastic diseases (eg, benign or malignant neoplastic diseases) in which galectin is at least partially etiologically involved by inhibiting a process facilitated by an increase in galectin. With respect to the composition or compound. In some embodiments, it relates to a method of treating a neoplastic disease (eg, benign or malignant neoplastic disease) in which galectin is at least partially etiologically involved by inhibiting a process facilitated by an increase in galectin. .. In some embodiments, the composition or compound can be used to treat or prevent the growth, invasion, metastasis, and angiogenesis of tumor cells. In some embodiments, the composition or compound can be used to treat primary and secondary cancers.

Aspects of the invention include other antitumor agents, including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1, anti-PDL1), other immunomodulators including but not limited to anti-OX40, and a plurality. Mechanism of composition or compound for treating neoplastic disease in combination with multiple other antitumor agents.

In some embodiments, therapeutically effective amounts of the compound or composition are combined without limitation with, but not limited to, therapeutically effective amounts of various anti-inflammatory agents, vitamins, other pharmaceuticals and dietary supplements or supplements. , Fits and can be effective.

Galectin Galectin (also known as galaptin or S-lectin) is a family of lectins that bind to beta galactoside. Galectins as a generic name was proposed for a family of animal lectins in 1994 (Barondes, SH, et al .: Galectins: a family of animal beta-galactoside-binding lectins. Cell 76, 597-598, 1994). This family is defined by having at least one carbohydrate recognition domain (CRD) that has an affinity for β-galactoside and sharing specific sequence elements. Due to further structural characterization, galectins are divided into three subgroups: (1) galectins with a single CRD; (2) galectins with two CRDs linked by a linker peptide; and (3) different types of N-terminus. It is classified into a group with one member (galectin-3) with one CRD bound to the domain; The galectin carbohydrate recognition domain is a beta sandwich of about 135 amino acids. The two sheets are slightly bent and have 6 strands forming a concave surface, also called the S-plane, and 5 strands forming a convex surface, which is the F-plane. The concave surface forms a groove to which carbohydrates bind (Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). "Introduction to galectins". Glycoconj. J. 19 (7-9): 433-40) ..

Various biological phenomena such as development, differentiation, morphogenesis, tumor metastasis, apoptosis, RNA splicing and many others have been shown to be associated with galectin.

In general, the carbohydrate domain binds to galactose residues associated with glycoproteins. Galactin is a residue of galactose bound to other organic compounds such as lactose [(β-D-galactoside) -D-glucose], N-acetyl-lactosamine, poly-N-acetyllactosamine, galactomannan, or fragments of pectin. Shows affinity for groups. However, it should be noted that galactose itself does not bind to galectin.

Plant polysaccharides such as pectin and modified pectin have been shown to bind to galectin proteins, presumably based on their inclusion of galactose residues presented in the context of macromolecules, in this case of animal cells. It is a complex carbohydrate rather than a glycoprotein in the case.

At least 15 mammalian galectin proteins have been identified in tandem with one or two carbohydrate domains.

Galectin proteins are found in the intracellular space to which they are assigned many functions and are also secreted into the extracellular space where they have different functions. In extracellular space, galectin proteins are associated with galactose-containing glycoproteins, such as facilitating interactions between glycoproteins that can regulate function, or, in the case of endogenous membrane glycoprotein receptors, modifying cell signaling. Can have multiple functions mediated by the interactions of (Sato et al "Galectins as danger signals in host-pathogen and host-tumor interactions: new members of the growing group of" Alarmins. "In" Galectins "( Klyosov, et al eds.), John Wiley and Sons, 115-145, 2008, Liu et al "Galectins in acute and chronic inflammation," Ann. NY Acad. Sci. 1253: 80-91, 2012). Extracellular space Galectin proteins in can further promote cell-cell and cell matrix interactions (Wang et al., "Nuclear and cytoplasmic localization of galectin-1 and galectin-3 and their roles in pre-mRNA splicing." In "Galectins" (Klyosov et al eds.), John Wiley and Sons, 87-95, 2008). With respect to intracellular space, galectin function appears to be more related to protein-protein interactions, Cellular vesicle transport appears to be associated with interactions with glycoproteins.

Galectin has been shown to have a domain that promotes homodimerization. Therefore, galectin can function as a "molecular adhesive" between glycoproteins. Galectin is found in multiple cell compartments, including the nucleus and cytoplasm, and is secreted into the extracellular space, where it interacts with the cell surface and extracellular matrix glycoproteins. The mechanism of molecular interaction can depend on localization. Galectin can interact with glycoproteins in the extracellular space, but in the intracellular space the interaction of galectin with other proteins generally occurs via the protein domain. In extracellular space, cell surface receptor association can increase or decrease the ability of receptor signaling or interaction with ligands.

Galectin proteins are significantly increased in many animal and human disease states, including but not limited to diseases associated with inflammation, fibrosis, autoimmunity, and tumors. Galectin is directly involved in the etiology of the disease, as described below. For example, disease states that may depend on galectin include, but are not limited to: systemic insulin resistance, acute and chronic inflammation, allergic diseases, asthma, dermatitis, autoimmune diseases, and inflammatory. And degenerative arthritis, immune-mediated neurological disease, multi-organ fibrosis (including but not limited to liver, lung, kidney, pancreas, and heart), inflammatory bowel disease, atherosclerosis, heart failure, ocular Inflammatory diseases, a wide variety of cancers.

In addition to the disease state, galectin is an important regulatory molecule in regulating the response of immune cells to vaccination, exogenous pathogens and cancer cells.

Those skilled in the art may bind to galectin and / or alter the affinity of galectin for glycoproteins, reduce atypical or homozygous interactions between galectins, or alter the function, synthesis, or metabolism of galectin proteins. It will be appreciated that the resulting compounds may have important therapeutic effects on galectin-dependent diseases.

Galectin proteins such as galectin-1 and galectin-3 have been shown to be significantly increased in inflammation, fibrotic diseases, and neoplasms (Ito et al. "Galectin-1 as a potentiate target for cancer therapy: role". in the tumor microenvironment ", Cancer Metastasis Rev. PMID: 22706847 (2012), Nangia-Makker et al. Galectin-3 binding and metastasis," Methods Mol. Biol. 878: 251-266, 2012, Canesin et al. Galectin- 3 expression is associated with bladder cancer progression and clinical outcome, "Tumour Biol. 31: 277-285, 2010, Wanninger et al." Systemic and hepatic vein falectin-3 are increased in patients with alcoholic liver cirrhosis and negatively correlate with liver function , "Cytokine. 55: 435-40, 2011). In addition, experiments show that galectins, especially galectin-1 (gal-1) and galectin-3 (gal-3), are directly involved in the etiology of these classes of diseases (Toussaint et al., " Galectin-1, a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion. ", Mol. Cancer. 11:32, 2012, Liu et al 2012, Newlaczyl et al.," Galectin-3-a jack-of- all-trades in cancer, "Cancer Lett. 313: 123-128, 2011, Banh et al.," Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis, "Cancer Res. 71: 4423-31 , 2011, Lefranc et al., "Galectin-1 mediated biochemical controls of melanoma and glioma aggressive behavior," World J. Biol. Chem. 2: 193-201, 2011, Forsman et al., "Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis, "Arthritis Reum. 63: 445-454, 2011, de Boer et al.," Galectin-3 in cardiac remodeling and heart failure, "Curr. Heart Fail. Rep. 7, 1-8, 2010, Poland et al., "Galectin-3 in heart failure: high levels are associated with all-cause mortality," Int J. Cardiol. 150: 361-364, 2011, Ohshima et al., "Galectin 3 and its binding protein in rheumatoid arthritis, "Arthritis Rheum. 48: 2788-2795, 2003).

High levels of serum galectin-3 have been shown to be associated with some human diseases, including more malignant heart failure, so the galectin-3 trial was used to identify high-risk patients in patient care. Make it an important part. The galectin-3 trial may help physicians determine which patients are at increased risk of hospitalization or death. For example, the BGM galectin-3® study is an in vitro diagnostic device that quantitatively measures galectin-3 in serum or plasma and is clinically assisted in assessing the prognosis of patients diagnosed with chronic heart failure. Can be used in combination with evaluation. Measurement of the concentration of the endogenous protein galectin-3 can be used to predict or monitor disease progression or therapeutic effect in patients treated with cardiac resynchronization therapy (see US 8,672,857).

Galectin-3 has been shown to be elevated in patients with metabolic disorders and in obese populations with diabetes associated with systemic insulin resistance. High levels of serum galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is a persistent illness that can be resolved but can be prevented with care. It is one of the most common metabolic syndromes in the world. Diabetes is primarily associated with the chronic complications of the central and peripheral nervous systems. Diabetes mellitus is a common metabolic syndrome of diabetes in which glucose is not used by the body and is stored in the blood, which can damage the kidneys, nerves, heart, eyes, and other complications. ..

Insulin resistance Insulin resistance is a hallmark of patients with complications from diabetes (T2DM) and is one of the clinical features of metabolic syndrome (MetS). MetS is a series of biochemical and metabolic disorders estimated to affect more than 20% of American adults (aged 20+), or approximately 50 million Americans. This number could increase dramatically in the future, as the obesity epidemic shows no signs of reversal.

Insulin resistance, a major feature of type 2 diabetes, can develop in patients with type 1 diabetes when clinically designated as having double diabetes. Patients with double diabetes always have type 1 diabetes, but with insulin resistance complications. Obesity is the most common reason for developing insulin resistance, and type 1 diabetes itself is not caused by obesity.

People with type 1 diabetes are more likely to become obese than anyone else and may suffer from insulin resistance.

Insulin is a hormone with diverse functions such as stimulating the transport of nutrients to cells, regulating various enzyme activities, and regulating energy homeostasis. These functions include glucose metabolism via intracellular signaling pathways in the liver, adipose tissue, and muscle. In the liver, insulin resistance increases glucose production in the liver. In adipose tissue, insulin resistance results in an anti-lipolytic free fatty acid outflow from adipocytes and affects lipase activity, which increases circulating free fatty acids.

Recent studies have shown that plasma levels of galectin-3 are significantly elevated in human and animal obesity models.

In obesity, macrophages and other immune cells have been reported to be recruited to insulin target tissues to promote chronic inflammatory conditions and insulin resistance. Galectin-3, which is known to be secreted primarily by macrophages, may play an important role in this inflammatory process and therefore reduces insulin sensitivity in association with inflammation.

The insulin receptor is a transmembrane protein activated by bound insulin, IGF-I, IGF-II and belongs to the class of tyrosine kinase receptors. Insulin receptors play an important role in the regulation of glucose homeostasis when dysfunction or metabolic disorders can result in a range of clinical manifestations, including but not limited to diabetes. The insulin receptor is encoded by a single gene, INSR, that can produce either IR-A or IR-B isoforms during transcription. After translation, these isoforms result in the formation of proteolytically cleaved α and β subunits, which combine to form the final transmembrane insulin receptor of approximately 320 kDa.

Insulin receptor-insulin interaction is a checkpoint for Ras mitogen-activated protein kinase (MAPK), which mediates the second pathway, gene expression, and also in the PI3K-AKT pathway, which controls cell proliferation and differentiation. affect. The insulin receptor substrate (IRS) is a common intermediate that contains four different family members, the IRS1-4. Insulin receptor substrate-1 (IRS1) is usually involved in defects in insulin signaling. Insulin receptor activation increases tyrosine phosphorylation of IRS1 which initiates signal transduction. However, when serine 307 is phosphorylated, signal transduction is reduced. Negative IR or IRS1 inflammation-related regulators, such as cytokine signaling (Soc) suppressors, can promote ubiquitination, with the small protein ubiquitin binding to other target proteins, for example. Alternates functionality and subsequent degradation, such as IRS inactivation.

Some aspects of the invention relate to compounds and the use of compounds that inhibit galectin-3 and treat insulin resistance.

Modified forms of natural oligosaccharide ligands capable of binding to the galectin inhibitors galectin-1 and / or galectin-3, such as guar gum-derived pectin and galactomannan (WO 2013040316, US 20110294755, WO 2015138438). reference). Synthetic digalactoside such as lactose, N-acetyllactosamine (LacNAc) and thiolactoside are effective against pulmonary fibrosis and other fibrotic diseases (WO 2014067986 A1, incorporated herein by reference in its entirety). ).

Many derivatives with enhanced affinity for CRD, which have a higher affinity for galactose or lactose, due to advances in protein crystallography and the availability of high resolution 3D structures of the carbohydrate recognition domain (CRD) of many galectins. Was generated (WO 2014067986, incorporated herein by reference in its entirety). These compounds have been shown to be effective in treating animal models of pulmonary fibrosis, which are thought to mimic human idiopathic pulmonary fibrosis (IPF). For example, thio-digalactopyranosyl substituted with 3-fluorophenyl-2,3-triazole group (TD-139) has been reported to bind to galectin-3 and be effective in a mouse model of pulmonary fibrosis. Has been done. Compounds required intratracheal infusion or pulmonary administration using a nebulizer (US8703720, US7700763, US7638623 and US7230096, which are incorporated herein by reference in their entirety).

Aspects of the invention relate to novel compounds that mimic the natural ligands of galectin proteins. In some embodiments, the compound mimics the natural ligand of galectin-3. In some embodiments, the compound mimics the natural ligand for galectin-1. In some embodiments, the compound mimics the natural ligand of galectin-8. In some embodiments, the compound mimics the natural ligand of galectin-9.

In some embodiments, the compound is composed of a galactose-Se core attached to the anomeric carbon on galactose and has a mono, di, or oligomeric structure that acts as a linker to other parts of the molecule. In some embodiments, the galactose-Se core binds to other sugars / amino acids / acids / groups that bind galectin CRD (as shown in Figure 1 in the high resolution 3D structure of galectin-3), along with CRD. Enhances the affinity of the compound for. In some embodiments, the galactose-Se core can bind to other sugars / amino acids / acids / groups that bind to "site B" of the galectin CRD (in the high resolution 3D structure of galectin-3, Figure 1). (As shown in), the affinity of the compound for CRD can be enhanced.

According to some embodiments, the compound interacts with Site A and / or Site C to further improve its association with CRD and enhance its potential as a therapeutic target for galectin-dependent pathologies. Can have substitutions. In some embodiments, the substituents can be selected by in silico analysis (computer-assisted molecular modeling), as described herein. In some embodiments, a binding assay with the galectin protein of interest can be used to further screen for substituents. For example, compounds can be screened using a galectin-3 binding assay and / or an in vitro inflammation and fibrosis model of activated cultured macrophages. (See Chavez-Galan, L. et al., Immunol. 2015; 6: 263).

According to some embodiments, the compound comprises one or more specific substitutions of galactose-Se in the core. For example, core galactose-Se can be replaced with specific substituents that interact with residues within the CRD. Such substituents can dramatically increase compound association and potential efficacy, as well as "pharmaceutical" properties.

Selenium Selenium five possible oxidation state (-2,0, + 2, + 4 and +6) because it has a, well represented in a variety of compounds with different chemical properties. In addition, selenium can be replaced by selenium in substantially all inorganic and organic sulfur compounds.

Most selenium compounds (organic and inorganic) are easily absorbed from the diet and transported to the liver, the major organ of selenium metabolism. The general metabolism of selenium compounds follows three major pathways, depending on their chemical properties: redox-active selenium compounds, methylselenol and selenoamino acid precursors.

Selenium is commonly known as an antioxidant because it is present in selenoproteins such as selenocysteine, but it can also be toxic. However, the toxicity of selenium depends, strictly speaking, on the concentration and species. One class of selenium compounds is a potent inhibitor of cell growth with significant tumor specificity (Misra, 2015). Sodium selenite has been studied as a cytotoxic agent for advanced cancers (see SECAR, Brodin, Ola et al., 2015).

Galactoside-Selenium Compounds Aspects of the present invention relate to compounds comprising a pyranosyl and / or furanosyl structure attached to a selenium atom on the anomer carbon of pyranosyl and / or furanosyl.

In some embodiments, specific aromatic substitutions can be added to the galactose score or heteroglycoside core to further enhance the affinity of the selenium-bound pyranosyl and / or furanosyl structure. Such aromatic substitutions enhance the interaction of the compound with the amino acid residues that make up the carbohydrate recognition domain (CRD) of the lectin (eg, arginine, tryptophan, histidine, glutamic acid, etc.) and enhance binding and binding specificity. Can be strengthened.

In some embodiments, the compound comprises a galactose or heteroglycoside core monosaccharide, disaccharide and oligosaccharide attached to a selenium atom on the anomeric carbon of the galactose or heteroglycoside.

In some embodiments, the compound is a symmetric digalactoside in which two galactosides are linked by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside in which two galactosides are attached by one or more selenium bonds and selenium is attached to the anomeric carbon of galactose. In some embodiments, the compound is a symmetric digalactoside in which two galactosides are attached by one or more selenium and one or more sulfur bonds, with selenium attached to the anomeric carbon of galactose. In yet another embodiment, the compound can be an asymmetric digalactoside. For example, a compound can have different aromatic or aliphatic substitutions on the galactose score.

In some embodiments, the compound is a symmetric galactoside in which a single galactoside has one or more seleniums on the anomeric carbon of galactose. In some embodiments, the galactoside has one or more selenium attached to the anomeric carbon of galactose and one or more sulfur attached to the selenium. In some embodiments, the compound can have different aromatic or aliphatic substituents on the galactose core.

Without being bound by theory, compounds containing Se-containing molecules maintain their chemical, physical and allosteric properties for specific interactions with lectins or galectins known to recognize carbohydrates. , It is thought to stabilize the compound metabolically. In some embodiments, the galactose digalactoside or oligosaccharide of the present invention is more metabolically stable than a compound having an O-glycoside bond.

In some embodiments, the galactose digalactoside or oligosaccharide of the present invention is more metabolically stable than a compound having an S-glycoside bond.

Aspects of the invention relate to compounds based on other galactoside structures with selenium bridges [X] to other galactoses, hydroxylcyclohexanes, aromatic moieties, alkyls, aryls, amines, or amides.

As used herein, the term "alkyl group" means that it comprises 1 to 12 carbon atoms, such as 1 to 7 or 1 to 4 carbon atoms or 3 to 7 carbon atoms. means. In some embodiments, the alkyl group can be straight or branched. In some embodiments, the alkyl group can also form a ring containing 3-7 carbon atoms, preferably 3, 4, 5, 6, or 7 carbon atoms. Therefore, alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl. , 2,2-Dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, And 1-methylcyclopropyl is included.

As used herein, the term "alkenyl group" is meant to include 2-12, eg, 2-7 or 3-7 carbon atoms. The alkenyl group contains at least one double bond. In some embodiments, the alkenyl group is vinyl, allyl, gnat-1-enyl, gnat-2-enyl, 2,2-dimethylethenyl, 2,2-dimethylprop-1-enyl, pent-1-. Enyl, pent-2-enyl, 2,3-dimethylbut-1-enyl, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, propa-1,2-dienyl, 4-methylhex-1- Includes allyl, cycloprop-1-enyl group, and others.

As used herein, the term "alkoxy group" refers to an alkoxy group containing 1 to 12 carbon atoms and can include one or more unsaturated carbon atoms. In some embodiments, the alkoxy group comprises 1-7 or 1-4 carbon atoms, which may contain one or more unsaturated carbon atoms. Therefore, the term "alkoxy group" refers to a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, a pentoxy group, an isopentoxy group, a 3-methylbutoxy group, 2,2-Dimethylpropoxy group, n-hexoxy group, 2-methylpentoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, n-heptoxy group, 2-methylhexoxy group, 2,2- Includes dimethylpentoxy group, 2,3-dimethylpentoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, and 1-methylcyclopropyloxy group.

As used herein, the term "aryl group" is meant to contain 3-12 carbon atoms. The aryl group can be a phenyl group or a naphthyl group. The above groups may, of course, be substituted with other known substituents within the field of organic chemistry. These groups may also be substituted with two or more of the substituents. Examples of substituents are halogen, alkyl, alkenyl, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups. Halogen substituents can be bromo, fluoro, iodo, and chloro. Alkyl groups are as defined above, containing 1-7 carbon atoms. Alkenyl is as defined above, containing 2-7, preferably 2-4 carbon atoms. Alkoxy contains 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, and may contain unsaturated carbon atoms, as defined below. There may be a combination of substituents such as trifluoromethyl.

As used herein, the term "heteroaryl group" means containing any aryl group containing 4-18 carbon atoms, i.e., at least one atom of the ring is a heteroatom. Not carbon. In some embodiments, the heteroaryl group may be a pyridine or an indole group.

The above groups may be substituted with other known substituents within the field of organic chemistry. These groups may be substituted with two or more substituents. Examples of substituents are halogen, alkoxy, nitro, sulfo, amino, hydroxy, and carbonyl groups. Halogen substituents can be bromo, fluoro, iodo, and chloro. Alkyl groups are as defined above, containing 1-7 carbon atoms. Alkenyl is as defined above, containing 2-7 carbon atoms, eg 2-4. Alkoxy contains 1 to 7 carbon atoms, for example 1 to 4 carbon atoms and may contain unsaturated carbon atoms, as defined below.

式1

式2
[式中、
Xは、セレンである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、NH、CH₂、Se、S、SO₂、PO₂、アミノ酸、分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式疎水性炭化水素誘導体およびそれらの組み合わせからなる群から選択される；
Zは、O、S、N、CH、Se、S、P、および3つ以上の原子の複素環置換を含む疎水性炭化水素誘導体からなる群から選択される；
R₁、R₂、およびR₃は独立して、CO、O₂、SO₂、 PO₂、PO、CH、水素、またはこれらの組み合わせ、ならびに、a)少なくとも3つの炭素からなるアルキル基、少なくとも3つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基で置換された少なくとも3つの炭素からなるアルキル基、アミノ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基、b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基、c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基、d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基、ならびにe)サッカリド、置換サッカリド、D-ガラクトース、置換D-ガラクトース、C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース、水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体、アミノ基、置換アミノ基、イミノ基、および置換イミノ基からなる群から選択される]
で示されるモノマー-セレンポリヒドロキシル化-シクロアルカン化合物またはその薬学的に許容される塩もしくは溶媒和物である。 Monomer-Selenium Polyhydroxylation-Cycloalkane In some embodiments, the compound is of formula (1) or formula (2):

Equation 1

Equation 2
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is hydrophobic, linear and cyclic hydrophobic, containing O, S, NH, CH ₂ , Se, S, SO ₂ , PO ₂ , amino acids, and heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , and R ₃ are independently CO, O ₂ , SO ₂ , PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least three carbons, at least. It consists of an alkenyl group consisting of 3 carbons, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and at least 3 carbons substituted with an amino group. Alkyl group, alkenyl group consisting of at least 3 carbons substituted with amino group, alkyl group consisting of at least 3 carbons substituted with both amino group and carboxy group, at least substituted with both amino group and carboxy group An alkenyl group consisting of three carbons and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy Phenyl group substituted with group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least one alkylamino group Phenyl group substituted with, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and at least one substituted carbonyl group Phenyl group substituted with, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one Phenyl group substituted with nitro group, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkyl Amino group substituted naphthyl group, at least one hydroxy group substituted naphthyl group, at least one carbonyl group substituted naphthyl group and at least one substituted carbonyl group substituted naphthyl group, d) heteroaryl Group, heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, few Heteroaryl groups substituted with at least one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heterozygous substituted with at least one amino group Aryl groups, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, with at least one carbonyl group Heteroaryl groups substituted with substituted heteroaryl groups and at least one substituted carbonyl group, as well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazole- Selected from the group consisting of 1-yl-substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocycles and derivatives, amino groups, substituted amino groups, imino groups, and substituted imino groups. Ru]
Monomer-selenium polyhydroxylation-cycloalkane compound represented by or a pharmaceutically acceptable salt or solvate thereof.

Oligomer selenium polyhydroxylation and dimer selenium polyhydroxylation-cycloalkane compound In some embodiments, the compound is a dimer-polyhydroxylation-cycloalkane compound. In some embodiments, the compound is an oligomeric selenium polyhydroxylated-cycloalkane compound having three or more units.

式3

式4
[式中、
Xは、セレンである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、S、SO₃、PO₂、アミノ酸、分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式疎水性炭化水素誘導体およびそれらの組み合わせからなる群から選択される；
Zは、O、S、N、CH、Se、S、SO₂、PO₂、および3つ以上の原子の複素環置換を含む疎水性炭化水素誘導体からなる群から選択される；
nは、≦24である；
R₁およびR₂は独立して、CO、O₂、SO₂、SO、PO₂、PO、CH、水素、またはこれらの組み合わせ、ならびに、a)少なくとも3つの炭素からなるアルキル基、少なくとも3つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基で置換された少なくとも3つの炭素からなるアルキル基、アミノ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基、b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基、c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基、d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基、ならびにe)サッカリド、置換サッカリド、D-ガラクトース、置換D-ガラクトース、C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース、水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体；アミノ基、置換アミノ基、イミノ基、および置換イミノ基からなる群から選択される]
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物である。 In some embodiments, the compounds are represented by the following general formulas (3) and (4):

Equation 3

Equation 4
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic open chain and cyclic containing O, S, C, NH, CH ₂ , Se, S, SO ₃ , PO ₂ , amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrophobic hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, SO ₂ , PO ₂ , and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
n is ≤24;
R ₁ and R ₂ are independently CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least 3 carbons, at least 3 An alkenyl group consisting of carbon, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and an alkyl group consisting of at least 3 carbons substituted with an amino group. , An alkenyl group consisting of at least 3 carbons substituted with an amino group, an alkyl group consisting of at least 3 carbons substituted with both an amino group and a carboxy group, and at least 3 substituted with both an amino group and a carboxy group. An alkenyl group consisting of carbon and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy group Substituted phenyl group, substituted phenyl group with at least one nitro group, substituted phenyl group substituted with at least one sulfo group, substituted phenyl group substituted with at least one amino group, substituted with at least one alkylamino group Phenyl group substituted, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and substituted with at least one substituted carbonyl group Phenyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one nitro group Phenyl group substituted with, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkylamino group Phenyl group substituted with, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one carbonyl group and naphthyl group substituted with at least one substituted carbonyl group, d) heteroaryl group, Heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, at least 1 Heteroaryl groups substituted with one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heteroaryl groups substituted with at least one amino group, Heteroaryl group substituted with at least one alkylamino group, heteroaryl group substituted with at least one dialkylamino group, heteroaryl group substituted with at least one hydroxy group, substituted with at least one carbonyl group Heteroaryl groups substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl. -Substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocyclics and derivatives; selected from the group consisting of amino groups, substituted amino groups, imino groups, and substituted imino groups]
A compound represented by (1) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, n = 1. In some embodiments, n = 2. In some embodiments, n = 3.

As used herein, the term "alkyl group" refers to an alkyl group containing 1 to 7 carbon atoms, which may contain one or more unsaturated carbon atoms. In some embodiments, the alkyl group comprises 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms. The carbon atom of the alkyl group can form a straight chain or a branched chain. The carbon atom of the alkyl group may form a ring containing 3, 4, 5, 6, or 7 carbon atoms. Therefore, as used herein, the term "alkyl group" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2, 2-Dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.

In some embodiments, the compound is a 3-derivatized diselenogalactoside with fluorophenyltriazole.

式7
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物に関する。 In one aspect, the present invention relates to equation (7):

Equation 7
With respect to the compound represented by, or a pharmaceutically acceptable salt or solvate thereof.

式(5)

式(6)
[式中、
Xは、Se、Se-Se、Se-S；S-Se、Se-SO₂、またはSO₂-Seである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、P、アミノ酸、分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式疎水性炭化水素誘導体およびそれらの組み合わせからなる群から選択される；
Zは、O、S、N、CH、Se、S、P、および3つ以上の原子の複素環置換を含む疎水性炭化水素誘導体からなる群から選択される；
R₁、R₂、R₃およびR₄は独立して、CO、O₂、SO₂、SO、PO₂、PO、CH、水素、またはこれらの組み合わせ、ならびに、a)少なくとも3つの炭素からなるアルキル基、少なくとも3つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基で置換された少なくとも3つの炭素からなるアルキル基、アミノ基で置換された少なくとも3つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも3つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基、b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基、c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基、d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基、ならびにe)サッカリド、置換サッカリド、D-ガラクトース、置換D-ガラクトース、C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース、水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体、アミノ基、置換アミノ基、イミノ基、および置換イミノ基からなる群から選択される]
で示される化合物またはその薬学的に許容される塩もしくは溶媒和物である。 In some embodiments, the compounds are represented by the following general formulas (5) and (6):

Equation (5)

Equation (6)
[During the ceremony,
X is Se, Se-Se, Se-S; S-Se, Se-SO ₂ , or SO ₂ -Se;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic linear and cyclic hydrophobic hydrocarbon derivative containing O, S, C, NH, CH ₂ , Se, P, amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D and Selected from a group of combinations of them;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , R ₃ and R ₄ independently consist of CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) at least 3 carbons. Alkyl group, alkenyl group consisting of at least 3 carbons, alkyl group consisting of at least 3 carbons substituted with carboxy group, alkenyl group consisting of at least 3 carbons substituted with carboxy group, at least 3 substituted with amino group An alkyl group consisting of one carbon, an alkenyl group consisting of at least three carbons substituted with an amino group, an alkyl group consisting of at least three carbons substituted with both an amino group and a carboxy group, and both an amino group and a carboxy group. An alkenyl group consisting of at least three carbons substituted, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, Phenyl group substituted with at least one alkoxy group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least 1 A phenyl group substituted with one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and at least one Phenyl group substituted with one substituted carbonyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group , A naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, A naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) Heteroaryl group, heteroaryl group substituted with at least one carboxy group, heteroary substituted with at least one halogen Aryl group, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, substituted with at least one amino group. Heteroaryl groups substituted, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, at least one Heteroaryl groups substituted with carbonyl groups and heteroaryl groups substituted with at least one substituted carbonyl group, as well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -Triazole-1-yl-substituted D-galactose, hydrogen, alkyl group, alkenyl group, aryl group, heteroaryl group, and heterocycle and derivative, amino group, substituted amino group, imino group, and substituted imino group. Selected from]
A compound represented by (1) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the halogen is a fluoro, chloro, bromo or iodo group.

In some embodiments, the compound has the formula shown in Table 1 below and is an inhibitor of galectin-3.

Table 1 shows non-limiting examples of the monomeric Se galactoside.
table 1

In some embodiments, the compound has the formula shown in Table 2 below and is an inhibitor of galectin-3.

Table 2 shows a non-limiting example of dimer Se saccharides.
Table 2

In some embodiments, the compound has the formula shown in Table 3 below and is an inhibitor of galectin-3.

Table 3 shows non-limiting examples of oligo-Se saccharides.
Table 3

Tetramer Se-galactoside is expected to have a higher affinity for CRD compared to the trimmer structure due to the potential for further interactions between the hydroxyl group and amino acids near the CRD (see Example 14).

Without being bound by theory, the galactose-selenium compounds described herein are difficult to hydrolyze (metabolize) and oxidize in their structure, eg, unsubstituted aromatic rings, carbon-oxygen systems, carbon. -Because it is nitrogen-based, stability is improved.

Computational Ligand-Protein Affinity Scoring Standard assays for assessing the binding capacity of a ligand to a target molecule are known in the art and include, for example, ELISA, Western blot and RIA. Suitable assays are described in detail herein. In some embodiments, binding kinetics (eg, binding affinity) can be evaluated by standard assays known in the art, such as Biacore analysis. Assays for assessing the effects of compounds on the functional properties of galectin are described in more detail herein.

One method of determining protein-ligand binding affinity uses a structure-based model that can predict the protein-ligand complex interaction that occurs when a ligand binds to a protein. Such structures can be studied by X-ray crystallography. In some embodiments, the compound of interest can be screened in silico and a scoring system known in the art can be used to predict the affinity of the ligand for the lectin or galectin protein.

In some embodiments, computational modeling can be used to facilitate structure-based drug design. In silico models can also visually inspect and avoid possible protein-compound interactions, conformational strains, and steric collisions. In some embodiments, protein-ligand affinity can be scored using Glide (Schroedinger, Portland OR). The combination of ligand position and orientation with respect to the protein, along with flexible docking, is called the ligand pose, and Glide's ligand pose is scored on the Glide Score. The glide score is a quantitative measure that provides an estimate of the ligand binding free energy. It has many terms such as force field (electrostatic, van der Waals, etc.) contributions, as well as terms that reward or penalize interactions that are known to affect ligand binding. It contains two energy components: the enthalpy of biological reactions and the contribution of entropy. The thermodynamic rationale for enthalpy-entropy compensation is based on the fact that the stronger the bond, the more negative the enthalpy and the concomitant decrease in entropy due to the formation of tight complexes. Therefore, the ligand having the lowest glide score can be selected.

Methods and compounds are provided for the inhibition of galectin-3 and / or galectin-1, but the in silico models, assays and compounds described herein can be applied to other galectin proteins and lectins. it can.

Based on the 1 KJR crystal structure of human galectin-3 CRD (Sorme, P. et al. (2005) J. Am. Chem. Soc. 127: 1737-1743), the known "activity" and "inactivity" of galectin-3. An improved incilico model of galectin-3 CRD was used using the "active" compound as a training and test set.
The 1KJR crystal structure was selected for a unique expansion cavity that allows for larger substituents (eg, indole or naphthalene) at the C3 position of galactose (Vargas-Berebgurl 2013, Barondes 1998, Sorme 2003). Table 4 shows the glide scores of various digalactosides having the same substituents: (1) thiogalactoside, galactoside, selenogalactoside, diselenogalactoside.

Table 4

Glide score data showed that the introduction of Se into the anomeric carbon (G-625) of galactose had the same score as the thiogalactoside (also called TD-139, G-240). The results also showed that thiogalactoside (TD-139) and selenogalactoside compound (G-625) have equivalent overall predicted predictors of free energy. Therefore, thiogalactoside (TD-139) and selenogalactoside compound (G-625) are expected to have equivalent affinity and inhibitory effect on galectin-3.

These compounds were tested for affinity with integrins and galectin-3. Surprisingly, the selenogalactoside compound (G-625) showed at least about 2-fold to at least about 3-fold better affinity for galectin-3 and integrins.

Due to the Se atom, the rest of the molecule (eg, G-625, etc.) is found in the TD-139, but in contrast to the TD-139, as shown in the Elisa-based and fluorescence polarization assays. Interactions with excellent affinity for galectin-3 can be achieved. In some embodiments, the selenogalactoside of formula (1) has a 2- or 3-fold stronger affinity for galectin-3 than TD-139. In some embodiments, the selenogalactoside of the invention has an affinity for galectin-3 that is at least 2-fold or at least 3-fold stronger than the corresponding thiogalactoside.

The "dragability" properties defined by computer structural analysis consider compounds for: (1) stereoisomerization, (2) position of hydroxyl groups on sugars (eg, axial or equatorial) and (3). Position and nature of substituents.

1) Stereoisomerization: Note that compounds with the same 2D nomenclature may have very different binding postures and different predicted binding free energy predictors, 3D structures that can have glide scores. Should.

2) Hydroxy group: The position of the hydroxyl group on the sugar (eg, axial or equatorial) plays an important role in compound binding. Specifically, the present invention relates to compounds that are galactose-based bonded to a selenium atom bonded to anomer carbon and that act as a linker to the rest of the molecule.

3) Substituents: According to some embodiments, the compound can reach amino acids that are known to play a role in ligand binding or are part of an unknown binding site. Or it can have a substituent designed to reach. Those skilled in the art will appreciate that galectin binds the monosaccharide galactose with a dissociation constant in the millimole range. Addition of N-acetylglucosamine to galactose has been shown to provide additional interaction with adjacent sites and increase affinity for galectin-3 by more than 10-fold (Bachhawat-Sikder Et al. FEBS Lett. 2001 Jun 29; 500 (1-2): 75-9).

Further addition of an unnatural derivative such as naphthol to the 3-position of the saccharide improves the affinity to the low micromolar range, eg 0.003 mM. This substitution utilizes a cation-pi interaction with the surface residue Arg 144.

The human galectin-3 cavity is shallow and has high solvent accessibility. Although highly hydrophilic, it can form cation-pi interactions with Arg144 and possibly Trp181 (Magnani 2009, Logan 2011). It has been shown that upon binding of the ligand, Arg144 moves 3.5A above the protein surface, creating a pocket for the arene-arginine interaction. It should be noted that Arg144 is not present in other galectins, such as Gal-1 and Gal-9, and is used in our in silico model. Similarly, potency can be improved by utilizing the cation-pi interaction with the surface residues of Arg186. For example, triazole substitution of galactose with C3 has been reported to increase galectin-3 affinity (Salameh BA et al. Bioorg. Med. Chem. Lett. 2005 Jul 15; 15 (14): 3344-6. .).

Tryptophan 181 at subsite C is conserved throughout the galectin family. The π-π stacking interaction between the Trp181 (W181) side chain and the carbohydrate residues contained within subsite C (galactose, the natural carbohydrate occupant) is all galectin-sugar complexes reported. Occurs in.

To develop an effective approach for the structure-based design of potent galectin inhibitors, such as galectin-3 inhibitors, carbohydrate recognition based on the three-dimensional structure and physiochemical properties of conserved binding motifs. It is important to understand the detailed molecular basis for. High resolution structural information is very helpful in this regard (see see Ultra-High-Resolution Structures and Water Dynamics, Saraboji, K. et al., Biochemistry. 2012 Jan 10; 51 (1): 296-306). It is clear that the galectin-3 CRD site is preconfigured to recognize carbohydrates, such as the oxygen framework (see Figure 2), but contains Se with 2- to 3-fold increased activity. It was not expected to recognize the compound.

In galectin-3 (see CRD amino acid near the binding pocket in Figure 3), the side chain of Arg144 is more mediated by the arginine-arene interaction (cation-π or π-π stacking interaction) with the aromatic moiety. Different conformations can be adopted due to the inherent flexibility that can contribute to the high affinity.

In some embodiments, the major residues of galectin affecting ligand affinity have been identified using computer alanine scanning mutagenesis (ASM) or "in silico alanine scans". ASM can be performed by sequentially substituting individual residues with alanine to identify residues involved in protein function, stability and shape. Each alanine substitution examines the contribution of individual amino acids to protein function.

To better understand the importance of residues in the CRD binding pocket (Figure 3), glide is a compound of formula 1 and a galectin-3 inhibitor, 3,3'-dideoxy-3,3'-di. -[4- (3-Fluorophenyl) -1H-1,2,3-triazole-1-yl] -1,1'-sulfandyl-di-D-galactopyranoside by docking An in silico alanine scan was performed (see TD139, WO2016005311A1, all disclosures are incorporated herein by reference). Residues predicted to be involved in binding were mutated, and mutations to alanine were expected to affect glide score results. The alanine scan was used to predict the importance of residues to ligand binding.

For example, galectin-3 R186S has been reported to abolish carbohydrate interactions. R186S selectively lost its affinity for LacNAc, a disaccharide moiety commonly found on glycoprotein glycans, and lost its ability to activate intracellular targeting to neutrophil leukocytes and vesicles ( Salomonsson E. et al., J Biol Chem. 2010 Nov 5; 285 (45): 35079-91)

Table 5 shows the in silico alanine scan comparison results using the TD-139 compound.
Table 5

Table 6 shows the in silico alanine scan comparison results using the G-625 compound represented by the formula 1.
Table 6

** dG> 100 suggests an increase in ligand binding due to mutation to alanine, and dG <100 suggests a decrease in ligand binding due to mutation.

These results suggest that the "molecular interaction profile" of TD-139 is different from that of G-625. Tables 5 and 6 show the interaction profiles predicted by the in silico model. TD139 is significantly affected by the introduction of the R186A mutation (there is a "~ 15% reduction" in the glide score, which is a predictor of free binding energy). On the other hand, R186A has less effect on G-625, and G-625 is more sensitive to the H158A mutation.

Surprisingly, alanine scans showed that residue N174 plays an important role in the binding of both TD-139 and G-625 compounds. Without being bound by theory, residue N174 helps place the galactose score in the "optimal position" and allows the CRD site to recognize carbohydrates such as the oxygen framework.

In silico alanine scans suggested that G-625 has a unique binding profile while maintaining interaction with known CRD residues such as Arg 162, Arg 186, Arg 144. Based on these results, we investigated the interaction with residues at site A: S237; site B: D148; site CD: A146, K176, G182 and E165; and site C loop at N166 (FIGS. 2 and 3). And improved the interaction with CRD.

Synthetic pathways The compounds of the invention can be prepared by the following general methods and procedures. If typical or preferred treatment conditions (eg, reaction temperature, time, molar ratio of reactants, solvent, pressure, pH, etc.) are indicated, other treatment conditions should also be used unless otherwise stated. You should understand that you can. Optimal reaction conditions may vary depending on the particular reactant, solvent used, pH, etc., but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

In some embodiments, the compounds were synthesized using the synthetic pathway shown in FIG.

For example, compound G-625 was prepared as detailed in Example 10.

Pharmaceutical Compositions Aspects of the invention relate to the use of the compounds described herein for the manufacture of agents. Some embodiments are compounds represented by formulas (1), (2), (3), (4), (5), (6) or (7) or pharmaceutically acceptable salts or solvents thereof. Regarding the use of Japanese products or the compounds. Some embodiments relate to the compounds of Tables 1-4 or the use of such compounds.

Aspects of the invention relate to pharmaceutical compositions containing one or more of the compounds described herein. In some embodiments, the pharmaceutical composition comprises one or more of: pharmaceutically acceptable adjuvants, diluents, excipients, and carriers.

The term "pharmaceutically acceptable carrier" can be administered to a subject (eg, a patient) with a compound of the invention, without disrupting its pharmacological activity, in a therapeutic or effective amount of the compound. Means a carrier or adjuvant that is non-toxic when administered at a dose sufficient to deliver.

"Pharmaceutically acceptable carrier" means any solvent or dispersion medium. The use of such media and compounds for pharmaceutically active substances is well known in the art. Preferably, the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration (eg, by injection or infusion). Depending on the route of administration, the active compound can be coated with a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.

Some aspects of the invention relate to pharmaceutical compositions containing the compounds of the invention and optionally pharmaceutically acceptable additives such as carriers or excipients. In some embodiments, the compounds represented by the formulas (1), (2), (3), (4), (5), (6) or (7) or pharmaceutically acceptable salts or solvents thereof. A pharmaceutical composition comprising a Japanese product and optionally a pharmaceutically acceptable additive such as a carrier or excipient. In some embodiments, a pharmaceutical composition comprising the compounds of Tables 1-4 and optionally pharmaceutically acceptable additives such as carriers or excipients.

In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable adjuvant, diluent, excipient or carrier, as well as the compounds described herein as pharmaceutically acceptable active ingredients. The pharmaceutical composition can include 1 to 99% by weight of a pharmaceutically acceptable adjuvant, diluent, excipient or carrier, and 1 to 99% by weight of the compounds described herein.

Adjuvants, diluents, excipients and / or carriers that can be used in the compositions of the invention are pharmaceutically acceptable, i.e. they are compatible with the compounds of the invention and other components of the pharmaceutical compositions. , And not harmful to those recipients. Adjuvants, diluents, excipients and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those of skill in the art.

Effective oral doses of the compounds of the invention to laboratory animals or humans can be formulated with various excipients and additives that enhance the absorption of the compounds through the stomach and small intestine.

The pharmaceutical composition of the present invention may contain two or more compounds of the present invention. The composition can also be used with other agents in the art for the treatment of related disorders.

In some embodiments, pharmaceutical compositions comprising one or more of the compounds described herein are for oral, intravenous, topical, intraperitoneal, nasal, oral, sublingual, or subcutaneous administration, or aerosols. Alternatively, it may be adapted for respiratory administration in the form of air-suspended micropowder, or for administration via the eye, intraocular, intravitreal or keratin.

In some embodiments, a pharmaceutical composition comprising one or more of the compounds described herein may be, for example, tablets, capsules, powders, injectable solutions, spray solutions, ointments, transdermal patches or suppositories. Can be in the form of.

Some aspects of the invention are pharmaceuticals comprising the compounds described herein or pharmaceutically acceptable salts or solvates thereof and optionally pharmaceutically acceptable additives such as carriers or excipients. Regarding the composition

Effective oral doses can be 10 to 100 times higher than effective parenteral doses.

Effective oral administration is given daily, in divided doses or twice, three times a week, or once a month.

In some embodiments, the compounds described herein can be co-administered with one or more other therapeutic agents. In certain embodiments, the additional agent has a different schedule that overlaps with the administration of the compounds of the invention separately (eg, sequentially), eg, with the administration of the compounds of the invention, as part of a multi-dose formulation. Can be administered at. In other embodiments, these agents may be part of a single dosage form or may be mixed with the compounds of the invention in a single composition. In yet another embodiment, these agents can be given as separate doses administered approximately simultaneously with the compounds of the invention. When the composition comprises a combination of a compound of the invention with one or more additional therapeutic or prophylactic agents, both the compound and the additional agent are about 1 to 1 of the dose administered in conventional monotherapy. It can be present at a dose level of 100%, more preferably about 5 to 95%.

In some embodiments, therapeutically effective amounts of the compound or composition are, but are not limited to, with various therapeutically effective amounts of anti-inflammatory agents, vitamins, other pharmaceuticals and dietary supplements or supplements, or combinations thereof. Combined and compatible and can be effective.

In some embodiments, the compounds represented by formulas (1), (2), (3), (4), (5), (6) or (7) or the compounds of Tables 1-4 or their pharmaceuticals. The salt or solvate allowed in is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, the compounds represented by formulas (1), (2), (3), (4), (5), (6) or (7) or the compounds of Tables 1-4 or their pharmaceuticals. The salt or solvate allowed in is administered with an activator and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, the compounds represented by formulas (1), (2), (3), (4), (5), (6) or (7) or the compounds of Tables 1-4 or their pharmaceuticals. Tolerable salts or solvates are administered with one or more antidiabetic agents. In some embodiments, administration of the compounds and activators of the invention produces a synergistic effect. In some embodiments, the active agent is an antidiabetic agent.

As used herein, the term "synergistic effect" means the correlation of two or more agents of the invention in which the combined action is greater than the sum of each acting separately. In some embodiments, the compounds and activators of the invention can be administered simultaneously or sequentially.

Aspects of the invention include checkpoint inhibitors (anti-CTLA2, anti-PD1, anti-PDL1), other immunomodulators including but not limited to anti-OX40, and other antitumor agents of multiple mechanisms. Concerning compositions or compounds for treating neoplastic diseases in combination with other antitumor agents, including but not limited to these.

Aspects of the invention include checkpoint inhibitors (anti-CTLA2, anti-PD1, anti-PDL1), other immunomodulators including but not limited to anti-OX40, and other antitumor agents of multiple mechanisms. Concerning compositions or compounds for treating neoplastic diseases in combination with other antitumor agents, including but not limited to these.

Therapeutic Methods Some aspects of the invention relate to the use of the compounds described herein or the compositions described herein for use in the treatment of disorders associated with binding of galectin to a ligand. In some embodiments, the galectin is galectin-3.

Some aspects of the invention relate to methods of treating various disorders associated with binding of galectin to a ligand. In some embodiments, the method comprises administering a therapeutically effective amount of at least one of the compounds described herein to a subject in need thereof. In some embodiments, the subject in need of it is a human with high levels of galectin-3. Levels of galectin, such as galectin-3, can be quantified using any method known in the art.

Some aspects of the invention are TGFβ1 (transforming growth factor) by reversing the interaction of galectin-3 with its receptor (TGFβ1-receptor) in order to restore normal tissue regeneration activity. Regarding the treatment method of the disease caused by the confusion in the activity of beta 1).

Some aspects of the invention are transforming involved in many cell and pathological processes in both adult and embryonic development, such as cell proliferation, cell differentiation, apoptosis, cell homeostasis and other cellular functions. Concerning the treatment of diseases associated with the growth factor beta signaling pathway.

Some aspects of the invention are methods of treating disorders associated with galectin binding, such as binding of galectin-3 to the insulin receptor or TGFb1 receptor in humans, wherein a therapeutically effective amount of the formula (1) , (2), (3), (4), (5), (6) or (7), or the compounds of Tables 1 to 4, or pharmaceutically acceptable salts or solvates thereof. It relates to a method involving administration to a subject in need.

Aspects of the invention relate to therapeutic compounds, compositions and methods of various disorders in which the lectin protein plays a role in the etiology, including but not limited to the treatment of systemic insulin resistance. In some embodiments, the compound is capable of reversing the binding of galectin-3 to the insulin receptor and / or enhancing its sensitivity to insulin activity in various tissues.

Aspects of the invention relate to compounds, compositions and methods for treating systemic insulin resistance, but not limited to this. In some embodiments, systemic insulin resistance is associated with obesity in which elevated galectin-3 interacts with the insulin receptor. In some embodiments, treatment with the compounds of the invention can restore sensitivity to insulin activity in a variety of tissues.

Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 1 diabetes. Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with type 2 diabetes (T2DM). Aspects of the invention relate to compounds, compositions and methods for the treatment of systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores the cell's sensitivity to insulin activity. In some embodiments, the compound inhibits the interaction of galectin-3 with the insulin receptor, interfering with insulin binding and the cellular glucose uptake mechanism. Aspects of the invention are compounds for treating mild inflammation due to elevated levels of free fatty acids and triglycerides that cause insulin resistance in skeletal muscle and liver, which contribute to the development of atherosclerotic vascular disease and NAFLD. , Compositions and methods. Aspects of the invention are compounds, compositions and methods for the treatment of polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance, and compensatory hyperinsulinemia. Regarding. Aspects of the invention relate to compounds, compositions and methods for the treatment of diabetic nephropathy and glomerulosclerosis due to attenuation of the integrin and TGFb receptor pathways in chronic renal disease. In some embodiments, the compound inhibits the overexpression of the TGFβ receptor signaling system caused by insulin resistance in diabetes, causes a decline in renal function, and reverses the established lesions of diabetic glomerulopathy. Can be made to.

In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, the compound is administered with an activator and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, the compound is administered with one or more antidiabetic agents. In some embodiments, administration of the compounds and activators of the invention produces a synergistic effect.

Aspects of the invention are treatments with compounds of the invention in some embodiments relating to compounds, compositions and methods for treating systemic insulin resistance associated with obesity in which elevated galectin-3 interacts with the insulin receptor. Can restore susceptibility to insulin activity in various tissues.

In some embodiments, the compounds or compositions of the invention that bind to the insulin receptor (also identified as IR, INSR, CD220, HHF5).

Aspects of the invention relate to compounds, compositions and methods for treating diseases caused by disruption of TGFb1 (transforming growth factor beta 1) activity.

In some embodiments, the disorder is an inflammatory disorder, such as inflammatory bowel disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.

In some embodiments, the disorder is fibrosis, such as liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, or fibrosis of any organ that impairs the normal functioning of the organ.

In some embodiments, the disorder is cancer.

In some embodiments, the disorder is an autoimmune disease such as rheumatoid arthritis and multiple sclerosis.

In some embodiments, the disorder is heart disease or heart failure.

In some embodiments, the disorder is a metabolic disorder, such as diabetes.

In some embodiments, the associated disorders are pathological angiogenesis, such as ocular angiogenesis, diseases or conditions associated with ocular angiogenesis, and cancer.

In some embodiments, the composition or compound can be used to treat non-alcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic disease or cancer. ..

In some embodiments, the composition can be used in the treatment of liver fibrosis, renal fibrosis, pulmonary fibrosis, or cardiac fibrosis.

In some embodiments, the composition or compound can enhance antifibrotic activity in organs, including but not limited to liver, kidney, lung, and heart.

In some embodiments, the composition or compound can be used to treat inflammatory disorders of the vascular system, including atherosclerosis and pulmonary hypertension.

In some embodiments, the composition or compound can be used in the treatment of heart disorders, including heart failure, arrhythmias, and uremic cardiomyopathy.

In some embodiments, the composition or compound can be used in the treatment of kidney disease, including glomerulopathy and interstitial nephritis.

In some embodiments, the composition or compound can be used in the treatment of inflammatory, proliferative and fibrous skin disorders, including but not limited to psoriasis and scleroderma.

Aspects of the invention relate to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.

Aspects of the invention include, but are not limited to, liver, kidney, lung, and heart inflammatory and fibrotic fibers in which galectin is at least partially involved in the etiology by enhancing antifibrotic activity in organs. On how to treat sexual disorders.

Aspects of the present invention relate to compositions or compounds having therapeutic activity for treating nonalcoholic steatohepatitis (NASH). In another aspect, the invention relates to a method of reducing pathological and disease activity associated with nonalcoholic steatohepatitis (NASH).

Aspects of the invention are methods of treating or treating inflammatory and autoimmune disorders in which galectin is at least partially involved in the etiology including, but not limited to, arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma, and inflammatory bowel disease. With respect to the composition or compound used in.

Aspects of the invention are for treating neoplastic diseases (eg, benign or malignant neoplastic diseases) in which galectin is at least partially etiologically involved by inhibiting a process facilitated by an increase in galectin. With respect to the composition or compound. In some embodiments, the present invention is a neoplastic disease (eg, benign or malignant neoplastic disease) in which galectin is at least partially involved in the etiology by inhibiting a process facilitated by an increase in galectin. Regarding the treatment method of. In some embodiments, the composition or compound can be used to treat or prevent the growth, invasion, metastasis, and angiogenesis of tumor cells. In some embodiments, the composition or compound can be used to treat primary and secondary cancers.

[式中、
Xは、セレンである；
Zは、炭水化物またはO、S、C、NH、CH₂、Se、アミノ酸からなるR₂およびR₃への結合である；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、アミノ酸、およびそれらの組み合わせからなる群から選択される；
R₁、R₂、およびR₃は独立して、CO、SO₂、SO、PO₂、PO、CH、水素、分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式炭化水素からなる群から独立して選択される]。 In some embodiments, the compound is the following monomer-selenium polyhydroxylated-cycloalkane compound or a pharmaceutically acceptable salt or solvate thereof:

[During the ceremony,
X is selenium;
Z is a bond to R ₂ and R ₃ consisting of carbohydrates or O, S, C, NH, CH ₂ , Se, amino acids;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is selected from the group consisting of O, S, C, NH, CH ₂ , Se, amino acids, and combinations thereof;
R ₁ , R ₂ , and R ₃ are independently hydrophobic direct, containing CO, SO ₂ , SO, PO ₂ , PO, CH, hydrogen, and heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected independently from the group consisting of chain and cyclic hydrocarbons].

In some embodiments, the hydrophobic linear and cyclic hydrocarbons are a) from an alkyl group consisting of at least 4 carbons, an alkenyl group consisting of at least 4 carbons, and at least 4 carbons substituted with a carboxy group. Alkyl group, alkenyl group consisting of at least 4 carbons substituted with carboxy group, alkyl group consisting of at least 4 carbons substituted with amino group, alkenyl group consisting of at least 4 carbons substituted with amino group, amino An alkyl group consisting of at least 4 carbons substituted with both a group and a carboxy group, an alkenyl group consisting of at least 4 carbons substituted with both an amino group and a carboxy group, and an alkyl substituted with one or more halogens. Group, b) Phenyl group substituted with at least one carboxy group, phenyl group substituted with at least one halogen, phenyl group substituted with at least one alkoxy group, phenyl group substituted with at least one nitro group , A phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group , Phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and phenyl group substituted with at least one substituted carbonyl group, c) naphthyl group, substituted with at least one carboxy group Phenyl group substituted, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, naphthyl group substituted with at least one nitro group, naphthyl substituted with at least one sulfo group A group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl substituted with at least one hydroxy group. Group, naphthyl group substituted with at least one carbonyl group and naphthyl group substituted with at least one substituted carbonyl group, d) heteroaryl group, heteroaryl group substituted with at least one carboxy group, at least one halogen Heteroaryl group substituted with, heteroaryl group substituted with at least one alkoxy group, with at least one nitro group Substituted heteroaryl groups, heteroaryl groups substituted with at least one sulfo group, heteroaryl groups substituted with at least one amino group, heteroaryl groups substituted with at least one alkylamino group, at least one Heteroaryl groups substituted with dialkylamino groups, heteroaryl groups substituted with at least one hydroxy group, heteroaryl groups substituted with at least one carbonyl group and heteroaryl groups substituted with at least one substituted carbonyl group , As well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl-substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, Heteroaryl groups, and heterocycles and derivatives; can include one of an amino group, a substituted amino group, an imino group, or a substituted imino group.

In some embodiments, the compound is a dimer-polyhydroxylated-cycloalkane compound.

[式中、
Xは、Se、Se-SeまたはSe-Sである；
Zは独立して、炭水化物(たとえば、オリゴマーSe-ガラクトシドを構成する)またはO、S、C、NH、CH₂、Se、およびアミノ酸からなるR₃およびR₄への結合から選択される；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Yは、O、S、C、NH、CH₂、Se、およびアミノ酸からなる群から選択される；
R₁、R₂、R₃、およびR₄は独立して、CO、SO₂、SO、PO₂、PO、CH、水素、および分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式炭化水素からなる群から独立して選択される]。 In some embodiments, the compound has the following general formula or is a pharmaceutically acceptable salt or solvate thereof:

[During the ceremony,
X is Se, Se-Se or Se-S;
Z is independently selected from the binding to R ₃ and R ₄ consisting of carbohydrates (eg, which make up the oligomer Se-galactoside) or O, S, C, NH, CH ₂ , Se, and amino acids;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is selected from the group consisting of O, S, C, NH, CH ₂ , Se, and amino acids;
R ₁ , R ₂ , R ₃ , and R ₄ independently contain CO, SO ₂ , SO, PO ₂ , PO, CH, hydrogen, and heterocyclic substituents with a molecular weight of approximately 50-200 D, Selected independently from the group consisting of hydrophobic straight chain and cyclic hydrocarbons].

In some embodiments, the hydrophobic linear and cyclic hydrocarbons include one of the following: a) substituted with an alkyl group consisting of at least 4 carbons, an alkenyl group consisting of at least 4 carbons, a carboxy group: Alkyl group consisting of at least 4 carbons, alkenyl group consisting of at least 4 carbons substituted with carboxy group, alkyl group consisting of at least 4 carbons substituted with amino group, at least 4 substituted with amino group An alkenyl group consisting of carbon, an alkyl group consisting of at least 4 carbons substituted with both amino and carboxy groups, an alkenyl group consisting of at least 4 carbons substituted with both amino and carboxy groups, and one or more. Halogen-substituted alkyl group, b) At least one carboxy group-substituted phenyl group, at least one halogen-substituted phenyl group, at least one alkoxy group-substituted phenyl group, at least one nitro Phenyl group substituted with group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, phenyl group substituted with at least one alkylamino group, at least one dialkylamino Phenyl group substituted with group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and phenyl group substituted with at least one substituted carbonyl group, c) naphthyl group, At least one naphthyl group substituted with at least one carboxy group, at least one halogen substituted naphthyl group, at least one alkoxy group substituted naphthyl group, at least one nitro group substituted naphthyl group, at least one Phenyl group substituted with sulfo group, naphthyl group substituted With at least one amino group, naphthyl group substituted with at least one alkylamino group, naphthyl group substituted with at least one dialkylamino group, at least one hydroxy group Phenyl group substituted with, naphthyl group substituted with at least one carbonyl group and naphthyl group substituted with at least one substituted carbonyl group, d) heteroaryl group, heteroaryl group substituted with at least one carboxy group , A heteroaryl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group. Terroraryl group, heteroaryl group substituted with at least one nitro group, heteroaryl group substituted with at least one sulfo group, heteroaryl group substituted with at least one amino group, substituted with at least one alkylamino group Heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, heteroaryl groups substituted with at least one carbonyl group and at least one substitution Heteroaryl groups substituted with carbonyl groups, as well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl-substituted D-galactose, hydrogen, Alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocycles and derivatives; amino groups, substituted amino groups, imino groups, or substituted imino groups.

[式中、
nは、≦24である；
Xは、Se、Se-SeまたはSe-Sである；
Wは、O、N、S、CH₂、NH、およびSeからなる群から選択される；
Y、およびZは独立して、O、S、C、NH、CH₂、Se、およびアミノ酸からなる群から選択される；
R₁およびR₂は独立して、CO、SO₂、SO、PO₂、PO、CH、水素、限定的ではないが：
a)少なくとも4つの炭素からなるアルキル基、少なくとも4つの炭素からなるアルケニル基、カルボキシ基で置換された少なくとも4つの炭素からなるアルキル基、カルボキシ基で置換された少なくとも4つの炭素からなるアルケニル基、アミノ基で置換された少なくとも4つの炭素からなるアルキル基、アミノ基で置換された少なくとも4つの炭素からなるアルケニル基、アミノ基およびカルボキシ基の両方で置換された少なくとも4つの炭素からなるアルキル基、アミノ基およびカルボキシ基の両方で置換された少なくとも4つの炭素からなるアルケニル基、および1つ以上のハロゲンで置換されたアルキル基；
b)少なくとも1つのカルボキシ基で置換されたフェニル基、少なくとも1つのハロゲンで置換されたフェニル基、少なくとも1つのアルコキシ基で置換されたフェニル基、少なくとも1つのニトロ基で置換されたフェニル基、少なくとも1つのスルホ基で置換されたフェニル基、少なくとも1つのアミノ基で置換されたフェニル基、少なくとも1つのアルキルアミノ基で置換されたフェニル基、少なくとも1つのジアルキルアミノ基で置換されたフェニル基、少なくとも1つのヒドロキシ基で置換されたフェニル基、少なくとも1つのカルボニル基で置換されたフェニル基および少なくとも1つの置換カルボニル基で置換されたフェニル基；
c)ナフチル基、少なくとも1つのカルボキシ基で置換されたナフチル基、少なくとも1つのハロゲンで置換されたナフチル基、少なくとも1つのアルコキシ基で置換されたナフチル基、少なくとも1つのニトロ基で置換されたナフチル基、少なくとも1つのスルホ基で置換されたナフチル基、少なくとも1つのアミノ基で置換されたナフチル基、少なくとも1つのアルキルアミノ基で置換されたナフチル基、少なくとも1つのジアルキルアミノ基で置換されたナフチル基、少なくとも1つのヒドロキシ基で置換されたナフチル基、少なくとも1つのカルボニル基で置換されたナフチル基および少なくとも1つの置換カルボニル基で置換されたナフチル基；および
d)ヘテロアリール基、少なくとも1つのカルボキシ基で置換されたヘテロアリール基、少なくとも1つのハロゲンで置換されたヘテロアリール基、少なくとも1つのアルコキシ基で置換されたヘテロアリール基、少なくとも1つのニトロ基で置換されたヘテロアリール基、少なくとも1つのスルホ基で置換されたヘテロアリール基、少なくとも1つのアミノ基で置換されたヘテロアリール基、少なくとも1つのアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのジアルキルアミノ基で置換されたヘテロアリール基、少なくとも1つのヒドロキシ基で置換されたヘテロアリール基、少なくとも1つのカルボニル基で置換されたヘテロアリール基および少なくとも1つの置換カルボニル基で置換されたヘテロアリール基；
e)サッカリド；置換サッカリド；D-ガラクトース；置換D-ガラクトース；C3-[1,2,3]-トリアゾール-1-イル-置換D-ガラクトース；水素、アルキル基、アルケニル基、アリール基、ヘテロアリール基、および複素環ならびに誘導体；アミノ基、置換アミノ基、イミノ基、または置換イミノ基；などの分子量が約50〜200 Dの複素環式置換基を含む、疎水性の直鎖および環式炭化水素からなる群から独立して選択される]。 In one aspect, the invention relates to the following compounds or pharmaceutically acceptable salts or solvates thereof:

[During the ceremony,
n is ≤24;
X is Se, Se-Se or Se-S;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y, and Z are independently selected from the group consisting of O, S, C, NH, CH ₂ , Se, and amino acids;
R ₁ and R ₂ are independent, CO, SO ₂ , SO, PO ₂ , PO, CH, hydrogen, but not limited:
a) Alkyl group consisting of at least 4 carbons, alkenyl group consisting of at least 4 carbons, alkyl group consisting of at least 4 carbons substituted with carboxy group, alkenyl group consisting of at least 4 carbons substituted with carboxy group, Alkyl groups consisting of at least 4 carbons substituted with amino groups, alkenyl groups consisting of at least 4 carbons substituted with amino groups, alkyl groups consisting of at least 4 carbons substituted with both amino and carboxy groups, An alkenyl group consisting of at least four carbons substituted with both amino and carboxy groups, and an alkyl group substituted with one or more halogens;
b) A phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, at least A phenyl group substituted with one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, at least A phenyl group substituted with one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group;
c) Naftyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, naphthyl substituted with at least one nitro group Group, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, naphthyl substituted with at least one dialkylamino group A group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group; and
d) Heteroaryl group, heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, heteroaryl group substituted with at least one alkoxy group, at least one nitro group Substituted heteroaryl groups, heteroaryl groups substituted with at least one sulfo group, heteroaryl groups substituted with at least one amino group, heteroaryl groups substituted with at least one alkylamino group, at least one Heteroaryl groups substituted with dialkylamino groups, heteroaryl groups substituted with at least one hydroxy group, heteroaryl groups substituted with at least one carbonyl group and heteroaryl groups substituted with at least one substituted carbonyl group ;
e) Saccharide; substituted saccharides; D-galactose; substituted D-galactose; C3- [1,2,3] -triazole-1-yl-substituted D-galactose; hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl Hydrophobic linear and cyclic carbides containing heterocyclic substituents having a molecular weight of about 50-200 D, such as groups and heterocycles and derivatives; amino groups, substituted amino groups, imino groups, or substituted imino groups; Selected independently of the group consisting of hydrogen].

Example

Compound Inhibition of Galectin to Bind to Labeled Probe An assay to develop a fluorescein-labeled probe that binds to galectin-3 and other galectin proteins and to measure the binding affinity of the ligand for the galectin protein using fluorescence localization (Fig. 5A and These probes have been used to establish 5B) (Soerme P, et al. Anal Biochem. 2004 Nov 1; 334 (1): 36-47).

The compounds described herein use this assay format to bind galectin-3 and other galectin proteins strongly (Fig. 5A), have high affinity for fluorescein-labeled probes, and about 5 nM to about 40 μM Replace with IC ₅₀ (50% inhibitory concentration). In some embodiments, the IC50 is from about 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM. In some embodiments, the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 μM. In some embodiments, the IC50 is from about 0.5 μM to about 10 μM. In some embodiments, the IC50 is from about 5 μM to about 40 μM.

The compounds claimed under the present invention were synthesized (see Tables 1, 2, 3 and 4) and tested for binding to CRD in a fluorescence polarization assay (Figure 5A) and showed inhibitory activity (Figure 7). ).

G-625: β-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -β-D-galactopira Nosyl 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -1-seleno-. G-625 has a single serene bridge between the two aryl-triazole-galactosides (see Table 2) and has been shown to inhibit Gal-3 binding in fluorescence polarization assays (Figure). 7).

G-626: β-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -β-D-galactopira Nosyl 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -1-seleno-. G-625 has a double serene bridge between the two aryl-triazole-galactosides (see Table 2) and has been shown to inhibit Gal-3 binding in fluorescence polarization assays (Figure). 7).

G-662: Sereno monosaccharides have been synthesized (see Table 1) and have been shown to inhibit Gal-3 binding in fluorescence polarization assays (Figure 7).

Compound inhibition of galectin binding using the FRET assay
The FRET assay (fluorescent resonance energy transfer) assay was developed to evaluate the interaction of galectin proteins with model fluorescently labeled probes, including but not limited to galectin-3 (see Figure 5B). Using this assay, the compounds described herein bind tightly to galectin-3, as well as other galectin proteins, and use this assay to make the probe a high affinity, about 5 nM to about 40 μM IC. Replace with ₅₀ (50% inhibitory concentration). In some embodiments, the IC50 is from about 5 nM to about 20 nM. In some embodiments, the IC50 is from about 5 nM to about 100 nM. In some embodiments, the IC50 is from about 10 nM to about 100 nM. In some embodiments, the IC50 is from about 50 nM to about 5 μM. In some embodiments, the IC50 is from about 0.5 μM to about 10 μM. In some embodiments, the IC50 is from about 5 μM to about 40 μM.

Compound inhibition of galectin binding to physiological ligands High levels of serum galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is a permanent illness that can be resolved but can be prevented with caution. Diabetes is one of the most common metabolic syndromes in the world. Diabetes is primarily associated with the chronic complications of the central and peripheral nervous systems. Diabetes mellitus is a commonly seen metabolic syndrome of diabetes in which the body is unable to use glucose and is stored in the blood, which damages the kidneys, nerves, heart, eyes, and other complications. May cause.

Insulin resistance is a hallmark of patients with complications from diabetes (T2DM) and is one of the definitive clinical features in metabolic syndrome (MetS), where MetS is found in adults (> 20 years) in the United States. It is estimated that more than 20% or about 50 million Americans are affected. This number could increase dramatically in the future, as the obesity epidemic shows no signs of reversal.

Insulin is a hormone with various functions such as stimulation of nutrient transport to cells, regulation of various enzyme activities, and regulation of energy homeostasis. These functions include glucose metabolism via intracellular signaling pathways in the liver, adipose tissue, and muscle. In the liver, insulin resistance increases glucose production in the liver. In adipose tissue, insulin resistance affects lipase activity, which results in anti-lipolysis, affects the outflow of free fatty acids from adipocytes, and increases circulating free fatty acids.

Recent studies also show that plasma levels of galectin-3 are significantly elevated in human and animal obesity models.

In obesity, macrophages and other immune cells have been reported to be recruited to insulin target tissues to promote chronic inflammatory conditions and insulin resistance. Galectin-3, which is known to be secreted primarily by macrophages, may play an important role in this inflammatory process, thus linking inflammation with reduced insulin sensitivity. Inhibition of galectin-3 may be a new drug target for the treatment of insulin resistance.

Insulin receptor-insulin interaction is a checkpoint for the second pathway, the Ras mitogen-activated protein kinase (MAPK), which mediates gene expression, and controls cell growth and differentiation PI3K-AKT. It also affects the route. The insulin receptor substrate (IRS) is a common intermediate that contains four different family members, the IRS1-4. Insulin receptor substrate-1 (IRS1) is usually involved in defects in insulin signaling. Insulin receptor activation increases tyrosine phosphorylation of IRS1 which initiates signal transduction. However, when serine 307 is phosphorylated, signal transduction is reduced. Negative IR or IRS1 inflammation-related regulators, such as cytokine signaling (Soc) suppressors, can promote ubiquitination, with the small protein ubiquitin binding to other target proteins, for example. Alternates functionality and subsequent degradation, such as IRS inactivation.

The compounds claimed under the present invention were synthesized (see Tables 1, 2, 3 and 4) and tested for inhibitory activity in the insulin receptor-galectin-3 interaction (Fig. 6B).

For example, G-625: β-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -β-D- Galacopyranosyl 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -1-seleno-. G-625 has a single serene bridge between the two aryl-triazole-galactosides (see Table 2) and has been shown to be inhibitory in the insulin receptor-galectin-3 interaction (Figure). 8).

G-662: Sereno monosaccharide was synthesized (see Table 1) and showed inhibitory activity in the interaction of insulin receptor and galectin-3 (Fig. 8).

The compounds claimed under the present invention were synthesized (see Tables 1, 2, 3 and 4) and tested for their inhibitory activity on the TGF-β-1 receptor-galectin-3 interaction. This interaction of the TGF-β receptor with galectin-3 is an important pathological step in many inflammatory and fibrotic pathways. We have shown that the compounds described herein are inhibitors of this interaction (Fig. 9).

For example, G-625: β-D-galactopyranoside, 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -β-D- Galacopyranosyl 3-deoxy-3- (4- (3-fluorophenyl) -1H-1,2,3-triazole-1-yl) -1-seleno-. G-625 has a single serene bridge between two aryl-triazole-galactosides (see Table 2) and has been shown to be inhibitory in the TGF-β receptor-galectin-3 interaction. (Fig. 9).

G-662: Sereno monosaccharides were synthesized (see Table 1) and showed inhibitory activity in the interaction of TGF-β receptor and galectin-3 (Fig. 9).

Binding of Compounds to Amino Acid Residues in Galectin Proteins Heteronuclear NMR spectroscopy includes, but is not limited to, galectin-3 to assess interacting residues on the galectin-3 molecule. It is used to evaluate the interaction with the compounds described in the book.

Uniformly ¹⁵ N-labeled Gal-3 was expressed in BL21 (DE3) competent cells (Novagen), grown in minimal medium, purified on a lactose affinity column, and as described above for Gal-1 production. Fractionation on a gel filtration column (Nesmelova IV, Pang M, Baum LG, Mayo KH. 1H, 13C, and 15N backbone and side-chain chemical shift assignments for the 29 kDa human galectin-1 protein dimer. Biomol NMR Assign 2008 Dec 2 (2): 203-205).

Uniformly ¹⁵ N labeled Gal-3 was dissolved in 20 mM potassium phosphate buffer at pH 7.0 at a concentration of 2 mg / ml and prepared using a 5% H ₂ O / 5% D ₂ O mixture. Will be done. ¹ H- ¹⁵ N HSQC NMR experiments are used to investigate the binding of the series of compounds described herein. ¹ H and ¹⁵ N resonance assignments for recombinant human Gal-3 have been previously reported (Ippel H, et al. (1) H, (13) C, and (15) N backbone and side-chain chemical shift assignments. for the 36 proline-containing, full length 29 kDa human chimera-type galectin-3. Biomol NMR Assign 2015 Apr; 9 (1): 59-63.).

NMR experiments are performed at 30 ° C. on a Bruker 600 MHz, 700 MHz or 850 MHz spectrometer equipped with an H / C / N triple resonance probe and an x / y / z triaxial pulsed field gradient unit. Gradient-sensitive enhanced versions of 2D ¹ H- ¹⁵ N HSQC apply to 256 (t1) x 2048 (t2) composite data points in the nitrogen and proton dimensions, respectively. Raw data was converted and processed using NMRPipe and analyzed using NMRview.

These experiments show the differences between the compounds described herein in the binding residues of the carbohydrate binding domain of galectin-3.

Cellular Activity of Cytokine Activity Related to Inhibition of Galectin Binding Example 1 describes the ability of a compound of the present application to inhibit the binding of a physiological ligand to a galectin molecule. In the experiments of this example, the functional effects of these binding interactions were evaluated.

One of the interactions with galectin-3 that is inhibited by the compounds described herein was the TGF-β receptor. Therefore, experiments were conducted to evaluate the effect of the compound on TGR-β receptor activity in cell lines. A second messenger that treats various TGF-β-responsive cell lines, including but not limited to LX-2 and THP-1 cells, with TGF-β and includes, but is not limited to, phosphorylation of various intracellular SMAD proteins. Cellular response was measured by observing system activation. After confirming that TGF-β activates the second messenger system of various cell lines, cells were treated with the compounds described herein. These experiments showed that these compounds inhibited the TGF-β signaling pathway and confirmed that the binding interaction inhibition described in Example 1 plays a physiological role in the cell model.

Cell assays were also performed to assess the physiological importance of inhibiting the interaction of galectin-3 with various integrin molecules. Studies of cell-cell interactions were performed using monocytes that bind to vascular endothelial cells and other cell lines. It has been found that treatment of cells with the compounds described herein inhibits these integrin-dependent interactions, and the inhibition of binding interactions described in Example 1 plays a physiological role in the cell model. Was confirmed.

Bioassay procedure:
The procedure for MCF-7 cells (colon cancer) was as follows:
1. 1. MCF-7 cells were resuspended in medium containing 4X Pen / Strep (penicillin / streptomycin) and 0.25% fetal bovine serum (Gibco lot number 1202161).
2. Approximately 4,000-10,000 cells / well, passages 5 to up to 30) were added to 100 μl of medium and the cells were incubated at 37 ° C. for at least 24 hours.
3. 3. The compounds tested were serially diluted in assay medium, typically in the range of 100 μg / ml to 20 ng / mL, as described above.
4. 100 ml of the serially diluted compound was added twice to the cells of the assay plate. The final volume of each well was 200 ml (including 2x Pen / Strep, 0.25% FBS and the indicated compound).
Five. Cells were incubated at 37 ° C for 60-80 hours.
6. 20 ml of Promega Substrate [CellTiter 96 Aqueous One Solution] reagent was added to each well.
7. 7. Cells were incubated at 37 ° C. for 4-8 hours and OD was read at 490 nm.

The procedure for HTB-38 cells (breast cancer) was as follows:
1. 1. HTB-38 cells were resuspended in medium containing 8 ng / ml h-IFN-γ, 4X Pen / Stre and 10% fetal bovine serum (Gibco lot number 1260930).
2. Cells were transferred to the assay plate at 100 μl / well (4,000-10,000 cells / well, passages 4-30).
3. 3. The compounds tested were serially diluted in assay medium, typically in the range of 100 μg / ml to 20 ng / mL, as described above.
4. 100 μl / well serially diluted compound was added to cells twice. The final volume of each well is 200 μl and contains 4 ng / ml h-IFN-γ, 2x Pen / Strep.
Five. Cells were incubated at 37 ° C for 60-80 hours.
6. 20 μl of Promega Substrate [CellTiter 96 Aqueous One Solution] reagent was added to each well.
7. 7. Cells were incubated at 37 ° C. for 4-8 hours and OD was read at 490 nm.

Cell motility assays are performed to assess the physiological importance of inhibiting the interaction of galectin-3 with various integrins and other cell surface molecules as defined in Example 1. Cell studies are performed using multiple cell lines in a semipermeable membrane separation well device. Treatment of cells with the compounds described herein has been found to inhibit cell motility, confirming that the binding interaction inhibition described in Example 1 plays a physiological role in the cell model.

In vitro inflammation model (monocyte-based assay)
A model of macrophage polarity was set up using PMA (Phorbol 12-Millistate 13-acetate), starting from THP-1 monocyte cultures that differentiate into inflammatory macrophages for 2-4 days. Once differentiated (M0 macrophages), macrophages were induced in the inflammatory stage for 1-3 days using LPS or LPS and IFN-γ for macrophage activation (M1). The sequences of cytokines and chemokines were analyzed to confirm the polarization of THP-1-derived macrophages at the inflammatory stage. The effect of anti-galectin-3 compounds on macrophage polarization, proliferation or cytotoxicity assay (novel tetrazolium compound [3- (4,5-dimethyl-2-yl) -5- (3-carboxymethoxyphenyl) -2- ( 4-sulfophenyl) -2H-tetrazolium, intramolecular salt; MTS] and CellTiter 96® (registered trademark) AQueous One Solution Cell Proliferation Assay] and chemokine monosphere chemistry containing an electronic coupling agent (phenazine etsulfate; PES) Determine the number of viable cells in the inflammatory stage as assessed by quantitative measurements of attractant protein-1 (MCP-1 / CCL2), a key protein that regulates monocytic / macrophage migration and invasion in the cellular process of inflammation. Initially evaluated by monitoring cell viability using colorimetric method (using tetrazolium reagent). Later tests were performed on the expression and secretion of other cytokines and chemokines to derive the active compound.

THP-1 cells are stimulated by endotoxin, a microorganism that converts cells into inflammatory macrophages (M1) that secrete inflammatory cytokines such as monocyte chemoattractant protein 1 (MCP-1).

In this example, the method steps were:
1) THP-1 cells were cultured in a medium containing gentamicin.
2) Transfer THP-1 cells to 96-well plate wells and incubate at 2,000 cells / well for 2 days in assay medium containing 10 ng / ml PMA.
3) Continuously dilute the test compound in a medium containing LPS (10 ng / ml).
4) Add 100 ml of compound / LPS solution to each well to bring the final assay volume of each well, which also contains gentamicin and 5 ng / ml PMA, to 200 ml.
5) Incubate cells for up to 8 days.
6) Take 60 μl samples every other day for bioassay.
7) At completion, add 15 ml of Promega Substrate CellTiter 96 Aqueous One Solution to each well and monitor cytotoxicity (at 490 nm).
8) For evaluation of cell biomarkers, cells are washed with 1 XPBS and extracted with 200 μl lysis buffer for 1 hour. The extract is spanned down for 10 minutes and a 120 μl sample is removed from the top. All samples are stored at -70 ° C until testing.

Evaluation of Absorption, Distribution, Metabolism, and Excretion of Compounds The compounds described herein can be subjected to solubility (thermodynamic and kinetic methods), various pH changes, biorelated media (FaSSIF, FaSSGF, FeSSIF). Evaluate physicochemical properties including, but not limited to, solubility, Log D (octanol / water and cyclohexane / water), plasma stability, and blood distribution.

The compounds described herein are evaluated for in vitro permeability properties including, but not limited to, PAMPA (Parallel Artificial Membrane Permeability Assay), Caco-2, and MDCK (Wild Type).

The compounds described herein can be used in a variety of pathways, including mice (Swiss albino, C57, Balb C), rats (Wistar, Sprague Dolly), rabbits (New Zealand White), dogs (Beagle), crab quizzes, etc. The pharmacokinetic properties of animals, including, but not limited to, oral, intravenous, intraperitoneal, and subcutaneous pharmacokinetics, tissue distribution, brain-plasma ratio, bile excretion, and material balance will be evaluated.

The compounds described herein are evaluated for protein binding, including but not limited to plasma protein binding (ultrafiltration and equilibrium dialysis) and microsome protein binding.

The compounds described herein include cytochrome P450 inhibition, cytochrome P450 time-dependent inhibition, metabolic stability, liver microsome metabolism, S-9 fraction metabolism, effects on cryopreserved hepatocytes, plasma stability and GSH trapping. Evaluate in vitro metabolism, but not limited to these.

The compounds described herein are evaluated for the identification of metabolites, including but not limited to the identification of in vitro (microsomes, S9 and hepatocytes) and in vivo samples.

Affinities of Oligomer Se-Galactoside The affinities of the tetramer Se-galactoside and trimmer Se-galactoside in Table 3 were assayed using a fluorescence polarization assay. The tetramer Se-galactoside is expected to have a higher affinity for CRD than the trimmer structure due to the potential interaction between the hydroxyl group and the amino acid near the CRD.

Cell Culture Adipocyte Model Cell culture and insulin resistance model used 3T3-L1 fibroblasts differentiated into adipocytes, cultured in DMEM containing 10% FCS and GlutaMAX, as previously reported ( Shewan, AM, van Dam, EM, Martin, S., Luen, TB, Hong, W., Bryant, NJ, and James, DE (2003) "GLUT4 recycles via a trans-Golgi network (TGN) subdomain enriched in Syntaxins 6 and 16 but not TGN38: involvement of an acidic targeting motif ". Mol. Bio. Cell 14, 973-986). Various insulin resistance models were used. 3T3-L1 adipocytes with various doses of insulin (10 nM-100 nM) or 0.1 M-1 M dexamethasone (DEX) for chronic exposure to insulin at 37 ° C. for 8-24 hours, or complete MEDM The cells were cultured at 37 ° C. for 48 hours with 1 to 20 ng / ml TNF in the medium. The medium was replaced with fresh medium containing TNF twice daily. After insulin resistance treatment, cells were washed and serum was starved for 1-2 hours prior to insulin stimulation and evaluation of insulin regulatory kinases and processes. This protocol has previously been shown to be suitable for returning cells to baseline levels of GLUT4 translocation (Hoehn, KL, Hohnen-Behrens, C., Cederberg, A., Wu, LE, Turner). , N., Yuasa, T., Ebina, Y., and James, DE (2008) IRS1-independent defects define major nodes of insulin resistance. Cell Metab. 7, 421-433).

Experiments were performed with 3T3-L1 fibroblasts differentiated into adipocyte cultures according to the Promega protocol:
1. On day 1, 1 ml of a vial of 3T3L1 cells with low passage numbers was thawed and combined with 9 ml of maintenance medium (MM). The cells were centrifuged at 200 xg for 10 minutes and the liquid medium was aspirated.
2. 2. The cell pellet was resuspended in 11 ml MM. Cells were seeded in 96-well plates with 20,000 cells per 100 μl.
3. 3. Cells were grown at 37 ° C. at 5% CO2 until confluent and medium was changed every 2 days. Due to the weak adhesion of these cells during differentiation, the cells were seeded on collagen coated plates (Corning, Cat. # 356650). The removal and addition of medium was performed at the slowest possible pipetting rate.
On day 4.5, the medium was replaced with 100 μl of differentiation medium I (DM-I) and the replacement was continued every 2 days.
5. On day 12, the medium was replaced with 100 μl of differentiation medium II (DM-II).
6. On day 14, the medium was replaced with 100 μl MM. The exchange was continued every two days.
7. Insulin response was measured between 8-11 days.

3T3L1 adipocytes were assayed as follows:
1. 1. The medium was replaced with 100 μl serum-free MM 1 day prior to the assay.
2. 2. On the day of the assay, the medium was replaced with 100 μl DMEM (Life Technologies, Catalog No. 11966) without serum or glucose containing various insulin concentrations. Cells were incubated in 5% CO ₂ at 37 ° C. for 1 hour.
3. 3. The medium was removed, 50 μl of 2DG (1 mM) in PBS was added, and the cells were incubated at 25 ° C. for 10 minutes.
4. 25 μl of stop buffer was added and the sample was shaken lightly.
5. 25 μl of neutralization buffer was added and the sample was shaken lightly.
6.2 100 μl of 2DG6P detection reagent was added, and the sample was shaken gently and incubated at 25 ° C. for 1 hour.

The luminescence was integrated and recorded with a luminometer for 0.3-1 seconds to evaluate the cellular effect of galectin-3 on glucose uptake.

Adipocyte differentiation is monitored by a variety of distinct insulin-related activation markers, including insulin receptor (IR) expression and insulin-induced activation, not limited to IR kinase activity within minutes of exposure to insulin. It was. Inhibition of this insulin activation by treatment with galectin-3. The effect of galectin-3 on IR was also monitored by glucose uptake.

The compounds described herein have been found to inhibit the effects of galectin-3 and the reversal of insulin resistance, restore glucose uptake, and the physiology and potential of systemic insulin resistance in obesity-related diabetes. The therapeutic role was confirmed.

G-625 synthesis procedure
G-625 compound was synthesized using the following scheme (see Figure 4).
step 1:

(2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -4-azido-6-((4-methylbenzoyl) seranyl) tetrahydro-2H-pyran-3,5-diyldiacetate (3) :
(2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -4-azido-6-((4-methylbenzoyl) seranyl) tetrahydro-2H-pyran-3,5 in EtOAc (30 mL) -To a solution of diyldiacetate (1, 1.6 g, 4.06 mmol), add tetra-n-butyl ammonium hydrogensulfate (2.75 g, 8.12 mmol) and aqueous Na ₂ CO ₃ (16 mL, 16 mmol) to room temperature. And the reaction mixture was stirred at room temperature for 3 hours. Upon completion, water (30 mL) was added to the reaction mixture to stop the reaction and extract with EtOAc (3 x 15 mL). The combined organic layers are dried (Na ₂ SO ₄ ), filtered, concentrated in vacuum and the residue purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 0-30% EtOAc / Hexanes]. The title compound was obtained as a white solid (1.38 g, 66%).

¹ H-NMR (400 MHz; CDCl ₃ ): δ 2.04 (s, 3H), 2.06 (s, 3H), 2.18 (s, 3H), 2.45 (s, 3H), 2.76 -2.80 (m, 1H), 4.03 --4.17 (m, 3H), 5.44 --5.53 (m, 3H), 7.27 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H).

Step-2:

(2S, 2'S, 3R, 3'R, 4S, 4'S, 5R, 5'R, 6R, 6'R)-Serenobis (6- (acetoxymethyl) -4-azidotetrahydro-2H-pyran-2,3, 5-Triyl) Tetraacetate (5):
(2R, 3R, 4S, 5R, 6S) -2- (acetoxymethyl) -4-azido-6-((4-methylbenzoyl) seranyl) tetrahydro-2H-pyran-3,5 in DMF (4 mL) -A solution of diyl diacetate (3, 100 mg, 0.19 mmol) was degassed with argon for 20 minutes. The mixture is cooled to -15 ° C and (2R, 3R, 4S, in Cs ₂ CO _{3 (} 127 mg, 0.79 mmol), dimethylamine (2 M THF solution) (0.39 mL, 0.78 mmol) and DMF (2 mL), Add a solution of 5R) -2- (acetoxymethyl) -4-azido-6-bromotetrahydro-2H-pyran-3,5-diyldiacetate (307 mg, 0.78 mmol) and degas again with argon for 20 minutes. did. The reaction mixture was stirred at the same temperature for 5 minutes. After checking the TLC, water (10 mL) was added to the reaction mixture to stop the reaction and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with saline, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude residues were purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 0% -50% EtOAc / Hexanes] to give the title compound as a colorless viscous solid (66 mg, 48%). ).

MS: m / z 707 (M + AcOH) ⁺ (ES ⁺ )
^{1 1} H-NMR (crude) (400 MHz; CDCl ₃ ): δ 2.04 − 2.19 (m, 18H), 2.87 − 2.98 (m, 2H), 4.09 − 4.17 (m, 6H), 4.60 − 4.82 (m, 6H) ).

Step-3:

(2S, 2'S, 3R, 3'R, 4S, 4'S, 5R, 5'R, 6R, 6'R)-Serenobis (6- (acetoxymethyl) -4- (4- (3-fluorophenyl) -1H) -1,2,3-triazole-1-yl) tetrahydro-2H-pyran-2,3,5-triyl) tetraacetate (7):
(2S, 2'S, 3R, 3'R, 4S, 4'S, 5R, 5'R, 6R, 6'R)-selenobis (6- (acetoxymethyl) -4-azidotetrahydro-2H in toluene (4 mL) -DIPEA (0.07 mL, 0.366 mmol) in a solution of pyran-2,3,5-triyl) tetraacetate (5,130 mg 0.183 mmol) and 1-ethynyl-3-fluorobenzene (6,115 mg, 0.918 mmol). ) And CuI (34 mg, 0.183 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, water (20 mL) was added to the reaction mixture to stop the reaction and extract with EtOAc (3 x 15 mL). The combined organic layers were filtered through a pad of Celite bed, washed with EtOAc, dried (Na ₂ SO ₄ ), concentrated in vacuo and the residue was washed with Et ₂ O (10 mL) to the title compound (7). Was obtained as a white solid (164 mg, 94%).

MS: m / z 949 (M + H) ^{+ (} ES ⁺ )

¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 1.83 (s, 3H), 1.85 (s, 3H), 1.90 --2.07 (m, 12H), 4.07-4.13 (m, 4H), 4.32-4.40 (m, 2H), 5.36 (d, J = 9.5 Hz, 1H), 5.48 -5.49 (m, 3H), 5.64 --5.73 (m, 4H), 7.18 (t, J = 8.4 Hz, 2H), 7.47- 7.51 (m, 2H), 7.68 --7.74 (m, 4H), 8.76 (d, J = 10.3 Hz, 2H).

Step-4:

(2R, 2'R, 3R, 3'R, 4S, 4'S, 5R, 5'R, 6S, 6'S)-6,6'-Serenobis (4- (4- (3-fluorophenyl) -1H-1) , 2,3-Triazole-1-yl) -2- (Hydroxymethyl) tetrahydro-2H-pyran-3,5-diol) (GTJC-010-01):
(2S, 2'S, 3R, 3'R, 4S, 4'S, 5R, 5'R, 6R, 6'R)-selenobis (6- (acetoxymethyl) -4- (4- (4- (4- (4)) in MeOH (10 mL) 3-Fluorophenyl) -1H-1,2,3-triazole-1-yl) tetrahydro-2H-pyran-2,3,5-triyl) In a solution of tetraacetate (7,200 mg, 0.21 mmol), NaOMe (0.4 mL, 0.42 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours. Upon completion, the reaction mixture was acidified with Amberlite 15H (pH -6), filtered, washed with MeOH and concentrated in vacuo. Preparative HPLC of crude residue (reverse phase, X BRIDGE Shield RP, C-18, 19 x 250 mm, 5 μ, gradient 50% to 82% ACN / 5 Mm water containing ammonium bicarbonate, 214 nm, RT: 7.8 minutes ) To give the title compound as a white solid (GTJC-010-01, 18 mg).

LCMS (Method A): m / z 697 (M + H) ^{+ (} ES ⁺ ), 4.51 minutes, 96% purity.

¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 3.49 --3.61 (m, 4H), 3.72 (t, J = 6.2 Hz, 2H), 3.99 (dd, 2.9 & 6.6 Hz, 2H), 4.36- 4.43 (m, 2H), 4.70 (t, J = 5.5 Hz, 1H), 4.82 (dd, 2.8 & 10.5 Hz, 2H), 5.19 (d, J = 9.7 Hz, 2H), 5.31 (d, J = 7.2) Hz, 2H), 5.40 (d, J = 6.6 Hz, 2H), 7.12 --7.17 (m, 2H), 7.46 --7.51 (m, 2H), 7.66 (dd, J = 2.3 & 10.2 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 8.67 (s, 2H).

CMS (Method A): Instrument: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 100 mm; Gradient [hours (minutes) / solvent B / A (%) ]: 0.00 / 2, 2.00 / 2, 7.00 / 50, 8.50 / 80, 9.50 / 2, 10.0 / 2; Solvent: Solvent A = 5 mM ammonium acetate aqueous solution; Solvent B = Acetonitrile; Injection volume 1 μL; Detection wavelength 214 nm Column temperature 30 ° C; flow velocity 0.3 mL / min.

All publications and patents referred to herein are herein in their entirety by reference, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. Is incorporated into. I would like to mention the international application number PCT / US17 / 20658 filed March 3, 2017, which is incorporated by reference in its entirety.

Claims (29)

A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (1):

Equation (1)
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is hydrophobic, linear and cyclic hydrophobic, containing O, S, NH, CH ₂ , Se, S, SO ₂ , PO ₂ , amino acids, and heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , and R ₃ are independently CO, O ₂ , SO ₂ , PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least three carbons, at least. It consists of an alkenyl group consisting of 3 carbons, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and at least 3 carbons substituted with an amino group. Alkyl group, alkenyl group consisting of at least 3 carbons substituted with amino group, alkyl group consisting of at least 3 carbons substituted with both amino group and carboxy group, at least substituted with both amino group and carboxy group An alkenyl group consisting of three carbons and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy Phenyl group substituted with group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least one alkylamino group Phenyl group substituted with, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and at least one substituted carbonyl group Phenyl group substituted with, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one Phenyl group substituted with nitro group, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkyl Amino group substituted naphthyl group, at least one hydroxy group substituted naphthyl group, at least one carbonyl group substituted naphthyl group and at least one substituted carbonyl group substituted naphthyl group, d) heteroaryl Group, heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, few Heteroaryl groups substituted with at least one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heterozygous substituted with at least one amino group Aryl groups, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, with at least one carbonyl group Heteroaryl groups substituted with substituted heteroaryl groups and at least one substituted carbonyl group, and e) saccharides; substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazole- Selected from the group consisting of 1-yl-substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocycles and derivatives, amino groups, substituted amino groups, imino groups, and substituted imino groups. Ru]
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (2):

Equation (2)
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic open chain and cyclic containing O, S, C, NH, CH ₂ , Se, S, SO ₃ , PO ₂ , amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrophobic hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , and R ₃ are independently CO, O ₂ , SO ₂ , PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least three carbons, at least. It consists of an alkenyl group consisting of 3 carbons, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and at least 3 carbons substituted with an amino group. Alkyl group, alkenyl group consisting of at least 3 carbons substituted with amino group, alkyl group consisting of at least 3 carbons substituted with both amino group and carboxy group, at least substituted with both amino group and carboxy group An alkenyl group consisting of three carbons and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy Phenyl group substituted with a group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least one alkylamino group Phenyl group substituted with, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and at least one substituted carbonyl group Phenyl group substituted with, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one Phenyl group substituted with nitro group, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkyl Amino group substituted naphthyl group, at least one hydroxy group substituted naphthyl group, at least one carbonyl group substituted naphthyl group and at least one substituted carbonyl group substituted naphthyl group, d) heteroaryl Group, heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, few Heteroaryl groups substituted with at least one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heterozygous substituted with at least one amino group Aryl groups, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, with at least one carbonyl group A substituted heteroaryl group and a heteroaryl group substituted with at least one substituted carbonyl group, and e) saccharides; substituted saccharides; D-galactose; substituted D-galactose; C3- [1,2,3] -triazole- 1-Il-substituted D-galactose; selected from the group consisting of hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocycles and derivatives; amino groups, substituted amino groups, imino groups, and substituted imino groups. Ru]
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (3):

Equation (3)
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic open chain and cyclic containing O, S, C, NH, CH ₂ , Se, S, SO ₃ , PO ₂ , amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrophobic hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, SO ₂ , PO ₂ , and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
n is ≤24;
R ₁ and R ₂ are independently CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or combination of these and a) Alkyl group consisting of at least 3 carbons, from at least 3 carbons Alkenyl group, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, an alkyl group consisting of at least 3 carbons substituted with an amino group, amino From an alkenyl group consisting of at least 3 carbons substituted with a group, an alkyl group consisting of at least 3 carbons substituted with both amino and carboxy groups, and from at least 3 carbons substituted with both amino and carboxy groups Alkenyl group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, substituted with at least one alkoxy group. Phenyl group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, substituted with at least one alkylamino group Phenyl group, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and substituted with at least one substituted carbonyl group Phenyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, substituted with at least one nitro group Phenyl group substituted, naphthyl group substituted with at least one sulfo group, naphthyl group substituted With at least one amino group, naphthyl group substituted with at least one alkylamino group, substituted with at least one dialkylamino group Phenyl group, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one carbonyl group and naphthyl group substituted with at least one substituted carbonyl group, d) heteroaryl group, at least one carboxy Heteroaryl group substituted with group, at least one haloge Heteroaryl group substituted with at least one alkoxy group, heteroaryl group substituted with at least one nitro group, heteroaryl group substituted with at least one sulfo group, at least one A heteroaryl group substituted with one amino group, a heteroaryl group substituted with at least one alkylamino group, a heteroaryl group substituted with at least one dialkylamino group, a heteroaryl substituted with at least one hydroxy group Groups, heteroaryl groups substituted with at least one carbonyl group and heteroaryl groups substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1 , 2,3] -Triazole-1-yl-substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocyclics and derivatives; amino groups, substituted amino groups, imino groups, or substitutions. Selected from the group consisting of imino groups]
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (4):

Equation (4)
[During the ceremony,
X is selenium;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic open chain and cyclic containing O, S, C, NH, CH ₂ , Se, S, SO ₃ , PO ₂ , amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D. Selected from the group consisting of hydrophobic hydrocarbon derivatives and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, SO ₂ , PO ₂ , and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
n is ≤24;
R ₁ and R ₂ are independently CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) an alkyl group consisting of at least 3 carbons, at least 3 An alkenyl group consisting of carbon, an alkyl group consisting of at least 3 carbons substituted with a carboxy group, an alkenyl group consisting of at least 3 carbons substituted with a carboxy group, and an alkyl group consisting of at least 3 carbons substituted with an amino group. , An alkenyl group consisting of at least 3 carbons substituted with an amino group, an alkyl group consisting of at least 3 carbons substituted with both an amino group and a carboxy group, and at least 3 substituted with both an amino group and a carboxy group. An alkenyl group consisting of carbon and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, at least one alkoxy group Substituted phenyl group, substituted phenyl group with at least one nitro group, substituted phenyl group substituted with at least one sulfo group, substituted phenyl group substituted with at least one amino group, substituted with at least one alkylamino group Phenyl group substituted, phenyl group substituted with at least one dialkylamino group, phenyl group substituted with at least one hydroxy group, phenyl group substituted with at least one carbonyl group and substituted with at least one substituted carbonyl group Phenyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group, at least one nitro group Phenyl group substituted with, naphthyl group substituted with at least one sulfo group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, at least one dialkylamino group Phenyl group substituted with, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one carbonyl group and naphthyl group substituted with at least one substituted carbonyl group, d) heteroaryl group, Heteroaryl group substituted with at least one carboxy group, heteroaryl group substituted with at least one halogen, at least 1 Heteroaryl groups substituted with one alkoxy group, heteroaryl groups substituted with at least one nitro group, heteroaryl groups substituted with at least one sulfo group, heteroaryl groups substituted with at least one amino group, Heteroaryl group substituted with at least one alkylamino group, heteroaryl group substituted with at least one dialkylamino group, heteroaryl group substituted with at least one hydroxy group, substituted with at least one carbonyl group Heteroaryl groups substituted with at least one substituted carbonyl group, and e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -triazol-1-yl. -Substituted D-galactose, hydrogen, alkyl groups, alkenyl groups, aryl groups, heteroaryl groups, and heterocyclics and derivatives; selected from the group consisting of amino groups, substituted amino groups, imino groups, and substituted imino groups]
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. The method of claim, wherein n = 1. The method according to claim 3, wherein n = 3. The method according to claim 4, wherein n = 1. The method according to claim 4, wherein n = 3. A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (5):

Equation (5)
[During the ceremony,
X is Se, Se-Se, Se-S; S-Se, Se-SO ₂ , or SO ₂ -Se;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is a hydrophobic linear and cyclic hydrophobic hydrocarbon derivative containing O, S, C, NH, CH ₂ , Se, P, amino acids, heterocyclic substituents with a molecular weight of approximately 50-200 D and Selected from a group of combinations of them;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , R ₃ and R ₄ independently consist of CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) at least 3 carbons. Alkyl group, alkenyl group consisting of at least 3 carbons, alkyl group consisting of at least 3 carbons substituted with carboxy group, alkenyl group consisting of at least 3 carbons substituted with carboxy group, at least 3 substituted with amino group An alkyl group consisting of one carbon, an alkenyl group consisting of at least three carbons substituted with an amino group, an alkyl group consisting of at least three carbons substituted with both an amino group and a carboxy group, and both an amino group and a carboxy group. An alkenyl group consisting of at least three carbons substituted, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, Phenyl group substituted with at least one alkoxy group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least 1 A phenyl group substituted with one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and at least one Phenyl group substituted with one substituted carbonyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group , A naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, A naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) Heteroaryl group, heteroaryl group substituted with at least one carboxy group, heteroary substituted with at least one halogen Aryl group, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, substituted with at least one amino group. Heteroaryl groups substituted, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, at least one Heteroaryl groups substituted with carbonyl groups and heteroaryl groups substituted with at least one substituted carbonyl group, as well as e) saccharides, substituted saccharides, D-galactose, substituted D-galactose, C3- [1,2,3] -Triazole-1-yl-substituted D-galactose, hydrogen, alkyl group, alkenyl group, aryl group, heteroaryl group, and heterocycle and derivative, amino group, substituted amino group, imino group, and substituted imino group. Selected from]
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (6):

Equation (6)
[During the ceremony,
X is Se, Se-Se, Se-S; S-Se, Se-SO ₂ , or SO ₂ -Se;
W is selected from the group consisting of O, N, S, CH ₂ , NH, and Se;
Y is selected from the group consisting of O, S, C, NH, CH ₂ , Se, amino acids and combinations thereof;
Z is selected from the group consisting of O, S, N, CH, Se, S, P, and hydrophobic hydrocarbon derivatives containing heterocyclic substitutions of 3 or more atoms;
R ₁ , R ₂ , R ₃ and R ₄ independently consist of CO, O ₂ , SO ₂ , SO, PO ₂ , PO, CH, hydrogen, or a combination thereof, and a) at least 3 carbons. Alkyl group, alkenyl group consisting of at least 3 carbons, alkyl group consisting of at least 3 carbons substituted with carboxy group, alkenyl group consisting of at least 3 carbons substituted with carboxy group, at least 3 substituted with amino group An alkyl group consisting of one carbon, an alkenyl group consisting of at least three carbons substituted with an amino group, an alkyl group consisting of at least three carbons substituted with both an amino group and a carboxy group, and both an amino group and a carboxy group. An alkenyl group consisting of at least three carbons substituted, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, Phenyl group substituted with at least one alkoxy group, phenyl group substituted with at least one nitro group, phenyl group substituted with at least one sulfo group, phenyl group substituted with at least one amino group, at least 1 A phenyl group substituted with one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and at least one Phenyl group substituted with one substituted carbonyl group, c) naphthyl group, naphthyl group substituted with at least one carboxy group, naphthyl group substituted with at least one halogen, naphthyl group substituted with at least one alkoxy group , A naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one amino group, a naphthyl group substituted with at least one alkylamino group, A naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) Heteroaryl group, heteroaryl group substituted with at least one carboxy group, heteroary substituted with at least one halogen Aryl group, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, substituted with at least one amino group. Heteroaryl groups substituted, heteroaryl groups substituted with at least one alkylamino group, heteroaryl groups substituted with at least one dialkylamino group, heteroaryl groups substituted with at least one hydroxy group, at least one Heteroaryl groups substituted with carbonyl groups and heteroaryl groups substituted with at least one substituted carbonyl group, and e) saccharides; substituted saccharides; D-galactose; substituted D-galactose; C3- [1,2,3] -Triazole-1-yl-substituted D-galactose; hydrogen, alkyl group, alkenyl group, aryl group, heteroaryl group, and heterocyclic and derivative; group consisting of amino group, substituted amino group, imino group, and substituted imino group. Selected from]
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. The method according to any one of claims 1 to 10, wherein the halogen is a fluoro, chloro, bromo or iodo group. A method for treating systemic insulin resistance, which is a therapeutically effective amount formula (7):

Equation (7)
A method comprising administering to a subject in need thereof a compound represented by, or a pharmaceutically acceptable salt or solvate thereof. The method of any of claims 1-10 or 12, wherein the compound has a binding affinity for galectin. The method of any of claims 1-10 or 12, wherein the compound has a binding affinity for galectin-3. The method of any of claims 1-10 or 12, wherein the step of administration comprises administering a compound and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. The method of any of claims 1-10 or 12, wherein in the step of administration, the compound is administered with the activator. 12. The step of administration according to any one of claims 1-10 or 12, comprising administering a compound, a synergistic activator and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. Method. The method of claim 15 or 16, wherein in the step of administration, the activator is an immunomodulator, an anti-inflammatory agent, a vitamin, a dietary supplement, a supplement, or a combination thereof. The method of any of claims 1-10 or 12, for treating systemic insulin resistance associated with type 1 diabetes. The method of any of claims 1-10 or 12 for treating systemic insulin resistance associated with type 2 diabetes (T2DM). The method of any of claims 1-10 or 12 for treating systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. The method of any of claims 1-10 or 12, wherein treatment with a compound restores the sensitivity of cells to insulin activity. The method of any of claims 1-10 or 12, wherein the compound inhibits the interaction of galectin-3 with the insulin receptor, thereby interfering with insulin binding and cellular glucose uptake mechanisms. Claims 1-10 or 12 for the treatment of mild inflammation due to elevated levels of free fatty acids and triglycerides that cause insulin resistance in skeletal muscle and liver that contribute to the development of atherosclerotic vascular disease and NAFLD. The method described in either. The method of any of claims 1-10 or 12 for the treatment of polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance. The method of any of claims 1-10 or 12 for the treatment of diabetic nephropathy and glomerulosclerosis due to attenuation of the integrin and TGFb receptor pathways in chronic renal disease. The compounds inhibit the overexpression of the TGFβ receptor signaling system caused by insulin resistance in diabetes, cause a decline in renal function, and reverse the established lesions of diabetic glomerulosis, claims 1-10. Or the method according to any of 12. The method of any of claims 1-10 or 12 for the treatment of obstructive sleep apnea (OSA) associated with insulin resistant obesity and diabetes. The method of any of claims 1-10 or 12, wherein the step of administration comprises administering a compound and a synergistically active antidiabetic agent.

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