HK1196548A

HK1196548A - Usage of compound for preparing compositions for treating diabetes

Info

Publication number: HK1196548A
Application number: HK14110037.8A
Authority: HK
Inventors: 刘胜勇; 温武哲
Original assignee: 国鼎生物科技股份有限公司
Priority date: 2012-12-28
Filing date: 2014-10-08
Publication date: 2014-12-19

Description

Use of compound for preparing composition for treating diabetes

This application claims priority to U.S. patent No. 61/582,155, filed on 30.12.2011 with the full disclosure of this application incorporated by reference.

Technical Field

The invention relates to an application of cyclohexenone compound in preparing a composition for treating diabetes.

Background

Diabetes mellitus, the scientific name diabetes mellitus, commonly referred to as diabetes, is a group of people with metabolic disorders of hyperglycemia, either because the body cannot produce enough insulin, or because the cells cannot respond to the insulin produced. This hyperglycemia produces the typical symptoms of polyuria (frequent urination), severe thirst (increased thirst), and polyphagia (increased hunger).

There are three main types of diabetes. Type 1 diabetes is caused by the body's inability to produce insulin, and therefore, currently, the person needs to inject insulin. Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM), and juvenile onset diabetes. Type 2 diabetes is caused by insulin resistance (a condition in which cells cannot properly utilize insulin), sometimes combined with absolute insulin deficiency (insulin deficiency). Type 2 diabetes is known as non-insulin dependent diabetes mellitus, and adult onset diabetes (adult-oneset diabetes). Gestational diabetes mellitus (getationaliabetes) is a condition in which a pregnant woman has not suffered diabetes before pregnancy and has a high blood glucose value during pregnancy. Gestational diabetes may contribute to the development of type 2 diabetes.

Other forms of diabetes include: congenital diabetes (genetic diabetes) due to genetic defects in insulin secretion, cystic fibrosis-related diabetes (cystic fibrosis-related diabetes), steroid diabetes (steroidiabetes) due to high doses of glucocorticoids, and various forms of monogenic diabetes.

The main objective in treating diabetes is to minimize any rise in blood glucose (glucose) without causing abnormally low blood glucose values.

Disclosure of Invention

The invention provides application of a compound in preparing a composition for treating diabetes, which comprises the following components in a certain aspect: administering to a subject a therapeutically effective amount of a cyclohexenone compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, having the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

each R₁、R₂And R₃Each independently is hydrogen, methyl, or (CH)₂)_m-CH₃；

R₄Is NR₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆Halogen, 5-or 6-membered ring lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, or glucosyl; wherein, 5 or 6 membered cyclic lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted with a substituent of haloalkyl;

each R₅And R₆Each independently is hydrogen or C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In another aspect, the present invention provides a use of a compound for preparing a composition for inhibiting an increase in blood glucose level (blood sugar level) in a subject, comprising: administering a therapeutically effective amount of a cyclohexenone compound, or a pharmaceutically acceptable salt thereof, a metabolite thereof, a solvate thereof, or a prodrug thereof, to a subject affected by a disease caused by hyperglycemia, glucose intolerance, or abnormal glucose (abnormal glucose), and having the following structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₄Is NR₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆Halogen, 5-or 6-membered ring lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, or glucosyl; wherein, 5 or 6 membered cyclic lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, and glucosylIs optionally via one or more compounds selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted with a substituent of haloalkyl;

each R₅And R₆Each independently of the other being hydrogen, or C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In another aspect, the present invention provides a use of a compound for the preparation of a composition for inhibiting an increase in blood glucose level in a subject, comprising: administering a therapeutically effective amount of a cyclohexenone compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, to a subject affected by a disease caused by hyperglycemia, glucose intolerance, or abnormal glucose, and having the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In another aspect, the present invention provides a method for treating or reducing the risk of a disease in a subject caused by hyperglycemia, glucose intolerance, or abnormal glucose, comprising: administering a therapeutically effective amount of a cyclohexenone compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, to a subject affected by a disease, and the cyclohexenone compound having the following structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

The contents of all documents, patents, and patents in application mentioned in the present specification are incorporated by reference, i.e., each document, patent, or patent in application specifically and individually mentioned in the present specification is incorporated by reference.

Except in very specific cases, diabetes is a chronic disease that is difficult to treat. The treatment regimen focuses on maintaining the blood glucose level as close to normal ("euglycemia") as possible without causing hypoglycemia. This is usually achieved by diet, exercise and use of appropriate drugs (insulin for type 1 diabetes, oral drugs, and possibly insulin for type 2 diabetes).

Typically type 1 diabetes is treated with a combination of conventional and NPH insulin, or synthetic insulin analogs. When insulin is used in type 2 diabetes, the depot is usually added initially while the oral administration of the drug is continued. The insulin dose is then increased until the effect is present. In some embodiments of the invention, the cyclohexenone compound is extracted from natural sources and can reduce complications and/or side effects. In some embodiments of the invention, a method is provided for treating diabetes by administering a cyclohexenone compound provided herein to a subject (e.g., a human). Wherein the cyclohexenone compound has a therapeutic effect on a subject receiving diabetes (see examples 1 to 7).

In some embodiments, there is provided a use of a compound for the preparation of a composition for treating diabetes, comprising: administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, having the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In some embodiments, the method inhibits an increase in blood glucose level in the subject. In some embodiments, the cyclohexenone compound inhibits an increase in blood glucose levels in the subject. In some embodiments, the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes. In some embodiments, the subject is a human. Please refer to examples 2 to 8.

In some embodiments, the preparation has

The cyclohexenone compounds of structure may be synthesized or semi-synthesized from any suitable starting material. In other embodiments, the cyclohexenone compound may be prepared by fermentation, or other similar methods. For example, in some cases, compound 1 (i.e., the well-known android quinol (Antroquinonol)^TMOr Antroq)) or compound 3 can be prepared from 4-hydroxy-2,3-dimethoxy-6-methylcyclohexa-2,5-dienone (4-hydroxy-2, 3-dimethoxy-6-methylcyclohexoxa-2, 5-dienone). Non-limiting examples of the compounds are shown below.

In other embodiments, has

The cyclohexenone compound of the structure is an organic solvent extract isolated from Antrodia camphorata. In some embodiments, the organic solvent is selected from the group consisting of alcohols (e.g., methanol, ethanol, propanol, or the like), esters (e.g., methyl acetate, ethyl acetate, or the like), alkanes (e.g., pentane, hexane, heptane, or the like), haloalkanes (e.g., methyl chloride, ethyl chloride, chloroform, methylene chloride, or the like), and the like. For example, exemplary compounds 1-7 are isolated from an organic solvent extract. In certain embodiments, the organic solvent is an alcohol; and in a particular embodiment, the alcohol is ethanol. In some embodiments, the cyclohexenone compound is isolated from an aqueous extract of Antrodia camphorata.

In some embodiments, R is hydrogen, C (= O) C₃H₈、C(=O)C₂H₅Or C (= O) CH₃. In some embodiments, R₁Is hydrogen or methyl. In certain embodiments, R₂Is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R₃Is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R₄Is halogen, NH₂、NHCH₃、N(CH₃)₂、OCH₃、OC₂H₅、C(=O)CH₃、C(=O)C₂H₅、C(=O)OCH₃、C(=O)OC₂H₅、C(=O)NHCH₃、C(=O)NHC₂H₅、C(=O)NH₂、OC(=O)CH₃、OC(=O)C₂H₅、OC(=O)OCH₃、OC(=O)OC₂H₅、OC(=O)NHCH₃、OC(=O)NHC₂H₅Or OC (= O) NH₂. In some embodiments, R₄Is C₂H₅C(CH₃)₂OH、C₂H₅C(CH₃)₂OCH₃、CH₂COOH、C₂H₅COOH、CH₂OH、C₂H₅OH、CH₂Ph、C₂H₅Ph、CH₂CH=C(CH₃)(CHO)、CH₂CH=C(CH₃)(C(=O)CH₃) 5-or 6-membered ring lactone, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, or glucosyl; wherein, 5 or 6 membered cyclic lactone, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted by a substituent of haloalkyl. In certain embodiments, R₄Is CH₂CH=C(CH₃)₂. In a particular embodiment, the compound is

In some embodiments, there is provided a use of a compound for the preparation of a composition for inhibiting an increase in blood glucose level in a subject, comprising: administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, to a subject affected by a disease caused by hyperglycemia, glucose intolerance, or abnormal glucose, and the compound has the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In some embodiments, the method of inhibiting an increase in blood glucose level in a subject suffering from a disease caused by hyperglycemia, glucose intolerance, or abnormal glucose, which is diabetes, or a diabetic complication, the diabetic complication comprising: diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic lethargy, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic diarrhea, diabetic microangiopathy, diabetic uterine sclerosis, diabetic heart disease, diabetic neuropathy, diabetic nephropathy, diabetic bullous disease, diabetic cataract, diabetic skin disease, diabetic scleropathy, diabetic retinopathy, O-bird disease, or diabetic blood circulation disorder. In some embodiments, the disease caused by hyperglycemia, glucose intolerance, or abnormal glucose is type 1, type 2, or gestational diabetes, or a complication thereof. In some embodiments, the subject is a human.

Glucose intolerance (Impaired glucose tolerance) or glucose intolerance is the prediabetic state of hyperglycemia that is associated with insulin resistance and increases the risk of cardiovascular pathology. Years of IGT may contribute to type 2 diabetes. IGT is also a risk factor for mortality.

Hyperglycemia or hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood.

In some embodiments, there is provided a use of a compound for the manufacture of a composition for treating or reducing the risk of a disease in a subject caused by hyperglycemia, glucose intolerance or abnormal glucose, comprising: administering to a subject affected by a disease a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, having the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₄Is NR₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆Halogen, 5 or 6Cyclic lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, or glucosyl; wherein, 5 or 6 membered cyclic lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted with a substituent of haloalkyl;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In some embodiments, the disease caused by hyperglycemia, glucose intolerance, or abnormal glucose is diabetes or diabetic complications, including: diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic lethargy, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic diarrhea, diabetic microangiopathy, diabetic uterine sclerosis, diabetic heart disease, diabetic neuropathy, diabetic nephropathy, diabetic bulla disease (diabetic bulla), diabetic cataract, diabetic skin disease, diabetic scleroderma, diabetic retinopathy, avian diabetes (necrobiosis lipoidietamicum), or diabetic blood circulation disorder. In some embodiments, the disease caused by hyperglycemia, glucose intolerance, or abnormal glucose is type 1, type 2, or gestational diabetes, or a complication thereof. In some embodiments, the cyclohexenone compound inhibits or reduces blood glucose levels in a subject. In some embodiments, the subject is a human.

In some embodiments, the cyclohexenone compounds provided herein have a therapeutic effect of reducing blood glucose in a subject. Please refer to example 2.

Specific medical and medical specialization terms

Unless otherwise indicated, all terms used herein, including those used in the specification and claims, are to be understood as defined below. It is to be understood that, unless the context clearly dictates otherwise, both the singular and the plural are intended to be encompassed by the singular references "a" and "an" in the specification and the claims of this invention. Any known method, including mass spectrometry, NMR, HPLC, protein chemistry techniques, biochemical techniques, recombinant DNA techniques, and pharmacological techniques may be used in the present invention, unless otherwise specified. As used herein, unless otherwise specified, "or" and "means" and/or "in the present application. Furthermore, the terms "comprising", "including" and "containing" are non-limiting terms. In addition, the section headings are for organizational purposes only and are not meant to be used to limit the scope of the invention.

The term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl group can be a saturated alkyl group (meaning not containing any carbon-carbon double or triple bonds), or the alkyl group can be an unsaturated alkyl group (meaning containing at least one carbon-carbon double or triple bond). The alkyl group, whether saturated or unsaturated, may be a branched or straight chain alkyl group.

An "alkyl" group can have 1 to 12 carbon atoms; even though the present invention also includes "alkyl" groups having undefined numerical ranges, the numerical ranges such as "1 to 12" represent each integer in the range; for example, "1 to 12 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and the like up to 12 carbon atoms. The alkyl group of the compounds of the present invention mayC₁-C₈Alkyl "or other similar definitions. For example, by way of illustration only, "C₁-C₈Alkyl means one, two, three, four, five, six, seven, or eight carbon atoms in the alkyl chain. In addition, an embodiment of the alkyl group is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, allyl, 2-butenyl, 3-butenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. In one embodiment, the alkyl group is C₁-C₈An alkyl group.

The term "alkylene" refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be formed into an alkylene group by removing a second hydrogen atom from the alkyl group. In one embodiment, the alkylene is C₁-C₁₂An alkylene group. In another embodiment, the alkylene is C₁-C₈An alkylene group. Typical alkylene groups include, but are not limited to: -CH₂-、-CH(CH₃)-、-C(CH₃)₂-、-CH₂CH₂-、-CH₂CH(CH₃)-、-CH₂C(CH₃)₂-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-, and the like.

As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the aromatic ring is a carbon atom. The aromatic ring may be formed from five, six, seven, eight, nine, or more than nine carbon atoms. In addition, the aromatic ring may be optionally substituted. In one embodiment, aryl is phenyl or naphthyl. In one embodiment, aryl is phenyl. In one embodiment, aryl is C₆-C₁₀And (4) an aryl group. Depending on the structure, the aryl group can be a single radical or a diradical (e.g., arylene). In one embodiment, the arylene group is C₆-C₁₀An arylene group. Examples of arylene groups include, but are not limited to: 1, 2-phenylene (phenyl-1,2-ene), 1, 3-phenylene (phenyl-1,3-ene), and 1, 4-phenylene (phenyl-1, 4-ene).

The term "aromatic ring" refers to a planar ring having a delocalized pi-electron system, wherein the delocalized pi-electron system comprises 4n +2 pi-electrons, and n is an integer. The aromatic ring may consist of five, six, seven, eight, nine, ten, or more than ten atoms. In addition, the aromatic ring may be optionally substituted. The term "aromatic ring" includes: carbocyclic aryl ("" aryl "", e.g., phenyl), and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridyl). In addition, the term "aromatic ring" includes monocyclic or fused-ring polycyclic (e.g., rings that share adjacent pairs of carbon atoms) groups.

The terms "halo", "halogen", or "halide" refer to fluorine, chlorine, bromine, or iodine.

The term "cyclic lactone" refers to a cyclic ester, which is the condensation product of an alcohol group-OH and a carboxyl group-COOH in the same molecule. The cyclic lactone is characterized in that it is a closed ring consisting of more than two carbon atoms and a single oxygen atom, and has a ketone group = O on the carbon atom adjacent to the oxygen.

The term "heterocycle" refers to heteroaromatic rings (i.e., heteroaryl) and heterocycloalkyl rings having one to four heteroatoms in the ring, wherein each heteroatom in the ring is selected from the group consisting of O, S and N, and each heterocyclic group in the ring system has 4 to 10 atoms, provided that either ring does not contain two adjacent O or S atoms. The ring system of the non-aromatic heterocyclic group (i.e., the heterocycloalkyl group) includes groups having only 3 atoms, but the ring system of the aromatic heterocyclic group needs to have at least 5 atoms. Heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl (aziridinyl). An example of a 4-membered heterocyclic group is azetidinyl (azetidinyl). An example of a 5-membered heterocyclic group is thiazolyl (thiazolyl). An example of a 6-membered heterocyclic group is pyridyl (pyridil), and an example of a 10-membered heterocyclic group is quinolyl (quinolinyl). Examples of non-aromatic heterocyclic groups include: pyrrolidinyl (pyrrolidinyl), tetrahydrofuranyl (tetrahydrofuranyl), dihydrofuranyl (dihydrofuranyl), tetrahydrothienylethyl (tetrahydrothienyl), oxazolidinyl (oxazolidinonyl), tetrahydropyranyl (tetrahydropyranyl), dihydropyranyl (dihydropyranyl), tetrahydrothiopyranyl (tetrahydrothiopyranyl), piperidinyl (piperidyl), morpholinyl (morpholino), thiomorpholinyl (thiomorpholinyl), thioxanyl (thiocyanyl), piperazinyl (piperazinyl), aziridinyl (azidinyl), azetidinyl (azepinyl), ethoxymethylanyl (oxolanyl), trimethylene sulfide (thietanyl), homopiperidinyl (homopiperidyl), oxprenyl (oxypentanyl), thietanyl (azetidinyl), oxapinyl (oxapinyl), dioxanyl (tetrahydrothianaphthyrinyl), tetrahydrothiopyranyl (3, 6-pyridyl), tetrahydrothiopyranyl (3, 2, 3-2, 6-pyrrolinyl), tetrahydrothiopyranyl (tetrahydrothiopyranyl), tetrahydrothiopyranyl (tetrahydrothiazepinyl), tetrahydrothiopyranyl (3, 6-pyridyl), tetrahydrothiopyranyl (tetrahydrothiopyranyl), tetrahydrothiopyranyl (piperanyl), tetrahydrothiopyranyl (thiazinyl), tetrahydrothiopyranyl (3, 6-pyridyl), tetrahydrothiopyranyl (thianaphtinyl), tetrahydrothiopyranyl (3, 2, 6-pyrrolinyl), tetrahydrothiopyranyl (piperanyl), tetrahydrothiopyranyl, 3-thianaphtinyl), and (thianaphtinyl), thianaphtinyl (piperanyl), thianaphtinyl), indolinyl (indolinyl), 2H-pyranyl (2H-pyranyl), 4H-pyranyl (4H-pyranyl), dioxanyl (dioxanyl), 1,3-dioxolanyl (1,3-dioxolanyl), pyrazolinyl (pyrazolinyl), dithianyl (dithianyl), dithiolanyl (dithianyl), dihydropyranyl (dihydropyranyl), dihydrothienyl (dihydrothienyl), dihydrofuranyl (dihydrofuranyl), pyrazolidinyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazolidinyl (imidazolidinyl), 3-azabicyclo [3.l.0] hexanyl (3-azabicyclo [3.l.0] hexinyl), 3-azabicyclo [4.1.0] heptanyl (3-azabicyclo [4.1.0] heptanyl), 3-indolinyl (4H-pyridyl), and indolinyl (3H-indolinyl). Examples of the aromatic heterocyclic group include: pyridyl (pyridyl), imidazolyl (imidazolyl), pyrimidinyl (pyridyl), pyrazolyl (pyridyl), thiazolyl (triazolyl), pyrazinyl (pyrazoyl), tetrazolyl (tetrazolyl), furyl (furyl), thienyl (thienyl), isoxazolyl (isoxazolyl), thiazolyl (thiazolyl), oxazolyl (oxazolyl), isothiazolyl (isothiazolyl), pyrrolyl (pyridyl), quinolyl (quinolyl), isoquinolyl (isoquinolyl), indolyl (indolyl), benzimidazolyl (benzimidazolyl), benzofuranyl (benzofuranyl), cinnolinyl (cinnolinyl), indazolyl (indolizolyl), indolizine (indolizinyl), phthalazinyl (phthalazinyl), pyridazinyl (pyridyl), triazinyl (triazinyl), pyrazoyl (triazolyl), pyrazoyl (thiazolyl), benzofuranyl (thiazolyl), benzoquinonyl (thiazolyl), benzoxazolyl (thiazolyl) (benzoxazolyl), thienyl (pyridyl), benzoxazolyl) (benzoxazolyl), benzoxazolyl (pyridyl) (benzoxazolyl), (pyridyl) (benzoxazolyl) (pyridyl), benzoxazolyl) (pyridyl) (pyridyl), pyridyl (pyridyl), pyridazinyl) (pyridyl) (pyridyl), pyridazinyl) (pyridyl), pyridyl) (pyridyl), (pyridyl) (, Quinazolinyl (quinazolinyl), quinoxalinyl (quinoxalinyl), naphthyridinyl (naphthyridinyl), and furopyridinyl (furylpyridinyl). The aforementioned groups may be C-linked or N-linked. For example, the group derived from pyrrole may be pyrrol-1-yl (N-linked), or pyrrol-3-yl (C-linked). Furthermore, the groups derived from imidazole may be imidazol-1-yl or imidazol-3-yl (all N-linkages), or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linkages). Heterocyclic groups include benzo-fused ring systems. The non-aromatic heterocyclic ring may be substituted with one or two oxygen groups (= O), such as pyrrolin-2-one (pyrrolidin-2-one).

As used herein, the term "alkenyl" refers to straight, branched, or cyclic hydrocarbon groups (also referred to as "cycloalkenyl"), wherein "alkenyl" contains 2-10 carbons and contains at least one carbon-carbon double bond formed upon removal of two hydrogens. In some embodiments, the alkenyl group can be a mono-radical or a di-radical (e.g., alkenylene) group, depending on the structure. In some embodiments, the alkenyl group is optionally substituted. Examples of alkenyl groups may include, but are not limited to: vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl (3-cecenyl).

As used herein, the term "alkynyl" refers to straight, branched, or cyclic hydrocarbon groups (also referred to as "cycloalkynyl"), wherein "alkynyl" contains 2-10 carbons and contains at least one carbon-carbon triple bond formed upon removal of four hydrogens. In some embodiments, alkynyl groups can be mono-or di-radical (e.g., alkynylene), depending on the structure. In some embodiments, the alkynyl group is optionally substituted. Examples of alkynyl groups may include, but are not limited to: acetylene, propyne, butyne, pentyne, hexyne, heptyne, and other similar groups.

In the present invention, the term "alkoxy" refers to an alkyl group as defined herein appended to the parent molecular group through an oxygen atom. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentoxy, and hexoxy.

As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and can include cycloalkyl groups that are saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative examples of cycloalkyl groups include, but are not limited to, the following:

in some embodiments, the cycloalkyl group is a mono-or di-radical (e.g., cycloalkylene) group, depending on the structure.

In the present invention, "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy groups in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, when two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same as each other. In other embodiments, when two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as each other. Furthermore, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halogen atom is fluorine. In certain embodiments, the oxyhalogen group is optionally substituted.

As used herein, the term "glucosyl group" includes D-or L-type glucosyl groups wherein the glucosyl group is attached through any hydroxyl group on the glucose ring.

The term "acceptable" with respect to a formulation, composition, or ingredient of the present invention, means not having a long-lasting deleterious effect on the general health of the subject being treated.

Antrodia camphorata is a fungus of family Hymenochaetaceae (Meripilaceae). The fruiting body of Antrodia camphorata is generally flat or grows on the growing surface to extend outwards, and the fruiting layer (hymenium) is exposed outwards; in addition, the periphery may be slightly raised and assume a narrow cradle shape. Most species of antrodia camphorata grow in temperate and frigid forests and cause brown rot (brown rot). In addition, some special species of the fungus have medicinal properties, and are commonly used as Chinese herbal medicines in taiwan.

As used herein, the term "carrier" refers to a relatively nontoxic chemical compound or agent that facilitates the delivery of a compound to a cell or tissue.

In the present invention, the term "co-administration" includes administration of a selected therapeutic agent to a patient, and also includes treatment methods in which the agent is administered in the same or different manner, or at the same or different time of administration.

The term "diluent" refers to a compound that is used to dilute the compound used prior to administration. Diluents can also be used to stabilize compounds because they provide a more stable environment. Salt buffers commonly used in the art, which may be used to control or maintain pH, may also be used as diluents, including but not limited to phosphate buffered solutions.

In the present invention, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent or compound administered sufficient to alleviate, to some extent, one or more of the symptoms or diseases being treated. Thus, the symptoms, condition, or cause of the disease can be slowed and/or alleviated, or any other desired alteration to the physiological system achieved. For example, an "effective amount" for therapeutic use refers to the amount of a composition required to provide clinically significant improvement in a disease condition, wherein the composition comprises a compound disclosed herein. In addition, in various instances, an appropriate "effective" dose can be determined by techniques such as dose escalation testing.

In the present invention, the terms "increase" or "enhancing" refer to increasing or prolonging the efficacy or duration of a desired effect. Thus, the term "increase" or "potentiation" with respect to the effect of a potentiating therapeutic agent refers to the ability to increase or prolong the effect of the other therapeutic agent in the system, regardless of its potency or duration. As used herein, an "enhanced effective dose" refers to a sufficient dose to enhance the effect of another therapeutic agent in a desired system.

In the present invention, the term "metabolite" refers to a derivative of a compound formed by metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound formed by the metabolism of the compound. In addition, as used herein, the term "metabolism" refers to all processes (including, but not limited to, hydrolysis and enzymatic catalysis) in which a particular component is altered by an organism. Thus, enzymes can make specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyl transferase (uridylphosphateglucuronidase) catalyzes the transfer of active glucuronic acid molecules to aromatic, aliphatic, carboxylic, amine and sulfhydryl (sulphydryl) free groups. In the present invention, the metabolite of the compound is selectively produced by: administering a compound to a subject and analyzing a tissue sample of the subject, or culturing a compound and liver in vitro and analyzing the resulting compound.

In the present invention, the term "pharmaceutical composition" means a product obtained by mixing or combining more than one active ingredient, and includes fixed and non-fixed compositions of active ingredients. The term "fixed composition" refers to a composition in which the active ingredient (a compound, such as the cyclohexenone compound of the invention) and an adjuvant are administered to a patient simultaneously in a single unit or dosage form. The term "non-fixed composition" means that the active ingredient (a compound, such as the cyclohexenone compound of the present invention) and an adjuvant are administered to a patient in separate forms simultaneously, concurrently, or sequentially with no specific time interval limitation, wherein such administration provides an effective level of both compounds in the patient. In addition, non-fixed compositions may also be used in cocktail therapy, such as: three or more active ingredients are administered.

The term "pharmaceutical composition" refers to a mixture of a compound (i.e., the cyclohexenone compound of the present invention) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients. The pharmaceutical composition facilitates administration of the compound to a species. Various techniques for administering compounds known in the art include, but are not limited to: intravenous injection, oral administration, spray administration, parenteral administration (parenteral administration), ocular administration, pulmonary administration (inhalation administration), and external administration.

In addition, the term "subject" or "patient" includes mammals; and examples of mammals include, but are not limited to, any species of the mammalia class: humans, non-human primates such as orangutan and other ape and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. In one embodiment, the mammal is a human.

In the present invention, the term "treatment" includes: a condition that alleviates, or ameliorates at least one of a disease or symptom by prevention and/or treatment, prevents other conditions, inhibits the disease or symptom (e.g., inhibits the development of the disease or symptom), alleviates the disease or symptom, restores the disease or symptom, alleviates the symptom caused by the disease or symptom, or terminates the disease or symptom.

Route of administration

Routes of administration for which the present invention is useful include, but are not limited to: the composition can be administered orally, intravenously, enterally, spray, parenterally, ocularly, pulmonarily, mucosally, topically, vaginally, otically, nasally, or topically. Furthermore, examples of parenteral administration include: intramuscular, subcutaneous, intravenous, intraspinal injection, and also includes intracerobrospinal, direct intraperitoneal, intralymphatic, intranasal injection.

In certain embodiments, the compounds of the invention are generally formulated in depot or sustained release formulations and administered by local rather than systemic administration, e.g., by direct injection of the compound into the viscera. In certain embodiments, the drug may be administered in a long acting dosage form by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Moreover, in other embodiments, the drug may be administered from a targeted drug delivery system (e.g., liposomes labeled with organ-specific antibodies). In this embodiment, the liposomes are targeted to and selectively absorbed by an organ. In yet another embodiment, the compounds of the present invention may be formulated as a fast-release, slow-release, or immediate-release dosage form. In yet another embodiment, the compounds of the present invention may be administered topically.

In certain embodiments, the cyclohexenone compound, or a pharmaceutically acceptable salt thereof, a metabolite thereof, a solvate thereof, or a prodrug thereof, is administered parenterally or intravenously. In other embodiments, the cyclohexenone compound, or a pharmaceutically acceptable salt thereof, a metabolite thereof, a solvate thereof, or a prodrug thereof, is administered by injection. In some embodiments, the cyclohexenone compound, or a pharmaceutically acceptable salt thereof, a metabolite thereof, a solvate thereof, or a prodrug thereof, is administered orally.

Pharmaceutical dosage forms

In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof; and a pharmaceutically acceptable excipient, and the compound has the following structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₄Is NR₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆Halogen, 5-or 6-membered ring lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, or glucosyl; wherein, 5 or 6 membered cyclic lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, and glucosyl are optionally substituted with one or more groups selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted with a substituent of haloalkyl;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In certain embodiments, the cyclohexenone compound, or a pharmaceutically acceptable salt thereof, a metabolite thereof, a solvate thereof, or a prodrug thereof, of the pharmaceutical composition has the following structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

In some embodiments, R is hydrogen, C (= O) C₃H₈、C(=O)C₂H₅Or C (= O) CH₃. In some embodiments, each R₁、R₂And R₃Each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. In certain embodiments, R₁Is hydrogen, or methyl. In certain embodiments, R₂Is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, R₃Is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R₄Is halogen, NH₂、NHCH₃、N(CH₃)₂、OCH₃、OC₂H₅、C(=O)CH₃、C(=O)C₂H₅、C(=O)OCH₃、C(=O)OC₂H₅、C(=O)NHCH₃、C(=O)NHC₂H₅、C(=O)NH₂、OC(=O)CH₃、OC(=O)C₂H₅、OC(=O)OCH₃、OC(=O)OC₂H₅、OC(=O)NHCH₃、OC(=O)NHC₂H₅Or OC (= O) NH₂. In certain embodiments, R₄Is C₂H₅C(CH₃)₂OH、C₂H₅C(CH₃)₂OCH₃、CH₂COOH、C₂H₅COOH、CH₂OH、C₂H₅OH、CH₂Ph、C₂H₅Ph、CH₂CH=C(CH₃)(CHO)、CH₂CH=C(CH₃)(C(=O)CH₃) 5 or 6 membered ring lactone, aryl, or glucosyl; wherein the 5 or 6 membered ring lactone, aryl, and glucosyl are optionally substituted with one or more groups selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted by a substituent of haloalkyl. In certain embodiments, R₄Is CH₂COOH、C₂H₅COOH、CH₂OH、C₂H₅OH、CH₂Ph、C₂H₅Ph、CH₂CH=C(CH₃)(CHO)、CH₂CH=C(CH₃)(C(=O)CH₃) 5 or 6 membered ring lactone, aryl, or glucosyl; wherein the 5-or 6-membered cyclic lactone, aryl, and glucosyl are optionally substituted with one or more groups selected from NR₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl, and C₁-C₈Substituted by a substituent of haloalkyl.

In certain embodiments, the compound is selected from the group consisting of:

in certain embodiments, the compound is selected from the group consisting of:

in some embodiments, the compounds of the present invention can be prepared as a pharmaceutical composition. In certain embodiments, the pharmaceutical compositions may be prepared in a conventional manner using one or more physiologically acceptable carriers; and the physiologically acceptable carriers include excipients and auxiliaries, which aid the processing of the active compounds to prepare pharmaceutically usable preparations. The appropriate dosage form is selected according to the route of administration. Any pharmaceutically acceptable technique, carrier, and excipient may be suitable for preparing the pharmaceutical composition of the invention: remington The Science and Practice of pharmacy, ninth edition (Easton, Pa.: Mack Publishing Company, 1995); hoover, John e., Remington's Pharmaceutical Sciences, Mack Publishing co, Easton, Pennsylvania 1975; liberman, h.a. and Lachman, l., eds., pharmaceutical dosage Forms, Marcel Decker, New York, n.y., 1980; and pharmaceutical dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl 999).

The present invention provides a pharmaceutical composition comprising a compound (e.g., the cyclohexenone compound of the present invention) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the compounds are administered as pharmaceutical compositions, in which a compound (e.g., the cyclohexenone compounds of the invention) and other active ingredients may be combined, as in combination therapy. The invention includes all combinations of active ingredients as described in the description of the invention in the section on combination therapy. In certain embodiments, the pharmaceutical composition comprises more than one compound (i.e., a cyclohexenone compound of the invention).

The pharmaceutical composition of the present invention refers to a mixture of a compound (e.g., the cyclohexenone compound of the present invention) and other compounds, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients. In certain embodiments, the pharmaceutical composition can facilitate administration of the compound to a subject. In some embodiments, the therapeutic methods or uses of the invention involve administering a therapeutically effective amount of a compound (e.g., a cyclohexenone compound of the invention) in a pharmaceutical composition to a subject having a disease or disorder to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective dose will vary with the severity of the disease, the age and health of the subject, the potency of the compound, and other factors. In addition, the compounds of the present invention may be used alone or in combination with more than one therapeutic agent (as a component of a mixture).

In one embodiment, the compound (e.g., a cyclohexenone compound of the present invention) is prepared in the form of an aqueous solution. In certain embodiments, and by way of illustration only, examples of aqueous solutions may be selected from physiologically compatible buffers (e.g., Hank's solution, Ringer's solution, or physiological saline), in other embodiments, compounds (e.g., cyclohexenone compounds of the present invention) may be formulated for mucosal administration.

In another embodiment, the compounds of the present invention may be formulated into oral dosage forms. Here, the compound comprising the cyclohexenone compound of the present invention is prepared by mixing the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds of the present invention can be formulated in oral dosage forms, examples of which include lozenges, powders, troches, pills, capsules, lotions, gels, medicated syrups, elixirs, syrups, suspensions, and the like.

In a particular embodiment, oral dosage forms are prepared by mixing one or more solid excipients with one or more compounds according to the invention, optionally grinding the resulting mixture, and, if desired, adding suitable auxiliaries, processing the powder mixture to form tablets or pill cores. In particular, suitable excipients are: fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; celluloses, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum arabic, methyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, a disintegrant is optionally added. By way of illustration only, examples of disintegrants may include: croscarmellose sodium (Croscarmellose sodium), polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate).

In one embodiment, the medicament, such as the core of the pill and the tablet, may be provided with more than one suitable coating. In certain embodiments, the concentrated saccharide solution is used to coat the pharmaceutical agent. The saccharide solution may optionally comprise: other additional ingredients, such as gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide; coating the solution; and suitable organic solvents or solvent mixtures, and such examples are for illustrative purposes only. Dyes and/or pigments may also optionally be added to the coating for identification purposes. In addition, dyes and/or pigments may optionally be used to indicate combinations of different active compound agents.

In certain embodiments, a therapeutically effective amount of at least one compound of the present invention can be prepared in a form other than an oral dosage form. Oral dosage forms include push-fit capsules made of gelatin, as well as soft and sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain embodiments, the push-fit capsule comprises the active ingredient mixed with one or more fillers. Examples of fillers may include: lactose, binders such as starch, and/or lubricants such as talc or magnesium stearate, optionally including stabilizers, as examples only. In other embodiments, soft capsules comprise one or more active compounds dissolved or suspended in a suitable liquid. Examples of suitable liquids include: more than one fatty oil, liquid paraffin, or liquid polyethylene glycol, and these examples are given for illustrative purposes only. In addition, a stabilizer may be optionally added.

In other embodiments, a therapeutically effective dose of at least one compound of the present invention may be formulated for buccal or sublingual administration. Examples of suitable dosage forms for buccal or sublingual administration include tablets, troches, or gels, and such examples are intended to be illustrative only. In still other embodiments, the compounds of the present invention may be formulated for parenteral injection, including those suitable for bolus injection (bolus injection) or continuous infusion. In certain embodiments, the injectable dosage form is in unit dosage form (e.g., ampoule form), or in multi-dose packaging. In addition, preservatives may optionally be added to the injectable form. In still other embodiments, the pharmaceutical composition of the compound (e.g., the cyclohexenone compound of the present invention) is dissolved in an oily or aqueous vehicle and formulated into a sterile suspension, solution, or emulsion suitable for parenteral injection. Parenteral formulations may optionally include formulatory agents such as suspending, stabilizing, and/or dispersing agents. In a particular embodiment, the pharmaceutical dosage form for parenteral administration comprises an aqueous solution of the active compound in water-soluble form. In other embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Examples of suitable oil-soluble solvents or vehicles for use in the pharmaceutical compositions of the present invention may include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes, and these examples are for illustrative purposes only. In particular embodiments, the aqueous injection suspension comprises a substance that increases the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. In addition, the suspension may optionally include suitable stabilizers or agents to enhance the solubility of the compound for preparing highly concentrated solutions. Alternatively, in other embodiments, the active ingredient may be presented in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In one embodiment, the compound (e.g., the cyclohexenone compound of the present invention) is prepared as a solution for parenteral injection by a method of the present invention or a method known in the art, and administered using an auto-injector. Automatic injections are disclosed in U.S. patent nos. 4,031,893, 5,358,489, 5,540,664, 5,665,071, 5,695,472, and W0/2005/087297, the disclosures of each of which are incorporated herein by reference. Generally, all autoinjectors contain a volume to be injected of a solution containing a compound (e.g., a cyclohexenone compound of the invention). Further, the auto-injector comprises: a storage space for containing a solution, the storage space being in fluid communication with a needle for administration; and an automatic needle insertion mechanism that inserts the needle onto a patient to deliver the medicament to the patient. For example, a syringe may provide about 0.3mL, 0.6mL, 1.0mL, or other suitable volume of solution and contain a concentration of about 0.5mg to 50mg of a compound (e.g., a cyclohexenone compound of the invention) per 1mL of solution. Furthermore, each syringe may deliver only one dose of the compound.

In still other embodiments, a compound (e.g., a cyclohexenone compound of the invention) may be administered topically. The compounds of the present invention can be formulated into various compositions for external administration, such as solutions, suspensions, emulsions, gels, slurries, sticks, salves, creams, ointments, and the like. In addition, such pharmaceutical compositions may optionally contain solubilizers, stabilizers, tonicity enhancing agents (tonicityenhancing agents), buffers, or preservatives.

In yet another embodiment, the compound (e.g., a cyclohexenone compound of the present invention) may be administered by percutaneous absorption. In particular embodiments, the skin-absorptive dosage form may be a dermal administration device or dermal administration patch, and may be an oil-soluble emulsifier, or a buffered aqueous solution dissolved and/or dispersed in a polymer or adhesive. In various embodiments, such patches are used for continuous, intermittent, or on-demand administration. In other embodiments, iontophoretic patch (ionophoretic patch) and the like may be used for transdermal administration of a compound (e.g., a cyclohexenone compound of the present invention). In certain embodiments, the skin absorbing patch is capable of controlled delivery of a compound (e.g., a cyclohexenone compound of the invention). In particular embodiments, slowing the rate of absorption can be achieved by using rate controlling films, or confining the compound to a polymer matrix or colloid. In another embodiment, absorption enhancers may also be used to aid absorption. The absorption enhancer or carrier may include an absorbable pharmaceutically acceptable solvent, which may aid in the passage of the compound through the skin. For example, in one embodiment, the dermal administration device is in the form of a bandage comprising: a back film; a storage space for receiving the compound and selectively receiving the carrier; a selective rate control barrier for delivering the drug to the skin of the subject at a controlled and predetermined rate over an extended period of time; and a safety component for ensuring the safety of the device to the skin.

The skin-absorptive dosage forms of the present invention can be administered using a variety of devices known in the art. Examples of devices may include, but are not limited to, the devices described in U.S. Pat. nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,334,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801, and 6,946,144.

The skin-absorptive pharmaceutical forms of the present invention may contain specific pharmaceutically acceptable excipients known in the art. In one embodiment, the skin-absorptive dosage form of the present invention comprises at least three components:

(1) a compound agent (e.g., a cyclohexenone compound of the present invention);

(2) a penetration enhancer; and

(3) an aqueous adjuvant.

In addition, the skin-absorptive dosage form may include other ingredients such as, but not limited to: gelling agents, cream or ointment bases, and the like. In some embodiments, the skin-absorptive dosage form further includes a woven or non-woven backing material to aid in absorption and to prevent the skin-absorptive dosage form from detaching from the skin. In other embodiments, the skin-absorptive dosage forms of the present invention are maintained in a saturated or supersaturated state to aid in the diffusion of the pharmaceutical agent into the skin.

In other embodiments, a compound (e.g., a cyclohexenone compound of the present invention) may be prepared for administration by inhalation. Various dosage forms suitable for inhalation administration include, but are not limited to, spray, mist or powder form. Pharmaceutical compositions of compounds (e.g., cyclohexenone compounds of the invention) are typically administered by pressurized devices or nebulizers in combination with a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas) in the form of an aerosol spray. In certain embodiments, the unit dose of the pressurized spray is determined by a valve to deliver a metered dose. In certain embodiments, gelatin capsules and stored pharmaceutical packs (for example only) for use in an inhaler or insufflator may be prepared as a powder mix comprising a compound and a suitable powder base such as lactose or starch.

Dosage forms for intranasal administration are those known in the art and are described in U.S. patent publication nos. 4,476,116, 5,116,817, and 6,391,452, each of which is incorporated herein by reference. The pharmaceutical formulation prepared according to the above method or other methods known in the art may be prepared as a solution in physiological saline, wherein the pharmaceutical formulation includes a compound (e.g., the cyclohexenone compound of the present invention), and the solution may include benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. For example, reference may be made to Ansel, H.C.et al, Pharmaceutical document Forms and Drug Delivery System, sixth edition (1995). Preferably, such compositions and medicaments are prepared with suitable non-toxic pharmaceutically acceptable ingredients. Such components may be referenced to reference data commonly used in the art, such as REMINGTON: THESCIENCE AND PRACTICE PHARMACY, 21 st edition, 2005. In addition, the carrier can be properly selected according to the required characteristics of the dosage form of the nasal cavity medicament, such as: solutions, suspensions, ointments, or gels, and the like. Intranasal dosage forms typically contain large amounts of water as well as the active ingredient. In addition, minor amounts of other ingredients may be included, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents, or buffers, as well as other stabilizing and solubilizing agents. Preferably, the intranasal administration form is of an isotonic pressure with respect to the nasal secretions.

When administered by inhalation, the compounds of the present invention may be formulated as a spray, mist or powder. The pharmaceutical compositions of the present invention are generally administered by pressurized devices or nebulizers, in combination with a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas) in the form of a mist spray. In the case of a pressurized spray, the unit dose is determined by a valve to deliver a metered dose. Additionally, gelatin capsules and stored cartridges useful in inhalers or insufflators, for example only, may be prepared as powder mixtures containing a compound of the invention and a suitable powder base such as lactose or starch.

In still other embodiments, the compounds (e.g., cyclohexenone compounds of the present invention) may be formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal sprays, suppositories, colloidal suppositories, or retention enemas, which comprise a well-known suppository base (e.g., cocoa butter or other glycerides), and synthetic polymers (e.g., polyvinylpyrrolidone, PEG, and the like). In addition, in suppository formulations of the composition, cocoa butter may optionally be combined with a low melting wax (such as, but not limited to, a mixture of fatty acid glycerides), which will melt first.

In a particular embodiment, the pharmaceutical compositions are prepared in any known manner with one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds and are suitable for use in medicine. In addition, an appropriate dosage form may be selected according to the selected route of administration. Any pharmaceutically acceptable technique, carrier, and excipient may optionally be used, as appropriate and consistent with the knowledge known in the art. Pharmaceutical compositions comprising a compound, such as the cyclohexenone compounds of the present invention, may be prepared by known methods, such as, for example only, known mixing, dissolving, grinding, pill making, powdering, emulsifying, encapsulating, coating or tableting processes.

The pharmaceutical composition may include: at least one pharmaceutically acceptable carrier, diluent or excipient; and at least one compound of the present invention (e.g., a cyclohexenone compound of the present invention) as an active ingredient. The active ingredient is in the form of a free acid or a free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions of the present invention include crystalline forms (i.e., polymorphs) as well as active metabolites of such compounds having the same activity. Tautomers of the compounds described herein are also incorporated within the scope of the compounds described herein. In addition, the compounds of the present invention may also include non-solvent forms, as well as solvent forms, wherein the solvent form is the use of pharmaceutically acceptable solvents, such as water, ethanol, and the like. In the present invention, the solvent form of the compound is also incorporated in the scope of the present disclosure. In addition, the pharmaceutical composition may optionally include other drugs or agents, carriers, adjuvants (such as preservatives, stabilizers, wetting agents, or emulsifiers), solution promoters, salts for adjusting osmotic pressure, buffers, and/or other therapeutically effective substances.

In the present invention, the method for preparing the composition containing the compound of the present invention comprises: the compounds are formulated with one or more low activity and pharmaceutically acceptable excipients or carriers and prepared in solid, semi-solid or liquid form. Solid compositions include, but are not limited to: powders, lozenges, dispersible granules, capsules, and suppositories. The liquid composition comprises: a solution in which a compound is dissolved; an emulsion containing the compound; or a solution containing liposomes, colloidal particles, or nanoparticles, wherein the liposomes, colloidal particles, or nanoparticles are encapsulated with a compound of the invention. Semi-solid compositions include, but are not limited to: a gel, a suspension, or a cream. The pharmaceutical composition of the present invention may be in the form of: liquid solutions or suspensions, solid forms which may form a solution or suspension in a liquid prior to use, or emulsions. These compositions may optionally also contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents and the like.

In some embodiments, the pharmaceutical composition of the invention comprising at least one compound (e.g., the cyclohexenone compound of the invention) is in a liquid form, wherein the agent is in solution, suspension, or both. Generally, when the composition is administered as a solution or suspension, the first portion of the agent is in the form of a solution and the second portion of the agent is in a particular form, such as a suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is in the form of an aqueous solution.

In certain embodiments, the pharmaceutical aqueous suspension includes more than one polymer as a suspending agent. The polymer may include water-soluble polymers such as cellulose polymers (e.g., hydroxypropylmethylcellulose), and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Specific pharmaceutical compositions of the invention include mucoadhesive polymers (mucoadhesive polymers) which may be selected from the group consisting of: carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil (polycarbophil), acrylic acid/butyl acrylate copolymer, sodium alginate (sodium alginate), and dextran.

The pharmaceutical composition also optionally comprises a solubilizing agent to aid in the solubility of the compound (e.g., the cyclohexenone compound of the invention). The term "solubilizing agent" generally includes: a reagent that can be used to form a micellar solution (micella solution) or can form a true solution (true solution) of the reagent. In addition, certain nonionic surfactants such as polysorbate80 (polysorbate80) may also be used as solubilizing agents, and the solubilizing agents may also be ophthalmically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers.

Furthermore, the pharmaceutical composition may optionally include one or more pH adjusting agents or buffers. Wherein the pH adjusting agent or buffer comprises: acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; alkalis such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethyl aminomethane (tris-hydroxymethyl aminomethane); and buffer substances such as citrate/glucose (dextrose), sodium bicarbonate, and ammonium chloride. The amounts of such acids, bases, and buffering substances are those that maintain the pH of the composition within an acceptable range.

In addition, the pharmaceutical composition may optionally include more than one salt in an amount necessary to maintain the osmolality of the composition within an acceptable range. Salts that may be used include: a cation of sodium, potassium, or ammonium; and the anion of chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or sulfite. Further, examples of suitable salts include: sodium chloride, potassium chloride, sodium thiosulfate, sodium sulfite, and ammonium sulfate.

Other pharmaceutical compositions optionally include more than one preservative to inhibit microbial activity. Suitable preservatives include: mercury-containing substances such as phenylmercuric borate (merfen) and thimerosal (thiomersal); stabilized chlorine dioxide (chlorine dioxide); and quaternary amine compounds such as benzalkonium chloride (benzalkonium chloride), cetyltrimethylammonium bromide (cetyltrimethylammonium bromide), and cetylpyridinium chloride (cetylpyridinium chloride).

In other pharmaceutical compositions, more than one surfactant may be included to enhance physical stability or for other purposes. Suitable nonionic surfactants include: polyoxyethylene fatty acid glycerides (polyoxyyethylene fatty acid glycerides) and vegetable oils, such as: polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers (polyoxyethylenes) and alkylphenyl ethers, such as octylphenol polyether 10(octoxynol10), octylphenol polyether 40.

In still other pharmaceutical compositions, more than one antioxidant may be included to increase the desired chemical stability. Suitable antioxidants include (for example only): ascorbic acid and sodium metabisulfite (sodium metabisulfite).

In a particular embodiment, the pharmaceutical aqueous suspension composition is packaged as a single dose and in a non-reclosable container. Alternatively, multiple dose reclosable containers may be used, whereby the composition typically includes a preservative.

In another embodiment, administration systems for hydrophobic pharmaceutical compounds may also be used. For example, the present invention may employ liposomes and emulsifiers as vehicles or carriers for administration. In certain embodiments, organic solvents such as N-methylpyrrolidone may be used. In other embodiments, the compounds of the invention may be administered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. In addition, various sustained release materials may also be used in the present invention. In some embodiments, the sustained release capsule can release the compound over several hours, even over 24 hours. Depending on the chemical properties and biological stability of the therapeutic agent, additional technical methods for protein stabilization may be used.

In certain embodiments, the agents of the present invention may include one or more antioxidants, metal chelators, thiol-containing compounds, and/or other generally conventional stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine (methionine), (c) about 0.1% to about 2% w/v monothioglycerol (monothioglycerol), (d) about 1mM to about 10mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f)0.003% to about 0.02% w/v polysorbate80 (polysorbate80), (g)0.001% to about 0.05% w/v polysorbate 20, (h) arginine (argine), (i) heparin (hein), (j) dextran sulfate (dextran sulfate), (k) cyclodextrin (cyclodextrin), (l) pentosan polysulfate (pentasaccharide) and other heparinoid (heparin), and (magnesium ion such as divalent magnesium ion and zinc ion; or (n) mixtures thereof.

Combination therapy

In general, when combination therapy is used, the compositions and other agents of the invention are not administered in the same pharmaceutical composition, and in some embodiments, are administered by different routes of administration due to the different physical and chemical properties of the compounds. In some embodiments, the initial administration is according to a predetermined method, and the professional can vary the dosage, method of administration, and time of administration according to the observed effect.

In some embodiments, the effective therapeutic dose may be varied when the drugs are administered in combination therapy. In addition, combination therapy also includes periodic therapy with multiple doses between the start and the end, which aids in patient clinical therapy management. In combination therapies described in the present invention, the dosage of co-administered compounds may vary depending on the combination drug form used, the particular drug used, the disease, condition, or disorder being treated, and the like.

It is understood that in some embodiments, the medication used to treat, prevent, or ameliorate symptoms of relief may vary depending on various factors. These factors include: the disease to which the subject is infected, and the age, weight, sex, diet, and medication of the subject. Thus, in other embodiments, the actual nature of the drug therapy may vary widely and, therefore, the manner of drug therapy described herein may vary.

The present concepts encompass the combination of compounds (e.g., the cyclohexenone compounds described herein) with other diabetes therapeutic agents. In some embodiments, examples of diabetes therapeutic agents include, but are not limited to, the following: insulin; sensitizers (i.e., biguanides (e.g., metformin (metformin)), thiazolidinediones (e.g., pioglitazone (Actos)), secretagogues (i.e., sulfonylureas, e.g., tolbutamide (Orinase), acetylbenzenesulfonylcyclohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide (Diabinese), glipizide (Glucotrol), glitazone (Diabet, Micronase, Glynase), glimepiride (Amaryl), gliclazide (Diamicron), and non-sulfonylurea secretagogues, e.g., meglitinides, repaglinides (Prandin), nateglinide (Starlix)), Injectable simulated secretion (Injectable peptides such as, e.g., grape protein-like peptide analogs (e.g., peptides (Exenatide), nateglinide-4, linagliclatide (Aclutetide Lys), and gastric inhibitory peptides such as peptide analogs (GIP 37, GIP-3583, and peptide analogs (I-P), (Pro3) GIP, GLP-1 and analogs thereof); other similar peptide analogs (e.g., vildagliptin (galvus), saxagliptin (oncoglyza), and linagliptin (tradjenta); dextrin analogs (e.g., pramlintide).

In some embodiments, a compound (i.e., the cyclohexenone compound described herein) is used in combination with the following type 1 and/or type 2 diabetes therapeutic agents to treat diabetes mellitus-NN 1250/insulin degludec, Dapagliflozin, Aleglitazar; DiaPep277, GAD-alum/rhGAD65, Otelixizumab, MGA031/hOKT3 γ 1/teplizumab (Ala-Ala), Arxxant, and the like.

In some embodiments, the cyclohexenone compounds described herein are combined with other diabetes therapeutic agents, including additional therapies and treatment regimens along with other agents. In some embodiments, the additional therapy and treatment regimen may comprise another diabetes therapy. Alternatively, in some embodiments, the additional therapies and treatment regimens include the use of other agents to treat the side effects of the agent or an additional condition associated with diabetes in the combination therapy. In another embodiment, an adjuvant or enhancer is administered in conjunction with the combination therapy described herein.

In some embodiments, there is provided a composition for treating diabetes, comprising: a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof; and one or more therapeutic agents for diabetes, wherein the compound has the following structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen, or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

Detailed Description

Example 1: preparation of exemplary Cyclohexenone Compounds

Putting about 100 g of antrodia cinnamomea mycelium, fruiting body or mixture of the antrodia cinnamomea mycelium and the fruiting body into a triangular conical flask, adding water and alcohol (70-100% ethanol water solution) according to a proper proportion, and stirring for at least 1 hour at 20-25 ℃. Subsequently, the mixture was filtered through a filter paper and a 0.45 μm filter, and the extract (extract) was collected.

The collected antrodia camphorata extract is analyzed by a High Performance Liquid Chromatograph (HPLC) with a chromatography tube (column) of RP18, methanol (A) and 0.3% acetic acid water solution (B) are used as mobile phases (the solution gradient is 0-10 minutes, the proportion of B is 95-20%, 10-20 minutes, the proportion of B is 20-10%, 20-35 minutes, the proportion of B is 10-10%, 35-40 minutes and the proportion of B is 10-95%), the extract is extracted at the flow rate of 1ml per minute, and the column extract is analyzed by an ultraviolet-visible light full-wavelength detector.

The 21.2-21.4 min eluate was collected and concentrated to give a pale yellow liquid product (compound 5). After analysis, the compound 5 is 4-hydroxy-5- (11-hydroxy-3,7, 11-trimethyl-2, 6-dodecadiene) -2, 3-dimethoxy-6-methyl-2-cyclohexenone (4-hydroxy-5- (11-hydroxy-3,7, 11-trimethyloda-2, 6-dieny1) -2, 3-dimethoxy-6-methoxylox-2-enone)), the molecular weight of which is 408, and the molecular formula of which is C₂₄H₄₀O₅. The Nuclear Magnetic Resonance (NMR) analysis values are as follows:

¹H-NMR(CDC1₃)δ(ppm):1.21,1.36,1.67,1.71,1.75,1.94,2.03,2.07,2.22,2.25,3.68,4.05,5.71,5.56

¹³C-NMR(CDC1₃)δ(pprn):12.31,16.1,16.12,17.67,25.67,26.44,26.74,27.00,30.10,40.27,43.34,59.22,60.59,71.8,120.97,123.84,124.30,131.32,134.61,135.92,138.05,160.45,197.11

compound 5: 4-hydroxy-5- (11-hydroxy-3,7, 11-trimethyl-2, 6-dodecadienyl) -2, 3-dimethoxy-6-methyl-2-cyclohex-enone

The 23.7-24.0 min eluate was collected and concentrated to give a pale yellow liquid product (Compound 7). After analysis, the compound 7 is 4-hydroxy-2,3-dimethoxy-5- (11-methoxy-3,7, 11-trimethyl-2, 6-dodecadiene) -6-methyl-2-cyclohexenone (4-hydroxy-2,3-dimethoxy-5- (11-methoxy-3,7, 11-trimethyloda-2, 6-dienyl) -6-methycylohex-2-enone), the molecular weight is 422, and the molecular formula is C₂₅H₄₂O₅. The Nuclear Magnetic Resonance (NMR) analysis values are as follows:

¹H-NMR(CDC1₃)δ(ppm):1.21,1.36,1.71,1.75,1.94,2.03,2.07,2.22,2.25,3.24,3.68,4.05,5.12,5.50,5.61

¹³C-NMR(CDC1₃)δ(pprn):12.31,16.1,16.12,17.67,24.44,26.44,26.74,27.00,37.81,39.81,40.27,43.34,49.00,59.22,60.59,120.97,123.84,124.30,135.92,138.05,160.45,197.12

compound 7: 4-hydroxy-2,3-dimethoxy-5- (11-methoxy-3,7, 11-trimethyl-2, 6-dodecadien) -6-methyl-2-cyclohex-enone

Collecting and concentrating the 25-30 min extractive solution to obtain light yellow brown liquid product, i.e. 4-hydroxy-2,3-dimethoxy-6-methyl-5- (3,7, 11-trimethyl-2, 6, 10-dodecatriene) -2-cyclohexenone

(4-hydroxy-2,3-dimethoxy-6-methyl-5- (3,7, 11-trimethylodeca-2, 6,10-trienyl) cyclohex-2-enone) (Compound 1). After analysis, the molecular formula of the compound 1 is C₂₄H₃₈O₄Molecular weight is 390 and melting point is 48-52 ℃. The Nuclear Magnetic Resonance (NMR) analysis values are as follows:

¹H-NMR(CDC1₃)δ(ppm):1.51,1.67,1.71,1.75,1.94,2.03,2.07,2.22,2.25,3.68,4.05,5.07,5.14

¹³C-NMR(CDC1₃)δ(pprn):12.31,16.1,16.12,17.67,25.67,26.44,26.74,27.00,39.71,39.81,40.27,43.34,59.22,60.59,120.97,123.84,124.30,131.32,135.35,135.92,138.05,160.45,197.12

compound 1: 4-hydroxy-2,3-dimethoxy-6-methyl-5- (3,7, 11-trimethyl-2, 6, 10-dodecatriene) -2-cyclohexenone

In animal experiments, rats were fed compound 1 and the metabolite of compound 1 (i.e., compound 6) was obtained from urine samples thereof. The compound 6 is 4-hydroxy-2,3-dimethoxy-6-methyl-5- (3-methyl-2-hexenoic acid) -2-cyclohexenone (4-hydroxy-2,3-dimethoxy-6-methyl-5- (3-methyl-2-heterocyclic) cyclohexen-2-one), the molecular weight is 312, and the molecular formula is C₁₆H₂₄O₆. In addition, the compound 1 is placed in an environment with the temperature higher than 40 ℃ for 6 hours to obtain a compound 4, namely 3,4-dihydroxy-2-methoxy-6-methyl-5- (3,7, 11-trimethyl-2, 6, 10-dodecatriene) -2-cyclohexenone (3,4-dihydroxy-2-methoxy-6-methyl-5- (3,7, 11-trimethylodeca-2, 6, 10-triene 1) cyclohexox-2-enone), the molecular weight of which is 376, and the molecular formula of which is C₂₃H₃₆O₄。

Alternatively, exemplary compounds may be prepared from 4-hydroxy-2, 3-dimethoxy-6-methyl-2, 5-cyclohexenone (4-hydroxy-2,3-dimethoxy-6-methyl-cyclohexa-2, 5-dione) or similar compounds. Likewise, others have

The cyclohexenone compounds of the structure may also be isolated from Antrodia camphorata, or prepared synthetically or semi-synthetically using appropriate starting materials. One skilled in the art can select appropriate conditions to carry out the synthesis of the compound.

Example 2: treatment of STZ-induced diabetes patterns in rats

The effect of treatment of a subject suffering from diabetes with the exemplary cyclohexenone compound 1 was observed in a Sprague-Dawley rat model over a period of 4 weeks. This example describes the results of this experiment.

In the in vivo mode, SD rats were injected via low dose streptozotocin (STZ, 60mg/kg) to establish a rat model for diabetes. The same batch of rats was fed with normal diet (NRC) as a control group (n = 4).

Study groups were: group A: group without treatment for diabetes, n = 6; group B: AopE + STZ + compound 1, n = 4. The control group showed an average of about 100mg/dl of blood glucose before feeding. Group A rats showed an average blood glucose of about 400-500 mg/dl. Group a rats also showed typical symptoms of diabetes, e.g., high glucose in the urine and frequent urination (frequency urination). Group B (treatment group) had the following blood glucose values before meal intake:

ID number	Blood glucose level at week 4	Blood glucose level at week 2
			1	147mg/dl	421mg/dl
2	149mg/dl	330mg/dl
			3	89mg/dl	261mg/dl
4	388mg/dl	484mg/dl

Furthermore, group B rats showed a reduction in diabetic symptoms: small amounts of glucose in urine, small amounts of urine and weight loss.

Example 3: blood glucose control effects of Compound 1 on type 1 diabetic patients

The object of the invention is to evaluate: whether Compound 1 has the effect of reducing the risk of or treating type 1 diabetes. In particular, whether compound 1 contributes to lowering blood glucose; whether compound 1 reduces the development of type 1 diabetes.

Study type: intervention (Interventional).

Research and design:

configuration: random;

target class: safety and drug efficacy studies

An intervention mode: parallel distribution

Blinding (masking): double blind (subject, caregiver, researcher)

Measurement of primary results

To confirm the decreased postprandial glucagon (glucogon) release, the area of the glucagon at 3 hours of the curve (AUC) was evaluated during the 4 hour diet tolerance test (media tolerance test).

Time frame: after 16 weeks of treatment, primary outcome measurements were recorded. Designing a safety issue: there are.

Secondary result measurement

The secondary purpose is as follows: 1. after 16 weeks of treatment with compound 1, a 0.3% reduction in A1c was demonstrated in type 1 diabetic patients. 2. Changes in total insulin amount, basal insulin amount, and single insulin amount were evaluated for compound 1. Time frame: secondary outcome measures were recorded 16 weeks after treatment. Designing a safety issue: is.

Standard of diabetic patients

Suitable for study age: age 18 to 70 (150 subjects)

Suitability for the study of sex: and (4) amphiprotic.

Receiving healthy volunteers: and no.

Standard of merit

Inclusion criteria

Signing an informed consent form before performing any relevant action

Male or female aged 18 to 70 years

Type 1 diabetes mellitus lasts for more than 1 year

Treatment with MDI or CSII therapy for at least 3 months prior to screening visit (screening visit); stable insulin amounts for at least one month

Pramlintide (pramlintide), saxagliptin (saxagliptin), metformin (metformin) or sitagliptin (sitagliptin) were not used one month before filing

A1c7.5-10%

Willingness to fix at least 2 to 4 blood glucose measurements per day

BMI≤35kg/m2

Ability and willingness to follow a protocol including daily oral dosage of study drug or placebo (placebo), and CGM wear for one week

Willingness to complete telephone and outpatient visits

Has the ability to speak, read and write English

Exclusive standard

Using oral, inhaled or premixed insulin

Pregnant persons who did not use the appropriate birth control method or who attempted to become pregnant during the study

In the first 3 months, severe hypoglycemia requires urgent treatment

Use of systemic or inhaled sebo-hormones (corticosterioids)

History of abnormal heme

Diagnosis of anemia

Performing renal transplantation operation, performing dialysis, and calculating creatinine clearance (secretion) of 2.0mg/dl or 50mL/min

Severe retinopathy requiring laser treatment or vitrectomy

History of pancreatic cancer

Large area skin changes/diseases with restrictions on fitting sensors on normal skin

Known to be allergic to adhesives

Known to be allergic to study drugs

Engaging in other investigational study protocols within 30 days prior to enrollment

Any other circumstance determined by the researcher, such as the possibility of rendering the subject unsuitable for the trial, reducing the subject's suitability for the trial, or undermining the effectiveness of informed consent.

The study provides results for patients taking compound 1 for treatment of type 1 diabetes. This result is clinically significant.

Example 4: efficacy and safety of Compound 1 in adult subjects with type 2 diabetes

The purpose of the invention is as follows: subjects with type 2 diabetes were evaluated for safety and efficacy of multiple doses of compound 1, once daily (QD).

Study form: and (4) intervening.

Research and design:

configuration: random;

target class: safety and drug efficacy studies

An intervention mode: parallel distribution

Blind installation: double blind (subject, caregiver, researcher, result evaluator)

Measurement of primary outcome

Glycosylated Hemoglobin (Glycosylated Hemoglobin) is changed from a basic value

Time frame: week 12 or last visit. Designing a safety issue: is free of

Measurement of secondary outcome

The glycosylated hemoglobin is changed from a basal value. Time frame: weeks 4 to 8 or last visit.

Designing a safety issue: none.

Fasting plasma glucose was changed from basal. Time frame: weeks 1,2, 4, 8 and 12 or last visit. Designing a safety issue: none.

Body weight was changed from basal values. Time frame: weeks 4, 8 and 12 or last visit. Designing a safety issue: none.

During the treatment period, the number of patients with elevated conditions in which alanine aminotransferase (alanine aminotransferase) is 3 times greater than the upper limit of normal values. Time frame: week 12 or last visit; designing a safety issue: none.

Blood concentration of the compound obtained by a sparse sampling population method (sparse sampling population approximately). Time frame: week 12 or last visit; designing a safety issue: none.

Standard of diabetic patients

Suitable for study age: age 18 to 80 (300 subjects)

Suitability for the study of sex: and (4) amphiprotic.

Receiving healthy volunteers: and no.

Standard of merit

Inclusion criteria

There were no diagnostic records of type 2 diabetes with chronic use of anti-diabetic therapy, and 8-week diet and exercise.

Diagnostic record of type 2 diabetes with a stable dose of metformin (metformin) as monotherapy for at least 3 months prior to screening.

Including glycosylated hemoglobin between 7.5% and 10.0%.

The fasting C-peptide concentration is greater than or equal to 0.8ng per mL.

Any other stable long-term medications for at least 4 weeks were taken prior to screening.

Body mass index at screening greater than or equal to 23kg/m2 and less than 45kg/m2

The ability and willingness of a home blood glucose meter to monitor his or her own blood glucose concentration.

Screening throughout the study period, sexually viable women with fertility potential must agree to use an appropriate method of contraception and not be pregnant nor lactating.

Single-blind study medication (single-blind medical) was performed by researchers during the run-in phase with a compliance of at least 75% and no more than 125% based on the number of tablets.

Exclusive standard

In repeated measurements, the systolic pressure is greater than 160mm Hg or the diastolic pressure is greater than 100mm Hg.

Prior to screening, any history of bladder cancer or a history of cancer with remission over five years (a history of basal cell carcinoma or squamous cell carcinoma of the skin of stage 1 was allowed).

Glycosylated hemoglobin is less than 7.5% and greater than 10.0%.

In the screening, Creatine phosphokinase (Creatine phosphokinase) was greater than or equal to 5 times the upper limit of normal.

Hemoglobin is less than or equal to 12g per dL for men and less than or equal to 10g per dL for women.

Alanine aminotransferase and aspartate aminotransferase are greater than or equal to 2.5 times the upper limit of normal.

In the screening, the total bilirubin is greater than or equal to 1.5 times the upper limit of the normal value.

The serum triglyceride concentration is greater than or equal to 400mg per dL.

Glomerular filtration rate was estimated to be less than or equal to 60mL per minute using dietary modification with the renal disease equation or the Cockroft-Gault equation.

Abnormal thyroid stimulating hormones are defined in central laboratory lines (Central laboratory norms).

The test results for hepatitis B surface antigen or hepatitis C antibody were positive.

At the time of screening, the ratio of urinary albumin (Urine albumin) to creatinine was greater than or equal to 1000. mu.g per mg.

Microscopic or macroscopic history of hematuria.

Two consecutive unexplained positive dip-stick (dip-stick) urine analysis results and greater than or equal to 3 red blood cells per high performance area in two consecutive measurements.

There were laser treatment records for proliferative retinopathy of diabetes within 6 months prior to screening.

From the observer's point of view, diabetic gastroparesis is moderate or severe, and thus may reduce the absorption of study drugs.

The subject has Heart failure of New York Heart Association type III or IV.

Coronary angioplasty, coronary stenting, coronary bridging, myocardial infarction, unstable angina, clinically significant abnormalities in the electrocardiogram, cerebrovascular accident, or end-station hypoxic episodes have occurred within 6 months prior to screening.

Any records of heme abnormalities that may affect the glycosylated hemoglobin assay.

Treatment with probucol (probucol) was randomized over 1 year.

Donated or received any blood product within 12 weeks prior to screening.

Treatment was received for more than 7 days and within 8 weeks before random or required or continuous administration of any unallowable drugs, prescription drugs, herbal treatments or over-the-counter drugs that might interfere with the study drug assessment, including:

oral or systemic injection of glucocorticosteroids

Weight loss medicine for prescription or non-prescription

Peroxisome proliferator-activated receptor promoters (Peroxisome proliferator-activator agonists) including fibric acid derivatives

Nicotinic acid (Niacin)

Ezetimibe (Ezetemibe)

Bile acid binders (double-acid binding agents)

Rodenticide (warfarin)

Phenytoin (phenytoin)

Any variation of lipid lowering drugs (varying dose or drug)

Long-term treatment with insulin.

Any study drug was received within 4 weeks prior to screening.

Record of infection with hepatitis B, hepatitis C or human immunodeficiency virus.

Exhibit excessive sensitivity to compound 1 or its excipients.

Drug abuse or alcohol abuse notes within 2 years prior to screening.

Any physical or mental illness, or a condition that a researcher judges may affect life expectancy or may make it difficult to successfully manage and pay close attention to the subject according to the protocol.

The study provides results for patients taking compound 1 for the treatment of type 2 diabetes. These results are clinically significant.

Example 5: medicine form for intestinal tract external administration

100mg of the compound of the present invention or a salt thereof is dissolved in DMSO and then mixed with 10mL of 0.9% sterile physiological saline to prepare a pharmaceutical composition suitable for parenteral injection administration. The mixture is packaged in a dosage unit form suitable for administration by injection.

Example 6: oral dosage form

Exemplary compound 1, 100mg, was mixed with corn oil, 100mg, to prepare a pharmaceutical composition for oral administration. The mixture is packaged in capsules in the form of an oral dosage unit suitable for oral administration.

In some examples, 100mg of a compound of the invention is mixed with 750mg of starch and the mixture is packaged in an oral dosage unit, such as a hard gelatin capsule suitable for oral administration.

Example 7: sublingual (hard lozenge) dosage forms

100mg of a compound of the present invention was mixed with 420mg of powdered sugar, and then mixed with 1.6mL of corn syrup, 2.4mL of distilled water, and 0.42mL of peppermint extract to prepare a pharmaceutical composition (e.g., a hard lozenge) for buccal administration. The mixture is then carefully milled and the milled mixture is poured into a mold to form a tablet suitable for buccal administration.

Example 8: inhalation composition

20mg of the compound described in the present invention was mixed with 50mg of anhydrous citric acid and 100mL of 0.9% sodium chloride solution to prepare an inhalable pharmaceutical composition. The mixture is incorporated into an inhalation unit (e.g., a spray suitable for inhalation administration).

While preferred embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Various changes, modifications, and substitutions will occur to those skilled in the art without departing from the scope of the invention. In addition, various modifications to the embodiments of the present invention should be construed to implement the present invention. In addition, the scope of the claims of the present application should be determined only by the language of the claims, and all methods and structures described in the language of the claims of the present application and all equivalents thereof should be understood to be encompassed by the present invention.

Claims

1. Use of a compound for the preparation of a composition for the treatment of diabetes comprising: administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, having the structure:

wherein each X and Y is independentlyIs immediately oxygen and NR₅Or sulfur;

r is hydrogen or C (= O) C₁-C₈An alkyl group;

each R₁、R₂And R₃Each independently of the other is hydrogen, methyl or (CH)₂)_m-CH₃；

R₄Is NR₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆Halogen, 5-or 6-membered ring lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl or glucosyl; wherein, 5 or 6 membered cyclic lactone, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl and glucosyl are optionally substituted with one or more groups selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl and C₁-C₈Substituted with a substituent of haloalkyl;

each R₅And R₆Each independently is hydrogen or C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

2. The use of claim 1, wherein the method inhibits an increase in blood glucose level in the subject.

3. The use of claim 2, wherein the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes.

4. The use of claim 1, wherein the compound inhibits an increase in blood glucose level in the subject.

5. Use of a compound for the preparation of a composition for inhibiting an increase in blood glucose level (blood sugar level) in a subject, comprising: administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof, to a subject affected by a disease caused by hyperglycemia, glucose intolerance or abnormal glucose, wherein the compound has the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen or C (= O) C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

6. The use of claim 5, wherein the disease due to hyperglycemia, or glucose intolerance or abnormal glucose is diabetes or diabetic complications comprising: diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic lethargy, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic diarrhea, diabetic microangiopathy, diabetic uterine sclerosis, diabetic heart disease, diabetic neuropathy, diabetic nephropathy, diabetic bullous disease, diabetic cataract, diabetic skin disease, diabetic scleropathy, diabetic retinopathy, O-bird disease or diabetic blood circulation disorder.

7. The use according to claim 5, wherein the disease due to hyperglycemia, glucose intolerance or abnormal glucose is type 1, type 2 or gestational diabetes mellitus or a complication thereof.

8. Use of a compound for the manufacture of a composition for treating or reducing the risk of a disease in a subject caused by hyperglycemia, glucose intolerance or abnormal glucose, comprising: administering to a subject affected by the disease a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof, having the structure:

wherein each X and Y is independently oxygen, NR₅Or sulfur;

r is hydrogen or C (= O) C₁-C₈An alkyl group;

each R₅And R₆Each independently is hydrogen or C₁-C₈An alkyl group;

R₇is C₁-C₈Alkyl, OR₅Or NR₅R₆；

m is 1 to 12; and

n is 1 to 12.

9. The use of claim 8, wherein the disease due to hyperglycemia, glucose intolerance or abnormal glucose is diabetes or diabetic complications comprising: diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic lethargy, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic diarrhea, diabetic microangiopathy, diabetic uterine sclerosis, diabetic heart disease, diabetic neuropathy, diabetic nephropathy, diabetic bullous disease, diabetic cataract, diabetic skin disease, diabetic scleropathy, diabetic retinopathy, O-bird disease or diabetic blood circulation disorder.

10. The use according to claim 8, wherein the disease due to hyperglycemia, glucose intolerance or abnormal glucose is type 1, type 2 or gestational diabetes mellitus or a complication thereof.

11. The use of claim 8, wherein the compound inhibits an increase in blood glucose level in the subject.

12. The use of claim 1, wherein the compound or pharmaceutically acceptable salt thereof, metabolite thereof, solvate thereof or prodrug thereof is administered orally, parenterally, intravenously or by injection.

13. The use of claim 1, wherein the subject is a human.

14. The use according to claim 1, wherein R is hydrogen, C (= O) C₃-C₈、C(=O)C₂H₅Or C (= O) CH₃。

15. The use of claim 1, wherein each R is₁、R₂And R₃Each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.

16. The use of claim 15, wherein R₁Is hydrogen or methyl.

17. The use of claim 15, wherein R₂Is hydrogen or methyl.

18. The use of claim 1, wherein R₄Is C₁-C₈Alkyl, optionally substituted with one or more groups selected from the group consisting of: NR (nitrogen to noise ratio)₅R₆、OR₅、OC(=O)R₇、C(=O)OR₅、C(=O)R₅、C(=O)NR₅R₆、C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₈Cycloalkyl and C₁-C₈Substituted by a substituent of haloalkyl.

19. The use of claim 18, wherein R₄Is CH₂CH=C(CH₃)₂。

20. The use as claimed in claim 1, wherein the compound is