CN1690057B - Selenophen derivatives and their use for prevention and/or treatment of diseases relative to protein aging - Google Patents
Selenophen derivatives and their use for prevention and/or treatment of diseases relative to protein aging Download PDFInfo
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- CN1690057B CN1690057B CN200410034011A CN200410034011A CN1690057B CN 1690057 B CN1690057 B CN 1690057B CN 200410034011 A CN200410034011 A CN 200410034011A CN 200410034011 A CN200410034011 A CN 200410034011A CN 1690057 B CN1690057 B CN 1690057B
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- selenophen
- ethyl
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- 230000002265 prevention Effects 0.000 title claims 2
- 230000032683 aging Effects 0.000 title 1
- 201000010099 disease Diseases 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 102000004169 proteins and genes Human genes 0.000 title 1
- 108090000623 proteins and genes Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 29
- 150000003839 salts Chemical class 0.000 claims abstract 4
- 208000019693 Lung disease Diseases 0.000 claims abstract 3
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract 3
- -1 phenol compound Chemical class 0.000 claims abstract 3
- 208000002177 Cataract Diseases 0.000 claims abstract 2
- 206010020772 Hypertension Diseases 0.000 claims abstract 2
- 206010038687 Respiratory distress Diseases 0.000 claims abstract 2
- 210000004072 lung Anatomy 0.000 claims abstract 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract 2
- 230000000391 smoking effect Effects 0.000 claims abstract 2
- 230000037303 wrinkles Effects 0.000 claims abstract 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 8
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 6
- 238000000034 method Methods 0.000 claims 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 5
- 150000008065 acid anhydrides Chemical class 0.000 claims 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
- 229910052736 halogen Inorganic materials 0.000 claims 4
- 230000002140 halogenating effect Effects 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 238000002360 preparation method Methods 0.000 claims 3
- 239000000047 product Substances 0.000 claims 3
- 230000036344 tooth staining Effects 0.000 claims 3
- ULOCHOLAPFZTGB-UHFFFAOYSA-N 1,3-benzothiazol-3-ium;bromide Chemical compound [Br-].C1=CC=C2SC=[NH+]C2=C1 ULOCHOLAPFZTGB-UHFFFAOYSA-N 0.000 claims 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 2
- 229960003328 benzoyl peroxide Drugs 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical group [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims 2
- 230000006378 damage Effects 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 238000005984 hydrogenation reaction Methods 0.000 claims 2
- 150000002460 imidazoles Chemical class 0.000 claims 2
- 239000004615 ingredient Substances 0.000 claims 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- 239000011259 mixed solution Substances 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 108010005094 Advanced Glycation End Products Proteins 0.000 claims 1
- 206010003210 Arteriosclerosis Diseases 0.000 claims 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- 206010061481 Renal injury Diseases 0.000 claims 1
- 208000017442 Retinal disease Diseases 0.000 claims 1
- 206010038923 Retinopathy Diseases 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- 208000011775 arteriosclerosis disease Diseases 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 210000004204 blood vessel Anatomy 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000005336 cracking Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 208000014674 injury Diseases 0.000 claims 1
- 208000037806 kidney injury Diseases 0.000 claims 1
- 210000000214 mouth Anatomy 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 208000033808 peripheral neuropathy Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000012313 reversal agent Substances 0.000 claims 1
- 230000037394 skin elasticity Effects 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract 2
- 230000007170 pathology Effects 0.000 abstract 2
- 206010002482 Angiosclerosis Diseases 0.000 abstract 1
- 102000004877 Insulin Human genes 0.000 abstract 1
- 108090001061 Insulin Proteins 0.000 abstract 1
- 235000021120 animal protein Nutrition 0.000 abstract 1
- 235000013339 cereals Nutrition 0.000 abstract 1
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940125396 insulin Drugs 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 210000000578 peripheral nerve Anatomy 0.000 abstract 1
- 235000021118 plant-derived protein Nutrition 0.000 abstract 1
- 210000001525 retina Anatomy 0.000 abstract 1
- 150000003346 selenoethers Chemical class 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
The invention relates to the selenide and phenol compound provided with general formula I, and its geometric isomer, and acceptable salt in pharmacy, and the definition of each group in the formula isfollowing the patent guidebook; the invention also relates to the method for producing compound in formula I, medicinal compound provided with such compounds and such compounds are used for: a. increasing the elasticity of skin or decreasing the wrinkle of skin, to preventing or treating non-insulin dependency diabetes, the complication of diabetes, complication impair, vessel impair or preventing or treating angiosclerosis, hypertension, retina pathology, crystallin impair, cataract, peripheral nerve pathology, lung AGEs formed by smoking, which arised to lung diseases such as pulmonary fibrosis, respiratory distress, ostarthritis; b. the medicine for preventing or converting the bedye of teeth in mouth ostarthritis; c. keeping fresh for all kinds of grain, plant, and animal protein.
Description
Technical field
The present invention relates to new selenophen analog derivative, its geometrical isomer and pharmacy acceptable salt thereof, their preparation method, contain their medicinal compositions.The invention still further relates to described compound and be used for (i) increase skin elasticity or reduce wrinkle of skin, prevent or treat (ii) non insulin dependent diabetes; The (iii) complication of diabetes; (iv) kidney injury; (v) blood vessel injury or prevention or the treatment arteriosclerosis; (vi) hypertension; (vii) retinopathy; (viii) crystallin damage; (ix) cataract; (x) peripheral neuropathy; Pulmonary disorders such as (xi) formation of the lung AGEs that causes of smoking, and consequent pulmonary fibrosis, respiratory distress; (xii) osteoarthritis; Perhaps be used for the purposes that oral local administration is used to prevent or reverse tooth staining; The fresh-keeping purposes that perhaps is used for various foodstuff products plants or animal proteinum.
Background technology
There is reaction between known sugars and the albumen, as far back as 1912, Maillard finds glucose and other reducing sugars and amino acid reaction, formed stable brown pigment through a series of dehydrogenation rearrangement, discover that further storage and heat food also can produce this pigment that is formed by sugar and polypeptide, the formation of corresponding this pigment has reduced proteic biological activity, and relevant application patent can be with reference to using patent U.S.08/588249.The reducing sugar of this non-enzymatic catalysis and the reaction of free amino acid can form a kind of stable by product that contains diketo, are exactly known Amadori product.Particularly the β side chain residue of protoheme surface amino groups acid and glucose response generate protoheme A1c.Such reaction also can take place in other albumen in the body, such as lens, and collagen protein and neuroprotein.(Advanced Glycation; Chemistry, Bilolgy, andImplications for Diabetes and Aging, Advances in Pharmacology, Vol.23, pp.1-34 Academic Press 1992) above-mentioned being reflected at can quicken under the situation that the diabetes glucose level increases to take place, and also above-mentioned reaction can take place under the euglycemia state.The formation of aging course and lipofuscin simultaneously is closely related, and same collagen protein wears out and can simulate with sugar and collagen protein external.The collagen product of glucose induction has been caused the crosslinking reaction between the albumen like this by other albumen capture reactions.This glucose induction crosslinking reaction produced is exactly advanced glycation end products (advanced glycation endproducts, AGEs), known AGEs is relevant with the complication of diabetes, normal aging course also causes the increase of AGEs, thereby intravital AGEs is not only because its unusual pathological chemistry structure but also can be caused the pathological change that complicated diabetes are relevant with aging by some specific acceptors identification.
The methods of treatment that some accumulation aspects by stoping AGEs have been arranged at present.One of them method sees U.S.4758583, its guide's thing aminoguanidine and analogue thereof can stop the formation of AGEs, thereby be AGEs by having stoped glycation product further to be transformed, also stoped AGEs simultaneously and organized further crosslinked with early stage glycation product reaction.The validity of this method is estimated on the animal model of diabetes and aging rat, also comprises as great vessels other indexs of kidney and europathology aspect simultaneously.People such as Vlassara sum up these data.(Vlassara?et?al，1994?Biology?of?Diseases.“Pathogenic?effects?of?advanced glycation：biochemical，biologic?andclinical?implications?for?diabetes?and?aging”Laboratory?Investigation70：138-151；Brownlee，1995，“The?pathological?implications?of?proteinglycation”Clin.Invest.Med.，18：275-281；and?Brownlee，1995，“Advanced?protein?glycation?in?diabetes?and?aging，”Ann.Rev.Med.46：223-34.)
The another kind of method of controlling AGEs in the tissue has particularly formed in tissue and the method for cumulative AGEs cross-linking products (these cross-linking products cause clinical or subclinical pathological change) is the AGEs cross-linking products that reverse or cracking have formed.People such as Vassan prove that the method for this cracking AGEs is effective.(vassan et al Nature.1996 Vol382 (18) 275-278) is at United States Patent (USP) U.S.5656261 and use the chemical entities of announcing in the patent 08/588249 and 08/848776, the AGEs crosslinking structure that preparation, method can be have in vivo formed with external cracking.Studies show that the cardiovascular disorder that this compounds causes for aging has good effect.(Wolffenbuttel et al., 1998, " Breakers ofAdvanced Glycation End Products Restores Large Artery Properitesin Experimental Diabetes " Proc.Nat.Acad.Sci.U.S.A.95:4630-4634) diabetes rat in 9 weeks has given to reverse in AGEs cracking agent 1-3 week because the Aorta sclerosis that diabetes cause in these researchs.The parameter of improving has cardiac output, Peripheral resistance, body arterial compliance, aorta input resistance, and carotid artery conformability.(U.S.6319934)
Summary of the invention
The objective of the invention is to seek and developmental function in the small molecules cracking agent of AGEs, thereby being used for the AGEs that cracking formed stops protein-crosslinking, to crosslinked protein cleavage, thereby promote proteic metabolism, thus further improve since AGEs in vivo increase the various pathological changes that cause.The present invention has been found that the compound of general formula I can be used for the treatment of and/or prevent the multiple disease that is caused by protein glycosylation.It is used for (i) increases skin elasticity or reduces wrinkle of skin, prevents or treat (ii) non insulin dependent diabetes; The (iii) complication of diabetes; (iv) kidney injury; (v) blood vessel injury or prevention or the treatment arteriosclerosis; (vi) hypertension; (vii) retinopathy; (viii) crystallin damage; (ix) cataract; (x) peripheral neuropathy; Pulmonary disorders such as (xi) formation of the lung AGEs that causes of smoking, and consequent pulmonary fibrosis, respiratory distress; (xii) osteoarthritis; Perhaps be used for the purposes that oral local administration is used to prevent or reverse tooth staining; The fresh-keeping purposes that perhaps is used for various food plants or animal proteinum.
The present invention relates to compound, its geometrical isomer or its pharmaceutically useful salt or the hydrate of formula I,
Wherein:
X independently is selected from hydrogen; C
1～C
8The straight or branched alkyl; C
2～C
8The straight or branched thiazolinyl
Y is O, perhaps S,
R
1Independently be selected from hydrogen; Perhaps be selected from 1～3 group: C in following a group
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, perfluor C
1-6Alkyl, carboxylic acid amides, carboxamide groups C
1-6Alkyl, nitro, carboxylic C
1-6Alkyl, C
1-6Carbalkoxy, C
1-6Carbalkoxy C
1-6Alkyl, C
1-6Alkyl, C
1-6Alkane sulfydryl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, sulfamyl, amidino groups, two C
1-6Alkylamino, C
1-6Alkylamino, C
1-6Alkylamino C
1-6Alkyl, aryl amine, oxygen, halogen, amino, hydroxyl, sulfydryl, cyano group, thiocyanogen, selenium cyano group, trifluoromethyl, trifluoromethoxy,
R
2Independently be selected from the heteroaryl that contains 5～14 atoms, contain 1 nitrogen-atoms in the heteroaryl at least, comprise 1～6 in the heteroaryl and be selected from following heteroatoms: O, S, N; Described heteroaryl can not be substituted or is selected from following substituting group by 1～3 and replaces: C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkyl, perfluor C
1-6Alkyl, carboxylic acid amides, carboxamide groups C
1-6Alkyl, nitro, carboxylic C
1-6Alkyl, C
1-6Carbalkoxy, C
1-6Carbalkoxy C
1-6Alkyl, C
1-6Alkyl, C
1-6Alkane sulfydryl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, sulfamyl, amidino groups, two C
1-6Alkylamino, C
1-6Alkylamino, C
1-6Alkylamino C
1-6Alkyl, aryl amine, oxygen, halogen, amino, hydroxyl, sulfydryl, cyano group, thiocyanogen, selenium cyano group, trifluoromethyl, trifluoromethoxy,
Z
-Be pharmaceutically acceptable halogen ion or acid group.
According to a preferred embodiment of the invention, the present invention relates to pharmaceutically available salt of the compound, its geometrical isomer of general formula I or its:
Wherein:
X independently is selected from hydrogen; Methyl; Ethyl or propyl group,
Y is O, perhaps S,
R
1Independently be selected from hydrogen; Perhaps be selected from 1～3 group in following a group: oxygen, methoxyl group, halogen, amino, hydroxyl, sulfydryl, cyano group, thiocyanogen, selenium cyano group, trifluoromethyl, trifluoromethoxy,
R
2Independently be selected from thiazole, benzothiazole, hydrogenation benzothiazole, imidazoles, benzoglyoxaline, hydrogenated benzimidazoles, oxazole; Described heterocycle can not be substituted or is selected from following substituting group by 1～3 and replaces: C
1～C
4Alkyl, C
1～C
4Alkoxyl group, C
1～C
4Hydroxyalkyl, C
1～C
6Alkoxyalkyl, C
1～C
6Carbalkoxy, C
1～C
8Alkoxycarbonyl alkyl, oxygen, halogen, amino, hydroxyl, sulfydryl, cyano group, thiocyanogen, selenium cyano group, trifluoromethyl, trifluoromethoxy,
Z
-Be pharmaceutically acceptable halogen ion or acid group, as F
-, Cl
-, Br
-, I
-, perhaps methanesulfonate, tosic acid root.
Formula I compound of the present invention, its geometrical isomer or its pharmacy acceptable salt be the compound in the table 1 preferably, but these compounds and do not mean that any limitation of the invention.
Preferred compound in the table 1. formula I selenophen compounds
The preferred compound of the present invention is:
3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-4,5,6,7-tetrahydro benzothiazol drone bromide
5-(2-acetoxyl group-ethyl)-4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
3-methyl isophthalic acid-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-3H-imidazoles drone bromide.
The present invention relates to the method for the compound, its geometrical isomer or its pharmacy acceptable salt that prepare general formula I on the other hand, and it comprises the replacement selenophen analog derivative with formula II
R wherein
1Definition with Chinese style I compound of the present invention
With the acid anhydrides of tool formula III, under the mixed liquid existence condition of formula III and acid composition, react,
Wherein X and Y are with the definition of Chinese style I compound of the present invention
Obtain formula V compound
R wherein
1, X and Y be with the definition of Chinese style I compound of the present invention,
The compound of formula V is carried out halogenating reaction to be generated and obtains formula VI compound
R wherein
1, X and Y are with the definition of Chinese style I compound of the present invention; A is a leavings group, is selected from F, Cl, Br or I,
Compound and R with formula VI
2Reaction generates and obtains formula I compound
R wherein
1, R2, X, Y and Z are with the definition of Chinese style I compound of the present invention.
The present invention further represents reaction scheme 1 with reaction scheme 1 about the method for preparation I compound
R wherein
1, R
2, X, Y, Z definition cotype I compound; A is a leavings group, comprises F, Cl, Br, I.
In reaction scheme 1, comprise step 1:
In step 1, formula III and acid are mixed placement according to a certain percentage as phosphoric acid or sulfuric acid, mixed ratio optimum mole ratio is a formula III: sour as phosphoric acid or sulfuric acid=4.5～5.8: 1.Formula II compound and formula III is mixed according to 1: 1～3 mol ratio, at room temperature stir, drip a certain amount of formula III compound and sour mixture then, drip and finish, room temperature reaction 1h is warmed up to 70～80 ℃ of reaction 4h then.Reaction finishes, and adds a certain amount of water in reaction solution, uses ethyl acetate extraction again, ester layer anhydrous sodium sulfate drying.The filtering siccative obtains ester layer evaporated under reduced pressure the crude product of formula V compound.The crude product method purifying of silica gel column chromatography, employed here silica gel is conventional silica gel for chromatography, granularity 10～40u, perhaps 100-200 order or 200-300 order.Eluent is formulated by single or multiple solvent, preferably presses the mixed solvent of different ratios (as 1: 5-1: 20, volume ratio) preparation by ethyl acetate and sherwood oil (30-60 ℃ of sherwood oil or 60-90 ℃ of sherwood oil) or with hexanaphthene.Obtain The compounds of this invention V behind the purifying;
Step 2:
In step 2, with formula V compound and liquid bromine or cupric bromide (CuBr
2) reaction, cupric bromide (CuBr most preferably here
2) reaction, the ingredient proportion of reaction is 1: 1～3, and the best is 1: 2, and reflux is 4 hours to 24 hours under the condition that with organic solvent such as ethyl acetate or chloroform is solvent.Reaction finishes, the filtering insolubles, and filtrate is used the saturated aqueous common salt thorough washing, tells organic layer, the organic layer anhydrous sodium sulfate drying.Filtration obtains organic layer such as ester layer, and evaporated under reduced pressure obtains crude product.The crude product method purifying of silica gel column chromatography, employed here silica gel is conventional silica gel for chromatography, granularity 10～40u, perhaps 100-200 order or 200-300 order.Eluent is formulated by single or multiple solvent, preferably presses the mixed solvent of different ratios (as 1: 8-15, volume ratio) preparation by ethyl acetate and sherwood oil (30-60 ℃ of sherwood oil or 60-90 ℃ of sherwood oil) or with hexanaphthene.Obtain The compounds of this invention VI behind the purifying;
Step 3:
In step 3, with formula VI compound and R
2, R
2With Chinese style I compound of the present invention, in dipole solvent, comprise protonated solvent, as: C
2～C
3Alcohol; With non-protonization solvent, as: N-crassitude diketone, N, dinethylformamide, dimethyl amine, methyl-sulphoxide and acetonitrile are preferably acetonitrile here.Reacting by heating under 80 ℃～82 ℃ condition, 1 hour to 96 hours reaction times.Reaction finishes, and cool to room temperature filters and obtains solid.The method of solid purifying comprises following two kinds:
Method 1: with the method purifying of silica gel column chromatography, employed here silica gel is conventional silica gel for chromatography, granularity 10～40u, perhaps 100-200 order or 200-300 order.Eluent is formulated by single or multiple solvent, preferably presses the mixed solvent of different ratios (1: 5-1: 20, volume ratio) preparation by methyl alcohol and sherwood oil (30-60 ℃ of sherwood oil or 60-90 ℃ of sherwood oil) or with hexanaphthene.Obtain The compounds of this invention I behind the purifying.
Method 2: crude product C
1～C
3Pure and mild C
3～C
5The mixed solvent recrystallization formed according to a certain percentage of ester, mixed ratio is 2: 5～100: 1, is preferably 5: 2.
As required, resulting compound can adopt suitable salt to change another kind of salt into.
Further aspect of the present invention relates to pharmaceutical composition, and it comprises at least a general formula I selenophen compounds or its geometrical isomer or its pharmacy acceptable salt and pharmaceutical carrier or vehicle.
Medicinal compositions among the present invention can prepare by methods known in the art, as with formula I selenophen compounds, geometrical isomer or its pharmacy acceptable salt and pharmaceutical carrier or mixed with excipients.
Further aspect of the present invention relates at least a formula I selenophen compounds, geometrical isomer or its pharmacy acceptable salt are used to prevent and/or treat the product of the various diseases that protein glycosylation causes in preparation purposes.
The invention still further relates to the method that prevents and/or treats the aging various diseases that is caused of protein glycosylation, it comprises that at least a formula I selenophen compounds, geometrical isomer or its pharmacy acceptable salt that will prevent and/or treat significant quantity give to prevent and/or treat the patient of the aging various diseases that is caused of protein glycosylation.
The glycosylated protein that the present invention mentioned is including, but not limited to human body protein, and it also comprises plant or animal organ's albumen in the food, thereby compound disclosed by the invention or its composition can be used for fresh-keeping purposes.
According to the present invention, the pharmacologically acceptable salt of The compounds of this invention comprises its inorganic salt or organic salt, and wherein salt includes but not limited to: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, oxalate, pivalate, adipate, alginate, lactic acid salt, Citrate trianion, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and embonate.
According to the present invention, used formula II compound among the present invention, formula III compound and R
2The compound that maybe can obtain by means known in the art for known compound.
Medicinal compositions involved in the present invention is to be used for the treatment of usefulness in vivo, and has biocompatibility.Medicinal compositions is meant the preparation of effective therapeutic dose that the present invention is mentioned or contains the acceptable pharmaceutical carrier of The compounds of this invention that the selection of pharmaceutical carrier is according to purposes involved in the present invention and used specific product formulation or form.This medicinal compositions can be prepared into various forms according to the different dosing method.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
According to the present invention, medicinal compositions of the present invention comprises formula I selenophen compounds of the present invention, geometrical isomer or its pharmacy acceptable salt and one or more suitable pharmaceutically acceptable carrier of effective dose.The pharmaceutical carrier here includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The compounds of this invention is the potent crosslinking protein cracking agent of a class, and the present invention has been found that the compound of general formula I can be used for the treatment of and/or prevent the multiple disease that is caused by protein glycosylation.The compounds of this invention can be used for but be not limited to (i) increasing skin elasticity or reducing wrinkle of skin, prevents or treat (ii) non insulin dependent diabetes; The (iii) complication of diabetes; (iv) kidney injury; (v) blood vessel injury or prevention or the treatment arteriosclerosis; (vi) hypertension; (vii) retinopathy; (viii) crystallin damage; (ix) cataract; (x) peripheral neuropathy; Pulmonary disorders such as (xi) formation of the lung AGEs that causes of smoking, and consequent pulmonary fibrosis, respiratory distress; (xii) osteoarthritis; The fresh-keeping purposes that perhaps is used for various food plants or animal proteinum.
The present invention can expanded application in stoping or reversing because the tooth staining that the non-enzymatic glycosylation in the oral cavity causes.The therapeutic regimen that contains compound of the present invention can change according to mentioned purposes.
The non-enzymatic reaction that occurs in the oral cavity can cause tooth staining.At present employed anti-moth erosion agent can be quickened this carbonylation reaction and further cause the painted of tooth.The cationic germicide that a nearest class has anti-moth erosion function is used for the cleaning of conventional oral cavity.These cationic antibacterial agent have the A Laixi fourth, cetyl pyridinium oxymuriate or the like.And these preparations can quicken a step Maillard reaction crucial in the glycosylation, and then painted (Nordbo, J.Dent.Res., the 58:1429 (1979)) of acceleration tooth.And be reported in that observation in vitro has arrived Tubulicid and benzalkonium chloride can catalysis glycosylation (brownization reaction).Because the Maillard reaction, Tubulicid adds the formation of having quickened pigment in sugar and the amino acid whose mixture.
For these reasons, compound involved in the present invention and medicinal compositions thereof can be used for the oral cavity.Especially for the additive in oral cavity scavenging solution and the toothpaste.
In the such use of relevant compound of the present invention, nontoxic and pharmaceutically acceptable carrier can adopt easily that form is applied in Jiekouye gargle and the toothpaste.
According to the present invention, the medicinal array configuration of compound of the present invention can be used with following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer is as subcutaneous, vein, intramuscular, intraperitoneal, in the sheath, in the ventricle, breastbone interior and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenously application method.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, including, but not limited to tablet, and capsule, the aqueous solution or aqeous suspension.Wherein, the general carrier that uses of tablet comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The general thinner that uses of capsule preparations comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents in the above oral preparations form, perfume compound or tinting material.
When local medication, particularly treat local external application easy to reach and suffer from face or organ, as eyes, when skin or lower intestinal tract nervous system disease, compound of the present invention can be made different local application's dosage forms according to different trouble faces or organ, specifies as follows:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also compound can be made paste form such as vaseline paste in addition.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, and wherein activeconstituents suspends or is dissolved in one or more carriers.Here the spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension, or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, The compounds of this invention is decided by all multifactor at different patients' specific using dosage and using method, comprise patient's age, body weight, sex, the natural health situation, nutritional status, the activity intensity of compound, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor judge.Here using dosage is between 0.01～100mg/kg body weight/day, wherein generally at 1mg/kg-30mg/kg.
Embodiment
The present invention can obtain explanation by the following examples, but these embodiment do not constitute any limitation the present invention.
Melting point compound is measured by SRY-1 type fusing point instrument, and temperature is not calibrated.
1HNMR spectrum is measured by Bruker ARX 400 type nuclear magnetic resonance spectrometers, and mass spectrum is measured by the Zabspect high-resolution mass spectrometer.
Embodiment 1:1-selenophen-2-base-ethyl ketone
Get mixed placement of 8.5g diacetyl oxide and 1.7g phosphoric acid and become catalyzer.
Get 2.5g, the diacetyl oxide of the selenophen of 19.1mmol (MW131.04) and 1.06g adds in the round-bottomed flask of 10ml; Stirring at room drips the 1.28g catalyzer then, dropwises, and room temperature reaction 1h is warmed up to 70～80 ℃ of reaction 4h then.Reaction finishes, and adds a certain amount of water in reaction solution, and fully mixed the stirring used the ethyl acetate extraction mixture, ester layer anhydrous sodium sulfate drying again.The filtering siccative obtains ester layer evaporated under reduced pressure the crude product of 1-selenophen-2-base-ethyl ketone.The crude product method purifying of silica gel column chromatography, eluent is an ethyl acetate: sherwood oil=1: 15 obtains weak yellow liquid behind the purifying.Productive rate 97.0%.
1H?NMR(400MHz，CDCl
3)δ＝2.586(s，3H，CH
3)；7.398(q，1H)；7.9121(q，1H)；8.377(dd，1H)
FAB?MS：m/z＝174.04(100)[M
+]
Embodiment 2:2-bromo-1-selenophen-2-base-ethyl ketone
Get the 8.5g cupric bromide, add in the 40ml ethyl acetate, be heated to backflow.2-ethanoyl-2-selenophen that other gets 3.3g (19.0mmol) is dissolved in the 10ml ethyl acetate, joins rapidly in the reaction solution of backflow.Finish, continue at reflux 12h.Reaction finishes, the filtering insolubles, and filtrate is used the saturated aqueous common salt thorough washing, divides the ester output layer, ester layer anhydrous sodium sulfate drying.Filtration obtains the ester layer, and evaporated under reduced pressure obtains crude product.The crude product method purifying of silica gel column chromatography, eluent is an ethyl acetate: sherwood oil=1: 25 obtains weak yellow liquid behind the purifying.Productive rate 91.6%.
1H?NMR(400MHz，CDCl
3)δ＝4.392(s，2H)；7.439(m，1H)；8.030(q，1H)；8.478(dd，1H)
FAB?MS：m/z＝253.0(97)[M
+].
Embodiment 3:1-selenophen-2-base-1-acetone
Get mixed placement of 6.8g propionic anhydride and 0.9g phosphoric acid and become catalyzer.
Get 2.5g, the propionic anhydride of the selenophen of 19.1mmol (MW131.04) and 1.4g adds in the round-bottomed flask of 10ml; Stirring at room drips the 1.6g catalyzer then, dropwises, and room temperature reaction 1h is warmed up to 70～80 ℃ of reaction 4h then.Reaction finishes, and adds a certain amount of water in reaction solution, and fully mixed the stirring used the ethyl acetate extraction mixture, ester layer anhydrous sodium sulfate drying again.The filtering siccative obtains ester layer evaporated under reduced pressure the crude product of 2-propionyl-2-selenophen.The crude product method purifying of silica gel column chromatography, eluent is an ethyl acetate: sherwood oil=1: 15 obtains weak yellow liquid behind the purifying.Productive rate 87.5%.
1H?NMR(400MHz，CDCl
3)δ＝2.728(t，3H，CH
3)；5.398(q，2H，CH
2)；7.438(q，1H)；8.450(dd，1H)；8.593(d，1H)
FAB?MS：m/z＝188.05(100)[M
+]
Embodiment 4:2-bromo-1-selenophen-2-base-1-acetone
Get the 15.1g cupric bromide, add in the 100ml ethyl acetate, be heated to backflow.Other gets 1-selenophen-2-base-1-acetone solution of 6.3g (33.7mmol) in the 20ml ethyl acetate, joins rapidly in the reaction solution of backflow.Finish, continue at reflux 12h.Reaction finishes, the filtering insolubles, and filtrate is used the saturated aqueous common salt thorough washing, divides the ester output layer, ester layer anhydrous sodium sulfate drying.Filtration obtains the ester layer, and evaporated under reduced pressure obtains crude product.The crude product method purifying of silica gel column chromatography, eluent is an ethyl acetate: sherwood oil=1: 25 obtains weak yellow liquid 6.2g behind the purifying.Productive rate 69.0%.
1H?NMR(400MHz，CDCl
3)δ＝1.904(d，3H，J＝6.72Hz)；5.168(q，1H)；7.428(q，1H)；8.069(d，1H)；8.448(d，1H)
FAB?MS：m/z＝266.9(85)[M
+].
Illustrative embodiment 5 can be by the method preparation identical with embodiment 5, just with identical or different reactant VI and reactant R
2Be prepared respectively.Reacting phenomenon is not exclusively the same in different reaction process, and what have promptly generates a large amount of precipitations in reaction is carried out, have after reaction finishes, leave standstill after separate out precipitation.These reactions are filtered and are obtained precipitation, will precipitate with the anhydrous methanol dissolving again, obtain target compound behind the method processing purifying of method with silica gel column chromatography or recrystallization according to embodiment 5.
Embodiment 5:4,5-dimethyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
With 4 of 0.8g, 5-dimethylthiazole (R
2, 0.0071mol) with 2-bromo-1-selenophen-2-base-1-acetone of 2.83g ((VI, 0.011mol) mixed, add the 15ml acetonitrile, reflux 12h under 80 ℃～82 ℃ condition.Reaction finishes, and cool to room temperature filters and obtains solid.The method of solid purifying comprises following two kinds:
Method 1: with the method purifying of silica gel column chromatography, eluent is a methyl alcohol: sherwood oil=1: 10 obtains faint yellow solid 1.54g, productive rate 56.72%, mp 146-147 ℃ behind the purifying.
Method 2: be to obtain faint yellow solid 1.38g, productive rate 51.04%, mp 146-147 ℃ behind 5: 2 the mixed solution recrystallization with ethanol and ethyl acetate ratio.
1H?NMR(400MHz，DMSO-d
6)δ＝1.993(d，3H，J＝7.28)；2.367(s，3H，C
4)；2.530(s，3H，C
5)；6.739(t，J
1＝7.28Hz，J
2＝＝7.00Hz，1H)；7.669(q，1H)；8.703(t，2H)；8.933(t，1H)；10.215(s，1H，C
2)。
FAB MS:m/z=300.1 (100) [M
+], 159.0 (16), 140.1 (7), 114.1 (12), 78.1 (3) ultimate analyses, theoretical value: C
12H
14NOSSeBr (379.18): C, 38.01; H, 3.72; N, 3.69
Measured value: C, 37.89; H, 3.54; N, 3.51
Embodiment 6:4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
Prepare this compound by embodiment 5 methods, just R
2Be the 4-methylthiazol.Product is a white crystals, productive rate 37.25%, mp 192-194 ℃
1H?NMR(400MHz，DMSO-d
6)δ＝2.001(d，J＝7.28，3H)；2.506(s，3H)；6.755(q，J
1＝7.28Hz，J
2＝7.00Hz，1H)；7.665(t，J
1＝4.48Hz，J
2＝5.04Hz，1H)；8.112(s，1H)；8.705(d，J＝3.36Hz，1H)；8.925(d，J＝5.32Hz，1H)；10.381(s，1H，C
2)。
EI?MS：m/z＝286.1(100)[M
+]，223.1(6)，188.1(4)，159.0(10)，131.1(11)，100.1(15)
Ultimate analysis, theoretical value: C
11H
12NOSSeBr (365.15): C, 36.18; H, 3.31; N, 3.84
Measured value: C, 35.97; H, 3.24; N, 3.52
Embodiment 7:5-(2-hydroxyethyl)-4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
Prepare this compound by embodiment 5 methods, just R
2Be 5-(2-hydroxyethyl)-4-methylthiazol.Product is a white crystals, productive rate 39.08%, mp 127-130 ℃
1H NMR (400MHz, DMSO-d
6) δ=1.995 (d, J=7.00,3H); 2.399 (s, 3H); 3.057 (t, J
1=5.32Hz, J
2=5.60Hz, 2H); 3.661 (s, 2H); 5.278 (brs, 1H, OH); 6.765 (q, J
1=7.28Hz, J
2=7.00Hz, 1H); 7.670 (q, J
1=3.92Hz, J
2=4.20Hz, 1H); 8.714 (q, J
1=4.20Hz, J
2=3.09Hz, 1H); 8.928 (d, J=4.32Hz, 1H); 10.268 (s, 1H, C
2).
FAB?MS：m/z＝330.1(100)[M
+]188.1(4)，159.0(10)，144.1(17)，131.1(2)
Ultimate analysis, theoretical value: C
13H
16NO
2SSeBr (409.2): C, 38.16; H, 3.94; N, 3.42
Measured value: C, 37.97; H, 3.65; N, 3.38
Embodiment 8:3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-4,5,6,7-tetrahydro benzothiazol drone bromide
Prepare this compound by embodiment 5 methods, just R
2Be 4,5,6, the 7-tetrahydro benzothiazol.Product is a white crystals, productive rate 22.27%, mp 87-90 ℃
1H?NMR(400MHz，DMSO-d
6)δ＝1.810(m，4H)；1.986(d，J＝7.29，3H)；2.388(d，J＝6.44，1H)；2.925(t，J
1＝16.80，J
2＝17.93，2H)；3.041(d，J＝16.24，1H)；6.718(q，J
1＝6.16Hz，J
2＝7.00Hz，1H)；7.663(q，J＝4.20Hz，1H)；8.7.03(s，1H)；8.928(dd，J＝4.48Hz，1H)；10.280(s，1H，C
2)。
FAB?MS：m/z＝326.1(100)[M
+]，300.1(21)，166.2(6)，159.0(11)，140.1(22)
Ultimate analysis, theoretical value: C
14H
16NOSSeBr (405.21): C, 41.50; H, 3.98; N, 3.46
Measured value: C, 41.79; H, 3.69; N, 3.21
Embodiment 9:5-(2-acetoxyl group-ethyl)-4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
Prepare this compound by embodiment 5 methods, just R
2Be 5-(2-acetoxyl group-ethyl)-4-methylthiazol.Product is faint yellow crystallization, productive rate 53.17%, mp 79-81 ℃
1H?NMR(400MHz，DMSO-d
6)δ＝2.001(d，J＝7.28，3H)；2.026(s，3H)；2.431(s，3H)；3.329(t，2H)；4.229(t，2H)；6.832(q，J
1＝7.29Hz，J
2＝7.00Hz，1H)；)；7.671(t，J
1＝4.48Hz，J
2＝5.04Hz，1H)；8.742(d，J＝3.92，1H)；8.931(d，J＝5.61Hz，1H)；10.339(s，1H，C
2)。FAB?MS：m/z＝372.0(21)[M
+]，159.0(100)，125.0(25)
Ultimate analysis, theoretical value: C
15H
18NO
3SSeBr (451.24): C, 39.93; H, 4.02; N, 3.10
Measured value: C, 39.41; H, 3.97; N, 3.04
HRMS theoretical value C
15H
18NO
3SSe:372.0173 measured value: 372.0036
Embodiment 10:3-methyl isophthalic acid-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-3H-imidazoles drone bromide
Prepare this compound by embodiment 5 methods, just R2 is the 1-Methylimidazole.Product is the faint yellow crystallization of flakey, productive rate 84.91%, mp 67-69 ℃
1H?NMR(400MHz，DMSO-d6)δ＝1.832(d，J＝7.56，3H)；3.912(s，3H)；6.456(q，J＝7.28Hz，1H)；7.632(q，J1＝4.20Hz，J2＝3.92Hz，1H)；7.771(s，1H)；7.893(s，1H)；8.492(d，J＝3.36Hz，1H)；8.868(dd，J1＝0.80Hz，J2＝4.48Hz，1H)；9.358(s，1H，C2)。
FAB?MS：m/z＝269.0(100)[M+]，159.0(4)，109.1(9)，83.1(40)
Embodiment 11:4,5-dimethyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
With the 2-bromo-1-selenophen-2-base-ethyl ketone (0.0088mol) and 4 of 0.5g of 2.23g, 5-dimethylthiazole (0.0042mol) is mixed, adds the 15ml acetonitrile, reflux 8h under 80 ℃～82 ℃ condition.Reaction finishes, and cool to room temperature filters and obtains solid.The method of solid purifying comprises following two kinds:
Method 1: with the method purifying of silica gel column chromatography, eluent is a methyl alcohol: sherwood oil=1: 10 obtains faint yellow solid 0.85g, productive rate 55.19%, mp 146-147 ℃ behind the purifying.
Method 2: with ethanol and ethyl acetate ratio is that 20: 1 mixed solution recrystallization obtains faint yellow crystallization, productive rate 46.75%, mp 195-197 ℃.
1H?NMR(400MHz，DMSO-d
6)δ＝2.327(s，3H，C
4)；2.538(s，3H，C
5)；6.338(s，2H)；)；7.645(q，J
1＝3.92Hz，J
2＝5.32Hz，1H)；8.432(dd，J＝3.08，1H)；8.884(dd，J＝4.68Hz，1H)；9.995(s，1H，C
2)。
FAB?MS：m/z＝286.1(100)[M
+]，145.0(3)，114.1(3)
Ultimate analysis, theoretical value: C
11H
12NOSSeBr (365.15): C, 36.18; H, 3.312; N, 3.84; Br, 21.88
Measured value: C, 36.45; H, 3.21; N, 4.00; Br, 21.95
Embodiment 12:4-methyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
Prepare this compound by embodiment 11 methods, just R
2Be the 4-methylthiazol.Product is a yellow crystal, productive rate 73.42%, mp 220-221 ℃
1H?NMR(400MHz，DMSO-d
6)δ＝2.444(s，3H)；6.347(s，2H)；)；7.648(t，J
1＝5.32Hz，J
2＝3.92Hz，1H)；8.089(s，1H)；8.430(d，J＝3.64Hz，1H)；8.881(d，J＝5.04Hz，1H)；10.126(d，J＝2.53Hz，1H，C
2)。
FAB?MS：m/z＝272.1(100)[M
+]，159.2(5)，145.0(3)，113.1(3)，100.1(7)
Ultimate analysis, theoretical value: C
10H
10NOSSeBr (351.12): C, 34.12; H, 2.87; N, 3.99; Br, 22.76
Measured value: C, 34.45; H, 2.74; N, 3.93; Br, 22.76
Embodiment 13:4-methyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-5-vinyl-thiazole drone bromide
Prepare this compound by embodiment 11 methods, just R
2Be 4-methyl-5-vinyl-thiazole.Brown oil, productive rate 25.61%.
1H?NMR(400MHz，DMSO-d
6)δ＝2.451(s，3H)；5.681(d，J＝10.92，1H)；6.009(d，J＝17.37，1H)；6.349(s，2H)；)；7.081(q，J
1＝11.48Hz，J
2＝10.92Hz，1H)；7.651(s，1H)；8.441(s，1H)；8.880(d，J＝5.76Hz，1H)；10.119(s，1H，C
2)。
FAB?MS：m/z＝298.2(100)
Embodiment 14:5-(2-hydroxyethyl)-4-methyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-thiazole drone bromide
Prepare this compound by embodiment 11 methods, just R
2Be 5-(2-hydroxyethyl)-4-methylthiazol.Product is a yellow crystal, productive rate 60.96%, mp 185-187 ℃
1H?NMR(400MHz，DMSO-d
6)δ＝2.357(s，3H)；3.067(t，J＝5.60Hz，2H)；3.667(t，J＝5.60Hz，2H)；6.334(s，2H)；7.640(q，J
1＝4.92Hz，J
2＝4.82Hz，1H)；)；8.432(dd，J
1＝3.08Hz，J
2＝0.84Hz，1H)；8.880(d，1H)；10.013(s，1H，C
2)。
EI?MS：m/z＝315.99(31)，251.86(21)，181.0(25)，156.9(100)，143.1(30)，131.0(25)，112.0(80)，100.0(7)，
HRMS theoretical value C
12H
14NO
2SSe:315.9910 measured value: 315.9914
The ELISA shaker test of embodiment 15 cracking AGE-BSA-collagen cross-linking structures
With AGE-BSA be coated on crosslinked, the external preparation of rat tail glue protein AGEs crosslinking structure on the 96 hole enzyme plates, employing ELISA method assessing compound is to the crosslinked splitting action of AGEs.
The 96 hole enzyme plate preparations of tail glue primordial covering:
(body weight 200 ± 20g), tail is got in acute execution to normal Wister rat, carries out with lower tail collagen protein preparation process under 4 ℃.At first, extract tail tendon collagen silk, wash and remove non-collagen silk tissue, wash 3 times through distilled water again, shred, be soaked in 4 ℃ of 1 week in 0.1% Glacial acetic acid with physiological saline, during jolt often.Centrifugal with 8000g * 30min at last, collect centrifugal supernatant collagen solution, protein content is measured in the dilution back.With every hole 70 μ g collagen proteins, full hole bag is by 96 hole enzyme plates (Costar), and 4 ℃, 24h abandon coating buffer, air-dry under the aseptic condition, preservative film bag quilt, and 4 ℃ of storages are standby.
The AGE-BSA preparation:
(Roch) 50mg/ml and 0.5M glucose are in 0.2MPBS (PH7.4) for bovine serum albumin BSA (V), and under 37 ℃ of aseptic conditions, lucifuge was hatched 3-4 month, and making it form glycosylation BSA is BSA-AGEs.Simultaneously, the BSA with no glucose prepares sugar based BSA.In 0.01MPBS (pH7.4) dialyzate, dialyse then, remove unreacted glucose, fluorescent scanning (Exi/Em (395/460nm)), and SDS-PAGE identifies that BSA-AGEs forms, and adopts the Lowery method to carry out protein quantification simultaneously.
The analysis determining method flow process:
Tail glue primordial covering 96 orifice plates are expired in the hole and acid collagen 1h with pH7.4 PBS; 37 ℃ of SuperBlock (PIERCE), sealing 1h; PBST (PBS-Tween) washes plate 3 times, vibrates 1 minute at every turn; Dilute AGE-BSA with PBS, add in the capable hole of A, B, C, the D of 96 orifice plates with the AGE-BSA 100 μ l that obtain maximum degree of crosslinking concentration, the BSA of same concentrations adds in the capable hole of E, F, G, H, 1 is listed as PBS in preceding 3 holes, as system and reagent blank, 37 ℃, 4h makes it and collagen cross-linking; PBST washes plate 4 times, and 1min at interval vibrates; Test-compound adopts the pH7.4PBS dilution, gets 100 μ l/ holes and is added on crosslinked and each 4 hole, BSA hole of AGE-BSA respectively, and the same manner adds PBS 100 μ l/ holes and contrasts as non-cracking, hatches 16h for 37 ℃; PBST washes plate 4 times, and 1min at interval vibrates; Add 37 ℃ of the 80 μ l/ hole anti-BSA antibody of rabbit (1: 500), 50min; PBST washes plate 4 times, and 1min at interval vibrates; Add 37 ℃ of 80 μ l/ hole horseradish peroxidase-labeled goat anti-rabbit iggs (1: 1000), 50min; PBST washes plate 3 times, and 1min at interval vibrates; Add substrate solution TMB (3,3 ', 5,5 '-tetramethyl benzidine) 100 μ l/ pore chamber temperature, black out 20min; With 2mol/L H2SO4 termination reaction; In the 10min, under the BOBRAD Model550 plate reading machine 450nm, the OD value is read in the zeroing of plate blank well.
Data analysis:
Average OD value adopts 4 hole mean values.
Proofread and correct the OD mean value in the OD mean value-BSA hole in OD=AGE-BSA hole
Cleavage rate is represented with the percentage that the OD value reduces:
[the OD mean value in (the OD mean value in PBS hole-be subjected to reagent thing hole OD mean value)/PBS hole] * %
Cleavage rate the results are shown in following table 0.1, under 1mmol/L or the low concentration according to the above-mentioned steps test-compound:
(following result is the mean value of The selection result more than 5 times)
ELISA measures the cleavage rate of formula I preferred compound to the AGE-BSA-collagen cross-linking
Claims (12)
1. the selenophen compounds of general formula I, its raceme, steric isomer, and pharmacy acceptable salt,
Wherein:
X is selected from hydrogen, methyl, ethyl or propyl group,
Y is O,
R
1Be hydrogen,
R
2Be selected from thiazole, benzothiazole, hydrogenation benzothiazole or imidazoles, it is not substituted or is selected from following substituting group by 1～3 and replaces: hydroxyl C
1-6Alkyl, carboxylic C
1-6Alkyl, C
1-6Carbalkoxy C
1-6Alkyl, C
1-6Alkyl, halogen, hydroxyl,
Z
-Be its pharmaceutically acceptable acid group or halogen ion.
2. the described compound of claim 1:
Wherein:
X is selected from hydrogen, methyl,
Y is O,
R
1Be hydrogen,
R
2Be selected from thiazole, benzothiazole, hydrogenation benzothiazole, imidazoles; It is not substituted or is selected from following substituting group by 1～3 and replaces: C
1～C
4Alkyl, C
1～C
4Hydroxyalkyl, C
1-6Carbalkoxy C
1-6Alkyl, halogen, hydroxyl,
Z
-Be halogen ion F
-, Cl
-, Br
-, I
-, perhaps methanesulfonate, tosic acid root.
3. be selected from following compound:
4,5-dimethyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide,
4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide,
5-(2-hydroxyethyl)-4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide,
3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-4,5,6,7-tetrahydro benzothiazol bromide,
5-(2-acetoxyl group-ethyl)-4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide,
3-methyl isophthalic acid-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-3H-imidazolium bromide,
4,5-dimethyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide,
4-methyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide,
4-methyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-5-vinyl-thiazole bromide, or
5-(2-hydroxyethyl)-4-methyl-3-(2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide.
4. the compound of claim 3, wherein said compound is:
3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-4,5,6,7-tetrahydro benzothiazol bromide,
5-(2-acetoxyl group-ethyl)-4-methyl-3-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-thiazole bromide, or
3-methyl isophthalic acid-(1-methyl-2-oxygen-2-selenophen-2-base-ethyl)-3H-imidazolium bromide.
5. pharmaceutical composition, it contains each described compound of claim 1～4, its raceme, steric isomer or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier.
6. the method for preparing the described compound of claim 1, this method comprise the replacement selenophen analog derivative with formula II
R wherein
1Definition with claim 1 Chinese style I compound
With the acid anhydrides of formula III, under the mixed solution existence condition of formula III and acid composition, react,
Wherein X and Y are with the definition of claim 1 Chinese style I compound
Obtain formula V compound
R wherein
1, X and Y be with the definition of claim 1 Chinese style I compound,
The compound of formula V is carried out halogenating reaction to be generated and obtains formula VI compound
R wherein
1, X and Y are with the definition of claim 1 Chinese style I compound; A is a leavings group, is selected from F, Cl, Br or I,
Compound and R with formula VI
2Reaction generates and obtains formula I compound
R wherein
1, R
2, X, Y and Z
-Definition with claim 1 Chinese style I compound.
7. the method for preparation formula VI in the claim 6, this method comprises the replacement selenophen analog derivative with formula II
R wherein
1Definition with claim 1 Chinese style I compound
With the acid anhydrides of formula III, the mixed solution of forming at formula III and phosphoric acid or sulfuric acid (IV) reacts under the condition of catalyzer
Wherein X is selected from methyl, ethyl or propyl group; Y is selected from O; The ingredient proportion of the replacement selenophen analog derivative of the acid anhydrides of formula III and formula II is 1: 1～3; Formula III and phosphoric acid or sulfuric acid can be mixed into catalyzer (IV) with arbitrary proportion;
Obtain formula V compound
R wherein
1Definition with claim 1 Chinese style I compound; X is selected from methyl, ethyl or propyl group; Y is selected from O,
The compound of formula V is carried out halogenating reaction to be generated and obtains formula VI compound
R wherein
1Definition with claim 1 Chinese style I compound; X is selected from methyl, ethyl or propyl group; Y is selected from O; A is a leavings group, is selected from F, Cl, Br or I.
8. the method for claim 7 is characterized in that:
The ingredient proportion of the replacement selenophen analog derivative of the acid anhydrides of formula III and formula II is 1: 1.5;
The formula III of composition catalyzer (IV) and phosphoric acid or vitriolic ratio are 4.5～5.8: 1;
The acid of forming catalyzer (IV) with formula III is phosphoric acid or sulfuric acid;
Described leavings group A is Br; And/or
It is cupric bromide (CuBr that formula V compound carries out the used halogenating agent of halogenating reaction
2).
9. each compound or its raceme, steric isomer, pharmacy acceptable salt of claim 1～4 is used to suppress or/and the end-use of cracking advanced glycation end products in preparation.
10. the purposes of claim 9, wherein said product are to be used for (i) to increase skin elasticity or reduce wrinkle of skin, prevent or treat (ii) non insulin dependent diabetes; The (iii) complication of diabetes; (iv) kidney injury; (v) blood vessel injury or prevention or the treatment arteriosclerosis; (vi) hypertension; (vii) retinopathy; (viii) crystallin damage; (ix) cataract; (x) peripheral neuropathy; (xi) formation of the lung AGEs that causes of smoking, and consequent pulmonary disorder; (xii) osteoarthritis; Perhaps be used for the purposes that oral local administration is used to prevent or reverse tooth staining; The fresh-keeping product that perhaps is used for various food plants or animal proteinum.
11. the purposes of claim 10, wherein said pulmonary disorder are pulmonary fibrosis or respiratory distress.
12. the purposes of claim 9, wherein said product are used for the reversal agent of tooth staining or the preparation that uses as other oral cavity is used to prevent and reverse tooth staining.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200410034011A CN1690057B (en) | 2004-04-21 | 2004-04-21 | Selenophen derivatives and their use for prevention and/or treatment of diseases relative to protein aging |
| PCT/CN2005/000153 WO2005103046A1 (en) | 2004-04-21 | 2005-02-03 | Selenophen derivatives and the use of preventing and/or treating the diseases relating to protein aging thereof |
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| CN200410034011A CN1690057B (en) | 2004-04-21 | 2004-04-21 | Selenophen derivatives and their use for prevention and/or treatment of diseases relative to protein aging |
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| CN103601684B (en) * | 2013-11-29 | 2016-01-20 | 沈阳药科大学 | 5-arylseleno benzimidazoles compound and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6319934B1 (en) * | 1998-11-10 | 2001-11-20 | Alteon, Inc. | Reversing advanced glycosylation cross-links using heterocyclic-substituted thiazolium compounds |
| US20020055527A1 (en) * | 2000-02-23 | 2002-05-09 | Dilip Wagle | Thiazolium compounds and treatments of disorders associated with protein aging |
-
2004
- 2004-04-21 CN CN200410034011A patent/CN1690057B/en not_active Expired - Fee Related
-
2005
- 2005-02-03 WO PCT/CN2005/000153 patent/WO2005103046A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6319934B1 (en) * | 1998-11-10 | 2001-11-20 | Alteon, Inc. | Reversing advanced glycosylation cross-links using heterocyclic-substituted thiazolium compounds |
| US20020055527A1 (en) * | 2000-02-23 | 2002-05-09 | Dilip Wagle | Thiazolium compounds and treatments of disorders associated with protein aging |
Non-Patent Citations (5)
| Title |
|---|
| B.H.ELOKHINA et.al..Synthesis of 2-(acylmethyl)benzo-1,3-oxathiolesfromacetylenic ketones.Khimiya Geterotsiklicheskikh Soedinenee10.1975,101328-1329. * |
| B.H.ELOKHINAet.al..Synthesisof2-(acylmethyl)benzo-1 3-oxathiolesfromacetylenic ketones.Khimiya Geterotsiklicheskikh Soedinenee10.1975 |
| Gerald S.Jones et.al..Selenium-sulfur analogs.6. Selenioisoteres of levamisole.Journal of Heterocyclic Chemistry20.1983,20523-526. * |
| H.H. MAGDESIEVA et.al..Synthesis of selenophene alpha-amino alcohols.Khimiya Geterotsiklicheskikh Soedinenii5.1972,5626-628. |
| H.H. MAGDESIEVA et.al..Synthesis of selenophene alpha-amino alcohols.Khimiya Geterotsiklicheskikh Soedinenii5.1972,5626-628. * |
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| WO2005103046A1 (en) | 2005-11-03 |
| CN1690057A (en) | 2005-11-02 |
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