CN101684102B - Phenoxyacetic acid ester pyrazine derivative as well as preparation method and applications thereof - Google Patents
Phenoxyacetic acid ester pyrazine derivative as well as preparation method and applications thereof Download PDFInfo
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- CN101684102B CN101684102B CN2008101668895A CN200810166889A CN101684102B CN 101684102 B CN101684102 B CN 101684102B CN 2008101668895 A CN2008101668895 A CN 2008101668895A CN 200810166889 A CN200810166889 A CN 200810166889A CN 101684102 B CN101684102 B CN 101684102B
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- acid
- methyl
- trimethylpyrazine
- compound
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- -1 Phenoxyacetic acid ester pyrazine derivative Chemical class 0.000 title claims abstract description 118
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxy-acetic acid Natural products OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 108010010234 HDL Lipoproteins Proteins 0.000 claims abstract description 9
- 102000015779 HDL Lipoproteins Human genes 0.000 claims abstract description 9
- 210000002966 serum Anatomy 0.000 claims abstract description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 29
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 13
- 235000019260 propionic acid Nutrition 0.000 claims description 13
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 2
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- 150000001721 carbon Chemical group 0.000 description 22
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 125000003545 alkoxy group Chemical group 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 18
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 13
- 125000002252 acyl group Chemical group 0.000 description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 150000002632 lipids Chemical class 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
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- 230000008025 crystallization Effects 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- LAXOCXPBJXIBHO-UHFFFAOYSA-N (3,5,6-trimethylpyrazin-2-yl)methanol Chemical compound CC1=NC(C)=C(CO)N=C1C LAXOCXPBJXIBHO-UHFFFAOYSA-N 0.000 description 8
- 208000031226 Hyperlipidaemia Diseases 0.000 description 8
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- 238000005406 washing Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
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- 230000000694 effects Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000026106 cerebrovascular disease Diseases 0.000 description 6
- 230000002526 effect on cardiovascular system Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- 208000024172 Cardiovascular disease Diseases 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 5
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- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- BLHRKINRDDJFCT-UHFFFAOYSA-N (3,5,6-trimethylpyrazin-2-yl)methyl propanoate Chemical class CCC(=O)OCC1=NC(=C(N=C1C)C)C BLHRKINRDDJFCT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- AQOLXHCCIXUOMO-UHFFFAOYSA-N (3,5,6-trimethylpyrazin-2-yl)methyl 2-(4-hydroxyphenoxy)propanoate Chemical class N=1C(C)=C(C)N=C(C)C=1COC(=O)C(C)OC1=CC=C(O)C=C1 AQOLXHCCIXUOMO-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 108010023302 HDL Cholesterol Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61P3/06—Antihyperlipidemics
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
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- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
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Abstract
The invention relates to a new phenoxyacetic acid ester pyrazine derivative presented by a formula (1) as well as a preparation method, applications, a pharmaceutically acceptable salt, salts, an enantiomer, a non-enantiomer, a racemic mixture and a non-enantiomer mixture thereof, wherein atomic groups R1-R12 have prescriptive meanings. In addition, the invention also relates to preparation methods of the new compound and the pharmaceutically acceptable salt thereof. The compound lowers the level of serum triglyceride and has the functions of reducing serum cholesterol, increasing the level of high-density lipoprotein and improving the action of the hemorheology.
Description
Technical field
The present invention relates to the phenoxyacetic acid ester pyrazine derivative that a class is new.The invention still further relates to preparation method and the application of this compounds in the control cardiovascular and cerebrovascular diseases of this compounds.
Background technology
Blood fat is the general name of contained lipid material in blood, and lipid is comprised of fat and lipoid again.Lipid in blood mainly comprises free cholesterol, cholesterol ester, triglyceride, free fatty acids and phosphatide.Blood fat contains in the lipid total amount and accounts for seldom a part in human body, but it transport between each tissue, often can reflect the interior lipid metaboilic level of body.The content of blood fat is not constant. but fluctuation within the specific limits.The lipophorin of lipid in blood plasma is combined and formed lipoprotein and be dissolved in blood plasma and transported and metabolism.Lipoprotein is large spherical granules, and inside is nonpolar, and outside is polarity.Lipoprotein mainly comprises chylomicron (TG), vldl (VLDL-C), low-density lipoprotein (LDL-C), intermediate density lipoprotein (IDL-C), high-density lipoprotein (HDL) (HDL-C).
Hyperlipemia usually can cause a series of diseases, comprises the high-risk diseases such as atherosclerosis, coronary heart disease, apoplexy, myocardial infarction.Since the nineties in 20th century, along with the continuous increase of people's income and the rapid raising of standard of living, obese people is explosive increase, and hyperlipidemia patient quantity rapidly rises.A data presentation of a few days ago announcing, China more than 18 years old in the crowd hyperlipemia number reach 1.6 hundred million: more than 35 years old in the crowd, there are 2,500 ten thousand people to suffer from hypertension and hyperlipidaemia simultaneously, three one-tenth current medical science of blood fat compliance rate less than generally believe, hyperlipidaemia is one of important factor in the cardiovascular and cerebrovascular diseases genesis mechanism, and cardiovascular and cerebrovascular disease concurrent high sticky blood often, therefore, correct blood fat disorder, reduce blood viscosity, the control cardiovascular and cerebrovascular diseases is had to great value.
At present, both at home and abroad clinically blood lipid-lowering medicine commonly used have: bile acide chelating, nicotinic acid class, benzene oxygen aromatic acid derivative, HMG-CoA reductase inhibitor etc.Although they have certain drug effect, curative effect is relatively single, to reducing blood viscosity, improves poor or not effect of hemorheology effect.
Summary of the invention
The invention provides a kind of new phenoxyacetic acid ester pyrazine derivative and salt thereof as shown in structural formula (I) that has, its structural formula is as shown in (I):
Wherein: ● R
1, R
2, R
3, R
4, R
5identical or different each other, represent independently of one another hydrogen, alkyl containing 1～6 carbon atom, nitro, halogen, amino, acyl group, sulfahydantoin, carboxyl, hydroxyl, hydroxyl substituted alkyl containing 1～6 carbon atom, alkoxyl group containing 1～6 carbon atom, carbalkoxy containing 2～6 carbon atoms, formamyl, thioureido, alkyl sulfur compounds containing 1～6 carbon atom, alkyl sulfonated bodies containing 1～6 carbon atom, amino methyl, cyano group, the group that contains the unsaturated double-bond of 2～4 carbon atoms, the group that contains unsaturated three key of 2～4 carbon atoms, cycloalkyl containing 3～6 carbon atoms, aryl, substituted aryl, aralkyl, substituted aralkyl, aryloxy, substituted aryloxy, aryl carbonyl, substituted aryl carbonyl, aryloxycarbonyl, substituted aryloxycarbonyl etc.
● R
6, R
7, R
8, R
9each other identical or different, represent independently of one another hydrogen, containing the alkyl of 1～6 carbon atom, containing the alkoxyl group of 1～6 carbon atom, containing the hydroxyl substituted alkyl of 1～6 carbon atom, containing the cycloalkyl of 3～6 carbon atoms.R
2and R
3can be that identical substituting group can be also different substituting group.
● R
10, R
11, R
12each other identical or different, represent independently of one another hydrogen, containing the alkyl of 1～6 carbon atom, containing the alkoxyl group of 1～6 carbon atom, carbalkoxy containing 2～6 carbon atoms, carboxyl, containing the hydroxyl substituted alkyl of 1～6 carbon atom, containing cycloalkyl, aryl or the substituted aryl of 3～6 carbon atoms.
● the integer that n is 1-6.
Preferred compound in the present invention is more such compounds, in formula:
● R
1, R
2, R
3, R
4, R
5identical or different each other, can be hydrogen, nitro, halogen, amino, acyl group, sulfahydantoin, carboxyl, hydroxyl, formamyl, thioureido, amino methyl, cyano group independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be containing the alkyl, particularly methyl of 1～6 carbon atom, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, tertiary hexyl etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be containing 1～6 hydroxyl substituted alkyl, particularly methylol, hydroxyethyl, hydroxypropyl, hydroxyl normal-butyl, hydroxyl isobutyl-, hydroxyl n-pentyl, hydroxyl isopentyl, hydroxyl hexyl, hydroxyl isohexyl etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be containing the alkoxyl group, particularly methoxyl group of 1～6 carbon atom, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, positive hexyloxy, different hexyloxy, tertiary hexyloxy etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be containing the carbalkoxy, particularly methoxycarbonyl of 2～6 carbon atoms, ethoxycarbonyl, positive the third oxygen carbonyl, isopropyl oxygen carbonyl, positive butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, positive penta oxygen carbonyl, isoamyl oxygen carbonyl, uncle's penta oxygen carbonyl etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be containing the alkyl sulfur compounds, particularly methylthio group of 1～6 carbon atom, ethylmercapto group, positive rosickyite base, isopropyl sulfenyl, positive butylthio, isobutyl sulfenyl, tertiary butylthio, positive penta sulfenyl, isoamyl sulfenyl, uncle's penta sulfenyl, just own sulfenyl, dissident's sulfenyl, tertiary own sulfenyl etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be containing the alkyl sulfonated bodies, particularly methylsulfonic acid base of 1～6 carbon atom, ethyl sulfonic acid base, positive propanesulfonic acid base, isopropyl sulfonic group, positive fourth sulfonic group, isobutyl sulfonic group, tertiary fourth sulfonic group, positive penta sulfonic group, isoamyl sulfonic group, uncle's penta sulfonic group, just own sulfonic group, dissident's sulfonic group, tertiary own sulfonic group etc. independently of one another;
R
1, R
2, R
3, R
4, R
5each other identical or different, can be group, particularly vinyl containing the unsaturated double-bond of 2～4 carbon atoms, propenyl, allyl group, butenyl, butadienyl etc. independently of one another;
R
1, R
2, R
3, R
4, R
5each other identical or different, can be group, particularly ethynyl containing unsaturated three key of 2～4 carbon atoms, proyl, propargyl, butynyl etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be cycloalkyl, particularly cyclopropyl, methyl cyclopropyl, dimethyl cyclopropyl, ethyl cyclopropyl, the methylcyclopentyl containing 3～6 carbon atoms independently of one another, cyclohexyl etc.;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be that the substituting group here is alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin particularly, carboxyl, hydroxyl etc. containing the cycloalkyl of the replacement of 3～6 carbon atoms independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be aryl, particularly phenyl, naphthyl and other fragrant heterocycles etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be substituted aryl independently of one another, the substituting group here is alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin particularly, carboxyl, hydroxyl etc.;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be aralkyl, particularly benzyl, styroyl, hydrocinnamyl, benzene sec.-propyl, menaphthyl, naphthalene ethyl, naphthalene propyl group, naphthalene sec.-propyl and other fragrant Heterocyclylalkyls independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be substituted aralkyl independently of one another, the substituting group here is alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin particularly, carboxyl, hydroxyl etc.;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be aryloxy, particularly phenoxy group, benzyloxy, benzene oxyethyl group, benzene propoxy-, naphthalene methoxyl group, naphthalene methoxyl group, naphthalene oxyethyl group, naphthalene propoxy-and other fragrant heterocyclic oxy groups independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be substituted aryloxy independently of one another, the substituting group here is alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin particularly, carboxyl, hydroxyl etc.;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be aryl carbonyl, particularly benzoyl, naphthoyl, phenylacetyl, naphthalene ethanoyl and other aromatic heterocyclic carbonyls etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be substituted aryl carbonyl independently of one another, the substituting group here is alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin particularly, carboxyl, hydroxyl etc.;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be aryloxycarbonyl, particularly carbobenzoxy, benzene methoxycarbonyl, benzene ethoxycarbonyl, phenylpropyl alcohol oxygen carbonyl, naphthalene methoxycarbonyl, naphthalene methoxycarbonyl, naphthalene ethoxycarbonyl, naphthalene the third oxygen carbonyl and other aromatic heterocyclic oxygen base carbonyls etc. independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be substituted aryloxycarbonyl independently of one another, the substituting group here is alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin particularly, carboxyl, hydroxyl etc.;
● R
6, R
7, R
8, R
9identical or different each other, can be hydrogen independently of one another;
R
6, R
7, R
8, R
9identical or different each other, can be containing the alkyl, particularly methyl of 1～6 carbon atom, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, tertiary hexyl etc. independently of one another;
R
6, R
7, R
8, R
9identical or different each other, can be containing the alkoxyl group, particularly methoxyl group of 1～6 carbon atom, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, positive hexyloxy, different hexyloxy, tertiary hexyloxy etc. independently of one another;
R
6, R
7, R
8, R
9each other identical or different, can be hydroxyl substituted alkyl, particularly methylol containing 1～6 carbon atom, hydroxyethyl, hydroxypropyl, hydroxyl normal-butyl, hydroxyl isobutyl-, hydroxyl n-pentyl, hydroxyl isopentyl, hydroxyl hexyl, hydroxyl isohexyl etc. independently of one another;
R
6, R
7, R
8, R
9identical or different each other, can be cycloalkyl, particularly cyclopropyl, methyl cyclopropyl, dimethyl cyclopropyl, ethyl cyclopropyl, the methylcyclopentyl containing 3～6 carbon atoms independently of one another, cyclohexyl etc.;
● R
10, R
11, R
12identical or different each other, can be hydrogen, carboxyl independently of one another;
R
10, R
11, R
12identical or different each other, can be containing the alkyl, particularly methyl of 1～6 carbon atom, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, tertiary hexyl etc. independently of one another;
R
10, R
11, R
12identical or different each other, can be containing the alkoxyl group, particularly methoxyl group of 1～6 carbon atom, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, positive hexyloxy, different hexyloxy, tertiary hexyloxy etc. independently of one another;
R
10, R
11, R
12each other identical or different, can be carbalkoxy, particularly methoxycarbonyl containing 2～6 carbon atoms, ethoxycarbonyl, positive the third oxygen carbonyl, isopropyl oxygen carbonyl, positive butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, positive penta oxygen carbonyl, isoamyl oxygen carbonyl, uncle's penta oxygen carbonyl etc. independently of one another;
R
10, R
11, R
12each other identical or different, can be hydroxyl substituted alkyl, particularly methylol containing 1～6 carbon atom, hydroxyethyl, hydroxypropyl, hydroxyl normal-butyl, hydroxyl isobutyl-, hydroxyl n-pentyl, hydroxyl isopentyl, hydroxyl hexyl, hydroxyl isohexyl etc. independently of one another;
R
10, R
11, R
12identical or different each other, can be cycloalkyl, particularly cyclopropyl, methyl cyclopropyl, dimethyl cyclopropyl, ethyl cyclopropyl, the methylcyclopentyl containing 3～6 carbon atoms independently of one another, cyclohexyl etc.;
R
10, R
11, R
12each other identical or different, can be independently of one another aryl or substituted aryl as phenyl, benzyl, nitrophenyl, halogenophenyl, hydroxyl for phenyl, alkoxyphenyl radical etc.;
● the integer that n is 1-6.
More preferably compound in the present invention is more such compounds, in formula:
● R
1, R
2, R
3, R
4, R
5identical or different each other, can be hydrogen, nitro, halogen, amino, acyl group, sulfahydantoin, carboxyl, hydroxyl, formamyl, thioureido, amino methyl, cyano group independently of one another;
R
1, R
2, R
3, R
4, R
5identical or different each other, can be alkyl, particularly methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl independently of one another; Can be hydroxyl substituted alkyl, particularly methylol, hydroxyethyl, hydroxypropyl; Can be alkoxyl group, particularly methoxyl group, oxyethyl group, positive propoxy; Can be carbalkoxy, particularly methoxycarbonyl, ethoxycarbonyl, positive the third oxygen carbonyl; Can be cycloalkyl, particularly cyclopropyl, cyclobutyl, cyclopentyl; Can be cycloalkyl, particularly methyl cyclopropyl, dimethyl cyclopropyl, ethyl cyclopropyl, the methylcyclopentyl replaced, methoxyl group cyclopropyl, nitro cyclopropyl, halogen cyclopropyl, amino cyclopropyl, acyl group cyclopropyl; Can be phenyl, naphthyl, substituted phenyl and substituted naphthyl (particularly by alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin, phenyl and naphthyl that carboxyl, hydroxyl replace); It can be aralkyl, the substituted benzene alkyl of benzyl, styroyl, hydrocinnamyl, benzene sec.-propyl and phenyl ring (particularly by alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin, benzyl, styroyl, hydrocinnamyl, benzene sec.-propyl that carboxyl, hydroxyl etc. replace) particularly; Can be the substituted phenylcarbonyl group of aryl carbonyl, particularly benzoyl, phenylacetyl and phenyl ring (particularly by alkyl, alkoxyl group, nitro, halogen, amino, acyl group, sulfahydantoin, benzoyl, phenylacetyl that carboxyl, hydroxyl etc. replace);
● R
6, R
7, R
8, R
9identical or different each other, can be hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, methylol, hydroxyethyl, hydroxypropyl, hydroxyl normal-butyl, hydroxyl isobutyl-cyclopropyl, methyl cyclopropyl, dimethyl cyclopropyl, ethyl cyclopropyl, methylcyclopentyl independently of one another, cyclohexyl etc.;
● R
10, R
11, R
12identical or different each other, can be hydrogen, carboxyl, methyl, ethyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxycarbonyl, methylol, hydroxyethyl independently of one another.
● n is 2-3, more preferably 1.
For instance, the compounds of this invention is following compound:
● 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-[α-(4-chloro-phenyl-)-4-tolyl] oxygen]-2-Methyl Butyric Acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-[4-(2,4 dichloro benzene oxygen base) phenoxy group] propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● [p-4-chlorobenzoyl-β-aminoethyl benzene oxygen] isopropylformic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-(4-chlorophenoxy)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-(4-hydroxyphenoxy) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-(4-methoxyphenoxy) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters;
● 2-(4-amino-benzene oxygen)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters.
● 2-(4-sec.-propyl phenoxy group)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters
● 2-[4-(the chloro-benzyloxy of 4-)-phenyl oxygen]-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters
● 2-(4-xenyl oxygen)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters
● 2-(4-isobutyryl-phenyl oxygen)-2 Methylpropionic acid isopropyl ester 3,5,6-trimethylpyrazine-2-yl-methyl esters
● 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester hydrochloride
Term " halogen " as definition or part definition comprises fluorine, chlorine, bromine and iodine herein.
One skilled in the art will appreciate that formula (I) compound may contain chiral centre.While in formula (I) compound, containing chiral centre, can there be enantiomeric forms in it.Shown in formula (I), pure optically active isomer, mixture of enantiomers, non-enantiomer mixture, racemic mixture and the above-claimed cpd thereof of structure, mixture pharmacy acceptable salt all belong to scope of the present invention.
The compounds of this invention can be realized according to following method and step.
Those skilled in the art can be by making compound (II) and (III) esterification or ester substitution reaction prepare compound shown in formula of the present invention (I).The reaction formula of this reaction is as follows:
Wherein, R
1～R
12as defined in the above; R
13can be for hydroxyl, halogen atom, containing the alkoxyl group of 1～6 carbon atom, the alkoxyl group here is such as being methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, positive hexyloxy, different hexyloxy, tertiary hexyloxy etc.;
This reaction is under normal condition, by esterification or transesterification reaction, completes.This reaction can be carried out under the condition of catalyst-free, also can under the effect of catalyzer, complete, this catalyzer can be mineral acid (as: hydrogen chloride gas, the vitriol oil, phosphoric acid, perchloric acid, Tetrafluoroboric acid etc.), organic acid (as: Phenylsulfonic acid, methylsulfonic acid, p-methyl benzenesulfonic acid, trifluoroacetic anhydride etc.), (as: three fluoridize roc, aluminum chloride, ferric sulfate, Sc (OTf) in Lewis acid
3deng), bases (sodium alkoxide, sodium hydroxide, potassium hydroxide), tetrachloro aluminium ether complexes, dicyclohexyl carbodiimide, sulfonic acid type strong-acid ion exchange resin etc.Temperature of reaction is 0-100 ℃, and preferably 20-60 ℃ sometimes in order to control the speed of reaction, can carry out, by rare gas element (N at higher or lower than this temperature
2) protect and sometimes can reduce the generation of side reaction.Reaction is to carry out in suitable solvent, this solvent take do not hinder the reaction as good, normally used solvent is the solvent (as ether, methylene dichloride, chloroform, benzene, toluene, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane etc.) of boiling point higher than temperature of reaction.If R7 is halogen atom, the reaction in can add organic bases as acid binding agent, this acid binding agent take do not hinder the reaction as good, can be triethylamine, pyridine, N, dinethylformamide, DMA, N, the inertia reagent such as N-Dimethylamino pyridine, Tetramethyl Ethylene Diamine.
Above-mentioned compound (I) can separate and obtain by following manner, and as distillation, recrystallization, column chromatography chromatogram etc., the corresponding acceptable salt of pharmacology is also to obtain by the way, and the said salt of the present invention comprises their optical isomer.
The present invention, except relating to shown in formula (I) compound, also relates to its pharmacy acceptable salt.Pharmacy acceptable salt is particularly suitable for medical applications because with initial or basic Compound Phase ratio, their solubleness in water is larger.There is basic nitrogen in the compounds of this invention, therefore can prepare salify by sour addition with pharmaceutically acceptable mineral acid and organic acid, mineral acid is hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, organic acid is carbonic acid for example, acetic acid, oxalic acid, Phenylsulfonic acid, tosic acid, to bromo-benzene sulfonic acid, succinic acid, phenylformic acid, Citric Acid, ethyl sulfonic acid, fumaric acid, glyconic acid, oxyacetic acid, isethionic acid, lactic acid, lactobionic acid, toxilic acid, oxysuccinic acid, methylsulfonic acid, succsinic acid, tosic acid, tartrate and trifluoroacetic acid, amino acid etc.Therefore, this class pharmacy acceptable salt comprises vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, octylate, acrylate, formate, isobutyrate, hydrochlorate more, caprate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1, the 4-diacid salt, 3-cyclohexyne-2, the 5-diacid salt, benzoate, chloro-benzoate, phenylacetate, phenpropionate, benzenebutanoic acid salt, Citrate trianion, lactic acid salt, hippurate, beta-hydroxy-butanoic acid salt, glycollate, maleate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate, glutaminate, arginic acid salt, lysine salt etc.With regard to medical purpose, particularly preferred use villaumite.
Can also there be various polymorphics in the compounds of this invention, for example amorphous form and crystallization sexual type.All crystal formations of the compounds of this invention all comprise within the scope of the invention.
Compound in the present invention (I) is a kind of novel cpd, it is on the basis of hypolipidemic activity, it has increased the hemorheology effect, to reach reducing blood-fat and to improve hemorheological unification, the control cardiovascular and cerebrovascular diseases is had to important clinical value.The present invention adopts qualified one-level Kunming kind
mouse model, carried out the preliminary screening of pharmacodynamics, research shows that the compounds of this invention can significantly reduce TG, TC content in the hyperlipidemia mice serum that egg-nog brings out, HDL-C, LDL-C content, along with the increase of dosage, reducing blood lipid strengthens gradually, wherein the compounds of this invention (I) experimental group 80mg/kg group reducing blood lipid is better than the 40mg/kg group, and the prompting the compounds of this invention has obvious reducing blood lipid.The result of study that affects on the rheology of experimental hyperlipidemia mouse blood shows, the whole blood viscosity of experimental group rat (height is cut, hanged down and cut), Plasma Viscosity, erythrocyte aggregation index are compared with model group, all significantly reduce, show that the compounds of this invention has the obvious hemorheology effect that improves.
Compound of the present invention (I) has obvious reducing blood lipid to Mammals (as people, rat, mouse, cavy, dog and pig), for example: it can reduce serum triglyceride level, reduce serum cholesterol, the high density lipoprotein increasing level, improve blood flow and other cardiovascular and cerebrovascular diseases.It is a kind of good hypolipidemic, be oral or the injection be all safe, it can be made into various suitable formulations, as tablet, pulvis, capsule, injection and suppository.Certainly adopt which type of formulation will depend on concrete condition.The oral dosage of conventional treatment is 40-300mg/kg, and be administered three times every day.
Embodiment 1 compound of below only take is example, and the pharmacodynamic action result of the compounds of this invention is described.
Choose qualified one-level Kunming kind
70 of mouse, be divided into 7 groups at random, and 10 every group, Normal group, model group, medicine (compound (I)) 20,40,80mg/kg and Simvastatin 12.5mg/kg, fenofibrate 37.5mg/kg positive drug control group.Each administration group is the corresponding tested medicine of ig respectively, normal group and the isometric physiological saline of model group ig, every day 1 time, continuous 30 days.16h after last gavages medicine, each experimental group (except Normal group), mouse is abdominal injection 75% egg-nog respectively, 0.5mL/ only, 20h takes a blood sample by eye socket, measure serum TG, TG, HDL-C, the content of LDL-C, hemorheology index is surveyed soon instrument by full-automatic viscosity and is measured whole blood viscosity (η b), Plasma Viscosity (η p), erythrocyte aggregation index (AI) index under high, medium and low shear rate.Get right lobe of liver fixed part hepatic tissue, 10% formaldehyde is fixed, and HE dyeing, carry out the histopathology detection, observation liver fat degenerative condition.
In the model group mice serum, TG, TC level are apparently higher than normal mouse; After giving compound (I), high dose group TG, TC all obviously descend, with the model group comparing difference, significant (P<0.05) is arranged, with fenofibrate control group and Simvastatin control group comparing difference without significant (P > 0.05), in, small dose group and high fat control group comparing difference do not have significant (P > 0.05), in Table 1.
The impact (x ± s, n=10) of table 1 compound (I) on experimental hyperlipidemia mouse TG, TC
#P<0.05, compare with normal group ##P<0.01;
*p<0.05,
*compare with the model group group P<0.01
In the model group mice serum, the LDL level is apparently higher than normal mouse; After giving Compound I, high dose group LDL obviously reduces, and with the model group comparing difference, significant (P<0.05) is arranged, and LDL/HDL and model group comparing difference remarkable (P<0.01); Although middle dosage HDL and LDL and model group comparing difference are without significant (P > 0.05), LDL/HDL and model group comparing difference be (P<0.01) significantly; Low dose of and model group relatively, each index there are no significant meaning (P > 0.05).In Table 2.
The impact (x ± s, n=10) of table 2 compound (I) on experimental hyperlipidemia mouse HDL, LDL
#P<0.05, compare with normal group ##P<0.01;
*p<0.05,
*compare with the model group group P<0.01
Finding under the pathology of livers sight glass, as shown in Figure 1.Result shows, normal rats hepatic tissue structural integrity, clear, the liver lobule structure is normal, and central vein is large and wall is thin, and liver cell is arranged in the liver rope, around central vein, radially distribute, cell is Polygons, and light microscopic drag group is similar to normal group with heavy dose group hepatic pathology Histological change, has no light and dyes, loose steatosis, the phenomenons such as inflammatory cell infiltration of reaching of kytoplasm.
Model group mouse η
b, η
p, the AI level is apparently higher than normal mouse; After giving compound (I), high dosage and middle dosage group η
b, η
p, AI obviously reduces, and with the model group comparing difference, significant (P<0.05) arranged.In Table 3.
Table 3 compound (I) is on the rheol impact of experimental hyperlipidemia mouse blood (x ± s, n=10)
#P<0.05, compare with normal group ##P<0.01;
*p<0.05,
*compare with the model group group P<0.01
Above result shows, compound (I) has significant reducing blood lipid, with fenofibrate, Simvastatin, compares, and it has the stronger hemorheology effect that improves.
The accompanying drawing explanation:
Fig. 1: Microscopic observation pathology of livers result
A: normal group (* 100)
B: model group (* 100)
C: heavy dose of group of compound (I) (* 100)
Embodiment:
The specific embodiment below comprised, for the preparation method is described, does not impose any restrictions present disclosure.Agents useful for same and intermediate or can be provided by business, or can according to the normative document method, easily be prepared by those skilled personnel of organic synthesis field.Those persons skilled in the art of this area are known also has other to prepare the method for the compounds of this invention.
Embodiment 1
2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
13.5g (0.04mol) 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionyl chloride is joined in the 120mL methylene dichloride and is down to 0 ℃ after stirring and dissolving, then add 6.1g (0.04mol) 2-methylol-3, 5, 6-trimethylpyrazine and 10mL triethylamine, finish rear stirring at room 4 hours, filter, the filtrate water washing, twice of dichloromethane extraction of water layer, after the combined dichloromethane layer, with saturated sodium bicarbonate aqueous solution, wash, separate organic layer, anhydrous magnesium sulfate drying, filter, filtrate is concentrated into dry, add the dehydrated alcohol crystallization, leach the crystallization of separating out, the dry 7.5g yellow solid that obtains, this solid is 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3 through structural identification, 5, 6-trimethylpyrazine-2-yl-methyl esters, fusing point: 145～147 ℃, ultimate analysis: theoretical value (%): C:66.296, H:5.564, N:6.185, measured value (%): C:66.045, H:5.570, N:6.245, infrared spectra (KBr compressing tablet): 3443cm-1,3093cm-1,2952cm-1,2920cm-1,1733cm-1,1648cm-1,1599cm-1,1417cm-1,1277cm-1,1145cm-1,1012cm-1,928cm-1,856cm-1,763cm-1, 1H-NMR (CDCl3): δ 1.7122 (3H, s ,-CH3), δ 2.3937～2.4866 (3H, s ,-CH3), δ 5.2863 (2H, s ,-CH2-), δ 6.8499～7.7110 (8H, multiplet, Ar-H), ESI mass spectrum [M+H]
+: 452m/z
Embodiment 2
2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
13.5g (0.04mol) 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionyl chloride is joined in the 100mL trichloromethane and is down to 0 ℃ after stirring and dissolving, then add 6.1g (0.04mol) 2-methylol-3, 5, 6-trimethylpyrazine and 10mLN, dinethylformamide, finish rear stirring at room 6 hours, filter, the filtrate water washing, twice of chloroform extraction of water layer, after merging the trichloromethane layer, with saturated sodium bicarbonate aqueous solution, wash, separate organic layer, anhydrous magnesium sulfate drying, filter, filtrate is concentrated into dry, add the acetonitrile crystallization, leach the crystallization of separating out, the dry 6.9g yellow solid that obtains, this solid is 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3 through structural identification, 5, 6-trimethylpyrazine-2-yl-methyl esters, fusing point: 146～147 ℃.
Embodiment 3
2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
Preparation method according to embodiment 1, with 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2-methyl-prop acyl chlorides and 2-methylol-3,5, the 6-trimethylpyrazine, operation can obtain 2-[4-(2,2-dichloro cyclopropyl) phenoxy group in accordance with the law]-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters.ESI mass spectrum [M+H]
+: 424m/z
Embodiment 4
2-[α-(4-chloro-phenyl-)-4-tolyl] oxygen]-2-Methyl Butyric Acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
Preparation method according to embodiment 1, with 2-[α-(4-chloro-phenyl-)-4-tolyl] oxygen]-2-methylbutyryl chlorine and 2-methylol-3,5, the 6-trimethylpyrazine, operation can obtain 2-[α-(4-chloro-phenyl-)-4-tolyl in accordance with the law] oxygen]-2-Methyl Butyric Acid 3,5,6-trimethylpyrazine-2-yl-methyl esters.ESI mass spectrum [M+H]
+: 454m/z.
Embodiment 5
2-[4-(2,4 dichloro benzene oxygen base) phenoxy group] propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
According to the preparation method of embodiment 1, with 2-[4-(2,4 dichloro benzene oxygen base) phenoxy group] propionyl chloride and 2-methylol-3,5,6-trimethylpyrazine, operation can obtain 2-[4-(2 in accordance with the law, the 4-dichlorophenoxy) phenoxy group] propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters.ESI mass spectrum [M+H]
+: 462m/z.
Embodiment 6
[p-4-chlorobenzoyl-β-aminoethyl benzene oxygen] isopropylformic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
According to the preparation method of embodiment 1, with p-4-chlorobenzoyl-β-aminoethyl benzene oxygen] isobutyryl chloride and 2-methylol-3,5, the 6-trimethylpyrazine, operation can obtain [p-4-chlorobenzoyl-β-aminoethyl benzene oxygen] isopropylformic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters in accordance with the law.ESI mass spectrum [M+H]
+: 497m/z.
Embodiment 7
2-(4-chlorophenoxy)-2 Methylpropionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
According to the preparation method of embodiment 1, with 2-(to chlorophenoxy)-2-methyl-prop acyl chlorides and 2-methylol-3,5,6-trimethylpyrazine, operation can obtain 2-(4-chlorophenoxy)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters in accordance with the law.ESI mass spectrum [M+H]
+: 450m/z.
Embodiment 8
2-(4-hydroxyphenoxy) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters
According to the preparation method of embodiment 1, with 2-(4-hydroxyphenoxy) propionyl chloride and 2-methylol-3,5,6-trimethylpyrazine, operation can obtain 2-(4-hydroxyphenoxy) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters in accordance with the law.ESI mass spectrum [M+H]
+: 317m/z.
Embodiment 9
2-(4-methoxyphenoxy) propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
According to the preparation method of embodiment 1, with 2-(4-methoxyphenoxy)-propionyl chloride and 2-methylol-3,5,6-trimethylpyrazine, operation can obtain 2-(4-methoxyphenoxy) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters in accordance with the law.ESI mass spectrum [M+H]
+: 331m/z.
Embodiment 10
2-(4-amino-benzene oxygen)-2 Methylpropionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
According to the preparation method of embodiment 1, with 2-(4-amino-benzene oxygen)-2-methyl-prop acyl chlorides and 2-methylol-3,5, the 6-trimethylpyrazine, operation can obtain 2-(4-amino-benzene oxygen)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters in accordance with the law.ESI mass spectrum [M+H]
+: 330m/z.
Embodiment 11
2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
By 15.9g (0.05mol) 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid, 7.6g (0.05mol) 2-methylol-3; 5; the 6-trimethylpyrazine adds 5g tosic acid and 150mL toluene to join in reaction flask; stirring heating refluxes 8 hours; filter; the filtrate water washing; water layer toluene extracting twice, with the saturated sodium bicarbonate aqueous solution washing, separate organic layer after the combining methylbenzene layer; anhydrous magnesium sulfate drying; filter, filtrate is concentrated into dry, adds the dehydrated alcohol crystallization; leach the crystallization of separating out, the dry 5.1g yellow solid that obtains.
Embodiment 12
2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
Tosic acid in above-described embodiment 11 is substituted with sulfuric acid, and operation can obtain 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl esters in accordance with the law.
Embodiment 13
2-(4-sec.-propyl phenoxy group)-2 Methylpropionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
By 11.1g (0.05mol) 2-(4-sec.-propyl phenoxy group)-2 Methylpropionic acid 7.6g (0.05mol) 2-methylol-3,5, the 6-trimethylpyrazine adds 4.5g Tetrafluoroboric acid and 150mL toluene to join in reaction flask, stirring heating refluxes 6 hours, filter, the filtrate water washing, water layer toluene extracting twice, with the saturated sodium bicarbonate aqueous solution washing, separate organic layer, anhydrous magnesium sulfate drying after the combining methylbenzene layer, filter, filtrate is concentrated into dry, uses the column chromatography separated product, the dry 4.4g yellow solid that obtains.ESI mass spectrum [M+H]
+: 357m/z.
Embodiment 14
2-[4-(the chloro-benzyloxy of 4-)-phenyl oxygen]-2 Methylpropionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
By 2-[4-(the chloro-benzyloxy of 4-)-phenyl oxygen]-2 Methylpropionic acid (21.0g, 0.066mmol), 2-methylol-3,5,6-trimethylpyrazine (9.7g, 0.064mmol), join in the there-necked flask of 250ml.Add 150mlTHF that said mixture is dissolved, with ice-water bath, this solution is cooled to 0 ℃～5 ℃ subsequently.Under the condition of magnetic agitation, to THF (10ml) solution that drips DCC (0.13g, 0.063mmol) in reaction soln (noting the observing response heat release).Monitor reaction process with TLC, under the condition of normal temperature magnetic agitation, reaction is spent the night.Second day, be spin-dried for reaction soln, adds the 150ml ethyl acetate to dissolve remaining solid, then with the sodium carbonate solution washing once, water washing three times.The organic phase anhydrous magnesium sulfate drying that separatory separates.Filtration is spin-dried for ethyl acetate, and obtains the 12.7g yellow solid product with the silica gel chromatography column purification.ESI mass spectrum [M+H]
+: 456m/z.
Embodiment 15
2-(4-xenyl oxygen)-2 Methylpropionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters
Add 2-(4-xenyl oxygen)-2 Methylpropionic acid methyl esters (13.5g in the there-necked flask of 100ml, 0.05mol) and 2-methylol-3,5,6-trimethylpyrazine (9.1g, 0.061mmol), be placed in the oil bath of 100 ℃, mechanical stirring, after mixture is all melted, add catalyzer to add sodium alkoxide, connect prolong and collect small molecules product methyl alcohol, and the constant nitrogen that passes into is beneficial to overflowing of methanol gas.The output of the methyl alcohol that each weighing in 15 minutes is collected is until constant weight, to determine the level of response of transesterify.After reaction finishes, what product was purified with column chromatography arrives faint yellow product 7.8g.ESI mass spectrum [M+H]
+: 391m/z.
Embodiment 16
2-(4-isobutyryl-phenyl oxygen)-2 Methylpropionic acid isopropyl ester 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl esters:
Catalyzer sodium methylate in above-described embodiment 15 is replaced with sodium isopropylate; with 2-(4-isobutyryl-phenyl oxygen)-2 Methylpropionic acid isopropyl ester and 2-methylol-3; 5; the 6-trimethylpyrazine is starting raw material; operation can obtain 2-(4-isobutyryl-phenyl oxygen)-2 Methylpropionic acid isopropyl ester 3 in accordance with the law; 5,6-trimethylpyrazine-2-yl-methyl esters, faint yellow solid.ESI mass spectrum [M+H]
+: 385m/z.
Embodiment 17
2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5, the preparation of 6-trimethylpyrazine-2-yl-methyl ester hydrochloride:
By embodiment 1 products therefrom 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3; 5; after 6-trimethylpyrazine-2-yl-methyl esters dissolves with a little anhydrous diethyl ether; add the salt acid ether; should there be a large amount of white precipitate crystallizations to produce; this crystallization is 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester hydrochloride.
According to preferred embodiment, the present invention is described.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, within it all should be understood to be in protection scope of the present invention.
Claims (8)
1. formula (I) compound or its pharmacy acceptable salt:
Wherein:
● R
1, R
2, R
4, R
5identical or different each other, representative independently of one another:
Hydrogen, hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, positive propoxy;
● the benzyloxy that R3 is selected from phenyl, benzyl, the benzyl replaced by halogen, benzoyl, the benzoyl replaced by halogen, phenoxy group, the phenoxy group replaced by halogen, benzyloxy, is replaced by halogen;
● R
6～R
9identical or different each other, representative independently of one another: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-;
● R
10～R
12identical or different each other, representative independently of one another: hydrogen, methyl, ethyl, methoxyl group, oxyethyl group;
● n is 1.
2. formula as required for protection as claim 1 (I) compound, it is selected from:
● 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5,6-trimethylpyrazine-2-base-methyl esters;
● 2-[α-(4-chloro-phenyl-)-4-tolyl] oxygen]-2-Methyl Butyric Acid 3,5,6-trimethylpyrazine-2-base-methyl esters;
● 2-[4-(2,4 dichloro benzene oxygen base) phenoxy group] propionic acid 3,5,6-trimethylpyrazine-2-base-methyl esters;
● 2-[4-(the chloro-benzyloxy of 4-)-phenyl oxygen]-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-base-methyl esters;
● 2-(4-xenyl oxygen)-2 Methylpropionic acid 3,5,6-trimethylpyrazine-2-base-methyl esters;
● 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) propionic acid 3,5,6-trimethylpyrazine-2-base-methyl ester hydrochloride.
3. one kind prepares the method for compound (I) as claimed in claim 1, it is characterized in that comprising by following compounds (II) and (III) by esterification, obtains the step of compound (I):
Wherein, R
1～R
12definition is definition as claimed in claim 1, R
13be selected from hydroxyl, halogen, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, positive hexyloxy, different hexyloxy, tertiary hexyloxy.
4. method as claimed in claim 3, it also comprises by compound (I) by with pharmaceutically acceptable mineral acid or organic acid reaction, preparing the step of corresponding pharmacy acceptable salt.
5. a pharmaceutical composition, it comprises that compound as claimed in claim 1 or 2 or its pharmacy acceptable salt are effective constituent, and pharmaceutically acceptable auxiliary material.
6. pharmaceutical composition according to claim 5, is characterized in that described pharmaceutical composition is that tablet, capsule, injection, oral preparation, dripping pill, emulsion, suspensoid, lyophilized injectable powder, sustained release dosage, control-released agent, mouth collapse agent or effervescent.
7. the described compound of claim 1 or 2 or its pharmacy acceptable salt are for the preparation of reducing blood-fat or the application in improving hemorheological medicine.
8. the described compound of claim 1 or 2 or its pharmacy acceptable salt are in the purposes for the preparation of reducing serum triglyceride, in reducing the medicine of serum cholesterol or high density lipoprotein increasing.
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| PCT/CN2009/072733 WO2010034212A1 (en) | 2008-09-28 | 2009-07-13 | Phenoxy acetic acid pyrazine ester derivatives, the preparation methods and uses thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267327A (en) * | 1978-03-23 | 1981-05-12 | Farmitalia Carlo Erba S.P.A. | 2-Hydroxymethyl-pyrazine derivatives and process for their preparation |
| CN1424313A (en) * | 2002-12-20 | 2003-06-18 | 山东大学 | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof |
| CN101037416A (en) * | 2007-04-25 | 2007-09-19 | 吉林省药物研究所 | 2,5,6-three substitution pyrazine derivatives |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267327A (en) * | 1978-03-23 | 1981-05-12 | Farmitalia Carlo Erba S.P.A. | 2-Hydroxymethyl-pyrazine derivatives and process for their preparation |
| CN1424313A (en) * | 2002-12-20 | 2003-06-18 | 山东大学 | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof |
| CN101037416A (en) * | 2007-04-25 | 2007-09-19 | 吉林省药物研究所 | 2,5,6-three substitution pyrazine derivatives |
Non-Patent Citations (3)
| Title |
|---|
| LIU, Xinyong等.Synthesis of the novel ligustrazine derivatives and their protective effect on injured vascular endothelial cell damaged by hydrogen peroxide..《Bioorganic & Medicinal Chemistry Letters》.2003,第13卷(第13期),第2123-2126页. |
| LIU, Xinyong等.Synthesis of the novel ligustrazine derivatives and their protective effect on injured vascular endothelial cell damaged by hydrogen peroxide..《Bioorganic & * |
| Medicinal Chemistry Letters》.2003,第13卷(第13期),第2123-2126页. * |
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