CN109651349A - The novel crystal forms and preparation method and application of sulfonamides compound - Google Patents
The novel crystal forms and preparation method and application of sulfonamides compound Download PDFInfo
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- CN109651349A CN109651349A CN201910012300.4A CN201910012300A CN109651349A CN 109651349 A CN109651349 A CN 109651349A CN 201910012300 A CN201910012300 A CN 201910012300A CN 109651349 A CN109651349 A CN 109651349A
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- crystal forms
- novel crystal
- sulfonamides
- compound
- sulfonamides compound
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- 239000013078 crystal Substances 0.000 title claims abstract description 35
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 29
- -1 sulfonamides compound Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 10
- 238000005259 measurement Methods 0.000 claims abstract description 6
- 229910016523 CuKa Inorganic materials 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 23
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- QNFVXSQPOIREPV-UHFFFAOYSA-N butan-2-one;methylsulfinylmethane Chemical compound CS(C)=O.CCC(C)=O QNFVXSQPOIREPV-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- 150000000183 1,3-benzoxazoles Chemical class 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 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 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000240602 cacao Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229960004329 metformin hydrochloride Drugs 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of medicaments, and in particular to a kind of novel crystal forms of sulfonamides compound and its preparation method and application.The chemical formula of the sulfonamides compound such as formula (I) is shown:Wherein, the sulfonamides compound uses CuKa ray as in characteristic X-ray powder measurement, and map has the following 2 θ angle of diffraction and D value, and the errors of the 2 θ angles of diffraction is 0.2.The novel crystal forms activity of sulfonamides compound of the invention is strong, and hypoglycemic effect is good；Stability is good；It is suitble to preparation technical process and long term storage.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of novel crystal forms of sulfonamides compound and preparation method thereof and answer
With.
Background technique
At present the antidiabetic medicine of clinical use mainly have insulin type, sulfonylurea, melbine class and recently
Alpha-glucosidase inhibitor and Studies of The Insulin Sensitizer Thiazolidinediones drug of listing etc..These drugs have good treatment
The shortcomings that imitating, but long-term efficacy cannot be maintained caused by being used for a long time there are still drug, and easily cause hypoglycemia, weight
Increase and generate many adverse reactions such as hepatotoxicity wind agitation.
Therefore, one of the hot spot that new hypoglycemic medicine is domestic and international the world of medicine's research is found.
A kind of sulphur such as flowering structure is disclosed in Chinese invention patent 201210575394.4 (authorization on March 11st, 2015)
Aminated compounds:
Wherein:
X is S or O atom；
N=1,2,3 or 4；
R1With R2It is simultaneously or separately hydrogen or C1-C4 alkyl；
R3、R4With R5It is simultaneously or separately hydrogen, C1-C6 alkyl, C1-C4 alkoxy, halogen, single or multiple halogen replace C1-C4
Alkyl, cyano, phenyl, monohaloalkyl phenyl, C1-C4 alkoxyl phenyl, C1-C4 alkyl sulphonyl, any in bromomethyl carbonyl
Kind.
When X is O atom；N=2；R1With R2For methyl, R3、R4With R5Respectively hydrogen, hydrogen, 4- bromophenyl when, the entitled N- of chemistry
(3- (4- (benzoxazoles -2- base) -2,6-dimethyl-piperizine -1- base) propyl) -4'- bromine biphenylyl -4- sulfonamide, i.e. chemical combination
Object I, chemical structural formula:
Chemical compounds I, white solid, 193.2 DEG C -194.1 DEG C of fusing point；With good hypoglycemic activity.
The present inventor is in subsequent further investigation chemical compounds I, i.e. N- (3- (4- (benzoxazoles -2- base) -2,6- dimethyl piperazine
Piperazine -1- base) propyl) during -4'- bromine biphenylyl -4- sulfonamide, finding it, there are a kind of novel crystal forms, are different from above-mentioned
Report in patent, novel crystal forms activity is strong, and stability is good, has certain superiority, is suitble to preparation technical process and long-term
Storage.
Summary of the invention
The purpose of the present invention is to provide novel crystal forms of a kind of sulfonamides compound and its preparation method and application.
The present invention to achieve the above object, using following technical scheme:
A kind of novel crystal forms of sulfonamides compound, the chemical formula of the sulfonamides compound such as formula (I) are shown:
Wherein, the sulfonamides compound use CuKa ray as characteristic X-ray powder measurement in, map have with
The lower 2 θ angles of diffraction and D value, the error of the 2 θ angles of diffraction are 0.2.
| Serial number | 2θ | D value | I/I0 |
| 1 | 5.1523(18) | 17.138(6) | 49.03 |
| 2 | 10.3417(18) | 8.5469(15) | 29.33 |
| 3 | 12.8701(9) | 6.8729(5) | 34.97 |
| 4 | 13.333(5) | 6.635(2) | 18.44 |
| 5 | 15.646(3) | 5.6593(10) | 24.84 |
| 6 | 18.6756(15) | 4.7475(4) | 83.13 |
| 7 | 20.112(2) | 4.4115(5) | 100.00 |
| 8 | 20.3934(12) | 4.3513(2) | 52.90 |
| 9 | 20.703(3) | 4.2868(6) | 11.06 |
| 10 | 23.357(3) | 3.8055(4) | 10.66 |
| 11 | 25.9469(14) | 3.43117(18) | 29.22 |
| 12 | 26.4547(17) | 3.3665(2) | 13.40 |
| 13 | 26.926(3) | 3.3086(3) | 10.00 |
Novel crystal forms are white crystalline powder, 162.5 DEG C -163.1 DEG C of fusing point.
The invention also includes a kind of methods of novel crystal forms for preparing the sulfonamides compound, using following step: will
Compound (I) is dissolved in the dimethyl sulfoxide butanone mixed liquor of 4-5 mass times, is heated to reflux dissolution, is subsequently cooled to 10
DEG C -20 DEG C, heat preservation stands 5-7 hour, and crystallization, filtering is precipitated, and room temperature in vacuo degree 0.04-0.07Mpa drying 3-5 hours obtains
The novel crystal forms of above compound I.
The mass ratio of dimethyl sulfoxide and butanone in the dimethyl sulfoxide butanone mixed liquor are as follows: 8:2.
The invention also includes the application of the novel crystal forms of the sulfonamides compound described in one kind, the sulfonamides compound
It is applied to treatment diabetes after novel crystal forms and carrier, excipient or diluent composition composition.
Compared with prior art, the beneficial effects of the present invention are:
The novel crystal forms activity of sulfonamides compound of the invention is strong, and hypoglycemic effect is good；Stability is good；It is suitble to preparation process mistake
Journey and long term storage.
Detailed description of the invention:
Fig. 1 shows the x-ray diffraction pattern of the novel crystal forms of sulfonamides compound of the present invention.
Specific embodiment:
In order to make those skilled in the art more fully understand technical solution of the present invention, implement below with reference to best
The present invention is described in further detail for example.
The present invention to achieve the above object, using following technical scheme:
A kind of novel crystal forms of sulfonamides compound, the chemical formula of the sulfonamides compound such as formula (I) are shown:
Preparation method with blood sugar reducing function compound (I) novel crystal forms: its process includes: that chemical compounds I is dissolved in 4-5 matter
It in dimethyl sulfoxide/butanone of the 8:2 (mass ratio) of amount times, is heated to flowing back, after dissolution, is subsequently cooled to 10 DEG C -20 DEG C, protects
Temperature stands 5-7 hours, and crystallization is precipitated, and filtering, room temperature in vacuo degree 0.04-0.07Mpa is 3-5 hours dry, obtains above compound
I novel crystal forms.This operation is necessary to obtaining above-mentioned novel crystal forms.
Chemical compounds I used, i.e. N- (3- (4- (benzoxazoles -2- base) -2,6-dimethyl-piperizine -1- base) propyl) -4'-
Bromine biphenylyl -4- sulfonamide, synthesizes according to the method that Chinese invention patent 201210575394.4 provides, and white solid melts
193.2 DEG C -194.1 DEG C of point；Purity 98.5% (HPLC normalization method).Chemical structure mass spectrum (Ms) confirmation, it was demonstrated that chemical structure
It is correct.
Novel crystal forms are white crystalline powder, 162.5 DEG C -163.1 DEG C of fusing point；Purity (HPLC method) 99.6%.
The x-ray diffraction pattern of the crystalline powder is shown in attached drawing 1.Instrument model and determination condition: Rigaku D/max
2500 type diffractometers；CuKa 40Kv 100mA；2 θ scanning ranges: 0-50 °.
Wherein, the sulfonamides compound novel crystal forms use CuKa ray as characteristic X-ray powder measurement in, map
With the following 2 θ angle of diffraction and D value, the error of the 2 θ angles of diffraction is 0.2.As table 1 is shown:
Table 1
| Serial number | 2θ | D value | I/I0 |
| 1 | 5.1523(18) | 17.138(6) | 49.03 |
| 2 | 10.3417(18) | 8.5469(15) | 29.33 |
| 3 | 12.8701(9) | 6.8729(5) | 34.97 |
| 4 | 13.333(5) | 6.635(2) | 18.44 |
| 5 | 15.646(3) | 5.6593(10) | 24.84 |
| 6 | 18.6756(15) | 4.7475(4) | 83.13 |
| 7 | 20.112(2) | 4.4115(5) | 100.00 |
| 8 | 20.3934(12) | 4.3513(2) | 52.90 |
| 9 | 20.703(3) | 4.2868(6) | 11.06 |
| 10 | 23.357(3) | 3.8055(4) | 10.66 |
| 11 | 25.9469(14) | 3.43117(18) | 29.22 |
| 12 | 26.4547(17) | 3.3665(2) | 13.40 |
| 13 | 26.926(3) | 3.3086(3) | 10.00 |
Novel crystal forms are white crystalline powder, 162.5 DEG C -163.1 DEG C of fusing point.
All characteristic peaks such as table 2 is shown:
Table 2
The measurement of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allow to have one
Fixed reasonable error range, error range are ± 0.2 °.
Crystal compound I has having structure feature:
A further object of the present invention provides the pharmaceutical composition comprising chemical compounds I novel crystal forms.Medicine group of the invention
It is as follows to close object preparation: using standard and conventional technique, makes acceptable solid carrier knot on the compounds of this invention and galenic pharmacy
It closes, solid dosage forms, including tablet, discrete particles, capsule, sustained release tablets, sustained release pellet etc. is made.Solid carrier can be at least
A kind of substance can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent, adhesive, disintegrating agent and package
Agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, propylene glycol, polyoxyethylene sorbitan monoleate, dextrin, shallow lake
Powder, gelatin, cellulose substances such as methylcellulose, microcrystalline cellulose, low melt point paraffin, polyethylene glycol, mannitol, cocoa
Rouge etc..
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can be according to patient
The state of an illness, diagnosis the case where be specifically applied, the amount or concentration of compound used are in a wider range
It adjusts, the amount range of reactive compound is 1%~40% (weight) of composition.
One of component and method for preparing tablet: dosage/piece is given below
Supplementary material is pre-dried, is sieved with 100 mesh sieve spare.First by the supplementary product starch of recipe quantity, Sodium carboxymethyl starch, hard
Fatty acid magnesium, talcum powder mix well.Bulk pharmaceutical chemicals chemical compounds I -8 is added in auxiliary material with being incremented by dilution method, each added-time is sufficiently mixed
It is 2-3 times even, guarantee that bulk pharmaceutical chemicals are mixed well with auxiliary material, cross 20 meshes, dry 2h, dry particl cross 16 in 55 DEG C of ventilated drying ovens
Mesh sieve measures intermediates content, is uniformly mixed, the tabletting on tablet press machine.
The present invention also provides application of the chemical compounds I novel crystal forms in manufacture treatment diabetes medicament.
Blood sugar reducing function test: the oral sugar tolerance model of mouse (oral glucose tolerance test, OGTT)
Measurement, sample configuration, dosage, experimentation are consistent with the method that Chinese invention patent 201210575394.4 provides.To small
The experimental result of mouse blood glucose inhibiting effect such as table 3 is shown:
Table 3
| Compound | Inhibiting rate/% |
| Blank control group | - |
| The chemical compounds I of novel crystal forms | 85 |
| Uncrystallized compound I | 69 |
| Metformin hydrochloride | 20 |
As a result: the hypoglycemic activity of the chemical compounds I of novel crystal forms greatly enhances, and inhibiting rate is increased to 85% by 69%.
The above is only a preferred embodiment of the present invention, for those of ordinary skill in the art, according to the present invention
Thought, there will be changes in the specific implementation manner and application range, and the content of the present specification should not be construed as to the present invention
Limitation.
Claims (5)
1. a kind of novel crystal forms of sulfonamides compound, which is characterized in that the chemical formula of the sulfonamides compound such as formula (I) is shown
Out:
Wherein, the sulfonamides compound use CuKa ray as characteristic X-ray powder measurement in, map have following 2 θ
The angle of diffraction and D value, the error of the 2 θ angles of diffraction are 0.2.
2. the novel crystal forms of sulfonamides compound according to claim 1, which is characterized in that novel crystal forms are white crystalline powder
End, 162.5 DEG C -163.1 DEG C of fusing point.
3. a kind of method for the novel crystal forms for preparing the described in any item sulfonamides compounds of claim 1-2, which is characterized in that adopt
With following step: compound (I) is dissolved in the dimethyl sulfoxide butanone mixed liquor of 4-5 mass times, reflux dissolution is heated to,
10 DEG C -20 DEG C are subsequently cooled to, heat preservation stands 5-7 hours, and crystallization is precipitated, and filters, and room temperature in vacuo degree 0.04-0.07Mpa is dry
3-5 hours, obtain the novel crystal forms of above compound I.
4. the preparation method of the novel crystal forms of sulfonamides compound according to claim 3, which is characterized in that the diformazan
The mass ratio of dimethyl sulfoxide and butanone in base sulfoxide butanone mixed liquor are as follows: 8:2.
5. a kind of application of the novel crystal forms of the described in any item sulfonamides compounds of claim 1-2, which is characterized in that with load
It is applied to treatment diabetes after body, excipient or diluent composition composition.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012314A (en) * | 2012-12-25 | 2013-04-03 | 天津商业大学 | Sulfonamide compound and preparation method as well as application thereof |
| CN104693192A (en) * | 2013-12-09 | 2015-06-10 | 天津药物研究院 | Crystal form A of compound as well as preparation method and application thereof |
| CN106661032A (en) * | 2014-06-25 | 2017-05-10 | 武田药品工业株式会社 | 1,3-substituted 2-aminoindole derivatives and analogues useful in the treatment or prevention of diabetes mellitus, obesity and inflammatory bowel disease |
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2019
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012314A (en) * | 2012-12-25 | 2013-04-03 | 天津商业大学 | Sulfonamide compound and preparation method as well as application thereof |
| CN104693192A (en) * | 2013-12-09 | 2015-06-10 | 天津药物研究院 | Crystal form A of compound as well as preparation method and application thereof |
| CN106661032A (en) * | 2014-06-25 | 2017-05-10 | 武田药品工业株式会社 | 1,3-substituted 2-aminoindole derivatives and analogues useful in the treatment or prevention of diabetes mellitus, obesity and inflammatory bowel disease |
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