CN105315301B - The citrate of the inhibitor of thiadiazole DPP IV - Google Patents
The citrate of the inhibitor of thiadiazole DPP IV Download PDFInfo
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- CN105315301B CN105315301B CN201410381575.2A CN201410381575A CN105315301B CN 105315301 B CN105315301 B CN 105315301B CN 201410381575 A CN201410381575 A CN 201410381575A CN 105315301 B CN105315301 B CN 105315301B
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Engineering & Computer Science (AREA)
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- Life Sciences & Earth Sciences (AREA)
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Abstract
The invention provides a kind of citrate of the inhibitor of thiadiazole DPP IV, the purposes that the disease that DPP IV suppresses especially treats type II diabetes is benefited from its preparation method, its pharmaceutical composition and its treatment.It has been investigated that the citrate of the compounds of this invention compared with other salt such as fumarate, benzoate, has unexpected advantage：The citrate of the compounds of this invention is easy into salt, can facilitate, be inexpensive, being prepared in high yield；The citrate of the compounds of this invention has preferable pharmacokinetic parameter, such as higher bioavilability；The citrate of the compounds of this invention has more preferable chemically and physically stability, such as under high temperature or super-humid conditions or during preparation and storage, and the formation of impurity is lacked.
Description
Technical field
The invention belongs to medicinal chemistry art, it is related to the acid-addition salts of thiadiazole DPP-IV inhibitor, and in particular to formula I
The new pharmaceutically acceptable acid-addition salts of compound, more particularly to the citrate of type I compound, its preparation method, its
The purposes that the disease that DPP-IV suppresses especially treats type II diabetes is benefited from pharmaceutical composition and its treatment.
Background technology
It is the structural formula of type I compound below：
Chinese patent application CN102807568 disclose its concrete structure, its preparation method and its treat or prevent by
Purposes in the medicine of the disease suppressed beneficial to DPP-IV.But the specific salt of type I compound is not disclosed.
It has been found that the medicine of more preferable patent medicine characteristic can be turned into using the citrate of type I compound as therapeutic agent.
The content of the invention
One aspect of the present invention provides a kind of 8- ((R) -3- amino-piperadine -1- bases) -1- ([1,2,5] thiadiazoles simultaneously [3,4-
B] pyridine -5- methyl) -7- (2- butine -1- bases) -3- methyl-xanthines (there is the structure such as following formula I, call type I compound in the following text)
Acid-addition salts.
Wherein it is described acid selected from citric acid, fumaric acid, maleic acid, benzoic acid, oxalic acid, acetic acid, p-methyl benzenesulfonic acid, sulfuric acid or
Hydrochloric acid.
The present invention specifically provides a kind of citrate of type I compound.
The citrate of the type I compound of the present invention, the wherein mol ratio of type I compound and citric acid are 1:0.5~2,
It is preferred that 1:0.5~1.5, most preferably 1:0.9~1.
The present invention provides single citrate of type I compound, and its structural formula is as follows：
On the other hand, the present invention provides a kind of preparation method of the acid-addition salts of type I compound, and this method is included formula I
Compound mixes with respective acids in the appropriate solvent system being made up of the mixture of single solvent or multi-solvents, separates afterwards
To the acid-addition salts of type I compound.
Specifically, the present invention provides a kind of method for the citrate for preparing above-mentioned type I compound, and this method is included formula
I compound mixes with citric acid in the appropriate solvent system being made up of the mixture of single solvent or multi-solvents, rear separation
Obtain the citrate of type I compound.
In certain embodiments, the present invention provides a kind of method for the single citrate for preparing type I compound, this method bag
Include and mix in the appropriate solvent system being made up of the mixture of single solvent or multi-solvents type I compound with citric acid,
Single citrate of isolated type I compound afterwards, the wherein mol ratio of type I compound and citric acid are 1:1~1.2, preferably
Mol ratio is 1:1~1.1.
Wherein type I compound refers to method of the open source literature for example disclosed in Chinese patent application CN102807568 and entered
It is prepared by row.
Wherein reaction temperature is 0-50 DEG C.Suitable reaction temperature is 0-35 DEG C.
Wherein reaction can be carried out under the protection of the inert gases such as nitrogen, reaction time 1-5h.
Wherein described solvent includes ethers, alcohols, ketone, nitrile, esters, alkanes and alkyl halide hydro carbons, specifically
Solvent such as tetrahydrofuran, dioxane, isopropyl ether, ether, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, first
Acetoacetic ester, hexane, dichloromethane, chloroform.
The citrate of the type I compound of the present invention can be separated using technology well known in the art, such as filtering,
Concentration, spray drying etc..It can also be further dried using standard technique, the conventional meanses such as recrystallization can also be passed through
The citrate of the type I compound of the present invention is purified.
Another further aspect, the present invention provide a kind of pharmaceutical composition, and it contains the formula I of the therapeutically effective amount as active ingredient
The citrate and pharmaceutically acceptable carrier of compound.Specifically, wherein the citrate of type I compound is the chemical combination of formula I
Single citrate of thing.
Further, the present invention provides the citrate of type I compound and prepared containing their pharmaceutical composition
The disease that DPP-IV suppression is benefited from treatment especially treats purposes in the medicine of type II diabetes.Specifically, wherein formula I is changed
The citrate of compound is single citrate of type I compound.
It has been investigated that the citrate of type I compound has compared with other salt such as fumarate, benzoate
Unexpected advantage：The citrate of type I compound is easy into salt, can facilitate, be inexpensive, being prepared into high yield
Arrive；The citrate of type I compound has preferable pharmacokinetic parameter, such as higher bioavilability；Type I compound
Citrate there is more preferable chemically and physically stability, such as under high temperature or super-humid conditions or in preparation and storage period
Between, the formation of impurity is lacked.
Embodiment
The present invention can be described in more detail in the following examples, but the invention is not limited in any way.
According to CN102807568 record, type I compound is prepared.
Embodiment 1The preparation of single citrate of type I compound
At room temperature, type I compound (2g, 4.3mmol) and citric acid (0.9g, 4.7mmol) are held in acetone (20ml)
Continuous stirring 2h.Cold filtration, 50 DEG C of vacuum drying oven are dried under reduced pressure, and obtain single citrate (2.5g) of type I compound.
Embodiment 2The preparation of single citrate of type I compound
At 50 DEG C, by type I compound (2g, 4.3mmol) and citric acid (0.99g, 5.16mmol) in ethanol (4ml) and second
In acetoacetic ester (16ml), 2h is persistently stirred.Cold filtration, 50 DEG C of vacuum drying oven are dried under reduced pressure, and obtain single citric acid of type I compound
Salt (2.6g).
Embodiment 3The preparation of the citrate of type I compound
At room temperature, by type I compound (2g, 4.3mmol) and citric acid (0.75g, 3.9mmol) in acetone (20ml),
Persistently stir 2h.Cold filtration, 50 DEG C of vacuum drying oven are dried under reduced pressure, and obtain the citrate (2.3g) of type I compound, the wherein formula
Type I compound and the mol ratio of citric acid are 1 in the citrate of I compound:0.9.
Embodiment 4The Pharmacokinetic Evaluation of type I compound acid-addition salts
Test objective：By machin, gavage gives the different salt forms of type I compound respectively for this experiment, obtains theirs
Basic pharmacokinetic parameter, with more different salt forms under same dose inside exposed amount and bioavilability etc.
Difference.
Experimental animal：
Kind, strain：Machin (common grade)
Sex and quantity：9,6 female 3 is male
Weight range：2.7-4.8kg
Source and animal quality certification number：Hainan Xin Zhengyuan bio tech ltd SCXK (fine jade) 2011-0002 was tested
Journey：
Machin is randomly divided into 3 groups, every group 3 according to body weight harmony principle.Wherein A groups：Give type I compound
Single fumarate (dosage 12.55mg/kg), B groups：Single benzoate (dosage 12.69mg/kg) of type I compound is given,
C groups：Give single citrate (dosage 14.21mg/kg) of type I compound.
1st, need testing solution is prepared：Precision weighs three kinds of salt into solution bottle, measures appropriate ultra-pure water, adds stirring and dissolving
Mix, used after preparation in 4 hours.
2nd, it is administered
Method of administration：Intranasal gastric infusion
Capacity is administered：5ml/kg
Administration frequency：Single-dose
Injection speed：The about 0.5ml/ seconds
3rd, take a blood sample
Blood sampling site：Small saphenous vein
Sampling quantity：1ml venous blood is gathered into the vacuum blood collection tube of EDTA-K2 anti-freezings.
Whole blood pre-treatment：Blood collection is placed in ice chest (2~8 DEG C) to after in the pipe of EDTA-K2 anti-freezings processing,
Freezen protective in -80 DEG C of refrigerators is placed in centrifuging (3500rpm, 10min) separated plasma in 1h.
Blood sampling time point：Before administration (0min) and administration after 5min (± 30s), 15min (± 30s), 30min (± 30s),
1h(±2min)、2h(±2min)、4h(±5min)、6h(±5min)、8h(±5min)、12h(±5min)、24h(±
10min)。
4th, plasma sample pre-processes：30 μ L machins plasma samples are taken into 1.5mL centrifuge tube, 100 μ L is added and contains
20ng/mL internal standard (stable) acetonitrile solution, it is vortexed and mixes 1min, 12000rpm centrifugation 5min, 90 μ L of supernatant liquid of transfer to 96
Hole is entered in model, adds 100 μ L50% acetonitrile-aqueous solution into corresponding each hole, and vibration on the oscillator mixes 5min,
Enter LC-MS/MS analyses.
5th, data processing：Machin individual blood concentration-time data use pharmacokinetics professional software Phoenix
Non- compartment model (Non-Compartmental Model) fitting in WinNonlin 6.3, which is asked, calculates pharmacokinetics ginseng
Number.The results detailed in following table：
Experiment conclusion：
Single citrate of type I compound has bigger exposed amount (C for more other groups in cynomolgus monkeymaxAnd AUC), it is raw
More other groups of thing availability is more preferable.
Claims (12)
1. the citrate of type I compound, wherein type I compound have following structure：
2. the mol ratio of the citrate of the type I compound described in claim 1, wherein type I compound and citric acid is 1:0.5
~2.
3. the mol ratio of the citrate of the type I compound described in claim 1, wherein type I compound and citric acid is 1:0.5
~1.5.
4. the mol ratio of the citrate of the type I compound described in claim 1, wherein type I compound and citric acid is 1:0.9
~1.
5. the citrate of the type I compound described in claim 1, its structural formula is as follows：
6. a kind of preparation method of the citrate of the type I compound any one of claim 1-5, including formula I is changed
Compound mixes with citric acid in the appropriate solvent system being made up of the mixture of single solvent or multi-solvents, rear isolated
The citrate of type I compound.
7. the preparation method of the citrate of the type I compound described in claim 6, wherein reaction temperature are 0 DEG C to 50 DEG C.
8. the preparation method of the citrate of the type I compound described in claim 6, wherein described solvent includes ethers, alcohol
Class, ketone, nitrile, esters, alkanes and alkyl halide hydro carbons.
9. the preparation method of the citrate of the type I compound described in claim 6, wherein described solvent includes tetrahydrochysene furan
Mutter, dioxane, isopropyl ether, ether, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, Ethyl formate, hexane, two
Chloromethanes, chloroform.
10. a kind of pharmaceutical composition, it contains the type I compound any one of the claim 1-5 of therapeutically effective amount
Citrate and pharmaceutically acceptable carrier.
Suppress 11. the citrate of the type I compound any one of claim 1-5 benefits from DPP-IV in preparation treatment
Disease medicine in purposes.
12. the purposes described in claim 11, wherein the disease for benefiting from DPP-IV suppression is type II diabetes.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410381575.2A CN105315301B (en) | 2014-08-05 | 2014-08-05 | The citrate of the inhibitor of thiadiazole DPP IV |
| PCT/CN2015/086121 WO2016019868A1 (en) | 2014-08-05 | 2015-08-05 | Salt of thiadiazole derivative dpp-iv inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410381575.2A CN105315301B (en) | 2014-08-05 | 2014-08-05 | The citrate of the inhibitor of thiadiazole DPP IV |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105315301A CN105315301A (en) | 2016-02-10 |
| CN105315301B true CN105315301B (en) | 2018-04-03 |
Family
ID=55243694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410381575.2A Active CN105315301B (en) | 2014-08-05 | 2014-08-05 | The citrate of the inhibitor of thiadiazole DPP IV |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN105315301B (en) |
| WO (1) | WO2016019868A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19727707A1 (en) * | 1997-06-30 | 1999-01-07 | Bayer Ag | Preparation of 4- and 5-chloro- or bromo-methyl-2,1,3-benzo-thiadiazoles |
| US6500804B2 (en) * | 2000-03-31 | 2002-12-31 | Probiodrug Ag | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
| CN102807568B (en) * | 2011-05-31 | 2015-11-25 | 正大天晴药业集团股份有限公司 | Thiadiazoles derivative class DPP-IV inhibitor |
| AR086675A1 (en) * | 2011-06-14 | 2014-01-15 | Merck Sharp & Dohme | PHARMACEUTICAL COMPOSITIONS OF COMBINATIONS OF INHIBITORS OF DIPEPTIDIL PEPTIDASA-4 WITH SIMVASTATIN |
-
2014
- 2014-08-05 CN CN201410381575.2A patent/CN105315301B/en active Active
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- 2015-08-05 WO PCT/CN2015/086121 patent/WO2016019868A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016019868A1 (en) | 2016-02-11 |
| CN105315301A (en) | 2016-02-10 |
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Effective date of registration: 20190603 Address after: 222069 No. 16 Jinqiao Road, Dapu Industrial Zone, Lianyungang Economic and Technological Development Zone, Lianyungang City, Jiangsu Province Co-patentee after: Capital Pharmaceutical Holdings (Beijing) Co., Ltd. Patentee after: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Address before: 222069 No. 16 Jinqiao Road, Dapu Industrial Zone, Lianyungang Economic and Technological Development Zone, Jiangsu Province Co-patentee before: Beijing Centaurus Biopharma Technology Co., Ltd. Patentee before: Lianyungang Runzhong Pharmaceutical Co.,Ltd. |
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Address after: 222069 No. 16 Jinqiao Road, Dapu Industrial Zone, Lianyungang Economic and Technological Development Zone, Lianyungang City, Jiangsu Province Patentee after: LIANYUNGANG RUNZHONG PHARMACEUTICAL Co.,Ltd. Patentee after: Capital Pharmaceutical Holdings (Beijing) Co.,Ltd. Address before: 222069 No. 16 Jinqiao Road, Dapu Industrial Zone, Lianyungang Economic and Technological Development Zone, Lianyungang City, Jiangsu Province Patentee before: LIANYUNGANG RUNZHONG PHARMACEUTICAL Co.,Ltd. Patentee before: Shouyao holding (Beijing) Co.,Ltd. |