668270-12-0 Usage
Uses
Different sources of media describe the Uses of 668270-12-0 differently. You can refer to the following data:
1. Linagliptin (TrajentaR, TradjentaTM, TrazentaTM, TrayentaTM) is an oral, highly selective inhibitor of dipeptidyl peptidase-4 and is the first agent of its class to be eliminated predominantly via a nonrenal route. Linagliptin is indicated for once daily use for the treatment of adults with type 2 diabetes mellitus.
2. A novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor with potential use in the treatment of type 2 diabetes.
3. dipeptidypeptidase inhibitor, antidiabetic
4. highly potent CD26 inhibitor
5. Labeled Linagliptin, intended for use as an internal standard for the quantification of Linagliptin by GC- or LC-mass spectrometry.
Treatment of Type 2 diabetes
Linagliptin acts to lower blood glucose levels by inhibiting the enzyme DPP-4, thereby preventing the degradation of the incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide) and attenuating postprandial glucose excursions. By selectively targeting DPP-4, linagliptin potentially causes a more physiologically based control of glucose-dependent postprandial glucose excursions and of fasting blood glucose, both of which are mediated by effects of glucose on insulin and glucagon secretion. An advantage of linagliptin is that since incretin-stimulated release of insulin is glucose dependent, linagliptin is associated with a low incidence of hypoglycaemia. Moreover, DPP-4 inhibitors have a low potential for drug-drug interactions (with the exception of saxagliptin, which is metabolized by cytochrome P450 [CYP] 3A4/5), are generally well tolerated and have minimal or neutral effects on bodyweight.
Pharmacokinetics
Linagliptin shows modest oral bioavailability, and it is rapidly absorbed. The maximum plasma concentration at steady state is reached on average 1.5 hours after administration of linagliptin 5 mg, once daily . Linagliptin half-life is 131 hours. No relevant food effects were observed on the absorption profile of linagliptin. Unlike other DPP-4 inhibitors, linagliptin excretion is not performed by the kidneys, but rather through the enterohepatic system.
Description
Linagliptin (trade names Tradjenta and Trajetna) is an inhibitor of
dipeptidyl peptidase-4 (DPP-4) that was approved by the U.S. FDA in May
2011 for the treatment of Type 2 diabetes along with diet and exercise.
Linagliptin (BI-1356) has been
described as a potent highly selective, slow-off rate and long acting inhibitor of DPP-4. Linagliptin arose from optimization efforts of xanthine-based
DPP-4 inhibitors with the initial lead identified from an HTS campaign.
After optimizing the activity of the initial micromolar lead, two issues that needed to be addressed were activity for hERG and muscarinic receptor M1.
Introduction of a butynyl group at the N7 position of the xanthine ring gave
much reduced M1 affinity with no measureable hERG activity. Linagliptin
inhibits DPP-4 with an IC50=1 nM and is highly selective (>10,000-fold)
against DPP-8 and DPP-9. Linagliptin shows no interactions with CYPs up
to 50 mM. The described synthesis of linagliptin starts with 8-bromoxanthine,
which is alkylated at the N-7 position to introduce the butyne group,
followed by alkylation of the N-1 group to introduce the methyl-quinazoline
group. Displacement of the bromide with (R)-Boc-3-amino-piperidine
followed by deprotection gives linagliptin. When administered to db/db
mice orally, linagliptin dose dependently reduced glucose excursion from
0.1 mg/kg (15% inhibition) to 1 mg/kg (66% inhibition).
Originator
Boehringer Ingelheim (United States)
Definition
ChEBI: A xanthine that is 7H-xanthine bearing (4-methylquinazolin-2-yl)methyl, methyl, but-2-yn-1-yl and 3-aminopiperidin-1-yl substituents at positions 1, 3, 7 and 8 respectively (the R-enantiomer). Used for treatment of type
I diabetes.
Brand name
Tradjenta
Clinical Use
Type 2 diabetes mellitus
Synthesis
The synthesis of linagliptin began from commercially available
8-bromo-3-methylxanthine (171). Sequential alkylations
of guanine derivative 171 at N-7 with butyn-2-yl bromide
in the presence of N,N-diisopropylethylamine and N-1 with 2-
(chloromethyl)-4-methylquinazoline (173) in the presence of
potassium carbonate, yielded N1,N7-dialkylated xanthine 174 in
85% yield. This material was further condensed with (R)-3-Bocaminopiperidine
(175) in the presence of potassium carbonate to
give aminopurine dione 176 in 88% yield. Finally, the primary
amine of 176 was liberated with trifluoroacetic acid in methylene
chloride to produce linagliptin (XV) in 91% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: effects possibly reduced by rifampicin.
Metabolism
Minimal metabolism to inactive metabolites.
Approximately 80% is eliminated in the faeces and 5% in
the urine.
Check Digit Verification of cas no
The CAS Registry Mumber 668270-12-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,6,8,2,7 and 0 respectively; the second part has 2 digits, 1 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 668270-12:
(8*6)+(7*6)+(6*8)+(5*2)+(4*7)+(3*0)+(2*1)+(1*2)=180
180 % 10 = 0
So 668270-12-0 is a valid CAS Registry Number.
InChI:InChI=1/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1
668270-12-0Relevant articles and documents
Preparation method of linagliptin for treating type II diabetes mellitus
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Paragraph 0085-0094, (2021/03/30)
The invention provides a preparation method of linagliptin for treating type II diabetes mellitus, which comprises the following steps: by using methylurea and ethyl cyanoacetate as raw materials, carrying out cyclization reaction to form a compound II, carrying out bromination reaction on the compound II to generate a compound III, carrying out condensation reaction on the compound III and 1-amino-2-butyne to generate a compound IV, making the compound IV, formic acid and an iodine source react in an organic solution to generate a compound V, reacting the compound V and a compound VI under the conditions of DMF and anhydrous potassium carbonate, reacting with (R)-3-Boc-aminopiperidine (VIII), and recrystallizing to obtain a pure target compound I, namely linagliptin. The invention provides a novel preparation method of linagliptin, which has the advantages of simple method, high reaction yield, avoidance of side reaction, cheap raw materials, reduction of the reaction cost, increase of the yield of the target compound, and suitableness for industrial large-scale production.
Novel preparation process of linagliptin
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, (2021/01/24)
The invention discloses a novel preparation process of linagliptin. 8-bromo-3-methyl xanthine (SM1) is used as an initial raw material, DMF is used as a solvent and reacts with 1-bromo-2-butyne (SM2)under the alkaline condition to obtain an intermediate I, then the intermediate I reacts with 2-chloromethyl-4-methyl quinazol (SM3) under the solvent system to obtain an intermediate II, the intermediate II and (R) 3-aminopiperidine dihydrochloride (SM4) are subjected to a substitution reaction, and finally anti-type 2 diabetes drug linagliptin (I) is prepared. By adopting a one-pot method, the method has the advantages that the raw material cost is low, the yield is high, the post-treatment operation of each step of chemical reaction in multi-step reaction is reduced, the production period is greatly shortened, few impurities are generated in the reaction, the product quality is high, the use amount of chemical reagents is relatively reduced, and the method is relatively green and environment-friendly, and is beneficial to industrial production.
Preparation method of linagliptin
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Paragraph 0009; 0032; 0034-0036; 0038, (2021/06/21)
The invention relates to a preparation method of linagliptin. The method comprises the following steps: taking a raw material I, namely 2-chloromethyl-4-methylquinazoline, and a raw material II, namely 8-bromo-7-(2-butynyl)-3-methyl-1H-purine-2, 6 (3H, 7H)-diketone as raw materials, performing reaction to obtain an intermediate III, namely 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl)-methyl]-1H-purine-2, 6-diketone, and performing reaction with a raw material IV: (R)-3-aminopiperidine hydrochloride to prepare a target product. In the reaction process, a protecting group does not need to be added, the step of removing the protecting group after the reaction is completed is omitted, and the generation of reaction byproducts in the process of removing the protecting group is reduced. The solvents used in the method are beneficial to recycling, low in price, environment-friendly, green and environmentally friendly, and the obtained product is high in yield, high in purity and suitable for large-scale production.
