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Home> Encyclopedia >Pharmaceutical Intermediates>Organic Intermediate>Pharmaceutical
Linagliptin structure
Linagliptin structure

Linagliptin

Iupac Name:8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione
CAS No.: 668270-12-0
Molecular Weight:472.54
Modify Date.: 2022-11-02 17:22
Introduction: Linagliptin (trade names Tradjenta and Trajetna) is an inhibitor ofdipeptidyl peptidase-4 (DPP-4) that was approved by the U.S. FDA in May2011 for the treatment of Type 2 diabetes along with diet and exercise. Linagliptin (BI-1356) has beendescribed as a potent highly selective, slow-off rate and long acting inhibitor of DPP-4. Linagliptin arose from optimization efforts of xanthine-basedDPP-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 gavemuch reduced M1 affinity with no measureable hERG activity. Linagliptininhibits 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 upto 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-quinazolinegroup. Displacement of the bromide with (R)-Boc-3-amino-piperidinefollowed by deprotection gives linagliptin. When administered to db/dbmice orally, linagliptin dose dependently reduced glucose excursion from0.1 mg/kg (15% inhibition) to 1 mg/kg (66% inhibition). View more+
1. Names and Identifiers
1.1 Name
Linagliptin
1.2 Synonyms

(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione 1H-Purine-2,6-dione, 8-((3R)-3-amino-1-piperidinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-((4-methyl-2-quinazolinyl)methyl)- 8-[(3R)-3-AMino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-Methyl-1-[(4-Methyl-2-quinazolinyl)Methyl]-1H-purine-2,6-dione 8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-3,7-dihydro-1H-purine-2,6-dione 8-[(3R)-3-AMino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-Methyl-1-[(4-Methyl-2-quinazolinyl)Methyl]-1H-purine-2,6-d 8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Bi 1356 BI-1356 BI-1356-BS Ondero Tradjenta Trajenta

1.3 CAS No.
668270-12-0
1.4 CID
10096344
1.5 EINECS(EC#)
1308068-626-2
1.6 Molecular Formula
C25H28N8O2 (isomer)
1.7 Inchi
InChI=1S/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
1.8 InChkey
LTXREWYXXSTFRX-QGZVFWFLSA-N
1.9 Canonical Smiles
CC#CCN1C2=C(N=C1N3CCCC(C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
1.10 Isomers Smiles
CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
2. Properties
2.1 Density
1.39
2.1 Melting point
202 oC
2.1 Boiling point
661.189°C at 760 mmHg
2.1 Refractive index
1.717
2.1 Flash Point
353.675°C
2.1 Precise Quality
472.23400
2.1 PSA
116.86000
2.1 logP
1.91270
2.1 Solubility
<1 mg/mL
2.2 Color/Form
Powder
2.3 Decomposition
Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides.
2.4 pKa
10.01±0.20(Predicted)
2.5 Water Solubility
<1 mg/mL
2.6 Stability
Stable if stored as directed; avoid strong oxidizing agents
3. Use and Manufacturing
3.1 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.
3.2 Usage
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.
4. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

no data available

2.2 GHS label elements, including precautionary statements

Pictogram(s) no data available
Signal word

no data available

Hazard statement(s)

no data available

Precautionary statement(s)
Prevention

no data available

Response

no data available

Storage

no data available

Disposal

no data available

2.3 Other hazards which do not result in classification

no data available

6. Other Information
6.0 Target
Value
6.1 DPP-4 (cell-free assay)
1 nM
6.2 Uses

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.

6.3 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. 

6.4 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.

6.5 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).
6.6 Originator
Boehringer Ingelheim (United States)
6.7 Uses
A novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor with potential use in the treatment of type 2 diabetes.
6.8 Uses
dipeptidypeptidase inhibitor, antidiabetic
6.9 Uses
highly potent CD26 inhibitor
6.10 Uses
Labeled Linagliptin, intended for use as an internal standard for the quantification of Linagliptin by GC- or LC-mass spectrometry.
6.11 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.
6.12 Brand name
Tradjenta
6.13 Chemical 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.

7. Computational chemical data
  • Molecular Weight: 472.54g/mol
  • Molecular Formula: C25H28N8O2
  • Compound Is Canonicalized: True
  • XLogP3-AA: 1.9
  • Exact Mass: 472.23352217
  • Monoisotopic Mass: 472.23352217
  • Complexity: 885
  • Rotatable Bond Count: 4
  • Hydrogen Bond Donor Count: 1
  • Hydrogen Bond Acceptor Count: 7
  • Topological Polar Surface Area: 114
  • Heavy Atom Count: 35
  • Defined Atom Stereocenter Count: 1
  • Undefined Atom Stereocenter Count: 0
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
  • CACTVS Substructure Key Fingerprint: AAADceB78AAAAAAAAAAAAAAAAAAAAWAAAAA8WLEAAAAAAFix/AAAHgAQAAAADCjBnwQz8PdMEADoEydydACCgC0nEqAJ2KG4dNiIaKrA2fGUJIholyLIyGcQgIAOAAAAAAACAAAAAAAAAAQAAAAAAAAAAA==
8. Question & Answer
  • What is Linagliptin? Jul 01 2020
    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 ...
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