87679-37-6

Usage

Uses

Used in Pharmaceutical Industry:
Trandolapril is used as an antihypertensive agent for the treatment of hypertension. As an ACE inhibitor, it helps regulate blood pressure by blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.
Used in Pharmaceutical Industry:
Trandolapril is used as an ACE inhibitor to study its effects on the responsiveness of human retinal endothelial cells (HRECs) to vascular endothelial growth factor (VEGF). This application aids in understanding the drug's potential impact on retinal health and vascularization.
Used in Antibacterial Applications:
Although not its primary use, Trandolapril has also been explored for its antibacterial properties, indicating potential applications in the development of new antimicrobial agents.

Biochem/physiol Actions

Trandolapril is an ACE inhibitor. Trandolapril differs from other ACE inhibitors in that it has a longer biological half-life and a high degree of lipophilicity.

Clinical Use

Angiotensin converting enzyme inhibitor: Hypertension Heat failure After myocardial infarction

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs. Antihypertensives: increased risk of hyperkalaemia, hypotension and renal failure with ARBs and aliskiren. Bee venom extract: possible severe anaphylactoid reactions when used together. Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity. Cytotoxics: increased risk of angioedema with everolimus. Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics. ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect. Gold: flushing and hypotension with sodium aurothiomalate. Lithium: reduced excretion (possibility of enhanced lithium toxicity). Potassium salts: increased risk of hyperkalaemia. Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity.

Metabolism

Trandolapril is metabolised in the liver to the active trandolaprilat and to some inactive metabolites. About 33% of an oral dose of trandolapril is excreted in the urine, mainly as trandolaprilat; the rest is excreted in the faeces.

InChI:InChI=1/C24H34N2O5/c1-3-31-24(30)19(14-13-17-9-5-4-6-10-17)25-16(2)22(27)26-20-12-8-7-11-18(20)15-21(26)23(28)29/h4-6,9-10,16,18-21,25H,3,7-8,11-15H2,1-2H3,(H,28,29)/t16-,18+,19-,20-,21-/m0/s1

Upstream product

• 82717-96-2 [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine 
• 80828-13-3 rac-trans-octahydroindole-2-carboxylic acid 
• 84793-24-8 N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride 
• 145438-94-4 (2S,3aR,7aS)-octahydroindolecarboxylic acid 
• 114192-42-6 N-[(S)-1-carbethoxy-3-phenyl-propyl]-S-alaninoyl chloride hydrochloride 
• 881637-74-7 (2S,3aR,7aS)-perhydroindole-2-carboxylic acid trimethyl silyl ester 
• 82717-90-6 cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, phenylmethylester 
• 145641-35-6 phenylmethyl-(2S,3aR,7aS)-octahydroindole-2-carboxylate hydrochloride 
• 82717-97-3 octahydroindole-2-carboxylic acid benzyl ester hydrochloride 
• 237421-54-4 tert-butyl (2S,4R)-N-tert-butoxycarbonyl-4-(prop-2-enyl)pyroglutamate 
• 237421-53-3 tert-butyl (2S,4S)-N-tert-butoxycarbonyl-4-(prop-2-enyl)pyroglutamate 
• 91229-91-3 tert-butyl (S)-N-tert-butoxycarbonylpyroglutamate 
• 35418-16-7 L-t-butyl pyroglutamate 
• 98677-37-3 trandolapril benzyl ester 

Downstream Products

• 82717-96-2 [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine 

Relevant academic research and scientific papers

A Stereoselective Synthesis of the ACE Inhibitor Trandolapril

A conceptually novel and stereoselective synthesis of the enantiopure octahydroindole building block and its conversion into the ACE inhibitor trandolapril was achieved. Key steps include the α-allylation of a protected l -pyroglutamic acid derivative, a highly diastereoselective Hosomi-Sakurai reaction and a Ru-catalyzed ring-closing metathesis of a 4,5-diallylated proline. This way, the synthesis of trandolapril was efficiently achieved in 25% overall yield (12 steps).

PROCESS FOR THE PREPARATION OF AMIDES OF N-[1-(S)-(ETHOXYCARBONYL)-3-PHENYLPROPYL]-L-ALANINE

A process for the production of amides of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine is described. The process can be used for the production of key intermediates and finally the ACE inhibitors such as Ramipril, Enalapril, Quinapril, Trandolapril, Delapril and Moexipril starting from N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine by the reaction with the appropriate amines.

PROCESS FOR THE SYNTHESIS OF AN ACE INHIBITOR

A process for the synthesis of trandolapril which comprises condensing N-[I-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride with trans octahydro-1H- indole-2-carboxylic acid in a first organic solvent comprising a water immiscible inert organic solvent and in the presence of a base, and isolating trandolapril from a second organic solvent. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride may also be condensed with (2S,3aR,7aS) octahydro-1H-indole-2-carboxyIic acid in a first organic solvent and in the presence of a base, and trandolapril isolated. There is also provided a process for the resolution of racemic trans octahydro-1H-indole-2-carboxylc acid.

Method for producing {n-[1-(s)-carbalkoxy-3-phenylpropyl]-s-alanyl-2s, 3ar, 7as-octahydroindole-2-carboxylic acid} compounds

A method for preparing optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid} and pharmaceutically acceptable salts thereof, wherein a racemic mixture of optionally substituted trans-octahydroindole-2-carboxylic acid is reacted with the N-carboxyanhydride of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine}, which is optionally substituted on the phenyl ring, in a suitable inert solvent, and subsequently the resulting optionally substituted {N-[1-S-carbalkoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid}, preferably trandolapril, is isolated, and polymorphic forms A and B of trandolapril.

Process for the preparation of intermediates of trandolapril and use thereof for the preparation of trandolapril

A process for the preparation of an intermediate of trandolapril, (2S,3aR,7aS)-perhydroindole-2-carboxylic acid of Formula II is provided. Also provided are processes for preparing trandolapril.

Process for the synthesis of ?2S, 3aR, 7aS|-octahydroindole-2-carboxylic acid and its conversion to trandolapril

The present invention describes a novel method for the synthesis of (2S,3aR,7aS)-octahydroindole-2-carboxylic acid of formula III using a new intermediate of formula II and conversion of the product of formula-III to trandolapril of formula I

PREPARATION OF TRANDOLAPRIL

A process for preparing trandolapril, (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, and intermediates that are useful in the process.

METHOD FOR PRODUCING {N-[1-(S)-CARBALKOXY-3-PHENYLPROPYL]-S-ALANYL-2S, 3AR, 7AS-OCTAHYDROINDOL-2-CARBOXYLIC ACID} COMPOUNDS

The invention relates to a method for producing optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid} and the pharmaceutically acceptable salts thereof. To this end, a racemic mixture of optionally substituted trans-octahydroindol-2-carboxylic acid is reacted with the N-carboxyanhydride of {N-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-L-alanine}, which is optionally substituted on the phenyl ring, in an appropriate inert solvent, and the obtained optionally substituted {N-[1-(S)-carbalkoxy-3-phenylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid}, preferably trandolapril, is subsequently isolated, as well as polymorphous forms A and B of trandolapril.

A METHOD FOR THE PREPARATION OF (2S, 3AR, 7AS)-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID AS KEY INTERMEDIATE IN THE PREPARATION OF TRANDOLAPRIL BY REACTING A CYCLOHEXYL AZIRIDINE WITH A DIALKYL MALONATE

A method for the synthesis of a compound of formula (I) as a mixture of enantiomers, formula (I) (wherein R1 is H or an acid protective group and H+A- indicates an optional acid with which the compound of formula (I) may form an ammonium salt) said method comprising; A) reacting a cyclohexyl aziridine with a dialkyl malonate, whereby to provide a trans-fused 3-alkylcarbonyl-octahydro-indol-2-one; B) decarbonylation at the 3-position, conversion of the ketone of the resulting trans-octahydro-indol-2-one to an optionally protected carboxylic acid group; and C) optionally removing any N-substitution if necessary.

NOVEL CRYSTALLINE FORMS OF TRANDOLAPRIL

The present invention relates to two novel crystalline polymorphs of trandolapril, processes for their preparation and the pharmaceutical compositions containing them.