Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 A) C–C bonds, (3) enhanced π-character of C–C bonds, and (4) C–H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects, (c) increasing metabolic stability, (d) increasing brain permeability, (e) decreasing plasma clearance, (f) contributing to an entropically more favorable binding to the receptor, (g) conformational restriction of peptides/peptidomimetics to prevent proteolytic hydrolysis, and (h) altering drug pKa to reduce its P-glycoprotein e...

The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.

Compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provided as well.

Compounds and compositions for delivering active agents

A new chiral phosphine−phosphite ligand, (R)-2-(diphenylphosphino)-1,1‘-binaphthalen-2‘-yl (S)-1,1‘-binaphthalene-2,2‘-diyl phosphite [(R,S)-BINAPHOS, (R,S)-2a], was synthesized. Its Rh(I) complex was prepared, and its structure has been characterized by 1H and 31P NMR spectroscopy. Using Rh(I) complexes of (R,S)-2a and its enantiomer, highly enantioselective hydroformylation of styrene has been performed (94% ee, iso/normal = 88/12). The catalyst system was also effective for a variety of other olefins. Some other phosphine−phosphite ligands bearing 1,1‘-binaphthyl and biphenyl backbones, such as (S)-3,3‘-dichloro-6-(diphenylphosphino)-2,2‘,4,4‘-tetramethylbiphenyl-6‘-yl (R)-1,1‘-binaphthalene-2,2‘-diyl phosphite [(S,R)-BIPHEMPHOS, (S,R)-5a], (R,R)-2a, (R,S)-2b, (R)-2c, and (R)-5b, were tested for asymmetric hydroformylation. The results indicate that the sense of enantioface selection for the prochiral olefins is mainly determined by the absolute configuration of the phosphine site, for example, the (R)...

Highly Enantioselective Hydroformylation of Olefins Catalyzed by Rhodium(I) Complexes of New Chiral Phosphine−Phosphite Ligands

Tetrahedron report number 205

A series of chiral diphosphine ligands denoted as PQ-Phos was prepared by atropdiastereoselective Ullmann coupling and ring-closure reactions. The Ullmann coupling reaction of the biaryl diphosphine dioxides is featured by highly efficient central-to-axial chirality transfer with diastereomeric excess >99%. This substrate-directed diastereomeric biaryl coupling reaction is unprecedented for the preparation of chiral diphosphine dioxides, and our method precludes the tedious resolution procedures usually required for preparing enantiomerically pure diphosphine ligands. The effect of chiral recognition was also revealed in a relevant asymmetric ring-closure reaction. The chiral tether bridging the two aryl units creates a conformationally rigid scaffold essential for enantiofacial differentiation; fine-tuning of the ligand scaffold (e.g., dihedral angles) can be achieved by varying the chain length of the chiral tether. The enantiomerically pure Ru- and Ir-PQ-Phos complexes have been prepared and applied to...

A new class of versatile chiral-bridged atropisomeric diphosphine ligands: remarkably efficient ligand syntheses and their applications in highly enantioselective hydrogenation reactions.

A series of 1-aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives were synthesized and evaluated as potential antidepressants. Compounds with the Z configuration were synthesized from 1-aryl-2-oxo-3-oxabicyclo[3.1.0]hexane and those with the E configuration from (E)-1-phenyl-2-(hydroxymethyl)cyclopropanecarboxylic acid. The compounds were evaluated in animal tests designed to reveal potential antidepressant activity and the existence of undesirable side effects. Several derivatives were more active than imipramine and desipramine. On the basis of its activity in pharmacological animal tests of antidepressant activity and its potential lack of side effects, 1-phenyl-1-[(diethylamino)carbonyl]-2- (aminomethyl)cyclopropane hydrochloride, midalcipran (INN), was selected for further development. This compound is currently in phase III clinical evaluation.

1-Aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants

A Convenient One-Step Synthesis of Glycidyl Ethers

This invention relates to new chemical compounds useful as drugs, as well as to pharmaceutical compositions containing the same. The new products are aromatic keto acid compounds with antiinflammatory as well as analgetic and hypocholesteremic activity and having the general formula ##STR1## wherein R1 is hydrogen, halogen, phenyl, halophenyl, phenoxy, or substituted phenoxy. R2 is hydrogen or alkoxy. R1 and R2 may form a ring, for instance: phenyl or cyclohexyl. R3 is always other than hydrogen, being either methyl (CH3) or methylene. When R3 is CH3, a double bond is present between the A and B carbons. When R3 is a methylene connected by a double bond to the B carbon, there can be only a single bond between the A and B carbons. The remaining valences of the A carbon atom are satisfied by hydrogen atoms. R4 may be OH, alkoxy, ##STR2## The drugs containing these active principles are useful in the prevention and treatment of inflammatory syndromes, pain, and conditions involving excess cholresterol.

Henri Cousse

Papers

Tetrahedron report number 205

1-Aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants

A Convenient One-Step Synthesis of Glycidyl Ethers

Aromatic keto acids and derivatives having analgetic, antiinflammatory, and hypocholesterolemizing action

Synthèse, structure et activité hypocholestérolémiante d'une série d'acides γ-aryl, γ-oxo butyriques substitués et dérivés