122-09-8

Allosteric modulation offers an alternate approach to target the cannabinoid type-1 receptor (CB1) for therapeutic benefits. Examination of the two widely studied prototypic CB1 negative allosteric modulators (NAMs) Org27569 and PSNCBAM-1 revealed structural resemblance and similar structure–activity relationships (SARs). In silico docking and dynamics simulation studies using the crystal structure of CB1 co-bound with CP55,940 and Org27569 suggested that Org27569 and PSNCBAM-1 occupied the same binding pocket and several common interactions were present in both series with the CB1 receptor. A new scaffold was therefore designed by merging the key structural features from the two series and the hybrids retained these binding features in the in silico docking studies. In addition, one such hybrid displayed similar functions to Org27569 in dynamic simulations by preserving a key R2143.50-D3386.30 salt bridge and maintaining an antagonist-like Helix3-Helix6 interhelical distance. Based on these results, a series of hybrids were synthesized and assessed in calcium mobilization, [35S]GTPγS binding and cAMP assays. Several compounds displayed comparable potencies to Org27569 and PSNCBAM-1 in these assays. This work offers new insight of the SAR requirement at the allosteric site of the CB1 receptor and provides a new scaffold that can be optimized for the development of future CB1 allosteric modulators.

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Direct and selective synthesis of primary amines from easily available precursors is attractive yet challenging. Herein, we report the rapid synthesis of primary amines from alkenes via metal-free regioselective hydroamination at room temperature. Ammonium carbonate was used as ammonia surrogate for the first time, allowing for efficient conversion of terminal and internal alkenes into linear, α-branched, and α-tertiary primary amines under mild conditions. This method provides a straightforward and powerful approach to a wide spectrum of advanced, highly functionalized primary amines which are of particular interest in pharmaceutical chemistry and other areas.

The present invention relates to a novel process for the preparation of phenyl ethyl amine derivatives by reacting a phenyl ethyl hydroxy compound with hydrogen cyanide followed by in situ hydrolysis.

A catalytic intermolecular amination of nonactivated tertiary C(sp3)-H bonds (BDE of 96 kcal·mol-1) is reported for substrates displaying an activated benzylic site (BDE of 85 kcal·mol-1). The tertiary C(sp3)-H bond is selectively functionalized to afford α,α,α-Trisubstituted amides in high yields. This unusual site-selectivity results from the synergistic combination of Rh2(S-Tfpttl)4, a rhodium(II) complex with a well-defined catalytic pocket, with tert-butylphenol sulfamate (TBPhsNH2), which leads to a discriminating rhodium-bound nitrene species under mild oxidative conditions. This catalytic system is very robust, and the reaction was performed on a 50 mmol scale with only 0.01 mol % of catalyst. The TBPhs group can be removed under mild conditions to afford the corresponding NH-free amines.

A quinone-mediated general synthetic platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles, via a nucleophilic α-amino radical intermediate. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the functionalization of drug molecules.

3,3-Disubstituted tetrahydroisoquinolines are prepared in one step from Michael acceptors and 2-phenylethylamines under Pd catalysis and Ag2CO3 as an oxidant. Presumably, activation of an ortho C-H bond of the aromatic ring with Pd(II) is directed by the primary amine to form a palladacycle. Insertion of the olefin, subsequent conjugated addition of the amine, and reductive elimination of Pd(0) affords the expected products. Silver carbonate is not necessary when 2-phenylethylamines are converted previously to N-benzoyloxy-2-phenylethylamines.

Benzenesulfonyl-asymmetric ureas are provided for the treatment of conditions modulated by the ghrelin receptor.

Na2S2O8-promoted decarboxylative cyclization of biaryl-2-oxamic acid for phenanthridinones has been developed. This work illustrates the first example of intramolecular decarboxylative amidation of unactivated arene under transition-metal-free conditions. Additionally, this approach provides an efficient and economical method to access biologically interesting phenanthridinones, an important structure motif in many natural products. (Chemical Equation Presented).

The C-alkylation of nitroalkanes under mild conditions has been a significant challenge in organic synthesis for more than a century. Herein we report a simple Cu(I) catalyst, generated in situ, that is highly effective for C-benzylation of nitroalkanes using abundant benzyl bromides and related heteroaromatic compounds. This process, which we believe proceeds via a thermal redox mechanism, allows access to a variety of complex nitroalkanes under mild reaction conditions and represents the first step toward the development of a general catalytic system for the alkylation of nitroalkanes.

Provided herein are (alpha-substituted aralkylamino or heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, e.g., a compound of Formula 1, and their pharmaceutical compositions, preparation, and use as agents or drugs for treating proliferative diseases

A sulfonamide-based protecting group (PG), (9H-fluoren-9yl)methanesulfonyl (Fms), which can be used in a similar way to the well-established Fmoc PG, was developed. The advantages of this new PG were demonstrated in the successful formation of a phosphonamide between an N-Fmsprotected a-phosphonoalanine monoester and secondary alkylamines, including (R)-2-phenylethylamine, (S)-phenylalanine iert-butyl ester (H-Phe-OtBu), H-Pro-Gly-OtBu, and H-Phe-Phe-OtBu, without formation of oxazaphospholine, which is a serious problem associated with the Fmoc PG. The success should pave the way to the solid-phase synthesis of unnatural peptides substituted with a-amino phosphonic acid (AP) at essentially any arbitrary position without significant modification of the Fmoc-based chemistry that has been accumulated since Carpino's report in 1970. The N-Fms-AP monomer would attract much attention in the field of peptide mimetics.

Novel β2-agonists with a 5-hydroxy-4H-benzo[1,4]oxazin-3-one moiety as head group are described. Systematic chemical variations at the phenethylamine residue of these compounds lead to the discovery of compound 6m as potent, full agonist of the β2-adrenoceptor with a high β1/β2-selectivity. Molecular modeling revealed an interaction between the carboxylic acid group of 6m and a lysine residue (K305) of the β2-receptor as putative explanation for the high observed selectivity. Further, compound 6m displayed in a guinea pig in vivo model a complete reversal of acetylcholine induced bronchoconstriction which lasted over the complete study time of 5 h.

A variety of amines including even sterically less demanding and highly nucleophilic secondary amines have been efficiently deprotected without decarboxylative N-allylation from the corresponding N-allyloxycarbonyl (N-AOC) compounds by using a catalytic amount of [CpRu-(IV)(π-C3H 5)(2-quinolinecarboxylato)]PF6 in the presence of 1 molar amount of trifluoromethanesulfonic acid, the general utility of which has been demonstrated by the efficient synthesis of a collagen protein unit tripeptide, Pro-Pro-Gly.

The present invention relates to pyridines, pyrimidines and derivatives thereof, and pharmaceutically acceptable salts thereof. Also included is a method of treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic beta cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount a compound as described above.

Tertiary carbinamines (t-alkyl amines) can be conveniently obtained by dephosphorylation of diethyl N-t-alkylphosphoramidates 1 with 20% hydrochloric acid-tetrahydrofuran (1:1 v/v).

Ritter reaction of tertiary alcohols with chloroacetonitrile and subsequent cleavage of chloroacetyl group in the resulting chloroacetamide with thiourea is an efficient procedure for synthesis of tert-alkylamines.

The present invention features calcilytic compounds. "Calcilytic compounds" refer to compounds able to inhibit calcium receptor activity. Also described are the use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient; and techniques which can be used to obtain additional calcilytic compounds.

Substitution of the (CH3)2CH=CH group by (CH3)2C=N in linalool as well as by the (CH3)2CH-CH2 group in linalool and in sila-linalool does not lead to noticeable changes of their scent qualities.On the contrary, substitution of the OH group at the tertiary C atom by NH2 or CH3 - hydride isosteric to OH according to Grimm - affords fishy or etheric instead of the original flowery smells thus indicating a transition to different basic classes of odor.Similar results were obtained with the linalool-like scents of benzyldimethylcarbinol and phenylethyldimethylcarbinol.Therefor the theory of Amoore, after which only shape and size of molecules are ruling their odor qualities, must be called in question. - Keywords: Perfumes; Sila Perfumes; Isosteric Compounds; Silazanes; Olfactoric Theories.

The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are compounds of the formula STR1 and the non-toxic pharmaceutically acceptable salts thereof, wherein D is the residue of a centrally acting primary, secondary or tertiary amine and STR2 is an unsubstituted or substituted dihydropyridyl, dihydroquinolyl or dihydroisoquinolyl radical. The corresponding ionic pyridinium, quinolinium and isoquinolinium salts STR3 X-, wherein X- is the anion of a non-toxic pharmaceutically acceptable acid, are also disclosed.

The paper describes the synthesis and the pharmacological evaluation of some derivatives of betaxolol, all with an N-aralkylamine instead of the tertiobutylamine. These compounds have been tested for β1-adrenergic receptor antagonism on guinea pig atria, β2-adrenergic receptor antagonism on guinea pig trachea and α-adrenergic blocking activity on rat aorta. Compound U12 with a marked α-blocking activity and compound R8 with a β1/α ratio = 1 were selected for a haemodynamic study in the dog. The decrease in cardiac work and the diminution of total peripheral resistance exhibited by U12 are consistent with a dual α/β-blocking agent. Finally, structure-activity relationships are discussed.

Electrochemical reduction of tertiary nitroalkanes, 2-substituted-1,1-dimethyl-1-nitroethanes (1), was investigated in aqueous buffer solutions.In polarography, 1 with a phenyl group and/or a hydroxyl group at the 2-position showed an ill-defined wave in the weakly acidic and neutral pH region at relatively high negative potentials, in addition to a well-defined wave arising from the reduction of 1 to the corresponding hydroxylamine (2).Controlled potential electrolysis of 1 at the potential of the former wave gave the 1,1-dimethylethylamines (3) as well as the hydroxylamines 2.The amines 3 are formed exclusively from 2, probably via the O-protonated form.It is suggested that a phenyl group at the 2-position facilitates the reduction of 2 to 3 by enhancing the adsorption of 2 at the mercury cathode and that a hydroxyl group, while it interferes with the adsorption, assists the reduction by intramolecular hydrogen-bonding to stabilize the O-protonated form of 2.Keywords - tertiary nitroalkane; alkylhydroxylamine; electrochemical reduction; polarography; controlled potential electrolysis.

The synthesis and chemical reactions of a series of thiadiaziridine 1,1-dioxides (2) are described.The thermal stability is highly dependent on the R group and in one case (R = tert-octyl) is postulated that the thermolysis initially produces a diradical intermediate which can be trapped or further fragments to give a nitrene.A temperature-dependent NMR study on the coalescence of the diastereotopic α-methyl protons of 2b gives a ΔG = 20 kcal*mol-1.

Rate studies on five azoalkanes (4a-e) have been studied to assess important radical stabilizing effects.MO calculations of spin densities for three radicals with pi systems are correlated with kinetic rates of radical formation.

3'-Hydroxy-2-[N-methyl-N-(1,1-dimethyl-2-phenethyl)amino]acetophenone (TVX 960) is shown to be only partially stable in solution; hydrolysis occurs at neutral to alkaline pH-values. Proteolytic splitting in artificial intestinal liquid with pancreatin is particularly strong while in artificial stomach juice practically no breakdown occurs. In vitro studies show TVX 960 to be extensively stable in dog plasma. Approx. 95% of the compound is intact after 160 min, the rest is being broken down to mephentermine. In whole blood, however, more than 50% is broken down under the same conditions. In liver homogenates of dogs and rats, a strong breakdown occurs at approx. the same rates; the proportion of mephentermine in the liver homogenate of dogs is, however, lower than that in the liver homogenate of rats. In vivo studies in man show that following oral administration of equimolar quantities of TVX 960 and mephentermine certain differences exist with regard to renal elimination. No intact or glucuronide-conjugated TVX 960 are excreted. The amounts of mephenterine, phentermine and other basic metabolites over the first 4 h following administration of TVX 960 is approx. 4 times as high as following administration of mephentermine. Over the period from 8-60 h, however, the proportion of renally eliminating amines following administration of mephentermine is higher than following administration of TVX 960. Blood level determination in man shows that TVX 960 has a higher rate of absorption than mephentermine. The elimination (from blood) is also quicker following administration of TVX 960 than following mephentermine. The degree of N-demethylation differs following administration of the 2 compounds. Despite the hydrolytic or proteolytic instability of TVX 960 the proportion of phentermine in the blood is higher at first. From the differing phentermine/mephentermine ratios in the blood it can be seen that the N-demethylation occurring in vivo represents mainly the primary breakdown step of TVX 960. The phentermine/mephentermine ratio in the urine confirms that N-demethylation is to be regarded as the primary breakdown step.