Glacial Acetic Acid Catalyzed Synthesis, Physicochemical and Biological Evaluation of Benzodiazepines as Potent CNS Agents.

BACKGROUND: Approach for green chemistry for chemical synthesis is found to be very efficient as it makes the reaction more easily, less tedious, maximize desired products and minimize by-products. MATERIALS & METHODS: Utilizing this approach 1, 5-benzodiazepines and its derivatives have been synthesized and evaluated for skeletal muscle and antianxiety activity. 1, 5-benzodiazepine derivatives have attracted great attention due to its diversity of pharmacological activities and its application in heterocyclic synthesis and medicines. The target compounds were synthesized by first reacting o-phenylenediamine with acetophenone to yield 1, 5-benzodiazepines. In the next step the NH of 1, 5-benzodiazepines were chloroacetylated and then the chloro group was substituted with different anilines. The structures were confirmed on the basis of their TLC, IR, 1H NMR and CHN elemental studies. The physicochemical parameters were determined for BBB penetration through online software. RESULTS: The Log P values of the compounds tested showed that compounds have the potential to be CNS active. The compounds were evaluated for the skeletal muscle relaxant activity and antianxiety activity. It was investigated that 1, 5-benzodiazepines derivatives possess significant differences between control group and treated group. CONCLUSION: Among these derivatives, the compound bearing chloro group possesses the highest skeletal muscle relaxant and antianxiety activity.

Synthesis, Computational and Pharmacological Evaluation of N-(2-benzoyl- 4-chlorophenyl)-2-(4-(Substituted Phenyl) Piperazin-1-yl) Acetamides as CNS Agents.

BACKGROUND: A series of new N-(2-benzoyl-4-chlorophenyl)-2-(4-(substituted phenyl) piperazin-1-yl) acetamides (3a-j) have been synthesized by the chloroacetylation of 2-amino-5- chlorbenzophenone which was further reacted with substituted phenylpiperazine. MATERIAL: The chemical structures of the compounds were confirmed on the basis of their TLC, IR, 1HNMR, 13CNMR and by elemental analysis. The physicochemical similarity of the target compounds with respect to standard drug diazepam was assessed by calculating from a set of physicochemical properties using software programs. CONCLUSION: Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABAA receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The anxiolytic and skeletal muscle relaxant activity of the target compounds (3a-j) were evaluated in albino mice. Among them, compound 3h showed potent anxiolytic and skeletal muscle relaxant activity.

Hypnotic profile of imines from benzimidazole chalcones: mechanism of synthesis, DFT studies and in silico screening.

A series of 1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] amino}-1,3,4-thiadiazole-2- thiols (6a-6f) were synthesized by the acid catalyzed nucleophilic addition reaction between 1-(1H-benzimidazol-2-yl)-3- phenylprop-2-en-1-ones (4a-4f) and 5-amino-1,3,4-thiadiazole-2-thiol. All the synthesized compounds were characterised by IR, (1)HNMR, (13)CNMR, Mass and elemental analyses. A transition state calculation obtained from DFT study to explore the molecular mechanism of action of the synthetic route. The mechanism of synthesis revealed that the imidazole system can make an increase in the electrophilic character of carbonyl carbon in the benzimidazole chalcones. So the electron deficient carbonyl carbon could be efficiently attacked on the amino group of 1,3,4-thiadiazole ring to forms an imine linkage between the two heterocyclic systems. All the titled derivatives at a dose level of 10mg/kg body weight potentiate the hypnotic action of Phenobarbitone (at a dose of 10mg/kg body weight i.p.). The compounds such as 6b, 6a, and 6c showed a significant percentage increase in sleeping time relative to the control experiment 423.8, 387.6 and 329.5 respectively. The preclinical evaluation of the compounds was ascertained by blood-brain barrier, human oral absorption prediction and in silico toxicity assessment.

Behavioural effects of thieno and pyrazolo [2,1] benzothiazepine derivatives in mice.

Behavioural studies were conducted in mice with a number of hetero[2,1]benzothiazepine derivatives, analogues of tianeptine. Previously published studies in mice have shown that some of these compounds were effective in the tetrabenazine and Porsolt tests. In the present study, four of the 15 compounds under study potentiated the actions of 5-hydroxytryptophan (5-HTP, 50 mg/kg i.p.), but no significant antagonism of the apomorphine (16 mg/kg s.c.)-induced hypothermia and potentiation of the amphetamine actions was found. Moreover, some of them inhibited the stereotyped behaviour and/or climbing behaviour of low doses of apomorphine and compound 2 was effective in the plus-maze test. These compounds also produced a slight inhibition of exploratory behaviour in the holeboard test. On the other hand, no significant muscle relaxant and anticonvulsant activities were observed at any dose employed. Together, these data suggest that some of the compounds under study combine the antidepressant effects with additional neuroleptic or anxiolytic activities in mice.

Synthesis and pharmacological screening for muscle relaxant, anticonvulsant, and sedative activities of certain organic compounds produced by Michael addition.

Michael addition of certain nucleophiles on alpha, beta-unsaturated ketones 1 led to the formation of adducts 2-7 as well as the reaction of arylidene derivatives with secondary amines afforded the amino compounds 9 and 11. Also, dialkylmalonates were treated with alpha-cyano cinnamide to afford 13. On the other hand, double Michael cycloaddition of ethylcyanoacetate or tetrachlorophthalic anhydride to the suitable divinylketone were synthesized to produce 15-17. Selected compounds (13 and 6) were screened for muscle relaxant, anticonvulsant, and sedative activities using established pharmacological models. Their activities were compared with that of phenobarbital sodium taken as standard. Compound 6 was the most potent muscle relaxant while compounds 13a and 13c offered the highest anticonvulsant activity. Meanwhile compound 13c showed the highest potentiation of phenobarbital induced sleep in mice.

[New findings on the synthesis of the centrally acting muscle relaxant chlormezanone and its resolution of a gram scale using a Chiralcel OD column]. / Neue Befunde zur Synthese des chiralen Muskelrelaxans Chlormezanon und dessen Racematspaltung an einer präparativen Chiralcel OD-Säule.

2-(4-Chlorophenyl)-4-metathiazanone (2) is the intermediate product for the two step-synthesis of chlormezanone (1), a centrally acting muscle relaxant. The second step includes the oxidation of its sulfur atom. It has been found that the foregoing reaction of 4-chlorobenzaldehyde with methylamine forming the hemiaminale and the subsequent addition of beta-mercaptopropionic acid leads to a remarkable better yield (67% of th.) than the route via the hemimercaptale (42% of th.). 2 could be oxidized with sodium perborate superior to potassium permanganate. The racemic chlormezanone (1) is resolved quickly on a gram scale by preparative column chromatography on a Chiralcel OD column (tris(3,5-dimethyl-phenyl-carbamoyl)cellulose on silicagel). The resolution needed only 40 min, if flow rate, composition of the mobile phase and temperature as the most important factors are determined prior with an analytical column. Both dissociation constants could be determined for the first time with the aid of a log pKa-Titrator of the Sirius Co., which needs for the registration of the curves only 15-17 min in the pH range of 2-12. This speed outplayed the disturbing cleavage of the S-C bond of chlormezanone at strong acidic and alkaline pH values.

Indanylidenes. 1. Design and synthesis of (E)-2-(4,6-difluoro-1-indanylidene)acetamide, a potent, centrally acting muscle relaxant with antiinflammatory and analgesic activity.

The design of rigid cyclic analogues derived from cinnamamide 1, (E)-N-cyclopropyl-3-(3-fluorophenyl)prop-2-enamide, and beta-methylcinnamamide 2, (E)-N-cyclopropyl-3-(3-fluorophenyl)but-2-enamide, has led to the discovery of the potent, centrally acting muscle relaxant (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 17. Compound 17 also possesses potent antiinflammatory and analgesic activity. This paper describes the synthesis and the muscle relaxant, antiinflammatory, and analgesic structure-activity relationships of 17 and 67 of its analogues. Compound 17 has been taken into phase I clinical trials.

Indanylidenes. 2. Design and synthesis of (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, a potent antiinflammatory and analgesic agent without centrally acting muscle relaxant activity.

Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, 2. Compound 2 is a potent antiinflammatory and analgesic agent without centrally acting muscle relaxant activity.

Dantrolene analogues revisited: general synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle.

The general synthesis of dantrolene analogues with various substituents on its phenyl ring has been developed via palladium-catalyzed cross-coupling reactions, the Stille or Suzuki reaction, as the key step. The effects of synthesized analogues have been evaluated by two kinds of Ca(2+) release modes from sarcoplasmic reticulum (SR) of mouse skeletal muscle fibers based on: (1) the measurement of twitch contraction caused by the physiological Ca(2+) release (PCR) of intact skeletal muscle and (2) the rate of Ca(2+)-induced Ca(2+) release (CICR) in saponin-treated skinned muscle fibers. Although dantrolene, a lead compound, inhibits both twitch contraction and CICR, some structurally modified analogues exhibit one or the other of these effects. The methoxy congener, GIF-0185, potently inhibits the twitch contraction without affecting the CICR, while GIF-0166 and GIF-0248, the ortho-nitro regioisomer and ortho, ortho-dinitro substituted analogues, respectively, doubly potentiate the CICR exclusively.

Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha 1 selective ligands.

New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.

[Synthesis and pharmacological study of three 1-alkyl-3-(ethoxycarbonylmethylene)-2-oxo quinoxalines]. / Synthèse et étude pharmacologique de trois dérivés alkylés de la 3-(éthoxycarbonylméthylène)- 2-oxo quinoxaline.

The acute toxicity study and the psychotropic activity of three alkylated derivatives of 3-(ethoxycarbonylmethylene) -2-oxo quinoxaline did not demonstrate any toxicity of these products at therapeutic dosages. In the animal, these compounds have sedative, myorelaxant and anxiolytic properities.

Synthesis of optically active NC-1800, a therapeutic agent for urinary disturbance.

A new synthetic method for chiral oxazolidinone derivatives, therapeutic agents for treating urinary disturbance, is described. The condensed compound obtained from chiral 1-amino-3-phenyl-2-propanol and 1-phenyl-3-morpholino-1-propanone was reduced with Me4NBH(OAc)3 to give the intermediate, 1-(3-morpholino-1-phenylpropyl)amino-3-phenyl-2-propanol (MAPP) in 34% diastereomeric excess (d.e.). MAPP was converted to an urethane and purified by recrystallization of its methanesulfonate, to afford a single isomer, (2R)-1-[N-[(1S)-3-morpholino-1-phenylpropyl]-N -ethoxycarbonyl]amino-3-phenyl-2-propanol methanesulfonate (4-A. methanesulfonate).

[3H]Azidodantrolene: synthesis and use in identification of a putative skeletal muscle dantrolene binding site in sarcoplasmic reticulum.

Dantrolene sodium is a medically important hydantoin derivative that interferes with release of Ca2+ from intracellular stores of skeletal muscle by an unknown mechanism. Identification of the molecular target of dantrolene would greatly aid in understanding both the mechanism of action of the drug and the dynamics of intracellular Ca2+ release in muscle. [3H]Azidodantrolene was designed and synthesized as a photoaffinity analogue in order to identify a putative dantrolene receptor in skeletal muscle. Introduction of 1 mole-atom of tritium into aldehyde 5b was required during radioligand synthesis in order to ensure high enough specific activity for detection of photo-cross-linked proteins by fluorographic methods. This was accomplished by reduction of ester 3 with custom synthesized, 100% tritium-labeled lithium triethylborotritide, followed by oxidation to 5b by manganese(IV) oxide. Compound 6b was demonstrated to be >/=95% tritium-labeled at the imine position by NMR spectroscopy, and the specific radioactivity of [3H]azidodantrolene sodium was empirically determined by HPLC and liquid scintillation counting to be 24.4 Ci/mmol, approximately 85% of theoretical maximum. [3H]Azidodantrolene was found to be pharmacologically active in ligand-receptor binding studies with skeletal muscle sarcoplasmic reticulum membranes. Photo-cross-linking experiments analyzed by SDS-PAGE and tritium fluorography have identified a approximately 160-kDa specifically labeled protein as the putative, intracellular, skeletal muscle dantrolene receptor. This photolabeled protein comigrates with a protein in Western blots immunologically cross-reactive to a polyclonal anti-rabbit skeletal muscle ryanodine receptor antibody. Thus, the putative dantrolene receptor may be related to the skeletal muscle ryanodine receptor.

Benzodiazepine receptor ligands. 4. Synthesis and pharmacological evaluation of 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2,4] benzotriazine 5-oxides.

The synthesis of new 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2, 4]benzotriazine 5-oxides and their binding activities at the central benzodiazepine receptor (BZR) are reported. The derivatives substituted at the 3-position with electron-rich five-membered rings, such as pyrrole 11, 2-thiophene 13c, or 3-thiophene 13d, showed good affinity values for BZR. In in vivo tests the 3-(thien-3-yl)-8-chloropyrazolo[5,1-c][1,2,4] benzotriazine 5-oxide (13d) showed selective anticonvulsant activity.

Study of the antidepressant activity of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives.

A series of 23 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives were tested for acute toxicity and antidepressant activity in mice. Eight of the 23 compounds tested clearly antagonised the tetrabenazine effects and four of them (5, 7, 19, 23) showed activity values ranging from 40 to 75%, close to those shown by imipramine and viloxazine, the drugs chosen as reference standards. Compounds 7, 19 and 23 were also notably effective in the Porsolt test, shortening the immobility period of mice by more than 20%. The values obtained were very close to those elicited by imipramine and viloxazine. The most effective compounds in these tests were found among those bearing a primary amine or a benzoylamino group at the position 3 of the thieno[2,3-d]pyrimidine general structure (7, 19 and 23). The substitution of the thioxocarbonyl group at position 2 by a methylmercapto substituent maintained the activity (23). Compounds 7, 19 and 23 were chosen as prototypes for the design of new molecules with better antidepressant activity. These compounds did not present the adverse anticholinergic effects found in most tricyclic antidepressant drugs.

[Synthesis and pharmacologic study of 1,5-benzodiazepine-2,4-diones and their alkyl derivatives]. / Synthèse et étude pharmacologique des 1,5-benzodiazépine-2,4-diones et de leurs dérivés alkylés.

From the pharmacodynamic studies of 1,5-benzodiazepin-2,4-diones and alkyl derivatives prepared in our laboratories, we can conclude that these products are not toxic at therapeutic dosage. They have sedative, myorelaxant and anxiolytic actions. The two products alkylated by allyl bromide have also hypnotic, sedative and anticonvulsant properties.

[Synthesis and pharmacologic study of 1,5-benzodiazepine-2,4-dithiones and their alkyl derivatives]. / Synthèse et étude pharmacologique des 1,5-benzodiazépine-2,4-dithiones et de leurs dérivés alkylés.

From the pharmacodynamic studies of 1,5-benzodiazepine-2,4-dithiones and alkyl derivatives, we can conclude that these products are not toxic at therapeutic dosage. They have sedative, myorelaxant and anxiolytic actions.

CNS effects of a series of 1,2,4-triazolyl heterocarboxylic derivatives.

A series of 1,2,4-triazolyl heterocarboxylic derivatives were tested for acute toxicity and CNS effects in mice. Several of these compounds demonstrated clear psychostimulant effects. Other components of the series, however, showed a definite central depressant activity. Some of the screened derivatives showed interesting anxiolytic properties.

Synthesis of some indane derivatives of central muscle relaxant and anticonvulsant profiles.

A series of 2,2-bis(hydroxymethyl)indane derivatives 1a-f, 2a-e and 3a-f were synthesized to investigate their central muscle relaxant and anticonvulsant activities. The synthesized compounds 1a-f, 2a-e and 3a-f were found to be devoid of central muscle relaxant activity using meprobamate (100 mg/kg) as a reference standard. However, they showed remarkable anticonvulsant properties in a dose of 80 mg/kg (s.c.) compared with diphenylhydantoin sodium (80 mg/kg) as a reference standard.

Agents for the treatment of overactive detrusor. IX. Synthesis and pharmacological properties of metabolites of N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine (FK584) in human urine.

We synthesized the racemates of the five presumed metabolites (1b-f) of (S)-(--)-N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (FK584, S(--)-1a), a novel agent for the treatment of overactive detrusor syndrome, in order to confirm the structures of the metabolites and also to evaluate their inhibitory activity against detrusor contraction. (+/-)-N-tert-Butyl-4-(4-hydroxyphenyl)- and 4-(4-hydroxyphenyl)- and 4-phenyl-2-cyclopentenylamines (1b--e) were synthesized via 5-(4-methoxyphenyl)- and 5-(4-benzyloxy-3-methoxyphenyl)-5-phenyl-2-cyclopenten-1-one (9g, h), respectively. Compounds 1b-f prepared in this study were identical with the metabolites in human urine in gas chromatography-mass spectrometry and analytical HPLC. The inhibitory activity of compounds 1b-f against detrusor contraction in vitro induced by electrical field stimulation in guinea-pigs was less potent than that of FK584.