Clodazon

Clodazon
Clinical data
Other names	AW 14'2446
Identifiers
CAS Number	4755-59-3;
PubChem CID	20883;
ChemSpider	19652;
UNII	X82H6JOC4H;
ChEMBL	ChEMBL2110801;
CompTox Dashboard (EPA)	DTXSID30197194 ;
Chemical and physical data
Formula	C22H25N3O3
Molar mass	379.460 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN(C)CCCN1C2=C(C=C(C=C2)Cl)N(C1=O)C3=CC=CC=C3;
	InChI InChI=1S/C18H20ClN3O/c1-20(2)11-6-12-21-16-10-9-14(19)13-17(16)22(18(21)23)15-7-4-3-5-8-15/h3-5,7-10,13H,6,11-12H2,1-2H3; Key:VWXGRWMELBPMCU-UHFFFAOYSA-N;

Clodazon (AW 142446) is an antidepressant drug investigated in Germany in the 1960s. In animal models, clodazon inhibits the catalepsy induced by tetrabenazine and it potentiates the effect of catecholamines, both effects being of the order experienced with imipramine. In clinical trials, about 2/3 of the patients showed a positive antidepressive effect with few side effects.

Pharmacology:^[1]^[2]

Synthesis

The synthesis of clodazon is delineated in the patent:^[3]

Clodazon synthesis

5-Chloro-2-nitrodiphenylamine [25781-92-4] (1) is reduced to 5-chloro-N-phenylbenzene-1,2-diamine [68406-47-3] (2). Treatment of this with phosgene (caution) would give 3-phenyl-5-chloro-benzimidazolin-2-one [54986-47-9] (3). Base catalyzed treatment of this with 1-bromo-3-chloropropane provided PC20506309 (structure not shown). Displacement of the remaining halogen atom leaving group by dimethylamine completes the construction of sidechain and thus the synthesis of clodazon (4).

[54986-47-9] ~98%:^[4]~90%:^[5]

The crystal structure is monoclinic with space group P2₁/c with unit cell parameters a=5.898 b=31.911 c=10.817 Å with β=103.52°. Unit cell volume is 1989.3 Å³.^[6]

References

^ Stille G, Lauener H, Eichenberger E (August 1968). "Ein Antidepressivum aus der Gruppe der 2-Benzimidazolinone". International Pharmacopsychiatry. 1 (3–4): 214–210. doi:10.1159/000467934.
^ Arnold OH, Guss OH (February 1969). "[Clinical experiences with the antidepressive agent AW 14'2446 (Clodazon)]". Wiener Medizinische Wochenschrift. 119 (7): 130–133. PMID 5772001.
^ BE659364 (1965) idem Hunziker Fritz, US3338916 (1967 to A Wander S A Dr).
^ Bianchi M, Butti A, Rossi S, Barzaghi F, Marcaria V (1981). "Compounds With Antiulcer and Antisecretory Activity. I: 3-Aryl-benzimidazolin-2-ones and -thiones". European Journal of Medicinal Chemistry. 16 (4): 321–326.
^ Pizzotti M, Cenini S, Quici S, Tollari S (1994). "Role of alkali halides in the synthesis of nitrogen containing heterocycles by reductive carbonylation of aromatic nitro-derivatives catalysed by Ru3(CO)12". Journal of the Chemical Society, Perkin Transactions 2 (4): 913. doi:10.1039/p29940000913.
^ Lambert P, Evrard G, Durant F, Germain G, Declercq JP (1 August 1978). "5-Chloro-1-[3-(dimethylamino)propyl]-1,3-dihydro-3-phenyl-2 H -benzimidazol-2-one monohydrochloride monohydrate (clodazone)". Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry. 34 (8): 2656–2658. Bibcode:1978AcCrB..34.2656L. doi:10.1107/S0567740878008894.

[1] Stille G, Lauener H, Eichenberger E (August 1968). "Ein Antidepressivum aus der Gruppe der 2-Benzimidazolinone". International Pharmacopsychiatry. 1 (3–4): 214–210. doi:10.1159/000467934.

[2] Arnold OH, Guss OH (February 1969). "[Clinical experiences with the antidepressive agent AW 14'2446 (Clodazon)]". Wiener Medizinische Wochenschrift. 119 (7): 130–133. PMID 5772001.

[3] BE659364 (1965) idem Hunziker Fritz, US3338916 (1967 to A Wander S A Dr).

[4] Bianchi M, Butti A, Rossi S, Barzaghi F, Marcaria V (1981). "Compounds With Antiulcer and Antisecretory Activity. I: 3-Aryl-benzimidazolin-2-ones and -thiones". European Journal of Medicinal Chemistry. 16 (4): 321–326.

[5] Pizzotti M, Cenini S, Quici S, Tollari S (1994). "Role of alkali halides in the synthesis of nitrogen containing heterocycles by reductive carbonylation of aromatic nitro-derivatives catalysed by Ru3(CO)12". Journal of the Chemical Society, Perkin Transactions 2 (4): 913. doi:10.1039/p29940000913.

[6] Lambert P, Evrard G, Durant F, Germain G, Declercq JP (1 August 1978). "5-Chloro-1-[3-(dimethylamino)propyl]-1,3-dihydro-3-phenyl-2 H -benzimidazol-2-one monohydrochloride monohydrate (clodazone)". Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry. 34 (8): 2656–2658. Bibcode:1978AcCrB..34.2656L. doi:10.1107/S0567740878008894.

[1]

[2]

[3]

[4]

[5]

[6]