MOLINDONE, молиндон موليندون 吗茚酮

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ChemSpider 2D Image | Molindone | C16H24N2O2

MOLINDONE

C₁₆H₂₄N₂O_{2,, 276.374}

SPN 810, SPN 801M, AFX 2201

cas 15622-65-8 hcl

Molindone is used for the management of the manifestations of psychotic disorders.

Schizophrenia

молиндон

موليندون

吗茚酮

(±)-Molindone

2376

3-Ethyl-2-methyl-5-(4-morpholinylmethyl)-1,5,6,7-tetrahydro-4H-indol-4-one [ACD/IUPAC Name]

3-Ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydro-4H-indol-4-one

4H-Indol-4-one, 3-ethyl-1,5,6,7-tetrahydro-2-methyl-5-(4-morpholinylmethyl)-

7416-34-4 [RN]

RT3Y3QMF8N

UNII:RT3Y3QMF8N

Supernus Pharmaceuticals , under license from Afecta Pharmaceuticals , is developing molindone hydrochloride (SPN-810; SPN-801M; AFX-2201; presumed to be Zalvari), as a capsule formulation, for the potential oral treatment of conduct disorder in patients with attention deficit hyperactivity disorder. In 3Q15, the company initiated two phase III trials (CHIME 1 and CHIME 2) for compulsive aggression in ADHD. In November 2019, the trial was expected to complete in June 2020.

Molindone, sold under the brand name Moban, is an antipsychotic which is used in the United States in the treatment of schizophrenia.^[1]^[2] It works by blocking the effects of dopamine in the brain, leading to diminished symptoms of psychosis. It is rapidly absorbed when taken orally.

It is sometimes described as a typical antipsychotic,^[3] and sometimes described as an atypical antipsychotic.^[4]

Molindone was discontinued by its original supplier, Endo Pharmaceuticals, on January 13, 2010.^[5]

An indole derivative effective in schizophrenia and other psychoses and possibly useful in the treatment of the aggressive type of undersocialized conduct disorder. Molindone has much lower affinity for D2 receptors than most antipsychotic agents and has a relatively low affinity for D1 receptors. It has only low to moderate affinity for cholinergic and alpha-adrenergic receptors. Some electrophysiologic data from animals indicate that molindone has certain characteristics that resemble those of clozapine. (From AMA Drug Evaluations Annual, 1994, p283)

Availability and Marketing in the USA

After having been produced and subsequently discontinued by Core Pharma in 2015-2017, Molindone is available again from Epic Pharma effective December, 2018.^[6]

Adverse effects

The side effect profile of molindone is similar to that of other typical antipsychotics. Unlike most antipsychotics, however, molindone use is associated with weight loss.^[4]^[7]

Chemistry

Synthesis

Molindone synthesis: SCHOEN KARL, J PACHTER IRWIN; BE 670798 (1965 to Endo Lab).

Condensation of oximinoketone 2 (from nitrosation of 3-pentanone), with cyclohexane-1,3-dione (1) in the presence of zinc and acetic acid leads directly to the partly reduced indole derivative 6. The transformation may be rationalized by assuming as the first step, reduction of 2 to the corresponding α-aminoketone. Conjugate addition of the amine to 1 followed by elimination of hydroxide (as water) would give ene-aminoketone 3. This enamine may be assumed to be in tautomeric equilibrium with imine 4. Aldol condensation of the side chain carbonyl group with the doubly activated ring methylene group would then result in cyclization to pyrrole 5; simple tautomeric transformation would then give the observed product. Mannich reaction of 6 with formaldehyde and morpholine gives the tranquilizer molindone (7).

US-20200262788

Process for preparing molindone and its intermediates useful for treating schizophrenia..

Molindone is chemically known as 4H-Indol-4-one, 3-ethyl-1,5,6,7-tetrahydro-2-methyl-5-(4-morpholinylmethyl) and represented by formula I. Molindone is indicated for management of schizophrenia and is under clinical trial for alternate therapies.

The compound molindone, process for its preparation and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 3,491,093. Another application WO 2014042688 discloses methods of producing molindone. Since there are very limited methods for preparation of molindone reported in literature there exist a need for alternate process for preparation of molindone. The present invention provides novel process for preparation of Molindone (I) and its salts.

EXAMPLES

Example 1: Preparation of methyl 2-chloro-2-ethyl-3-oxobutanoate

A mixture of methyl acetoacetate (100 g), potassium tertiary butoxide (101.5 g) and tetrahydrofuran (400 ml) was stirred and a solution of ethyliodide (141 g) in tetrahydrofuran (200 ml) was added to it. The reaction mixture was stirred at 60° C. for about 15 hours. Water (250 ml) was added to the reaction mixture at 25° C. followed by addition of dichloromethane (500 ml). The organic layer was separated and concentrated. To the concentrate was added dichloromethane (1000 ml) and sulfuryl chloride (93.7 g) and the solution was stirred for about 18 hours at 25-30° C. Water (500 ml) was added to the reaction mixture. The organic layer was separated and concentrated to give the title compound.

Example 2: Preparation of 3-chloropentan-2-one

A mixture of methyl 2-chloro-2-ethyl-3-oxobutanoate (98.8 g) and water (240 ml) was treated with sulfuric acid (260 g) and stirred for 90 minutes at 75-80° C. The reaction mixture was poured into water (500 ml) and dichloromethane (500 ml). The organic layer was separated and concentrated. The concentrate was subjected to fractional distillation and pure compound was collected.

Example 3: Preparation of 3-chloropentan-2-one

A mixture of petane-2-one (15 g), acetic acid (60 ml) and N-chlorosuccinimide (24.4 g) was stirred for about 18 hours at 80-85° C. The reaction mixture was cooled and dichloromethane (100 ml) was added to it. The mixture was treated with sodium bicarbonate solution. The organic layer was separated and concentrated to give the title compound (2).

Example 4: Preparation of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (4)

A mixture of 3-bromopentan-2-one (17 g), cyclohexane-1,3-dione (11.5 g), triethyl amine (15.6 g) and acetonitrile (100 ml)) was stirred for about 2 hours at 55-60° C. The reaction mixture was concentrated and ethyl acetate (170 ml) and water (85 ml) was added. The organic layer separated and concentrated. The residue was subjected to column chromatography (ethylacetate: cyclohexane). The title compound was obtained. ¹H NMR (500 MHz, CDCl ₃), δ 5.14 (S 1H), δ 4.37 (d 1H), δ 2.50-2.55 (m 2H) δ 2.35-2.38 (m 2H), δ 2.16 (s 3H), δ 2.00-2.05 (m 2H) δ 1.88-1.90 (m 2H), δ 1.00-1.02 (m 3H); ¹³C NMR (500 MHz, CDCl ₃), 206.04, 199.34, 176.63, 103.70, 77.12, 36.62, 28.88, 25.44, 21.00, 16.55, 9.41 ppm; Dept135 NMR (500 MHz, CDCl ₃): 103.70, 83.78, 36.62, 28.87, 28.65, 25.45, 24.69, 21.00, 9.41 ppm; Mass: [M+1]=197.

Example 5: Preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)

A mixture of 2-(2-oxopentan-3-yl)cyclohexane-1,3-dione (10 g), acetic acid (40 ml) and ammonium acetate (19.6 g) was stirred for about 3 hours at 95-100° C. The reaction mixture was cooled and concentrated. To the residue a mixture of ethyl acetate (60 ml) and water (50 ml) was added. The organic layer separated and concentrated to give the title compound.

Example 6: Preparation of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5)

A mixture of cyclohexane-1,3-dione (3 g), dimethyl sulfoxide (15 ml), triethyl amine (2.7 g) and 3-chloropentan-2-one (3.2 g) was stirred for about 24 hours at 40-45° C. Aqueous ammonia (15 ml) was added to the mixture and stirred for about 10 hours at 25-30° C. A mixture of water (60 ml) and ethyl acetate (30 ml) was added to it. The organic layer separated and concentrated. The residue was subjected to column chromatography (ethyl acetate/n-hexane). The title compound was obtained.

Example 7: Preparation of Molindone Hydrochloride

A mixture of 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (5 g), morpholine (4.42 g), paraformaldehyde (1.52 g) and ethanol (70 ml) was stirred for about 24 hours at 75-80° C. The reaction mixture was concentrated and water (50 ml) was added to the residue. The mixture was treated with concentrated hydrochloric acid followed by aqueous ammonia in presence of ethyl acetate. The organic layer was separated and concentrated to obtain molindone as a residue. Isopropanol hydrochloride was added to the residue and stirred for 30 minutes at 25-30° C. The solution was concentrated and ethyl acetate (15 ml) was added. The solid was filtered, washed with ethyl acetate and dried to obtain molindone hydrochloride.

References

^ “molindone”. F.A. Davis Company.
^ “Molindone”.
^ Aparasu RR, Jano E, Johnson ML, Chen H (October 2008). “Hospitalization risk associated with typical and atypical antipsychotic use in community-dwelling elderly patients”. Am J Geriatr Pharmacother. 6 (4): 198–204. doi:10.1016/j.amjopharm.2008.10.003. PMID 19028375.
^ Jump up to:^a ^b Bagnall A, Fenton M, Kleijnen J, Lewis R (2007). Bagnall A (ed.). “Molindone for schizophrenia and severe mental illness”. Cochrane Database Syst Rev (1): CD002083. doi:10.1002/14651858.CD002083.pub2. PMID 17253473.
^ https://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050794.htm
^ “NEWS”. www.epic-pharma.com. Retrieved 2018-12-12.
^ Allison DB, Mentore JL, Heo M, et al. (1999). “Antipsychotic-induced weight gain: a comprehensive research synthesis”. Am J Psychiatry. 156 (11): 1686–96. doi:10.1176/ajp.156.11.1686 (inactive 2020-01-22). PMID 10553730. Free full text

Molindone
Clinical data

Pronunciation	/moʊˈlɪndoʊn/ moh-LIN-dohn
Trade names	Moban
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a682238
Pregnancy category	C
Routes of administration	By mouth (tablets)
ATC code	N05AE02 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	1.5 hours
Excretion	Minor, renal and fecal
Identifiers
IUPAC name [show]
CAS Number	7416-34-4
PubChem CID	23897
IUPHAR/BPS	207
DrugBank	DB01618
ChemSpider	22342
UNII	RT3Y3QMF8N
KEGG	D08226
ChEMBL	ChEMBL460
CompTox Dashboard (EPA)	DTXSID9023332
ECHA InfoCard	100.254.109
Chemical and physical data
Formula	C₁₆H₂₄N₂O₂
Molar mass	276.380 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C2c1c(c([nH]c1CCC2CN3CCOCC3)C)CC
InChI [hide] InChI=1S/C16H24N2O2/c1-3-13-11(2)17-14-5-4-12(16(19)15(13)14)10-18-6-8-20-9-7-18/h12,17H,3-10H2,1-2H3 Key:KLPWJLBORRMFGK-UHFFFAOYSA-N

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