Clomipramine

Structural formula
General
Non-proprietary name	Clomipramine
other names	3-chloro-10,11-dihydro- N , N -dimethyl-5 H -dibenzo [ b , f ] azepine-5-propanamine ( IUPAC )
Molecular formula	C 19 H 23 ClN 2 C 19 H 23 ClN 2 HCl ( hydrochloride )
External identifiers / databases
CAS number 303-49-1 17321-77-6 (hydrochloride) EC number 206-144-2 ECHA InfoCard 100.005.587 PubChem 2801 ChemSpider 2699 DrugBank DB01242 Wikidata Q58713
Drug information
ATC code	N06 AA04
Drug class	Tricyclic antidepressants
properties
Molar mass	314.85 g mol −1 351.32 g mol −1 (hydrochloride)
Melting point	194 ° C ( hydrochloride polymorph I ) 189 ° C ( hydrochloride polymorph II ) 179 ° C ( hydrochloride polymorph III )
boiling point	160-170 ° C (0.3 Torr) 152-160 ° C (0.4 torr)
pK s value	6.7
solubility	Water: 0.29 mg l −1 (25 ° C) (base)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302-312-332 P: 280
Toxicological data	613 mg kg −1 ( LD 50 ,  rat ,  oral ) 380 mg kg −1 ( LD 50 ,  mouse ,  oral ) 27 mg kg −1 ( LD 50 ,  mouse ,  iv ) 914 mg kg −1 ( LD 50 ,  rat ,  oral , hydrochloride) 26 mg kg −1 ( LD 50 ,  rat ,  iv , hydrochloride) 470 mg kg −1 ( LD 50 ,  mouse ,  oral , hydrochloride) 22 mg kg −1 ( LD 50 ,  mouse ,  iv , hydrochloride) 383 mg kg −1 ( LD 50 ,  dog ,  oral , hydrochloride) 32 mg kg −1 ( LD 50 ,  dog ,  iv , hydrochloride)
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Clomipramine is a chemical compound from the dibenzazepine group . It is used as a drug from the group of tricyclic antidepressants , almost exclusively in the form of the more water-soluble hydrochloride . Clomipramine is a derivative of imipramine , another tricyclic antidepressant. It differs from this only in an additional chlorine substituent.

To this day, clomipramine has served as the standard of comparison in the development of new psychotropic drugs for the treatment of obsessive-compulsive disorder . Because of its high effectiveness, clomipramine was included as the only drug in the WHO list of essential drugs in the category of obsessive compulsive disorders .

history

Clomipramine was developed by the Swiss pharmaceutical company Geigy (now Novartis) in the 1960s . In Germany it is still marketed by Dolorgiet Arzneimittel under the trade name Anafranil ^® ; it is now available as a generic from numerous manufacturers.

Mode of action

Clomipramine mainly has a drive-enhancing and mood- enhancing effect . The mood-enhancing effect of clomipramine starts in about 1–2 weeks, the anti-obsessive (effect against obsessive-compulsive symptoms) a little later.

It is characterized by a dual principle of action - namely serotonin and norepinephrine reuptake inhibition, accompanied by α1-adrenoreceptor blockade. The down-regulation of the β-adrenoreceptors is one of the therapeutic effects. Clomipramine also inhibits acid sphingomyelinase in the lysosomal lipid metabolism and thus belongs to the pharmacological group of FIASMAs .

application

Clomipramine is in the treatment of obsessive-compulsive disorder significantly more effective than the SSRI . It has a broad therapeutic spectrum: It is widely used in the therapy of severe, treatment-resistant and chronic depression and anxiety (e.g. agoraphobia ), with well-documented success.

The active ingredient is also used to treat cataplexy , one of the four main symptoms of the sleep disorder narcolepsy .

Extraction and presentation

A two-stage synthesis starts from 3-chloro-10,11-dihydro-5 H -dibenzo [ b , f ] azepine, which is first deprotonated with sodium amide and then reacted with 3-dimethylaminopropyl chloride.

In a further three-stage synthesis, the dibenzazepine starting compound is first converted into a carbamoyl chloride intermediate by means of phosgene . In the second step arises with 3-dimethylamino-1-propanol, a carbamate , which then at temperatures between 160 ° C and 210 ° C decarboxylated is.

Physical Properties

Clomipramine hydrochloride occurs in three polymorphic forms. The melting points are 194 ° C for polymorph I, 189 ° C for polymorph II and 179 ° C for polymorph III. Polymorph I is the thermodynamically stable form. The other two polymorphs are metastable and are monotropic to polymorph I.

unwanted effects

The side effects correspond to those of the substance group of the tricyclic antidepressants , in particular anticholinergic effects.

The mutagenicity is unclear ; animal experiments on the fruit fly Drosophila showed a mutagenic effect, i. H. there were changes in the genome. It is unclear what this means for humans.

pregnancy

There is clear evidence of risks to the human fetus if ingested during pregnancy, but the therapeutic benefits to the mother may outweigh this. The use of clomipramine during pregnancy should only be considered if there is a compelling indication and if there is no alternative with a lower risk.

No teratogenic effects have been observed in animal studies . However, when administered prenatally and during breastfeeding, clomipramine can cause behavioral disorders in the offspring of the dams.

Driving ability

You may experience blurred vision, drowsiness, and other central nervous system symptoms that can affect driving and using machines.

Interactions

By inhibiting enzymes, grapefruit juice can reduce the breakdown of clomipramine in the liver and thus increase the bioavailability of the psychotropic drug by about four times.

Neonatal clomipramine

Since 1982, scientists have used the neonatal clomipramine technique to raise animals used in depression research. When 8-21 day old rats are given clomipramine, they develop a condition as adults that is similar to depression in humans.

Trade names

Monopreparations

Anafranil (D, A, CH), various generics

literature

• Markus Gastpar (Ed.): Clomipramin. Balance sheet and perspective. 13 tables. Thieme, Stuttgart / New York 1996, ISBN 3-13-104261-3 .

Web links

• Vetpharm entry on clomipramine , accessed August 11, 2012.

Individual evidence

1. ↑ ^{a b c d} M. Kuhnert-Brandstätter, L. Linsmayer, G. Kramer: Thermoanalytical investigations of psychotropic substances of the type of modification products of phenothiazine and butyrophenones for isomorphism and polymorphism. I. In: Microchim Acta . 83, 1984, pp. 103-119, doi: 10.1007 / BF01237265 .
2. ^ PN Craig, BM Lester, AJ Saggiomo, C. Kaiser, CL Zirkle: Analogs of Phenothiazines. I. 5H-Dibenz [b, f] azepine and Derivatives. A New Isostere of Phenothiazine. In: J. Org. Chem. 26, 1961, pp. 135-138, doi: 10.1021 / jo01060a032 .
3. ↑ patent CH371799 (1958) Geigy AG.
4. ↑ I. Zahradnik, I. Minarovič, A. Zahradnikova: J. Pharm Exp Therap... 324, 2008, pp. 977-984.
5. ↑ Entry on clomipramine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
6. ↑ ^{a b} Data sheet Clomipramine hydrochloride from Sigma-Aldrich , accessed on March 23, 2011 ( PDF ).
7. ↑ ^{a b c d e f g h i j k} A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications. 4th edition. Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 .
8. ↑ ^{a b} entry on clomipramine. In: Römpp Online . Georg Thieme Verlag, accessed on July 12, 2011.
9. ^ WHO Model List of Essential Medicines . (PDF, 431 kB). 17th list, March 2011.
10. ↑ J. Kornhuber, M. Muehlbacher, S. Trapp, S. Pechmann, A. Friedl, M. Reichel, C. Mühle, L. Terfloth, T. Groemer, G. Spitzer, K. Liedl, E. Gulbins, P Tripal: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . tape 6 , no. 8 , 2011, p. e23852 , doi : 10.1371 / journal.pone.0023852 .
11. ^ DA Geller, J. Biederman, SE Stewart, B. Mullin, A. Martin, T. Spencer, SV Faraone: Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder. In: The American Journal of Psychiatry. 160, No. 11, 2003, pp. 1919-1928. PMID 14594734 . doi : 10.1176 / appi.ajp.160.11.1919 (free full text).
12. ↑ S3 guideline for non-restful sleep / sleep disorders of the German Society for Sleep Research and Sleep Medicine (DGSM). In: AWMF online (as of 2009)
13. ↑ M. Schachter, JD Parkes: Fluvoxamine and clomipramine in the treatment of cataplexy. In: J Neurol Neurosurg Psychiatry. 43, No. 2, February 1980, pp. 171-174. PMID 6766990 , PMC 490494 (free full text, PDF).
14. ↑ ^{a b c} Specialist information from the Swiss drug compendium for Anafranil ^® from Novartis Pharma Switzerland - as of May 2009.
15. ↑ German specialist information: Anafranil; Status: May 2007.
16. ↑ Patrick Terheyden, Angela Krackhardt, Thomas Eigenler: System therapy of melanoma. Use of immune checkpoint inhibitors and inhibition of intracellular signal transduction. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., (July 22nd) 2019, pp. 497–504, here: p. 511.
17. ↑ G. Vogel, D. Neill, M. Hagler, D. Kors: A new animal model of endogenous depression: a summary of present findings . In: Neurosci Biobehav Rev . tape 14 , no. 1 , 1990, p. 85-91 , PMID 2183099 .
18. ↑ J. Velazquez-Moctezuma, A. Aguilar-Garcia, O. Diaz-Ruiz: Behavioral effects of neonatal treatment with clomipramine, scopolamine, and idazoxan in male rats . In: Pharmacol. Biochem. Behav. tape 46 , no. 1 , September 1993, p. 215-217 , PMID 7902983 .
19. ↑ Red List online, as of June 2010.
20. ↑ AM comp. d. Switzerland, as of June 2010.
21. ↑ AGES-PharmMed, as of June 2010.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !