The story of methylphenidate begins with the recognition that piperazine derivatives, used as diuretics in the late 19^th century possessed significant stimulating properties.

Chemische Industrie Basel (CIBA) is a Swiss pharmaceutical company where Max Hartmann, a chemist, in the early 20^th century synthesized a piperidine,  allyl-phenyl-cinchoninate, a powerful treatment for “uric acid diathesis”.  Hartmann continued his research with piperidines, and in 1924, he synthesized N-diethyl-3-pyridinecarboxamide, a strong analeptic that was to be called nikethamide or picolinamide. With Werner Boshard, Hartmann published in 1941 an article on pyridine-3-acetic acid. Three years after, subsequent transformations and reductions of some pyridil acetic acids, led to the isolation of phenyl-α -pyridil-2-acetic acid.  Leandro Panizzon (1944), a medicinal chemist of CIBA, leads the synthesis of methyl-α- phenyl-piperidine-2-acetate (methylphenidate).   

In 1950, Panizzon and Hartmann, developed an improved synthesis for mehylphenidate and obtained a US patent for its preparation. However, it was only in 1954 that Meier, Gross and Tripod revealed that this substance has stimulating properties. In the same year, methylphenidate, with the brand name, Ritalin was patented by CIBA in the US for treating psychological disorders.  By 1955, Ritalin passed the safety requirements of the US Food and Drug Administration in effect at the time, and in 1956, it was introduced for clinical use. In 1957, it was marketed in Europe to treat fatigue, psychasthenia or depression. 

The substance was first used intravenously for the treatment of barbiturate intoxication (Rosenberg, Rape and Rumble, 1959), but by the end of the 1950s it found its place in the treatment of narcolepsy (Yoss and Daly, 1959) and in “some abnormal psychical conditions” primarily, first described by English physician George Frederic Still in 1902 that was to be referred to “minimal brain dysfunction” first, and  ”attention deficit hyperactivity disorder” subsequently (Lytton and Knobel, 1959).

The overall clinical profile of methylphenidate resembles that of amphetamine with the exception that its anorexic effects and actions on the peripheral circulation are less marked. It acts by inhibiting dopamine reuptake and with much less effect on norepinephrine reuptake (Findling, 2008).      

References:

Findling RL. Evolution of the treatment of attention –deficit-hyperactivity  disorder in children: A review . Clin Ther 2008; 30: 942-57.

Hartmann M, Bosshard W. Über die Pyridin-3-essigsäure (β-Homo nicotine säure). Helv Chim Acta 1941; 24: 81-35.  

Lytton GJ, Knobel M. Diagnosis and treatment of behavior disorders in children Dis Nerv Syst 1959; 20: 334-40.

Meier R, Gross F, Tripod J. Ritalin , eine neuartige Syntetische Verbindung mit spezifischer zentrale verregenden Wirkungscomponente. Klin Wochenschrift 1954; 32: 445-50.

Panizzon L. La preparazione  di piridil-e piridilarilac – tonitr ilie di alcuni prodotti transformazione (part la).  Helv Chim Acta 1944; 2: 1748-56. 

Rosenberg DG, Rape WC, Rumble LJ. Parenteral mehylphenidate administration HCl (Ritalin) in barbiturate intoxication. J Med Assoc  Ga 1959; 48: 19-21.

Some abnormal psychological conditions in children. Lancet 1902; 1: 1008-12.

Yoss RE, Daly DD. Treatment of narcolepsy with Ritalin. Neurology 1959; 9: 171-3.

Eric Konofal
June 27, 2013