58-00-4

Usage

Uses

Used in Medical Applications:
Apomorphine is used as a treatment for acute poisoning, particularly in cases where it can act as a powerful emetic to induce vomiting and help eliminate the toxic substance from the body.
Used in Neurology:
In the field of neurology, apomorphine is utilized in the diagnosis and treatment of parkinsonism. As a dopamine D2 agonist, it helps alleviate the symptoms of this neurodegenerative disorder by targeting the dopamine receptors in the brain.
Used in Allergy and Immunology:
Apomorphine also serves as a weak sensitizer in the field of allergy and immunology, where it can be used to study the body's immune response to various substances.

Indications

Apomorphine (Uprima) is a short-acting central and peripheral dopamine receptor agonist that can elicit male sexual responses. Dopamine appears to have an important role in normal erectile function. Apomorphine is a D1-like,D2-like dopamine receptor agonist.Apomorphine is not a new drug, and it has been used with limited success in ameliorating the symptoms of Parkinson’s disease and to induce emesis. It is not orally active except for a special buccal formulation, but it can be given parenterally, usually subcutaneously. Apomorphine is rapidly cleared from the kidney because of its high lipid solubility, its large volume of distribution, and its rapid metabolism.

Synthesis Reference(s)

Journal of the American Chemical Society, 72, p. 494, 1950 DOI: 10.1021/ja01157a129

Hazard

Poison; central nervous system effects.

Clinical Use

Aside from sildenafil, apomorphine is one of the few orally active (buccal route) pharmacological agents used in the treatment of ED. Apomorphine stimulates penile erection in both normal men and in men who are impotent. Apomorphine can be the drug of choice in patients with coexisting benign prostatic hyperplasia (BPH), coronary artery disease, and hypertension.

Side effects

When formulated into a controlled release sublingual capsule, apomorphine becomes a very effective orally active drug representative of a new class of centrally acting drugs useful in the treatment of ED. It has a narrow range (2 to 6 mg) of effective doses for its erectogenic actions, with the higher doses being more effective in inducing erections.Apomorphine can cause nausea, emesis, drowsiness, and dizziness.

Safety Profile

Poison by ingestion,subcutaneous, intravenous, and intraperitoneal routes.Experimental reproductive effects. Central nervous systemeffects. A powerful emetic. A weak sensitizer and maycause contact dermatitis. When heated to decomposition itemits hig

Purification Methods

Crystallise R-apomorphine from CHCl3 and a little pet ether, also from Et2O with 1 mol of Et2O which it loses at 100o. It sublimes in a high vacuum. It is white but turns green in moist air or in alkaline solution. UV: max 336, 399 (98% EtOH). The di-O-methylether is an oil b 175o/high vacuum, whose picrate crystallises from MeOH and has m 140o (dec). The di-O-acetate crystallises from EtOAc/pet ether with m 127-128o, [] D -88o (c 1, 0.1 N HCl). The di-O-benzoyl derivative has m 156-158o (from EtOH) and []D +43.44o (c 3.3, CHCl3). [Pachorr et al. Chem Ber 35 4377 1902, Beilstein 21 H 246.] NARCOTIC.

InChI:InChI=1/C17H17NO2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20H,7-9H2,1H3/p+1/t13-/m1/s1

Upstream product

• 124-41-4 sodium methylate 
• 42337-34-8 10,11-bis-benzoyloxy-6-methyl-aporphane 
• 57-27-2 MORPHIN 
• 76-57-3 codeine 
• 58534-36-4 (R)-MDO-Apomorphine 
• 7664-93-9 sulfuric acid 
• 106262-09-3 3,6-bis-benzoyloxy-4,5-epoxy-17-methyl-morphin-7-ene 
• 7647-01-0 hydrogenchloride 
• 86119-84-8 phosphoric acid 
• 467-08-3 6-chloro-4,5-epoxy-3-methoxy-17-methyl-morphin-7-ene 
• 466-95-5 8-chloro-4,5-epoxy-3-methoxy-17-methyl-morphin-6-ene 
• 38291-33-7 (R)-10,11-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 39478-63-2 10,11-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 60048-95-5 8β-chloro-4,5α-epoxy-17-methyl-morphin-6-en-3-ol 

Downstream Products

• 6191-56-6 diacetyl apomorphine 
• 42337-34-8 10,11-bis-benzoyloxy-6-methyl-aporphane 
• 58534-36-4 (R)-MDO-Apomorphine 
• 314-19-2 apomorphine hydrochloride 
• 38291-33-7 (R)-10,11-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 157643-43-1 (RS)-10-tert-butyldiphenylsilyloxy-11-hydroxyaporphine 
• 42337-29-1 Di-isobutyryl-apomorphin 
• 314-19-2 (±)-apomorphine hydrochloride 
• 157643-44-2 (RS)-10-tert-butyldiphenylsilyloxy-11-methoxyaporphine 
• 210830-70-9 Trifluoro-methanesulfonic acid (R)-10-(tert-butyl-diphenyl-silanyloxy)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl ester 
• 210830-71-0 (R)-10-(tert-Butyl-diphenyl-silanyloxy)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline 
• 83247-89-6 (R)-(-)-11-hydroxyaporphine hydrobromide 
• 210830-69-6 (R)-10-(tert-Butyl-diphenyl-silanyloxy)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-ol 

Relevant academic research and scientific papers

Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor

Bivalent ligands represent useful tools to investigate the phenomenon of GPCR dimerization. We synthesized bivalent ligands based on (R)-apomorphine with variations in spacer length, and assessed these compounds in functional and binding assays at the dopamine D2 receptor. The results present novel SAR for bivalent ligands targeting the D2R, and identify a relationship for spacer length with ligand potency, efficacy and affinity. The Royal Society of Chemistry.

APOMORPHINE·PALMITIC ACID COCRYSTAL SOLID PARTICLE CRYSTALLINE FORM

A pharmaceutical composition comprising apomorphine (APO) in a solid crystalline form, wherein the solid crystalline form is an APO·palmitic acid cocrystal solid particle crystalline form.

Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

Convergent total synthesis of (±)-apomorphine hydrochloride was accomplished by an approach that employs in the key step a sequence of transformations involving a [4+2]-cycloaddition reaction followed by a hydrogen migration. Through this sequence of transformations, the desired aporphine core was obtained regioselectively in 75% isolated yield. Since only one regioisomer was produced in the key step of the synthesis, a polar [4+2]-cycloaddition mechanism was proposed. Furthermore, NMR experiments and theoretical calculations were carried out to elucidate the hydrogen migration mechanism. (±)-Apomorphine hydrochloride was achieved after 9 steps in an overall yield of 8% involving benzyne chemistry.

CRYSTAL FORMS OF APOMORPHINE AND USES THEREOF

The present invention provides solid crystalline forms of apomorphine free base or a hydrate, solvate, or co-crystals thereof. Such crystalline forms may be advantageous over amorphous forms of apomorphine, e.g., amorphous salt forms such as acid addition salts of apomorphine, because of their increased/greater stability and/or improved pharmacological properties, e.g., decreased adverse reactions at the site of administration. The invention further provides liquid formulations obtained by dissolving said crystalline forms of apomorphine in a solvent, as well as a method for treatment of a neurological or movement disorder, e.g., Parkinson's disease, or a condition associated therewith, by administration of said liquid formulations.

Enhancement of transdermal apomorphine delivery with a diester prodrug strategy

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K′), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm2/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm2/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine.

FACILE 'ONE POT' PROCESS FOR APOMORPHINE FROM CODEINE

An improved method for producing apomorphine and derivatives thereof is provided. The method is a convenient 'one-pot' process, comprising the conversion of codeine into apomorphine without isolating the apocodeine intermediate. Use of water reactive scavengers, reagents that will react irreversibly with water, decreases side product formation and allows the use of milder reaction conditions. This one-pot synthesis of apomorphine from codeine provides a faster reaction with improved yields at temperatures lower as compared to conventional methods. The lower operating temperatures and less volatile reactants make the method particularly useful for large-scale manufacturing.

Microwave-promoted acid-catalyzed rearrangement of morphinans - A high-yield synthesis of R(-)-apomorphine

The microwave-promoted acid-catalyzed rearrangement of morphine (1), codeine (2), and thebaine (3) was investigated. In all cases, a significant improvement in the yields were achieved compared to the traditional techniques. R(-)-Apomorphine (4), which is a clinically important dopamine agonist, was synthesized from morphine (1) in 75% yield. Copyright Taylor & Francis Group, LLC.

PROCESS FOR MAKING APOMORPHINE AND APOCODEINE

There is provided an improved and convenient process for the synthesis of aporphines, such as apomorphine and apocodeine, by the rearrangement of the corresponding morphine or codeine derivatives. The use of a suitable water scavenger in an acid catalyzed rearrangement of the morphine derivatives unexpectedly results in a reaction temperature convenient for plant operation without sacrificing product. The method of the present invention also alleviates the cumbersome operations that were employed in the prior art to eliminate water from the reaction mixture at the elevated temperatures. This process is adaptable for the general preparation of other aporphines from the corresponding morphine congeners.

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(-)-apomorphine and (R)-(-)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(-)-apomorphine (R)-1 and (R)-(-)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.

LANTHANIDE-INDUCED SHIFTS OF STERICALLY HINDERED AROMATIC o-DIMETHOXY COMPOUNDS: MODEL COMPOUNDS AND o-DIMETHOXYCOUMARINS

The lanthanide-induced shifts (LIS) of a series of sterically hindered o-dimethoxy compounds, characterized by a 3-substituted 1,2-dimethoxy unit as a structural element, were simulated in model calculations.Development of a generally suitable computational model for aromatic o-dimethoxycompounds allows prediction of relative LIS values for o-dimethoxy complexation.The model was used for several naturally occurring dimethoxycoumarins taking into account the population ratios of the two possible co-ordinating sites in these molecules (o-dimethoxy and lactone carbonyl).