555-30-6 Usage
Description
Methyldopa is an α-methoxylated derivative of levodopa that exhibits hypotensive action
by reducing overall peripheral vascular resistance and reducing heart work.
Antihypertensive action of methyldopa consists of the biotransformation of methyldopa
into methylnoradrenaline (methylnorepinephrine), which acts as a “pseudo neurotransmitter.”
The current, universally accepted point of view is that the action of methyldopa is carried
out through the CNS, where methylnorepinephrine, a powerful stimulant of
α-adrenergic receptors of the medulla, inhibits the vasomotor center.
Originator
Aldometil,MSD,W. Germany,1962
Uses
Different sources of media describe the Uses of 555-30-6 differently. You can refer to the following data:
1. It is prescribed for arterial hypertension and hypertensive crises.
2. L-(-)-a-Methyldopa is an anti-Parkinson’s drug that has been used in anti-Parkinson’s mixtures.
3. Antihypertensor;L-aromatic aminoacid decarboxylase inhibitor
4. vitamin, coenzyme B12
Definition
ChEBI: A derivative of L-tyrosine having a methyl group at the alpha-position and an additional hydroxy group at the 3-position on the phenyl ring.
Manufacturing Process
The dl-α-methyl-3,4-dihydroxyphenylalanine may be made as described in US
Patent 2,868,818. Five-tenths of a gram of 3-hydroxy-4-
methoxyphenylalaninewas dissolved in 20 ml of concentrated hydrochloric
acid, the solution saturated with hydrogen chloride and heated in a sealed
tube at 150°C for 2 hours. The dark reaction mixture was concentrated to
dryness in vacuo, excess acid removed by flushing several times with ethanol.
On dissolving the dark residue in a minimum amount of water and adjusting
the clarified solution to pH 6.5 with ammonium hydroxide the compound
separated in fine crystals which were filtered, washed with alcohol and ether.
The crystalline product had a MP of 299.5 to 300°C with decomposition.
Then, as described in US Patent 3,158,648, the optical isomers may be
resolved as follows. 37 g of racemic α-methyl-3,4-dihydroxyphenylalanine are
slurried at 35°C in 100 cc of 1.0 N hydrochloric acid. The excess solids are
filtered leaving a saturated solution containing 34.6 g of racemic amino acid of
which about 61% is present as the hydrochloride. The solution is then seeded
at 35°C with 7 g of hydrated L-α-methyl-3,4-dihydroxyphenylalanine (6.2 g of
anhydrous material). The mixture is then cooled to 20°C in 30 minutes and
aged one hour at 20°C. The separated material is isolated by filtration,
washed twice with 10 cc of cold water and dried in vacuo. The yield of product
is 14.1 g of L-α-methyl-3,4-dihydroxyphenylalanine in the form of a
sesquihydrate of 100% purity as determined by the rotation of the copper
complex.
Therapeutic Function
Antihypertensive
Biological Functions
The spectrum of activity of α-methyldopa (Aldomet)
lies between those of the more potent agents, such as
guanethidine, and the milder antihypertensives, such as
reserpine. α-Methyldopa is a structural analogue of dihydroxyphenylalanine
(dopa) and differs from dopa
only by the presence of a methyl group on the -carbon
of the side chain.
General Description
Different sources of media describe the General Description of 555-30-6 differently. You can refer to the following data:
1. Methyldopa differs structurally from L-DOPA only in the presence of a -methyl group. Originally synthesized as an AADC inhibitor,methyldopa ultimately decreases the concentration of DA,NE, E, and serotonin in the CNS and periphery. However,its mechanism of action is not caused by its inhibition ofAADC but, rather, by its metabolism in the CNS to its activemetabolite ( β-methylnorepinephrine). Methyldopa istransported actively into CNS via an aromatic amino acidtransporter, where it is decarboxylated by AADC in thebrain to (1R,2S)- α-methyldopamine. This intermediate, inturn, is stereospecifically β-hydroxylated by DBH to givethe (1R,2S)-α-methylnorepinephrine. This active metaboliteis a selective α2-agonist because it has correct(1R,2S) configuration . It is currently postulated that α-methylnorepinephrine acts on α2-receptors in theCNS in the same manner as clonidine, to decrease sympatheticoutflow and lower blood pressure.
2. Colorless or almost colorless crystals or white to yellowish-white fine powder. Almost tasteless. In the sesquihydrate form. pH (saturated aqueous solution) about 5.0.
Air & Water Reactions
Very hygroscopic. Slightly water soluble. May be sensitive to prolonged exposure to air and light. The stability of aqueous solutions is markedly dependent on pH, oxygen and the amount of initial reactant. Aqueous solutions are stable for up to 50 hours in acid and neutral pH (6.2). At pH 8.0, decomposition products are formed in 3 to 5 hours. Solutions develop a red tint that becomes progressively darker (eventually forming a black precipitate).
Reactivity Profile
Methyldopa undergoes catalytic oxygenation in the presence of magnesium, cupric, cobalt, nickel and ferric ions . A weakly acidic amino acid.
Fire Hazard
Flash point data for Methyldopa are not available; however, Methyldopa is probably combustible.
Biological Activity
L-aromatic amino acid decarboxylase inhibitor. Antihypertensive.
Mechanism of action
A number of theories have been put forward to account
for the hypotensive action of α-methyldopa. Current
evidence suggests that for α-methyldopa to be an antihypertensive
agent, it must be converted to α-methylnorepinephrine;
however, its site of action appears to be
in the brain rather than in the periphery. Systemically administered
α-methyldopa rapidly enters the brain,
where it accumulates in noradrenergic nerves, is converted
to α-methylnorepinephrine, and is released.
Released α-methylnorepinephrine activates CNS α-
adrenoceptors whose function is to decrease sympathetic
outflow. Why α-methylnorepinephrine decreases sympathetic
outflow more effectively than does the naturally
occurring transmitter is not entirely clear.
Pharmacology
The primary hemodynamic alteration responsible for
the hypotensive effects of α-methyldopa remains in dispute.
When the patient is supine, the reduction in blood
pressure produced by α-methyldopa correlates best
with a decrease in peripheral vascular resistance, cardiac
output being only slightly reduced. When the patient
is upright, the fall in blood pressure corresponds
more closely with a reduced cardiac output.
An important aspect of α-methyldopa’s hemodynamic
effects is that renal blood flow and glomerular filtration
rate are not reduced. As occurs with most sympathetic
depressant drugs and vasodilators, long-term
therapy with α-methyldopa leads to fluid retention,
edema formation, and plasma volume expansion.While
data conflict somewhat, it is generally thought that -
methyldopa suppresses plasma renin activity.
Pharmacokinetics
The oral bioavailability of methyldopa ranges from 20 to 50% and varies among individuals. Optimum blood pressure
response occurs in 12 to 24 hours in most patients. After withdrawal of the drug, blood pressure returns to
pretreatment levels within 24 to 48 hours. Methyldopa and its metabolites are weakly bound to plasma proteins.
Although 95% of a dose of methyldopa is eliminated in hypertensive patients with normal renal function, with a plasma
half-life of approximately 2 hours, in patients with impaired renal function the half-life is doubled to approximately 3 to
4 hours, with about 50% of it excreted. Orally administered methyldopa undergoes presystemic first-pass metabolism in
the gastrointestinal (GI) tract to its 3-O-monosulfate metabolite. Sulfate conjugation occurs to a greater extent when
the drug is given orally than when it is given intravenously (IV). Its rate of sulfate conjugation is decreased in patients
with renal insufficiency. Methyldopa is excreted in urine as its mono-O-sulfate conjugate. Any peripherally
decarboxylated α-methylnorepinephrine is metabolized by catecho-o-methyltransferase (COMT) and monoamine
oxidase (MAO).
Methyldopate is slowly hydrolyzed in the body to form methyldopa. The hypotensive effect of IV methyldopate begins in
4 to 6 hours and lasts 10 to 16 hours.
Clinical Use
α-Methyldopa is not generally believed to be suitable
for monotherapy of primary hypertension. Because
plasma volume increases as the duration of α-methyldopa
therapy is extended, the drug should be used in
conjunction with a diuretic; this will produce a significantly
greater fall in blood pressure than would occur
with either drug used alone. Because α-methyldopa lowers
blood pressure without compromising either renal
blood flow or the glomerular filtration rate, it is particularly
valuable in hypertension complicated by renal disease.
However, if end-stage renal failure accompanies severe
hypertension,α-methyldopa may not be effective.
The presence of α-methyldopa and its metabolites
in the urine reduces the diagnostic value of urinary catecholamine
measurements as an indicator of pheochromocytoma,
since these substances interfere with the fluorescence
assay for catecholamines.
Side effects
The most commonly encountered side effects of α-
methyldopa are sedation and drowsiness.These CNS effects
are probably the result of reductions in brain catecholamine
levels. Other side effects, also typical of
sympathetic depression, are dry mouth, nasal congestion,
orthostatic hypertension, and impotence.
Autoimmune reactions associated with α-methyldopa
treatment include thrombocytopenia and leukopenia.
Since a few cases of an α-methyldopa–induced hepatitis
have occurred, the drug is contraindicated in
patients with active hepatic disease. Flulike symptoms
also are known to occur.
Safety Profile
Poison by
intraperitoneal route. Moderately toxic by
ingestion and intravenous routes. Human
systemic effects by ingestion: fasciculations,
hallucinations, distorted perceptions,
tremors, allergic dermatitis, necrotic
gastrointestinal changes. An experimental
teratogen. Human reproductive effects:
menstrual cycle changes or disorders, effects
on newborn including abnormal neonatal
measures and growth statistics, biochemical
and metabolic changes. Experimental reproductive effects. Mutation data
reported. When heated to decomposition it
emits toxic fumes of NOx
Synthesis
Methyldopa, (-)-3-(3,4-dihydroxyphenyl)-2-methylalanine (22.2.5), is
synthesized by a few methods that are only slightly different. The first method is from 3,4-
dimethoxyphenylacetone, which undergoes a Strecker–Zelinski reaction using
potassium cyanide and ammonium carbonate, to give 4-methyl-4-(3,4-dimethoxybenzylhydantoine
(22.3.3), which is further hydrolyzed in the presence of barium hydroxide
to give ()-3-(3,4-dimethoxyphenyl)-2-methylalanine (22.3.4). This undergoes
acetylation at the amino group, and the racemic mixture is then separated using
(-)-1-phenylethylamine. The isolated isomer is hydrolyzed using hydrobromic acid, which
simultaneously removes the methoxy- and acetyl groups to give the desired
(-)-3-(3,4-dihydroxyphenyl)-2-methylalanine (22.3.5) [8–10]. Alternative syntheses have
been proposed.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Antidepressants: avoid concomitant use with
MAOIs.
Lithium: neurotoxicity (without increased plasma lithium concentrations).
Salbutamol: acute hypotension reported with
salbutamol infusions.
Metabolism
Approximately 50% of an orally administered dose of
α-methyldopa is absorbed from the gastrointestinal
tract. Both peak plasma drug levels and maximal blood
pressure–lowering effects are observed 2 to 6 hours after
oral administration. A considerable amount of unchanged
α-methyldopa and several conjugated and decarboxylated
metabolites can be found in the urine.
Check Digit Verification of cas no
The CAS Registry Mumber 555-30-6 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 5,5 and 5 respectively; the second part has 2 digits, 3 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 555-30:
(5*5)+(4*5)+(3*5)+(2*3)+(1*0)=66
66 % 10 = 6
So 555-30-6 is a valid CAS Registry Number.
InChI:InChI=1/C10H13NO4/c1-11-7(10(14)15)4-6-2-3-8(12)9(13)5-6/h2-3,5,7,11-13H,4H2,1H3,(H,14,15)
555-30-6Relevant articles and documents
Synthetic method of methyldopa
-
Paragraph 0010; 0024, (2016/10/08)
The invention discloses a synthetic method of methyldopa. The method specifically comprises the steps that 3,4-dimethoxybenzaldehyde and 2-acetyl amino propionic acid methyl ester are used as raw materials, and condensation, reduction, deprotection and purification are performed. The synthetic path is simple, the yield is high, and the product purity is good.
Polyunsaturated fatty acid derivatives, pharmaceutical compositions containing the same, method for the preparation thereof, and their use as medicament
-
, (2008/06/13)
The compounds of the Formula (I) STR1 wherein R1 is a C18-24 alkenyl containing at least two double bonds, or --(CH2)n --CH(NH2)m --COOH X is 0, NH or C1-4 alkyl-N, Y is CONH2, COOH or COOMe, wherein Me is hydrogen metal, and R2 is a side chain of a any amino acid except L-GLU or L-ASP at α-position or a group of Formula wherein k is zero or an integer of 1, n is zero or an integer of 1 to 3, m is zero or an integer of 1 to 4, A is hydroxyl or one A is hydroxyl and the other A is hydrogen. M is H or R1 --CO and X and R1 are as defined above and their salts having tyrosine kinase inhibitor activity can be used as antitumor agents.
New aspects of β-lactam chemistry: β-lactams as chiral building blocks
Ojima, Iwao,Shimizu, Nobuko,Qiu, Xiaogang,Chen, Hauh-Jyun C.,Nakahashi, Kazuaki
, p. 649 - 658 (2007/10/02)
Recent advances on the new aspects of β-lactam chemistry in which β-lactams are used as chiral building blocks for the synthesis of a variety of α-amino acids, 4α-alkyl-α-aminoacids, oligopeptides, labeled peptides, azetidines, amino alcohols, etc., are reviewed.The topics include new and effective routes to dipeptides via homochiral β-lactams obtained by extremely stereoselective cycloadditions of chiral ketenes to chiral imines, a novel route to labeled peptides through extremely stereoselective and stereospecific reductive cleavage of β-lactams on a palladium catalyst, and new efficient syntheses of α-alkyl-α-amino acids and their peptides by the highly effective asymmetric alkylations of β-lactam lithium enolates followed by hydrogenolysis or Birch reduction.Mechanism of those highly selective unique reactions are discussed.
