10118-90-8 Usage
Uses
Used in Pharmaceutical Industry:
Minocycline is used as an antibiotic for the treatment of infections caused by susceptible bacteria. It exhibits broad-spectrum antibacterial and antiprotozoan activity by binding to the 30S and 50S ribosomal sub-units, blocking protein synthesis.
Used in Dermatology:
Minocycline is used as a treatment for skin infections, particularly for inflammatory lesions of non-nodular moderate-to-severe acne vulgaris and other skin infections such as MRSA and Lyme disease.
Used in Urology:
Minocycline is used as a treatment for urinary tract infections caused by susceptible bacteria.
Used in Gastroenterology:
Minocycline is used as a treatment for gallbladder infections caused by susceptible bacteria.
Used in Pulmonology:
Minocycline is used as a treatment for respiratory tract infections such as bronchitis, pneumonia, and sinusitis caused by susceptible bacteria.
Used in Infectious Diseases:
Minocycline is used as a treatment for Rocky Mountain spotted fever, typhus, and other infections caused by the typhus group of bacteria, as well as tick fevers caused by rickettsiae.
References
https://en.wikipedia.org/wiki/Minocycline
http://www.medicinenet.com/minocycline-oral/article.htm
http://bodyandhealth.canada.com/drug/getdrug/ratio-minocycline
Originator
Minocin,Lederle ,US,1971
Indications
The tetracycline antibiotic minocycline (Minocin) is
modestly effective in the treatment of rheumatoid
arthritis and is generally well tolerated. Radiographic
evidence of its efficacy as a DMARD is lacking, although
clinical symptoms do abate. It can be useful in
the treatment of early, mild disease.
Manufacturing Process
Preparation of 7-(N,N'-Dicarbobenzyloxyhydrazino)-6-Demethyltetracycline: A1.0 g portion of 6-demethyltetracycline was dissolved in a mixture of 9.6 ml oftetrahydrofuran and 10.4 ml of methanesulfonic acid at -10°C. The mixturewas allowed to warm to 0°C. A solution of 0.86 g of dibenzyl azodicarboxylatein 0.5 ml of tetrahydrofuran was added dropwise and the mixture was stirredfor 2 hours while the temperature was maintained at 0°C. The reactionmixture was added to ether. The product was filtered off, washed with etherand then dried. The 7-(N,N'-dicarbobenzyloxyhydrazino)-6-demethyltetracycline was identified by paper chromatography.Reductive Methylation of 7-(N,N'-Dicarbobenzyloxyhydrazino)-6-Demethyl-6-Deoxytetracycline to 7-Dimethylamino-6-Demethyl-6-Deoxytetracycline: Asolution of 100 mg of 7(N,N'-dicarbobenzyloxyhydrazino)-6-demethyl-6-deoxytetracycline in 2.6 ml of methanol, 0.4 ml of 40% aqueous ormaldehyde solution and 50 mg of 5% palladium on carbon catalyst washydrogenated at room temperature and two atmospheres pressure. Uptake ofthe hydrogen was complete in 3 hours. The catalyst was filtered off and thesolution was taken to dryness under reduced pressure. The residue wastriturated with ether and then identified as 7-dimethylamino-6-demethyl-6-deoxytetracycline by comparison with an authentic sample, according to USPatent 3,483,251.
Therapeutic Function
Antibiotic
World Health Organization (WHO)
Minocycline, a semi-synthetic tetracycline derivative was
introduced in 1967. It is used today in the treatment of bacterial, rickettsial and
amoebic infections. Symptoms described as dizziness or vertigo have been
recognized in association with minocycline administration, however, these
symptoms are usually not severe. Minocycline is registered in many countries and
the World Health Organization is not aware that registration has been refused
elsewhere.
Antimicrobial activity
It exhibits the broad-spectrum activity
typical of the group, but retains activity against some strains
of Staph. aureus resistant to older tetracyclines. It is active
against β-hemolytic streptococci and some tetracycline-
resistant
pneumococci. It is also active against some enterobacteria
resistant to other tetracyclines, probably because
some Gram-negative efflux pumps remove minocycline less
effectively
than other tetracyclines. Some strains of H. influenzae resistant
to other tetracyclines are susceptible. Sten. maltophilia
is susceptible, as are most strains of Acinetobacter spp.
and L. pneumophila.
It is notable for its activity against Bacteroides and
Fusobacterium spp., and is more active than other tetracyclines
against C. trachomatis, brucellae and nocardiae. It inhibits
Mycobacterium tuberculosis, M. bovis, M. kansasii and M. intracellulare
at 5–6 mg/L. Candida albicans and C. tropicalis are also
slightly susceptible.
Pharmaceutical Applications
A semisynthetic tetracycline derivative supplied as the hydrochloride
for oral administration.
Pharmacokinetics
Oral absorption： 95–100%
Cmax 150 mg oral： 4 mg/L after 2h
300 mg oral： 2 mg/L after 2 h
Plasma half-life： 12–24 h
Volume of distribution： 80–115 L
Plasma protein binding： 76%
Absorption
Food does not significantly affect absorption, which is depressed
by co-administration with milk. It is chelated by metals and
suffers the effects of antacids and ferrous sulfate common to
tetracyclines. On a regimen of 100 mg every 12 h, steady-state
concentrations ranged between 2.3 and 3.5 mg/L.
Distribution
The high lipophilicity of minocycline provides wide distribution
and tissue concentrations that often exceed those of
the plasma. The tissue:plasma ratio in maxillary sinus and
tonsillar tissue is 1.6： that in lung is 3–4. Sputum concentrations
may reach 37–60% of simultaneous plasma levels.
In bile, liver and gallbladder the ratios are 38, 12 and 6.5,
respectively.
Prostatic and seminal fluid concentrations range from 40%
to 100% of those of serum. CSF penetration is poor, especially
in the non-inflamed state. Concentrations in tears and
saliva are high, and may explain its beneficial effect in the
treatment of meningococcal carriage.
Metabolism
Biotransformation to three microbiologically inactive
metabolites occurs in the liver： the most abundant is
9-hydroxyminocycline.
Excretion
Only 4–9% of administered drug is excreted in the urine, and
in renal failure elimination is little affected. Neither hemodialysis
nor peritoneal dialysis affects drug elimination. Fecal excretion is relatively low and evidence for enterohepatic
recirculation remains uncertain. Despite high hepatic excretion,
dose accumulation does not occur in liver disease, such
as cirrhosis. Type IIa and type IV hyperlipidemic patients
show a decreased minocycline clearance of 50%, suggesting
that dose modification may be necessary.
Clinical Use
There appear to be few situations in which it has a unique
therapeutic advantage over other tetracyclines. Its use has been
tempered by the high incidence of vestibular side effects.
Although used in the long-term management of acne, the
potential for skin pigmentation must be considered. Because
of its high tissue concentrations, it may occasionally provide a
useful alternative to other agents for the treatment of chronic
prostatitis. It has a role in the treatment of sexually transmitted
chlamydial infections.
Side effects
Minocycline shares the untoward reactions common to the
group with gastrointestinal side effects being most common,
and more prevalent in women. Diarrhea is relatively
uncommon, presumably as a result of its lower fecal concentrations.
Hypersensitivity reactions, including rashes,
interstitial nephritis and pulmonary eosinophilia, are occasionally
seen.
Staining of the permanent dentition occurs with all tetracyclines;
a side effect that appears to be unique to minocycline
is that of tissue discoloration and skin pigmentation. Tissues
that may become pigmented include the skin, skull and other
bones and the thyroid gland, which at autopsy appears blackened.
The pigmentation tends to resolve slowly with discontinuation
of the drug and is related to the length of therapy.
Three types of pigmentation have been identified:
? A brown macular discoloration (‘muddy skin syndrome’),
which occurs in sun-exposed parts and is histologically
associated with melanin deposition.
? Blue–black macular pigmentation occurring within
inflamed areas and scars associated with hemosiderin
deposition.
? Circumscribed macular blue–gray pigmented areas
occurring in sun-exposed and unexposed skin, which
appears to be linked to a breakdown product of
minocycline.
CNS toxicity has been prominent, notably benign intracranial
hypertension, which resolves on discontinuation of the
drug, and, more commonly, dizziness, ataxia, vertigo, tinnitus,
nausea and vomiting, which appear to be more frequent
in women. These primarily vestibular side effects have ranged
in frequency from 4.5% to 86%. They partly coincide with
plasma concentration peaks, but their exact pathogenesis has
yet to be determined.
Synthesis
Minocycline, 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12 a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacencarboxamide (32.3.17), is synthesized
from 6-dimethyl-tetracycline (32.3.11), which is synthesized as a result of the vital activity
of S. aureofaciens, in which the mechanism of transferring methyl groups is disrupted, or
from a common strain of the same microorganisms, but with the addition of compounds
such as ethionin, D-norleucine or D-methionine to the medium for developing this actinomycete, which are antimetabolytes of methionine, the primary donor of methyl groups in
microbiological synthesis of tetracycline molecules. Hydrogenolysis of the aforementioned
6-demethyltetracycline (32.3.11) with hydrogen using a palladium on carbon catalyst gives
4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-napthacencarboxamide (32.3.12), which is nitrated at position 9 by potassium nitrate in
aqueous hydrofluoric acid, which forms the nitro compound (32.3.13). This is reduced to
the corresponding amino derivative (32.3.14) by hydrogen over platinum dioxide. The
resulting aminophenyl compound (32.3.14) is then nitrated with nitric acid in the presence
of sulfuric acid to make 7-nitro-9-amino-4-naphthacencarboxamide (32.3.15). This undergoes diazotization when reacted with butylnitrate in sulfuric acid, and the resulting diazo
derivative (32.3.16) is reduced with hydrogen using a palladium on carbon catalyst. During
this, the product is deazotized, while the nitro group is simultaneously reduced to an amino
group, which undergoes exhaustive methylation by formaldehyde into minocycline
(32.3.17).
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced anticoagulant
effect of coumarins and phenindione.
Oestrogens: possibly reduced contraceptive effect of
oestrogens (risk probably small).
Retinoids: possibly increased risk of benign
intracranial hypertension - avoid.
Metabolism
Undergoes some metabolism in the liver, mainly to
9-hydroxyminocycline.
Dosage forms
Up to 200 mg daily in divided doses.
Check Digit Verification of cas no
The CAS Registry Mumber 10118-90-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,0,1,1 and 8 respectively; the second part has 2 digits, 9 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 10118-90:
(7*1)+(6*0)+(5*1)+(4*1)+(3*8)+(2*9)+(1*0)=58
58 % 10 = 8
So 10118-90-8 is a valid CAS Registry Number.
InChI:InChI=1/C23H27N3O7/c1-25(2)12-5-6-13(27)15-10(12)7-9-8-11-17(26(3)4)19(29)16(22(24)32)21(31)23(11,33)20(30)14(9)18(15)28/h5-6,9,11,17,27,29-30,33H,7-8H2,1-4H3,(H2,24,32)/t9-,11-,17-,23-/m0/s1
10118-90-8Relevant articles and documents
Palladium catalyzed C-N bond formation in the synthesis of 7-amino-substituted tetracyclines.
Koza, Darrell J,Nsiah, Yaw A
, p. 5025 - 5027 (2002)
A facile synthesis of 7-alkylamino- and 7-cycloalkylaminotetracycline derivatives has been accomplished using an in situ generated aminostannane precursor. This procedure is advantageous in that it allows the concise synthesis of a number of unreported tetracycline derivatives that are cumbersome to prepare through traditional methods. These compounds are crucial to understanding structure activity relationships in the D-ring of tetracycline-type antibiotics and the acquired efflux resistance mechanism to this class of antibiotics.
Synthesis method of minocycline hydrochloride
-
Paragraph 0022; 0048-0051, (2021/03/31)
The invention discloses a preparation method of minocycline hydrochloride. The preparation method is characterized by comprising the following steps: with demeclocycline hydrochloride as an initial raw material, carrying out a dehydroxylation reaction to obtain 6-deoxy-6-demeclocycline (intermediate I for short); carrying out acetyl protection on the intermediate I to obtain 3,10,12,12a-tetraacetyl-6-deoxy-6-demeclocycline (intermediate II for short); carrying out the BuchwaldHartwig reaction on the intermediate II to obtain 3,10,12,12a-tetraacetylminocycline (intermediate III for short); hydrolyzing the intermediate III to obtain minocycline free alkali (intermediate IV for short); and salifying the intermediate IV to obtain minocycline hydrochloride. According to the invention, nitrification, diazotization and azo reactions used in traditional minocycline hydrochloride synthesis processes are avoided, so dangerous factors in the production process are reduced, operation is simple, environmental pollution is avoided, and the method has industrial production prospects.
Synthetic method of minocycline and derivative of minocycline
-
Paragraph 0024; 0025, (2019/09/13)
The invention relates to a synthetic method of minocycline and substituted minocycline, and especially synthesis of 9-amino minocycline. 9-amino minocycline is an important intermediate of tigecycline, and tigecycline is mostly used for control on multiple resistant bacteria. The raw materials are easily available; the synthetic route is short; reaction conditions are mild; the yield is high; thetechnology is simple; and the synthetic method is suitable for large scale production.
Preparation method of minocycline hydrochloride
-
, (2017/08/30)
The invention provides a preparation method of minocycline hydrochloride. The preparation method comprises the following steps: 1) preparing sancycline: preparing the sancycline by taking demeclocycline hydrochloride as a raw material; 2) preparing 7-iodosancycline: under a strong acid condition, taking N-iodosuccinimide and the sancycline to react to prepare a reaction solution, namely the 7-iodosancycline; 3) preparing the minocycline hydrochloride: taking the 7-iodosancycline and dimethylaminotrimethyl tin to react in an amine solvent and an amide solvent under the action of a palladium complex catalyst to prepare a reaction solution, and adjusting the pH (Potential of Hydrogen) of the reaction solution to be 0.8 to 1.0 with concentrated hydrochloric acid; after de-coloring with active carbon, adjusting the pH of the reaction solution to be 3.8 to 4.0 with ammonia water; freezing and crystallizing; after filtering, drying a filter cake to obtain the minocycline hydrochloride. The minocycline hydrochloride prepared by the preparation method has the advantages of low cost, stable structure, few isomer impurities, low content of epimers and relatively high product purity.
Tigecycline impurity process for stereoselective preparation of
-
Paragraph 0041; 0042, (2017/06/24)
The invention discloses a tigecycline impurity stereoselective preparation method. According to the invention, minocycline hydrochloride is adopted as a raw material, and is stirred in lower alkanol and liquid acid; the temperature is increased to 35-45 DEG C; the temperature is maintained and a reaction is allowed for 2-5h; the temperature is reduced, and the pH value of the mixed liquid is regulated to 6.5-8.5, such that solid is precipitated; a reaction is carried out for 2h under controlled temperature; the pH value is retested and the pH value is not changed; the material is filtered; a lower alkanol solvent is used for washing a filter cake; and drying is carried out, such that tigecycline impurity E is obtained. The purity can be higher than 98.0%, and a yield is higher than 50%.
MINOCYCLINE DERIVATIVES
-
Paragraph 0052-0053, (2014/10/04)
This invention relates generally to minocycline derivatives, and to compositions, including pharmaceutical compositions, containing such minocycline derivatives. The invention also relates to methods of synthesizing minocycline derivatives and to methods for using such minocycline derivatives as anti-bacterial agents for treating or preventing infections.
Substituted Tetracycline Compounds
-
Page/Page column 107, (2010/12/29)
The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms.
TETRACYCLINE COMPOUNDS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AND RELATED METHODS OF TREATMENT
-
Page/Page column 36, (2010/04/25)
The present invention pertains, at least in part, to substituted tetracycline compounds. The present invention also pertains to methods for treating rheumatoid arthritis in a subject, comprising administering to the subject a tetracycline compound of the invention.
CRYSTALLINE MINOCYCLINE BASE AND PROCESSES FOR ITS PREPARATION
-
Page/Page column 8, (2008/12/08)
The invention provides crystalline minocycline base. In particular, three crystalline polymorphic forms, designated Form I, Form Il and Form III, of minocycline base are provided. These are characterised by XRD and IR data. Processes for preparing the new polymorphic forms are also provided. For example, Form I is prepared by dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallisation from the mixture.
10-substituted tetracyclines and methods of use thereof
-
Page/Page column 32, (2010/11/26)
10-Substituted tetracycline compounds are described.
