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## ATISOBAN

ATOSIBAN

cas 90779-69-4

WeightAverage: 994.19
Monoisotopic: 993.441208989

Chemical FormulaC43H67N11O12S2

(2S)-5-amino-2-{[(2S)-1-[(4R,7S,10S,13S,16R)-13-[(2S)-butan-2-yl]-7-(carbamoylmethyl)-16-[(4-ethoxyphenyl)methyl]-10-[(1R)-1-hydroxyethyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosane-4-carbonyl]pyrrolidin-2-yl]formamido}-N-(carbamoylmethyl)pentanamide

• Oxytocin, 1-(3-mercaptopropanoic acid)-2-(O-ethyl-D-tyrosine)-4-L-threonine-8-L-ornithine-
• 1,2-Dithia-5,8,11,14,17-pentaazacycloeicosane, cyclic peptide deriv.
• Antocile
• Antocin
• Antocin II

Product Ingredients

• CAP-449
• CAP-476
• CAP-581
• F-314
• ORF 22164
• ORF-22164
• RW-22164
• RWJ 22164
• RWJ-22164

Atosiban, sold under the brand name Tractocile among others, is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985.[5] Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women.

The most commonly reported side effect is nausea.[4]

Atosiban is an inhibitor of the hormones oxytocin and vasopressin. It is used intravenously to halt premature labor. Although initial studies suggested it could be used as a nasal spray and hence would not require hospital admission, it is not used in that form. Atobisan was developed by the Swedish company Ferring Pharmaceuticals. It was first reported in the literature in 1985. Atosiban is licensed in proprietary and generic forms for the delay of imminent pre-term birth in pregnant adult women.

## Medical uses

Atosiban is used to delay birth in adult women who are 24 to 33 weeks pregnant, when they show signs that they may give birth pre-term (prematurely).[4] These signs include regular contractions lasting at least 30 seconds at a rate of at least four every 30 minutes,[4] and dilation of the cervix (the neck of the womb) of 1 to 3 cm and an effacement (a measure of the thinness of the cervix) of 50% or more.[4] In addition, the baby must have a normal heart rate.[4]

## Pharmacology

### Mechanism of action

Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist (VOTra). Atosiban inhibits the oxytocin-mediated release of inositol trisphosphate from the myometrial cell membrane. As a result, reduced release of intracellular, stored calcium from the sarcoplasmic reticulum of myometrial cells and reduced influx of Ca2+ from the extracellular space through voltage-gated channels occur. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua.[6]

In human preterm labour, atosiban, at the recommended dosage, antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence.

## Other uses

### Atosiban use after assisted reproduction

Atosiban is useful in improving the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with repeated implantation failure.[7] The pregnancy rate improved from zero to 43.7%.[8]

First- and second-trimester bleeding was more prevalent in ART than in spontaneous pregnancies. From 2004 to 2010, 33 first-trimester pregnancies with vaginal bleeding after ART with evident uterine contractions, when using atosiban and/or ritodrine, no preterm delivery occurred before 30 weeks.[9]

In a 2010 meta-analysis,[10] nifedipine is superior to β2 adrenergic receptor agonists and magnesium sulfate for tocolysis in women with preterm labor (20–36 weeks), but it has been assigned to pregnancy category C by the U.S. Food and Drug Administration, so is not recommended before 20 weeks, or in the first trimester.[9] A report from 2011 supports the use of atosiban, even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy.[7]

## Pharmacovigilance

Following the launch of atosiban in 2000, the calculated cumulative patient exposure to atosiban (January 2000 to December 2005) is estimated as 156,468 treatment cycles. To date, routine monitoring of drug safety has revealed no major safety issues.[11]

## Regulatory affairs

Atosiban was approved in the European Union in January 2000 and launched in the European Union in April 2000.[12][4] As of June 2007, atosiban was approved in 67 countries, excluding the United States and Japan.[12] It was understood that Ferring did not expect to seek approval for atosiban in the US or Japan, focusing instead on development of new compounds for use in Spontaneous Preterm Labor (SPTL).[12] The fact that atosiban only had a short duration before it was out of patent that the parent drug company decided not to pursue licensing in the US.[13]

## Systematic reviews

In a systematic review of atosiban for tocolysis in preterm labour, six clinical studies — two compared atosiban to placebo and four atosiban to a β agonist — showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo. When compared with β agonists, atosiban increased the proportion of women undelivered by 48 hours and was safer compared to β agonists. Therefore, oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.[14]

A 2014 systematic review by the Cochrane Collaboration showed that while atosiban had fewer side effects than alternative drugs (such as ritodrine), other beta blockers, and calcium channel antagonists, it was no better than placebo in the major outcomes i.e. pregnancy prolongation or neonatal outcomes. The finding of an increase in infant deaths in one placebo-controlled trial warrants caution. Further research is recommended.[15]

PATENT

WO 2021207870

Atosiban (Atosiban) is an oxytocin and vasopressin V1A combined receptor antagonist, which can be used as a competitive antagonist of cyclic peptide oxytocin receptors in the uterus, decidua and fetal membrane. Atosiban is a disulfide-bonded cyclic polypeptide composed of 9 amino acids. It is a modified oxytocin molecule at positions 1, 2, 4 and 8. The N-terminal of the peptide is 3-mercaptopropionic acid (thiol and [ Cys] 6 thiol forms a disulfide bond), the C-terminal is in the form of an amide, and the second amino acid at the N-terminal is ethylated [D-Tyr(Et)] 2 . Atosiban is generally present in medicines in the form of acetate salt, commonly known as atosiban acetate. Its chemical formula is C 45 H 71 N 11 O 14 S 2 , its molecular weight is 994.19, and its structural formula is as follows:

[0003]

[0004]

In the prior art, atosiban is usually synthesized by a solid-phase peptide synthesis (SPPS) method, an amino resin is used as a starting carrier resin, and protected amino acids are sequentially connected, and the obtained atosiban is oxidized and then cleaved to obtain atosiban. However, the above-mentioned existing process has high cost, generates a large amount of solvent waste, and is not easy to monitor during the cyclization process. In addition, the above-mentioned prior art has deficiencies in the overall yield of crude peptides. Moreover, due to the existence of D-Tyr(Et) in the structure of atosiban, Fmoc-D-Tyr(Et) easily undergoes a racemization reaction during the peptide attachment process, resulting in [Tyr(Et) 2 ]-A The impurity of tosiban, which is similar in polarity to atosiban itself, is difficult to completely remove through purification, thus affecting the quality of atosiban.

[table 0001]

Table 3 List of intermediates and Fmoc protected amino acids

[0043]

[table 0002]

[0045]

According to the most preferred embodiment of the present invention, the method of the present invention comprises the following steps:

[0046]

The first step: Fmoc-Gly Rink resin can be directly purchased, which reduces the first step of synthesis and improves the synthesis efficiency;

[0047]

The second step: preparing a deprotection solution: the deprotection solution is a mixture of piperidine/N,N-dimethylformamide, preferably piperidine/N,N-dimethylformamide in a volume ratio of 1/4.

[0048]

The third step: preparation of Fmoc-Orn(Boc)-Gly Rink resin: deprotect the Fmoc-Gly Rink resin obtained in the first step, wash with DMF, add Fmoc-Orn(Boc)-OH in DMF solution, Condensation reaction is carried out under the condition of peptide coupling condensing agent to obtain Fmoc-Orn(Boc)-Gly Rink resin;

[0049]

The fourth step: preparation of Fmoc-Pro-Orn(Boc)-Gly Rink resin: the peptide resin obtained in the fourth step is deprotected and washed, and then reacted with Fmoc-Pro-OH under the condition of a peptide coupling agent to obtain Fmoc-Pro-Orn(Boc)-Gly Rink resin;

[0050]

The fifth step: preparation of Fmoc-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin. The peptide resin obtained in the fifth step is deprotected and washed, and then reacted with Fmoc-Cys(Trt)-OH under the condition of peptide coupling agent to obtain Fmoc-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin;

[0051]

The sixth step: preparation of Fmoc-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin. The peptide resin obtained in the sixth step is deprotected and washed, and then reacted with Fmoc-Asn-OH under the condition of peptide coupling agent to obtain Fmoc-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin ;

[0052]

The seventh step: preparation of Fmoc-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin. The peptide resin obtained in the seventh step was deprotected and washed, and then reacted with Fmoc-Thr(tBu)-OH under the condition of a peptide coupling agent. Obtain Fmoc-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin;

[0053]

The eighth step: preparation of Fmoc-Ile-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin. The peptide resin obtained in the eighth step is deprotected and washed, and then reacted with Fmoc-Ile-OH under the condition of a peptide coupling agent to obtain Fmoc-Ile-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn (Boc)-Gly Rink resin;

[0054]

The ninth step: preparation of Fmoc-D-Tyr(RT)-Ile-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin. The peptide resin obtained in the ninth step is deprotected and washed, and then reacted with Fmoc-D-Tyr(ET)-OH under the condition of a peptide coupling agent to obtain Fmoc-D-Tyr(RT)-Ile-Thr(tBu )-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin;

[0055]

The tenth step: preparation of Mpa(Trt)-D-Tyr(ET)-Ile-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin. The peptide resin obtained in the tenth step is deprotected and washed, and then reacted with Mpa(Trt) under the condition of a peptide coupling agent to obtain Mpa(Trt)-D-Tyr(ET)-Ile-Thr(tBu)-Asn -Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin;

[0056]

The eleventh step: Mpa(Trt)-D-Tyr(ET)-Ile-Thr(tBu)-Asn-Cys(Trt)-Pro-Orn(Boc)-Gly Rink resin in TFA/TIS/EDT/H2O =90/54/10/5 TFA, cleaved for 3 hours, and filtered to obtain crude peptide solution;

[0057]

The twelfth step: sedimentation and washing of the crude peptide solution with methyl tert-butyl ether, centrifugation at 2000 rpm, and vacuum drying to obtain a pale yellow solid powder of atosiban linear crude peptide;

[0058]

The thirteenth step: prepare three solutions for atosiban cyclization: solution A-sodium acetate buffered aqueous solution, solution B-aqueous solution of linear peptide atosiban crude peptide acetic acid, solution C: 30%-60% hydrogen peroxide solution ;

[0059]

The fourteenth step: Mix the above three solutions of A, B, and C at 15-25 ° C, and stir for 1-3 hours after mixing, so that the Mpa at the 1st position and the Cys at the 6th position form a disulfide bond to obtain Cyclized atosiban crude peptide.

[0060]

Step fifteen: Purify crude atosiban by preparative high performance liquid chromatography with a water/acetonitrile gradient from 100% water to 100% acetonitrile in 20 minutes.

[0061]

The sixteenth step: freeze-dry the purified atosiban solution at -50 to -70° C. for 18-48 hours with a freeze dryer.

[0062]

The purity of atosiban obtained by the method of the invention is more than 99.5%, and the total product yield is 55%-65%.

[0063]

The advantage of the method for preparing atosiban of the present invention is:

[0064]

The traditional SPPS synthesis of atosiban usually produces a large amount of waste with high disposal costs. This process adopts high-temperature SPPS process and selects different condensing agent combinations, which is faster than the conventional SPPS process, the product purity can reach more than 99.9%, the purity is better than that of the conventional atosiban process, the impurity content is low, and the product quality is high. The total yield can reach 55%-65%.

### Detailed ways

[0065]

The invention will now be described with reference to specific embodiments. It must be understood that these examples are merely illustrative of the invention and are not intended to limit the scope of the invention. Unless otherwise stated, percentages and parts are by weight. Unless otherwise specified, experimental materials and reagents used in the following examples were obtained from commercial sources.

[0066]

Example 1:

[0067]

Using Rink-Fmoc-Gly resin (40 g, substitution amount 0.61 mmol/g) as the starting material, the stepwise Fmoc-SPPS (solid phase peptide synthesis) method was used to synthesize the peptide. Fmoc deprotection was performed with piperidine in DMF (1:4 v/v). Subsequently, other amino acids in the sequence are connected in the following order, and the coupling reagents are N,N-diisopropylcarbodiimide, 2-(7-benzotriazole)-N,N,N’,N ‘-Tetramethylurea hexafluorophosphate mixed in a volume ratio of 1:1, Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ile-OH, Fmoc-D-Tyr(ET)-OH, Mpa(Trt). Coupling and deprotection of amino acids were carried out at 90°C for 2-3 min and monitored with the Kaiser test. The peptide was cleaved with the lysing solution of TFA for 3 hours, precipitated and washed twice with methyl tert-butyl ether, and after centrifugal drying, the atosiban linear crude peptide was cyclized by the method of liquid phase synthesis, and the volume ratio was 1: 2:2 A solution-acetic acid-sodium acetate buffer aqueous solution (concentration is 30g/L), B solution-linear peptide atosiban crude peptide acetic acid aqueous solution and C solution: 60% hydrogen peroxide solution.

[0068]

The crude peptide yield was 85%. Crude atosiban was purified by preparative high performance liquid chromatography with a water/acetonitrile gradient from 100% water to 100% acetonitrile in 20 minutes. The purified atosiban solution is freeze-dried at -50 to -70° C. for 18 hours with a freeze dryer, the obtained atosiban has a purity of more than 99.5%, and the total product yield is 56%.

[0069]

Example 2:

[0070]

Using Rink-Fmoc-Gly resin (40 g, substitution amount 0.36 mmol/g) as the starting material, the stepwise Fmoc-SPPS (solid phase peptide synthesis) method was used to synthesize the peptide. Fmoc deprotection was performed with piperidine in DMF (1:4 v/v). Subsequently, the other amino acids in the sequence are connected in the following order, and the coupling reagents are N,N-tert-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and Oxyma, which are mixed in a volume ratio of 1:1:1 , Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ile-OH, Fmoc-D- Tyr(ET)-OH, Mpa(Trt). Coupling and deprotection of amino acids were carried out at 90°C for 2-3 min and monitored with the Kaiser test. The peptide was cleaved with the lysing solution of TFA for 3 hours, precipitated with methyl tert-butyl ether and washed twice, and after centrifugal drying, the atosiban linear crude peptide was cyclized by the method of liquid phase synthesis, and the volume ratio was 1: 3:2 solution A-formic acid-sodium formate buffer aqueous solution (concentration 25g/L), solution B-linear peptide atosiban crude peptide formic acid aqueous solution and solution C: 30% hydrogen peroxide solution, and oxygen was introduced.

[0071]

The crude peptide yield was 83%. Crude atosiban was purified by preparative high performance liquid chromatography with a water/acetonitrile gradient from 100% water to 100% acetonitrile in 20 minutes. The purified atosiban solution is freeze-dried at -50 to -70° C. for 18 hours with a freeze dryer, the obtained atosiban has a purity greater than 99.5%, and the total product yield is 57%.

[0072]

Example 3:

[0073]

Using Rink-Fmoc-Gly resin (40 g, substitution amount 0.36 mmol/g) as the starting material, the stepwise Fmoc-SPPS (solid phase peptide synthesis) method was used to synthesize the peptide. Fmoc deprotection was performed with piperidine in DMF (1:4 v/v). Subsequently, other amino acids in the sequence were connected in the following order, and the coupling reagents were N,N-diisopropylethylamine, 2-(7-benzotriazole)-N,N,N’,N’- Two kinds of tetramethylurea hexafluorophosphate mixed in a 1:1 volume ratio, Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn-OH, Fmoc- Thr(tBu)-OH, Fmoc-Ile-OH, Fmoc-D-Tyr(ET)-OH, Mpa(Trt). Coupling and deprotection of amino acids were carried out at 75°C for 2-3 min and monitored with the Kaiser test. The peptide was cleaved with the lysing solution of TFA for 3 hours, precipitated and washed twice with methyl tert-butyl ether, and after centrifugal drying, the atosiban linear crude peptide was cyclized by the method of liquid phase synthesis, and the volume ratio was 1: 2:3 solution A-sodium phosphate buffered aqueous solution (concentration 15g/L), solution B-linear peptide atosiban crude peptide phosphoric acid aqueous solution and solution C: DMSO aqueous solution (volume 1:1).

[0074]

The crude peptide yield was 80%. Crude atosiban was purified by preparative high performance liquid chromatography with a water/acetonitrile gradient from 100% water to 100% acetonitrile in 20 minutes. The purified atosiban solution is freeze-dried at -50 to -70 DEG C for 28 hours with a freeze dryer, the obtained atosiban has a purity of more than 99.5%, and the total product yield is 55%.

[0075]

Example 4:

[0076]

Using Rink-Fmoc-Gly resin (40 g, substitution amount 0.36 mmol/g) as the starting material, the stepwise Fmoc-SPPS (solid phase peptide synthesis) method was used to synthesize the peptide. Fmoc deprotection was performed with piperidine in DMF (1:3 by volume). Subsequently, the other amino acids in the sequence were connected in the following order, and the coupling reagents were selected from 2-oxime ethyl cyanoacetate, N,N-diisopropylcarbodiimide, and 1-hydroxybenzotriazole in a volume ratio of 1. :1:1 mix, Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ile-OH , Fmoc-D-Tyr(ET)-OH, Mpa(Trt). Coupling and deprotection of amino acids were carried out at 80°C for 2-3 min and monitored with the Kaiser test. The peptide was cleaved with the lysing solution of TFA for 3 hours, precipitated with methyl tert-butyl ether and washed twice, and after centrifugal drying, the atosiban linear crude peptide was cyclized by the method of liquid phase synthesis, and the volume ratio was 1: 3:4 solution of A-trifluoroacetic acid-aqueous ammonia solution (concentration of 45 g/L), solution B-aqueous solution of linear peptide atosiban crude peptide trifluoroacetic acid and solution C: saturated aqueous iodine solution.

[0077]

The crude peptide yield was 78%. Crude atosiban was purified by preparative high performance liquid chromatography with a water/acetonitrile gradient from 100% water to 100% acetonitrile in 20 minutes. The purified atosiban solution is freeze-dried at -50 to -70° C. for 38 hours with a freeze dryer, the obtained atosiban has a purity of more than 99.5%, and the total product yield is 52%.

PATENT

WO/2022/141615

Atosiban Acetate Injection was first listed in Austria on March 23, 2000 under the trade name: Atosiban, a new type of anti-prematurity drug developed by Ferring GmbH, which is an oxytocin The analog is a competitive antagonist of oxytocin receptors in the uterus, decidua, and fetal membranes. It is a first-line drug recommended by the European Medical Association; it can inhibit the binding of oxytocin and oxytocin receptors, thereby directly inhibiting the effect of oxytocin. In the uterus, it can inhibit uterine contraction; it can also inhibit the hydrolysis of phosphatidylinositol.

Atosiban is a cyclic nonapeptide whose molecular formula is C 43 H 67 N 11 O 12 S 2 ; molecular weight is 994.19; CAS registration number is 90779-69-4; its peptide sequence is as follows:

Cyclo[Mpa-D-Tyr(Et)-Ile-Thr-Asn-Cys]-Pro-Orn-Gly-NH 2

In the Chinese patents with announcement numbers CN101314613B and CN101696236B, the solid-phase synthesis of atosiban uses Rink Amide AM Resin resin solid-phase coupling stepwise to obtain Mpa(Trt)-D-Tyr(Et)-Ile-Thr(tBu)- Asn(Trt)-Cys(Trt)-Pro-Orn(Boc)-Gly-Resin is directly oxidized in solid phase to generate disulfide bonds, and then cleaved to obtain atosiban. The Rink Amide AM Resin resin used in the prior art needs to be cracked under a strong acid environment, which is not conducive to product stability and has a greater operational risk; Mpr and Cys both have sulfhydryl groups, and the sulfhydryl groups have the ability to capture tBu to generate double tBu impurities, When the peptide resin after solid-phase oxidation is cleaved to remove the protective group and resin, due to the presence of tBu or tBu source Boc protective group, it requires high capture agent, which is not conducive to product quality control and reduces product yield.

The Chinese patent with publication number CN105408344B discloses a method for synthesizing atosiban starting from Fmoc-Orn-Gly-NH2, wherein Fmoc-Orn-Gly-NH2 is connected to trityl through the side chain of ornithine On the base resin, impurities can be effectively controlled. However, using dipeptide and trityl-type resin for coupling, the resin attached to the Orn side chain of the dipeptide increases the steric hindrance of the subsequent Pro coupling and prolongs the coupling time, which is easy to cause missing peptide impurities.

Example 1. Synthesis of Fmoc-Pro-Orn-Gly-NH 2 tripeptide

[0027]

Fmoc-Pro-OH (134.94 g, 400 mmol) and N-hydroxysuccinimide (46.00 g, 400 mmol) were weighed into 1600 ml of tetrahydrofuran, and stirred at room temperature. The temperature was controlled at about 5°C, and a solution of DCC (90.72g, 440mmol) in tetrahydrofuran (320ml) was slowly added and stirred at room temperature for 2.5h, filtered, concentrated and added to petroleum ether for recrystallization to precipitate a solid, washed and dried, and the obtained activated ester was The solid was dissolved in 400 ml of tetrahydrofuran, and H-Orn(Boc)-NH 2 (92.92 g, 400 mmol) was dissolved in 300 ml of tetrahydrofuran and slowly added dropwise to the above solution. After dropping, the reaction was continued at room temperature. Concentrate to dryness under reduced pressure, add N-hydroxysuccinimide (46.00 g, 400 mmol) and 1600 ml of tetrahydrofuran to dissolve, and stir at room temperature. The temperature was controlled at about 5°C, and a solution of DCC (90.72g, 440mmol) in tetrahydrofuran (320ml) was slowly added and stirred at room temperature for 2.5h, filtered, concentrated and added to petroleum ether for recrystallization to precipitate a solid, washed and dried, and the obtained activated ester was The solid was dissolved in 400 ml of tetrahydrofuran, and H-Gly-NH 2 (29.64 g, 400 mmol) was dissolved in 300 ml of tetrahydrofuran and slowly added dropwise to the above solution, and the reaction was continued at room temperature after dropping, and the monitoring of the raw materials was completed. The reaction was filtered, and the filtrate was concentrated under reduced pressure. Dry, add 1000 mL of 5% TFA/DCM solution to the reaction solution, continue to react for 1 h, and concentrate to dryness to obtain a yellow oil, which is recrystallized from isopropanol to obtain 171.56 g of white solid with a yield of 69%.

[0028]

Example 2. Synthesis of Fmoc-Pro-Orn (trityl resin)-Gly-NH 2 peptide resin with a degree of substitution of 0.42 mmol/g

[0029]

Trityl resin (37.5 g, 30 mmol, substitution degree: 0.80 mmol/g) was weighed into a solid-phase reaction synthesis column. 400 mL of dry DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*400 mL of dry DMF, and the DMF was removed. Fmoc-Pro-Orn-Gly-NH 2 (37.30 g, 60 mmol) prepared in Example 1 , DIEA (11.63 g, 90 mmol) were added, 100 mL of dry DMF was added to dissolve and clarified, added to the resin to react for 2 h, and methanol (9.61 mmol) was added. g, 300 mmol) reacted for 20 min, sucked dry, washed the resin with 3*400 mL of CH 2 Cl 2 , and removed CH 2 Cl 2 . The resin was taken out and dried under vacuum at 25-35° C. to obtain 52.14 g of Fmoc-Pro-Orn (trityl resin)-Gly-NH 2 resin with a measured substitution degree of 0.42 mmol/g.

[0030]

Example 3. Synthesis of Fmoc-Pro-Orn(2-CTC Resin)-Gly-NH 2 peptide resin with a degree of substitution of 0.50 mmol/g

[0031]

2-CTC Resin resin (30.0 g, 30 mmol, substitution degree: 1.00 mmol/g) was weighed into a solid-phase reaction synthesis column. 400 mL of dry DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*400 mL of dry DMF, and the DMF was removed. Fmoc-Pro-Orn-Gly-NH 2 (37.30 g, 60 mmol) prepared in Example 1 , DIEA (11.63 g, 90 mmol) were added, 100 mL of dry DMF was added to dissolve and clarified, added to the resin to react for 2 h, and methanol (9.61 mmol) was added. g, 300 mmol) reacted for 20 min, sucked dry, washed the resin with 3*400 mL of CH 2 Cl 2 , and removed CH 2 Cl 2 . The resin was taken out and dried under vacuum at 25-35° C. to obtain 43.80 g of Fmoc-Pro-Orn(2-CTC Resin)-Gly-NH 2 resin with a measured substitution degree of 0.50 mmol/g.

[0032]

Example 4. Synthesis of Fmoc-Pro-Orn (4-methyl-trityl resin)-Gly-NH 2 peptide resin with a degree of substitution of 0.50 mmol/g

[0033]

4-methyl-trityl resin (33.33 g, 30 mmol, substitution degree: 0.90 mmol/g) was weighed into a solid-phase reaction synthesis column. 400 mL of dry DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*400 mL of dry DMF, and the DMF was removed. Fmoc-Pro-Orn-Gly-NH 2 (37.30 g, 60 mmol) prepared in Example 1 , DIEA (11.63 g, 90 mmol) were added, 100 mL of dry DMF was added to dissolve and clarified, added to the resin to react for 2 h, and methanol (9.61 mmol) was added. g, 300 mmol) reacted for 20 min, sucked dry, washed the resin with 3*400 mL of CH 2 Cl 2 , and removed CH 2 Cl 2 . The resin was taken out and dried under vacuum at 25-35° C. to obtain 43.89 g of Fmoc-Pro-Orn (4-methyl-trityl resin)-Gly-NH 2 resin with a measured substitution degree of 0.50 mmol/g.

[0034]

Example 5. Synthesis of Fmoc-Pro-Orn (4-methoxy-trityl resin)-Gly-NH 2 peptide resin with a degree of substitution of 0.50 mmol/g

[0035]

4-Methoxy-trityl resin (30.0 g, 30 mmol, substitution degree: 1.00 mmol/g) was weighed into a solid-phase reaction synthesis column. 400 mL of dry DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*400 mL of dry DMF, and the DMF was removed. Fmoc-Pro-Orn-Gly-NH 2 (37.30 g, 60 mmol) prepared in Example 1 , DIEA (11.63 g, 90 mmol) were added, 100 mL of dry DMF was added to dissolve and clarified, added to the resin to react for 2 h, and methanol (9.61 mmol) was added. g, 300 mmol) reacted for 20 min, sucked dry, washed the resin with 3*400 mL of CH 2 Cl 2 , and removed CH 2 Cl 2 . The resin was taken out and dried under vacuum at 25-35° C. to obtain 43.69 g of Fmoc-Pro-Orn (4-methoxy-trityl resin)-Gly-NH 2 resin with a measured substitution degree of 0.50 mmol/g.

[0036]

Example 6. Synthesis of Atosiban Linear Peptide Resin 1

[0037]

Fmoc-Pro-Orn (trityl resin)-Gly-NH 2 (35.71 g) prepared in Example 2 was weighed into a solid-phase reaction synthesis column. 400 mL of DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*200 mL of dry DMF, and the DMF was removed. 200 mL of DBLK solution (20% piperidine/DMF solution, V/V) was added and deprotected twice, the first time was 5 min and the second time was 15 min. After deprotection, the resin was washed with 200 mL of DMF each time, and washed 6 times. After the fourth washing, a little resin was taken with a glass rod. The ninhydrin test was positive, indicating that Fmoc had been removed.

[0038]

Weigh 17.57g Fmoc-Cys(Trt)-OH and 4.86g HOBt, add 100mL DMF to dissolve, after complete dissolution, cool the solution to below 5°C, then add 5.68g DIC (pre-cooled to <0°C), Activated in the solution for about 3 to 5 minutes, the activated solution was added to the reaction column under control, and reacted at 20 to 35 °C for 2 to 3 hours. The ninhydrin test was negative. The reaction solution was removed, and 200 mL of DMF was added to wash the resin. 6 times. After washing, the washing liquid was removed to obtain Fmoc-Cys(Trt)-Pro-Orn (trityl resin)-Gly-NH 2 .

[0039]

Repeat the step of receiving the peptide and remove the Fmoc protective group. According to the amino acid sequence of atosiban, Fmoc-Cys(Trt)-Pro-Orn (trityl resin)-Gly-NH 2 was coupled to Fmoc- Asn-OH, Fmoc-Thr-OH, Fmoc-Ile-OH, Fmoc-D-Tyr(Et)-OH, Mpa(Trt)-OH give Mpa(Trt)-D-Tyr(Et)-Ile-Thr- Asn-Cys(Trt)-Pro-Orn (trityl resin)-Gly- NH2 . After washing with DMF, the washing solution was removed. The resin was washed with 200 ml of DCM each time, 4 times, 5 min/time, the DCM was removed, and the resin was vacuum-dried at room temperature (20-35° C.) until it was quicksand. The peptide resin was 48.72g after drying, and the resin weight gain was 89.0%.

[0040]

Example 7. Synthesis of atosiban linear peptide resin 2

[0041]

Fmoc-Pro-Orn(2-CTC Resin)-Gly-NH 2 (30.00 g) prepared in Example 3 was weighed into a solid-phase reaction synthesis column. 400 mL of DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*200 mL of dry DMF, and the DMF was removed. 200 mL of DBLK solution (20% piperidine/DMF solution, V/V) was added and deprotected twice, the first time was 5 min and the second time was 15 min. After deprotection, the resin was washed with 200 mL of DMF each time, and washed 6 times. After the fourth washing, a little resin was taken with a glass rod. The ninhydrin test was positive, indicating that Fmoc had been removed.

[0042]

Weigh 17.57g Fmoc-Cys(Trt)-OH and 13.65g HBTU, add 100mL DMF to dissolve, after complete dissolution, cool the solution to below 5°C, then add 5.82g DIEA (pre-cooled to <0°C), put Activated in the solution for about 3 to 5 minutes, the activated solution was added to the reaction column under control, and reacted at 20 to 35 °C for 2 to 3 hours. The ninhydrin test was negative. The reaction solution was removed, and 200 mL of DMF was added to wash the resin. 6 times. After washing, the washing solution was removed to obtain Fmoc-Cys(Trt)-Pro-Orn(2-CTC Resin)-Gly-NH 2 .

[0043]

Fmoc-D-Tyr(Et)-OH (86.30 g, 200 mmol) and N-hydroxysuccinimide (23.00 g, 200 mmol) were weighed into 800 ml of tetrahydrofuran, and stirred at room temperature. The temperature was controlled at about 5°C, and a solution of DCC (45.36g, 220mmol) in tetrahydrofuran (160ml) was slowly added and stirred at room temperature for 2.5h, filtered, concentrated and added to petroleum ether for recrystallization to precipitate a solid, washed and dried, and the obtained activated ester was The solid was dissolved in 200 ml of tetrahydrofuran, and H-Ile-OH (26.24 g, 200 mmol) was dissolved in 150 ml of tetrahydrofuran and slowly added dropwise to the above solution. After dropping, the reaction was continued at room temperature. The monitoring of the raw materials was completed. After filtration, the solution was concentrated under reduced pressure. , the concentrated solution was added to petroleum ether to separate out the solid, the solid was washed and then dried, recrystallized and dried with isopropanol to obtain 75.60 g of Fmoc-D-Tyr(Et)-Ile-OH with a yield of 75%.

[0044]

Repeat the step of receiving the peptide and removing the Fmoc protective group. According to the amino acid sequence of atosiban, sequentially couple Fmoc-Asn on Fmoc-Cys(Trt)-Pro-Orn(2-CTC Resin)-Gly-NH 2 -OH, Fmoc-Thr-OH, Fmoc-D-Tyr(Et)-Ile-OH, Mpa(Trt)-OH to give Mpa(Trt)-D-Tyr(Et)-Ile-Thr-Asn-Cys(Trt )-Pro-Orn( 2 -CTC Resin)-Gly-NH2 . After washing with DMF, the washing solution was removed. The resin was washed with 200 ml of DCM each time, 4 times, 5 min/time, the DCM was removed, and the resin was vacuum-dried at room temperature (20-35° C.) until it was quicksand. The peptide resin was 42.77g after drying, and the resin weight gain rate was 87.4%.

[0045]

Example 8. Synthesis of atosiban linear peptide resin 3

[0046]

Fmoc-Pro-Orn (4-methyl-trityl resin)-Gly-NH 2 (30.00 g) prepared in Example 4 was weighed into a solid-phase reaction synthesis column. 400 mL of DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*200 mL of dry DMF, and the DMF was removed. 200 mL of DBLK solution (20% piperidine/DMF solution, V/V) was added and deprotected twice, the first time was 5 min and the second time was 15 min. After deprotection, the resin was washed with 200 mL of DMF each time, and washed 6 times. After the fourth washing, a little resin was taken with a glass rod, and the ninhydrin test was positive, indicating that Fmoc had been removed.

[0047]

Weigh 17.57g Fmoc-Cys(Trt)-OH, 13.65g HBTU and 4.05g HOBt, add 100mL DMF to dissolve, after complete dissolution, cool the solution to below 5°C, then add 5.82g DIEA (pre-cooled to <0 ℃), activate in the solution for about 3-5min, add the activated solution to the reaction column, react at 20-35 ℃ for 2-3h, the ninhydrin test is negative, remove the reaction solution, add 200mL of DMF The resin was washed 6 times. After washing, the washing liquid was removed to obtain Fmoc-Cys(Trt)-Pro-Orn(4-methyl-trityl resin)-Gly-NH 2 .

[0048]

Mpa(Trt)-OH (69.69 g, 200 mmol) and N-hydroxysuccinimide (23.00 g, 200 mmol) were weighed into 800 ml of tetrahydrofuran, and stirred at room temperature. The temperature was controlled at about 5°C, and a solution of DCC (45.36g, 220mmol) in tetrahydrofuran (160ml) was slowly added and stirred at room temperature for 2.5h, filtered, concentrated and added to petroleum ether for recrystallization to precipitate a solid, washed and dried, and the obtained activated ester was The solid was dissolved in 200 ml of tetrahydrofuran, and HD-Tyr(Et)-OH (41.85 g, 200 mmol) was dissolved in 150 ml of tetrahydrofuran and slowly added dropwise to the above solution. After dropping, the reaction was continued at room temperature. Concentrate under reduced pressure, add the concentrated solution to petroleum ether to precipitate a solid, wash the solid and then dry it, recrystallize and dry with isopropanol to obtain Mpa(Trt)-D-Tyr(Et)-OH 77.98g, yield 72%.

[0049]

Repeat the step of receiving the peptide and removing the Fmoc protective group, according to the amino acid sequence of atosiban, on Fmoc-Cys(Trt)-Pro-Orn (4-methyl-trityl resin)-Gly- NH 2 Fmoc-Asn-OH, Fmoc-Thr-OH, Fmoc-Ile-OH, Mpa(Trt)-D-Tyr(Et)-OH were sequentially coupled to obtain Mpa(Trt)-D-Tyr(Et)-Ile-Thr -Asn-Cys(Trt)-Pro-Orn(4-methyl-trityl resin)-Gly- NH2 . After washing with DMF, the washing solution was removed. The resin was washed with 200 ml of DCM each time, 4 times, 5 min/time, the DCM was removed, and the resin was vacuum-dried at room temperature (20-35° C.) until it was quicksand. The peptide resin was 42.91g after drying, and the resin weight gain rate was 88.3%.

[0050]

Example 9. Synthesis of atosiban linear peptide resin 4

[0051]

Fmoc-Pro-Orn (4-methoxy-trityl resin)-Gly-NH 2 (30.00 g) prepared in Example 5 was weighed into a solid-phase reaction synthesis column. 400 mL of DMF was added to swell for 30 min, and the DMF was removed. The resin was washed with 3*200 mL of dry DMF, and the DMF was removed. 200 mL of DBLK solution (20% piperidine/DMF solution, V/V) was added and deprotected twice, the first time was 5 min and the second time was 15 min. After deprotection, the resin was washed with 200 mL of DMF each time, and washed 6 times. After the fourth washing, a little resin was taken with a glass rod. The ninhydrin test was positive, indicating that Fmoc had been removed.

[0052]

Fmoc-Asn-OH (70.87 g, 200 mmol) and N-hydroxysuccinimide (23.00 g, 200 mmol) were weighed into 800 ml of tetrahydrofuran, and stirred at room temperature. The temperature was controlled at about 5°C, and a solution of DCC (45.36g, 220mmol) in tetrahydrofuran (160ml) was slowly added and stirred at room temperature for 2.5h, filtered, concentrated and added to petroleum ether for recrystallization to precipitate a solid, washed and dried, and the obtained activated ester was The solid was dissolved in 200 ml of tetrahydrofuran, and H-Cys(Trt)-OH (79.96 g, 200 mmol) was dissolved in 150 ml of tetrahydrofuran and slowly added dropwise to the above solution. After dropping, the reaction was continued at room temperature. Concentrate under reduced pressure, add the concentrated solution to petroleum ether to precipitate a solid, wash the solid and then dry, recrystallize and dry with isopropanol to obtain Fmoc-Asn-Cys(Trt)-OH 102.17g, yield 73%.

[0053]

Weigh 20.99g Fmoc-Asn-Cys(Trt)-OH and 13.65g HCTU, add 100mL DMF to dissolve, after complete dissolution, cool the solution to below 5°C, then add 5.82g DIEA (pre-cool to <0°C) , activate in the solution for about 3-5min, add the activated solution to the reaction column, react at 20-35°C for 2-3h, the ninhydrin test is negative, remove the reaction solution, add 200mL of DMF to wash the resin , wash 6 times. After washing, the washing liquid was removed to obtain Fmoc-Asn-Cys(Trt)-Pro-Orn(4-methoxy-trityl resin)-Gly-NH 2 .

[0054]

Repeat the step of receiving the peptide and removing the Fmoc protective group. According to the amino acid sequence of atosiban, in Fmoc-Asn-Cys(Trt)-Pro-Orn(4-methoxy-trityl resin)-Gly- Fmoc-Thr-OH, Fmoc-Ile-OH, Fmoc-D-Tyr(Et)-OH, Mpa(Trt)-OH were sequentially coupled on NH 2 to obtain Mpa(Trt)-D-Tyr(Et)-Ile- Thr-Asn-Cys(Trt)-Pro-Orn(4-methoxy-trityl resin)-Gly- NH2 . After washing with DMF, the washing solution was removed. The resin was washed with 200 ml of DCM each time, 4 times, 5 min/time, the DCM was removed, and the resin was vacuum-dried at room temperature (20-35° C.) until it was quicksand. The peptide resin was 42.28g after drying, and the resin weight gain was 84.0%.

[0055]

Example 10. Synthesis of atosiban crude peptide 1

[0056]

Configure 487.2ml of TFA/DCM=2/98 (V/V) lysis solution, cool to 5-10°C, add 48.72g of peptide resin prepared in Example 6 into the lysis solution, at room temperature (20-35°C) React for 5h, filter, wash the peptide resin twice with acetonitrile, 50ml/time, combine into the filtrate, spin the filtrate to dry, obtain a solid after drying, wash with isopropyl ether, filter, and dry under reduced pressure at 20-35°C to constant weight To obtain 14.77g of atosiban linear peptide, dissolve 14.30g of atosiban linear peptide in 0.75L of glacial acetic acid, add 6.75L of water to dilute, add 0.1M/L iodine ethanol solution dropwise until the solution changes color, react at room temperature for 1.0h, That is, the crude atosiban peptide is obtained, and its HPLC spectrum is shown in Figure 1.

[0057]

Example 11. Synthesis of atosiban crude peptide 2

[0058]

Configure TFA/DCM=5/95 (V/V) lysate 448.6ml, cool to 5～10℃, add 42.77g of peptide resin prepared in Example 7 into the lysate, at room temperature (20～35℃) React for 3h, filter, wash the peptide resin twice with acetonitrile, 50ml/time, combine into the filtrate, spin the filtrate, dry to obtain a solid, wash with isopropyl ether, filter, and dry under reduced pressure at 20-35°C to constant weight To obtain 14.21g of atosiban linear peptide, dissolve 14.21g of atosiban linear peptide in 1.5L of glacial acetic acid, add 6L of water to dilute, add 0.1M/L iodoethanol solution dropwise until the solution changes color, react at room temperature for 1.0h, that is The crude atosiban peptide was obtained, and its HPLC chromatogram was similar to that in Figure 1.

[0059]

Example 12. Synthesis of atosiban crude peptide 3

[0060]

Configure 450.5ml of TFA/DCM=20/80(V/V) lysis solution, cool to 5～10℃, add 45.05g of peptide resin prepared in Example 8 into the lysis solution, at room temperature (20～35℃) React for 2h, filter, wash the peptide resin twice with acetonitrile, 50ml/time, combine into the filtrate, spin the filtrate to dry, obtain a solid after drying, wash with isopropyl ether, filter, and dry under reduced pressure at 20-35°C to constant weight To obtain 14.63g of atosiban linear peptide, dissolve 14.63g of atosiban linear peptide in 1.5L of glacial acetic acid, add 6L of water to dilute, add 10% hydrogen peroxide solution, and react at room temperature for 1.0h to obtain atosiban Crude peptide, its HPLC chromatogram is similar to Figure 1.

[0061]

Example 13. Synthesis of atosiban crude peptide 4

[0062]

Configure TFA/DCM=1/99 (V/V) lysate 442.7ml, cool to 5～10℃, add 44.27g of peptide resin prepared in Example 9 into the lysate, at room temperature (20～35℃) React for 5h, filter, wash the peptide resin twice with acetonitrile, 50ml/time, combine into the filtrate, spin the filtrate to dry, obtain a solid after drying, wash with isopropyl ether, filter, and dry under reduced pressure at 20-35°C to constant weight To obtain 14.13 g of atosiban linear peptide, dissolve 14.13 g of atosiban linear peptide in 1.5 L of glacial acetic acid, add 6 L of water to dilute, add 30% hydrogen peroxide solution, and react at room temperature for 1.0 h to obtain atosiban Crude peptide, its HPLC chromatogram is similar to Figure 1.

[0063]

Example 14. Purification of atosiban crude peptide 1

[0064]

The atosiban crude peptide prepared in Example 10 was dissolved in 15% acetonitrile aqueous solution and filtered, purified by preparative reverse-phase HPLC (C18 column), transferred to salt, collected more than 99% of the fraction, concentrated and lyophilized to obtain 10.12g , the yield is 64%, the purity is 99%, and the HPLC spectrum of the obtained atosiban peptide is shown in Figure 2.

[0065]

Example 15. Purification of atosiban crude peptide 2

[0066]

The crude atosiban peptide obtained in Example 11 was dissolved in a 15% acetonitrile aqueous solution and filtered, purified by preparative reverse-phase HPLC (C18 column), transferred to salt, collected more than 99% of the fraction, concentrated and lyophilized to obtain 9.80 g , the yield is 62%, the purity is 99%, and the obtained atosiban peptide HPLC spectrum is similar to Figure 2.

[0067]

Example 16. Purification of atosiban crude peptide 3

[0068]

The crude atosiban peptide obtained in Example 12 was dissolved in a 15% acetonitrile aqueous solution and filtered, purified by preparative reverse-phase HPLC (C18 column), transferred to salt, collected more than 99% of the fraction, concentrated and lyophilized to obtain 10.28g , the yield is 65%, the purity is 99%, and the HPLC spectrum of the obtained atosiban peptide is similar to that in Figure 2.

[0069]

Example 17. Purification of atosiban crude peptide 4

[0070]

The crude atosiban peptide obtained in Example 13 was dissolved in 15% acetonitrile aqueous solution and filtered, purified by preparative reverse-phase HPLC (C18 column), transferred to salt, collected more than 99% of the fraction, concentrated and lyophilized to obtain 10.27g , the yield is 65%, the purity is 99%, and the HPLC spectrum of the obtained atosiban peptide is similar to that in Figure 2.

PATENT

Atosiban is a nonapeptide which contains three non-natural amino acids: D-Tyr(Et), Mpa and Orn, and a pair of disulfide bonds looped between Mpa and Cys, the structural formula is:
c[Mpa-D-Tyr(Et)-Ile-Thr-Asn-Cys]-Pro-Orn-Gly-NH2.

By means of competing for oxytocin receptor with oxytocin, Atosiban can inhibit the combination between oxytocin and oxytocin receptor, and directly prevent the oxytocin from acting on uterus, and then inhibit the uterine contraction; as another hand, atosiban can also inhibit the hydrolysis of phosphatidylinositol and then block the generation of messenger and activity of Ca2+, with the decreasing of activity from oxytocin, the contraction of uterine is indirectly inhabited.

At present, there are many reports about synthesis process method in China and abroad A report in China shows that the inventor found a simple process by adopting solid phase oxidation, resulting in a low purity crude product, with low yield and low application value. The aforementioned reports about atosiban synthesis process reveal that most of them adopt the method using Boc solid phase synthetic and cleaving peptide with liquid ammonia, then oxidating with liquid phase oxidation, and purifying. Those respective processes result in “the three wastes” and are too complex for industrial production. See U.S. Pat. No. 4,504,469.

Example 1Preparing the Linear Atosiban Peptide Resin

(i) 6.25 g of Rink Amide resin (substitutability=0.8 mmol/g) is put into a reaction bottle, DMF is added into the bottle and washed twice, then swelled for 30 min with DMF. Fmoc protecting group of Rink Amide resin is removed with 30-40 ml of 20% DBLK, washed for 4 times with DMF, then washed twice with DCM after removal, the product is detected by ninhydrin detecting method, the resin is reddish-brown.

(ii) 4.46 g of Fmoc-Gly-OH and 2.43 g of HOBt dissolved in a suitable amount of DMF, which had been pre-activated with 3.05 ml DIC; the mixture is, added to the reaction bottle, and reacted for 2 h, the resin is negative by ninhydrin detecting method, after the reaction, the product is washed for 4 times with DMF, then washed twice with DCM, if the resin is positive, repeating the above condensation reaction until negative.

(iii) Fmoc-Orn(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ile-OH, Fmoc-D-Tyr(ET)-OH and Mpa(Trt)-OH are coupled orderly.

Example 2Cleaving the Linear Atosiban Peptide Resin

5.15 g of linear atosiban is prepared by washing the linear atosiban peptide resin obtained from Example 1 for 3 times with 30 ml of methanol, adding the dry resin obtained to 150 ml of mixed solution with a volume ratio of TFA:H2O=95:5, reacting for 2 hours at 25° C. and filtering, washing the resin for 3 times with few trifluoroacetic acid, combining the filtrate and pouring into 1500 ml glacial ether, making rest for 2 hours, centrifugally separating the linear atosiban, washing for 3 times, and drying in a vacuum drier, MS: 995.3, HPLC: 91.5%, content: 65.5%, synthesis yield: 68%.

Example 3Oxidizing the Linear Atosiban

2.85 g of atosiban acetate is prepared by dissolving the linear atosiban obtained from Example 2 in 250 ml of 5% acetonitrile aqueous solution, adjusting the pH value to 8 to 9 with 30% ammonia water, adding 0.60 g of H2O2, reacting for 10 min at 25° C., monitoring with HPLC (HPLC: 75.6%), filtering after reaction, purifying filtrate by preparative RP-HPLC (column C18 or C8), transferring salt, and freeze-drying, MS: 994.5, HPLC: 99.4%.

Example 4Oxidizing the Linear Atosiban

3.01 g of atosiban acetate is prepared by dissolving the linear atosiban obtained from Example 2 in 250 ml of 10% acetonitrile aqueous solution, adjusting the pH value to 8 to 9 with 30% ammonia water, adding 0.85 g of H2O2, reacting for 30 min at 25° C., monitoring with HPLC (HPLC: 89.5%), filtering after reaction, purifying filtrate by preparative RP-HPLC (column C18 or C8), transferring salt, and freeze-drying, MS: 994.5, HPLC: 99.6%.

Example 5Oxidizing the Linear Atosiban

2.95 g of atosiban acetate is prepared by dissolving the linear atosiban obtained from Example 2 in 250 ml of 10% acetonitrile aqueous solution, adjusting the pH value to 8 to 9 with 30% ammonia water, adding 0.85 g of H2O2, reacting for 60 min at 25° C., monitoring with HPLC (HPLC: 83.5%), filtering after reaction, purifying filtrate by preparative RP-HPLC (column C18 or C8), transferring salt, and freeze-drying, MS: 994.5, HPLC: 99.4%.

The above is the further detailed description of the invention in conjunction with specific preferred examples, but it should not be considered that the specific examples of the invention are only limited to the these descriptions. For one of ordinary skill in the art, many deductions and replacements can be made without departing from the inventive concept. Such deductions and replacements should fall within the scope of protection of the invention.

### Clips

https://www.mdpi.com/1420-3049/27/6/1920/htm

Figure 1. Structure of Atosiban, pentapeptide intermediate, BSA and NHS ester.

Figure 2. Synthesis of Boc-Cys(Bzl)-Pro-COOH using BSA/NHS as coupling agents.

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### Clinical trials

#### Atosiban vs. nifedipine

A 2013 retrospective study comparing the efficacy and safety of atosiban and nifedipine in the suppression of preterm labour concluded that atosiban and nifedipine are effective in delaying delivery for seven days or more in women presenting with preterm labour.[16] A total of 68.3% of women in the atosiban group remained undelivered at seven days or more, compared with 64.7% in the nifedipine group.[16] They have the same efficacy and associated minor side effects.[16] However, flushing, palpitation, and hypotension were significantly higher in the nifedipine group.[16]

A 2012 clinical trial compared tocolytic efficacy and tolerability of atosiban with that of nifedipine.[17] Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours, respectively (p=.03).[17] Atosiban has fewer failures within 48 hours.[17] Nifedipine may be associated with a longer postponement of delivery.[17]

A 2009 randomised controlled study demonstrated for the first time the direct effects of atosiban on fetal movement, heart rate, and blood flow.[18] Tocolysis with either atosiban or nifedipine combined with betamethasone administration had no direct fetal adverse effects.[18]

#### Atosiban vs. ritodrine

Multicentre, controlled trial of atosiban vs. ritodrine in 128 women shows a significantly better tocolytic efficacy after 7 days in the atosiban group than in the ritodrine group (60.3 versus 34.9%), but not at 48 hours (68.3 versus 58.7%). Maternal adverse events were reported less frequently in the atosiban group (7.9 vs 70.8%), resulting in fewer early drug terminations due to adverse events (0 versus 20%). Therefore, atosiban is superior to ritodrine in the treatment of preterm labour.[19]

## Brand names

In India it is marketed under the brand name Tosiban by Zuventus healthcare ltd.

## References

1. ^ “Atosiban International Drug Names”Drugs.com. 10 April 2020. Retrieved 29 April 2020.
2. ^ “Tractocile 7.5 mg/ml Solution for Injection – Summary of Product Characteristics (SmPC)”(emc). Retrieved 29 April 2020.
3. ^ “Tractocile 7.5 mg/ml Concentrate for Solution for Infusion – Summary of Product Characteristics (SmPC)”(emc). 24 June 2013. Retrieved 29 April 2020.
4. Jump up to:a b c d e f g “Tractocile EPAR”European Medicines Agency (EMA). Retrieved 29 April 2020.  This article incorporates text from this source, which is in the public domain.
5. ^ Akerlund M, Carlsson AM, Melin P, Trojnar J (1985). “The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin”. Acta Obstet Gynecol Scand64 (6): 499–504. doi:10.3109/00016348509156728PMID 4061066S2CID 25799128.
6. ^ Sanu O, Lamont RF (2010). “Critical appraisal and clinical utility of atosiban in the management of preterm labor”Ther Clin Risk Manag6: 191–199. doi:10.2147/tcrm.s9378PMC 2861440PMID 20463780.
7. Jump up to:a b Chou PY, Wu MH, Pan HA, Hung KH, Chang FM (June 2011). “Use of an oxytocin antagonist in in vitro fertilization-embryo transfer for women with repeated implantation failure: a retrospective study”Taiwan J Obstet Gynecol50 (2): 136–40. doi:10.1016/j.tjog.2011.04.003PMID 21791296.
8. ^ Lan, VT; Khang, VN; Nhu, GH; Tuong, HM (September 2012). “Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure”. Reprod Biomed Online25 (3): 254–60. doi:10.1016/j.rbmo.2012.05.014PMID 22818095.
9. Jump up to:a b Wu, MY; Chen, SU; Yang, YS (December 2011). “Using atosiban in uterine contractions of early pregnancies after assisted reproduction”J Formos Med Assoc110 (12): 800. doi:10.1016/j.jfma.2011.11.016PMID 22248840.
10. ^ Conde-Agudelo, A; Romero, R; Kusanovic, JP (2011). “Nifedipine in the management of preterm labor: a systematic review and metaanalysis”Am J Obstet Gynecol204 (2): 134.e1–134.e20. doi:10.1016/j.ajog.2010.11.038PMC 3437772PMID 21284967.
11. ^ Lamont, Ronald F; Kam, KY Ronald (March 2008). “Atosiban as a tocolytic for the treatment of spontaneous preterm labor”. Expert Review of Obstetrics & Gynecology3 (2): 163–174. doi:10.1586/17474108.3.2.163ISSN 1747-4108.
12. Jump up to:a b c Lamont, Ronald F.; Kam, KY Ronald (2008). “Atosiban as a tocolytic for the treatment of spontaneous preterm labor”. Expert Review of Obstetrics & Gynecology3 (2): 163–174. doi:10.1586/17474108.3.2.163.
13. ^ Lamont CD, Jørgensen JS, Lamont RF (September 2016). “The safety of tocolytics used for the inhibition of preterm labour”. Expert Opinion on Drug Safety15 (9): 1163–73. doi:10.1080/14740338.2016.1187128PMID 27159501S2CID 4937942It was for this reason and the fact that Tractocile (atosiban) only had a short duration before it was out of patent that the parent drug company decided not to pursue licensing in the USA.
14. ^ Coomarasamy, A; Knox, EM; Gee, H; Khan, KS (November 2002). “Oxytocin antagonists for tocolysis in preterm labour — a systematic review”. Med Sci Monit8 (11): RA268–73. PMID 12444392.
15. ^ Flenady, Vicki; Reinebrant, Hanna E.; Liley, Helen G.; Tambimuttu, Eashan G.; Papatsonis, Dimitri N. M. (6 June 2014). “Oxytocin receptor antagonists for inhibiting preterm labour” (PDF). The Cochrane Database of Systematic Reviews (6): CD004452. doi:10.1002/14651858.CD004452.pub3ISSN 1469-493XPMID 24903678.
16. Jump up to:a b c d Saleh SS, Al-Ramahi MQ, Al Kazaleh FA (January 2013). “Atosiban and nifedipine in the suppression of preterm labour: a comparative study”. J Obstet Gynaecol33 (1): 43–5. doi:10.3109/01443615.2012.721822PMID 23259877S2CID 20753923.
17. Jump up to:a b c d Salim R, Garmi G, Nachum Z, Zafran N, Baram S, Shalev E (December 2012). “Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial”. Obstet Gynecol120 (6): 1323–31. doi:10.1097/aog.0b013e3182755dffPMID 23168756S2CID 22487349.
18. Jump up to:a b de Heus R, Mulder EJ, Derks JB, Visser GH (June 2009). “The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow”. J Matern Fetal Neonatal Med22 (6): 485–90. doi:10.1080/14767050802702349PMID 19479644S2CID 35810758.
19. ^ Shim JY, Park YW, YoonBH, Cho YK, Yang JH, Lee Y, Kim A. “Multicentre, parallelgroup, randomised, single-blind study of the safety and efficacy of atosibanversus ritodrine in the treatment of acute preterm labour in Korean women. BJOG 2006Nov;113(11):1228-34.

• “Atosiban”Drug Information Portal. U.S. National Library of Medicine.

Publication numberPriority datePublication dateAssigneeTitle

US4504469A *1982-12-211985-03-12Ferring AbVasotocin derivatives

WO2006119388A2 *2005-05-032006-11-09Novetide, Ltd.Methods for the production of peptide having a c-terminal amide

CN102127146A *2010-12-242011-07-20深圳翰宇药业股份有限公司Method for preparing atosiban acetate

DK0710243T3 *1993-06-292000-10-16Ferring BvSynthesis of cyclic peptides

CN101357937B *2007-07-312012-11-07上海苏豪逸明制药有限公司Method for synthesizing atosiban acetate from solid phase polypeptide

CN101314613B *2008-05-082012-04-25吉尔生化（上海）有限公司Solid phase synthesis method for atosiban

CN102127146B *2010-12-242013-04-24深圳翰宇药业股份有限公司Method for preparing atosiban acetate

CN102584953B *2012-02-092014-01-01深圳翰宇药业股份有限公司Purification method for atosiban

CN104098650B *2013-04-152019-04-09中国医学科学院药物研究所The synthesis and application of the intermediate of Atosiban

GB201310921D0 *2013-06-192013-07-31Chemical & Biopharmaceutical Lab Of Patras S APeptide-resin conjugate and use thereof

CN105949283A *2016-06-072016-09-21海南合瑞制药股份有限公司Atosiban acetate impurities and preparation and detection methods

CN106279367B *2016-08-152019-06-04海南合瑞制药股份有限公司A kind of atosiban acetate crystal and preparation method thereof

CN107312072A *2017-06-202017-11-03浙江湃肽生物有限公司A kind of method of purifies and separates Atosiban

ApplicationPriority dateFiling dateTitle

CN201010604790.62010-12-24

CN2010106047906A2010-12-242010-12-24Method for preparing atosiban acetate

CN2010106047902010-12-24

PCT/CN2011/0844142010-12-242011-12-22Method for preparing atosiban acetate

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////////////// ATOSIBAN, CAP-449, CAP-476, CAP-581, F-314, ORF 22164, ORF-22164, RW-22164, RWJ 22164, RWJ-22164

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## Medical uses

Tirzepatide in indicated to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.[2]

## Contraindications

Tirzepatide should not be used in people with a personal or family history of medullary thyroid cancer or in people with multiple endocrine neoplasia syndrome type 2.[2]

Preclinical, phase I, and phase II trials have indicated that tirzepatide exhibits similar adverse effects to other established GLP-1 receptor agonists, such as GLP-1 receptor agonist dulaglutide. These effects occur largely within the gastrointestinal tract.[5] The most frequently observed adverse effects are nausea, diarrhoea and vomiting, which increased in incidence with the dosage amount (i.e. higher likelihood the higher the dose). The number of patients who discontinued taking tirzepatide also increased as dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide.[6] To a slightly lesser extent, patients also reported reduced appetite.[5] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.[7][8]

## Pharmacology

Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human hormone which stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids which has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.[9] The compound is administered as a weekly subcutaneous injection.[10] It completed phase III trials globally in 2021.[11][12]

### Mechanism of action

Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist.[3] Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor.[13] However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[13] Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.[3]

## Chemistry

### Structure

Tirzepatide is an analog of the human GIP hormone with a C20 fatty-diacid portion attached, used to optimise the uptake and metabolism of the compound.[9] The fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue. This arrangement allows for a much longer half life, extending the time between doses, because of its high affinity to albumin.[14]

### Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[15] This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment.

Large-scale manufacturing processes have been reported for this compound.[16]

## History

Indiana-based pharmaceutical company Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[15] The patent was published late that year. After passing phase 3 clinical trials, Lilly applied for FDA approval in October 2021 with a priority review voucher.[17]

Following the completion of the pivotal SURPASS-2 trial no. NCT03987919, the company announced on 28 April that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes.[18] Alongside results from the SURMOUNT-1 trial no. NCT04184622, they suggest that tirzepatide may potentially be a competitor for existing diabetic medication semaglutide, manufactured by Novo Nordisk.[19][20]

In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication semaglutide (an injected analogue of the hormone GLP-1), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to semaglutide (1.86%).[21] A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin).[3] Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[3] A meta-analysis published by Dutta et al. showed that over 1-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction. Tirzepatide is perhaps the most potent agent developed to date to tackle the global problem of “diabesity“.[22]

## Society and culture

### Names

Tirzepatide is the international nonproprietary name (INN).[23]

## References

1. Jump up to:a b “Highlights of prescribing information” (PDF). accessdata.fda.gov. FDA. May 2022. Retrieved 14 May 2022.
2. Jump up to:a b c d e f g h i “FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes”U.S. Food and Drug Administration (FDA) (Press release). 13 May 2022. Retrieved 13 May 2022.  This article incorporates text from this source, which is in the public domain.
3. Jump up to:a b c d e Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. (January 2021). “Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes”The Journal of Clinical Endocrinology and Metabolism106 (2): 388–396. doi:10.1210/clinem/dgaa863PMC 7823251PMID 33236115.
4. ^ Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. (December 2018). “LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept”Molecular Metabolism18: 3–14. doi:10.1016/j.molmet.2018.09.009PMC 6308032PMID 30473097.
5. Jump up to:a b Min T, Bain SC (January 2021). “The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials”Diabetes Therapy12 (1): 143–157. doi:10.1007/s13300-020-00981-0PMC 7843845PMID 33325008.
6. ^ Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. (November 2018). “Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial”The Lancet392 (10160): 2180–2193. doi:10.1016/S0140-6736(18)32260-8PMID 30293770.
7. ^ Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. (June 2020). “Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens”Diabetes, Obesity & Metabolism22 (6): 938–946. doi:10.1111/dom.13979PMC 7318331PMID 31984598.
8. ^ Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á (February 2022). “Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial”. JAMA327 (6): 534–545. doi:10.1001/jama.2022.0078PMID 35133415.
9. Jump up to:a b Ahangarpour M, Kavianinia I, Harris PW, Brimble MA (January 2021). “Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design”. Chemical Society Reviews. Royal Society of Chemistry. 50 (2): 898–944. doi:10.1039/d0cs00354aPMID 33404559S2CID 230783854.
10. ^ Bastin M, Andreelli F (2019). “Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential”Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy12: 1973–1985. doi:10.2147/DMSO.S191438PMC 6777434PMID 31686879.
11. ^ “Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly’s SURPASS program” (Press release). Eli Lilly and Company. 17 February 2021. Retrieved 28 October 2021 – via PR Newswire.
12. ^ “Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes”Business Insider. RTTNews. 19 October 2021. Retrieved 28 October 2021.
13. Jump up to:a b Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. (September 2020). “Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist”JCI Insight5 (17). doi:10.1172/jci.insight.140532PMC 7526454PMID 32730231.
14. ^ Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, et al. (October 2021). “The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs”Scientific Reports11 (1): 21179. Bibcode:2021NatSR..1121179Odoi:10.1038/s41598-021-00654-3PMC 8551270PMID 34707178.
15. Jump up to:a b US patent 9474780, Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, “GIP and GLP-1 co-agonist compounds”, issued 2016-10-25, assigned to Eli Lilly and Co
16. ^ Frederick MO, Boyse RA, Braden TM, Calvin JR, Campbell BM, Changi SM, et al. (2021). “Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing”. Organic Process Research & Development25 (7): 1628–1636. doi:10.1021/acs.oprd.1c00108S2CID 237690232.
17. ^ Sagonowsky, Eric (26 October 2021). “As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth”Fierce Pharma. Retrieved 9 April 2022.
18. ^ Kellaher, Colin (28 April 2022). “Eli Lilly’s Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study >LLY”Dow Jones Newswires. Retrieved 29 April 2022 – via MarketWatch.
19. ^ Kahan, Scott; Garvey, W. Timothy (28 April 2022). “SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide”healio.com. Retrieved 29 April 2022.
20. ^ Taylor, Nick Paul (28 April 2022). “SURMOUNT-able: Lilly’s tirzepatide clears high bar set by Novo’s Wegovy in obesity”FierceBiotech. Retrieved 29 April 2022.
21. ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes”. The New England Journal of Medicine385 (6): 503–515. doi:10.1056/NEJMoa2107519PMID 34170647S2CID 235635529.
22. ^ Dutta D, Surana V, Singla R, Aggarwal S, Sharma M (November–December 2021). “Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis”. Indian Journal of Endocrinology and Metabolism25 (6): 475–489. doi:10.4103/ijem.ijem_423_21.
23. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1). hdl:10665/330896.

• “Tirzepatide”Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT03954834 for “A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1)” at ClinicalTrials.gov
• Clinical trial number NCT03987919 for “A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2)” at ClinicalTrials.gov
• Clinical trial number NCT03882970 for “A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes (SURPASS-3)” at ClinicalTrials.gov
• Clinical trial number NCT03730662 for “A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)” at ClinicalTrials.gov
• Clinical trial number NCT04039503 for “A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5)” at ClinicalTrials.gov

CLIP

https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjarotm-tirzepatide-injection-first-and

FDA approves Lilly’s Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes

May 13, 2022

Mounjaro delivered superior A1C reductions versus all comparators in phase 3 SURPASS clinical trials

While not indicated for weight loss, Mounjaro led to significantly greater weight reductions versus comparators in a key secondary endpoint

Mounjaro represents the first new class of diabetes medicines introduced in nearly a decade and is expected to be available in the U.S. in the coming weeks

INDIANAPOLIS, May 13, 2022 /PRNewswire/ — The U.S. Food and Drug Administration (FDA) approved Mounjaro™ (tirzepatide) injection, Eli Lilly and Company’s (NYSE: LLY) new once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.

As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP and GLP-1, which are natural incretin hormones.1

“Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro’s efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials,” said Juan Pablo Frías, M.D., Medical Director, National Research Institute and Investigator in the SURPASS program.

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

The approval was based on results from the phase 3 SURPASS program, which included active comparators of injectable semaglutide 1 mg, insulin glargine and insulin degludec. Efficacy was evaluated for Mounjaro 5 mg, 10 mg and 15 mg used alone or in combination with commonly prescribed diabetes medications, including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Participants in the SURPASS program achieved average A1C reductions between 1.8% and 2.1% for Mounjaro 5 mg and between 1.7% and 2.4% for both Mounjaro 10 mg and Mounjaro 15 mg. While not indicated for weight loss, mean change in body weight was a key secondary endpoint in all SURPASS studies. Participants treated with Mounjaro lost between 12 lb. (5 mg) and 25 lb. (15 mg) on average.1

Side effects reported in at least 5% of patients treated with Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion (dyspepsia), and stomach (abdominal) pain. The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.1

“Lilly has a nearly 100-year heritage of advancing care for people living with diabetes – never settling for current outcomes. We’re not satisfied knowing that half of the more than 30 million Americans living with type 2 diabetes are not reaching their target blood glucose levels,” said Mike Mason, president, Lilly Diabetes. “We are thrilled to introduce Mounjaro, which represents the first new class of type 2 diabetes medication introduced in almost a decade and embodies our mission to bring innovative new therapies to the diabetes community.”

Mounjaro is expected to be available in the United States in the coming weeks. Lilly is committed to helping people access the medicines they are prescribed and will work with insurers, health systems and providers to help enable patient access to Mounjaro. Lilly plans to offer a Mounjaro savings card for people who qualify. Patients or healthcare professionals with questions about Mounjaro can visit www.Mounjaro.com or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).

Tirzepatide is also under regulatory review for the treatment of type 2 diabetes in Europe, Japan and several additional markets. A multimedia gallery is available on Lilly.com.

About the SURPASS clinical trial program
The SURPASS phase 3 global clinical development program for tirzepatide began in late 2018 and included five global registration trials and two regional trials in Japan. These studies ranged from 40 to 52 weeks and evaluated the efficacy and safety of Mounjaro 5 mg, 10 mg and 15 mg as a monotherapy and as an add-on to various standard-of-care medications for type 2 diabetes. The active comparators in the studies were injectable semaglutide 1 mg, insulin glargine and insulin degludec. Collectively, the five global registration trials consistently demonstrated A1C reductions for participants taking Mounjaro across multiple stages of their type 2 diabetes journeys, from an average around five to 13 years of having diabetes.2-8

• SURPASS-1 (NCT03954834) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=121), 10 mg (N=121) and 15 mg (N=120) as monotherapy to placebo (N=113) in adults with type 2 diabetes inadequately controlled with diet and exercise alone. From a baseline A1C of 7.9%, Mounjaro reduced participants’ A1C by a mean of 1.8%* (5 mg) and 1.7%* (10 mg and 15 mg) compared to 0.1% for placebo. In a key secondary endpoint, from a baseline weight of 189 lb., Mounjaro reduced participants’ weight by a mean of 14 lb.* (5 mg), 15 lb.* (10 mg) and 17 lb.* (15 mg) compared to 2 lb. for placebo.2,3
• SURPASS-2 (NCT03987919) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=470), 10 mg (N=469) and 15 mg (N=469) to injectable semaglutide 1 mg (N=468) in adults with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin alone. From a baseline A1C of 8.3%, Mounjaro reduced participants’ A1C by a mean of 2.0% (5 mg), 2.2%* (10 mg) and 2.3%* (15 mg) compared to 1.9% for semaglutide. In a key secondary endpoint, from a baseline weight of 207 lb., Mounjaro reduced participants’ weight by a mean of 17 lb. (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to 13 lb. for semaglutide.4,5
• SURPASS-3 (NCT03882970) was a 52-week study comparing the efficacy of Mounjaro 5 mg (N=358), 10 mg (N=360) and 15 mg (N=358) to titrated insulin degludec (N=359) in adults with type 2 diabetes treated with metformin with or without an SGLT-2 inhibitor. From a baseline A1C of 8.2%, Mounjaro reduced participants’ A1C by a mean of 1.9%* (5 mg), 2.0%* (10 mg) and 2.1%* (15 mg) compared to 1.3% for insulin degludec. From a baseline weight of 208 lb., Mounjaro reduced participants’ weight by a mean of 15 lb.* (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to an increase of 4 lb. for insulin degludec.6
• SURPASS-4 (NCT03730662) was a 104-week study comparing the efficacy and safety of Mounjaro 5 mg (N=328), 10 mg (N=326) and 15 mg (N=337) to insulin glargine (N=998) in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The primary endpoint was measured at 52 weeks. From a baseline A1C of 8.5%, Mounjaro reduced participants’ A1C by a mean of 2.1%* (5 mg), 2.3%* (10 mg) and 2.4%* (15 mg) compared to 1.4% for insulin glargine. From a baseline weight of 199 lb., Mounjaro reduced weight by a mean of 14 lb.* (5 mg), 20 lb.* (10 mg) and 23 lb.* (15 mg) compared to an increase of 4 lb. for insulin glargine.7
• SURPASS-5 (NCT04039503) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=116), 10 mg (N=118) and 15 mg (N=118) to placebo (N=119) in adults with inadequately controlled type 2 diabetes already being treated with insulin glargine, with or without metformin. From a baseline A1C of 8.3%, Mounjaro reduced A1C by a mean of 2.1%* (5 mg), 2.4%* (10 mg) and 2.3%* (15 mg) compared to 0.9% for placebo. From a baseline weight of 210 lb., Mounjaro reduced participants’ weight by a mean of 12 lb.* (5 mg), 17 lb.* (10 mg) and 19 lb.* (15 mg) compared to an increase of 4 lb. for placebo.8

*p<0.001 for superiority vs. placebo or active comparator, adjusted for multiplicity
p<0.05 for superiority vs. semaglutide 1 mg, adjusted for multiplicity

Mounjaro™ (tirzepatide) injection is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

PURPOSE AND SAFETY SUMMARY WITH WARNINGS
Important Facts About MounjaroTM (mown-JAHR-OH). It is also known as tirzepatide.

• Mounjaro is an injectable prescription medicine for adults with type 2 diabetes used along with diet and exercise to improve blood sugar (glucose).
• It is not known if Mounjaro can be used in people who have had inflammation of the pancreas (pancreatitis). Mounjaro is not for use in people with type 1 diabetes. It is not known if Mounjaro is safe and effective for use in children under 18 years of age.

Warnings
Mounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have a symptom, tell your healthcare provider.

• Do not use Mounjaro if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC).
• Do not use Mounjaro if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• Do not use Mounjaro if you are allergic to tirzepatide or any of the ingredients in Mounjaro.

Mounjaro may cause serious side effects, including:

Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.

Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery.

Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat.

Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.

Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro.

Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools.

Common side effects
The most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn’t go away.

Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch.

Before using

• Your healthcare provider should show you how to use Mounjaro before you use it for the first time.
• Before you use Mounjaro, talk to your healthcare provider about low blood sugar and how to manage it.

Review these questions with your healthcare provider:

• Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food?
• Do you take other diabetes medicines, such as insulin or sulfonylureas?
• Do you have a history of diabetic retinopathy?
• Are you pregnant or plan to become pregnant or breastfeeding or plan to breastfeed? It is not known if Mounjaro will harm your unborn baby.
• Do you take birth control pills by mouth? These may not work as well while using Mounjaro. Your healthcare provider may recommend another type of birth control when you start Mounjaro or when you increase your dose.
• Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements?

How to take

• Read the Instructions for Use that come with Mounjaro.
• Use Mounjaro exactly as your healthcare provider says.
• Mounjaro is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm.
• Use Mounjaro 1 time each week, at any time of the day.
• Do not mix insulin and Mounjaro together in the same injection.
• If you take too much Mounjaro, call your healthcare provider or seek medical advice promptly.

This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you.

MounjaroTM and its delivery device base are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Please click to access full Prescribing Information and Medication Guide.

TR CON CBS MAY2022

Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedIn. P-LLY

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Mounjaro™ (tirzepatide 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg) injection as a treatment to improve glycemic control in adults with type 2 diabetes, the timeline for supply of Mounjaro to become available, and certain other milestones and ongoing clinical trials of Mounjaro and reflects Lilly’s current beliefs and expectations. However, as with any pharmaceutical product or medical device, there are substantial risks and uncertainties in the process of research, development and commercialization. Among other things, there can be no guarantee that Mounjaro will be commercially successful, that future study results will be consistent with results to date, or that we will meet our anticipated timelines for the commercialization of Mounjaro. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

References

1. Mounjaro. Prescribing Information. Lilly USA, LLC.
2. Rosenstock, J, et. al. Efficacy and Safety of Once Weekly Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist Versus Placebo as Monotherapy in People with Type 2 Diabetes (SURPASS-1). Abstract 100-OR. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
3. Rosenstock, J, et. al. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6.
4. Frías JP, Davies MJ, Rosenstock J, et al; for the SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6)(suppl):503-515. doi: 10.1056/NEJMoa2107519
5. Frias, J.P. Efficacy and Safety of Tirzepatide vs. Semaglutide Once Weekly as Add-On Therapy to Metformin in Patients with Type 2 Diabetes. Abstract 84-LB. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
6. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4
7. Del Prato S, Kahn SE, Pavo I, et al; for the SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. doi: 10.1016/S0140-6736(21)02188-7
8. Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534-545. doi:10.1001/jama.2022.0078

CLIP

Lilly’s tirzepatide delivered up to 22.5% weight loss in adults with obesity or overweight in SURMOUNT-1

April 28, 2022

Participants taking tirzepatide lost up to 52 lb. (24 kg) in this 72-week phase 3 study

63% of participants taking tirzepatide 15 mg achieved at least 20% body weight reductions as a key secondary endpoint

INDIANAPOLIS, April 28, 2022 /PRNewswire/ — Tirzepatide (5 mg, 10 mg, 15 mg) achieved superior weight loss compared to placebo at 72 weeks of treatment in topline results from Eli Lilly and Company’s (NYSE: LLY) SURMOUNT-1 clinical trial, with participants losing up to 22.5% (52 lb. or 24 kg) of their body weight for the efficacy estimandi. This study enrolled 2,539 participants and was the first phase 3 global registration trial evaluating the efficacy and safety of tirzepatide in adults with obesity, or overweight with at least one comorbidity, who do not have diabetes. Tirzepatide met both co-primary endpoints of superior mean percent change in body weight from baseline and greater percentage of participants achieving body weight reductions of at least 5% compared to placebo for both estimandsii. The study also achieved all key secondary endpoints at 72 weeks.

For the efficacy estimand, participants taking tirzepatide achieved average weight reductions of 16.0% (35 lb. or 16 kg on 5 mg), 21.4% (49 lb. or 22 kg on 10 mg) and 22.5% (52 lb. or 24 kg on 15 mg), compared to placebo (2.4%, 5 lb. or 2 kg). Additionally, 89% (5 mg) and 96% (10 mg and 15 mg) of people taking tirzepatide achieved at least 5% body weight reductions compared to 28% of those taking placebo.

In a key secondary endpoint, 55% (10 mg) and 63% (15 mg) of people taking tirzepatide achieved at least 20% body weight reductions compared to 1.3% of those taking placebo. In an additional secondary endpoint not controlled for type 1 error, 32% of participants taking tirzepatide 5 mg achieved at least 20% body weight reductions. The mean baseline body weight of participants was 231 lb. (105 kg).

“Obesity is a chronic disease that often does not receive the same standard of care as other conditions, despite its impact on physical, psychological and metabolic health, which can include increased risk of hypertension, heart disease, cancer and decreased survival,” said Louis J. Aronne, MD, FACP, DABOM, director of the Comprehensive Weight Control Center and the  Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, obesity expert at NewYork-Presbyterian/Weill Cornell Medical Center and Investigator of SURMOUNT-1. “Tirzepatide delivered impressive body weight reductions in SURMOUNT-1, which could represent an important step forward for helping the patient and physician partnership treat this complex disease.”

For the treatment-regimen estimandiii, results showed:

• Average body weight reductions: 15.0% (5 mg), 19.5% (10 mg), 20.9% (15 mg), 3.1% (placebo)
• Percentage of participants achieving body weight reductions of ≥5%: 85% (5 mg), 89% (10 mg), 91% (15 mg), 35% (placebo)
• Percentage of participants achieving body weight reductions of ≥20%: 30% (5 mg, not controlled for type 1 error), 50% (10 mg), 57% (15 mg), 3.1% (placebo)

The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies approved for the treatment of obesity. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity, usually occurring during the dose escalation period. For those treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (24.6%, 33.3%, 31.0%), diarrhea (18.7%, 21.2%, 23.0%), vomiting (8.3%, 10.7%, 12.2%) and constipation (16.8%, 17.1%, 11.7%) were more frequently experienced compared to placebo (9.5% [nausea], 7.3% [diarrhea], 1.7% [vomiting], 5.8% [constipation]).

Treatment discontinuation rates due to adverse events were 4.3% (5 mg), 7.1% (10 mg), 6.2% (15 mg) and 2.6% (placebo). The overall treatment discontinuation rates were 14.3% (5 mg), 16.4% (10 mg), 15.1% (15 mg) and 26.4% (placebo).

Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and the potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

“Tirzepatide is the first investigational medicine to deliver more than 20 percent weight loss on average in a phase 3 study, reinforcing our confidence in its potential to help people living with obesity,” said Jeff Emmick, MD, Ph.D., vice president, product development, Lilly. “Obesity is a chronic disease that requires effective treatment options, and Lilly is working relentlessly to support people with obesity and modernize how this disease is approached. We’re proud to research and develop potentially innovative treatments like tirzepatide, which helped nearly two thirds of participants on the highest dose reduce their body weight by at least 20 percent in SURMOUNT-1.”

Tirzepatide is a novel investigational once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist, representing a new class of medicines being studied for the treatment of obesity. Tirzepatide is a single peptide that activates the body’s receptors for GIP and GLP-1, two natural incretin hormones. Obesity is a chronic, progressive disease caused by disruptions in the mechanisms that control body weight, often leading to an increase in food intake and/or a decrease in energy expenditure. These disruptions are multifactorial and can be related to genetic, developmental, behavioral, environmental and social factors. To learn more, visit Lilly.com/obesity.

Lilly will continue to evaluate the SURMOUNT-1 results, which will be presented at an upcoming medical meeting and submitted to a peer-reviewed journal. Additional studies are ongoing for tirzepatide as a potential treatment for obesity or overweight.

Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidity and is currently under regulatory review as a treatment for adults with type 2 diabetes. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Studies of tirzepatide in obstructive sleep apnea (OSA) and in morbidity/mortality in obesity are planned as well.

About SURMOUNT-1 and the SURMOUNT clinical trial program

SURMOUNT-1 (NCT04184622) is a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults without type 2 diabetes who have obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease. The trial randomized 2,539 participants across the U.S., Argentina, Brazil, China, India, Japan, Mexico, Russia and Taiwan in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide 10 mg and/or 15 mg is superior in percentage of body weight reductions from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo. Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg).

The SURMOUNT phase 3 global clinical development program for tirzepatide began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six clinical trials, four of which are global studies. Results from SURMOUNT-2, -3, and -4 are anticipated in 2023.

Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedInP-LLY

CLIP

# Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Newly published data show that participants maintained A1C and weight control up to two years in SURPASS-4, the largest and longest SURPASS trial completed to dateNo increased cardiovascular risk identified with tirzepatide; hazard ratio of 0.74 observed for MACE-4 events

SURPASS-4 is the largest and longest clinical trial completed to date of the phase 3 program studying tirzepatide as a potential treatment for type 2 diabetes. The primary endpoint was measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE) to assess CV risk. In newly published data from the treatment period after 52 weeks, participants taking tirzepatide maintained A1C and weight control for up to two years.

The overall safety profile of tirzepatide, assessed over the full study period, was consistent with the safety results measured at 52 weeks, with no new findings up to 104 weeks. Gastrointestinal side effects were the most commonly reported adverse events, usually occurring during the escalation period and then decreasing over time.

“We are encouraged by the continued A1C and weight control that participants experienced past the initial 52 week treatment period and up to two years as we continue to explore the potential impact of tirzepatide for the treatment of type 2 diabetes,” said John Doupis, M.D., Ph.D., Director, Diabetes Division and Clinical Research Center, Iatriko Paleou Falirou Medical Center, Athens, Greece and Senior Investigator for SURPASS-4.

Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.

SURPASS-4 was an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to titrated insulin glargine in 2,002 adults with type 2 diabetes with increased CV risk who were treated with between one and three oral antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2 inhibitor). Of the total participants randomized, 1,819 (91%) completed the primary 52-week visit and 1,706 (85%) completed the study on treatment. The median study duration was 85 weeks and 202 participants (10%) completed two years.

Study participants had a mean duration of diabetes of 11.8 years, a baseline A1C of 8.52 percent and a baseline weight of 90.3 kg. More than 85 percent of participants had a history of cardiovascular events. In the insulin glargine arm, the insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 100 mg/dL. The starting dose of insulin glargine was 10 units per day, and the mean dose of insulin glargine at 52 weeks was 43.5 units per day.

Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes, for chronic weight management and heart failure with preserved ejection fraction (HFpEF). It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH).

About SURPASS-4 and the SURPASS clinical trial program
SURPASS-4 (NCT03730662) is a randomized, parallel, open-label trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to insulin glargine in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The trial randomized 2,002 study participants in a 1:1:1:3 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or insulin glargine. Participants were located in the European Union, North America (Canada and the United States), Australia, Israel, Taiwan and Latin America (Brazil, Argentina and Mexico). The primary objective of the study was to demonstrate that tirzepatide (10 mg and/or 15 mg) is non-inferior to insulin glargine for change from baseline A1C at 52 weeks in people with type 2 diabetes and increased CV risk. The primary and key secondary endpoints were measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE). Study participants enrolled had to have a mean baseline A1C between 7.5 percent and 10.5 percent and a BMI greater than or equal to 25 kg/m2 at baseline. All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg). All participants in the titrated insulin glargine treatment arm started with a baseline dose of 10 units per day and titrated following a treat-to-target algorithm to reach a fasting blood glucose below 100 mg/dL.

The SURPASS phase 3 global clinical development program for tirzepatide has enrolled more than 20,000 people with type 2 diabetes across 10 clinical trials, five of which are global registration studies. The program began in late 2018, and all five global registration trials have been completed.

Approximately 34 million Americans2 (just over 1 in 10) and an estimated 463 million adults worldwide3 have diabetes. Type 2 diabetes is the most common type internationally, accounting for an estimated 90 to 95 percent of all diabetes cases in the United States alone2. Diabetes is a chronic disease that occurs when the body does not properly produce or use the hormone insulin.

////////////Tirzepatide, FDA 2022, APPROVALS 2022, Mounjaro, PEPTIDE, チルゼパチド ,  LY3298176,

UNIIOYN3CCI6QE

chart 1 Structure of GLP-1 & TZP & Exenatide & Somalutide

## MONENSIN

モネンシン;

MONENSIN

Elancoban [veterinary] (TN)

• Molecular FormulaC36H62O11
• Average mass670.871 Da

1,6-dioxaspiro[4.5]decane-7-butanoic acid, 2-[(2S,2’R,3’S,5R,5’R)-2-ethyloctahydro-3′-methyl-5′-[(2S,3S,5R,6R)-tetrahydro-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-2H-pyran-2-yl][2,2′-bifuran]-5-yl]-9-hydroxy-β-methoxy-α,γ,2,8-tetramethyl-, (αS,βR,γS,2S,5R,7S,8R,9S)-

17090-79-8[RN]

241-154-0[EINECS]

(2S,3R,4S)-4-[(2S,5R,7S,8R,9S)-2-{(2S,2’R,3’S,5R,5’R)-2-Ethyl-5′-[(2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyltetrahydro-2H-pyran-2-yl]-3′-methyloctahydro-2,2′-bifuran-5-yl}-9-hydroxy-2,8-di methyl-1,6-dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methylpentanoic acid

монензин[Russian]

مونانسين[Arabic]

Antibiotic, Antifungal, Antiprotozoal

Synonym(s):

Monensin A sodium salt

Empirical Formula (Hill Notation):C36H61NaO11

CAS Number:22373-78-0

Molecular Weight:692.85

Beilstein:4122200

Title: Monensin

CAS Registry Number: 17090-79-8

CAS Name: 2-[5-Ethyltetrahydro-5-[tetrahydro-3-methyl-5-[tetrahydro-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-2H-pyran-2-yl]-2-furyl]-2-furyl]-9-hydroxy-b-methoxy-a,g,2,8-tetramethyl-1,6-dioxaspiro[4.5]decane-7-butyric acid

Manufacturers’ Codes: A-3823A

Molecular Formula: C36H62O11, Molecular Weight: 670.87

Percent Composition: C 64.45%, H 9.32%, O 26.23%

Literature References: Polyether antibiotic. Major factor in antibiotic complex isolated from Streptomyces cinnamonensis. Discovery and isolation: Haney, Hoehn, Antimicrob. Agents Chemother.1967, 349. Production: Haney, Hoehn, US3501568 (1970 to Lilly). Structure: Agtarap et al.,J. Am. Chem. Soc.89, 5737 (1967). Crystal structure studies: Lutz et al.,Helv. Chim. Acta53, 1732 (1970); ibid.54, 1103 (1971). Fermentation studies: Stark et al.,Antimicrob. Agents Chemother.1967, 353. Chemistry: Agtarap, Chamberlin, ibid. 359. Stereocontrolled total synthesis: T. Fukuyama et al.,J. Am. Chem. Soc.101, 262 (1979); D. B. Collum et al.,ibid.102, 2117, 2118, 2120 (1980). 13C-NMR study: J. A. Robinson, D. L. Turner, Chem. Commun.1982, 148. Biosynthesis: Day et al.,Antimicrob. Agents Chemother.4, 410 (1973). Review: Stark, “Monensin, A New Biologically Active Compound Produced by a Fermentation Process”, in Fermentation Advances, Pap. Int. Ferment. Symp., 3rd, 1968, D. Perlman, Ed. (Academic Press, New York, 1969) pp 517-540.

Properties: Crystals, mp 103-105° (monohydrate). [a]D +47.7°. pKa 6.6 (in 66% DMF). Very stable under alkaline conditions. Slightly sol in water; more sol in hydrocarbons; very sol in other organic solvents. LD50 of monensin complex in mice, chicks (mg/kg): 43.8 ± 5.2, 284 ± 47 orally (Haney, Hoehn).

Melting point: mp 103-105° (monohydrate)

pKa: pKa 6.6 (in 66% DMF)

Optical Rotation: [a]D +47.7°

Toxicity data: LD50 of monensin complex in mice, chicks (mg/kg): 43.8 ± 5.2, 284 ± 47 orally (Haney, Hoehn)

Derivative Type: Sodium salt

Trademarks: Coban (Elanco); Romensin (Elanco); Rumensin (Elanco)

Molecular Formula: C36H61NaO11, Molecular Weight: 692.85

Percent Composition: C 62.41%, H 8.87%, Na 3.32%, O 25.40%

Properties: mp 267-269°. [a]D +57.3° (methanol). Slightly sol in water; more sol in hydrocarbons; very sol in other organic solvents.

Melting point: mp 267-269°

Optical Rotation: [a]D +57.3° (methanol)

Therap-Cat-Vet: Coccidiostat. Feed additive to improve feed efficiency in ruminants.

Monensin is a polyether antibiotic isolated from Streptomyces cinnamonensis.[1] It is widely used in ruminant animal feeds.[1][2]

The structure of monensin was first described by Agtarap et al. in 1967, and was the first polyether antibiotic to have its structure elucidated in this way. The first total synthesis of monensin was reported in 1979 by Kishi et al.[3]

SYN

SYN

Production / synthesis Monensin is produced in vivo by Streptomyces cinnamonensis as a natural defense against competing bacteria. Monensin presents a formidable challenge to synthetic chemists as it possesses 17 asymmetric centers on a backbone of only 26 carbon atoms. Although its total synthesis has been described (e.g., Kishi et al., 1979), the high complexity of monensin makes an extraction from the bacterium the most economical procedure for its production. The total synthesis has 56 steps and a yield of only 0.26%. The chemical precursors are 2-allyl-1,3-propanediol and 2- (furan-2-yl)acetonitrile. The method used for synthesizing monensin is based on the principle of “absolute asymmetric synthesis”. Molecules are constructed out of prefabricated building blocks in the correct conformation, aiming for higher yields of the desired enantiomer. New stereocenters are also introduced. Using this method, monensin is assembled in two parts, a larger right side and a smaller left one. The penultimate step is connecting the left and the right halves of monensin, which are independently generated, in an Aldol-condensation. The two halves’ keto end groups (C7/ C8) are linked by eliminating a water molecule. The C7 atom is favored over the C1 atom, because it is more reactive. For catalyzing this step, Yoshito Kishi’s group used iPr2NMgBr (Hauser base) and THF to coordinate it at a temperature of − 78°C. Thus, they were able to isolate the molecule in the right conformation at a ratio of 8:1. Due to the low temperature required for a high yield of the correct enantiomer, the reaction is very solw. One of the most difficult steps is the last one: the connection of the spiro center. This is due to a characteristic feature of spiro compounds; they open and close very easily. Therefore, the conditions for forming the right conformation must be optimal in the last step of synthesis. The biosynthesis in a cell culture of Streptomyces cinnamonensis involves a complex medium containing, among other components, glucose, soybean oil, and grit. Cultivation is carried out for a week at a temperature of 30°C and under constant aeration. Product isolation requires filtration, acidification to pH3, extraction with chloroform and purification with activated carbon. In this way, a few grams per liter of monensin are produced and isolated. For crystallization, azeotropic distillation is necessary. In vivo, polyether backbones are assembled by modular polyketide synthases and are modified by two key enzymes, epoxidase and epoxide hydrolase, to generate the product. Precursors of the polyketide pathway are acetate, butyrate and propionate.

SYN

The final-stage aldol addition in Yoshito Kishi‘s 1979 total synthesis of monensin. (1979). “Synthetic studies on polyether antibiotics. 6. Total synthesis of monensin. 3. Stereocontrolled total synthesis of monensin”. J. Am. Chem. Soc. 101 (1): 262–263. DOI:10.1021/ja00495a066.

SYN

A polyether antibiotic, Monensin was the first member of this class of molecules to be structurally characterized.1 The structural features of these polyethers comprise of a terminal carboxylic acid, multiple cyclic ether rings (ex. Tetrahydrofuran and tetrahydropyran), a large amount of stereocenters and (for many of these molecules) one or more spiroketal moieties.2 Monensin was introduced into the market in 1971 and is used to fight coccidial infections in poultry and as an additive in cattle feed.3 Of the 26 carbon atom’s in Monensin’s backbone, 17 are stereogenic and six of those are contiguous. Coupled with a spiroketal moiety, three hydrofuran rings and two hydropyran rings, the molecule was an attractive synthetic target.

1. Agtarap, A.; Chamberlain, J.W.; Pinkerton, M.; Stein-rauf, L. J. Am. Chem. Soc. 1967, 89, 5737 2. Polyether Antibiotics : Naturally Occurring Acid Ionophores. Westley J.W.; Marcel Dekker: New York (1982) Vol. 1-2. 3. Stark, W.M. In Fermentation Advances, Perlman, D., Ed., Academic Press: New York, 1969, 517

Retrosynthetic Analysis of Monensin

//////////

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## Mechanism of action

The structure of the sodium (Na+) complex of monensin A.

Monensin A is an ionophore related to the crown ethers with a preference to form complexes with monovalent cations such as: Li+, Na+, K+, Rb+, Ag+, and Tl+.[4][5] Monensin A is able to transport these cations across lipid membranes of cells in an electroneutral (i.e. non-depolarizing) exchange, playing an important role as an Na+/H+ antiporter. Recent studies have shown that monensin may transport sodium ion through the membrane in both electrogenic and electroneutral manner.[6] This approach explains ionophoric ability and in consequence antibacterial properties of not only parental monensin, but also its derivatives that do not possess carboxylic groups. It blocks intracellular protein transport, and exhibits antibioticantimalarial, and other biological activities.[7] The antibacterial properties of monensin and its derivatives are a result of their ability to transport metal cations through cellular and subcellular membranes.[8]

## Uses

Monensin is used extensively in the beef and dairy industries to prevent coccidiosis, increase the production of propionic acid and prevent bloat.[9] Furthermore, monensin, but also its derivatives monensin methyl ester (MME), and particularly monensin decyl ester (MDE) are widely used in ion-selective electrodes.[10][11][12]

In laboratory research, monensin is used extensively to block Golgi transport.[13][14][15]

## Toxicity

Monensin has some degree of activity on mammalian cells and thus toxicity is common. This is especially pronounced in horses, where monensin has a median lethal dose 1/100th that of ruminants. Accidental poisoning of equines with monensin is a well-documented occurrence which has resulted in deaths.[16]

## References

1. Jump up to:a b Daniel Łowicki and Adam Huczyński (2013). “Structure and Antimicrobial Properties of Monensin A and Its Derivatives: Summary of the Achievements”BioMed Research International2013: 1–14. doi:10.1155/2013/742149PMC 3586448PMID 23509771.
2. ^ Butaye, P.; Devriese, L. A.; Haesebrouck, F. (2003). “Antimicrobial Growth Promoters Used in Animal Feed: Effects of Less Well Known Antibiotics on Gram-Positive Bacteria”Clinical Microbiology Reviews16 (2): 175–188. doi:10.1128/CMR.16.2.175-188.2003PMC 153145PMID 12692092.
3. ^ Nicolaou, K. C.; E. J. Sorensen (1996). Classics in Total Synthesis. Weinheim, Germany: VCH. pp. 185–187. ISBN 3-527-29284-5.
4. ^ Huczyński, A.; Ratajczak-Sitarz, M.; Katrusiak, A.; Brzezinski, B. (2007). “Molecular structure of the 1:1 inclusion complex of Monensin A lithium salt with acetonitrile”. J. Mol. Struct. 871 (1–3): 92–97. Bibcode:2007JMoSt.871…92Hdoi:10.1016/j.molstruc.2006.07.046.
5. ^ Pinkerton, M.; Steinrauf, L. K. (1970). “Molecular structure of monovalent metal cation complexes of monensin”. J. Mol. Biol. 49 (3): 533–546. doi:10.1016/0022-2836(70)90279-2PMID 5453344.
6. ^ Huczyński, Adam; Jan Janczak; Daniel Łowicki; Bogumil Brzezinski (2012). “Monensin A acid complexes as a model of electrogenic transport of sodium cation”Biochim. Biophys. Acta1818 (9): 2108–2119. doi:10.1016/j.bbamem.2012.04.017PMID 22564680.
7. ^ Mollenhauer, H. H.; Morre, D. J.; Rowe, L. D. (1990). “Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity”Biochim. Biophys. Acta1031 (2): 225–246. doi:10.1016/0304-4157(90)90008-ZPMC 7148783PMID 2160275.
8. ^ Huczyński, A.; Stefańska, J.; Przybylski, P.; Brzezinski, B.; Bartl, F. (2008). “Synthesis and antimicrobial properties of Monensin A esters”. Bioorg. Med. Chem. Lett. 18 (8): 2585–2589. doi:10.1016/j.bmcl.2008.03.038PMID 18375122.
9. ^ Matsuoka, T.; Novilla, M.N.; Thomson, T.D.; Donoho, A.L. (1996). “Review of monensin toxicosis in horses”. Journal of Equine Veterinary Science16: 8–15. doi:10.1016/S0737-0806(96)80059-1.
10. ^ Tohda, Koji; Suzuki, Koji; Kosuge, Nobutaka; Nagashima, Hitoshi; Watanabe, Kazuhiko; Inoue, Hidenari; Shirai, Tsuneo (1990). “A sodium ion selective electrode based on a highly lipophilic monensin derivative and its application to the measurement of sodium ion concentrations in serum”Analytical Sciences6 (2): 227–232. doi:10.2116/analsci.6.227.
11. ^ Kim, N.; Park, K.; Park, I.; Cho, Y.; Bae, Y. (2005). “Application of a taste evaluation system to the monitoring of Kimchi fermentation”. Biosensors and Bioelectronics20 (11): 2283–2291. doi:10.1016/j.bios.2004.10.007PMID 15797327.
12. ^ Toko, K. (2000). “Taste Sensor”. Sensors and Actuators B: Chemical64 (1–3): 205–215. doi:10.1016/S0925-4005(99)00508-0.
13. ^ Griffiths, G.; Quinn, P.; Warren, G. (March 1983). “Dissection of the Golgi complex. I. Monensin inhibits the transport of viral membrane proteins from medial to trans Golgi cisternae in baby hamster kidney cells infected with Semliki Forest virus”The Journal of Cell Biology96 (3): 835–850. doi:10.1083/jcb.96.3.835ISSN 0021-9525PMC 2112386PMID 6682112.
14. ^ Kallen, K. J.; Quinn, P.; Allan, D. (1993-02-24). “Monensin inhibits synthesis of plasma membrane sphingomyelin by blocking transport of ceramide through the Golgi: evidence for two sites of sphingomyelin synthesis in BHK cells”. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism1166 (2–3): 305–308. doi:10.1016/0005-2760(93)90111-lISSN 0006-3002PMID 8443249.
15. ^ Zhang, G. F.; Driouich, A.; Staehelin, L. A. (December 1996). “Monensin-induced redistribution of enzymes and products from Golgi stacks to swollen vesicles in plant cells”. European Journal of Cell Biology71 (4): 332–340. ISSN 0171-9335PMID 8980903.
16. ^ “Tainted feed blamed for 4 horse deaths at Florida stable”. 2014-12-16.

///////////MONENSIN, Elancoban, VETERINARY, Coccidiostat, A-3823A, A 3823A

NEW DRUG APPROVALS

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## Difamilast

Difamilast

PMDA Moizerto, JAPAN APPROVED 2021/9/27

ジファミラスト

ディファミラスト;

N-({2-[4-(difluoromethoxy)-3-(propan-2-yloxy)phenyl]-1,3- oxazol-4-yl}methyl)-2-ethoxybenzamide

OPA-15406

Formula C23H24F2N2O5 937782-05-3 446.4439

MM 36; MM-36-Medimetriks-Pharmaceuticals; Moizerto; OPA-15406

Efficacy Anti-inflammatory, Phosphodiesterase IV inhibitor Treatment of atopic dermatitis

• Originator
Otsuka Pharmaceutical Development & Commercialization
• DeveloperMedimetriks Pharmaceuticals; Otsuka Pharmaceutical Development & Commercialization
• ClassBenzamides; Nonsteroidal anti-inflammatories; Oxazoles; Skin disorder therapies
• Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
• RegisteredAtopic dermatitis
• 27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
• 11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
• 28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)

Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).

PATENT

JP 2021059538

https://patentscope.wipo.int/search/en/detail.jsf?docId=JP322244172&_cid=P20-L1WXG6-04592-1

Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, inhibition of PDE4 increases intracellular cAMP concentration, and the increase in this concentration downregulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. .. Elevated cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, it is considered that the oxazole compound is suitable for use as an anti-inflammatory agent. For example, it may be useful for controlling skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated in the present specification by reference.
patcit 1 : International Publication No. 2007/058338 (Japanese Publication No. 2009-515872 )
patcit 2 : International Publication No. 2014/034958 (Japanese Publication No. 2015-528433 )
patcit 3 : International Publication No. 2017/115780

[Synthesis of Oxazole Compound (Type A Crystal)]
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).

[0060]

Ｎ−（｛２−［４−（ｄｉｆｌｕｏｒｏｍｅｔｈｏｘｙ）−３−ｉｓｏｐｒｏｐｏｘｙｐｈｅｎｙｌ］ｏｘａｚｏｌ−４−ｙｌ｝ｍｅｔｈｙｌ）−２−ｅｔｈｏｘｙｂｅｎｚａｍｉｄｅ
： ｗｈｉｔｅ ｐｏｗｄｅｒ．
Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）： δ ＝ ８．５６ （ｂｒ ｓ，
１Ｈ， ＮＨ）， ８．２３ （ｄｄ， Ｊ ＝ ７．６ Ｈｚ， １．６ Ｈｚ， １Ｈ， ＡｒＨ）， ７．６６ （ｓ， １Ｈ， ＡｒＨ）， ７．６３ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．５８ （ｄｄ， Ｊ ＝ ８．４ Ｈｚ， ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．４４−７．３９ （ｍ， １Ｈ， ＡｒＨ）， ７．２１ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．０８−７．０４ （ｍ， １Ｈ， ＡｒＨ）， ６．９４ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ６．６１ （ｔ， Ｊ ＝ ７５．２ Ｈｚ， １Ｈ， ＣＨＦ ）， ４．６８ （ｓｅｐｔ， Ｊ ＝ ６．０ Ｈｚ， １Ｈ， ＣＨ）， ４．６２
（ｄ， Ｊ ＝ ６．０ Ｈｚ， ２Ｈ， ＣＨ ）， ４．１７ （ｑ， Ｊ ＝ ６．９３， ２Ｈ， ＣＨ ）， １．４８ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ，
ＣＨ ）， １．３９ （ｄ， Ｊ ＝ ５．６ Ｈｚ， ６Ｈ， ２ＣＨ ）．
[Preparation of B-type crystal 2]
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).

[0072]
[Chem. 6]

[0073]
Compound (1) 20.00 g (66.8 mmol) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate to cool the mixture, and 11.48 g (100 mmol) of methanesulfonyl chloride was introduced into the compound (1) at 10 to 30 ° C. Stir for hours. Subsequently, 17.41 g (200 mmol) of lithium bromide was added, and the mixture was stirred at 20 to 35 ° C. for 1 hour. 100 mL of water was added to the reaction solution to separate the layers, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the mixture was concentrated again under reduced pressure. 200 mL of N, N-dimethylformamide and 17.33 g (93.6 mmol) of phthalimide potassium were added to the concentrated residue, and the mixture was reacted at 75 to 85 ° C. for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals, and the precipitated crystals were collected by filtration and dried at 80 ° C. to obtain 27.20 g (yield 95.01%) of compound (3).

[0074]
[Chem. 7]

[0075]
Compound (3) 20.00 g (46.7 mmol), 40 mL of a 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75 ° C. to separate the liquids. A mixed solution of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted again to 65 to 75 ° C. to separate the liquids. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. Precipitated crystals were collected by filtration to obtain 27.58 g of wet crystals of compound (4).

[0076]
Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and the mixture was stirred at 20 to 30 ° C. for 1 hour. To the reaction solution, 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and 20 to 30 were added. The reaction was carried out at ° C. for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. to separate the solutions. 60 mL of water and 6 mL of a 25%
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017115780

Production Example 1: Production 1 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.

[0146]
[Chem. 11]

[0147]

[0148]

1H-NMR (CDCl 3) δ: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2 Hz),6.66 (1H,t,J = 74.8 Hz),4.66(1H,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).

Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.

[0149]
[Chem. 12]

[0150]
10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40 ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added thereto at 20°C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.

[0151]
Production Example 3: Production of Compound (7)
Compound (7) was produced in accordance with the following reaction scheme.

[0152]
[Chem. 13]
Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.

[0160]
[Chem. 14]

[0161]
Synthesis of Compound (9)
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.

[0162]
1H-NMR (DMSO-d 6) δ: 8.22 (1H,s),7.94-7.86 (4H,m),7.58 (1H,d,J = 2.0 Hz),7.52 (1H,dd,J = 8.8 Hz,2.4 Hz),7.30 (1H,d,J = 8.4 Hz),7.14 (1H,t,J = 74.2 Hz),4.78-4.69 (3H,m),1.30 (6H,d,J = 6.0 Hz).

[0163]
Synthesis of Compound (10)
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.

[0164]
1H-NMR (DMSO-d 6) δ: 8.51 (3H,br-s),8.29 (1H,s),7.64 (1H,d,J = 2 Hz),7.59 (1H,dd,J = 8.0 Hz,1.6 Hz),7.37 (1H,d,J = 8.4 Hz),7.18 (1H,t,J = 74.0 Hz),4.72 (1H,sept,J = 6.1 Hz),4.03 (2H,s),1.33 (6H,d,J = 6.4 Hz).

[0165]
Synthesis of Compound (11)
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.

[0166]
1H-NMR (CDCl 3) δ: 8.56 (1H,br-s),8.23 (1H,dd,J = 7.6 Hz,1.6 Hz),7.66 (1H,s),7.63 (1H,d,J = 2.0 Hz),7.58 (1H,dd,J = 8.4 Hz,2.0 Hz),7.44-7.39 (1H,m),7.21 (1H,d,J = 8.0 Hz),7.08-7.04 (1H,mH),6.94 (1H,d,J = 8.0 Hz),6.61 (1H,t,J = 75.2 Hz),4.68 (1H,sept,J = 6.0 Hz),4.62 (2H,d,J = 6.0 Hz),4.17 (2H,q,J = 6.93),1.48 (3H,t,J = 7.2 Hz),1.39 (6H,d,J = 5.6 Hz).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019194211

*DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether,
DMF: N,N-dimethylformamide, 2-EBA: 2-Ethoxybenzoic acid,
WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

Type B Crystal Preparation 2
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).

[0072]

[0073]
20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto, and the mixture was stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 27.20 g (yield: 95.01%) of compound (3).

[0074]

[0075]
20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, thereby obtaining 27.58 g of compound (4) as a wet crystal.

[0076]
The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of the type B crystal (a seed crystal) was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 18.38 g (88.18%) of compound (5).

PATENT

WO2014034958A1

WO2007058338A2

WO2007058338A9

WO2007058338A3

US9181205B2

US2015239855A1

USRE46792E

US2020078340A1

US2017216260A1

US2019070151A1

US2009221586A1

US8637559B2

US2014100226A1

///////////

### Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

### Anthony Melvin Crasto Dr. | Facebook

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EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

/////////////Difamilast, JAPAN 2021, APPROVALS 2021, ジファミラスト ,  MM 36,  MM-36-Medimetriks-Pharmaceuticals,  Moizerto, OPA-15406, OPA 15406, 地法米司特

O=C(NCC1=COC(C2=CC=C(OC(F)F)C(OC(C)C)=C2)=N1)C3=CC=CC=C3OCC

INTrmediate No.CAS No.DIFAM-001177429-27-5DIFAM-00293652-48-3DIFAM-0031574285-26-9DIFAM-00470-23-5DIFAM-0051574285-28-1DIFAM-0061574285-30-5DIFAM-0071574285-32-7DIFAM-0081574285-36-1DIFAM-0091574285-38-3DIFAM-010DIFAM-0111574285-40-7DIFAM-0121574285-43-0DIFAM-013134-11-2Difamilast937782-05-3

## TOLDIMFOS SODIUM

TOLDIMFOS SODIUM

C9H12NNaO2P+  , 220.16

Toldimfos sodium

575-75-7

Sodium (4-(dimethylamino)-2-methylphenyl)phosphinate

UNII-6139240O1E

sodium;[4-(dimethylamino)-2-methylphenyl]-oxido-oxophosphanium

EINECS 209-391-4

C9H13NO2P.Na

DTXSID4060361

AKOS015960346

VZ33686

AC-10524

FT-0657398

575-75-7

Sodium (4-(dimethylamino)-2-methylphenyl)phosphinate

UNII-6139240O1E

sodium;[4-(dimethylamino)-2-methylphenyl]-oxido-oxophosphanium

Phosphinic acid, [4-(dimethylamino)-2-methylphenyl]-, sodium salt

6139240O1E

Phosphinic acid, (4-(dimethylamino)-2-methylphenyl)-, sodium salt

Phosphinic acid, P-(4-(dimethylamino)-2-methylphenyl)-, sodium salt (1:1)

Toldimfos is an aromatic phosphorus compound which falls between phosphorous itself and phosphoric acid in the stages of oxidation. Toldimfos sodium is the sodium salt of 2- methyl-4-(dimethylamino)phenylphosphinic acid. It is used to treat and prevent diseases associated with parturition and peri-partum period, developmental and nutritional disorders in young animals, and bone growth disorders and tetany or paresis caused by calcium, magnesium, and phosphorus metabolism disorders. Toldimfos has been used as a human medicine since 1920. While it is no longer indicated for human use, it is used in horses, cattle, sheep, pigs, and goats, and administered by intravenous, intramuscular, or subcutaneous injection. No specific data on the pharmacodynamic action of toldimfos was submitted. The precise mode of action of toldimfos is unknown and it is questionable whether the effect of toldimfos is simply a matter of the substitution of deficient phosphorus. It appears more likely that the effect of toldimfos arises due to multiple stimulation of metabolism with the body.

# Toldimfos sodium trihydrate

5787-63-3

Toldimfos [INN:BAN]
57808-64-7

Toldimfos Sodium

CAS Registry Number: 575-75-7

CAS Name: (4-Dimethylamino-o-tolyl)phosphonous acid sodium salt

Additional Names: sodium (4-dimethylamino-o-tolyl)phosphonate; p-dimethylamino-o-toluenephosphonous acid sodium salt

Molecular Formula: C9H13NNaO2P, Molecular Weight: 221.17

Percent Composition: C 48.87%, H 5.92%, N 6.33%, Na 10.39%, O 14.47%, P 14.00%

Literature References: Prepd from N,N-dimethyl-m-toluidine and phosphorus trichloride: Benda, Schmidt, DE397813 (1924 to Cassella), Frdl.14, 1409.

Derivative Type: Trihydrate

CAS Registry Number: 5787-63-3

Properties: Scales, needles, or prisms from alc. Freely sol in cold water, hot alcohol.

Therap-Cat-Vet: Phosphorus source.

SYN

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011026571

PATENT

China’s animal husbandry fast development is the important motivity that promotes China’s agricultural and rural economy development, improves farmers’ income.The disease relevant with Nutrition and Metabolism of serious harm animal health is in rising trend in recent years, the direct economic loss that raising poultry nutritive metabolic disease causes over ten billion to China’s animal husbandry every year, and indirect economic loss is difficult to estimate.

Due to the life-time service of chemicals, will cause some poultrys, poultry product drug residue is serious, this is harm humans healthy not only, also affecting the export of farm produce earns foreign exchange, therefore, tackle this problem, research and development are efficient, the new Nutrition and Metabolism medicine of low toxicity, wide spectrum will have huge market.

Toldimfos (Toldimfos Sodium) belongs to the nutritional supplementation medicine of phosphorus supplement, can be used as benzenephosphonic acid (Phenylphosphinicacid, BPA) succedaneum uses, can be used for treating the disease relevant with childbirth and perinatal stage of the food animals such as horse, cattle, pig, sheep, the diseases such as the bone lengthening obstacle being caused by calcium, magnesium, phosphorus metabolism obstacle.

Toldimfos has higher water solublity, mainly excretes through urine rapidly with the former medicine form of not metabolism in animal body, and the half-life is short, can in tissue, not accumulate.

Toldimfos is developed by German Hoechst company, the symptom such as since nineteen twenty, once physical weakness, chronic stress, depression, mental muscle power postoperative for human treatment, that catch was overtired.Now be not used in the mankind, be mainly used in animal.Its commodity are called onofosfan.

In sum, toldimfos, as a kind of nutritional supplementation medicine of new and effective noresidue, has wide market prospect in China.The development of this product will be made outstanding contributions to the sound development of China’s animal husbandry, remarkable economic and social benefits with application.

PATENT

///////////

### Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

### Anthony Melvin Crasto Dr. | Facebook

Anthony Melvin Crasto Dr. | twitter

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EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

//////////TOLDIMFOS SODIUM, HOECHST,  Foston, Tonofosfan,

O.O.O.[Na+].CN(C)c1ccc(c(C)c1)P(=O)[O-]

NEW DRUG APPROVALS

ONE TIME

## TRIAMCINOLONE

TRIAMCINOLONE

• Molecular FormulaC21H27FO6
• Average mass394.434 Da

(11β,16α)-9-Fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione

(8S,9R,10S,11S,13S,14S,16R,17S)-9-Fluor-11,16,17-trihydroxy-17-(hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-on

(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(hydroxyacétyl)-10,13-diméthyl-6,7,8,9,10,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrén-3-one

(8S,9R,10S,11S,13S,14S,16R,17S)-9-Fluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

124-94-7[RN]

16a-Hydroxy-9a-fluoroprednisolone

1ZK20VI6TY

204-718-7[EINECS]

755

9a-Fluoro-16a-hydroxyprednisolone

TU3850000

トリアムシノロン[Japanese]

Triamcinolone

CAS Registry Number: 124-94-7

CAS Name: (11b, 16a)-9-Fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione

Additional Names: D1-9a-fluoro-16a-hydroxyhydrocortisone; 9a-fluoro-16a-hydroxyprednisolone; D1-16a-hydroxy-9a-fluorohydrocortisone; 16a-hydroxy-9a-fluoroprednisolone

Manufacturers’ Codes: CL-19823

Trademarks: Aristocort (Lederle); Kenacort (BMS); Ledercort (tabl.) (Lederle); Omcilon (BMS); Tricortale (Bergamon); Volon (BMS)

Molecular Formula: C21H27FO6, Molecular Weight: 394.43

Percent Composition: C 63.95%, H 6.90%, F 4.82%, O 24.34%

Literature References: Prepn: Bernstein et al.,J. Am. Chem. Soc.78, 5693 (1956); 81, 1689 (1959); Thoma et al.,ibid.79, 4818 (1957); Bernstein et al., Allen et al.,US2789118US3021347 (1957, 1962, both to Am. Cyanamid). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.1, 367-396, 423-442 (1972); D. H. Sieh, ibid.11, 593-614, 651-661 (1982).

Properties: Crystals, mp 269-271°. mp also reported as 260-262.5°. [a]D25 +75° (acetone). uv max: 238 nm (e 15800).

Melting point: mp 269-271°; mp also reported as 260-262.5°

Optical Rotation: [a]D25 +75° (acetone)

Absorption maximum: uv max: 238 nm (e 15800)

………………………………

Derivative Type: 16,21-Diacetate

CAS Registry Number: 67-78-7

CAS Name: (11b,16a)-16,21-Bis(acetyloxy)-9-fluoro-11,17-dihydroxypregna-1,4-diene-3,20-dione

Trademarks: Cenocort (Central Pharm.); CINO-40 (Tutag); Tracilon (Savage)

Molecular Formula: C25H31FO8, Molecular Weight: 478.51

Percent Composition: C 62.75%, H 6.53%, F 3.97%, O 26.75%

Properties: Solvated crystals, mp 186-188° (with effervescence, mp 235° after drying). [a]D25 +22° (chloroform). uv max: 239 nm (e 15200).

Melting point: Solvated crystals, mp 186-188° (with effervescence, mp 235° after drying)

Optical Rotation: [a]D25 +22° (chloroform)

Absorption maximum: uv max: 239 nm (e 15200)

Therap-Cat: Glucocorticoid., Therap-Cat-Vet: Glucocorticoid., Keywords: Glucocorticoid.

///////////////////////

Triamcinolone Acetonide

CAS Registry Number: 76-25-5

CAS Name: (11b,16a)-9-Fluoro-11,21-dihydroxy-16,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione

Additional Names: 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone; 9a-fluoro-16a-hydroxyprednisolone acetonide; triamcinolone 16a,17-acetonide; 9a-fluoro-11b,21-dihydroxy-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione; 9a-fluoro-16a,17-isopropylidenedioxyprednisolone

Trademarks: Adcortyl (BMS); Azmacort (Aventis); Delphicort (Lederle); Extracort (Basotherm); Ftorocort (Gedeon Richter); Kenacort-A (BMS); Kenalog (Apothecon); Ledercort Cream (Lederle); Nasacort (Aventis); Respicort (Mundipharma); Rineton (Sanwa); Solodelf (Cyanamid); Tramacin (J & J); Triam (Lichtenstein); Tricinolon (Kaken); Vetalog (Solvay); Volon A (BMS); Volonimat (BMS)

Molecular Formula: C24H31FO6, Molecular Weight: 434.50

Percent Composition: C 66.34%, H 7.19%, F 4.37%, O 22.09%

Literature References: Prepd by stirring a suspension of triamcinolone in acetone in the presence of a trace of perchloric acid: Fried et al.,J. Am. Chem. Soc.80, 2338 (1958); Bernstein et al.,ibid.81, 1689 (1959); Bernstein, Allen, US2990401 (1961 to Am. Cyanamid). Alternate synthesis using 2,3-dibromo-5,6-dicyanoquinone: Hydorn, US3035050 (1962 to Olin Mathieson). Clinical trial in chronic asthma: I. L. Bernstein et al.,Chest81, 20 (1982). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.1, 397-421 (1972); D. H. Sieh, ibid.11, 615-649 (1982).

Properties: Crystals, mp 292-294°. [a]D23 +109° (c = 0.75 in chloroform). uv max (abs alc.): 238 nm (e 14600). Sparingly sol in methanol, acetone, ethyl acetate.

Melting point: mp 292-294°

Optical Rotation: [a]D23 +109° (c = 0.75 in chloroform)

Absorption maximum: uv max (abs alc.): 238 nm (e 14600)

………………..

Derivative Type: 21-Acetate

Properties: Crystals, mp 268-270°. [a]D23 +92° (c = 0.59 in chloroform).

Melting point: mp 268-270°

Optical Rotation: [a]D23 +92° (c = 0.59 in chloroform)

Derivative Type: 21-Disodium phosphate

CAS Registry Number: 1997-15-5

Molecular Formula: C24H30FNa2O9P, Molecular Weight: 558.44

Percent Composition: C 51.62%, H 5.41%, F 3.40%, Na 8.23%, O 25.79%, P 5.55%

………………….

Derivative Type: 21-Hemisuccinate

Molecular Formula: C28H35FO9, Molecular Weight: 534.57

Percent Composition: C 62.91%, H 6.60%, F 3.55%, O 26.94%

Therap-Cat: Glucocorticoid; antiasthmatic (inhalant); antiallergic (nasal).

Therap-Cat-Vet: Glucocorticoid.

Keywords: Antiallergic (Steroidal, Nasal); Antiasthmatic (Steroidal, Inhalant); Glucocorticoid.

//////////////////////////

Title: Triamcinolone Benetonide

CAS Registry Number: 31002-79-6

CAS Name: (11b,16a)-21-[3-(Benzoylamino)-2-methyl-1-oxopropoxy]-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione

Additional Names: 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone 21-ester with N-benzoyl-2-methyl-b-alanine; 9a-fluoro-16a-hydroxyprednisolone 16a,17a-acetonide 21-(b-benzoylamino)isobutyrate; triamcinolone acetonide b-benzoylaminoisobutyrate; TBI

Molecular Formula: C35H42FNO8, Molecular Weight: 623.71

Percent Composition: C 67.40%, H 6.79%, F 3.05%, N 2.25%, O 20.52%

Literature References: Prepn: C. Cavazza et al.,DE2047218eidem,US3749712 (1971, 1973 both to Sigma-Tau). Pharmacology: E. T. Ordonez, Arzneim.-Forsch.21, 248 (1971). Percutaneous absorption by rats and rabbits: W. H. Down et al.,Toxicol. Lett.1, 95 (1977). Clinical study: D. J. Tazelaar, J. Int. Med. Res.5, 338 (1977). HPLC analysis: S. Muck et al.,Boll. Chim. Farm.120, 240 (1981). For structure see Triamcinolone Acetonide.

Properties: Crystalline powder, mp 203-207°. [a]D20 +96 ±3° (c = 1 in ethanol). Sol in methanol, acetone, ethanol, dioxane, pyridine, DMF, chloroform. Insol in water.

Melting point: mp 203-207°

Optical Rotation: [a]D20 +96 ±3° (c = 1 in ethanol)

Therap-Cat: Glucocorticoid; anti-inflammatory (topical).

Keywords: Glucocorticoid

////////////////////////

Triamcinolone Hexacetonide

CAS Registry Number: 5611-51-8

CAS Name: (11b,16a)-21-(3,3-dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione

Additional Names: 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone, 21-(3,3-dimethylbutyrate); 21-tert-butylacetate-9a-fluoro-11b-hydroxy-16a,17a-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione; 21-(3,3-dimethylbutyryloxy)-9a-fluoro-11b-hydroxy-16a,17a-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione; triamcinolone acetonide tert-butyl acetate; TATBA

Manufacturers’ Codes: CL-34433

Trademarks: Aristospan (Fujisawa); Hexatrione (Lederle); Lederlon (Lederle); Lederspan (Lederle)

Molecular Formula: C30H41FO7, Molecular Weight: 532.64

Percent Composition: C 67.65%, H 7.76%, F 3.57%, O 21.03%

Literature References: The hexacetonide ester of the potent glucocorticoid, triamcinolone, q.v. Prepn of syringeable suspension: Nash, Naeger, US3457348 (1969 to Am. Cyanamid). Anti-inflammatory activity in rabbits: I. M. Hunneyball, Agents Actions11, 490 (1981). Early clinical studies: Bilka, Minn. Med.50, 483 (1967); Layman, Peterson, ibid. 669. Clinical studies of intra-articular therapy in arthritis: R. C. Allen et al.,Arthritis Rheum.29, 997 (1986); M. Talke, Fortschr. Med.104, 742 (1986). Toxicity study: Tonelli, Steroids8, 857 (1966). Comprehensive description: V. Zbinovsky, G. P. Chrekian, Anal. Profiles Drug Subs.6, 579-595 (1977). For structure see Triamcinolone Acetonide.

Properties: Fine, white, needle-like crystals, mp 295-296° (dec), also reported as mp 271-272° (dec). uv max (ethanol): 238 nm (e 15500). [a]D25 +90±2° (c = 1.13% in chloroform). Soly in g/100 ml at 25°: chloroform and dimethylacetamide >5; ethyl acetate 0.77, methanol 0.59, diethyl carbonate 0.50, glycerin 0.42, propylene glycol 0.13; absolute alcohol 0.03; water 0.0004.

Melting point: mp 295-296° (dec); mp 271-272° (dec)

Optical Rotation: [a]D25 +90±2° (c = 1.13% in chloroform)

Absorption maximum: uv max (ethanol): 238 nm (e 15500)

Therap-Cat: Anti-inflammatory.

Keywords: Glucocorticoid.

Product Ingredients

Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues.

Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others.[6] It is also used to prevent worsening of asthma and COPD.[6] It can be taken in various ways including by mouth, injection into a muscle, and inhalation.[6]

Common side effects with long-term use include osteoporosiscataractsthrush, and muscle weakness.[6] Serious side effects may include psychosis, increased risk of infections, adrenal suppression, and bronchospasm.[6] Use in pregnancy is generally safe.[7] It works by decreasing inflammation and immune system activity.[6]

Triamcinolone was patented in 1956 and came into medical use in 1958.[8] It is available as a generic medication.[9] In 2019, it was the 107th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[10][11]

PATENT

Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Skin diseases are the medical condition that affects the skin, hair, nails and related muscle and glands.

Skin disorders vary greatly in symptoms and severity. They can be temporary or permanent, and may be painless or painful. Some have situational causes, while others may be genetic. Some skin conditions are minor, and others can be lifethreatening.

There are many different types of skin disorders which include rashes, dermatoses or skin eruptions. Such rashes, dermatoses or skin eruptions include acute, inflammatory reactions of the skin caused by an allergic or irritant reaction, other forms of eczema, lichen simplex chronicus. Chronic nature includes seborrheic dermatitis, psoriasis, and atopic dermatitis or caused by infection, irritation or aggravation of another condition such as occurs with acne, other rashes, dermatoses or skin eruptions, inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, contact dermatitis, impetigo, urticarial and scabies.

Typical symptoms of the skin disorders include but not limited to raised bumps that are red or white, a rash, which might be painful or itchy, scaly or rough skin peeling skin, ulcers, open sores or lesions, dry, cracked skin, discolored patches of skin, fleshy bumps, warts, or other skin growths, changes in mole color or size a loss of skin pigment, excessive flushing or the like.

Atopic dermatitis (AD), also known as eczema or atopic eczema, is a type of inflammation of the skin (dermatitis). Atopic dermatitis (AD) is common worldwide. People of all ages from newborns to adults and older live with this condition. Symptoms range from excessively dry, itchy skin to painful, itchy rashes that cause sleepless nights and interfere with everyday life.

Topical corticosteroids have been the mainstay of treatment for atopic dermatitis over the past years, further the cure for atopic dermatitis involves Lifestyle modification, balanced diet intake, self-care measures, phototherapy, wet wrap therapy, use of medications like tacrolimus, pimecrolimus, crisaborole, dupilumab, ciclosporin, methotrexate, interferon gamma- lb, mycophenolate mofetil, and azathioprine or the like.

Triamcinolone Acetonide is a synthetic corticosteroid. Chemically it is [Pregna-1, 4-diene-3, 20-dione, 9-fluoro-l l, 21 -dihydroxy- 16, 17-[(1 methylethylidene) bis-(oxy)]-, (HP, 16a)-] with the empirical formula C24H31FO6 and molecular weight 434.50. Triamcinolone Acetonide is represented by compound of structural formula I

Triamcinolone Acetonide topical cream and ointment with strengths 0.025%, 0.1% and 0.5% (containing 0.25 mg/gm, 1 mg/gm & 5 mg/gm Triamcinolone Acetonide respectively) were approved in USA prior to Jan 1, 1982 under the trade name “Triamcinolone Acetonide” and were indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.

The commercially available products or product known in the prior art produces side effects such as burning, itching, irritation, or dryness of skin at site of application, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria.

Pediatric patients may demonstrate greater susceptibility to topical triamcinolone -induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic -pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome and intracranial hypertension have been reported in children receiving topical triamcinolone. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Chronic corticosteroid therapy may interfere with the growth and development of children.

Making low dose compositions can present technical and economic challenges that are not present for higher dose formulations.

Examples

The following table 1 shows cream formulation containing lOO.OOmcg per gm, 50.00mcg per gm and 25.00mcg per gm of Triamcinolone Acetonide

Table – 1: cream

Drug Strength IQOmcg/gm 50mcg/gm 25mcg/gm

lOO.OOmcg per gm and for lOOgm, it is lO.OOmg*

50.00mcg per gm and for lOOgm, it is 5.00mg*

25.00mcg per gm and for lOOgm, it is 2.50mg**

Manufacturing process:

a) Dispensing following excipients – isopropyl myristate, glyceryl monostearate and white soft paraffin in vessel I;

b) Dispensing the following excipients – polysorbate 40 and purified water in vessel II;

c) Dispensing the following excipients methyl paraben, propylene glycol in vessel III; wherein methyl paraben is dissolved in propylene glycol to form a clear solution;

d) Dispensing the following active & excipients triamcinolone acetonide or salt thereof, propylene glycol in vessel IV; wherein triamcinolone acetonide or salt thereof is dissolved in propylene glycol to form clear solution;

e) Adding content of step (c) into content of step (b) and stirring to form uniform and homogeneous emulsion;

f) Heating content of step (b) and step (a) at about 75 °C and stirring to form a homogenous uniform emulsion;

g) Cooling the above emulsion gradually to temperature of about 25 °C – 30°C h) Adding the content of step (d) to the primary emulsion of (f) with constant stirring; and

i) Making up the volume of the emulsion with purified water to the required quantity.

SYN

DOI: 10.1021/ja01516a043

CLIP

## Corticosteroids

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

### Triamcinolone

Triamcinolone, 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1, 4-dien-3,20-dione (27.1.61), differs from dexamethsone in terms of chemical structure in that the a methyl group at C16 is replaced with a hydroxyl group. It is synthesized from the 21-O-acetate of hydrocortisone 27.1.17. In the first stage, both carbonyl groups of this compound undergo ketalization by ethylene glycol. Next, the hydroxyl group in the resulting diketal 27.1.53 is replaced with chlorine using thionyl chloride, and the product undergoes dehydrochlorination using an alkaline, during which the 21-O-acetyl group also is hydrolyzed. Acetylating the hydroxyl group once again with acetic anhydride gives a triene 27.1.54. Reacting this with osmium tetroxide gives the vicinal diol 27.1.55. The secondary hydroxyl group at C16 of this product undergoes acetylation by acetic anhydride in pyridine, which forms the diacetate 27.1.56. Treating the product with N-bromoacetamide in chloric acid gives a bromohydrin (27.1.57), which upon reaction with potassium acetate is transformed to an epoxide (27.1.58). Opening of the epoxide ring, using hydrofluoric acid, gives the corresponding 9-fluoro-11-hydroxy derivative 27.1.59. Upon microbiological dehydrogenation, the C1–C2 bond is oxidized to a double bond, forming triamcinolone acetate (27.1.60), the acetyl group of which is hydrolyzed, forming the desired triamcinolone (27.1.61) [30–32].

Triamcinolone is similar to dexamethasone in terms of pharmacological action, and it is better tolerated in some cases. Synonyms of this drug are ledercort, cenocort, delsolon, and others.

SYN

## Drugs for Treating Respiratory System Diseases

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

### Triamcinolone–Nasacort

The synthesis of triamcinolone (23.2.1) starts from ketalization of cortisol 21-acetate (23.2.8) using ethylene glycol. Dehydration of the obtained compound (23.2.9) for creation of a double bond in position 16,17 of the steroid skeleton through the series of sequential reactions of chlorination, dehydrochlorination, hydrolysis, and acetylation produces 21-acetoxy-4,9(11),16-pregnatriene-3,20-dione (23.2.10), treatment of which with osmium tetroxide in benzene and pyridine produced diol (23.2.11), the secondary hydroxyl group of which, in position 16, was acetylated with acetic anhydride in pyridine to produce the diacetate (23.2.12). The obtained compound in dioxane and water was treated with N-bromoacetamide and 10% perchloric acid to yield bromohydrine (23.2.13). Dehydrobromination of the bromohydrine (23.2.13) with anhydrous potassium acetate in refluxing ethanol produced the epoxy-derivative (23.2.14). Opening of the epoxide ring in (23.2.14) with anhydrous hydrogen fluoride in chloroform produced (23.2.15). Microbiological dehydrogenation of the obtained product with Corynebacterium simplex produced crude diacetate (23.2.16), saponification of which produced triamcinolone (23.2.1) [108-110] (Scheme 23.7.).

Scheme 23.7. Synthesis of triamcinolone.

Triamcinolone is commonly used in the treatment of respiratory inflammation and improves airway reactivity, decreasing respiratory problems. Strangely, there are only few reviews of the pharmacotherapy of triamcinolone [111-113].

SYN

SYN

Glucocorticoids have a number of diverse effects in different body tissues. Glucocorticoids, in topical, oral and inhaled formulations, are useful for their anti-inflammatory and immunosuppressive properties. Several glucocorticoids such as budesonide and ciclesonide are used for treatment of several disorders.

The synthesis and purification of glucocorticoids have been disclosed at different instances. However, most of these synthetic procedures involve toxic solvents or long reaction times and are ineffective for large scale synthesis. For instance, US 3,92,9768 discloses a process for preparation of budesonide by reacting 16, 17-dihydroxy compound with aldehyde in solvents such as dioxane, methylene chloride or their combinations.

DE 4129535 discloses a process for the synthesis of Ciclesonide which involves the intermediate 16A, 17-[(7?,S)-cyclohexylmethylenedioxy]-l 13, 21-dihydroxy-pregna-l 4- dien-3,20-one which is obtained by an acid catalysed reaction of 11 , 16 , 17, 21-tetra hydroxypregna-l,4-dien-3,20-one with cyclohexane aldehyde.

WO 02/38584 discloses the synthesis of Ciclesonide by reacting corresponding 16, 17-ketals with a cyclohexane aldehyde in the presence of 70% perchloric acid, 1-nitropropane as solvent. However, perchloric acid is a dangerous solvent and can cause serious accidents with fatal consequences.

US Patent No. 6169178 relates to a process for the preparation of budesonide and of 16, 17- acetals of pregnane derivatives structurally co-related thereto comprising treating 16, 17-dios or of 16, 17-ketals or cyclic acetals with aldehydes in the presence of aqueous hydrobromic acid or hydroiodic acid used as reaction catalyst or solvents. However, hydroiodic and other hydrohalic solvents are corrosive, light sensitive and expensive. Further, these acids also post environmental problems. Notwithstanding the use of hydrohalo acids requires use of special equipment since they are extremely corrosive and consequently increase the cost of production.

US 5,55,6964 discloses a process for the preparation of budesonide by reacting 16 – Hydroxy Prednisolone in acetonitrile in the presence of /^-toluene sulfonic acid as a catalyst. There are certain other patents that use alkyl sulfonic acid instead of aryl sulfonic acid for the synthesis of budesonide or similar compounds. However, sulfonic acids are hazardous solvents and FDA has expressed significant concern over the presence or traces of sulfonic acid in pharmaceutical products. Hence, there is a need to have a process for the synthesis 16, 17- acetals of pregnane compounds that is industrially scalable and which does not involve the use of harmful solvents.

Example- 1: Process for preparation of 16-HPN from 3TR

Stage-I

Stage- 1 Stage-I I

Stage-IV

1 6-HPN acetate 1 6-HPN

Scheme 2: Synthesis of 16HPN from 3TR

Stage-I (oxidation)

Charge 750L of acetone (50 volume), 39L of purified water (2.60 volume) and 15 Kg of 3TR (40.93mol) in a SS Reactor at ambient temperature. Cool to -7°C to -5°C than added 6.0L of formic acid (159.03 mol) and 9.0 kg of potassium permanganate (56.95 mol). Maintain at – 5°Cto -3°C for 30 minutes. In-process check by TLC, 3TR should be less than 1.0%. Added 1.5kg sodium metabisulphite (7.89 mol solution in 12L of purified water at -5°C to -3°C then added 3.0 kg of hyflow super cell at 15°C (+2°C) and filter through 10.0 kg of hyflowbed at 27°C(+3°C) and wash with 150L of acetone Added 1.5 kg of activated charcoal, Stir and filter through hyflow bed and wash with 60L of acetone. Total filtrate was distilled under reduced pressure, while maintaining temperature below 45°C. Added 81L of purified water and cool to 5°C+5°C. Filter through centrifuge and wash with 156L of purified water. Wet material is dry at 60°+5°C till moisture less than 0.50%, Yield=15 kg, HPLC purity=98%.

Stage-II (Bromination)

Charge 75L of tetrahydrofuran, 16L of purified water and 15.0 kg of Stage-I (37.46 mol) in a glass reactor. Cool to -6°C (+2°C) and added 7.50 kg of dibromantin (26.23 mol) and 0.60L of perchloric acid (9.38 mol) and maintain at -6°C (+2°C) for one hour. In-process check by TLC, stage-I should be less than 0.50%. Reaction mass is quench in 390L of purified water at ~5°C. Raised the temperature to 25°C and maintained for 01 hour, filter through centrifuge and wash with 828L of purified water or till neutral pH. Wet material is dry at 40°C+5°C till moisture content should be less than 10%, Yield=21.0kg, HPLC purity=97%.

Stage-Ill (Debromination)

Charge 68.0L of N, N-dimethyl formamide(3.238volume) and 21.0kg of stage-II (42.22 mol) in glass reactor, start argon gas purging and cool to -5°C. Charge 13.0L of N,N- dimethylformamide (0.619volume) , 9.70L of dimethylsulfoxide(0.462volume), 1.62kg of chromium chloride hexahydrate (6.51 mol) and 1.94 kg of zinc dust (0.703 mol). Cool to – 10°Cand added 5.50L of thioglycolic acid (79.21 mol). Maintain for one hour while maintaining temperature around -10°C. In-process check by TLC, stage-II should be less than 1.0%. Added 310 L of purified water and cool to 0°C. Filter through centrifuge and wash with 1600L of purified water. Wet material is dry at 60°C+ (5°C) till moisture content less than 6.0%, Yield=15.0kg, HPLC Purity=90%.

Charge 150L of methylene chloride (10 volume), 150L of methanol (10 volume.) and 15.0kg (30.16 mol) of stage-Ill in a SS Reactor. Heat to clear solution then added 3.0 kg of activated charcoal (20%) and reflux for 04 hours, Filter through hyflow bed and wash with 75L of methylene chloride (5 volume), and 75L of methanol (5 volume) mixture. Total filtrate is distilled till last drop and added 75L (5 volume) of methylene dichloride, reflux for 04 hours than cool to 40°C+(5°C), Filter through centrifuge and wash with 15L (one volume) of methylene chloride. Wet material is dry at 60°C (+5°C) till moisture contents less than 1.0% (Yield =13.0kg, HPLC Purity=96%). Further charge 65.0L (5volume) of ethyl acetate and 13.0 kg (1.0 mol) of purified material. Heat to reflux and maintain for 04 hours under reflux, then cool to 40°C. Filter through centrifuge and wash with 13.0L (one volume) of ethyl acetate. Wet material is dry at 60°C (+5°C) till moisture contents less than 0.50%, Yield=12.0kg, HPLC Purity=98.6%.

Stage-IV (Deacetylation)

Charge 5.83L of methanol (10 volume) and 5.83L of methylene chloride (10 volume) in a glass flask and added 583 gm of 16-HPN acetate(1.397mol) at RT. Start argon gas purging and cool to 0°C to 5°C under argon purging. Prepare 11.66 gm of sodium hydroxide (0.2915mol) solution in 0.583L of methanol (one volume) under argon purging and cool to 0°Cto 5°C. Sodium hydroxide solution is charge in reaction mass at 0°C to 5°C. Maintained the reaction mass at 0°C to 5°C for one hour, In-process check by TLC against 16-HPN acetate it should be nil. Adjust pH to neutral by 21.40ml of acetic acid (0.3742 mol); distill under reduced pressure while maintaining temperature below 40°C, till dry. Cool to ambient temperature and added 1.166L of purified water (02 volume). Cool to 0°C and maintain for one hour. Filter and wash with 300ml of purified water. Dry at 60°C (+5°C) till moisture content less than 1.0%, Yield=490gm (93.50%), HPLC Purity=98.97%, Single impurity= 0.40%. Example 2: Process of synthesis of Budesonide from 16-HPN

16-HPN Budesonide

Charge 800 ml of aqueous hydrochloric acid (8 volume) in a glass flask, start nitrogen gas purging and Cool to -5°C and maintain for 15 min. then added 100 gm of stage-I (0.27 mol) at -5°C and stir for 15 min., added 30 ml of N-butyraldehyde (0.33 mol) while maintaining temperature -5°C to 0°C in around 30 minutes and maintain at 0°C to 5°C for 150 min. under stirring. In-process check by TLC against stage-I, it should be nil. Reaction mass is quench in 1200 ml of purified water (12 volume) at 5°C to 10°C and stir for 15 min. Added solution of 100 kg of sodium bicarbonate (1.19 mol) and 1 ml of purified water (10 volume) in reaction mass at 5°C to 10°C. Stir at 5°C to 10°C for 15 min. Filter and wash with purified water till neutral pH. Wet material is dry at 50°C (+5°C) till moisture contents less than 1.0 %, Yield =110 gm (96.49%), HPLC purity=96.45%, single impurity=1.29%, Epimer-A=47.76%, Epimer-B=49.69%.

(Purification)

Charge 2.5 L of methanol (25 volume) in a Glass flask and added 100 gm of above mentioned crude product. Dissolved at 25°C+5°C till clear solution, added 10 gm of activated charcoal and stir for 30 min. than filter through hyflow bed and wash with 200 ml of methanol (2 volume). Combined filtrates charged in a Glass flask and cool to 10°C to 15°C and added 5.40 L of purified water (54 volume) at 5°Cto 10°C, stir for 15min., filter and wash with purified water. Wet material is dry at 50°C (+5°C) under vacuum till moisture content less than 0.50%, Output=90.0gm, HPLC purity=99.66%, single impurity=0.1%, Epimer-A=44.47%, Epimer-B=55.01%.

Example 2.1: Scale-up process of manufacturing of Budesonide from 16-HPN

Charge 40 L of aqueous hydrochloric acid (8 volume) in a glass flask, start nitrogen gas purging and Cool to – 10°C and maintain for 15 min. then added 5.0 kg of stage-I (13.315 mol) at – 10°C and stir for 45 min. added 1.5 L of N-butyraldehyde (16.68 mol) while maintaining temperature -7°C to – 11°C in around 30 minutes and maintain at -2°C to -6°C for 60 min. under stirring In-process check by TLC against stage-I, it should be nil. Reaction mass is quench in 60 L of purified water (12 volume) at 5°C to 10°C and stir for 15 min. Added solution of 5.0 kg of sodium bicarbonate (59.525 mol) and 50L of purified water (10 volume) in reaction mass at 5°Cto 10°C. Stir at 5°C to 10°C for 15 min. Filter and wash with purified water till neutral pH. Wet material is dry at 50°C (+5°C) till moisture contents less than 1.0 %, Yield =5.293 kg (94.46%), HPLC purity=95.45%, single impurity=1.45%, Epimer-A=53.51 %, Epimer-B=43.78% Effect of temperature and its variation on epimer ratio (A and B) with respect to batch size (From lab to commercial batch)

Example 3: Process for synthesis ofCiclesonide from 16HPN

Preparation of cyclohexane carboxaldehydemetabisulphite complex

200gm of Cyclohexane carboxaldehyde (1.786 mol) was dissolved in 3.0L of denatured sprit (15 volume) and a solution of 190gm of sodium metabisulphite (1.827 mol) in 300ml of purified water (1.5 volume) was added. The resulting precipitate was filtered and washed with 1.0L of denatured sprit(5.0 volume) and dried under vacuum at 50°C, till moisture content less than 6.00%, Yield=400gm (97 %)

Stage I: Preparation of stage-I from 16-HPN

Cyclohexane carboxaldehyde

sodium metabisulphite complex

170gm of 16-HPN (0.4528 mol) was suspended in 3.40L of dichloromethane (20 volume) and treated with 340ml of 70% perchloric acid. (5.65 mol) and 110.5gm of cyclohexane carboxaldehyde metabisulphite complex (0.512 mol) was added in lots while maintaining the temperature between 0°Cto 5°C. The reaction mass was stirred at 0°C to 5°C for 03 hours. In- process check by TLC 16-HPN should be nil and then neutralized with 10% aqueous sodium bicarbonate solution. The organic layer was separated and concentrated under vacuum to obtain a residue which was stripped with methanol (1.0 volume). The solvent was concentrated and the residue was dissolved by refluxing in methanol (5.0 volume). The clear solution was cooled to 0°C to 5.0°C and the resulting solid was filtered and dried at 50°C till moisture content less than 0.50%, Yield=170.0gm (80.0%), HPLC purity=91.68%.

Stage -II Preparation of Ciclesonide from Stage -I

Stage-I Ciclesonide

158gm of stage-I (0.34mol) was suspended in 1.58L of methylene chloride (10.0 volume) at 25°C to 30°C. The reaction mass was chilled to 0°C to 5°C and 81.0ml of triethylamine(0.581 mol) was added, followed by the addition of 79.0ml of isobutyryl chloride [0.75 mol; diluted with 79.0 ml of methylene chloride (0.50 volume)] slowly at 0° to 5°C and maintained at same temperature for 60min. In-process check by TLC, Stage-I should be nil. The reaction mass was diluted with 2.53L of purified water (16.0 volume) , the organic layer was separated and washed with purified water till neutral pH, than organic layer was separated and concentrated under vacuum to obtained a residue. The residue was dissolved by refluxing in 948ml of methanol (6.0 volume); the clear solution was cooled to 0°C to 5°C under stirring and filtered. The product was dried under vacuum at ~50°C till moisture contents comes less than 0.50%, Yield=158.0 gm (87.0%), HPLC purity=95.74%.

(Purification)

120gm of Ciclesonide crude was dissolved by refluxing in 600ml of methanol. The clear solution was chilled to 20°C under stirring and filtered. The product was dried under vacuum at 90°C till moisture content less than 0.50%. Yield=105 gm (87.50%), HPLC purity=99.7 %.

Example 4: Process for synthesis of Desonide from 16HPN acetate

Stage-I : Preparation of Desonide acetate from 16 HPN acetate

Desonide acetate

16HPN acetate 190.0 ml of acetone (7.0 volume) was charged in a glass flask under nitrogen blanketing than added 27 gm of 16HPN acetate (0.0645mol) at ambient temperature. Temperature raised to 28°C (+2°C) and stir for 20 minutes. 1.35 ml of perchloric acid 70% (0.02 lmol) was added at 28°C (+2°C) and stir for 30 minutes. Temperature further raised to 35°C and stir for 60 minutes. In-process check by TLC against 16HPN acetate, it should be nil. Reaction mass cooled to 10°C, filtered and washed with purified water till neutral pH (~7) and finally washed with acetone. Wet material dried at 50°C+5°C till moisture content less than 0.50% to get stage-I. Yield =23gm (77.76%), HPLC Purity=98.28%

Stage-II: Preparation of Desonide from Desonide acetate

Desonide

Desonide acetate

200 ml of methanol (10 volume) and 200ml of methylene dichloride (10 volume) was charged in a glass flask and start argon gas purging. 20 gm of stage- 1st (0.0436mol) was added at ambient temperature. Cool to 0°C+5°C. 0.40gm of sodium hydroxide (O.Olmol) solution in 20ml of methanol (l.Ovolume) was added at 0°C+5°C. Stir at 0°C+5°C for 120 minutes. In-process check by TLC against stage- 1st it should be nil. Adjust pH to neutral (~7) by 2.0ml of acetic acid at 0°C+5°C. Distilled the solvent from reaction mass under vacuum while maintaining temperature below 40°C till the volume get reduced to 3 to 4 volume of the input. Cool to 0°C and further added 60ml of purified water and stir for 30 minutes. Filtered, washed with purified water till neutral pH (~7). Wet material dried at 50°C+5°C till moisture content less than 0.50% to get crude Desonide. Yield =14.70gm (80.92%), HPLC Purity=88.15%.

(Purification)

140 ml of methanol (10 volume) and 140 ml of methylene chloride (10 volume) was charged in a glass flask and added 14.0 gm of crude material (0.034mol) than stir till clear solution. Added 1.5 gm of activated charcoal and stir for 30 minutes than filtered through hyflow supercel bed and washed with 30ml of methanol and 30ml of methylene chloride mixture. Combined filtrate and distilled the solvent from reaction mass under vacuum while maintaining temperature below 40°C till the volume reduced to 3 to 4 volume of the input. Cool to 0°C. Filtered the reaction mass and washed with 10ml of precooled methanol. Wet material was dried at 50°C+5°C till moisture content less than 0.50% to get Desonide. Yield=8.60gm, HPLC Purity= 99.43%

lOOgm of 3TR (0.27 mol.)was suspended in 1300ml (13 volume) acetone. Cooled it to -5°C to -10°C than added 4.0 ml (0.062 mol.) perchloric acid solution and 50gm of dibromantin. Maintained the reaction at same temperature for 02 hours. In-process check by TLC against 3TR it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol.) in 5 lots and reaction was maintained at 35°C+2°C. In-process check by TLC against step-I reaction mass, it should be nil. Cooled to 0°C (+5°C) and adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol.). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C (+2°C) till moisture content less than 0.50%. Yield =87gm, (83.36%), HPLC Purity=97.883%.

Stage – II:

80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C (+2°C) than added 32ml of formic acid (0.85 mol.) and 48gm of potassium permagnate (0.30 mol.) at -5°C (+2°C). Reaction was maintained at – 5°C+2°Cfor one hour. In-process check by TLC against stage-I it should be nil. Added 8gm of sodium metabisulphite (0.042 mol.) In 80 ml purified water (01 volume) solution at -5°C (+2°C). Temperature raised up to 27°C and filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4volume of stage-I than cool to 0°C to 5°C and added 480ml of purified water stir and filter and washed with purified water to get wet stage-II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0%. Yield =78.30gm, (89.88%), HPLC Purity=99.178%. Stage -III:

Stage-ll Stage-

300ml of hydrofluoric acid (12.60mol) was cooled at -25°C to -30°C than added 75gm of stage-II (0.180mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II, it should be nil. Reaction mass was cooled to -50°C than added 45ml of acetone (0.60volume) at -45°C to -50°C. Reaction was maintained at -45°C to -50°C for 02 hours. In-process check by TLC against before acetone reaction mass. Added 565ml of purified water at 0°C and 340ml of liq. ammonia at ~20°C than reaction mass was quenched in 410ml of liq. ammonia and 735ml of purified water solution at 15°C (+2°C), stir and filter and washed with purified water till neutral pH. Wet material was dried at 45°C to 50°C, Yield =78.50gm, (91.48%), HPLC Purity=91.593%.

(Purification)

76 gm of stage-Ill Crude (0.16 mol.) was dissolved in 760ml of methylene chloride (lOvolume) and 760ml of methanol (lOvolume) mixture at ambient temperature. Stir till clear solution and added 7.6gm of activated charcoal (0. lOvolume) than stir for 30minutes, filter through hyflow bed and washed with methanol (one volume) and methylene chloride (one volume) mixture. Total filtrate was distilled under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°C and stir for 02 hours. Filtered and washed with minimum precooled methanol, Wet material was dried 45°C to 50°C till moisture contents less than 0.50%, Yield=62gm, HPLC Purity=98.633%.

Stage – IV (Process for synthesis of Triamcinolone acetonide from Stage – III):

Stage- Ill Triamcinolone acetonide

60gm of stage-Ill (0.13 mol) was dissolved in 600ml of methanol (lOvolume) and 600ml of methylene chloride (lOvolume) mixture under argon bubbling. Cool to -5°C+2°C and added 1.2gm of sodium hydroxide (0.03mol.) solution in 60ml of methanol (Olvolume) at -5°C (+2°C). Reaction maintained at -5°C (+2°C) for 03 hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral (~7) by adding 1.8ml of acetic acid at -5°C (+2°C). Reaction mass was distilled at below 40°C under vacuum till 3 to 4 volume of input. Cool to 30°C and added 120ml of purified water, stir for one hour than filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°C till moisture content less than 0.50%, Yield =52gm, (95.04%), HPLC Purity=99.21%

(Purification)

50gm of crude material (0.12 mol.) was dissolved in 1100ml of acetone (22volume) and 100ml of purified water (02volume) at 50°C than added 2.5gm of activated charcoal and stir for one hour at same temperature, Filter through hyflow bed and washed with 120ml of acetone (2.40volume). Filtrate was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°Cand maintained for one hour at same temperature. Filter and washed with water. Wet material was dried at 45°C to 50°C till moisture content less than 0.50%, Yield=43gm, HPLC Purity=99.40%.

Example 6: Process for synthesis of Flunisolide from 16HPN acetate Stage -I (Preparation of Desonide acetate from 16HPN acetate):

1 6 H PN acetate eson e acetate

140ml of acetone (7 volume) was charged in glass flask and start argon blanketing than added 20 gm of 16-HPN acetate (0.048mol) at ambient temperature. Cooled to 28°C (+2°C). 1.0ml of perchloric acid 70% (0.016mol) was added at 28°C (+2°) C and stirred for 30 minutes. Temperature raised up to 35°Cand stirred for 60 minutes. In-process check by TLC against 16-HPN acetate, it should be nil. Reaction mass was cooled to 10°C (+2°C). Reaction mass was filtered and washed with purified water till neutral pH (~7) to get wet material. Wet material was dried at 50°C+5°C till moisture content less than 0.50% to get stage-lst. Yield=17.40gm, (79.40%), HPLC Purity=98.241%.

Stage -II (Preparation of Desonide from Desonide acetate):

170ml of methanol (lOvolume) and 170ml of methylene chloride (lOvolume) was charged in a glass flask and start inert atmosphere. 17gm of stage-lst (0.037mol) was added at ambient temperature. Cooled to -5°C. 0.4gm of sodium hydroxide (O.Olmol) solution in 17ml of methanol was added at 0°C (+5°C). Reaction mass was stirred for 02 hours at 0°C (+5°C). In- process check by TLC against stage- 1st it should be nil. Neutral pH (~7) was adjusted by acetic acid. Reaction mass was distilled under vacuum at below 40°C till ~ 100ml. Concentrated mass was cooled to 0°C (+5°C) and stir for one hour. Reaction mass was filtered and washed with precooled methanol to get wet material. Wet material was dried at 50°C (+5°C) till moisture content less than 0.50% to get stage-2nd. Yield=14.0gm, (90.67%), HPLC Purity=99.426%, Single impurity=0.136%.

Stage -III (Preparation of Flunisolide acetate from Desonide):

Desonide Flunisolide acetate

50ml of isopropenyl acetate (5 volume) was charged in a glass flask and added lOgm of stage-2nd (0.024mol) at ambient temperature than heated to 65°C and added 1.5ml of methane sulphonic acid (0.023mol) and temperature raised up to 80°C and stir for one hour. In-process check by TLC against stage-2, it should be nil. Reaction mass cooled to 25°C and adjust pH neutral (~7) by triethylamine. Reaction mass was distilled under vacuum till last drop and degases with acetonitrile. 90ml of acetonitrile (09 volume) was added and cooled to -5°C and than further added 10ml of purified water. lOgm of selectfluor(0.028mol) was added in two lots at 0°C(+5°C) in 02 volume of acetonitrile. Reaction mass was stirred at 10°C to 15°C for 12 hours. In-process check by TLC against before selectfluor reaction mass it should be nil. Adjust pH neutral (~7) by liq. ammonia solution at 0°C+5°C. Reaction mass was quenched in 500ml of purified water (lOOvolume) at ambient temperature. Reaction mass was filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C+5°C till moisture content less than 0.50% to get stage-3rd. Yield=8.60gm, (75.17%), HPLC Purity= 94.12%.

Stage -IV (Preparation of Flunisolide from Flunisolide acetate):

Flunisolide acetate Flunisolide

80ml of methanol (lOvolume) and 80ml of methylene chloride (lOvolume) was charged in a glass flask under inert atmosphere at ambient temperature than added 8.0gm of stage-3r (0.017mol) at ambient temperature. Cooled to -5°C and added 0.16gm of sodium hydroxide (0.004mol) solution in 8ml of methanol at -5°C(+5°C) and stir for 02 hours at -5°C(+5°C). In-process check by TLC against stage-3 ‘ it should be nil. Adjust pH neutral(~7) by acetic acid and reaction mass was distilled under vacuum at below 40°C(+5°C) till ~40ml of volume. Cool to 0°C to 5°C and stir for one hour. Reaction mass was filtered and washed with precooled methanol to get wet material. Wet material was dried at 45°C (+5°C) till moisture content less than 0.50% to get Flunisolide crude. Yield=6.0gm, (82.30%), HPLC Purity=86.50%.

(Purification)

6.0gm of crude Flunisolide(0.014mol) was dissolved in 65ml of ethyl acetate (10.83volume) and 35ml of n-hexane (5.83volume) mixture and clear solution was passed through 60gm of silica gel column. Column was washed with 975ml of ethyl acetate (162.5volume) and 525ml of ft-hexane (87.5volume) mixture. Eluted fraction was distilled under vacuum till 3 to 4 volume of input than cooled it to 0°C and filter to get wet material. Wet material was dried at 50°C (+5°C) till moisture content less than 0.50% to get Flunisolide. Yield=4.28gm, HPLC Purity=95.60%.

Example 7: Process for synthesis of Triamcinolone from 3TR

S

lOOgm of 3TR (0.27mol) was suspended in 1300ml (13 volume) acetone. Cool to -5°C to- 10°C than added 4.0 ml (0.062mol) perchloric acid solution and 50gm of dibromantin. Reaction maintained at same temperature for 02 hours. In-process check by TLC against 3TR, it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol) in 5 lots and reaction was maintained at 35°C (+2°C). In-process check by TLC against step-I reaction mass, it should be nil. Cool to 0°C+5°Cand adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C (+2°C) till moisture content less than 0.50% to get stage-I. Yield=85.30gm, (81.74%), HPLC Purity=96.54%. Stage -II:

80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C (+2°C) than added 32ml of formic acid (0.85 mol.) and 48gm of potassium per magnate (0.30 mol) at -5°C (+2°C). Reaction was maintained at same temperature for one hour. In-process check by TLC against stage-I, it should be nil. Added sodiummetabisulphite solution (8 gm in 80 ml of water) at -5°C+2°C. Temperature was raised up to 27°C and filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4 volume of stage-I than further cooled to 0°C to 5°C and added 480ml of purified water, stirred, filter and washed with purified water to get wet stage- II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0% to get stage-II. Yield=82gm, (94.13%), HPLC Purity=97.75%.

Stage -III:

Stage-II Triamcinolone acetate

160ml of hydrofluoric acid (70%) (6.72mol) was cooled at -25°C to -30°C than added 40gm of stage-II (0.096mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II, it should be nil. Added 280ml of purified water at 0°C and 650ml of liq. ammonia at 20°C than reaction mass was quenched in 200ml of liq. ammonia and 500ml of purified water solution at 15°C(+2°C), stirred, filtered and washed with purified water till neutral pH(~7). Wet material was dried at 45°C to 50°C to get stage-Ill Yield=40gm, (95.42%), HPLC Purity=88.71%

(Purification)

40gm of stage-Ill crude (0.0916 mol) was refluxed in 160ml of acetone. Cool to 0°C. Filtered and washed with minimum precooled acetone. Wet material was dried at 50°C+5°C till moisture content comes less than 0.50% to get stage-Ill. Yield=24.9gm HPLC Purity=95.17%.

24gm of stage-Ill (0.055mol) was dissolved in 240ml of methanol (lOvolume) and 240ml of methylene chloride (lOvolume) mixture under argon bubbling. Cool to -5°C+2°C and added 0.48gm of sodium hydroxide (0.012mol) solution in 24ml of methanol (Olvolume) at – 5°C+2°C. Reaction was maintaining at -5°C (+2°C) for 03hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral by adding 0.70ml of acetic acid at -5°C (+2°C). Reaction mass distilled at below 40°C under vacuum till 04-05 volume of input. Cooled to 0°C+5°Cand stir for one hour than filtered and washed with minimum precooled methanol. Wet material was dried at 45°C to 50°C till moisture content less than 0.50%. Yield=18.50gm, (85.29%), HPLC Purity=98.60%.

Example 8: Process for synthesis of Triamcinolone Hexacetonide from 3TR

S

lOOgm of 3TR (0.27288 mol) was suspended in 1300ml (13 volume) acetone. Cool to -5°C to -10°C than added 4.0 ml (0.0625 mol) perchloric acid solution and 50gm of dibromantin. Reaction was maintained at same temperature for 02 hours. In-process check by TLC against 3TR, it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol) in 5 lots and reaction was maintained at 35°C (+2°C). In-process check by TLC against step-I reaction mass, it should be nil. Cool to 0°C (+5°C) and adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH. Wet material was dried at45°C(+2°C) till moisture content less than 0.50% to get stage-lst. Yield =87gm, (83.36%), HPLC Purity=97.883%. Stage-II :

80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C than added 32ml of formic acid (0.85 mol.) and 48gm of potassium permanganate (0.30 mol) at -5°C+2°C. Reaction maintained at -5°C (+2°C) for one hour. In-process check by TLC against stage-I, it should be nil. Added sodium metabisulphite solution (8 gm in 80 ml water) at -5°C (+2°C). Temperature raised up to 27°Cand filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4 volume of stage-I than cooled to 0°C to 5°C and added 480ml of purified water, stirred, filtered and washed with purified water to get wet stage-II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0% to get stage-2nd. Yield=78.30gm, (89.88%), HPLC Purity=99.18%.

Stage – III:

300ml of hydrofluoric acid (12.60mol) was cooled at -25°C to -30°C than added 75gm of stage-II (0.180mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II. It should be nil. Reaction mass was cooled to -50°C than added 45ml of acetone (0.60volume) at -45°C to -50°C. Reaction maintained at -45°Cto – 50°C for 02 hours. In-process check by TLC against reaction input, it should be nil. Added 565ml of purified water at 0°C and 340ml of liq. ammonia at 20°C than reaction mass was quenched in 410ml of liq. ammonia and 735ml of purified water solution at 15°C(+2°C), stirred, filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°Cto get stage-3rd. Yield=78.50gm, (91.48%), HPLC Purity=91.59%.

(Purification)

76 gm of stage-Ill Crude (0.16 mol) was dissolved in 760ml of methylene chloride (01 volume) and 760ml of methanol (lOvolume) mixture at ambient temperature. Stirred till clear solution and added 7.6gm of activated charcoal (0. lOvolume) than further stir for 30 minutes and filtered through hyflow bed and washed with methanol (one volume) and methylene chloride (one volume) mixture. Total filtrate was distilled under vacuum till 3 to 4 volume of input. Cooled to 0°C to 5°Cand stir for 02 hours. Filtered and washed with minimum precooled methanol. Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get purified stage-3rd. Yield=62gm, HPLC Purity=98.633%

Stage -IV : (Preparation of Triamcinolone acetonide from Stage – III)

Stage- Ill Triamcinolone acetonide

60gm of stage-Ill (0.1259 mol) dissolved in 600ml of methanol (lOvolume) and 600ml of methylene chloride (lOvolume) mixture under inert atmosphere. Cool to -5°C and added 1.2gm of sodium hydroxide (0.03mol) solution in 60ml of methanol (Olvolume) at -5°C (+2°C). Reaction maintained at -5°C+2°C for 03 hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral (~7) by adding 1.8ml of acetic acid at -5°C+2°C. Reaction mass was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to

30°C and added 120ml of purified water, stir for one hour than filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get stage-4111 (Triamcinolone acetonide). Yield=52gm, (95.04%), HPLC Purity=99.21%.

(Purification)

50gm of crude material (0.12 mol) dissolved in 1100ml of acetone (22volume) and 100ml of purified water (02volume) at 50°C than added 2.5gm of activated charcoal and stirred for one hour at same temperature. Filter through hyflow bed and washed with 120ml acetone (2.40volume). Filtrate was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°C and maintained for one hour at same temperature. Filtered and washed with water. Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get purified stage-4th. Yield =43gm, HPLC Purity=99.40%

-V: (Preparation of Triamcinolone Hexacetonide from Triamcinolone acetonide):

50ml of pyridine (lOvolume) charged in a glass flask and added lOgm of Triamcinolone acetonide (0.023mol) at ambient temperature. Heated to 80°C to 90°C than added 10ml of 3, 3-dimethyl butyryl chloride (O.l lmol) at 80°C to 90°C. Stirred at 80°C to 90°C for 02 hours. In-process check by TLC against Triamcinolone acetonide, it should be nil. Reaction mass cooled to ambient temperature and reaction mass was quenched in 1000ml of purified water (lOOvolume) at ambient temperature, stir for one hour than filtered and washed with purified water till neutral pH (~7). Wet material was dried at 50°C (+5°C) till moisture content less than 1.0% to get stage-5th (Triamcinolone Hexacetonide). Yield=12gm, (97.90%), HPLC Purity=98.63%.

(Purification)

120ml of methanol and 120ml of methylene chloride charged in a glass flask and added 12gm of crude material, stir till clear solution than added 1.2gm of activated charcoal and stir for 30 minutes. Filtered through hyflow bed and washed with 12ml of methanol and 12ml of methylene chloride mixture. Total filtrate was distilled under vacuum at below 40°C till 5 to 6 volume of crude. Cooled to 0°C+5°C and stir for one hour. Filtered and washed with 12ml of precooled methanol. Wet material was dried at 40°C+5°C till moisture content less than 0.50% to get TrimcinolneHexacetonide. Yield=8.8gm, HPLC Purity=99.625%//////////////////////////////////////////

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## Medical uses

Aristocort brand triamcinolone cream

Triamcinolone is used to treat a number of different medical conditions, such as eczemaalopecia areatalichen sclerosuspsoriasisarthritisallergiesulcerative colitislupussympathetic ophthalmiatemporal arteritisuveitisocular inflammationkeloidsurushiol-induced contact dermatitisaphthous ulcers (usually as triamcinolone acetonide), central retinal vein occlusion, visualization during vitrectomy and the prevention of asthma attacks.[12][13][14]

The derivative triamcinolone acetonide is the active ingredient in various topical skin preparations (cream, lotion, ointment, aerosol spray) designed to treat skin conditions such as rash, inflammation, redness, or intense itching due to eczema[15] and dermatitis.[16]

## Contraindications

Contraindications for systemic triamcinolone are similar to those of other corticoids. They include systemic mycoses (fungal infections) and parasitic diseases, as well as eight weeks before and two weeks after application of live vaccines. For long-term treatment, the drug is also contraindicated in people with peptic ulcers, severe osteoporosis, severe myopathy, certain viral infectionsglaucoma, and metastasizing tumours.[17]

There are no contraindications for use in emergency medicine.[4]

## Side effects

Further information: Glucocorticoid § Side effects

Side effects of triamcinolone are similar to other corticoids. In short-term treatment up to ten days, it has very few adverse effects; however, sometimes gastrointestinal bleeding is seen, as well as acute infections (mainly viral) and impaired glucose tolerance.[4]

Side effects of triamcinolone long-term treatment may include coughing (up to bronchospasms), sinusitismetabolic syndrome–like symptoms such as high blood sugar and cholesterol, weight gain due to water retention, and electrolyte imbalance, as well as cataractthrushosteoporosis, reduced muscle mass, and psychosis.[5][6][17] Triamcinolone injections can cause bruising and joint swelling.[5] Symptoms of an allergic reaction include rash, itch, swelling, severe dizziness, trouble breathing,[18] and anaphylaxis.[17]

## Overdose

No acute overdosing of triamcinolone has been described.[17]

## Interactions

Drug interactions are mainly pharmacodynamic, that is, they result from other drugs either adding to triamcinolone’s corticoid side effects or working against its desired effects. They include:[4][17]

Triamcinolone and other drugs can also influence each other’s concentrations in the body, amounting to pharmacokinetic interactions such as:[4][17]

## Pharmacology

### Mechanism of action

Further information: Glucocorticoid § Mechanism of action

Triamcinolone is a glucocorticoid that is about five times as potent as cortisol, but has very little mineralocorticoid effects.[4]

### Pharmacokinetics

When taken by mouth, the drug’s bioavailability is over 90%. It reaches highest concentrations in the blood plasma after one to two hours and is bound to plasma proteins to about 80%. The biological half-life from the plasma is 200 to 300 minutes; due to stable complexes of triamcinolone and its receptor in the intracellular fluid, the total half-life is significantly longer at about 36 hours.[4][5]

A small fraction of the substance is metabolized to 6-hydroxy- and 20-dihydro-triamcinolone; most of it probably undergoes glucuronidation, and a smaller part sulfation. Three quarters are excreted via the urine, and the rest via the faeces.[4][17]

Due to corticoids’ mechanism of action, the effects are delayed as compared to plasma concentrations. Depending on the route of administration and the treated condition, the onset of action can be from two hours up to one or two days after application; and the drug can act much longer than its elimination half-life would suggest.[4][5]

## Chemistry

Triamcinolone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is also known as 1-dehydro-9α-fluoro-16α-hydroxyhydrocortisone or 9α-fluoro-16α-hydroxyprednisolone as well as 9α-fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione.[20][21]

The substance is a light-sensitive, white to off-white, crystalline powder, or has the form of colourless, matted crystals. It has no odour or is nearly odourless. Information on the melting point varies, partly due to the substance’s polymorphism: 260 to 263 °C (500 to 505 °F), 264 to 268 °C (507 to 514 °F), or 269 to 271 °C (516 to 520 °F) can be found in the literature.[4]

Solubility is 1:500 in water and 1:240 in ethanol; it is slightly soluble in methanol, very slightly soluble in chloroform and diethylether, and practically insoluble in dichloromethane. The specific rotation is {\displaystyle [\alpha ]_{D}^{20}} +65° to +72° cm³/dm·g (1% in dimethylformamide).[4]

## Society and culture

In 2010, TEVA and Perrigo launched the first generic inhalable triamcinolone.[22]

According to Chang et al. (2014), “Triamcinolone acetonide (TA) is classified as an S9 glucocorticoid in the 2014 Prohibited List published by the World Anti-Doping Agency, which caused it to be prohibited in international athletic competition when administered orally, intravenously, intramuscularly or rectally”.[23]

## References

1. ^ “Kenalog Intra-articular / Intramuscular Injection – Summary of Product Characteristics (SmPC)”(emc). 10 June 2020. Retrieved 20 August 2020.
2. ^ “Nasacort Allergy 55 micrograms/dose Nasal Spray suspension – Summary of Product Characteristics (SmPC)”(emc). 30 August 2018. Retrieved 20 August 2020.
3. ^ “Adcortyl Intra-Articular/Intradermal Injection 10mg/ml – Summary of Product Characteristics (SmPC)”(emc). 11 December 2017. Retrieved 20 August 2020.
4. Jump up to:a b c d e f g h i j k l m n Dinnendahl V, Fricke U, eds. (2004). Arzneistoff-Profile (in German). Vol. 10 (19 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. Triamcinolon. ISBN 978-3-7741-9846-3.
5. Jump up to:a b c d e f Triamcinolone (systemic) Professional Drug Facts. Accessed 2020-08-19.
6. Jump up to:a b c d e f g “Triamcinolone Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
7. ^ “Triamcinolone Use During Pregnancy”Drugs.com. Retrieved 3 March 2019.
8. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 486. ISBN 978-3-527-60749-5.
9. ^ Vallerand, April Hazard (2018). Davis’s Drug Guide for Nurses. F.A. Davis. p. 365. ISBN 978-0-8036-7000-6.
10. ^ “The Top 300 of 2019”ClinCalc. Retrieved 16 October 2021.
11. ^ “Triamcinolone – Drug Usage Statistics”ClinCalc. Retrieved 16 October 2021.
12. ^ Triamcinolone – Drugs.com
13. ^ Triamcinolone Inhalation – Drugs.com
14. ^ Alcon Receives FDA Approval of Triesence Injectable Triamcinolone Suspension for Use in Eye Surgery – Drugs.com
15. ^ Chong M, Fonacier L (December 2016). “Treatment of Eczema: Corticosteroids and Beyond”. Clinical Reviews in Allergy & Immunology51 (3): 249–262. doi:10.1007/s12016-015-8486-7PMID 25869743S2CID 44337035.
16. ^ Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K, et al. (July 2014). “Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies”Journal of the American Academy of Dermatology71 (1): 116–32. doi:10.1016/j.jaad.2014.03.023PMC 4326095PMID 24813302Topical corticosteroids (TCS) are used in the management of AD in both adults and children and are the mainstay of anti-inflammatory therapy.
17. Jump up to:a b c d e f g Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Volon 4 mg-Tabletten.
18. ^ “Drugs and Treatments – Nasacort AQ Nasl – Patient Handout”WebMD. Retrieved 2008-03-24.
19. ^ Moore CD, Roberts JK, Orton CR, et al. (2012). “Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes”Drug Metab. Dispos41 (2): 379–389. doi:10.1124/dmd.112.046318PMC 3558858PMID 23143891.
20. ^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1228–. ISBN 978-1-4757-2085-3.
21. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 1054–. ISBN 978-3-88763-075-1.
22. ^ Perrigo Announces Launch Of Generic Version Of Nasacort AQ – CBS Detroit
23. ^ Chang CW, Huang TY, Tseng YC, Chang-Chien GP, Lin SF, Hsu MC (November 2014). “Positive doping results caused by the single-dose local injection of triamcinolone acetonide”Forensic Science International244: 1–6. doi:10.1016/j.forsciint.2014.07.024PMID 25126738.

///////////////TRIAMCINOLONE, TU3850000, トリアムシノロン , 去炎松 , Glucocorticoid

[H][C@@]12C[C@@H](O)[C@](O)(C(=O)CO)[C@@]1(C)C[C@H](O)[C@@]1(F)[C@@]2([H])CCC2=CC(=O)C=C[C@]12C

NEW DRUG APPROVALS

ONE TIME

## References

1. ^ World Health Organization (2021). “International Nonproprietary Names for Pharmaceutical Substances. Proposed INN: List 126” (PDF). WHO Drug Information35 (4): 1135.
2. ^ Xocova: Powerful New Japanese Pill for Coronavirus Treatment. BioPharma Media, February 2022
3. Jump up to:a b Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, et al. (January 2022). “Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”. bioRxivdoi:10.1101/2022.01.26.477782S2CID 246367525.
4. ^ “Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622”thepharmaletter.com. 31 January 2022.
5. ^ Shionogi’s new COVID pill appears to ease omicron symptoms. Nikkei Asia, 21 December 2021
6. ^ Japan to consider early approval for Shionogi COVID-19 pill. Japan Times, 8 February 2022