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N-[(2R)-2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide
LY-156735 (TIK-301, PD-6735) is a melatonin MT1 and MT2 agonist which is under development for the treatment of insomnia and other sleep disorders.[1]
Beta-methyl-6-chloromelatonin (PD-6735) is a melatonin MT1 and MT2 agonist which had been in phase II trials at Phase 2 Discovery for the treatment of sleep latency in patients with primary insomnia, however, no recent development has been reported.
The melatonin agonist exhibits high selectivity and provides a novel mode of action different from that of benzodiazepine receptor ligands currently on the market.
Furthermore, the drug candidate is believed to be non-addicting, therefore, offering an advantage over marketed sleep medications. Originally discovered by Lilly, PD-6735 was licensed to Phase 2 Discovery in 2002 for further development.
Orphan drug designation has been assigned in the U.S. for the treatment of circadian rhythm sleep disorders in blind people with no light perception and for the treatment of neuroleptic-induced tardive dyskinesia in schizophrenia patients.
In 2007, the product candidate was licensed to Tikvah Therapeutics by Phase 2 Discovery for worldwide development and commercialization for the treatment of sleep disorder, depression and circadian rhythm disorder.
beta -alkylmelatonins as ovulation inhibitors [US4997845]1991-03-05
BETA-ALKYLMELATONINS [EP0281242]1988-09-07 GRANT1992-08-12
The condensation of 6-chloro-5-methoxy-1H-indole (I) with Meldrum’s acid (II) and acetaldehyde (III) catalyzed by L-proline in acetonitrile gives the adduct (IV), which is treated with Cu and ethanol in refluxing pyridine to yield 3-(6-chloro-5-methoxy-1H-indol-3-yl)butyric acid ethyl ester (V). The reaction of (V) with hydrazine at 140 C affords the hydrazide (VI), which is treated with NaNO2 and Ac-OH to provide the corresponding azide that, without isolation, is thermolyzed and rearranged in toluene at 80?C to give 7-chloro-6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (VII). The cleavage of the lactam ring of (VII) with KOH in refluxing ethanol/water yields 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (VIII). The decarboxylation of (VIII) by means of refluxing aq. 3M HCl affords 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole (IX), which is finally acylated with acetic anhydride and pyridine in toluene to provide the target 6-chloromelatonin as a racemic compound.
EP 0281242;……….http://www.google.com/patents/EP0281242B1?cl=en
Example 3
…………………………………………….
PATENT
http://www.google.com/patents/EP0281242B1?cl=en
The intermediate diazonium salt (XIII) has been obtained as follows: the hydrogenation of 3-chloro-4-methoxynitrobenzene (XI) with H2 over Pt/Al2O3 in toluene gives the corresponding aniline (XII), which is diazotized with NaNO2/HCl and treated with sodium tetrafluoroborate to yield the target diazonium salt intermediate (XIII). The reduction of pulegone (I) with H2 over Pd/C gives the menthol (II), which is oxidized with CrO3/H2SO4 to yield 3(R),7-dimethyl-6-oxooctanoic acid (IV), which can also be obtained by direct oxidation of (l)-menthol (III) under the same conditions.
The oxidation of (IV) with trifluoroperacetic acid (trifluoroacetic anhydride/H2O2) in dichloromethane yields the 3(R)-methylhexanedioic acid isopropyl monoester (V), which is treated with NaOEt in ethanol to obtain the corresponding ethyl monoester (VI). The reaction of (VI) with diethyl carbonate, EtONa, and “Adogen 464” (a phase transfer catalyst) in ethanol affords 5,5-bis(ethoxycarbonyl)-3(S)-methylpentanoic acid (VII), which is treated with oxalyl chloride to provide the expected acyl chloride (VIII). The reaction of (VIII) with sodium azide and benzyl alcohol gives the intermediate azide that rearranges to the benzyl carbamate (IX).
The reductive cyclization of (IX) with H2 over Pd/C in ethanol yields 5(R)-methyl-2-oxopiperidine-3-carboxylic acid ethyl ester (X), which is condensed with the intermediate diazonium salt (XIII) to afford the hydrazono derivative (XIV). The cyclization of (XIV) in hot formic acid provides 7-chloro-6-methoxy-4(R)-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (XV), which is treated with KOH In refluxing ethanol/water to cleave the lactam ring, yielding 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (XVI). The decarboxylation of (XVI) by means of refluxing 3M HCl affords 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole (XVII), which is finally acylated with Ac2O and pyridine in toluene to provide the target 6-chloromelatonin as a pure enantiomer.
Example 7
 |
|
| Systematic (IUPAC) name | |
|---|---|
| N-[(2R)-(6-Chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide | |
| Clinical data | |
| Legal status |
?
|
| Identifiers | |
| CAS number | 118702-11-7  |
| ATC code | ? |
| PubChem | CID 219018 |
| ChemSpider | 189853  |
| Chemical data | |
| Formula | C14H17ClN2O2 |
| Molecular mass | 280.757 |
| HS Code: | 2935009090 |
|---|
Dorzolamide (trade name Trusopt) is a carbonic anhydrase inhibitor. It is an anti-glaucoma agent, and acts by decreasing the production of aqueous humour.[1] It is optically applied in the form of a 2% eye drops.[2]
This drug, developed by Merck, was the first drug in human therapy (market introduction 1995) which resulted from structure-baseddrug design. It was developed to circumvent the systemic side effects of acetazolamide which has to be taken orally.[2]
Dorzolamide hydrochloride is used to lower increased intraocular pressure in open-angle glaucoma and ocular hypertension.
It lowers IOP by about 20%.[2]
Ocular stinging, burning, itching and bitter taste.[2] it causes shallowing of the anterior chamber and leads to transient Myopia.
Dorzolamide Hydrochloride and its derivatives is known. U.S. Pat. No. 5,688,968 describes preparation of Dorzolamide HCl starting from chiral 5,6-dihydro-4-(S)-hydroxy-6-(S)-methyl-4H-thiopyran-7,7-dioxide, as depicted in scheme 1:
The process described in BP 0 296 879 (equivalent of U.S. Pat. No. 4,797,413) is of particular relevance. EP 0 296 879 describes the synthesis of Dorzolamide Hydrochloride starting from thiophene-2-thiol as depicted in scheme 2 and 3
The process described in EP 0,296,879 (scheme 2) has the following disadvantages: (a) The starting material Thiophene-2-thiol is unstable and undergoes oxidation to form disulfide, leading to lower yield of viii; (b) the yield of sulfonamide (xii) from sulphonic acid (x) is very poor (35%) and requires use of 18-crown-6 ether, which is expensive; (c) oxidation of alcohol (xiii) to sulfone is carried out using oxone which is expensive and hazardous; and separation of cis/trans isomer is done by column chromatography which is industrially inconvenient.
| Systematic (IUPAC) name | |
|---|---|
| (4S,6S)-2-ethylamino-4-methyl-5,5-dioxo- 5λ6,7-dithiabicyclo[4.3.0]nona-8,10-diene-8-sulfonamide |
|
| Clinical data | |
| Trade names | Trusopt |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a602022 |
|
|
| Legal status | |
| Routes | Topical (eye drops) |
| Pharmacokinetic data | |
| Protein binding | ~33% |
| Half-life | 4 months |
| Identifiers | |
| CAS number | 130693-82-2 120279-96-1 |
| ATC code | S01EC03 |
| PubChem | CID 5284549 |
| DrugBank | DB00869 |
| ChemSpider | 4447604 |
| UNII | 9JDX055TW1 |
| KEGG | D07871 |
| ChEBI | CHEBI:4702 |
| ChEMBL | CHEMBL218490 |
| Chemical data | |
| Formula | C10H16N2O4S3 |
| Molecular mass | 324.443 g/mol |
TRUSOPT® (dorzolamide hydrochloride ophthalmic solution) is a carbonic anhydrase inhibitor formulated for topical ophthalmic use.
Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is
 |
Its empirical formula is C10H16N2O4S3•HCl and its structural formula is:
 |
Dorzolamide hydrochloride has a molecular weight of 360.9 and a melting point of about 264°C. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.
TRUSOPT Sterile Ophthalmic Solution is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride. The pH of the solution is approximately 5.6, and the osmolarity is 260-330 mOsM. Each mL of TRUSOPT 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride). Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.
The dorzolamide hydrochloride product is prepared from the aminated intermediate of Formula IV by the following scheme.
[00056] Preparation of dorzolamide hydrochloride product from the animated intermediate of Formula IV
[00057] Fuming sulfuric acid (20%, 5 1) is cooled to -7°±2°C and the aminated intermediate of Formula IV (2.5 Kg) is added to it in portions during stirring. The temperature of the reaction mixture is increased to 20°+5°C during addition of the aminated intermediate of Formula IV. The reaction mixture is stirred for 22 hours at 20°±5°C. Thionyl chloride (20 1) is added to the stirred reaction mixture at 20±5°C. The reaction mixture is heated to 60°-65°C and stirred for 24 hours at this temperature. The mixture is cooled back to 40°±2°C and the excess amount of thionyl chloride is evaporated at this temperature under vacuum. (The volume of the residue: ~9 1.) The residue is cooled to -5°+2°C.
[00058] Ethyl acetate (75 1) is cooled to -10°±5°C and the residue is added to it at this temperature. The temperature of the diluted solution: 10°-25°C. Aqueous ammonia (25%, 75 1) is cooled to -10°±5°C and the residue is added to it at this temperature during effective stirring, while maintaining the temperature below 300C. The final pH: ~11. The slurry is cooled to 0°+2°C and stirred for 14 hours at this temperature. The formed ammonium sulfate is filtered and the cake is washed with ethyl acetate (2x 20 1 and 10 1). Ethyl acetate is evaporated from the filtrate at 38°±2°C under vacuum. The residue is heated to 38°±2°C, washed with toluene (3×37.5 1) at this temperature. Water (25 1) is added to the aqueous phase, cooled to 20°-25°C and extracted with ethyl acetate (3x 75 1, 37.5 1, and 37.5 1). The collected ethyl acetate phase is concentrated to ~ 100 1 at 38°±2°C under vacuum. The residue is cooled to 20°-25°C and hydrogen chloride in ethanol (5%, 10.8 1) is added to it during stirring. The formed slurry is stirred for 1 hour at 20°-25°C then cooled to 0°-4°C and stirred for 5 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with ethyl acetate (2×20 1) and dried at 55°-60°C under vacuum for 4-8 hours to give Dorzolamide hydrochloride salt (~2 Kg).
[00059] Crude Dorzolamide hydrochloride salt (9 Kg) is solved in water (225 1) at 20°-25°C and the pH is set to 8.0-8.5 by addition of 25% of aqueous ammonia (2 1). The formed slurry is extracted with ethyl acetate (5×72 1). The collected ethyl acetate phase is concentrated to 180 1 by vacuum distillation. The residue is cooled to 20°-25°C, ethyl acetate (45 1) and hydrogen chloride in ethanol (5%, 22.5 1) are added to it during stirring (pH:~1.0). The formed slurry is stirred for 1 hour at 20°-25°C then cooled to 0°-4°C and stirred for 5 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with ethyl acetate (2×30 1), and dried at 55°-60°C under vacuum for 4-8 hours to give purified Dorzolamide hydrochloride salt (~8.2Kg).
[00060] Purified Dorzolamide hydrochloride salt (8 Kg) dissolved in water
(24 1) at 95°-105°C and treated with active carbon (80 g). After filtration, the water solution is cooled gradually to 0°-4°C and stirred for 3-5 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with cooled water (2×5 1) and dried at 55°-60°C under vacuum for 4-8 hours to give crystallized DRZ HCl salt (~6.6 Kg).
http://www.google.com/patents/US20060142595
The invention provides a process for preparing 5,6-dihydro-4-(S)-(ethylamino)-6-(S)methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide hydrochloride of formula (I), comprising of nine steps, as depicted in scheme 4 below:
A mixture of compound from example 8 (15 gm0.0462 mole) and di-p-toluyl-D-tartaric acid monohydrate (4.55 gm, 0.01125 mole) in n-propanol (1600 ml) was heated to boiling and hot solution filtered through a filter-aid pad with a layer of charcoal. The filtrate was concentrated by boiling to a volume of about (400 ml) and then allowed to crystallize. After standing overnight the crystals were filtered off and material recrystallized twice more from n-propanol (400 ml) to yield a 2:1 salt of free base to acid. Combined mother liquors from this recrystallization were saved for stage B. The salt was then treated with a saturated solution of sodium bicarbonate and mid extracted with ethyl acetate. The organic extract were dried, filtered and concentrated to dryness to yield (3.2 gm) of freebase. The hydrochloride salt was prepared from 5,6 N HCl ethanol and crystallized from methanol-isopropanol to yield (2.83 gm) of (+) isomer, SOR 8.23 (C 0.9 methanol) M.P. 283-285° C. The combine mother liquor was treated with saturated solution of sodium bicarbonate and mixture extracted with ethyl acetate. The organic exacts were dried, filtered and concentrated to dryness. The residue was treated with di-p-toluyl-L-tartaric acid monohydrate (4.55 gm, 0.01125 mole) in n-propanol (1600 ml) and the isomer separated by the process described previously to give title compound (I) (3.75 gm, 22.48%) SOR=−8.34 (C 1, Methaol) M.P. 283 to 285° C.,
http://www.google.com/patents/WO2008135770A2?cl=en
Dorzolamide is chemically termed as (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H- thieno[2,3-/?]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride. Dorzolamide hydrochloride is represented by following structural Formula I:
HN ‘CH,
Formula I
Dorzolamide hydrochloride is known to be a carbonic anhydrase inhibitor useful in the treatment of ocular hypertension.
A process for the preparation of dorzolamide and its derivatives was first described in EP 0296879. The process of particular relevance is depicted in scheme 1. Scheme 1
(viϋ) (ix) Trans and Cis (x)
Trans (xi) Trans(+) (xii) ( I )
The process disclosed in scheme 1 has following disadvantages.
(a) The reduction of the ketone of sulfonamide (vi) using absolute ethanol is carried out at reflux and then stirred at room temperature for several hours to complete the reaction. This longer duration of reaction produces many impurities.
(b) Oxidation of alcohol (vii) to sulfone (viii) is carried out using oxone. The oxone has many disadvantages such as it is irritating to the eyes, skin, nose and throat. It should be used with adequate ventilation and exposure to its dust should be minimized. Traces of heavy metal salts catalyze the decomposition of oxone. It is practically insoluble in all organic solvents hence a phase transfer catalyst is required.
(c) Activation of the 4-hydroxy group of the sulfoaminated hydroxysulfone (viii) and nucleophilic substitution by desired ethylamine, results in all diastereomeric products (x) i.e. trans and cis isomers, which must be separated by column chromatography and resolved, further using resolving agent. As a result, product loss is greater when the desired product is the more active enantiomer.
An alternate route for the preparation of dorzolamide hydrochloride by the Ritter reaction is disclosed in EP0296879 and consists of the treatment of a aliphatic hydroxyl with a nitrile and a strong acid to form an amide. The process disclosed is as depicted in Scheme 2.
Scheme 2
(viii) (ix-a ) Trans and Cis (x)
Trans(+) (xii)
Trans (+/-) (xi) ( I )
The reaction involves conversion of hydroxysulfones (viii) to the corresponding acetoamidosulfones (ix-a) with retention of configuration followed by reduction of the amido group, chromatographic separation and resolution to obtain the desired trans isomer (I).
The prior art teaches the use of an excess quantity of sulfuric acid to carry out the Ritter reaction and hence a large quantity of ice is required for quenching the reaction mass. When the reaction mass in concentrated sulfuric acid comes into contact with ice, a large amount of localized heat is generated causing decomposition of material. Since a huge amount of water is required for quenching the reaction mass, the amount of ethyl acetate required for extraction is also substantially large. The work-up using water is not advisable nor applicable industrially.
United States Patent 5688968 describes an alternative route of preparation of dorzolamide hydrochloride starting from chiral 5,6-dihydro-4-(S)-hydroxy-6-(S)-methyl-4H-thiopyran-7,7- dioxide, as depicted in Scheme 3:
Scheme 3
(xiv) (XV)
(xiii)
(xvi) (xvii ) Trans:Cis:: 95: 5 (xviii)
HN CH,
(xix) ( I )
The process described in Scheme 3 has the following disadvantages: (a) Use of expensive chiral hydroxysulfone starting material. The process for the preparation of the chiral hydroxysulfone starting material is disclosed in U.S. Patents Nos. 5,157,129, 5,474,919 and 5,760,249. In these processes, the chiral hydroxysulfone is obtained by the asymmetric enzymatic reduction of the corresponding ketosulfone, or by cyclization of the chiral thienyl thiobutyric acid, obtained, in turn, from a chiral hydroxyester or lactone, and the subsequent stereospecific reduction of the resulting ketone, (b) The process according to this patent uses maleic acid to separate the undesired cis- isomer from dorzolamide. However this maleate salt formation to remove the cis isomer is only suitable when the ratio of trans/cis is greater than 95:5. That means, the maleate salt formation of dorzolamide does not the remove cis isomer exclusively when the cis isomer content is more than 5%. It sometimes requires repeated purification to achieve the desired chiral purity.
Another alternate route for the preparation of dorzolamide hydrochloride is disclosed in United States patent no.7109353 which involves the use of sodium perborate as an oxidant, as depicted in Scheme 4.
Scheme 4
chlorinating agent, cyclinization
Vl IV
VIl VlIl IX
The process disclosed in Scheme 4 has following disadvantages (a) Conversion of (i) to (ii) requires the mixture to be refluxed for 18-20 hrs which is time consuming and may cause impurity in the product.
(b) As the process uses the Ritter reaction to convert (vi) to (vii), a large amount of water is required to quench the hot mass of reaction which is not practical in an industrial set-up. (c) Sodium perborate is used as an oxidizing agent to convert (v) to (vi), which has got bleaching properties, and the handling of it may be injurious when done so for a prolonged period.
Yet another process for the preparation of dorzolamide is disclosed in United States publication no. 20060155132 which involves protecting the chiral 5,6-dihydro-4-(R)- hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran-7,7-dioxide as depicted in Scheme 5.
Scheme 5
protected amination benzyl sulphonyl chloride
The process disclosed in Scheme 5 has the following disadvantages, (a) The conversion process of compound (II) to (III) requires a very low temperature which ranges from -30° to 00C. (b) The amination process requires 16- 20 hrs, which is time consuming and may cause impurity in the product. All these disadvantages of the prior art are overcome by the process in accordance with the present invention.
Scheme 8
Example 4
Preparation of 5,6-Dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide
A suspension of 5,6-dihydro-4H-4-acetylamino-6-methylthieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide (83.25 gms, 0.24 moles) in THF (832 ml) was cooled to 00C and sodium borohydride (49.11 gms, 1.29 moles) was added in lots maintaining temperature below 5°C. Reaction mass was stirred for 15 minutes at 5°C and boron trifluoride diethyl- etherate (249.75 ml, 287.2 gms, 2.02 moles) was added below 5°C. The reaction mass was stirred for 5 hours at 0°C to 5°C. Temperature of the reaction mass was raised to 25°C to 300C and stirred for 18 hours. The reaction mass was quenched in 1M sulphuric acid solution (1082 ml) below 5°C, temperature raised to 25°C to 30°C and stirred for 1 hour. The solvent was distilled under reduced pressure at 800C. The reaction mass was cooled to 100C and p H adjusted to 7 – 8 using 50% sodium hydroxide solution. Material was extracted in 1665 ml ethyl acetate once and 832 ml twice. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulphate, charcoalised, filtered on hyflo, distilled to get title compound (77.42 gms). HPLC: 80:20::Trans:Cis
Example 7
Preparation of 5,6-Dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide hydrochloride
(a) Dorzolamide di-p-toluyl-L-tartrate salt as prepared in example 6 (44.26 gms, 0.085 moles) was taken in ethyl acetate (557.0 ml), basified with saturated sodium bicarbonate solution. Reaction mass was stirred for 15 minutes at 25°C to 3O0C and aqueous layer was extracted with ethyl acetate (278 ml X 2). The organic layers were combined, washed with brine solution, dried over sodium sulphate, and charcoalized. To the clear solution, IPA + HCL (16.35 ml, 0.089 moles) was added, stirred for 30 minutes and ethyl acetate was removed by distillation at atmospheric pressure at 85°C to about 280 ml volume, cooled to 25-3O0C, stirred for 12 hours at same temperature and filtered to get 26.0 gms of dorzolamide hydrochloride. Trans (-) dorzolamide hydrochloride > 99.5% Trans (+) dorzolamide hydrochloride < 0.5% Cis Isomer <0.1%
(b) Dorzolamide hydrochloride was obtained in a similar manner in quantitative yield from the salt of example 6(b).
(c) Dorzolamide hydrochloride was obtained in a similar manner in quantitative yield from the salt of example 6(c).
Example 8
Preparation of 5,6-Dihydro-4H-4-ethylamino-6-methylthieno[2,3-b]thiopyran-2- sulfonamide -7,7-dioxide hydrochloride without isolation of base
Dorzolamide di-p-toluyl-L-tartrate (50 gms, 0.096 moles) prepared as per example 6, was charged in a round bottom flask along with isopropanol (1000 ml). The reaction mass was heated to 800C and charged with IPA-HCI (20 ml) dropwise to pH 3 to 4. The reaction mass was heated to reflux for 5-10 minutes. The clear solution obtained was concentrated to 100 ml. The reaction mass was charged with 300 ml ethyl acetate, cooled to 25°C, stirred for 12 to 14 hours at same temperature. The resulting dorzolamide hydrochloride was isolated by filtration and washed with ethyl acetate (50 ml), dried under vacuum at 60- 65 0C for 5-6 hours. Yield- 30 gms.
Trans (-) dorzolamide hydrochloride > 99.5% Trans (+) dorzolamide hydrochloride < 0.5% Cis Isomer <0.1%
…………………………………………………………..
http://www.google.com/patents/EP0453288A1
………………………………………
http://www.google.com/patents/US20060155132
Dorzolamide hydrochloride, known chemically as 5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxyde hydrochloride, is a topically effective carbonic anhydrase inhibitor useful in the treatment of ocular hypertension.
Dorzolamide hydrochloride has the structure of Formula I:
U.S. Pat. Nos. 4,677,155 and 4,797,413 disclose Dorzolamide. In the prior art synthesis of dorzolamide, a chiral hydroxysulfone is used as a starting material. The chiral hydroxysulfone starting material can be obtained using the processes disclosed in U.S. Pat. Nos. 5,157,129, 5,474,919, and 5,760,249. In the disclosed processes, the chiral hydroxysulfone is obtained by the asymmetric enzymatic reduction of the corresponding ketosulfone, or by cyclization of the chiral thienyl thiobutyric acid, obtained, in turn, from a chiral hydroxyester or lactone, and the subsequent stereospecific reduction of the resulting ketone.
Processes for the preparation of dorzolamide hydrochloride are described in U.S. Pat. Nos. 4,797,413, 5,157,129, and 5,688,968 and in U.S. patent application Publication Ser. No. 2003/0220509. The disclosed processes involve conversion of a hydroxysulfone to the corresponding acetamidosulfone by a Ritter reaction with retention of configuration, followed by introduction of a sulfonamido group, and the subsequent reduction of the amido group to an amine, providing the desired product.
The process disclosed in U.S. Pat. No. 4,797,413 includes activation of the 4-hydoxy group of the sulfonaminated hydroxysulfone with tosyl chloride and the introduction of the desired alkylamino group by nucleophilic substitution, resulting in all diastereomeric products, which must be separated and resolved. As a result, at least 75 percent of the product is lost when the desired product is the more active enantiomer.
EXAMPLE 2
Preparation of 5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran 7,7-dioxide hydrochloride salt (Formula IV)
Tetrahydrofuran (50 l) and triethyl amine (4.8 l) are added to 4-(R)-hydroxy-5,6-dihydro-6-(S)-methyl-4H-thieno[2,3b]thiopyran-7,7-dioxide (5 Kg) and stirred under a nitrogen atmosphere at room temperature. The solution is cooled to −10° C. Benzylsulfonyl chloride (5.4 Kg) solved in THF (15 l) is added to the DRZ-19 THF solution in portions while maintaining the temperature below 0° C. The feeding funnel is washed with THF (2 l). The reaction mixture is stirred at 0° C. for 2-4 hours. The formed TEA HCl is filtered and the cake is washed with THF (2×10 l) Ethylamine in THF (30%, 63.7 l) is added to the filtrate and the reaction mixture is stirred at 20°-25° C. for 16 hours. Ethylamine gas prepared by heating of 70% EtNH2water solution (50 l) is absorbed in cooled THF (30 l). Water (20 l) is added to the reaction mixture and THF is evaporated from the filtrate at 40°±5° C. under vacuum. The residue is cooled to 20°-25° C., ethyl acetate (60 l) is added to it and stirred vigorously. After phase separation, the organic phase is washed with water (20 l). The ethyl acetate phase is heated to 40°±2° C. and hydrochloric acid (4M, ˜8-10 l) is added to it during stirring to set pH 2.0-2.5. The formed slurry is cooled to −8°±2° C. and stirred for 3 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with ethyl acetate (30 l) and dried at 55°-60° C. under vacuum for 4-8 hours to give the desired salt (˜5 Kg).
Preparation of dorzolamide hydrochloride product from the aminated intermediate of Formula IV
Fuming sulfuric acid (20%, 5 l) is cooled to −7°±2° C. and the aminated intermediate of Formula IV (2.5 Kg) is added to it in portions during stirring. The temperature of the reaction mixture is increased to 20°±5° C. during addition of the aminated intermediate of Formula IV. The reaction mixture is stirred for 22 hours at 20°±5° C. Thionyl chloride (20 l) is added to the stirred reaction mixture at 20°±5° C. The reaction mixture is heated to 60°-65° C. and stirred for 24 hours at this temperature. The mixture is cooled back to 40°±2° C. and the excess amount of thionyl chloride is evaporated at this temperature under vacuum. (The volume of the residue: ˜9 l.) The residue is cooled to −5°±2° C.
Ethyl acetate (75 l) is cooled to −10°±5° C. and the residue is added to it at this temperature. The temperature of the diluted solution: 10°-25° C. Aqueous ammonia (25%, 75 l) is cooled to −10°±5° C. and the residue is added to it at this temperature during effective stirring, while maintaining the temperature below 30° C. The final pH: ˜11. The slurry is cooled to 0°±2° C. and stirred for 14 hours at this temperature. The formed ammonium sulfate is filtered and the cake is washed with ethyl acetate (2×20 l and 10 l ). Ethyl acetate is evaporated from the filtrate at 38°±2° C. under vacuum. The residue is heated to 38°±2° C., washed with toluene (3×37.5 l) at this temperature. Water (25 l) is added to the aqueous phase, cooled to 20°-25° C. and extracted with ethyl acetate (3×75 l, 37.5 l, and 37.5 l). The collected ethyl acetate phase is concentrated to ˜100 l at 38°±2° C. under vacuum. The residue is cooled to 20°-25° C. and hydrogen chloride in ethanol (5%, 10.8 l) is added to it during stirring. The formed slurry is stirred for 1 hour at 20°-25° C. then cooled to 0°-4° C. and stirred for 5 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with ethyl acetate (2×20 l) and dried at 55°-60° C. under vacuum for 4-8 hours to give Dorzolamide hydrochloride salt (˜2 Kg).
Crude Dorzolamide hydrochloride salt (9 Kg) is solved in water (225 l) at 20°-25° C. and the pH is set to 8.0-8.5 by addition of 25% of aqueous ammonia (2 l). The formed slurry is extracted with ethyl acetate (5×72 l). The collected ethyl acetate phase is concentrated to 180 l by vacuum distillation. The residue is cooled to 20°-25° C., ethyl acetate (45 l) and hydrogen chloride in ethanol (5%, 22.5 l) are added to it during stirring (pH:˜1.0). The formed slurry is stirred for 1 hour at 20°-25° C. then cooled to 0°-4° C. and stirred for 5 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with ethyl acetate (2×30 l), and dried at 55°-60° C. under vacuum for 4-8 hours to give purified Dorzolamide hydrochloride salt (˜8.2 Kg).
Purified Dorzolamide hydrochloride salt (8 Kg) dissolved in water (24 l) at 95°-105° C. and treated with active carbon (80 g). After filtration, the water solution is cooled gradually to 0°-4° C. and stirred for 3-5 hours at this temperature. The slurry is filtered, the precipitated HCl salt is washed with cooled water (2×5 l) and dried at 55°-60° C. under vacuum for 4-8 hours to give crystallized DRZ HCl salt (˜6.6 Kg).
…………………………………………………………
Reaction of (I) with acetic anhydride-sulfuric acid in methylene chloride provided the sulfonic acid in 98% yield. Conversion to the sulfonyl chloride with phosphorous pentachloride in methylene chloride followed by treatment with aqueous ammonia gave the sulfonamide (II). Reduction of the carbonyl function with sodium borohydride and oxidation of the thiopyran sulfur with Oxone(R) yielded (IV). The 4-hydroxy substituent was converted to the acetylamino functionality under Ritter conditions. Reduction of (V) with borane-dimethylsulfide complex yielded (VI) as a mixture of diasteriomers. Chromatography on silica gel gave the trans-racemate, which was resolved into its individual enantiomers through the di-p-toluoyl-L-tartaric acid salt. The absolute configuration of the S,S-enantiomer, MK-507, was established by single crystal X-ray analysis.
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http://bonanzasite.com/synthesis-of-dorzolamide-hydrochloride
//////////A new synthesis of MK-0507 has been described: The condensation of 3(R)-(tosyloxy)butyric acid methyl ester (I) with lithium 2-thienylmercaptide (II) in formamide-THF gives 3(S)-(2-thienylthio)butyric acid methyl ester (III), which is hydrolyzed with aqueous HCl to the corresponding free acid (IV). The intramolecular Friedel-Crafts’cyclization of (IV) with trifluoroacetic anhydride yields 6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (V), which is reduced with LiAlH4 in toluene to afford 4(R)-hydroxy-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran (VI). Epimerization of (VI) with sulfuric acid gives the alcohol (VII) in a cis:trans ratio of 24:76%. Oxidation of (VII) with H2O2 and sodium tungstate yields the 7,7-dioxide (VIII; cis-trans mixture), which is acetylated with acetic anhydride to the acetate (IX). The reaction of (IX) with acetonitrile and sulfuric acid affords N-[6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl]acetamide 7,7-dioxide (X; cis-trans mixture), which is sulfonated with chlorosulfonic acid and then treated with SOCl2 to give 4-acetamide-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonyl chloride 7,7-dioxide (XI; cis-trans mixture). The reaction of (XI) with concentrated aqueous NH4OH in THF yields the corresponding sulfonamide (XII), which by reduction with BH3-dimethylsulfide in THF affords 4-(ethylamino)-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (XIII; cis-trans mixture). Finally, this mixture is treated with maleic acid in acetone and the resulting maleates are submitted to fractionated crystallization, giving the maleate of the (4S,6S)-isomer, which is treated first with NaHCO3 and then with HCl to give MK-0507; [alpha](25)589 -17.1 C (c 1, H2O).
 CAS NO. 130693-82-2, DORZOLAMIDE HCL H-NMR spectral analysis |
 CAS NO. 130693-82-2, DORZOLAMIDE HCL C-NMR spectral analysis |
CIPLA LIMITED; CURTIS, Philip, Anthony Patent: WO2008/135770 A2, 2008 ; Location in patent: Page/Page column 21-22 ;
RAGACTIVES, S.L. Patent: US2003/220509 A1, 2003 ; Location in patent: Page/Page column 12 ;
WO2011/101704 A1, ;
Literature References:
Carbonic anhydrase inhibitor. Prepn: J. J. Baldwin et al., EP 296879; eidem, US 4797413 (1988, 1989 both to Merck & Co.). Mechanism of action study: R.-F. Wang et al., Arch. Ophthalmol. 109, 1297 (1991).
HPLC determn in plasma and urine: B. K. Matuszewski, M. L. Constanzer, Chirality 4, 515 (1992).
Clinical evaluations in glaucoma and ocular hypertension: E. A. Lippa et al., Ophthalmology 98, 308 (1991); E. A. Lippa et al., Arch. Ophthalmol. 110, 495 (1992).
| Reference | ||
|---|---|---|
| 1 | * | KAMEI K. ET AL.: ‘Chemical structure, physico-chemical properties and stability of dorzolamide hydrochloride‘ IYAKUHIN KENKYU vol. 25, no. 6, 1994, pages 438 – 452, XP008040715 |
| 2 | * | QUINT M.-P. ET AL.: ‘Dorsolamide hydrochloride‘ ANALYTICAL PROFILES OF DRUG SUBSTANCES AND EXCIPIENTS vol. 26, 1999, pages 283 – 316, XP008040718 |
| EP2128161A1 * | May 30, 2008 | Dec 2, 2009 | Ragactives, S.L. | Process for obtaining 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-7,7-dioxide and its enantiomers, and applications thereof |
| WO2008135770A2 * | May 7, 2008 | Nov 13, 2008 | Cipla Ltd | Process for preparing dorzolam ide |
| WO2009144263A2 * | May 28, 2009 | Dec 3, 2009 | Ragactives, S.L.U. | PROCESS FOR OBTAINING 4-HYDROXY-6-METHYL-5, 6-DIHYDRO-4H-THIENO [2,3-b] THIOPYRAN-7, 7-DIOXIDE AND ITS ENANTIOMERS, AND APPLICATIONS THEREOF |
| WO2014005943A1 * | Jun 28, 2013 | Jan 9, 2014 | Zach System S.P.A. | Process for preparing enantiomerically enriched oxamides |
| US8263787 | May 7, 2008 | Sep 11, 2012 | Cipla Limited | Process for preparing dorzolamide |
| WO1994021645A1 * | Mar 16, 1994 | Sep 29, 1994 | Thomas J Blacklock | ENANTIOSELECTIVE SYNTHESIS OF 5,6-DIHYDRO-(S)-4-(ETHYLAMINO)-(S)-6-METHYL-4H-THIENO[2,3-b]THIOPYRAN-2-SULFONAMIDE 7,7-DIOXIDE AND RELATED COMPOUNDS |
| EP0296879A1 * | Jun 23, 1988 | Dec 28, 1988 | Merck & Co., Inc. | Substituted aromatic sulfonamides as antiglaucoma agents |
| US5474919 * | Sep 13, 1994 | Dec 12, 1995 | Merck & Co., Inc. | Bioconversion process for the synthesis of transhydroxy sulfone by Rhodotorula rubra or Rhodotorula piliminae |
| US5760249 * | Aug 28, 1996 | Jun 2, 1998 | Merck & Co., Inc. | Synthesis of hydroxysulfone and related compounds |
| US20060142595 * | Dec 28, 2004 | Jun 29, 2006 | Council Of Scientific & Industrial Research | Starting by reacting a 2-halothiophene with a Grignard reagent in a solvent in situ with sulfur, triethylamine hydrochloride, crotonic acid and a base; product is chlorinated, cyclized, chlorosulfonated and aminated, reduced, oxidized, amidated, hydrogenated, neutralized, recrystallized and resolved |
| US5157129 | Apr 18, 1990 | Oct 20, 1992 | Merck & Co., Inc. | Enantiospecific synthesis of s-(+)-5,6-dihydro-4-(r-amino)-4h-thieno(2,3-b)thiopyran-2-sulfonamide-7,7-dioxide |
| US5474919 | Sep 13, 1994 | Dec 12, 1995 | Merck & Co., Inc. | Bioconversion process for the synthesis of transhydroxy sulfone by Rhodotorula rubra or Rhodotorula piliminae |
| US5688968 | Jan 6, 1995 | Nov 18, 1997 | Merck & Co., Inc. | Enantioselective synthesis of 5,6-dihydro-(S)-4-(ethylamino)-(S)-6-methyl-4H-thieno 2,3-B!thiopyran-2-sulfonamide 7,7-dioxide |
| US5760249 | Aug 28, 1996 | Jun 2, 1998 | Merck & Co., Inc. | Synthesis of hydroxysulfone and related compounds |
| US7109353 | Dec 28, 2004 | Sep 19, 2006 | Council Of Scientific And Industrial Research | Process for preparing 5,6-dihydro-4-(S)-(ethylamino)-6-(S) methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide HCl |
| US20060155132 | Jan 6, 2006 | Jul 13, 2006 | Kovacs Laszlo Z | Method of making dorzolamide hydrochloride |
| EP0296879A1 | Jun 23, 1988 | Dec 28, 1988 | Merck & Co., Inc. | Substituted aromatic sulfonamides as antiglaucoma agents |
| WO1994021645A1 | Mar 16, 1994 | Sep 29, 1994 | Thomas J Blacklock | ENANTIOSELECTIVE SYNTHESIS OF 5,6-DIHYDRO-(S)-4-(ETHYLAMINO)-(S)-6-METHYL-4H-THIENO[2,3-b]THIOPYRAN-2-SULFONAMIDE 7,7-DIOXIDE AND RELATED COMPOUNDS |
| WO2008135770A2 | May 7, 2008 | Nov 13, 2008 | Cipla Ltd | Process for preparing dorzolam ide |
A key advisory committee of the US Food and Drug Administration (FDA) has voted in favour of licencing a copycat version of a biological drug. If approved, Sandoz’s Zarxio (filgrastim) would be the first ‘biosimilar’ drug available in the US.
read at……..http://www.rsc.org/chemistryworld/2015/01/us-poised-approve-first-biosimilar-drug
On 7 January, the FDA’s Oncological Drugs Advisory Committee unanimously cleared Sandoz’ version of filgrastim – marketed as Neupogen by Amgen – for all five indications approved for the Amgen drug. The medication is used to prevent infection and low white blood cell counts caused by chemotherapy.
| Systematic (IUPAC) name | |
|---|---|
| Human granulocyte colony stimulating factor | |
| Clinical data | |
| Trade names | Neupogen |
| AHFS/Drugs.com | monograph |
| Legal status |
?
|
| Identifiers | |
| CAS number | 143011-72-7 |
| ATC code | L03AA02 |
| DrugBank | DB00099 |
| UNII | PVI5M0M1GW |
| ChEMBL | CHEMBL1201567 |
| Chemical data | |
| Formula | C845H1343N223O243S9 |
| Molecular mass | 18802.8 g/mol |
Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation ofgranulocytes;[1] it is a pharmaceutical analog of naturally occurring G-CSF. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. The G-CSF then produced byE. coli is different from G-CSF naturally made in humans.
Filgrastim is marketed under several brand names, including:
| Company | Brand |
|---|---|
| Cadila Pharmaceuticals | Filcad |
| Abbott Laboratories | Imumax |
| Dr. Reddy’s Laboratories | Grafeel |
| Intas Biopharmaceuticals | Neukine |
| Amgen | Neupogen[2] |
| Emcure Pharmaceuticals | Emgrast |
| Reliance Life Sciences | Religrast |
| Sandoz | Zarzio |
| Biocon | Nufil |
Apricus Biosciences is currently developing and testing a product under the brand name Nupen which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.
Filgrastim is used to treat neutropenia,[3] stimulating the bone marrow to increase production of neutrophils. Causes of neutropenia include chemotherapy and bone marrow transplantation.
Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis for use in hematopoietic stem cell transplantation.
Mechanism of Action: Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology. G-CSF regulates the production of neutrophils within the bone marrow; endogenous G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells.
G-CSF is a colony stimulating factor which has been shown to have minimal direct in vivo or in vitro effects on the production of other haematopoietic cell types.NEUPOGEN (filgrastim) is the name for recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF). ref: [1]
Filgrastim should not be used in patients with known hypersensitivity to E. coli-derived proteins.
The most commonly observed adverse effect is mild-to-moderate bone pain after repeated administration and local skin reactions at the site of injection.[4] Other observed adverse effects include serious allergic reactions (including a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), ruptured spleen (sometimes resulting in death), alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis.[4] Severe sickle cell crises, in some cases resulting in death, have been associated with the use of filgrastim in patients with sickle cell disorders.[5]
Drug interactions between filgrastim and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes; this should be considered when interpreting bone-imaging results.[6]
Filgrastim has not been studied in pregnant women and its effects on the foetus is unknown. If taking filgrastim while pregnant, it is possible that traces of the drug could be found in the baby’s blood. It is not known if the drug can get into human breast milk.
Edoxaban, DU-176b
Edoxaban (DU-176b, trade names Savaysa, Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It was developed by Daiichi Sankyo and approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.[1] It was also approved by the FDA in January 2015 for the prevention of stroke and non–central-nervous-system systemic embolism.[2]
Daiichi Sankyo receives FDA approval for anti-clotting drug Savaysa
Japanese drug-maker Daiichi Sankyo has obtained approval from US Food and Drug Administration (FDA) for its anti-clotting drug Savaysa (edoxaban tablets)..8 JAN 2015
Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery
for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642 Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825, see s[pecific page 2808 for description ie 14/31 of pdf
WO 2010071121, http://www.google.com/patents/WO2010071121A1
WO 2007032498
N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide
Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.[1]
In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.[2]
Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).
Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement[3] (phase III early results compare well to enoxaparin[4]), and for stroke prevention in patients with atrial fibrillation[5][6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.
A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.[7]
PATENT
http://www.google.com/patents/WO2014081047A1?cl=en
Chemically, edoxaban is
N1– (5-chloropyridin-2-yl) -N2– ( (IS, 2R/4S) -4- [ (dimethylamino) carbo nyl] -2- { [ ( 5-methyl-4 , 5,6, 7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl ) carbonyl] amino}eyelohexyl) ethanediamide , represented by the following formula (A) :
(A) The p-toluenesulfonic acid monohydrate salt of compound A is represented b the following formula (B) :
(B)
Edoxaban is known as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (also referred to as activated factor X or FXa) , and is useful as a preventive and/or therapeutic drug for thrombotic diseases.
Several processes are known in the literature for preparing edoxaban for example, U.S. Patent No. 7365205; U.S. Publication No . 20090105491.
U.S. Patent No. 7365205 provides a process for the preparation of edoxaban, wherein the process involves the use of
(IS, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one, represented by the following formula (C) :
(C)
as an intermediate.
The present inventors have identified that
(IS, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one, represented by the following formula (I) :
( I )
could also be used as an intermediate for the preparation of FXa inhibitory compounds like edoxaban. The present inventors have found that replacement of
(IS, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one (C) with
(IS, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one (I) has a better atom economy and also an impact on cost.
A method for the synthesis of the
(IS, 4S, 5S) -4 -bromo- 6 -oxabicyclo [3.2.1] octan-7-one (I) was reported in Tetrahedron Letters, 51, (2010) Pages 3433-3435 which involves the reaction of ( IS) -cyclohex-3 -ene- 1-carboxylic acid represented by the following formula (II) :
( Π )
with N-bromosuccinimide in the presence of molecular sieves using dichloromethane as a solvent. However, this reaction is carried out in dark over a period of 7 hours and does not provide a pure product .
Tetrahedron, Vol. 28, Pages 3393 -3399 , 1972 provides a process for the preparation of 4 -bromo- 6 -oxabicyclo [3.2.1] octan-7-one which involves the addition of 20% excess of a 2M solution of bromine in chloroform to a stirred solution of cyclohex- 3 -ene- 1-carboxylic acid (0.04 mol) in chloroform (250 mL) in the absence of a base . Extraction with aqueous sodium bicarbonate followed by acidification gave, after extraction with ether and evaporation of the extract, a mixture of cis & trans 3 , 4-dibromocyclohexanecarboxylic acid (6.7 g) and evaporation of the chloroform layer afforded the bromolactone (0.59 g) . It further provides a process for the preparation of
4 -bromo-6 -oxabicyclo [3.2.1] octan-7-one which involves the treating of cyclohex-3-ene-l-carboxylic acid (0.08 mol) dissolved in chloroform (450 mL) with 20% excess bromine in the presence of an equimolar amount of triethylamine (8.1 g) . After extraction of the amine with 2N hydrochloric acid, and work-up, bromolactone (10.7 g) and a mixture of cis & trans 3 , 4 -dibromocyclohexanecarboxylic acid (6.6 g) were obtained.
Tetrahedron Vol. 48, No. 3, Pages 539-544, 1992 provides a process for the preparation of
(IS, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one (I) which involves the addition of 1M solution of bromine in chloroform (30 mL) at 0°C to a solution of ( IS) -cyclohex-3 -ene- 1-carboxylic acid (0.024 mol) of formula (II) in chloroform (600 mL) in the presence of an equimolar amount of triethylamine (3.33 mL) . After work-up, the crude bromolactone obtained was recrystallized from petroleum ether.
However, bromination using bromine does not provide a pure product in good yield.
Heterocycles, Vol. 23, No. 8, Pages 2035-2039, 1985 provides a process for the 4-bromo-6-oxabicyclo [3.2.1] octan-7-one which involves the addition of cyclohex-3-ene-l-carboxylic acid (1.0 mM) in 1 , 2 -dimethoxyethane (2 mL) to a stirred solution of 90% Lead (IV) acetate (1.1 or 2.2 mM) in 1 , 2 -dimethoxyethane (4 mL) followed by the addition of Zinc bromide (2.2 mM) in 1 , 2 -dimethoxyethane (4 mL) and continuing the stirring for 10-30 minutes at 0°C . The reaction mixture was poured into a solution of ice-cold water (30 mL) and 10% hydrochloric acid (10 mL) , and extracted with ether (50 mL X 3) . The combined ether extract was washed successively with saturated sodium hydrogen carbonate solution (20 mL) , 10% sodium thiosulphate solution (5 mL) , and brine (10 mL) , and dried over sodium sulphate. Evaporation of the solvent gave crude lactone which were separated and purified (42% yield) . However, this reaction does not provide a pure product in good yield.
Heterocycles, Vol. 31, No. 6, Pages 987-991, 1990 provides a method for bromolactonization using a
dimethylsulfoxide-trimethylsilyl bromide-amine system. The bromolactonization is carried out for 10 to 72 hours using different solvents and triethylamine or diisopropylethyl amine as base. However, this process does not provide a product in high yield. Further the process afforded the cis isomer exclusively. Journal of the Chemical Society, Perkin Transactions 1:
Organic and Bio-Organic Chemistry (1972-1999) (1994) , (7) , Pages 847-851 provides a method for bromolactonization using a
dimethylsulfoxide-trimethylsilyl bromide-amine system. The bromolactonization is carried out for 12 hours using
dimethylsulfoxide and chloroform solvent system and triethylamine or diisopropylethyl amine as base. However, this process resulted in a low yield of about 55%. Citation List
Patent Literature
PTLl: U.S. Patent No. 7365205
PTL2: U.S. Publication No. 20090105491.
Non Patent Reference
NPLl: Feng Chen et al . , Tetrahedron Letters, 51, (2010) Pages 3433-3435.
NPL2 : G. Belluci et al . , Tetrahedron, Vol. 28, No. 13, Pages 3393-3399, 1972.
NPL3 : Marco Chini et al ., Tetrahedron Vol .48, No. 3, Pages 539-544 , 1992.
NPL4 : Y. Fujimoto et al . , Heterocycles , Vol. 23, No. 8, Pages 2035-2039, 1985.
NPL5: C. Iwata et al . , Heterocycles, Vol. 31, No. 6, Pages 987-991, 1990. –
NPL6 : K. Miyashita et al . , Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1994) , (7) , Pages 847-851.
Summary of Invention
Technical Problem
It is an object of the present invention to solve the problems associated with the prior art, and to provide an improved and efficient method for the preparation of
(IS, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one of formula (I).
Solution to Problem As a result of conducting diligent studies to attain the object, the present inventors have found that: surprisingly, the use of N-bromosuccinimide or bromohydantoin (representative is
1, 3-dibromo-5, 5-dimethylhydantoin) as brominating agent in the presence of a base selected from calcium oxide or calcium hydroxide, in specific mole ratios in a solvent selected from the group consisting of dichloromethane , toluene, tetrahydrofuran, ethyl acetate, hexanes, cyclopentyl methyl ether (CPME) or a mixture thereof can efficiently produce a pure
( IS , 4S , 5S) -4 -bromo- 6 -oxabicyclo [3.2.1] octan- 7 -one (I) in better yields. The process provides obvious benefits with respect to economics, convenience to operate at a commercial scale.
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SEE
http://www.google.co.ug/patents/US20090105491
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PATENT
http://www.google.com/patents/EP2589590A1?cl=en
FREE BASE
TOSYLATE
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PATENT
http://www.google.com/patents/EP2589590A1?cl=en
Citation ListPatent Literatures
“First market approval in Japan for LIXIANA (Edoxaban)”. Press Release. Daiichi Sankyo Europe GmbH. 2011-04-22.
| [1] | 王利华, 赵丽嘉, 李文利, 等. 直接抑制凝血因子Xa 的口服抗凝药物Edoxaban Tosilate Hydrate [J]. 药物评价研究, 2011, 34(6): 478-481. |
| [2] | Ohta T, Komoriya S, Yoshino T, et al. Preparation of N,N’-bis( heterocyclicacyl) cycloalkanediamine and heterocyclediamine derivatives as inhibitors of activated blood coagulation factor X (factor Xa): WO, 2003 000657 [P]. 2003-01-03. (CA 2003, 138: 73271) |
| [3] | Ohta T, Komoriya S, Yoshino T, et al. Preparation of heterocyclic moiety-containing diamine derivatives as FXa inhibitors: WO, 2003 000680 [P]. 2003-01-03. (CA 2003, 138: 89801) |
| [4] | Mochizuki A, Nagata T. Triamine derivative: WO, 2006106963 [P]. 2005-03-31. (CA 2006, 145: 419128) |
| [5] | Kawanami K, Ishikawa H, Shoji M. Process for preparation of optically active (1S,3R,4R)-3-amino-4-hydroxy-N,Ndimethylcyclohexanecarboxamide derivative salt: WO, 2012002538 [P]. 2012-01-05. (CA 2012, 156: 122056) |
| [6] | Sato K, Kubota K. Process for producing optically active carboxylic acid: WO, 2010067824 [P]. 2010-06-17. (CA 2010, 153: 36882) |
| [7] | Yoshikawa K, Yokomizo A, Naito H, et al. Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: Exploration of 5-6fused rings |
| [8] | as alternative S1 moieties [J]. Bioorg Med Chem, 2009, 17(24): 8206-8220. |
| [9] | Sato K, Kawanami K, Yagi T. Process for the preparation of optically active cyclohexane-1,2-diamine derivative from 7-oxabicyclo[4.1.0]heptane compound: WO, 2007032498 |
| [10] | 2007-03-22. (CA 2007, 146: 358502) |
| [11] | Kawanami K. Method for the preparation of optically active diamine derivative: WO, 2010104106 [P]. 2010-09-16. (CA 2010, 153: 406061) |
| [12] | Koyama T, Kondo S. Process for the preparation of diamine derivative: WO, 2010104078 [P]. 2010-09-16. (CA 2010, 153: 382938) |
| [13] | Suzuki T, Ono M. Crystal of diamine derivative and method of producing same: WO, 2011115066 [P]. 2011-09-22. (CA 2011, 155: 467954) |
| US8357808 | 9 Sep 2011 | 22 Jan 2013 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
| US8394821 | 13 Jul 2011 | 12 Mar 2013 | Daiichi Sankyo Company, Limited | Activated blood coagulation factor inhibitor |
| US8404847 | 17 Jun 2011 | 26 Mar 2013 | Daiichi Sankyo Company, Limited | Method for producing diamine derivative |
| US8449896 | 16 Dec 2011 | 28 May 2013 | Daiichi Sankyo Company, Limited | Pharmaceutical composition having improved solubility |
| US8541443 | 19 Sep 2012 | 24 Sep 2013 | Daiichi Sankyo Company, Limited | Crystal of diamine derivative and method of producing same |
| US20130004550 * | 22 Aug 2012 | 3 Jan 2013 | Daiichi Sankyo Company, Limited | Sustained-release solid preparation for oral use |
| WO2014081047A1 | 22 Nov 2013 | 30 May 2014 | Daiichi Sankyo Company,Limited | Process for the preparation of (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1] octan-7-one |
| Molecular Formula | C24H30ClN7O4S.C7H7HSO3 |
| Molecular Weight | 720.26 |
| CAS Registry Number | 480449-71-6 (912273-65-5) |
Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274
Citation ListPatent Literature
SIMILAR
OTHER SALTS
Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C24H30ClN7O4S · HCl
Molecular Weight: 584.52 g.mol-1
Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:
formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.
UPDATE
2-amino-5-methyl-4,5,6,7-tetrahydro thiazolone [5,4-c] pyridine
UPDATE
Edoxaban, DU-176b
1H NMR PREDICTION
………….
13 C NMR
FREE BASE
Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2,S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (5) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyrzdine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (X) (103.2 g).
1H-NMR (CDCl3) δ : 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J = 15.4 Hz), 3.75 (1H, d, J = 15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J = 8.8, 0.6 Hz), 7. 68 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 8.16 (1H, dd, J = 8.8, 0.6 Hz), 8.30 (1H, dd, J = 2. 4, 0.6 Hz), 9.72 (1H, s).
MS (ESI) m/z: 548 (M+H)+.
| Molecular Formula | C24H30ClN7O4S.C7H7HSO3 | |
| Molecular Weight | 720.26 | |
| CAS Registry Number | 480449-71-6 (912273-65-5) |
TOSYLATE
N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (6.2 g) was dissolved in methylene chloride (120 ml). To the solution, a 1 mol/L solution of p-toluenesulfonic acid in ethanol (11.28 ml) was added, and the solvent was distilled off. To the residue, 15% hydrous ethanol (95 ml) was added, and the mixture was dissolved by stirring at 60°C. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain the title compound (X-a) (7.4 g).
1H-NMR (DMSO-d6) δ : 1. 45-1. 54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 1.8 Hz), 8.46 (1H, t, J = 1.8 Hz), 8.75 (1H, d, J = 6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s).
MS (ESI) m/z: 548 (M+H)+.
Anal.: C24H30ClN7O4S·C7H8O3S·H2O
Theoretical: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69.
Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79. mp (dec.): 245-248°C.
1H NMR PREDICTION, TOSYLATE
CAS NO. 1229194-11-9, N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate H-NMR spectral analysis
![N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate NMR spectra analysis, Chemical CAS NO. 1229194-11-9 NMR spectral analysis, N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate H-NMR spectrum](https://images-blogger-opensocial.googleusercontent.com/gadgets/proxy?url=http%3A%2F%2Fpic11.molbase.net%2Fnmr%2Fnmr_image%2F2015-01-11%2F001%2F717%2F1717235_1h.png&container=blogger&gadget=a&rewriteMime=image%2F*)
13 CNMR PREDICTION, TOSYLATE
CAS NO. 1229194-11-9, N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate C-NMR spectral analysis
![N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate NMR spectra analysis, Chemical CAS NO. 1229194-11-9 NMR spectral analysis, N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate C-NMR spectrum](https://images-blogger-opensocial.googleusercontent.com/gadgets/proxy?url=http%3A%2F%2Fpic11.molbase.net%2Fnmr%2Fnmr_image%2F2015-01-11%2F001%2F717%2F1717235_13c.png&container=blogger&gadget=a&rewriteMime=image%2F*)
………………
(Example 11) N 1 – (5-Chloro-2-yl) -N 2 – [(1S, 2R, 4S)-4-(dimethylcarbamoyl) -2 – {[(5-methyl-4,5 , 6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl] Etanjiamido (X) [Production method via Compound (1-p2)]
[0137]
In 10 mL test tube, compound (5-ms) (the compound of Reference Example 8) (100 mg, 0.216 mmol), Compound (1-p2) (81.4 mg, 0.216 mmol), K 3 PO 4 (91.7 mg, 0.432 mmol) and DMF (1 mL) was added, and the mixture was stirred at room temperature conditions for 3 hours. H To the reaction mixture 2 O (2 mL) was added and the resulting slurry was stirred at room temperature overnight, the solid was filtered. The resulting solid H 2 was washed with O (1 mL), was obtained by drying under reduced pressure the title compound (110.0 mg, 92.9%) as a solid.
[0138]
1 H-NMR (500 Hz, CDCl 3 ) delta: 9.72 (s, 1H), 8.30 (dd, 1H, J = 2.5, 0.5 Hz), 8.17 (dd, 1H, J = 9.0, 0.5 Hz), 8.03 (D , 1H, J = 8.5 Hz), 7.68 (dd, 1H, J = 9.0, 2.5 Hz), 7.39 (d, 1H, J = 8.5 Hz), 4.70-4.67 (m, 1H), 4.13-4.09 (m, 1H), 3.73 (d, 1H, J = 16.0 Hz), 3.70 (d, 1H, J = 16.0 Hz), 3.06 (s, 3H), 2.96-2.93 (m, 2H), 2.95 (s, 3H), 2.89-2.79 (m, 3H), 2.52 (s, 3H), 2.14-2.06 (m, 3H), 1.96-1.90 (m, 1H), 1.84-1.78 (m, 1H), 1.69-1.62 (m, 1H ).
Edoxaban, a factor Xa inhibitor, is supplied as edoxaban tosylate monohydrate. The chemical name is N-(5-Chloropyridin-2-yl)-N’-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl- 4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl] oxamide mono (4- methylbenzenesulfonate) monohydrate. Edoxaban tosylate monohydrate has the empirical formula C24H30ClN7O4S•C7H8O3S•H2O representing a molecular weight of 738.27. The chemical structure of edoxaban tosylate monohydrate is:
 |
It is a white to pale yellowish-white crystalline powder. The solubility of edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly soluble in water, pH 3 to 5 buffer, very slightly soluble at pH 6 to 7; and practically insoluble at pH 8 to 9.
SAVAYSA is available for oral administration as a 60 mg, 30 mg, or 15 mg round shaped, film-coated tablet, debossed with product identification markings. Each 60 mg tablet contains 80.82 mg edoxaban tosylate monohydrate equivalent to 60 mg of edoxaban. Each 30 mg tablet contains 40.41 mg edoxaban tosylate monohydrate equivalent to 30 mg of edoxaban. Each 15 tablet contains 20.20 mg edoxaban tosylate monohydrate equivalent to 15 mg of edoxaban.
The inactive ingredients are: mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, and carnauba wax. The color coatings contain hypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow (60 mg tablets and 15 mg tablets), and iron oxide red (30 mg tablets and 15 mg tablets).
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide
|
|
| Clinical data | |
| Trade names | Lixiana, Savaysa |
| AHFS/Drugs.com | Monograph |
| Pregnancy category |
|
| Legal status |
|
| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | 62%; Tmax 1–2 hours |
| Protein binding | 55% |
| Metabolism | Minimal hepatic |
| Biological half-life | 10–14 hours |
| Excretion | 50% renal; <50% bile |
| Identifiers | |
| CAS Registry Number | 912273-65-5  |
| ATC code | None |
| PubChem | CID: 25022378 |
| IUPHAR/BPS | 7575 |
| ChemSpider | 8456212  |
| UNII | NDU3J18APO |
| KEGG | D09710 |
| ChEBI | CHEBI:85973 |
| Chemical data | |
| Formula | C24H30ClN7O4S |
| Molecular mass | 548.056 g/mol |
/////////
SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html
Entinostat
CAS 209783-80-2
209784-80-5 (HCl)
Bayer Schering Pharma Aktiengesellschaft
Pyridin-3-ylmethyl N-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]carbamate
Entinostat, developed by Syndax Pharmaceuticals, is an oral selective histone deacetylase (HDAC) inhibitor primarily targeting class IHDACs (HDAC1, HDAC2, and HDAC3) . It was later licensed to
Jiangsu Hengrui Medicine Co., Ltd., for development and commercialization in China. In 2024, Entinostat has been approved by the NMPA for use in combination with exemestane to treat advanced breast cancer that is HR-positive and HER2-negative.
KHK and Syndax partner for breast cancer treatment entinostat in Japan and Korea
Japan-based Kyowa Hakko Kirin (KHK) has signed a license agreement with US-based Syndax Pharmaceuticals for the exclusive rights to develop and commercialise entinostat in Japan and Korea.
TOKYO and WALTHAM, Mass., Jan. 7, 2015 /PRNewswire/ — Kyowa Hakko Kirin Co., Ltd., (Headquarters: Chiyoda-ku, Tokyo; president and CEO: Nobuo Hanai, “Kyowa Hakko Kirin”) and Syndax Pharmaceuticals, Inc., (Waltham, Mass.; president and CEO:Arlene M. Morris, “Syndax”) today jointly announced that the companies have entered into a license agreement for the exclusive rights to develop and commercialize entinostat in Japan and Korea. Entinostat is a Class I selective histone deacetylase (HDAC) inhibitor being developed by Syndax in the United States and Europe in combination with hormone therapy for advanced breast cancer and immune therapy combinations in solid tumors.
Entinostat, also known as SNDX-275 and MS-275, is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers.[1]
Entinostat inhibits class I HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively.[2]
Entinostat (formerly known as MS-275) is a histone deacetylase (HDAC) inhibitor in phase III clincal trials at Syndax in combination with exemestane for the treatment of advanced HR-positive breast cancer.
Entinostat (MS-275) preferentially inhibits HDAC1 (IC50=300nM) over HDAC3 (IC50=8µM) and has no inhibitory activity towards HDAC8 (IC50>100µM). MS-275 induces cyclin-dependent kinase inhibitor 1A (p21/CIP1/WAF1), slowing cell growth, differentiation, and tumor development in vivo. Recent studies suggest that MS-275 may be particularly useful as an antineoplastic agent when combined with other drugs, like adriamycin.
In September 2013, Syndax Pharmaceuticals entered into a licensing, development and commercialization agreement with Eddingpharm in China and other asian countries. In 2013, a Breakthrough Therapy Designation was assigned to the compound for the treatment of locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer when added to exemestane in postmenopausal women whose disease has progressed following non-steroidal aromatase inhibitor therapy.
There is an ongoing phase II trial studying the effect of entinostat on Hodgkin’s lymphoma.[3] It is in other phase II trials for advanced breast cancer (in combination with aromatase inhibitors)[4] and for metastatic lung cancer (in combination with erlotinib).[5] As of September 2013, the Food and Drug Administration is working with the industry to design phase III clinical trials. They seek to evaluate the application of Entinostat for the reduction, or prevention of, treatment resistance to aromatase inhibitors in hormone receptor positive breast cancer.[6] Syndax pharmaceuticals currently holds the rights to Entinostat and recently received $26.6 million in funds to advance treatments of resistant cancers using epigenetic tools.[7]
PHASE 3………..SYNDAX, BREAST CANCER
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Entinostat, developed by Syndax Pharmaceuticals, is an oral selec
tive histone deacetylase (HDAC) inhibitor primarily targeting class I
HDACs (HDAC1, HDAC2, and HDAC3) [7]. It was later licensed to
Jiangsu Hengrui Medicine Co., Ltd., for development and commercial
ization in China. In 2024, Entinostat has been approved by the NMPA for
use in combination with exemestane to treat advanced breast cancer that
is HR-positive and HER2-negative. This approval is specifically for pa
tients whose disease has progressed following prior endocrine therapy
[8]. Entinostat inhibits HDACs, increasing histone acetylation and
reactivating tumor suppressor genes. This mechanism restores sensi
tivity to endocrine therapy and prevents cancer cell proliferation [9].
The therapeutic agent exerts its effects by modulating the tumor
microenvironment through the suppression of immune regulatory cells,
thereby augmenting the immune response. Its clinical efficacy was
confirmed in the E2112 trial (NCT02115282), a global Phase III study.
When used in combination with exemestane, Entinostat demonstrated
the ability to extend PFS in patients with HR-positive, HER2-negative
breast cancer [10]. The median PFS was significantly extended to 6.32
months, contrasting with the 3.72 months observed in the control
cohort. In terms of safety profile, Entinostat demonstrated favorable
tolerability. The frequently encountered adverse events were primarily
neutropenia, fatigue, and nausea. Severe neutropenia occurred in 43 %
of patients but was manageable with supportive care. Liver function
abnormalities were reported but manageable with dose adjustments
[11].
The synthetic route of Entinostat is shown in Scheme 2 [12].
Enti-001 is first treated with trifluoroacetic anhydride to afford
Enti-002. Reaction of Enti-002 with oxalyl chloride yields the acyl
chloride intermediate, which undergoes condensation with Enti-003 to
form Enti-004. Subsequent alkaline hydrolysis of Enti-004 produces
Enti-005. This compound is activated with CDI followed by reaction
with Enti-006 to generate Enti-007. The synthesis concludes with acidic removal of the Boc protecting group from Enti-007, yielding Entinostat
[8] W. Li, Z. Sun, Mechanism of action for HDAC inhibitors-insights from omics
approaches, Int. J. Mol. Sci. 20 (2019) 1616.
[9] N. Bharathy, N.E. Berlow, E. Wang, J. Abraham, T.P. Settelmeyer, J.E. Hooper, M.
N. Svalina, Z. Bajwa, M.W. Goros, B.S. Hernandez, J.E. Wolff, R. Pal, A.M. Davies,
A. Ashok, D. Bushby, M. Mancini, C. Noakes, N.C. Goodwin, P. Ordentlich, J. Keck,
D.S. Hawkins, E.R. Rudzinski, A. Mansoor, T.J. Perkins, C.R. Vakoc, J.E. Michalek,
C. Keller, Preclinical rationale for entinostat in embryonal rhabdomyosarcoma,
Skelet Muscle 9 (2019) 12.
[10] B. Xu, Q. Zhang, X. Hu, Q. Li, T. Sun, W. Li, Q. Ouyang, J. Wang, Z. Tong, M. Yan,
H. Li, X. Zeng, C. Shan, X. Wang, X. Yan, J. Zhang, Y. Zhang, J. Wang, L. Zhang,
Y. Lin, J. Feng, Q. Chen, J. Huang, L. Zhang, L. Yang, Y. Tian, H. Shang, Entinostat,
a class I selective histone deacetylase inhibitor, plus exemestane for Chinese
patients with hormone receptor-positive advanced breast cancer: a multicenter,
randomized, double-blind, placebo-controlled, phase 3 trial, Acta Pharm. Sin. B 13
(2023) 2250–2258.
[11] E.T. Roussos Torres, W.J. Ho, L. Danilova, J.A. Tandurella, J. Leatherman, C. Rafie,
C. Wang, A. Brufsky, P. LoRusso, V. Chung, Y. Yuan, M. Downs, A. O’Connor, S.
M. Shin, A. Hernandez, E.L. Engle, R. Piekarz, H. Streicher, Z. Talebi, M.A. Rudek,
Q. Zhu, R.A. Anders, A. Cimino-Mathews, E.J. Fertig, E.M. Jaffee, V. Stearns, R.
M. Connolly, Entinostat, nivolumab and ipilimumab for women with advanced
HER2-negative breast cancer: a phase Ib trial, Nat Cancer 5 (2024) 866–879.
[12] T. Suzuki, T. Ando, K. Tsuchiya, T. Nakanishi, A. Saito, S. Yamashita, G. Shiraishi,
E. Tanaka, Preparation of Benzamide Derivatives as Anticancer Agents, 1998
JP10152462
SEE SCHEME AT END
Patent
http://www.google.im/patents/WO2010022988A1?cl=en
In EP 0 847 992 A1 (which co-patent is US 6,794,392) benzamide derivatives as medicament for the treatment of malignant tumors, autoimmune diseases, de- rmatological diseases and parasitism are described. In particular, these derivatives are highly effective as anticancer drugs, preferred for the haematological malignancy and solid tumors. The preparation of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide is described on page 57, Example 48. The compound is neither purified by chromatography nor purified by treatment with charcoal. The final step of the process comprises the re- crystallization from ethanol.
Said compound has a melting point (mp) of 159 – 160 0C.
The IR spectrum shows the following bands: IR(KBr) cm“1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form.
In EP 0 974 576 B1 a method for the production of monoacylated phenylenediamine derivatives is described. The preparation of N-(2- aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl] benzamide is described on pages 12 to 13, Example 6. The final step of the process comprises the purification of the compound via silica gel column chromatography.
Said compound has a melting point (mp) of 159 – 160 0C.
The IR spectrum shows the following bands: IR(KBr) cm‘1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form. In J. Med. Chem. 1999, 42, 3001-3003, the synthesis of new benzamide derivatives and the inhibition of histone deacetylase (HDAC) is described. The process for the production of N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth- oxycarbonylaminomethyl] benzamide is described. The final step of the process comprises the purification of the compound via silica gel column chromatography (ethyl acetate).
Said compound has a melting point (mp) of 159 – 160 0C.
The IR spectrum shows the following bands: IR(KBr) cm‘1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form.
In WO 01/12193 A1 a pharmaceutical formulation comprising N-(2- aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl]benzamide is described.
In WO 01/16106 a formulation comprising N-(2-aminophenyl)-4-[N-(pyridine-3- yl)methoxycarbonylamino-methyl]benzamide, having an increased solubility and an improved oral absorption for benzamide derivatives, and pharmaceutically acceptable salts thereof are described.
In WO 2004/103369 a pharmaceutical composition is described which comprises histone deacetylase inhibitors. That application concerns the combined use of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino- methyl]benzamide together with different cancer active compounds. In fact that application is a later application, which is based on the above mentioned matter and thus concerns the Polymorph A form. Finally, JP 2001-131130 (11-317580) describes a process for the purification of monoacylphenylenediamine derivatives. In Reference Example 2, the process for the production of crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth-oxycarbonylaminomethyl] benzamide is described. Said compound has a melting point (mp) of 159 – 160 0C,
The IR spectrum shows the following bands: IR(KBr) cm“1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form.
Moreover, Working Example 1 describes the purification of crude N-(2- aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethyl] benzamide in aqueous acid medium together with carbon The final crystallization is done under aqueous conditions at 40-500C.
Following the description to that example it can be seen from the Comparative Examples 1 – 3 that the crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth- oxycarbonylaminomethyl] benzamide is not purified by dissolution under reflux conditions in either ethanol, methanol or acetonithle followed by a recrystalliza- tion at 2°C. As a result, these recrystallisations do not yield any pure compound.
In addition a “purification” of crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethyl] benzamide in ethanol under reflux conditions to- gether with carbon is dechbed. After filtering off the carbon the compound is re- crystallized at 2°C. The purification effect of this method is very limited. 1 ,1 % of an impurity remain in the N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethyl] benzamide. As a result, this procedure does not yield any pure compound.
None of the state of the art documents refer to a polymorph B of N-(2- aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl]benzamide and no physicochemical features of said compound are known. Several biological and clinical studies have been done with N-(2-aminophenyl)- 4-[N-(pyridine-3-yl) meth-oxycarbonylaminomethyl] benzamide. For example, Kummar et al., Clin Cancer Res. 13 (18), 2007, pp 5411-5417 describe a phase I trial of N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth-oxycarbonylaminomethyl] benzamide in refractory solid tumors. The compound was applied orally.
The crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]- benzamide of step a) can be produced according to the method described in example 6 of EP 0974 576 B1.
PATENT
http://www.google.co.in/patents/EP0974576A2?cl=en
Example 6Synthesis of N-(2-aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide (an example in which after activation with N,N’-carbonyldiimidazole, an acid was added to carry out reaction)
| Retention Time/min. | Area % | |
| Benzoylimidazole as Active Intermediate | 4.3 | 0.00 |
| Monoacylated Phenylenediamine | 4.7 | 98.91 |
| Diacylated Phenylenediamine | 11.7 | 1.09 |
Analysis data of the product
mp. 159-160°C
1H NMR (270MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J=5.9Hz), 4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J=7.3Hz), 6.78 (1H, d, J=7Hz), 6.97 (1H, t, J=7Hz), 7.17 (1H, d, J=8Hz), 7.3-7.5 (3H, m), 7.78 (1H, d, J=8Hz), 7.93 (2H, d, J=8Hz), 8.53 (1H, d, J=3.7Hz), 8.59 (1H, s), 9.61 (1H, s).
IR (KBr) cm-1: 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742
PATENT
WO 2009076206
http://www.google.com/patents/WO2009076206A1?cl=en
Suzuki et al (Suzuki et al Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives, J Med Chem 1999, 42, (15), 3001-3) discloses benzamide derivatives having histone deacetylase inhibitory activity and methods of making benzamide derivatives having histone deacetylase inhibitory activity. Suzuki et al is hereby incorporated herein by reference in its entirety.
[18] An example of the synthesis method of Suzuki et al to produce MS-275 via a three- step procedure in 50.96% overall yield is outlined in Scheme 3 below.
Scheme 3: Previous Procedure for Synthesis of MS-275 en rt, 4h
(used without purification)
[Overall yield: 0.91 x 0.56 x 100 = 50.96%;
MS-275 [19] In addition to the modest overall yield, the procedure of Suzuki et al has other disadvantages, such as a tedious method for the preparation of an acid chloride using oxalyl chloride and requiring the use of column chromatography for purification.
The synthesis of MS-275 is shown below in Scheme 4 as an example of Applicants invention of a two-step procedure: [37] Scheme 4: Preparation of MS-275
Scheme 4: New Synthesis of MS-275 (4)
Condensation of 3-(hydroxymethyl)pyridine (7) and 4-(aminomethyl)benzoic in the presence of CDI gave 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic Acid (8) in 91.0% yield. In the previous method of Suzuki et ah, the carboxylic acid derivative 8 was first converted into acyl chloride hydrochloride by treatment of oxalyl chloride in toluene and then reacted with imidazole to form the acylimidazole intermediate. (Suzuki et al., Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 1999, 42, (15), 3001-3.). However, Applicants synthesized the imidazolide of intermediate 8 by treatment with CDI at about 55-60 0C in THF. The imidazolide was cooled to ambient and further reacted in situ with 1,2-phenylenediamine in the presence of TFA to afford MS-275
(4).
Experimental Section
[62] iV-(2-Aminophenyl)-4-[iV-(pyridin-3-ylmethoxycarbonyl) aminomethyl] benzamide (4, MS-275).
[63] To a suspension of 4-[N-(Pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic
Acid (5.0 g, 0.017 mol) in THF (100 mL) was added CDI (3.12 g, 0.019 mol), and the mixture stirred for 3 h at 60 0C. After formation of acylimidazole the clear solution was cooled to room temperature (rt). To this was added 1,2-phenylenediamine (15.11 g, 0.14 mmol) and trifluoroacetic acid (1.2 mL, 0.015 mol) and then stirred for 16 h. The reaction mixture was evaporated to remove THF and crude product was stirred in a mixture of hexane and water (2:5, v/v) for 1 h and filtered and dried. The residue was stirred in dichloromethane twice to afford pure MS-275 (4) as off white powder 5.25 g, 80% yield:
mp 159-160 * C; IR (KBr) 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742 cm“1.
1H NMR (DMSO-J6) δ 4.28 (d, 2H, J = 5.9 Hz), 4.86 (s, 2H), 5.10 (s, 2H), 6.60 (t, IH, J = 7.3 Hz), 6.78 (d, IH, J = 7 Hz), 6.97 (t, IH, J= 7 Hz), 7.17 (d, IH, J= 8 Hz), 7.3-7.5(m, 3H), 7.78 (d, IH, J= 8 Hz), 7.93 (d, 2H, J = 8 Hz), 8.53 (d, IH, J = 3.7 Hz), 8.59 (s, IH), 9.61 (s, IH);
HRMS: calcd 376.1560 (C2iH2oN4θ3), found 376.1558. These spectral and analytical data are as previously reported in J Med Chem 1999, 42, (15), 3001-3.
[64] 4-[7V-(Pyridin-3-ylmethoxycarbonyI)aminomethyl] benzoic Acid (8) may be prepared as follows. To a suspension of l, l’-carbonyldiimidazole (CDI, 25.6 g, 158 mmol) in THF (120 mL) was added 3-pyridinemethanol (7, 17.3 g, 158 mmol) in THF (50 mL) at 10 0C, and the mixture stirred for 1 h at rt. The resulting solution was added to a suspension of 4-(aminomethyl)benzoic acid (22.6 g, 158 mmol), DBU (24.3 g, 158 mmol), and triethylamine (22.2 mL, 158 mmol) in THF (250 mL). After stirring for 5 h at rt, the mixture was evaporated to remove THF and then dissolved in water (300 mL). The solution was acidified with HCl (pH 5) to precipitate a white solid which was collected by filtration, washed with water (300 mL) and methanol (50 mL), respectively, and dried to yield pure 8 (41.1 g, 91% yield):
mp 207-208 0 C;
IR (KBr) 3043, 1718, 1568, 1434, 1266, 1 108, 1037, 984, 756 cm4; 1H NMR (DMSO-^6) δ 4.28 (d, 2H, J= 5.9 Hz), 5.10 (s, 2H), 7.3-7.5 (m, 3H), 7.7-8.1 (m, 4H), 8.5-8.7 (m, 2H). These spectral and analytical data are as previously reported in Suzuki et al, J Med Chem 1999, 42, (15), 3001-3.
PAPER
Volume 18, Issue 11, 1 June 2010, Pages 3925–3933
http://www.sciencedirect.com/science/article/pii/S0968089610003378
PAPER
see
Bioorg Med Chem 2008, 16(6): 3352
http://www.sciencedirect.com/science/article/pii/S0968089607010577
PAPER
see
Bioorganic and Medicinal Chemistry Letters, 2004 , vol. 14, 1 pg. 283 – 287
http://www.sciencedirect.com/science/article/pii/S0960894X03010539
PAPER
J Med Chem 1999, 42(15): 3001
http://pubs.acs.org/doi/abs/10.1021/jm980565u
N-(2-Aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide (1, MS-275). To a solution of imidazole (0.63 g, 9.2 mmol) in THF (20 mL) was added 3 (1 g, 2.9 mmol), and the mixture stirred for 1 h at room temperature. After imidazole hydrochloride was removed by filtration, 1,2-phenylenediamine (2.52 g, 23.2 mmol) and trifluoroacetic acid (0.2 mL, 2.6 mmol) were added to the filtrate and stirred for 15 h. The reaction mixture was evaporated to remove THF and partitioned between ethyl acetate (500 mL) and water (400 mL). The organic layer was washed with water and dried and then purified by silica gel column chromatography (ethyl acetate) to give 1 (0.62 g, 56% yield):
mp 159−160 °C;
1H NMR (DMSO-d6) δ 4.28 (d, 2H, J = 5.9 Hz), 4.86 (s, 2H), 5.10 (s, 2H), 6.60 (t, 1H, J = 7.3 Hz), 6.78 (d, 1H, J = 7 Hz), 6.97 (t, 1H, J = 7 Hz), 7.17 (d, 1H, J = 8 Hz), 7.3−7.5(m, 3H), 7.78 (d, 1H, J = 8 Hz), 7.93 (d, 2H, J = 8 Hz), 8.53 (d, 1H, J = 3.7 Hz), 8.59 (s, 1H), 9.61 (s, 1H);
IR (KBr) 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742 cm-1.
Anal. (C21H20N4O3) C, H, N.
………………………………………………………………………..
see
Bulletin of the Korean Chemical Society, 2014 , vol. 35, 1 pg. 129 – 134
http://koreascience.or.kr/article/ArticleFullRecord.jsp?cn=JCGMCS_2014_v35n1_129
PAPER
see
ChemMedChem, 2013 , vol. 8, 5 pg. 800 – 811
PAPER
see
ACS Medicinal Chemistry Letters, 2013 , vol. 4, 10 pg. 994 – 999
http://pubs.acs.org/doi/full/10.1021/ml400289e
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| EP0847992B1 * | Sep 30, 1997 | Jun 23, 2004 | Schering Aktiengesellschaft | Benzamide derivatives, useful as cell differentiation inducers |
| US7244751 * | Feb 2, 2004 | Jul 17, 2007 | Shenzhen Chipscreen Biosciences Ltd. | N-(2-amino-5-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide or other derivatives for treating cancer and psoriasis |
| Reference | ||
|---|---|---|
| 1 | * | MAI A: ‘Histone deacetylation in epigenetics: an attractive target for anticancer therapy‘ MED RES REV. vol. 25, no. 3, May 2005, pages 261 – 309 |
| 2 | * | SUZUKI T ET AL.: ‘Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives‘ J MED CHEM. vol. 42, no. 15, 29 July 1999, pages 3001 – 3003 |
| Names | |
|---|---|
| Preferred IUPAC name(Pyridin-3-yl)methyl ({4-[(2-aminophenyl)carbamoyl]phenyl}methyl)carbamate | |
| Other namesSNDX-275; MS-275 | |
| Identifiers | |
| CAS Number | 209783-80-2 |
| 3D model (JSmol) | Interactive image |
| ChEBI | CHEBI:132082 |
| ChEMBL | ChEMBL27759 |
| ChemSpider | 4111 |
| ECHA InfoCard | 100.158.999 |
| IUPHAR/BPS | 7007 |
| KEGG | D09338 |
| PubChem CID | 4261 |
| UNII | 1ZNY4FKK9H |
| CompTox Dashboard (EPA) | DTXSID0041068 |
InChI | |
| SMILES | |
| Properties | |
| Chemical formula | C21H20N4O3 |
| Molar mass | 376.4085 g/mol |
| Pharmacology | |
| ATC code | L01XH05 (WHO) |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).verify (what is ?)Infobox references | |
/////////////////approvals 2024, china 2024, Entinostat, SNDX 275, MS 275, Syndax, BAY 86-5274, BAY86-5274
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……
Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with awavelength of 693 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels.[1][2]
Verteporfin is also used off-label for the treatment of central serous retinopathy.[3]
Verteporfin, otherwise known as benzoporphyrin derivative (trade name Visudyne®), is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with a wavelength of 693 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels.
Verteporfin is given intravenously, 15 minutes before laser treatment.[1]
VISUDYNE® (verteporfin) for Injection is a light activated drug used inphotodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:
The chemical names for the verteporfin regioisomers are:
9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzo[b]porphine-9,13-dipropanoate
The molecular formula is C41H42N4O8 with a molecular weight of approximately 718.8. Each mL of reconstituted VISUDYNE contains:
| ACTIVE: | Verteporfin, 2 mg |
| INACTIVES: | Lactose, egg phosphatidylglycerol, dimyristoyl phosphatidylcholine, ascorbyl palmitate and butylated hydroxytoluene |
Most common side effects are blurred vision, headache, and local effects at the injection site. Also, photosensitivity; it is advised to avoid exposure to sunlight and unscreened lighting until 48 hours after the injection of verteporfin.[1]
None known. Verteporfin has no influence on the liver enzyme CYP3A4, which metabolises many pharmaceutical drugs.[1]
…………………..
http://www.google.com/patents/WO2011017809A1?cl=en
Verteporfin (CAS # 129497-78-5) is a benzoporphyrin derivative which has been used clinically for photodynamic therapy of age related macular degeneration (23).
Verteporfin is photoactivated for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular
degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with a wavelength of 693 ran in the presence of oxygen, the photoactivated verteporfin produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels. Benzoporphoryrins, are described for example, in US patents 5,095,030, 5,214,036, and 6,008,241.
Verteporfin (CAS # 129497-78-5) as used herein may include the two regioisomers as shown below:
and the 2 entantiomers of each of the two regioisomers as shown below:
The verteporfin as disclosed herein contains at least one chiral center and thus may exist in various stereoisomeric forms. If desired, such stereoisomers, including enantiomers, may be separated using techniques standard in the art (for example, chiral columns). However, racemic mixtures or mixtures containing more than one diastereomer may also be used and are contenplated herein. However, the compounds tested herein were in either of the trans entantiomers shown above. The compounds shown in Formulas IA, IB, Tables 1, 2 and Figure 10, are representative of the individual optical isomers, enantiomers or diastereomers as the case may be, as well as mixtures of these individual chiral isomers.
Visudyne™, as used herein, is the liposomal formulation of verteporfin used in humans for photodynamic therapy. Visudyne™ is given intravenously, usually within 15 minutes prior to laser treatment to eliminate the abnormal blood vessels in the eye in the treatment of wet macular degeneration. The verteporfin compound accumulates in these abnormal blood vessels and, when stimulated by a nonthermal red light laser with a wavelength of 693 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels. Patients given Visudyne™ experience photosensitivity and are advised to avoid exposure to sunlight and unscreened lighting for at least 48 hours after the injection of verteporfin.
In contrast to the current use of verteporfin in photodynamic therapy, subjects administered the BPDs described herein, in accordance with the methods and uses described herein, do not require photoactivation of the BPD via nonthermal red light laser with a wavelength of 693 nm or otherwise. The activity of the BPDs to inhibit early stage autophagy is independent of the activity associated with photoactivation and would likely be hindered by photoactivation. Accordingly, a person of skill in the art would appreciate that the precautions associated with photosensitivity should also apply to the present methods and uses (i.e. avoid exposure to sunlight and unscreened lighting for at least 48 hours after the injection of of the BPD).
| Patent | Submitted | Granted |
|---|---|---|
| Photodynamic therapy for the treatment of hair loss [US7090691] | 2004-01-22 | 2006-08-15 |
| PHOTOTHERAPY METHODS AND DEVICES COMPRISING EMISSIVE ARYL-HETEROARYL COMPOUNDS [US2012015998] | 2012-01-19 | |
| PHOTOTHERAPY DEVICES AND METHODS COMPRISING SUBSTITUTED CARBAZOLE COMPOUNDS [US2012016449] | 2012-01-19 | |
| PHOTODYNAMIC THERAPY FOR THE TREATMENT OF HAIR LOSS [US2008056996] | 2008-03-06 | |
| FACTOR VII CONJUGATES FOR SELECTIVELY TREATING NEOVASCULARIZATION DISORDERS [US2008206227] | 2008-08-28 | |
| Factor VII conjugates for selectively treating neovascularization disorders [US2006052286] | 2006-03-09 | |
| Methods of treating neuralgic pain [US2004220167] | 2004-11-04 |
| Systematic (IUPAC) name | |
|---|---|
| 3-[(23S,24R)-14-ethenyl-5-(3-methoxy-3-oxopropyl)-22,23-bis(methoxycarbonyl)-4,10,15,24-tetramethyl-25,26,27,28-tetraazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1,3,5,7,9,11(27),12,14,16,18(25),19,21-dodecaen-9-yl]propanoic acid | |
| Clinical data | |
| Trade names | Visudyne |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a607060 |
| Pregnancy cat. |
|
| Legal status | |
| Routes | Intravenous |
| Identifiers | |
| CAS number | 129497-78-5 |
| ATC code | S01LA01 |
| PubChem | CID 5362420 |
| DrugBank | DB00460 |
| ChemSpider | 21106402 |
| UNII | 0X9PA28K43 |
| KEGG | D01162 |
| ChEBI | CHEBI:60775 |
| ChEMBL | CHEMBL2218885 |
| Chemical data | |
| Formula | C41H42N4O8 |
| Molecular mass | 718.794 g/mol |
The ICH has recently published a Business Plan and a Concept Paper on the elaboration of a Q&A document on the ICH Q11 Guideline. Read more here.
ICH announces Q&A Document on Q11 Guideline – Main Focus: API Starting Materials
The ICH Q11 Guideline entitled “Development and Manufacture of Drug Substances” from May 2012 has been implemented in the three ICH regions EU, USA and Japan for 2 years now. It describes the approach to developing APIs based on an in-depth understanding of the manufacturing process and adequate strategies to control this process. The document indicates what information should be provided about the quality of the API in Module 3 of the CTD (Common Technical Document) within the framework of a marketing authorisation application.
In the meantime, there has been an accumulation of cases where the applicant and the regulatory authorities adopted different positions with regard to the interpretation of the requirements in this guideline. Particularly, this concerned the definition of starting materials for the manufacture of APIs. The standards according to which regulatory authorities accept a specific compound as a starting material are far from uniform across the 3 ICH regions, and, all the more across Europe. It is thus obvious that this – in the context of global authorisation procedures – costs a lot of time, energy and money.
The ICH has now faced this problem and created an Implementation Working Group (IWG) which has the task of elaborating a Q&A document on API Starting Materials. As is usual in such circumstances (see also our News from 10 December 2014), the ICH has justified the necessity of the Q&A document in a Business Plan and a Concept Paper – both entitled “Q11: Q&As on Selection and Justification of Starting Materials for the Manufacture of Drug Substances”. (Business Plan and Concept Paper are the 1st step of the ICH procedure consisting of 5 steps. The last step always ends with a “Harmonised Tripartite Guideline”.)
The Concept Paper provides further details about the benefits expected of the Q&A document for the industry, authorities and patients:
This Question-&-Answer document is certainly interesting for all those confronted with diverse regulatory expectations regarding starting materials in relation to supra-regional registration and marketing authorisation procedures. Yet, according to the timing indicated in both the Business Plan and the Concept Paper, a first draft of this document (as Step 2a/b) should be released in one year at the earliest, namely in November 2015.
CARIPRAZINE
CAS 839712-12-8 (free base)
CAS 1083076-69-0…HYDROCLORIDE SALT
trans-N-[4-[2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-dimethylurea
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea
trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine
trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea
IN PHASE 3 FOR MAJOR DEPRESSION
Cariprazine (RGH-188) is an antipsychotic drug under development by Gedeon Richter. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.[1] Positive Phase III study results were published for schizophrenia and maniaearly 2012, while Phase II studies in bipolar disorder I, and for bipolar depression are in progress.[2] Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder [3]
Forest Laboratories obtained a license on development (from the Richter – Hungary) and exclusive commercial rights in the US in 2004.
NEWS………….DUBLIN and BUDAPEST, Hungary, Jan. 6, 2015 /PRNewswire/ — Actavis plcand Gedeon Richter Plc. today announced that the U.S. Food and Drug Administration (FDA) has acknowledged receipt of Actavis’ New Drug Application (NDA) resubmission for its atypical antipsychotic cariprazine, a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors. The Prescription Drug User Fee Act (PDUFA) date is expected to be in the second quarter of 2015…….
Production building of the company in Budapest
Cariprazine is currently in clinical trials for schizophrenia and bipolar disorder. It has also been investigated as a potential adjunct in treatment-resistant major depressive disorder.[4]
Illustrated Pill Packaging
The most prevalent side effects for cariprazine include akathisia, insomnia, and weight gain. Cariprazine does not appear to impact metabolic variables or prolactin levles, and unlike many other antipsychotics, does not increase the electrocardiogram (ECG) QT interval. In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as “not greatly different from that seen in patient treated with placebo”[5] but a second called the incidence of movement-related disorders “rather high”[6][7] .
Cariprazine acts as an antipsychotic that is effective against the positive and negative symptoms of schizophrenia.[8] Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist. It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia.[9] Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine’s high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors.[8] Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[8][10] In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted.[8] This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.
Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity.[11] In monkey studies, the administration of increasing does of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94 % occupied, while at the lowest dose (1 μg/kg), receptors were 5 % occupied.[10]
| Receptor | Ki (nM)[4] | Pharmacodynamic action[4] |
|---|---|---|
| 5-HT1A | 3 | Partial agonism |
| 5-HT2A | 19 | Inverse agonism/antagonism |
| 5-HT2B | 0.58 | Inverse agonism/Antagonism |
| 5-HT2C | 134 | Inverse agonism/Antagonism |
| 5-HT7 | 111 | Antagonism |
| D2S | 0.69 | Partial agonism |
| D2L | 0.49 | Partial agonism |
| D3 | 0.085 | Partial agonism |
| H1 | 23 | Inverse agonism/antagonism |
Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic.[2] In rats, the oral bioavailability was 52 % (with a dose of 1 mg/kg).[7]
………………………
PATENT
http://www.google.com/patents/EP1663996A1?cl=en
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 )
Example 1 1-(2,3-dichlorophenyl)-[1,4]diazepine (starting material)
2.25 g (10 mmol) 1-bromo-2,3-dichloro-benzene was dissolved in dry toluene (50 ml), 2.3 (11 mmol) of [1 ,4]diazepine-1 -carboxylic acid tert-butylester was added followed by 0.2 g BINAP (2,2-bis(diphenylρhosphino)-1 ,1′-binaphtyl), 85 mg tris(dibenzylideneacetone)dipalladium(0) and 1.2 g (12mmol) sodium-tert-butoxyde. The reaction mixture was refluxed for eight hours and filtered. The organic layer was washed with water, dried and evaporated in vacuo. The residue was purified by chromatography and deprotected at 10 °C using 20 ml ethylacetate saturated with gaseous hydrochloric acid, the precipitate was filtered giving 2.1 g (yield: 75 %) hydrochloride salt of the title compound, melting at 182-3 °C. Example 2 Trans-N-{4-[2-[4-(2,3-dichloro-phenyl)-hexahydro-[1 ,4]diazepin-1-yl]-ethyl]- cyclohexyl}-carbamic acid tert-butylester (intermediate) 0.7 g (2.5 mmol) of 1 -(2,3-dichlorophenyl)-[1 ,4]diazepine hydrochloride and
0.6 g (2.5 mmol) of frat?s-2-{1 -[4-(N-tert-butyloxycarbonyl)amino]cyclohexyl}- acetaldehyde were dissolved in dichloroethane (35 ml), 0.35 ml (2.5 mmol) triethylamine was added, then 0.79 g (3.7 mmol) sodium triacetoxyborohydride was added portionswise and the reaction mixture was stirred for 20 hours at ambient temperature, then 20 % potassium carbonate solution in water (20 ml) was added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to give the title compound 1 .0 g (yield: 85.8 %), m.p.: 95-8 °C. Example 3
Trans-4-[2-[4-(2,3-dichloro-phenyl)-hexahydro-[1 ,4]diazepin-1-yl]-ethyl]- cyclohexylamine (intermediate)
0.93 g (2.1 mmol) frarjs-N-{4-[2-[4-(2,3-dichloro-phenyl)-hexahydro- [1 ,4]diazepin-1 -yl]-ethyl]-cyclohexyl}-carbamic acid tert-butylester was deprotected at
10 °C using 15 ml ethylacetate saturated with gaseous hydrochloric acid, after 4 hours the precipitate was filtered giving 0.91 g (yield: 98 %) dihydrochloride salt of the title compound, melting at 260-6 °C. Method A
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yi]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 ) 1 .39g (3 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-ρiperazin-1 -yl]-ethyl}- cyclohexyl-amine trihydrochloride was suspended in dichloromethane (100 ml), triethylamine (2.1 ml, 15 mmol) was added followed by 0.30 ml (3.3 mmol) N,N- dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature, filtered. The filtrate was washed with water (2 x 20 ml), dried and evaporated in vacuo. Recrystallizing from methanol gave the title compound (0.83 g, 65 %), melting at 212-4 °C.
Method B
7rans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-ethyl- urea (compound 2) 0.56g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}- cyclohexyl-amine was dissolved in dry dichloromethane (20 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was stirred with water, the precipitate was filtered, giving the title compound (0.33 g, 65 %). Melting point:
235-8 °C.
Method C rrans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 )
0.56g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}- cyclohexyl-amine trihydrochloride was suspended in dry dichloromethane (50 ml), triethylamine 0.77 ml, 6 mmol) was added and 0.13g (0.44 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature dimetilamine hydrochloride (0.49 g, 6 mmol) followed by triethylamine (0.84 ml, 6 mmol) was added and the stirring was continued for 20 hours. The mixture was filtered, the filtrate washed with water, dried and evaporated in vacuo. Recrystallizing the product from methanol gave the title compound (0.27 g, 52 %). Melting point: 212-4 °C.
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PATENT
http://www.google.com/patents/US20090023750
U.S. Patent Publication No. 2006/0229297 discloses (thio)-carbamoyl-cyclohexane derivatives that are D3 and D2 dopamine receptor subtype preferring ligands, having the formula (I):
(I)
wherein R1, R2, X, and n are as defined therein. One particular compound disclosed therein is trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, which is also known as trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, the structural formula for which is shown below:
Compounds of formula (I) act as a dopamine receptor antagonists, particularly D3/D2 receptor antagonists, and are useful in the treatment and prevention of pathological conditions which require modulation of dopamine receptors.
In some cases, an appropriate salt of an active may improve certain properties suitable for pharmaceutical compounds (i.e., stability, handling properties, ease of large scale synthesis, etc.). However, selection of a suitable salt for a particular active agent is not always straightforward, since the properties of salts of different compounds formed with the same salt forming agent may differ greatly. Moreover, formation of particular salts of a compound possessing more than one basic centre may be difficult to achieve in high yield due to formation of multiple products.
…………………..
see
WO 2011073705
http://www.google.com/patents/WO2011073705A1?cl=en
We have surprisingly found that by reacting trans 4-{2-[4-(2,3-dichlorophenyl)- piperazine-l-yl]-ethyl}-cyclohexylamine of formula (III)
with a carbonic acid derivative of general formula (VI)R-O-CO-Z (VI)
then reacting the compound of general formula (IV) obtained
with an amine derivative of general formula (V)
get the compounds of general formula (I)
EXAMPLES
The invention is illustrated by the following non-limiting examples.
Example 1
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid methylester 6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The so obtained suspension was added to a solution of 2.3 ml (0.03 mol) methyl chloroformate in 25 ml of dichloromethane at a temperature between 5-10°C. The reaction mixture obtained was stirred at a temperature between 20-25°C for 3 hours then extracted with 3×150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue was recrystallized from methanol. In this manner 4.5 g of the title product was obtained.
Yield: 72 %.
Melting point: 143-147 °C
Example 2
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid isopropylester
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C-on for one hour. The suspension was added to a solution of 3.7 g (0.03 mol) of isopropyl chloroformate in 30 ml of toluene at a temperature between 5-10°C. The reaction mixture was stirred at a temperature between 20-25°C for 3 hours and then extracted with 3×150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue obtained was recrystallized from isopropanole.
In this manner 4,4 g of title compound was obtained. Yield: 67 %.
Melting point: 128-131°C
Example 3
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C Example 4
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyI}-N,N-dimethylcarbamoyl- cyclohexylamine 4.4 g (0.011 mol) of trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}- cyclohexyl)-carbamic acid methylester was dissolved in 120 ml of dichloromethane. The solution obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (100 ml, 0.3 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 100 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 120 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 4.3 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C
Example 5
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine hydrochloride 6.45 g (0.015 mol) dihydrochloride of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %
Melting point: 221-224 °C
Example 6
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoil- cyclohexylamine hydrochloride 6.72 g (0.015 mol) dihydrochloride monohydrate of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25 °C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %.
Melting point: 221-224 °C
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SEE
http://www.google.com/patents/WO2014031162A1?cl=en
……………………………….
PAPER
Cariprazine, a potential atypical antipsychotic agent has been identified during the optimization of novel series of 4-aryl-piperazine derivatives. The recently available top line results from pivotal clinical trials demonstrated the safety and efficacy of cariprazine in bipolar mania and schizophrenia indications.
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Journal of Medicinal Chemistry, 2013 , vol. 56, 22 pg. 9199 – 9221
http://pubs.acs.org/doi/abs/10.1021/jm401318w
Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (2).(ref…………Ágai-Csongor, É.; Domány, G.; Nógrádi, K.; Galambos, J.; Vágó, I.; Keserű, G. M.; Greiner, I.; Laszlovszky, I.; Gere, A.; Schmidt, É.; Kiss, B.; Vastag, M.; Tihanyi, K.; Sághy,K.; Laszy, J.; Gyertyán, I.; Zájer-Balázs, M.; Gémesi, L.; Kapás, M.; Szombathelyi,Z.Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2receptors Bioorg. Med. Chem. Lett. 2012, 22, 3437– 3440)
the metabolite of the present invention is selected from:
0.8 g (1.6 mmol) trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea was dissolved in dichloromethane (60 ml). A solution of 0.54 g (2.4 mmol) 3-chloro-perbenzoic acid in dichloromethane (10 ml) was dropped in and the reaction mixture stirred for 24 hours at room temperature. The reaction was monitored by TLC. The solution was washed twice with saturated NaHCO3 solution, the organic layer dried and evaporated in vacuo. Flash chromatography gave 0.45 g (63.3%) of the title compound melting at 175-8° C.
Example 2Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea (compound C)
0.92 g (2 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (60 ml), triethylamine (1.26 ml, 9 mmol) was added followed by 0.21 ml (2.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature. The solution was washed with water (2×10 ml), dried and evaporated in vacuo. Purification with flash chromatography gave 0.66 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, melting at 196-8° C. This product was dissolved in dichloromethane (60 ml), then 6.4 ml (6.4 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added, followed by 25 ml saturated NaHCO3 solution. After separation the organic layer was dried and evaporated in vacuo. Purification with flash chromatography gave 0.4 g of the title compound, melting at 278-80° C.
Example 3Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (compound B)
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine (1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature methylamine (33% solution in ethanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (0.86 g, 65%) melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.34 g of title compound, melting at 237-41° C.
Example 4Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea (compound A)
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine 1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature ammonia (20% solution in methanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave 0.86 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.37 g of title compound, melting at 195-8° C.
| WO2005012266A1 * | May 21, 2004 | Feb 10, 2005 | Richter Gedeon Vegyeszet | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| WO2008142461A1 * | May 15, 2008 | Nov 27, 2008 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| WO2010070370A1 * | Dec 18, 2009 | Jun 24, 2010 | Richter Gedeon Nyrt. | Process for the preparation of piperazine compounds and hydrochloride salts thereof |
| WO2010070371A1 * | Dec 18, 2009 | Jun 24, 2010 | Richter Gedeon Nyrt. | Process for the preparation of piperazine derivatives |
| HU0302451A2 | Title not available |
| WO1996007331A1 * | Sep 8, 1995 | Mar 14, 1996 | Helena Halttunen | Composition comprising co-crystals, method for its manufacture, and its use |
| US20090023750 * | May 9, 2008 | Jan 22, 2009 | Richter Gedeon Nyrt. | Novel salts of piperazine compounds as d3/d2 antagonists |
| US20090030007 * | May 9, 2008 | Jan 29, 2009 | Forest Laboratories Holdings Limited | crystalline form of trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea hydrochloride (Form III) Cariprazine {RGH-188); Dysfunction of the dopaminergic neurotransmitter system is involved in the pathology of several neuropsychiatric and neurodegenerative disorders |
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Richter Gedeon Gyógyszergyár
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| Journal | Journal of Flow Chemistry |
| Publisher | Akadémiai Kiadó |
| ISSN | 2062-249X (Print) 2063-0212 (Online) |
| Subject | Flow Chemistry |
| Issue | Volume 4, Number 3/September 2014 |
| Pages | 110-112 |
| DOI | 10.1556/JFC-D-13-00036 |
, Carine Cerato-Noyerie17bis avenue de Valvins Corning European Technology Center F- 77210 Avon France
hornc@corning.com
http://www.akademiai.com/content/622t676074227362/?p=a966d2661bb04f91919c965b3dbff07c&pi=1
A convenient and simple PdCl2-based hydrogenation catalyst has been developed. The liquid, air, and moisture stable precursor is pumped into the reactor where it is temporarily immobilized and reduced on the channel surface into Pd(0), providing a constant high activity for hydrogenation reaction. The catalyst is leached with time, avoiding any kind of clogging problems during long time runs.
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