Saperconazole

Saperconazole

CAS  110588-57-3

 4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

 (±)-1-sec-butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2-1,2,4-triazolin-5-one

2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one

R-66905

MF: C35H38F2N8O4

MW: 672.72

Percent Composition: C 62.49%, H 5.69%, F 5.65%, N 16.66%, O 9.51%

Properties: Crystals from acetonitrile, mp 189.5°. Poorly sol in water.

Melting point: mp 189.5°

Therap-Cat: Antifungal.

Janssen Pharmacuetica N.V.

PHASE 2 

 

Systemic fungal diseases (systemic mycoses) are typically chronic conditions that develop very slowly. These diseases are often induced by opportunistic causative fungi that are not normally pathogenic and commonly live in the patient's body or are commonly found in the environment. While systemic fungal diseases used to be relatively rare in temperate countries, there has been an increasing incidence of numerous life-threatening systemic fungal infections that now represent a major threat to susceptible patients. Susceptible patients include immunocompromised patients, particularly those already hospitalized, and patients compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, invasive surgical techniques, prolonged exposure to antimicrobial agents, and the like, or by diseases or conditions such as cancer, leukemia, emphysema, bronchiectasis, diabetes mellitus, burns, and the like. The symptoms manifested by these fungal diseases are generally not intense, and may include chills, fever, weight loss, anorexia, malaise, and depression.
 The most common systemic fungal infections in humans are blastomycosis, candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis.
Fungal diseases are often confined to typical anatomic sites, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections appearing once the infection spreads from a primary site. For example, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Similarly, the primary form of coccidioidomycosis occurs as an acute, benign, self-limiting respiratory disease, which can then progress to a chronic, often-fatal infection of the skin, lymph glands, liver, and spleen. Other infectious diseases such as paracoccidioidomycosis and candidiasis present in different manners, and depending on the etiology, may exhibit several forms involving internal organs, the lymph nodes, skin, and mucous membranes. Diagnosis of specific fungal diseases can be made by isolation of the causative fungus from various specimens, such as sputum, urine, blood, or the bone marrow, or with certain fungus types, through evidence of tissue invasion.
 Many patients suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration, as such patients are often in a coma or suffering from severe gastroparesis. As a result, the use of insoluble or sparingly soluble antifungals such as itraconazole free base, which are difficult to administer intravenously to treat such patients, is significantly impeded.
 Local or superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, nails, or hair. Such infections may present as a mild inflammation, and can cause alternating remissions and eruptions of a gradually extending, scaling, raised lesion. Yeast infections, such as candidiasis and oral candidiasis (thrush), are usually localized to the skin and mucous membranes, with the symptoms varying depending on the site of infection. In many instances, such infections appear as erythematous, often itchy, exudative patches in the groin, axillas, umbilicus, between toes, and on finger-webs. Oral thrush involves an inflamed tongue or buccal mucosa, typically accompanied by white patches of exudate. Chronic mucocutaneous candidiasis is manifested in the form of red, pustular, crusted, thickened lesions on the forehead or nose.Itraconazole or (±)-£is-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(lH-l-2,4-triazol-l- ylmethyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl]- 1 -ρiperazinyl]phenyl]-2,4-dihydro-2-( 1 - methyl-propyl)-3H-l,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in US-4,267,179.

 

Its difluoro analog, saperconazole or (±)-_πs-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2- ( 1H- 1 ,2,4-triazol- 1-yl-methyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl] - 1 -piperazinyl]- phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in US-4,916,134. Both compounds exist as a mixture of four stereoisomers.

The development of effϊcaceous pharmaceutical compositions of itraconazole and saperconazole is hampered considerably by the fact that said compounds are only very sparingly soluble in water. The solubility of both compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and US-4,764,604.

Unexpectedly, it has now been found that each of the individual stereoisomers of itraconazole and saperconazole have greater water solubility than the diastereomeric mixtures of said compounds, in particular when complexed with cyclodextrin or its derivatives. As a result, pharmaceutical compositions having good bioavailability, yet comprising less cyclodextrin as a complexing agent, can be prepared. The present invention is concemced with the stereoisomeric forms of itraconazole (X = CI) and saperconazole (X = F), which may be represented by the formula

cis-©,and the pharmaceutically acceptable acid addition salt forms thereof. The three asterisks indicate the three chiral centers, and 'cis' means that the (lH-l,2,4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located at the same side of the plane defined by the 1,3-dioxolane ring.

The four possible stereoisomeric cis forms can be described using various rules of nomenclature. The following tables show the correlation among the C. A. stereochemical descriptor, the absolute configuration at each of the chiral centers and the specific optical

20 rotation [α]_jj in 1% methanol (itraconazole; table I) (saperconazole; table H).

Table I

itraconazole

Table π

saperconazole

Synthesis 

 US 4916134

 http://www.google.co.in/patents/US4916134

 

PATENT

WO 2005118577

Itraconazole is a broad-spectrum antifungal agent developed for oral, parenteral and topical use, and is disclosed in U.S. Patent No. 4,267,179. Itraconazole is a synthetic triazole derivative that disrupts the synthesis of ergosterol, the primary sterol of fungal cell membranes. This disruption appears to result in increased permeability and leakage of intracellular content, and at high concentration, cellular internal organelles involute, peroxisomes increase, and necrosis occurs.
As set forth in the USP Dictionary of Drug Names and USAN, itraconazole is defined as 4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, or alternatively, as (±)-l-5ec-butyl-4-[/7-[4-[/7-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-Δ²-l,2,4-triazolin-5-one. There are three asymmetric carbons in itraconazole: one in the sec-butyl side chain on the triazolone and two in the dioxolane ring. As a result, eight possible stereoisomers of itraconazole exist: (R,R,R), (S,S,S), (R,R,S), (S,S,R), (R,S,S), (R,S,R), (S,R,S), and (S,R,R).
 (±)Cz^'s-Itraconazole comprises a mixture of only those isomers that describe a "cis" relationship in the dioxolane ring, i.e., the (1Η-1, 2, 4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located on the same side of a plane defined by the 1, 3-dioxolane ring. By convention, the first represented chiral center is at the C-2 position of the dioxolane ring, the second is at the C-4 position of the dioxolane ring, and the third is in the sec-butyl group. Hence, (±)c.s-itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers.
 The four possible stereoisomeric cis forms of itraconazole, and
diastereomeric pairs thereof, are described in more detail in U.S. Patent Nos. 5,474,997 and 5,998,413. In general, the individual stereoisomeric forms of c s-itraconazole have antifungal properties, and contribute to the overall activity of (±)cw-itraconazole.
 (±)Ciy-Itraconazole free base is only very sparingly soluble in water, and thus it is extremely difficult to prepare effective pharmaceutical compositions containing the same. A number of means have been used to increase the solubility of itraconazole free base, including complexing or co-formulation with cyclodextrins or derivatives thereof, as described in U.S. Patent No. 4,764,604, U.S. Patent No.5,998,413, and U.S. Patent No. 5,707,975, and coating beads with a film comprising a hydrophilic polymer and itraconazole, as described in U.S. Patent No. 5,633,015.
[0014] Another approach to increase solubility of itraconazole focuses on preparation of the stereoisomers of c s-itraconazole, and in particular (2R, 4S) itraconazole, which may comprise a mixture of two diastereomers ((R,S,S) and
(R,S,R)), as described in U.S. Patent Nos. 5,414,997 and 5,998,413.

 Commercially available itraconazole (SPORANOX^® brand (±)cis-itraconazole, Janssen Pharmaceutica Products, L.P., Titusville, NJ, U.S.A.) is a free base and a racemic mixture of the cis isomer in the dioxolane ring and is represented by structural formula (I):

(i)

SPORANOX has been approved for use as an antifungal agent for treating immunocompromised and non-immunocompromised patients having: blastomycosis (pulmonary and extrapulmonary); histoplasmosis, including chronic cavitary pulmonary disease and disseminated non-meningeal histoplasmosis; and aspergillosis. In addition, in non-immunocompromised patients, it has been approved for treatment of onychomycosis. See generally, Physician 's Desk Reference, 56^th ed. (2002). The compound has also been investigated for use in coccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
Adverse effects associated with the administration of (±)cts-itraconazole free base include nausea, vomiting, anorexia, headache, dizziness, hepatotoxicity, and inhibition of drug metabolism in the liver, leading to numerous, clinically significant, adverse drug interactions. See, Physician 's Desk Reference, 56^th ed. (2002); Honig et al., J. Clin. Pharmacol. 33:1201-1206 (1993) (terfenadine interaction); Gascon and Dayer, Eur. J. Clin. Pharmacol., 41_:573-578 (1991) (midazolam interaction); and Neuvonen et al, Clin. Pharmacol. Therap., 60:54-61 (1996) (lovastatin interaction). Reactions associated with hypersensitivity, such as urticaria and serum liver enzymes elevation, are also associated with the administration of the drug. A more serious, though less common, adverse effect is hepatotoxicity. See, e.g., Lavrijsen et al., Lancet, 340:251-252 (1992).
 In addition, as discussed herein, c/s-itraconazole free base is only very sparingly soluble in water. Thus, due to its relative non-polarity and insolubility, itraconazole free base suffers from two other drawbacks: it cannot be readily formulated in parenteral solution, and it does not effectively penetrate the blood-brain barrier. The latter problem is exacerbated by drug interactions, such as one observed between itraconazole free base and valproate, as described in Villa et al. , Rev. Inst. Med. Trop., Sao Paulo, pp. 231-234 (Jul-Aug 2000), which is incorporated by reference herein in its entirety. In another case of CNS fungal infection, extremely high doses of itraconazole free base were used to treat residual aspergillus infection, as reported by Imai et al., Intern. Med, 38(10):829-832 (1999), which is incorporated by reference herein in its entirety. As a result, numerous therapeutic indications that require rapid achievement of effective blood levels or access to the CNS are difficult to treat or beyond treatment with itraconazole free base.
 Furthermore, the emergence of antifungal resistance (e.g., in Aspergillus fumigatus isolates as described by Dannaoui et al., J. Antimicrob. Chemother., 47:333-340 (2001), which is incorporated by reference herein in its entirety) presents an added challenge to the efficacy of itraconazole free base. For those strains of fungi that show resistance, high and relatively constant levels of itraconazole free base must be produced in the target organs of infected patients.
Over the years, a number of formulation routes have been used in order to enhance the adsorption and bioavailability of itraconazole. For example, the currently marketed SPORANOX^® solid dosage capsule form of itraconazole free base utilizes sugar-based beads coated with a hydrophilic polymer and an amorphous film of itraconazole. See Physicians Desk Reference, 56^th ed., pp.1800- 1804 (2002); and U.S. Patent No. 5,633,015. This dosage form requires up to two capsules three times daily depending on the condition being treated.
Even with the various formulation routes, the dosage amounts and dose frequency for itraconazole can be burdensome to patients. In addition, administration of existing dosage forms of itraconazole have shown significant variability in bioavailability and adsorption, which likely results from food effects. See, Physician 's

Desk Reference, 56^th ed., pp. 1800-1804 (2002). Thus, it would be desirable to increase bioavailability and adsorption and decrease the per-dose pill count and decrease dosing frequency (e.g., twice a day to once a day) associated with administration of itraconazole in order to provide an improvement over current therapy, particularly with regard to patient compliance, convenience, ease of ingestion, especially with regard to immunocompromized polypharmacy patients (e.g., AIDS or cancer patients).

Posaconazole and Saperconazole Chemistry and Uses
 Other related conazoles have also been discovered and used as antifungals. Two of these conazoles that are closely structurally related to itraconazole are posaconazole and saperconazole. Posaconazole (CAS Registry Number: 171228-49-2; CAS Name: 2,5-Anhydro-l ,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[l -[(1 S,2S)- 1 -ethyl-2-hydroxypropyl]- 1 ,5-dihydro-5-oxo-4H- 1 ,2,4-triazol-4-yl]phenyl]- 1 -piperazinyl]phenoxy]methyl]- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)-D-t/Veo-pentitol; Additional Name: (3R-c s)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(l,2,4-triazol-l-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin- 1 -yl]phenyl]-2-[l (S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-l,2,4-triazol-3-one) is represented by structural formula (II):

 

(II)

 Saperconazole (CAS Registry Number: 110588-57-3; CAS Name: 4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-2,4-dihydro-2-(l -methylpropyl)-3H- 1 ,2,4-triazol-3-one; Additional Name: (±)-l-sec-butyl-4-[ -[4-| -[[(2R* 4S*)-2-(2,4- difluorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-Δ2-l,2,4-triazolin-5-one) is represented by structural formula (III):

 

(III)

Consequently, there is a need for soluble forms of conazoles including cis itraconazole, posaconazole and saperconazole that can be readily formulated for use in various modes of administration, including parenteral and oral administration.

PATENT

EP 0283992

 

A. Preparation of intermediates: Example 1a) utilizing water separator, by 200 parts of glycerin, 90 parts of 1- (2,4-difluorophenyl) -2- (1H-1,2,4- three mixture of 1-yl) ethanone, 600 parts of methanesulfonic acid, 190 parts of benzene was stirred first at reflux for 3 hours, then stirred at room temperature overnight. The reaction mixture was added dropwise a solution of sodium bicarbonate. The product was extracted with chloroform, the extract was washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 80 parts (67.2%) (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (intermediate 1).

b) by 69 parts of 3,5-dinitrobenzoyl chloride, 80 parts of (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 400 parts of pyridine and 520 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in water. The product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was subjected to silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, to give 90 parts (70.4%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1 ylmethyl) -1,3-dioxolane-4-methanol 3,5-dinitrobenzoate (residue) (intermediate 2).

c) by 90 parts of (cis) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxo- dioxolan-4-methanol 3,5-dinitrobenzoate, 16 parts of 50% sodium hydroxide solution, 800 parts of 1,4-dioxane, 400 parts of water and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the product was extracted with dichloromethane, extracts washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 30 parts (56.0%) of cis -2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (residue) (intermediate 3).

d) by 11.4 parts of methanesulfonyl chloride, 25 parts of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1, mixture of 1,3-dioxolane-4-methanol, 300 parts of pyridine, 390 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in chloroform. The organic phase was dried, filtered and evaporated. The residue was triturated with dipropyl ether. The product was filtered off and dried, yielding 29.4 parts (93.2%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) - 1,3-dioxolane-4-methanol methanesulfonate (residue) of intermediate 4).

In a similar manner there were also prepared: cis-2- (2,4-difluorophenyl) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol mesylate ethanedioate (1/1) (interm. 5).

Example 2a) over 2 hours, dissolved in 100 parts of pyridine 121.2 parts of 2-naphthalenesulfonyl chloride was added dropwise to a stirred, was dissolved in 1300 parts of dichloromethane, and 122.0 parts of (cis + trans ) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 1.0 parts of N, N- dimethyl-4-pyridin-amine solution. Upon completion, stirring was continued at room temperature overnight. The reaction mixture was washed twice with water, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with chloroform. Pure fractions were collected, the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 102.3 parts (51.0%) of cis - [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-yl-methyl ) -1,3-dioxolan-4-yl] methyl] -2-naphthalene sulfonate; mp139.5 ℃ (intermediate 6).

Example 3a) at 70 ℃, under nitrogen atmosphere, by 9.0 parts of 4- [4- (4-nitrophenyl) -1-piperazinyl] phenol, 13.6 parts of cis-2- [2,4- difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol methanesulfonate ester, 6.0 parts of potassium hydroxide and 90 parts of a mixture of DMF was stirred overnight. After cooling, the reaction mixture was diluted with water. The precipitated product was filtered off and purified by silica gel column chromatography, the chloroform / ethyl acetate / hexane / methanol (500:300:200:0.5v / v / v / v) mixture as eluent. Pure fractions were collected, the eluent was evaporated. The residue was crystallized 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.69 parts (38.5%) of cis -1- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol - 1- ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl] -4- (4-nitrophenyl) piperazine; mp169.8 ℃ (Intermediate 7) .

b) at atmospheric pressure, 50 ℃, with 2 parts of 5% palladium - on-charcoal catalyst by 38.3 parts of cis -1- [4 - [[2- (2,4-difluorophenyl) -2- (1H -1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -4- (4-nitrophenyl) piperazine, 2 parts of a solution of thiophene (4% solution in methanol) and 600 parts of 2-methoxy-ethanol mixture. After absorption of the calculated amount of hydrogen finished, hot filtered to remove the catalyst, and the filtrate was saturated with water. After cooling, the precipitated product was filtered off, washed with water and 2-propanol and crystallized from 1,4-dioxane. The product was filtered off and dried, yielding 22.7 parts (62.6%) of cis-4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] aniline; mp193.0 ℃ (interm. 8).

Example 4a) by 10 parts of 2,4-dihydro-4- [4- [4- [4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1,2,4- triazol-3-one (U.S. Patent No. 4,267,179 in the implementation of the method in Example ⅩⅦ obtained), 1.5 parts of sodium hydride (50% dispersion), 300 parts of the mixture consisting of dimethyl sulfoxide, at 60 ℃ under a nitrogen atmosphere begging, stirring, until no bubble up. Was then added 5.24 parts of 2-bromopropane, and at 60 ℃, stirring was continued for 1 hour. Further added 1.5 parts of sodium hydride (50% dispersion) and stirring was continued until no more bubble up. Then 5.24 parts of 2-bromopropane was added, and the whole was stirred for 1 hour at 60 ℃. The reaction mixture was cooled, poured into water and the product was extracted with chloroform. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, the residue was crystallized in 1-butanol, yielding 5.2 parts (47% (2,4-dihydro-4- [4- [4- (4-methoxyphenyl ) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one; mp209.5 ℃ (intermediate 9).

b) by 4.7 parts of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one, a mixture of 75 parts of 48% aqueous hydrobromic acid was stirred at reflux for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in a mixture of methanol and water. With sodium bicarbonate solution, and the whole was, and the product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was triturated with 2-propanol, yielding 3.9 parts (86%) of 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2 - (1-methylethyl) -3H-1,2,4- triazol-3-one, mp208.4 ℃ (intermediate 10).
PATENT

EP 0228125

 

Literature References:

Orally active, fluorinated triazole antifungal. Prepn: J. Heeres et al., EP 283992; eidem, US 4916134 (1988, 1990 both to Janssen).

 

In vitro antifungal activity: F. C. Odds, J. Antimicrob. Chemother. 24, 533 (1989);

 

D. W. Denning et al., Eur. J. Clin. Microbiol. Infect. Dis. 9, 693 (1990).

 

In vivo efficacy vs Aspergillus species: J. Van Cutsem et al., Antimicrob. Agents Chemother. 33, 2063 (1989).

ChemMedChem (2010), 5(5), 757-69

Jingxi Huagong Zhongjianti (2009), 39(5), 8-12, 22

 

EP0006711A1 *	13 Jun 1979	9 Jan 1980	Janssen Pharmaceutica N.V.	Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles, processes for preparing them and compositions containing them
EP0118138A1 *	24 Jan 1984	12 Sep 1984	Janssen Pharmaceutica N.V.	((4-(4-(4-Phenyl-1-piperazinyl)phenoxymethyl)-1,3-dioxolan-2-yl)methyl)-1H-imidazoles and 1H-1,2,4-triazoles
DE2804096A1 *	31 Jan 1978	3 Aug 1978	Janssen Pharmaceutica Nv	1-(1,3-dioxolan-2-ylmethyl)-1h-imidazole und -1h-1,2,4-triazole und deren salze, verfahren zu ihrer herstellung und ihre verwendung bei der bekaempfung pathogener pilze und bakterien

 

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Novel Saperconazole Crystalline Forms and Related Processes, Pharmaceutical Compositions and Methods [US2007293674]	2007-12-20
NOVEL CRYSTALLINE FORMS OF CONAZOLES AND METHODS OF MAKING AND USING THE SAME [US2009088443]	2009-04-02
CONTROLLED RELEASE VEHICLES HAVING DESIRED VOID VOLUME ARCHITECTURES [US2014328884]	2012-12-17	2014-11-06
MOLECULES WITH POTENT DHFR BINDING AFFINITY AND ANTIBACTERIAL ACTIVITY [US2014329840]	2014-05-05	2014-11-06
FUNCTIONALLY-MODIFIED OLIGONUCLEOTIDES AND SUBUNITS THEREOF [US2014330006]	2012-11-15	2014-11-06
ASPARTYL-TRNA SYNTHETASE-FC CONJUGATES [US2014335087]	2012-12-27	2014-11-13
GASTRORETENTIVE CONTROLLED RELEASE VEHICLES THAT INCLUDE ETHYLENE COPOLYMERS, ETHYL CELLULOSES, AND/OR THERMOPLASTIC POLYURETHANES [US2014348936]	2012-12-17	2014-11-27
HISTIDYL-TRNA SYNTHETASE-FC CONJUGATES [US2014349369]	2014-03-14	2014-11-27

 

ASPARTYL-TRNA SYNTHETASES [US2014302075]	2012-12-06	2014-10-09
Rhinosinusitis Prevention and Therapy with Proinflammatory Cytokine Inhibitors [US2014311482]	2014-01-24	2014-10-23
POLYSACCHARIDE ESTER MICROSPHERES AND METHODS AND ARTICLES RELATING THERETO [US2014315720]	2014-04-04	2014-10-23
MODIFIED GREEN TEA POLYPHENOL FORMULATIONS [US2014256616]	2014-05-19	2014-09-11
PLANT-BASED COMPOSITIONS AND USES THEREOF [US2014260466]	2013-03-15	2014-09-18
PLANT-BASED COMPOSITIONS AND USES THEREOF [US2014271928]	2014-03-14	2014-09-18
LIGHT AND ULTRASONIC TRANSDUCER DEVICE [US2014276247]	2014-03-14	2014-09-18
LIGHT AND/OR ULTRASONIC TRANSDUCER DEVICE WITH SENSOR FEEDBACK FOR DOSE CONTROL [US2014276248]	2014-03-14	2014-09-18
PHOTOPROTECTIVE COMPOSITION CONTAINING AN UNMODIFIED GELLING STARCH AND POLYAMIDE PARTICLES [US2014287005]	2014-03-18	2014-09-25
STABILIZED CHEMICAL DEHYDRATION OF BIOLOGICAL MATERIAL [US2014227686]	2014-04-16	2014-08-14

 

METHODS RELATED TO TIM 3, A TH1-SPECIFIC CELL SURFACE MOLECULE, FOR ACTIVATING ANTIGEN PRESENTING CELLS [US2014242094]	2014-02-20	2014-08-28
NOVEL ENCOCHLEATION METHODS, COCHLEATES AND METHODS OF USE [US2014242153]	2014-01-30	2014-08-28
METHODS OF REDUCING THE PROLIFERATION AND VIABILITY OF MICROBIAL AGENTS [US2010197621]	2010-08-05
METHODS OF ADMINISTERING TOPICAL ANTIFUNGAL FORMULATIONS FOR THE TREATMENT OF FUNGAL INFECTIONS [US2010086504]	2010-04-08
COMPOSITIONS AND METHODS FOR INCREASING ERYTHROPOIETIN (EPO) PRODUCTION [US2014024699]	2011-12-09	2014-01-23
PROLONGED RELEASE BIOADHESIVE THERAPEUTIC SYSTEMS [US2013310335]	2013-07-26	2013-11-21
Pharmaceutical Composition [US2013315988]	2011-05-23	2013-11-28
Topical Foam Composition [US2013315998]	2013-08-05	2013-11-28
ANTIFUNGAL NAIL COAT AND METHOD OF USE [US2013323189]	2013-08-09	2013-12-05
TOPICAL FORMULATIONS, SYSTEMS AND METHODS [US2013337031]	2013-03-08	2013-12-19

///////Antifungal,  Triazoles,

 

CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F

Selurampanel, BGG 492

Selurampanel, BGG492, 
cas 912574-69-7
Chemical Formula: C16H19N5O4S
Exact Mass: 377.1158
UNII-7WG1MR7DAR;
N-(7-isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methanesulfonamide
N-[7-Isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]methanesulfonamide
PHASE 2 , FOR EPILEPSY, TITINUS
NOVARTIS INNOVATOR
Selurampanel (INN, code name BGG492) is a drug closely related to the quinoxalinedione series which acts as a competitive antagonist of the AMPA and kainate receptors and, as of 2015, is being investigated in clinical trials by Novartis for the treatment ofepilepsy.^[1][2][3] It has also been studied in the acute treatment of migraine, and was found to produce some pain relief, but with a relatively high rate of side effects.^[4]

PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006108591&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription
Example 44: N-[7-IsopropyI-6-(l-methyl-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yl]-methanesulfonamide
2-Amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

The 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester required for the coupling reaction described below was prepared according to the procedures described in WO 2004/033435 Al.
The l-methyl-5-tributylstannanyl-lH-pyrazole required for the coupling reaction was prepared according to the procedure described above.
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and l-methyl-5-tributylstannanyl-lH-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100 ⁰C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H- pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 21 A [M+H]⁺, rt 5.20 min).
2-(4-Chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

4-Chlorophenyl-chloroformate (88 μL, 1.1 equiv) was added to a solution of 2-amino-4-isopropyl-5-(2~ methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (156 mg, 0.57 mmol) in dioxane (1.5 mL). The mixture was stirred for 2 h (TLC control) at 80 ⁰C. The mixture was evaporated to dryness. The obtained yellow solid was used in the next step without further purification, (rt 6.77 min)
N-[7-Isopropyl-6-(2-methyl-2H-pyrazol-3 -yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl] -methanesulfonamide

CH₃SO₂NHNH₂ (79.5 mg, 1.1 equiv) and J-Pr₂NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80 ⁰C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH / DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3 ~yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]⁺, rt 4.20 min).

Patent	Submitted	Granted
Substituted 1H-quinazoline-2,4-diones useful as AMPA receptor ligands [US7655666]	2008-06-26	2010-02-02
N-(2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,4-dihydro-2H-quinazolin-3-yl)methanesulfonamide [US8012988]	2010-06-10	2011-09-06
2,4-DIOXO-1,4-DIHYDRO-2H-QUINAZOLIN-3-YL-SULFONAMIDE DERIVATIVES [US2013053381]	2011-05-18	2013-02-28
Use of 1H-quinazoline-2,4-diones [US2013090346]	2012-09-05	2013-04-11
Use of 1H-quinazoline-2,4-diones [US2013096145]	2011-06-24	2013-04-18
Use of 1H-quinazoline-2,4-diones [US2014163050]	2014-02-12	2014-06-12
FOMULATION COMPRISING 1 H-QUINAZOLINE-2, 4-DIONE AMPA RECEPTOR ANTAGONISTS, IN THE FORM OF IMMEDIATE RELEASE TABLETS AND PREPARATION THEREOF [US2012263791]	2010-12-21	2012-10-18
Use of 1H-Quinazoline-2,4-Diones [US2014018376]	2010-10-20	2014-01-16
1-H-QUINAZOLINE-2, 4-DIONES FOR USE IN THE TREATMENT OF NEURONAL CEROID LIPOFUSCINOSIS [US2012122903]	2010-07-23	2012-05-17

References

1. Faught, Edward (2014). “BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy”. Expert Opinion on Investigational Drugs 23 (1): 107–113.doi:10.1517/13543784.2014.848854. ISSN 1354-3784.
2.  Belcastro, Vincenzo; Verrotti, Alberto (2015). “Novel Molecular Targets for Drug-Treatment of Epilepsy”: 183–199.doi:10.1007/978-3-319-12283-0_10.
3.  Hanada, Takahisa (2014). “The AMPA receptor as a therapeutic target in epilepsy: preclinical and clinical evidence”. Journal of Receptor, Ligand and Channel Research: 39.doi:10.2147/JRLCR.S51475. ISSN 1178-699X.
4.  Gomez-Mancilla B, Brand R, Jürgens TP, et al. (February 2014). “Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks”. Cephalalgia 34 (2): 103–13.doi:10.1177/0333102413499648. PMID 23963355.

Selurampanel

Systematic (IUPAC) name
N-[7-Isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide
Identifiers
CAS Number	912574-69-7
ATC code	None
PubChem	CID 45381907
ChemSpider	32698379
Chemical data
Formula	C16H19N5O4S
Molar mass	377.418 g/mol

////Selurampanel, BGG492, 912574-69-7
CC(C)c1cc2c(cc1c3ccnn3C)c(=O)n(c(=O)[nH]2)NS(=O)(=O)C
CS(=O)(NN1C(NC2=C(C=C(C3=CC=NN3C)C(C(C)C)=C2)C1=O)=O)=O

see........https://newdrugapprovals.org/2016/02/17/selurampanel-bgg-492/

VISMODEGIB

Vismodegib

2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

Vismodegib; 879085-55-9; GDC-0449; 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide; Erivedge; HhAntag691; CUR-691
GDC-449
Hh-Antag691
HhAntag
R-3616
RG-3616 

421.29706 g/mol

C₁₉H₁₄Cl₂N₂O₃S

LAUNCHED 2012

Vismodegib is a Hedgehog Pathway Inhibitor. The mechanism of action of vismodegib is as a Smoothened Receptor Antagonist.

Hedgehog Antagonist GDC-0449 is an orally bioavailable small molecule with potential antineoplastic activity. Hedgehog antagonist GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO.

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.^[1] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011.^[2] The drug was developed by thebiotechnology/pharmaceutical company Genentech, which is headquartered at South San Francisco, California, USA.

Indication

Vismodegib is indicated for patients with basal cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.^[3] [4]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.^[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.^[5] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.^[6]

PAPER

Bioorg Med Chem Lett 2009, 19(19): 5576

http://www.sciencedirect.com/science/article/pii/S0960894X10012709

Figure 1.

Schematic for the discovery of 2 (GDC-0449) from 1, and the inspiration for further analogs 3 and 4

CN 103910671

http://www.google.com/patents/CN103910671A?cl=en

In embryonic development, Hedgehog signaling in cell differentiation, tissue development and organogenesis play an important role. In the adult body, Hedgehog signaling pathway is mainly in slumber, but when abnormal tissue growth and self-healing, Hedgehog pathway may be activated. With the in-depth study of the tumor, the presence of numerous evidence of abnormal tumor occurrence and the close relationship between Hedgehog signaling pathway, such as sporadic basal cell carcinoma, medulloblastoma, small cell lung cancer and gastrointestinal cancer and other diseases, therefore Hedgehog signaling pathway targeted anti-cancer therapy inhibitors become hot.

 Vismodegib chemical name 2_ chlorine -N_ (4_ chlorine _3_ (_2_ pyridyl) phenyl) _4_ (methylsulfonyl) benzamide, is by Roche's Genentech (Genentech) Hedgehog pathway inhibitors developed, and can be inhibited by binding seven transmembrane protein Smoothened (Smo), thereby preventing signal transduction. Vismodegib capsule in January 2012 I was approved and listed by the US Food and Drug Administration, under the trade name Erivedge, for the treatment of adults with the most common type of skin cancer - basal cell carcinoma. This medicine is not intended for surgery or radiotherapy of cancer and basal cell skin cancer locally advanced patients have been transferred. This was the first drug approved for the treatment of basal cell carcinoma.

W02006028958 Vismodegib disclose the following synthesis route:

 Route One Negishi coupling reactions

wherein, X1 is chloro, bromo or iodo; X2 is bromo, iodo or tosylate. The route to the 2-halo-pyridine as starting material an organic zinc compound, and then prepared by Negishi coupling reaction to give 2- (2-chloro-5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine in turn through a reduction reaction with acylation reaction, to give the final product Vismodegib. The key coupling step of the route using an organic zinc reagent required to react under strict anhydrous, anaerobic conditions.

 The second route Suzuki coupling reaction [0010]

 wherein, X2 is bromo, iodo or tosylate. The route from 3-halo-4-chloro-nitrobenzene as raw material, and 2-chloro-5-nitrophenyl boronic acid pinacol ester, and then reacted with a 2-halo-pyridine was prepared to give 2- (2-chloro 5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine then after reduction and acylation reaction, to give the final product Vismodegib. The key coupling step of the route using the Suzuki coupling reaction, organic boron reagent price to use expensive, high production costs.

 The route three Suzuki coupling reaction

wherein, X2 is bromo, iodo or tosylate. Similar to the second route, the route is still critical coupling step using a Suzuki coupling reaction, the same need to use expensive organic boron reagents, higher production costs.

 route four Stille coupling reaction

 The route to 2-p-toluenesulfonyl pyridine as starting material, is reacted with an organotin reagent, prepared to give pyridin-2-yl trimethyltin, then by Stille coupling reaction, was prepared to give 2- (2-chloro - 5- nitrophenyl) pyridine, followed by reduction reaction, acylation prepared to give Vismodegib. The key step of the route using the Stille coupling reaction, this step need to use expensive and toxic organotin reagents, and the need to carry out the reaction under strict anhydrous, anaerobic conditions.

A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising: a compound of formula III was prepared as a compound of Formula II;

Then, the compound of formula II with a compound of formula I, to give 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

Wherein, R1 is halogen or hydroxy, preferably chlorine, or a hydroxyl group.

2. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

3. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

Method 2 or claim 3,

Example 1: N--oxo-2- (2-chloro-5-nitrophenyl) pyridine

[0108] To a 100mL three-necked flask were added 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol potassium carbonate, 0.05mmol tri-butyl acetate button and 0.15mmol phosphorus tetrafluoroborate salt, 40ml of toluene, IS gas exchange three times, under argon at reflux for 2 days, then the reaction mixture was poured into 100mL of ethyl acetate, filtered, and the filtrate was washed with saturated brine, dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50), fractions were collected and the solvent was distilled off under reduced pressure to give a pale yellow solid, yield 60%.

 1HMffi (500Hz, DMS0_d6): 8.35 (m, 3H), 7.90 (d, 1Η), 7.62 (q, 1Η), 7.55 (m, 1Η), 7.48 (m, 1Η);

 MS: 251.1,253.1 ([Μ + Η] +).

2  Example: Ν--oxo-2- (2-chloro-5-nitrophenyl) pyridine

 To a 100mL three-necked flask 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol of potassium carbonate, 0.05mmol iodide and 0.1Ommoll, 10- Fei Luo Jie morpholine, 40ml of xylene, an argon gas exchange three times, under argon at reflux for 2 days, cooled to room temperature and then the reaction system was poured into 100mL methylene chloride, filtered and the filtrate washed with saturated brine, dried, filtered, The filtrate solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50) to give a pale yellow solid, yield 42%. .

3  Example: 2- (2-chloro-5-nitrophenyl) pyridine

After 3.0mmol N- oxo added to 100mL of Lord vial _2_ (2_ chloro _5_ nitrophenyl) pyrazole 唳, 15mmol phosphorus trichloride and 30ml of chloroform was heated at reflux for 12h, the reaction It was poured into 100mL of water and extracted with ethyl acetate (50ml X 2), and the combined organic phase was dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: petroleum ether / ethyl acetate = 20/1) , fractions were collected, the solvent was distilled off under reduced pressure to give a white solid, yield 95%.

 1Hnmr (SooHzJDCI3): 8.78 (d, 1H), 8.51 (d, 1H), 8.20 (m, 1H), 7.85 (m, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.40 (m, 1H);

MS: 235.1,237.1 ([M + H] +).

4 Example 2: Preparation 4_ chlorine _3_ (topiramate 唳 _2_ yl) aniline

 To a vial was added 100mL of Lord 20mmol2- (2- chloro-5-nitrophenyl) pyridine 唳, 50ml of acetic acid, heated to 80 ° C and stirred, and then slowly added IOOmmol iron, reaction 0.5h The reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X 3), the combined organic phases, the organic phase was washed with saturated sodium carbonate solution (50ml X 3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a pale yellow solid, yield 75%.

1HMflUSOOHz, DMS0_d6): 8.63 (m, 1H), 7.84 (m, 1H), 7.56 (d, 1H), 7.37 (m, 1H),

7.13 (d, 1H), 6.76 (d, 1H), 6.61 (q, 1H), 5.32 (s, 2H);

 MS: 205.1,207.1 ([M + H] +).

5 Example: 4-chloro-3- (pyridin 唳-2-yl) aniline

to 100mL of God-shaped flask 20mmol2_ (2_ chlorine _5_ nitrophenyl) pyridine Jie set, 50ml of methanol, Ig activated carbon, 2mmol FeOOH and 60mmol85% of hydrazine hydrate, heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution (20ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product was recrystallized from n-propanol to give a pale yellow solid, yield 96%.

6 Example 2: Preparation 4_-chloro-3- (2-yl) aniline

 20mmol N- oxo added to 100mL eggplant-shaped flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of acetic acid, heated to 80 ° C and stirred, and then iron powder was slowly added IOOmmol After 0.5h the reaction the reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X3), the combined organic phases were washed with saturated sodium carbonate solution (50ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propanol recrystallized to give a white solid, yield 70%.

Preparation 7.Α ~ chlorine -3_ (topiramate 唳 2-yl) aniline [0130] Example

 20mmol N- oxo added to 100mL eggplant type flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of methanol, Ig active carbon, 2mmol FeOOH 60mmol85% hydrazine hydrate and heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase (20mlX3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a white solid, yield 82%.

Vismodegib Preparation: 8 Example

In the Lord 50ml vial, the 1.50mmol2- chloro-4-methanesulfonyl-chloride in 15ml of dry tetrahydrofuran, cooled to ice bath O ~ 10 ° C, a solution of 4-chloro-3 - (pyridin-2-yl) aniline in anhydrous tetrahydrofuran (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction system was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

1HNMR (500Hz, DMS0_d6): 10.90 (s, 1H), 8.70 (d, 1H), 8.12 (d, 1H), 8.01 (t, 2H), 7.92 (m, 2H), 7.74 (q, 1H ), 7.69 (d, 1H), 7.58 (d, 1H), 7.44 (m, 1H), 3.34 (s, 3H).

 MS: 421.1,423.1 ([M + H] +).

Vismodegib Preparation: 9  Example

 In 50ml vial of God, will 1.50mmol2_ chlorine _4_ methylsulfonyl benzoic acid, 1.47mmol4_ chlorine _3_ (batch 唳 2-yl) aniline and triethylamine were dissolved in 25ml 2.5mmol anhydrous tetrahydrofuran in an ice bath to cool to O ~ 10 ° C, was added in portions N, N '- dicyclohexyl carbodiimide (DCC) 1.50mmol, After the addition, the reaction at room temperature 6h, after the reaction, white solid was removed by filtration, the filtrate was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 84%.

Vismodegib Preparation: 10 [0141] Example

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

CN 103910672

http://www.google.com/patents/CN103910672A?cl=en

Vismodegib PreparatioN

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

WO2006028958

https://www.google.co.in/patents/WO2006028958A2?cl=en

Example 1 General Procedure

Compounds of examples 2-51 were prepared according to the following general procedures.

A: Suzuki Coupling Procedure

2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene :ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 ⁰C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2 x 20 mL), dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

B: Negishi Coupling Procedure

X = I or Br R = H, 3-Me, 4-Me₅ 5-Me, 6-Me

Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-dried microwave vial charged with the appropriate aryl halide (1.0 eq) and Pd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in the microwave to 140 ⁰C for 10 minutes. The crude reaction mixture was concentrated and purified by chromatography on silica gel (conditions given below) to afford the desired product.

C: Iron Reduction of Aryl Nitro Group

R = I or pyridin-2-yl

The appropriate nitro aryl (1 mmol, 1 eq) in AcOH/EtOH (1:1, 0.42 M) was added slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2 M) at 60 °C. The solution was stirred at 70 ⁰C for 30-60 minutes. The reaction mixture was cooled to 23 ⁰C, filtered through celite, washed with ethyl acetate, and concentrated. The oily residue was dissolved in ethyl acetate (30 mL), washed with saturated aq. NaHCO₃ (2 x 15 rnL) and water (2 x 10 niL), dried (MgSO₄), and concentrated. The oily residue was used with out further purification.

D: Amide Bond Formation

R = I or pyridin-2-yI

Acid chloride (1.05-1.1 eq) was added to a solution of aniline (1.0 eq) and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature. The solution was stirred for 0.5-3 hours, poured onto saturated aq. NaHCO₃, extracted twice with methylene chloride, dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

E: EDC Amide Bond Formation

R = I or pyridin-2-yl

Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) and EDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution was stirred at 23 ⁰C for 2 hours, poured onto a 1 :1 mixture of saturated aq. NH₄Cl and water, extracted twice with methylene chloride, dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. F: addition of amines to 2-chloropyridine

NHRR' = ethanolamine, analine, benzylamine, 2-methylpropylamine, N-methylpiperazine, morpholine, 2-morpholinoethylamine

Primary or secondary amine (5 eq) in either BuOH or a mixture of BuOH/ethylene gylcol was heated to 170 to 220 ⁰C for 20 min in a sealed tube. The BuOH was removed under reduced pressure. In cases where ethylene glycol was used, the reaction was diluted with water, and the product was extracted into ethyl acetate, dried (MgSO^, and concentrated. The crude residue was purified by reverse phase HPLC to afford the desired product.

G: Amide bond coupling with HATU

HATU, DIPEA, DMF NaOH or NaHCO₃

ethyl acetate extraction

Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.1 eq), HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1 - 0.2 M). After stirring overnight, the reaction mixture was diluted with 0.1 N sodium hydroxide or saturated NaHCθ₃, extracted into ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried (MgSO₄), concentrated and the crude mixture was purified by reverse phase HPLC. H: Preparation of sulfonamide benzoic acids

Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine (1.1 eq) in 10-20% DEPEA/methanol (1 M) at 4 ⁰C. After 1 h, the reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC.

I : Stannylation of 2-pyridyl triflates

A solution of tetrakis-triphenylphosphinepalladium (0.04 eq.) in toluene (1 mL) was added to degassed solution of aryltriflate (1 eq), bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane. Heated to reflux for 2 hours, cooled to 23 ⁰C, diluted with ethyl acetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSO₄) and concentrated. The crude material was used without further purification.

J: Stannylation of substituted pyridines

^ιM^mβ^co3 n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to a solution of dimethylaminoethanol (3 eq) in hexane at 0 ⁰C. The solution was stirred at 0 ⁰C for thirty minutes before dropwise addition of the substituted pyridine (1 eq). The solution was stirred at 0 ⁰C for an additional hour, then cooled to -78 ⁰C. A solution of trialkyltin in hexane was added dropwise. The solution was stirred at -78 ⁰C for thirty minutes, warmed to 0 ⁰C, quenched with water, extracted twice with ether, dried (MgSO₄), and concentrated. K: Stille Coupling

Palladium catalyst (0.02 eq) was added to a degassed solution of aryliodide (1 eq), arylstannane (2 eq), and triphenylphosphine (0.16 eq) in NMP. Heated in the microwave to 130 ⁰C for 15 minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSC>₄), concentrated and purified by silica gel chromatography.

L: Synthesis of alky lethers

A solution of hydroxypyridine (1 eq), alkyliodide (excess), and cesium carbonate in NMP was heated in the microwave to 100⁰C for ten minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSC^), concentrated and purified by silica gel chromatography.

M: Methyl Ester Saponification

The methyl ester (leq) was hydrolyzed with LiOH (2eq) in 50/50 THF/water mix. Upon completion of the reaction the THF was evaporated under reduced pressure and the solution is acidified with HCl to pH 2. The resultant solid was filtered and dried to give the pure acid.

N: Bromination in the presence of a free acid functionality

The paramethylbenzoic acid (leq) was combined with Benzoyl Peroxide (O.leq) and N- Bromosuccinimde (0.9eq) in a solution of 5%AcOH in Benzene and heated in the microwave at 120°C for 5-15minutes. The product was separated from the starting material and di-bromo product via ISCO flash chromatography with an ethyl acetate (with 1% AcOH) and hexanes solvent system.

O: Sodium Methanesulfinate displacement of Bromine

To the bromine starting material (leq) was added sodium methanesulfinate (2eq) in DMF and heated to 120°C in the microwave for 5 minutes. Alternatively, the reaction was heated to 60°C in an oil bath for several hours until completed. Reaction mixture was concentrated under reduced pressure and extracted in ethyl acetate and water. The organic layer was dried over Magnesium Sulfate, filtered and concentrated in vacuo to yield generic methylsulfone.

P: Amine displacement of Bromine

To the bromo starting material (leq) was added appropriate amine (3eq) in either DMSO or BuOH and stirred at room temperature until complete. For less nucleophilic amines or anilines, the reactions were forced to completion using microwave conditions ranging from 150°-170°C for 15 minutes. Crude reactions were concentrated to dryness and either extracted with ethyl acetate and saturated bicarbonate if the reaction resulted in an intermediate or purified via HPLC if the reaction resulted in a final product.

Q: Thiol displacement of halogen

The paramethylbromo benzoate (leq) was treated with Potassium (or Cesium) Carbonate (1.5eq) and appropriate thiol derivative (l,leq) in DMF (or CH₃CN) and stirred overnight at room temperature. The DMF was evaporated in vacuo and the reaction was extracted with ethyl acetate and water. The organic layer was dried over Magnesium Sulfate , filtered and concentrated to yield the thiol or derivatized thiol compound.

R: Oxone Oxidation

oxone 2:1 MeOHTH₂O

Derivatized thiol (leq) was dissolved in MeOH while Oxone (2eq) was seperately dissolved in half the amount of water. Once all the oxone was dissolved, the solution was added to the thiol in MeOH solution at once and stirred until complete. The MeOH was evaporated in vacuo and the remaining water was extracted twice with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate and concentrated to yield the sulfone.

S: Thio lysis of epoxides at alumina surfaces

A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminum oxide (~70 eq) in diethyl ether was stirred for 3 h at room temperature while being monitored by TLC. The reaction mixture was filtered through Celite, washed with ethyl acetate and concentrated. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield β -hydroxysulfide product.

T: Conversion of nitrile group to carboxylic acid

R

A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in H₂O was heated to 120 ° C for 2h. The reaction mixture was cooled to room temperature and acidified with HCl to pH 2. The resulting solid was filtered to afford the pure acid product.

U. Alkylation of phenols

The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) and an alkyl bromide or alkyl iodide (1.0 to 2.0 eq.) were added, and the reaction was stirred at room temperature for 18 hrs or 5O⁰C for 1 to 24 hours. The reaction was quenched in water, and extracted with ethyl acetate twice. The organic extracts were washed with water once, brine once, dried with MgSC>₄, and evaporated to a crude oil which was purified on reverse phase HPLC.

V. Amide bond formation with an acid chloride and an aniline

The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml). MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, and the solution was stirred at room temperature for 18 hours. The reaction was diluted with methanol and dichloromethane, and filtered to remove the MP-Carbonate. The mother liquors were evaporated to a solid and purified by reverse phase HPLC.

W. Amidine formation from an imidate

A solution of freshly formed imidate in methanol was treated with a primary or secondary amine (1.5 eq.) at room temperature for 18 hours. The methanol was removed on a rotary evaporator and the residue purified by reverse phase HPLC.

Example 37 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4- methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide. MS (Ql) 421.0 (M)⁺. The product was then dissolved in 1 Ν HCI solution followed by freebasing with 0.5 Ν NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.

Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4- (methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-

(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with

Et₂O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO₃ and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone :EtOAc (80:20, approx lOmL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.

Patent

WO 2016020324, BASF AG, vismodegib , new patent

WO2016020324,  MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS

BASF SE [DE/DE]; 67056 Ludwigshafen (DE)

VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

formula 1

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.

The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.

Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.

Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.

The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).

The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.

A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.

Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.

Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy

.

Example 1 :

314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.

TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).

H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).

References

1.  "Vismodegib, First Hedgehog Inhibitor, Approved for BCC Patients".
2.  "Molecule of the Month". June 2011.
3.  "FDA approves Erivedge (vismodegib) capsule, the first medicine for adults with advanced basal cell carcinoma".
4.  Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge , NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.
5.  "Vismodegib (GDC-0449) Smoothened Inhibitor - BioOncology".
6.  H. Spreitzer (4 July 2011). "Neue Wirkstoffe – Vismodegib". Österreichische Apothekerzeitung (in German) (14/2011): 10.
7.  FDA Professional Drug Information

External links

• Erivedge® (vismodegib), a prescription oral medica on approved for advanced basal cell carcinoma treatment
• Efficacy and Safety of Vismodegib
• Food and Drug Administration (FDA) approved vismodegib

PatentSubmittedGranted

Pyridyl inhibitors of hedgehog signalling [US7888364]2006-03-232011-02-15

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2009281089]2009-11-12

ANTI-HEDGEHOG ANTIBODIES [US8030454]2010-01-072011-10-04

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2011092461]2011-04-21

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2012094980]2011-10-142012-04-19

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2013045240]2010-08-252013-02-21

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2014072630]2013-02-282014-03-13

Acyl guanidine derivatives modulating the hedgehog protein signaling pathway [US8889678]2010-07-192014-11-18

COMBINATION THERAPY [US2012184529]2012-01-032012-07-19

METHOD OF INHIBITING DYRK1B [US2014371251]2014-06-182014-12-18

USE OF SUBSTITUTED HEXITOLS INCLUDING DIANHYDROGALACTITOL AND ANALOGS TO TREAT NEOPLASTIC DISEASE AND CANCER STEM AND CANCER STEM CELLS INCLUDING GLIOBLASTOMA MULTIFORME AND MEDULLOBLASTOMA [US2014377336]2013-01-222014-12-25

SHH Regulation and Methods Thereof [US2012082623]2011-09-302012-04-05

NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS [US2015025070]2012-07-132015-01-22

Compositions and Methods for Modulating Neuron Degeneration and Neuron Guidance [US2011065645]2010-09-102011-03-17

SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS [US2014200217]2014-01-242014-07-17

CN101072755A *	Sep 2, 2005	Nov 14, 2007	遗传技术研究公司	Pyridyl inhibitors of hedgehog signalling
CN102731373A *	Jul 19, 2012	Oct 17, 2012	南京药石药物研发有限公司	Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)
US20080132698 *	Nov 30, 2006	Jun 5, 2008	University Of Ottawa	Use of N-oxide compounds in coupling reactions
US20090076266 *	Sep 10, 2008	Mar 19, 2009	The University Of Houston System	Copper-catalyzed c-h bond arylation

NON-PATENT CITATIONS

Reference
1	*	GEORGETTE M. CASTANEDO，等: "Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, 15 September 2010 (2010-09-15), pages 6748 - 6753
2	*	曹萌，等: "Vismodegib 的合成", 《第十一届全国青年药学工作者最新科研成果交流会论文集》, 21 June 2012 (2012-06-21)
3	*	耿一丁: "Vismodegib", 《中国药物化学杂志》, vol. 22, no. 3, 20 June 2012 (2012-06-20)
4	*	邢其毅，等: "《基础有机化学》", 31 December 2005, article "201310019450.0", pages: 896-897

Vismodegib

Systematic (IUPAC) name
2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Clinical data
Trade names	Erivedge
AHFS/Drugs.com	monograph
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU: X (High risk) US: D (Evidence of risk)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	31.8%
Protein binding	>99%
Metabolism	<2% metabolised byCYP2C9, CYP3A4, CYP3A5
Biological half-life	4 days (continuous use), 12 days (single dose)
Excretion	Faeces (82%), urine (4.4%)
Identifiers
CAS Number	879085-55-9
ATC code	L01XX43
PubChem	CID 24776445
IUPHAR/BPS	6975
DrugBank	DB08828
ChemSpider	23337846
UNII	25X868M3DS
ChEBI	CHEBI:66903
ChEMBL	CHEMBL473417
Synonyms	GDC-0449, RG-3616
Chemical data
Formula	C19H14Cl2N2O3S
Molar mass	421.30 g/mol

 update...............

Vismodegib Synthesis

WO2009126863A2: also see Ref. 1. It all started from here.

Identification:

1H NMR (Estimated) for Vismodegib

Experimental: ¹H NMR (400MHz, CDCl₃) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).
 nmr from net

SEE........https://newdrugapprovals.org/2016/02/16/vismodegib/  /////

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl