LY-156735 (TIK-301, PD-6735)….for the treatment of sleep latency in patients with primary insomnia

LY-156735 (TIK-301, PD-6735)….for the treatment of sleep latency in patients with primary insomnia

N-[(2R)-2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide

cas  118702-11-7

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

Preparation of β-Methyl-6-chloromelatonin
• Following the procedure of Example 1, a solution of 10.0 g (0.055 mole) of 5-methoxy-6-chloroindole, 3.1 ml (2.44 g, 0.055 mole) of acetaldehyde, and 7.94 g (0.055 mole) of Meldrum’s acid in 90 ml of acetonitrile was stirred for 48 hours. The solvent was removed under vacuum, and the adduct thus prepared was recrystallized by dissolving in warm toluene and immediately cooling. The adduct was obtained as slightly pink crystals; m.p. = 145°C; yield = 16.5 g (85%). The elemental analysis of the product showed a slightly elevated percentage of carbon. However, the NMR spectrum indicated that the product was pure and had the indicated structure.
  Analysis calc. for C₁₇H₁₈NO₅Cl

  Theory:

  C, 58.04; H, 5.16; N, 3.98; Cl, 10.08

  Found :

  C, 59.34; H, 5.15; N, 3.84; Cl, 9.69

• The solvolysis and decarboxylation of the adduct (11.0 g; 31.3 mmoles) using ethanol, pyridine, and copper dust was carried out by the procedure of Example 1. The yield of 3-(5-methoxy-6-chloro-1H-indol-3-yl)pentanoic acid ethyl ester, a pale yellow oil, after chromatography over silica gel using 10% EtOAc/90% toluene was 8.68 g (94%).
  Analysis calc. for C₁₅H₁₈NO₃Cl

  Theory:

  C, 60.91; H, 6.13; N, 4.74; Cl, 11.99

  Found :

  C, 60.67; H, 5.86; N, 4.93; Cl, 11.73

• A mixture of 8.68 g (29.3 mmoles) of the above ethyl ester and 6 ml of hydrazine hydrate was heated at 140°C under nitrogen in a flask fitted with an air cooled condensor. After 6½ hours, the excess hydrazine hydrate was removed under vacuum. The 2-methyl-2-(5-methoxy-6-chloro-3-indolyl)-propionhydrazide thus prepared was recrystallized from ethyl acetate; Yield = 7.13 g (86%); m.p. = 154-155°C.
  Analysis calc. for C₁₃H₁₆N₃O₂Cl

  Theory:

  C, 55.42; H, 5.72; N, 14.91; Cl, 12.58

  Found :

  C, 55.14; H, 5.51; N, 14.49; Cl, 12.78

• The above hydrazide (7.13 g, 25 mmoles) was converted to the corresponding acyl azide, the azide thermolyzed and rearranged at 80° in toluene, and the rearranged product cyclized with HCl according to the procedure of Example 1. The yield of crude, light tan, lactam, 1-oxo-4-methyl-6-methoxy-7-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, product, (m.p. = 249-252°C) was 4.77 g (72%).
  Analysis calc. for C₁₃H₁₃N₂O₂Cl

  Theory:

  C, 58.99; H, 4.95; N, 10.58

  Found :

  C, 59.45; H, 4.77; N, 10.72

• The crude lactam (4.77 g, 18 mmoles) was hydrolyzed with aqueous ethanolic KOH as described in Example 1. The yield of crude amino acid, 2-carboxy-3-(1-amino-2-propyl)-5-methoxy-6-chloroindole, was 3.98 g (78%). The crude product (3.0 g; 10.6 mmoles) was decarboxylated, using the procedure of Example 1, by refluxing in 100 ml of 3M HCl overnight. The acidic solution was decolorized with activated carbon and was then basified with 5M NaOH. The amine was extracted into diethyl ether. After drying the ether extract over Na₂SO₄, the diethyl ether was removed in vacuoleaving as a residue the crystallized tryptamine, 3-(1-amino-2-propyl)-5-methoxy-6-chloroindole; m.p. 133-4°C. The yield, after recrystallization from toluene/hexane, was 1.62 g (64%).
  Analysis calc. for C₁₂H₁₅N₂OCl

  Theory:

  C, 60.38; H, 6.33; N, 11.74; Cl, 14.85

  Found :

  C, 60.11; H, 6.05; N, 11.93; Cl, 15.06

• A solution of 1.51 g (6.3 mmoles) of the above tryptamine in 10 ml of toluene and 2.5 ml of pyridine was treated with 1.5 ml of acetic anhydride. After allowing the reaction mixture to stand for three hours at room temperature, the volatile materials were removed under vacuum. The residue was dissolved in ethyl acetate, and washed with aqueous NaHCO₃, and brine. The ethyl acetate solution was dried over Na₂SO₄, and the solvent removed by evaporation. The residual oil was crystallized from toluene/hexane yielding 6-chloro-β-methylmelatonin, (m.p. = 133-5°C; 1.09 g, 61%).
  Analysis calc. for C₁₄H₁₇N₂O₂Cl

  Theory:

  C, 59.89; H, 6.10; N, 9.98; Cl, 12.63

  Found :

  C, 60.03; H, 6.22; N, 9.75; Cl, 12.92

…………………………………………….

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

Preparation of S-(-)-β-methyl-6-chloromelatonin and R-(+)-β-methyl-6-chloromelatonin
• A solution of 4.0 g (21 mmoles) of 3-chloro-4-methoxynitrobenzene in 200 ml of toluene was hydrogenated over 0.4 g of 5% platinum on alumina. The catalyst was removed by filtration and the solvent evaporated from the filtrate. The crude 3-chloroanisidine prepared was placed in solution in diethyl ether and treated with ethereal HCl to produce the hydrochloride salt, which was collected and dried; weight = 2.48 g (61% yield).
• A mixture of 2.40 g (12.4 mmoles) of 3-chloroanisidine hydrochloride in 7 ml of 4M HCl was treated, at 0°C, with 0.86 g (12.5 mmoles) of sodium nitrite in 5 ml of water. After stirring at 0°C for an hour the solution was filtered and the filtrate added slowly to an ice cold solution of 2.6 g (24 mmoles) of sodium fluoroborate in 8 ml of water. After stirring at 0°C for an hour the salt was collected and washed successively with, cold 5% sodium fluoroborate solution, cold methanol, and ether. The dried 3-chloro-4-methoxybenzene diazonium fluoroborate thus prepared weighed 2.2 g (69% yield).
• A mixture of 2.03 g (11.0 mmole) of (R)-(-)-3-ethoxycarbonyl-5-methyl-2-piperidone and 30 ml of 0.75M NaOH was stirred at room temperature (24°C) overnight. The solution was cooled to 0°C and the pH lowered to 3.5 with 3M hydrochloric acid. The diazonium salt (2.8 g, 10.9 mmoles) was added in small portions and the reaction mixture cooled to about 0°C overnight. The product, R-(-)-3-(3-chloro-4-methoxy)phenylhydrazono-5-methyl-2-piperidone, was collected, washed with water, and dried; weight = 2.30 g (75% yield); m.p. = 205°C. A small sample was further purified by chromatography over a short silica gel column using ethyl acetate as the eluant. [α]²⁵ = -58° (c = 10, MeOH).
  Analysis calc. for C₁₃H₁₆N₃O₂Cl

  Theory:

  C, 55.42; H, 5.72; N, 14.91; Cl, 12.58

  Found :

  C, 55.79; H, 5.78: N, 14.72; Cl, 12.69

• A mixture of 2.20 g (7.8 moles) of the R-(-) hydrazone and 20 ml of 90% formic acid was heated at 85° for three hours then slowly diluted with an equal volume of water. The mixture was allowed to cool and then chilled overnight. The dark precipitate was collected, washed with water, then recrystallized from acetone/water, yielding 1.20 g (60% yield) of S-(-)-1-oxo-4-methyl-6-methoxy-7-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; m.p. = 248°C. [α]²⁵ = -12.2° (c = 10, MeOH).
  Analysis calc. for C₁₃H₁₃N₂O₂Cl

  Theory:

  C, 58.99; H, 4.95; N, 10.58; Cl, 13.39

  Found :

  C, 59.16; H, 4.88; N, 10.80; Cl, 13.15

• The conversion of (S)-(-)-lactam to (S)-(-)-6-chloro-β-methylmelatonin was carried out as described previously in Example 3. The product, S-(-)-β-methyl-6-chloromelatonin, was spectroscopically identical to the racemate, but gave an optical rotation of [α]²⁵ = -13.2° (c = 10, MeOH).
• (R)-(+)-6-chloro-β-methylmelatonin was synthesized from (S)-(+)-3-ethoxycarbonyl-5-methyl-2-piperidone in the same manner as described above. The stereoisomer was identical to the (S)-(-) material except for the sign of rotation.

LY-156,735

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

References

1. http://www.chemdrug.com/databases/8_0_unnmipljvsnjrcxn.html

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N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide

N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide

N-[2-(7-Benzyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide

N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide

Acetamide, N-​[2-​[7-​(cyclohexylmethyl)​-​1,​6-​dihydro-​2H-​indeno[5,​4-​b]​furan-​8-​yl]​ethyl]​-

339.47, C22 H29 N O2

cas 1287785-08-3

Melatonin MT2 Agonists

Takeda……..innovator

Treatment of Sleep Disorders,

• Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone synthesized and secreted principally in the pineal gland, increases in dark circumstances and decreases in light circumstances. Melatonin exerts suppressively on pigment cells and the female gonads, and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is expected to be used for the therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet-lag syndrome and various disorders related to aging, etc.
• Recently, it has been reported that the production of melatonin melatonin could reset the body’s aging clock (see Ann. N. Y. Acad. Sci., Vol. 719, pp. 456-460 (1994)). As previously reported, however, melatonin is easily metabolized by metabolic enzymes in vivo (see Clinical Examinations, Vol. 38, No. 11, pp. 282-284 (1994)). Therefore, it cannot be said that melatonin is suitable as a pharmaceutical substance.
• Various melatonin agonists and antagonists such as those mentioned below are known.

  • (1) EP-A-578620 discloses compounds of:

  
  

  • • 
    • (2) EP-A-420064 discloses a compound of:
      
    • (3) EP-A-447285 discloses a compound of:
      
    • (4) EP-A-662471 discloses a compound of:
      
    • (5) EP-A-591057 discloses a compound of:
      
    • (6) EP-A-527687 discloses compounds of:
      
      X=S, 0, Y=CH
      X=0, NH, Y=N
    • (7) EP-A-506539 discloses compounds of:
      
  • Tricyclic or more poly-cyclic compounds with a cyclic ether moiety, such as those mentioned below, are known.

    • (1) Compounds of:
      
      are disclosed in Tetrahedron Lett., Vol. 36, p. 7019 (1995).
    • (2) Compounds of:
      
      
      are disclosed in J. Med. Chem., Vol. 35, p. 3625 (1992).
    • (3) Compounds of:
      
      are disclosed in Tetrahedron, Vol. 48, p. 1039 (1992).
    • (4) Compounds of:
      
      are disclosed in Tetrahedron Lett., Vol. 32, p. 3345 (1991).
    • (5) A compound of:
      
      is disclosed in Bioorg. Chem., Vol. 18, p. 291 (1990).
    • (6) A compound of:
      
      is disclosed in J. Electroanal. Chem. Interfacial Electrochem., Vol. 278, p. 249 (1990).

    
    

    see

http://www.google.co.in/patents/EP0885210B1?cl=en

Highly Potent MT2-Selective Agonists

J. Med. Chem., 2011, 54 (9), pp 3436–3444

DOI: 10.1021/jm200221q

http://pubs.acs.org/doi/full/10.1021/jm200221q

N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide (15)

By a similar procedure that described for 8, 15 (79%) was obtained as a white solid; mp 133−134 °C (EtOAc/hexane).

1H NMR (CDCl3) δ 0.82−1.03 (2H, m), 1.06−1.32 (3H, m), 1.42−1.78 (6H, m), 1.96 (3H, s), 2.32 (2H, d, J = 7.2 Hz), 2.74 (2H, t, J = 7.2 Hz), 3.26 (2H, s), 3.32−3.52 (4H, m), 4.59 (2H, t, J= 8.6 Hz), 5.60 (1H, s), 6.59 (1H, d, J = 7.9 Hz), 7.11 (1H, d, J= 7.9 Hz).

MS (ESI) m/z 340 (M + H)+. Anal. (C22H29NO2) C, H, N.

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Rupatadine

Rupatadine

Rupatadine

CAS 158876-82-5,

8-Chloro-11-(1-((5-methylpyridin-3-yl)methyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-chloro-11-(1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin

UNII-2AE8M83G3E, UR 12592

Molecular Formula: C26H26ClN3

Molecular Weight: 415.95774 g/mol

Percent Composition: C 75.07%, H 6.30%, Cl 8.52%, N 10.10%

Properties: Creamy solid, mp 58-61°.

Melting point: mp 58-61°

Platelet activating factor receptor antagonist; Histamine H1 receptor antagonist

Allergic rhinitis; Urticaria

J. Uriach & Cia. S.A.

Uriach developed and launched rupatadine for treating of allergic rhinitis and urticaria. Family members of the product case EP577957, have SPC protection in the EU until 2016.

As of January 2015, Newport Premium™ reports that Cadila Pharmaceuticals is producing or capable of producing commercial quantities of rupatadine fumarate and holds an active USDMF since September 2012.

Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia, S. A.[1] and is marketed under several trade names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax and Ralif.

Therapeutic indications approved

Rupatadine fumarate has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and children over 12 years. The defined daily dose (DDD) is 10 mg orally.

Derivative Type: Fumarate

CAS Registry Number: 182349-12-8

Trademarks: Rupafin (Uriach)

Molecular Formula: C26H26ClN3.C4H4O4

Molecular Weight: 532.03

Percent Composition: C 67.73%, H 5.68%, Cl 6.66%, N 7.90%, O 12.03%

Derivative Type: Trihydrochloride

CAS Registry Number: 156611-76-6

Molecular Formula: C26H26ClN3.3HCl

Molecular Weight: 525.34

Percent Composition: C 59.44%, H 5.56%, Cl 26.99%, N 8.00%

Properties: Crystals from ethyl acetate + ether, mp 213-217°.

Melting point: mp 213-217°.

Therap-Cat: Antihistaminic.

Keywords: Antihistaminic; Tricyclics; Other Tricyclics; Platelet Activating Factor Antagonist.

Available form

Rupatadine is available as round, light salmon coloured tablets containing 10 mg of rupatadine (as fumarate) to be administered orally, once a day.

Side effects

Rupatadine is a non-sedating antihistamine. However, as in other non sedating second-generation antihistamines, the most common side effects in controlled clinical studies weresomnolence, headaches and fatigue.

Mechanism of action

Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF) according to in vitro and in vivo studies.[2]

Rupatadine possesses anti-allergic properties such as the inhibition of the degranulation ofmast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the TNF in human mast cells and monocytes.[3]

Pharmacokinetics

Rupatadine has several active metabolites such as desloratadine, 3-hydroxydesloratadine, 6-hydroxydesloratadine and 5-hydroxydesloratadine.

History

Rupatadine discovery, pre-clinical and clinical development was performed by J. Uriach y Cia, S. A., a Spanish pharmaceutical company. It was launched in 2003 in Spain by J. Uriach y Cia, S. A., with the brand name of Rupafin. The registration of the product is approved in 23 countries from the EU, 8 Central American countries, Brazil, Argentina, Chile, Turkey and 14 African countries.

Efficacy in humans

The efficacy of rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year.[3][4][5]

• Rupatadine (I) is an authorized antihistaminic agent and has IUPAC name 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, CAS number 158876-82-5 for the free base and the following chemical formula:

  
• Rupatadine is currently marketed in 10 mg (rupatadine) tablets as rupatadine fumarate (CAS 182349-12-8 for the fumarate salt) for the treatment of allergic rhinitis and urticaria in adults and teenagers.
• Rupatadine free base was first disclosed in EP0577957 .
• Spanish patent application ES2087818 discloses the monofumarate salt of rupatadine (i.e. rupatadine fumarate) and aqueous liquid pharmaceutical compositions of rupatadine fumarate. In particular, this document discloses a syrup containing rupatadine fumarate at 4 g/L, sucrose, a flavouring agent, a sweetening agent and water; and a solution for injection which contains rupatadine fumarate at 20 g/L, benzyl alcohol, propyleneglycol and water.
• EP0577957 discloses some liquid pharmaceutical compositions of rupatadine free base; compound 4 in EP0577957 is rupatadine free base. The formulations disclosed therein are identical to those disclosed in ES2087818 but rupatadine free base is used instead of rupatadine fumarate.
• Despite the aqueous liquid pharmaceutical compositions disclosed in EP0577957and ES2087818 , the inventors have found that the solubility in water of rupatadine fumarate is 2.9 g/L (see Reference example 1) and therefore these prior art formulations may have stability problems due to supersaturation of rupatadine free base or rupatadine fumarate and would not be suitable for use as a medicament.
• CN101669901 and CN101669926 disclose liquid formulations of rupatadine free base using cyclodextrins to dissolve rupatadine.
• CN101669901 is directed to liquid formulations of rupatadine free base for ophthalmic delivery comprising rupatadine, a solvent and a cyclodextrin.
• CN10169926 is directed to liquid formulations of rupatadine free base for nasal delivery comprising rupatadine, a solvent and a cyclodextrin. It is stated that rupatadine has low solubility in water (1.39 mg/mL to 0.82 mg/mL at pH 3.0 to 7.0, table 9 in CN10169926 ) and the problem of its low solubility is solved using cyclodextrins (tables 10-12 of CN10169926 ) in order to obtain liquid formulations.

The reaction of 2-cyano-3-methylpyridine (I) with H2SO4 in t-BuOH gives the N-tert-butylamide (II), which is treated with two equivalents of BuLi and the corresponding dianion alkylated with 3-chlorobenzyl chloride to afford amide (III). The treatment of (III) with POCl3 gives nitrile (IV) which is cyclized to ketone (V) by subsequent treatment with CF3SO3H and aqueous HCl. Reaction of ketone (V) with the Grignard derivative prepared from chloride (VI) affords alcohol (VII) which is finally dehydrated by H2SO4 to give UR-12592 (1), as shown in Scheme 20491401a. The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X) which is treated with SOCl2. Scheme 20491402a. Description White crystals, m.p. 196-8 癈. References 1. Carceller, E., Jim閚ez, P.J., Salas, J. (J. Uriach & Cia SA). Process for the preparation of 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4 -piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. ES 9602107.

The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X), which is treated with SOCl2.

………………………….

EXAMPLE 4

•  http://www.google.com/patents/EP0577957A1?cl=en

8-chloro-11-(1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin

• To a solution of 1.7 mL (15 mmol) of 3,5-lutidine in 100 mL of CCl₄ was added 2.6 g (15 mmol) of NBS and the mixture was stirred at reflux under an argon atmosphere for 2 h. Then, the mixture was allowed to cool, the solid obtained was filtered off and to the filtrate was added 2.4 g (7.5 mmol) of the compound obtained in preparation 1 and 20 mg of 4-(dimethylamino)pyridine. The resulting mixture was stirred at room temperature for 18 h and 1.68 mL of triethylamine was added. It was diluted with 100 mL of dichloromethane and washed with 0.5N NaHCO₃ solution and with water. The organic phase was dried over sodium sulfate and the solvent was removed, to give 5.7 g of a residue that was chromatographed on silica gel (chloroform : methanol : ammonia, 60 : 2 : 0.2). 1.3 g of the title compound of the example was obtained as a white solid (yield: 40%).
  mp: 58-61°C;
  IR (KBr) ν: 3419, 3014, 1635, 1576, 1472 cm⁻¹;
  ¹H RMN (80 MHz, CDCl₃) δ (TMS): 8.39 (m, 3H, ar), 7.48 (m, 1H, ar), 7.37 (m, 1H, ar), 7.12 (m, 4H, ar), 3.45 (s, 2H, CH₂N), 3.36 (m, 2H), 3.1-2.1 (m, 13H). ¹³C RMN (20.15 MHz, CDCl₃) δ (TMS): 157.20 (C), 148.93 (CH), 147.46 (CH), 146.48 (CH), 139.50 (C), 138.56 (C), 137.06 (CH), 133.3 (C), 132.54 (C), 130.67 (CH), 128.80 (CH), 125.85 (CH), 121.92 (CH), 59.84 (CH₂), 54.63 (CH₂), 31.70 (CH₂), 31.32 (CH₂), 30.80 (CH₂), 30.56 (CH₂), 18.14 (CH₃).

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WO2006114676

http://www.google.com/patents/WO2006114676A2?cl=en

Scheme-1

Example 1

Preparation of3-bromomethyl-5-methylpyridine hydrochloride: A mixture of carbon tetrachloride (4000ml), azobisisobutyronitrile (45.96gm, 0.279mol), 3,5-lutidine (150gm, 1.399mol) and N-bromosuccinamide (299.4gm, 1.682mol) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and solid is filtered. HCl gas is passed to the filtrate and solid obtained is separated and filtered. Yield is 196gm Yield is 67.66%. Example 2

Preparation of Rupatadine :

A mixture of desloratadine (5.0gm, 0.016mol), methylene chloride (15ml), tetrabutylammonium bromide (0.575gm, 0.0018mol) and sodium hydroxide solution (2.5gm, 0.064mol in 8ml water) is cooled to 0 to 50C. 3-bromomethyl-5- methylpyridine hydrochloride (7.18gm, 0.032mol) in methylene chloride (35ml) is added to above mixture. The reaction mixture is stirred at 0 to 50C for 1 hour and at room temperature for 12 hours. Layers are separated and organic layer is washed with dilute HCl solution and water. Methylene chloride is distilled. Yield = 9.5g %Yield =

67.66%.

Example 3

Preparation of “Rupatadine fumarate:

A solution of fumaric acid (3.3gm) in methanol (46ml) is added to solution of

Rupatadine (4.5gm) in ethyl acetate (30ml) at room temperature. The reaction mass is cooled to -5 to O0C for 4 hours. Rupatadine fumarate is separated filtered and Washed with ethylacetate. Yield = 5.5 gm.

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NEW PATENT

EP-02824103…An improved process for the preparation of rupatadine fumarate, Cadila Pharmaceuticals Ltd

Process for the preparing rupatadine intermediate (particularly 5-methylpyridine-3-methanol) comprises reduction of 5-methyl nicotinic acid alkyl ester using alkali metal borohydride is claimed. For a prior filing see WO2006114676, claiming the process for preparation of rupatadine fumarate.

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J. Med. Chem., 1994, 37 (17), pp 2697–2703

DOI: 10.1021/jm00043a009

http://pubs.acs.org/doi/abs/10.1021/jm00043a009

References

1. Patents: EP 577957, US 5407941, US 5476856
2. Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Queralt, M.; Puigdemont, A.; García-Rafanell, J.; Forn, J. (1997). “Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF)”. The Journal of Pharmacology and Experimental Therapeutics 280 (1): 114–121. PMID 8996188. edit
3. Picado, C. S. (2006). “Rupatadine: Pharmacological profile and its use in the treatment of allergic disorders”. Expert Opinion on Pharmacotherapy 7 (14): 1989–2001. doi:10.1517/14656566.7.14.1989. PMID 17020424. edit
4. Keam, S. J.; Plosker, G. L. (2007). “Rupatadine: A review of its use in the management of allergic disorders”. Drugs 67 (3): 457–474. doi:10.2165/00003495-200767030-00008. PMID 17335300. edit
5. Mullol, J.; Bousquet, J.; Bachert, C.; Canonica, W. G.; Gimenez-Arnau, A.; Kowalski, M. L.; Martí-Guadaño, E.; Maurer, M.; Picado, C.; Scadding, G.; Van Cauwenberge, P. (2008). “Rupatadine in allergic rhinitis and chronic urticaria”. Allergy 63: 5–28.doi:10.1111/j.1398-9995.2008.01640.x. PMID 18339040. edit

Literature References: Dual antagonist of histamine H1 and platelet-activating factor receptors. Prepn: E. Carceller et al., ES 2042421; eidem, US 5407941 (1993, 1995 both to Uriach);

eidem,J. Med. Chem. 37, 2697 (1994).

Mechanism of action: M. Merlos et al., J. Pharmacol. Exp. Ther. 280, 114 (1997).

Clinical trial in seasonal allergic rhinitis: F. Saint-Martin et al., J. Invest. Allergol. Clin. Immunol. 14, 34 (2004);

and comparison with ebastine: E. M. Guadaño et al., Allergy 59, 766 (2004).

Review of pharmacology and clinical development: N. Y. Van Den Anker-Rakhmanina, Curr. Opin. Anti-Inflam. Immunomod. Invest. Drugs 2, 127-132 (2000).

1 TO 8 OF 8
PATENT	SUBMITTED	GRANTED
8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine [US5407941]	1995-04-18
Treatment of PAF and histamine-mediated diseases with 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine [US5476856]	1995-12-19
Process for the synthesis of n-(5-methylnicotinoyl)-4 hydroxypiperidine, a key intermediate of rupatadine [US6803468]	2004-03-04	2004-10-12
$g(b)2-ADRENERGIC RECEPTOR AGONISTS [EP1003540]	2000-05-31
$g(b)2-ADRENERGIC RECEPTOR AGONISTS $g(b)2-ADRENERGIC RECEPTOR AGONISTS [EP1019360]	2000-07-19
8-Chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. [EP0577957]	1994-01-12	1995-07-12
NOVEL CRYSTALLINE FORM OF RUPATADINE FREE BASE [US2009197907]	2009-08-06
METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS [WO9966944]	1999-12-29

RUPATADINE

SYSTEMATIC (IUPAC) NAME
8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate
CLINICAL DATA
TRADE NAMES	Rupafin, Alergoliber, Rinialer, Pafinur, Rupax, Ralif
AHFS/DRUGS.COM	International Drug Names
LEGAL STATUS	Prescription drug
ROUTES	Oral
PHARMACOKINETIC DATA
PROTEIN BINDING	98–99%
METABOLISM	Hepatic, CYP-mediated
HALF-LIFE	5.9 hours
EXCRETION	34.6% urine, 60.9% faeces
IDENTIFIERS
CAS NUMBER	158876-82-5  (free base) 182349-12-8 (fumarate)
ATC CODE	R06AX28
PUBCHEM	CID 133017
CHEMSPIDER	117388
UNII	2AE8M83G3E
CHEMBL	CHEMBL91397
CHEMICAL DATA
FORMULA	C26H26ClN3
MOLECULAR MASS	415.958 g/mol

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