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Atagabalin

Trans-dimethyl gababutin; UNII-JT7957Q2FB;  223445-75-8;

2-[(3S,4S)-1-(aminomethyl)-3,4-dimethylcyclopentyl]acetic acid

DNC014878

AN-5147

PD-0200390

D09581

2-[(3S,4S)-1-(aminomethyl)-3,4-dimethyl-cyclopentyl]acetic acid

3,4-trans-2-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid

Cyclopentaneaceticacid, 1-(aminomethyl)-3,4-dimethyl-, (3S,4S)-

Pfizer Inc.  INNOVATOR

 

Atagabalin (PD-0200,390) is a drug developed by Pfizer and related to gabapentin, which similarly binds to the α2δ calcium channels (1 and 2).[1] It was under development as a treatment for insomnia,[2][3][4] but was discontinued following unsatisfactory trial results.

Gabapentin (Neurontin®) (1) was launched as an add-on therapy for epilepsy in 1994. Utility against neuropathic pain and anxiety have been reported preclinically and efficacy against neuropathic pain has been demonstrated clinically in humans. Pregabalin (Lyrica®) (2), has superior potency and pharmacokinetics to gabapentin and has been approved for the management of neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, adjunctive treatment of partial seizures, and fibromyalgia in the US.

Image for unlabelled figure

Gabapentin and pregabalin are thought to mediate their pharmacological actions through binding to the α2δ subunit of a voltage gated calcium channeland it has been shown that gabapentin and pregabalin bind to this α2δ subunit with IC50 values of 140 nM and 80 nM, respectively. We have recently disclosed our initial SAR investigations around five-membered ring gabapentin analogues, which we have termed gababutins.In that Letter, we investigated a range of 3-substituted gababutin analogues and identified the 3-(R)-methyl gababutins (3) and (4). Both (3) and (4) bind to the gabapentin binding site with high affinity but have different in vivo profiles, with (3) being effective on oral dosing in models of anxiety and (4) being effective on oral dosing in models of neuropathic pain.

SYNTHESIS

Figure imgf000036_0001

PATENT

WO 1999021824

http://www.google.co.in/patents/WO1999021824A1?cl=en

synthesis of 3-oxo-2,8-diazaspiro[4,5]decane-

8-carboxylic acid tert-butyl ester (P. W. Smith et al., J. Med. Chem., 1995;38:3772). The compounds may also be synthesized by the methods outlined by G. Satzinger et al., (Ger Offen 2,460,891; US 4,024,175, and Ger Offen 2,611,690; US 4,152,326) (General Schemes 3 and 4). The compounds may also be synthesized by the route outlined by G. Griffiths et al., Helv. Chim. Ada, 1991 ;74:309 (General Scheme 5). General Scheme 1

Figure imgf000031_0001

(i) Ethyl cyanoacetate, piperidine (Cope et al., J. Am. Chem. S c.,1941 ;63:3452); (ii) NaCN, EtOH/H2O; (iii) EtOH, HCl; (iv) H2O/H+; (v) H2, Rh/C, MeOH; (vi) HCl.

General Scheme 2

Figure imgf000032_0001
Figure imgf000032_0002

(i) Ph3P=CHCO2Me; (ii) MeNO2, 1,1,3,3-tetramethylguanidine; (iii) Raney nickel, EtOH/H2O; (iv) HCl.

General Scheme 3

Figure imgf000033_0001

(i) Ethylcyanoacetate, ammonia then H3θ+; (ii) H2SO4; (iii) AC2O; (iv) MeOH; (v) Curtius Reaction; (vi) HCl, H2O then anion exchange.

General Scheme 4

Figure imgf000034_0001

(i) Ethylcyanoacetate, ammonia then H3O ; (ii) H2SO4; (iii) AC2O; (iv) H2NOH; (v) PhSO2Cl; (vi) Et3N, MeOH; (vii) HCl, H O then anion exchange.

General Scheme 5

Figure imgf000035_0001
Figure imgf000035_0002

(i) Ethyl cyanoacetate, piperidine (Cope et al., J. Am. Chem. Soc, 1941 ;63:3452); (ii) NaCN, EtOH/H2O; (iii) BnOH, HCl; (iv) H2O/H+; (v) H2, Rh/C, MeOH.

EXAMPLE 1

Figure imgf000036_0001

Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeNO2,Bu4N+F”; (iϋ) H2, Ni; (iv) HCl Synthesis of (trans)-(3,4-Dimethyl-cyclopentylidene)-acetic acid ethyl ester (2)

NaH (60% dispersion in oil, 737 mg, 18.42 mmol) was suspended in dry tetrahydrofuran (50 mL) and cooled to 0°C. Triethylphosphonoacetate (3.83 mL, 19.30 mmol) was added and the mixture stirred at 0°C for 15 minutes. The ketone (1) (1.965 g, 17.54 mmol) in THF (10 mL) was then added and the mixture allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 mL) and water (150 mL). The organic phase was separated, washed with brine, dried (MgSO4) and the solvent removed in vacuo.

The residue was purified by flash chromatography (silica, ethyl acetate:heptane 1 :9) to give 3.01 g (94%) of (2) as a colorless oil.

*H NMR 400 MHz (CDCI3): δ 1.01 (3H, d, J = 6 Hz), 1.03 (3H, d, J = 6 Hz), 1.26

(3H, t, J = 7 Hz), 1.49 (2H, m), 2.07 (1H, m), 2.24 (1H, m), 2.61 (1H, m), 4.13 (2H, q, J = 7 Hz), 5.72 (1H, s).

MS (CI+) m/e: 183 ([MH+], 18%).

Synthesis of (trans)-(3,4-Dimethyl-l-nitromethyl-cyclopentyl)-acetic acid ethyl ester (3)

The unsaturated ester (2) (2.95 g, 16.2 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70°C with nitromethane (1.9 mL, 35.2 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 22 mL, 22.0 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 2N HCl (30 mL) followed by brine (50 mL). The organic phase was collected, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate :heptane 1 :9) to give 1.152 g (29%) of a clear oil. !H NMR 400 MHz (CDCI3): δ 0.98 (6H, d, J = 6 Hz), 1.10-1.39 (5H, m), 1.47

(2H, m), 1.87 (1H, m), 2.03 (1H, m), 2.57 (2H, ABq, J = 16, 38 Hz), 4.14 (2H, q, J = 7 Hz), 4.61 (2H, ABq, J = 12, 60 Hz).

MS (ES+) m/e: 244 ([MH+], 8%).

IR (film) v ein-1 : 1186, 1376, 1549, 1732, 2956. Synthesis of (±)-(trans)-7,8-Dimethyl-spiro[4.4]nonan-2-one (4)

The nitroester (3) (1.14 g, 4.7 mmol) was dissolved in methanol (50 mL) and shaken over Raney nickel catalyst under an atmosphere of hydrogen (40 psi) at 30°C. After 5 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 746 mg (95%) of a pale yellow oil which solidified on standing.

! H NMR 400 MHz (CDC13): δ 0.98 (6H, d, J = 6 Hz), 1.32 (2H, m), 1.46 (2H, m), 1.97 (2H, m), 2.27 (2H, ABq, J = 16, 27 Hz), 3.23 (2H, s), 5.62 (1H, br s). MS (ES+) m/e: 168 ([MH+], 100%). IR Cfilπ v cm-1 : 1451, 1681, 1715, 2948, 3196.

Synthesis of (±)-(trans)-(l-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid hydrochloride (5)

The lactam (4) (734 mg, 4.40 mmol) was heated to reflux in a mixture of 1 ,4-dioxan (5 mL) and 6N HCl (15 mL). After 4 hours, the mixture was cooled to room temperature, diluted with water (20 mL), and washed with dichloromethane

(3 x 30 mL). The aqueous phase was collected and the solvent removed in vacuo. The residue was triturated with ethyl acetate to give 675 mg (69%) of a white solid after collection and drying.

ΪH NMR 400 MHz (d6-DMSO): δ 0.91 (6H, d, J = 6 Hz), 1.18 (2H, m), 1.42 (2H, m), 1.72 (1H, m), 1.87 (1H, m), 2.42 (2H, ABq, J = 16, 24Hz), 2.90 (2H, ABq,

J = 12, 34 Hz), 8.00 (3H, br s), 12.34 (1H, br s).

MS (ES+) m/e: 186 ([MH-HC1J+, 100%).

PATENT

WO 2002000209

PATENT

http://www.google.co.in/patents/WO1999021824A1?cl=en

PATENT

WO 2007010387

http://www.google.com/patents/WO2007010387A2?cl=en

Figure imgf000031_0001

21 22

Figure imgf000031_0002

Scheme IH

 

PAPER

Synthesis and in vivo evaluation of 3,4-disubstituted gababutins
Bioorganic&Medicinal Chemistry Letters (2010), 20, (1), 248-251.

The synthesis of 3,4-trans-dimethyl cyclopentanone (14), is detailed in Scheme 1.

Reagents and conditions: (i) (−)-menthol, pyridine, CH2Cl2; (ii) butadiene, ...

Scheme 1.

Reagents and conditions: (i) (−)-menthol, pyridine, CH2Cl2; (ii) butadiene, TiCl4, toluene, −10 °C (100% yield, 65% de) or butadiene, Et2AlCl, toluene, −60 °C (64% yield, 95% de); (iii) LiAlH4, THF; recrystallisation from acetone; (iv) pyridine, MsCl, 0 °C, 18h (82%); (v) LiAlH4, diethyl ether, 40 °C, 2h (98%); (vi) KMnO4, nBu4NBr, H2O–CH2Cl2, rt, 18h; then SO2, 0 °C (82%); (vii) methanol, cH2SO4, rt, 18h (90%) (viii) KOtBu, THF, 75 °C, 3h (100%); (ix) DMSO, H2O, 140 °C, 4 h (86%).

 

Reagents and conditions: (i) triethylphosphonoacetate, NaH, THF, 0°C to rt ...

Scheme 3.

Reagents and conditions: (i) triethylphosphonoacetate, NaH, THF, 0 °C to rt (95%); (ii) MeNO2, TBAF, THF, reflux (65%); (iii) H2, Ni, MeOH; (iv) 6 N HCl, 1,4-dioxane, reflux (69% from nitroester).

References

 1  Blakemore DC, Bryans JS, Carnell P, Carr CL, Chessum NE, Field MJ, Kinsella N, Osborne SA, Warren AN, Williams SC (January 2010). “Synthesis and in vivo evaluation of bicyclic gababutins”. Bioorganic & Medicinal Chemistry Letters 20 (2): 461–4. doi:10.1016/j.bmcl.2009.11.118. PMID 20005103.

 

 

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Atagabalin
Atagabalin.svg
Systematic (IUPAC) name
[(3S,4S)-1-(aminomethyl)-3,4-dimethylcyclopentyl]acetic acid
Identifiers
CAS Registry Number 223445-75-8 
ATC code None
PubChem CID: 9794485
ChemSpider 7970252 Yes
UNII JT7957Q2FB Yes
ChEMBL CHEMBL593430 Yes
Chemical data
Formula C10H19NO2
Molecular mass 185.263 g/mol

//////C[C@H]1CC(C[C@@H]1C)(CC(=O)O)CN

READ IMAGABALIN, PD 217074


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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