BMS-582949 in phase 2 for Treatment of Antipsoriatics , Rheumatoid arthritis

BMS 582949, PS-540446

UNII-CR743OME9E

CAS 623152-17-0

4-[5-(N-Cyclopropylcarbamoyl)-2-methylphenylamino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide

Bristol-Myers Squibb CompanyM.Wt: 406.48
Cas : 623152-17-0 Formula: C22H26N6O2

BMS-582949 had been in phase II clinical trials at Bristol-Myers Squibb for the oral treatment of moderate to severe psoriasis and for the treatment of rheumatoid arthritis (RA) in combination with methotrexate and for the treatment of inflammation in atherosclerotic plaque. However, no recent development has been reported for this research.

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http://www.google.com/patents/WO2012031057A1?cl=en

The present invention generally relates to a method of treating resistant rheumatic disease, such as refractory rheumatoid arthritis, with a therapeutically effective amount of a dual action p38 inhibitor that is safe and well-tolerated. A dual action p38 kinase inhibitor is a compound that inhibits both activation of p38 kinase and p38 kinase activity in cells.

A large number of cytokines participate in the inflammatory response, including IL- 1 , IL-6, IL-8 and TNF-a. Overproduction of cytokines such as IL-1 and TNF-a are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others. See e.g., Henry et al., Drugs Fut. , 24: 1345- 1354 ( 1999); Salituro et al., Curr. Med. Ckem., 6:807-823 (1999)]. Important mediators of proinflammatory cytokines such as TNFct and IL-1 β,. as well as cellular responses to such cytokines production, are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. See e.g., Schieven, G.L., "The biology of p38 kinase: a central role in inflammation", Current Topics in Medicinal Chemistry, 5 :921 - 928 (2005). Accordingly, modulation of p38 kinase may be useful in the treatment of inflammatory disease including rheumatic diseases such as rheumatoid arthritis (RA).

Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-a for use in treating inflammatory diseases are disclosed in U.S. Patent Nos.

6,277,989 and 6, 130,235 to Scios, Inc; U.S. Patent. Nos. 6, 147,080 and 5,945,41 8 to Vertex Pharmaceuticals Inc; U.S. Patent Nos. 6,251 ,914, 5,977, 103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Patent Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01 /27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoHne derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors). Other compounds that inhibit p38 kinase are pyrrolotriazine aniline compounds, information on these compounds is disclosed in U.S. Patent Nos. 6,670,357; 6,867,300; 7,034, 151 ; 7, 160,883; 7,21 1,666; 7,253, 167; and U.S. Publication Nos. 2003/023283 1 (published Dec. 18, 2003); 2004/0229877 (published Nov. 1 8, 2004); 2005/0043306 (published Feb. 24, 2005; 2006/0003967 (published Jan. 5, 2006); 2006/0030708 (published Feb. 9, 2006); 2006/0041 124 (published Feb. 23, 2006); 2006/0229449 (published Oct. 12, 2006); 2006/0235020 (published Oct. 19, 2006); and 2007/0213300 (published Sept 13, 2007).

In particular, WO 2003/090912 (U.S. Patent Nos. 7, 160,883, 7,388,009, p38 inhibitor, BMS-582949 (Example 7,

including processes of making and uses thereof.

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http://www.google.com/patents/WO2003090912A9?cl=en

Examples 4-22

Compounds having the formula (Id), above, wherein R₄ has the values listed in the following Table, were prepared following the same procedure described for Example 3, using the appropriate amine in place of ra-butylamine.

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WO 2006020904

 http://www.google.com.br/patents/WO2006020904A1?cl=en

EXAMPLE IA St

Part a.

A solution of Example 1 (0.86 g, 2.20 mmol, 1.0 eq.) in THF (4.0 mL) and 1 N aqueous NaOH (9.0 mL, 4.1 eq.) was stirred at 6O⁰C overnight. After cooling to RT, the reaction mixture was concentrated in vacuo but not to dryness. To the solution at O⁰C was added 1 N aqueous hydrochloric acid until it was acidic and the precipitate was collected and dried to afford crude Example IA acid (0.51 g, 64.0 % yield). HPLC Ret. t. = 2.400 min.; LC/MS (M+H) ⁺ = 366.06⁺. The filtrate was then extracted with EtOAc (3x) and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give Example IA acid (0.035 g, 4.4 % yield). Part b.

A solution of Part a. acid (0.026 g, 0.071 mmol, 1.0 eq.), EDC (0.021 g, 0.11 mmol, 1.5 eq.), HOBt (0.015 g, 0.11 mmol, 1.5 eq), ^-propylamine (0.015 mL, 0.15 mmol, 2.1 eq.) and DIPEA (0.040 mL, 0.23 mmol, 3.2 eq.) in DMF (0.20 mL) was shaken at RT overnight. Water (1 mL) was added and the precipitate collected by filtration, washed with water, and dried to give Example IA amide (0.021 g, 70% yield); HPLC Ret. t. = 2.883 min.; LC/MS (M+H)⁺ = 421.18 ⁺.

EJiAMPLE 2 Direct Aminolysis Procedure

n-Buli/THF

Ester Compound I or Hexyllithium/THF

-^

,NH₉

1. Aminolysis with hexyllithium

To a dried 100 ml flask was added THF (10 ml) under nitrogen, which was then cooled to -10⁰C. Hexyllithium (2.3 M in hexane, 6.5 ml, 15.0 mmol) was added slowly (exothermic, temperature was up to 5°C), followed by dropwise addition of propylamine (1.01 g, 1.4 ml, 17.1 mmol) at such a rate to maintain the temperature below 5°C. The resulting mixture was stirred at O⁰C for 20 minutes. A suspension of ester compound I (1.0 g, 2.5 mmol) in THF (12 ml) was added over a 10 minute period (exothermic, T<5°C). After being stirred at 0⁰C for 20 minutes, the mixture was allowed to warm to room temperature and stirred for 5 hours. Ester compound I was <0.1 AP at this point by HPLC analysis. The mixture was cooled to -5⁰C. Acetic acid (2 ml) was added slowly to maintain the temperature <10°C. The resulting thick slurry was stirred at room temperature for 20 minutes, and then solvents were exchanged with DMF (15 ml) on a rotavapor. To the resulting yellow slurry, water (15 ml) was added slowly to keep T<25°C. During the addition of water, the slurry became a clear solution, and a new slurry was formed. The slurry was stirred at room temperature for overnight. In the morning the slurry was filtered and the solid was washed with DMF/water (1:1, 5 ml), water (5 ml) and acetone (5 ml). The cake was dried under vacuum at 55°C for 24 hours to afford 0.90 g of amide product II (yield: 87.2%) as a white solid. HPLC: 99.70 AP.

2. Aminolysis with n-butyllithium

To a dried 100 ml of flask was added THF (10 ml) under nitrogen and then cooled to -10⁰C. n-Butyllithium (2.5 M in hexane, 6.0 ml, 15.0 mmol) was added slowly, followed by dropwise addition of propylamine (0.98 g, 16.5 mmol) at such a rate to keep the temperature below 0⁰C. The resulting mixture was stirred at O⁰C for 20 minutes. A suspension of ester compound I (1.0 g, 2.5 mmol) in THF (12 ml) was added over a 10 minute period (T<5°C). After being stirred at O⁰C for 30 minutes, the mixture was allowed to warm to room temperature and stirred for overnight (~22h, Note 1). Compound I was not detected at this point by HPLC analysis. The mixture was cooled to -7°C. Acetic acid (2 ml) was added dropwise to maintain the temperature <10°C. The resulting thick slurry was stirred at 5⁰C for 2 hours and at room temperature for 20 minutes, followed by evaporation on a rotavapor to give a wet yellow solid. To this solid was added acetone (10 ml) and water (20 ml). The slurry was stirred at room temperature for one and half hours. Filtration gave a white solid. This solid was washed with 35% acetone in water (10 ml), water (5 ml) and acetone (5 ml). The cake was dried under vacuum at 55°C for the weekend to afford 0.94g of amide product II (yield: 91.0%) as a white solid. HPLC: 99.76 AP. Note 1: Compound I was -0.056 AP at 2.5 hours.

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WO 2003090912

 http://www.google.com/patents/WO2003090912A1?cl=en

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Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38a MAP kinase inhibitor for the treatment of inflammatory diseases
J Med Chem 2010, 53(18): 6629

http://pubs.acs.org/doi/abs/10.1021/jm100540x

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp² character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (7k)

A mixture of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid (6b) (2.16 g, 5.91 mmol), n-propylamine (1.0 mL, 12.2 mmol), BOP (3.40 g, 7.69 mmol), and N-methylmorpholine (2.5 mL, 22.7 mmol) in DMF (10 mL) was stirred at 50 °C for 3 h. The mixture was poured into a mixture prepared from saturated NaHCO₃ solution (60 mL) and water (60 mL). The precipitating product was collected by suction filtration was washed with water. This crude product was suspended into ethyl acetate (100 mL) and stirred at 70 °C for 1 h. Upon cooling to rt, the title compound (2.07 g, 86% yield) was collected as a white solid by suction filtration; 98% purity by HPLC. LCMS (EI)

m/z Calcd for C₂₂H₂₆N₆O₂ (M + H)⁺ = 407.21. Found: 407.22.

¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J = 3.6 Hz, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 3.20 (m, 2H), 2.87 (m, 1H), 2.82 (s, 3H), 2.25 (s, 3H), 1.54 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H), 0.68 (m, 2H), 0.59 (m, 2H).

¹³C NMR (125 MHz, DMSO-d₆) δ 167.3, 164.45, 155.3, 148.7, 138.8, 137.1, 133.0, 130.6, 127.2, 125.8, 119.6, 118.8, 114.4, 113.3, 41.0, 23.6, 23.1, 18.5, 12.1, 12.0, 6.2.

EXAMPLE 3

Direct Aminolysis

Ester Compound I

Amide Product II

Method A:

A solution of n-propylamine (6.5 eq) in THF (20 ml/g of ester compound I) was cooled to — 5°C and was slowly treated with 2.5 M solution of n-butyllithium (6.1 eq). The mixture was stirred for 10 minutes. At the end of the period, a slurry of ester compound I (1 eq) in THF (14 ml/g of ester compound I) was cannulated into the performed Li-NHPr solution. The reaction mixture was warmed to 25°C and stirred till all of ester compound I was consumed (~ 3 hours). After the reaction was judged to be completed by HPLC, the reaction mixture was cooled to ~0°C and was slowly treated with acetic acid (5 ml/g of ester compound I). The slurry was then warmed to -2O⁰C and was stirred for 1 hour. At the end of the period, the solvent was distilled under vacuum to the minimum volume and the concentrated slurry was diluted with a solution of acetone (10 ml/g of ester compound I) and water (20 ml/g of ester compound I). The slurry was stirred for 1 hour and was cooled to ~5°C. The slurry was filtered and the cake was washed with acetone (5 ml/g of ester compound I). The cake was dried to give the amide product II (typically in 85% yield and 99 AP).

Method B:

A solution of n-propylamine (20 eq) in 2,2,2-trifmoroethanol (10 ml/g of ester compound I) was slowly treated with 2.5 M solution of n-butyllithium (1.5 eq). The mixture was stirred for 5 minutes. At the end of the period, the starting material, ester compound I, was added and the reaction mixture was warmed to 90⁰C. The reaction mixture was held at 90⁰C for 24 hours and was allowed to cool to ~20°C. The reaction mixture was then analyzed by HPLC. Typically, analysis indicated there was only 1.57 AP of starting material left.

Method C:

A solution of n-propylamine (2 eq) in methylene chloride (10 ml/g of ester compound I) at 20⁰C was slowly treated with 2.0 M solution of trimethylaluminum (4 eq) in hexanes. The mixture was stirred for 15 minutes. At the end of the period, the starting material, ester compound 1 (1 eq), was added and the reaction mixture was warmed to 60⁰C. The reaction mixture was held at 60⁰C for 24 hours and was allowed to cool to ~20°C. The reaction mixture was then slowly quenched with aqueous HCl solution and analyzed by HPLC. Typically, analysis indicated there was 96.8AP of amide compound II product with 0.03 AP of the dipropylamide impurity.

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WO2003090912A1 *

15 abr. 2003

6 nov. 2003

Squibb Bristol Myers Co

Pyrrolo-triazine aniline compounds useful as kinase inhibitors

Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor.

Liu C, Lin J, Everlof G, Gesenberg C, Zhang H, Marathe PH, Malley M, Galella MA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K.

Bioorg Med Chem Lett. 2013 May 15;23(10):3028-33. doi: 10.1016/j.bmcl.2013.03.022. Epub 2013 Mar 15.

Methods: implementation of in vitro and ex vivo phagocytosis and respiratory burst function assessments in safety testing.

Freebern WJ, Bigwarfe TJ, Price KD, Haggerty HG.

J Immunotoxicol. 2013 Jan-Mar;10(1):106-17. doi: 10.3109/1547691X.2012.736427. Epub 2012 Nov 23.

Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.

Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, Dyckman AJ, Li T, Wityak J, Gillooly KM, Pitt S, Shen DR, Zhang RF, McIntyre KW, Salter-Cid L, Shuster DJ, Zhang H, Marathe PH, Doweyko AM, Sack JS, Kiefer SE, Kish KF, Newitt JA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K.

J Med Chem. 2010 Sep 23;53(18):6629-39. doi: 10.1021/jm100540x.

BMS-582949: crystalline form of a p38alpha inhibitor? WO2008079857.

Norman P.

Expert Opin Ther Pat. 2009 Aug;19(8):1165-8. doi: 10.1517/13543770902816160.

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BMS 587101…….The LFA-1 receptor antagonist in preclinical for the treatment of a variety of autoimmune and inflammatory diseases such as rheumatoid arthritis and psoriasis.

• C₂₆H₂₀Cl₂N₄O₄S
•  mass: 555.432373 Da

Bristol-Myers Squibb Company

read poster

 http://www.cerep.fr/cerep/users/pages/news/Publications/123.pdf

BMS-587101 acts as a leukocyte function-associated antigen-1 (LFA-1) receptor antagonist. Ref: Synfacts. 2010; 8, 0865-0865.

5-[(5s,9r)-9-(4-Cyanophenyl)-3-(3,5-Dichlorophenyl)-1-Methyl-2,4-Dioxo-1,3,7-Triazaspiro [4.4]non-7-Yl]methyl]-3-Thiophenecarboxylicacid

5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-ylmethyl]-thiophene-3-carboxylic Acid

3-Thiophenecarboxylic acid, 5-[[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl]- [ACD/Index Name]

5-{[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl}-3-thiophenecarboxylic acid [ACD/IUPAC Name]

5-{[(5S,9R)-9-(4-Cyanphenyl)-3-(3,5-dichlorphenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl}-3-thiophencarbonsäure [German] [ACD/IUPAC Name]

Acide 5-{[(5S,9R)-9-(4-cyanophényl)-3-(3,5-dichlorophényl)-1-méthyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]méthyl}-3-thiophènecarboxylique [French] [ACD/IUPAC Name]

2IC

BMS-587101

BMS-688521

data

MS (ESI)m/z553 (M-H)-;

1H NMR(500 MHz, DMSO-d6)δ

8.17 (1 H, s), 7.62 (2 H, d,J=8.07 Hz), 7.44 (1 H, s), 7.27 (3 H, m), 6.64 (2 H, s),

4.11 (1 H, d,J=13.45 Hz), 3.96 (1 H, d,J=14.12 Hz), 3.88 (1 H, dd,J=11.76, 5.71 Hz), 3.43 (2 H, br. s.),

3.27 (1 H, br. s.), 3.23 (3 H, s), 3.06 (1 H, d,J=10.08 Hz);

Anal.(C26H20Cl2N4O4S)Calcd.: C,56.22; H,3.63;Cl, 12.77; N,10.09; S,5.77;.

Found: C,55.95; H,3.59;Cl, 12.54; N,10.01; S,5.79;

ee =99.26±0.00 % [Chiralcel OJ-R, 150 x 4.6 mm, 5 um particle size, MeOH: CH3CN: 0.2% aq.H3PO4 (30:30:40)];

[α]D=-6.324 (c = 8.967 mg/mL, CHCl3);

Interaction between leukocyte function-associated antigen-1 (LFA-1), expressed on the surface of cytokine-stimulated cells, and intercellular adhesion molecule (I-CAM), found on the surface of both leukocytes and endothelium, plays a key function in the intercellular immune response, causing T-cell adhesion and subsequent migration through the blood vessel wall to the inflamed area.(1)

Small molecules which inhibit the LFA-1/I-CAM interaction are targeted as potential drugs for the treatment of a variety of autoimmune and inflammatory diseases such as rheumatoid arthritis and psoriasis.(2, 3) The LFA-1 receptor antagonist, BMS-587101, 1,(4, 5) was selected for clinical development, and we required a synthesis that would reliably generate kilogram quantities of API. This paper details the identification and development of a synthesis which enabled the realization of this goal.

BMS-587101 inhibits the interaction between leukocyte function-associated antigen-1 (LFA-1) and the intercellular adhesion molecule (ICAM), thereby offering a potential treatment for various autoimmune and inflammatory dis­eases, such as rheumatoid arthritis and psoriasis. A four-step multikilogram route to BMS-587101 (22% overall yield ) from the commercial hydantoin B features an efficient dipolar cycloaddition of an azomethine ylide generated by reaction of glycine with hexamethylenetetramine (HMTA).

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paper

http://pubs.acs.org/doi/abs/10.1021/op9003168

Org. Process Res. Dev., 2010, 14 (3), pp 553–561

DOI: 10.1021/op9003168

The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

Preparation of 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-ylmethyl]-thiophene-3-carboxylic Acid (1) Directly from 6

To a solution of 6 (46.9 kg, 77.6 mol) and 1,2-propanediol (11.8 kg) in tetrahydrofuran (41.7 kg) and water (266.8 kg) was added cold (0−10 °C) potassium hydroxide solution (1 N, 244.5 kg) at 8−12 °C in 0.5 h. The resulting biphasic mixture was stirred at 8−12 °C for 18−24 h until the reaction was complete (<1% 6 remaining as monitored by HPLC). The reaction mixture was washed with n-heptane (385.7 kg). The pH was adjusted to 7.5 with addition of 1.5 M citric acid (22.9 kg). Isopropyl acetate (817.8 kg) was charged, and 1.5 M citric acid_(aq) (22.9 kg) was added until a pH of 6.5 was attained. After agitating for 15 min and holding for 30 min, the aqueous layer was discarded, and the organic layer was washed with H₂O (470 kg). The solution was then polish filtered, and isopropylacetate (52.2 kg) was used to rinse the polish filter assembly. The solution was concentrated under reduced pressure (240 Torr) to a volume of 718 L at <45 °C. Seeds (500 g) were charged, and the distillation was continued until a volume of 207 L was attained. Heptane (117.8 kg) was charged, the slurry was cooled to 20 °C over 1.5 h and was subsequently wet milled until d₉₀ < 60 μm. The slurry was held for >2 h and filtered. The cake was washed with a 1:1 isopropyl acetate/heptane solution (109.7 kg) isopropyl acetate and dried in vacuum at 35−40 °C to a constant weight. Acid 1 (39.6 kg, 91.5% yield and 99.33 HPLC area % purity) was obtained as a white and sandy crystalline solid.

..............................

U.S. Patent 7,381,737 B2

http://www.google.com/patents/US7381737

IIIn:

Also provided are crystalline forms of solvates and salts of the substituted spiro-hydantoin compound (IIIn).

5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid.

EXAMPLES

The following examples illustrate embodiments of the inventive process, and are not intended to limit the scope of the claims. For ease of reference, the following abbreviations are used herein:

ABBREVIATIONS

• DMSO=dimethyl sulfoxide
• DTTA=(+)-Di-p-toluoyl-D-tartaric acid

Preparation 13-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione

Triethylamine (0.78 kg, 7.75 mol) was added in 15-30 minutes with stirring to a thin suspension of sarcosine ethylene hydrochloride (1.00 kg, 6.51 mol) in dichloromethane (6.00 L). After stirring at room temperature for 1.5-2.0 hours, the mixture was filtered to remove the resulting triethylamine hydrochloride salt. The salt cake was washed with dichloromethane (2.00 L). The filtrate was cooled to 0-5° C.

A solution of 3,5-dichlorophenyl isocyanate (1.47 kg, 7.81 mol) in dichloromethane was prepared at 20-25° C. The solution was added to the above cooled filtrate slowly in 30-60 minutes. The temperature was maintained below 10° C. during the addition. After the addition, the mixture was stirred at 20-25° C. for 12-14 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (16.00 L) was added in one portion. The resulting suspension was stirred at 20-25° C. for 2-3 hours and was then filtered. The filter cake was washed with TBME (4.50 L) and dried at maximum 40° C. to a constant weight. A suspension of the above filter cake in water (17.0 L, 10 L/kg input) was prepared and stirred at 20-25° C. for at least 16 hours. The suspension was filtered and the filter cake was washed with water (3×1.36 L) and dried at maximum 40° C. to a constant weight to a constant weight. 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.52 kg, 90%) was obtained as a white crystalline solid. mp=202-204° C. ¹H NMR (DMSO-d₆): 7.66 (1H, m), 7.51 (2H, m), 4.10 (2H, s), 3.35 (3H, s). ¹³C NMR (DMSO-d₆): 8 Carbons (169.30, 155.00, 134.98, 134.15, 127.59, 125.30, 51.75, 29.79). Anal. Calcd for C₁₀H₈Cl₂N₂O₂: C, 46.35; H, 3.11; N, 10.81; Cl, 27.36. Found: C, 46.43; H, 2.9; N, 10.73; Cl, 27.33.

Preparation 2(E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile

A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol) and pyrrolidone (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20-24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5-10 minutes. The suspension was cooled to 20-25° C. in 3-4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239-241° C. ¹H NMR (DMSO-d₆): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). ¹³C NMR (DMSO-d₆): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C₁₈H₁₁Cl₂N₃O₂: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.

Example 14-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt

A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.00 kg, 2.69 mol), glycine (0.50 kg, 6.72 mol) and hexamethylenetetramine (0.28 kg, 2.02 mol) in 1-methyl-2-pyrrolidinone (5.00 L) and toluene (2.50 L) was heated at 140° C. for 7-8 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, the mixture was cooled to 40-50° C. and filtered. The filtered solid was washed with toluene (0.67 L). To the filtrate was added HCl (1M, 13.33 L, 13.33 mol). The resulting biphasic mixture was heated to 50-60° C. and was stirred for 10-15 minutes. The aqueous phase was separated and the organic phase was washed with HCl (1M, 1.67 L, 1.67 mol) at 60-80° C. The aqueous phases were combined and were stirred at 80° C. for 2 hours. The solution was cooled slowly in 3-4 hours to 20-25° C. with gentle stirring and seeding. Crystallization occurred and the resulting suspension was put aside at 20-25° C. for at least 16 hours with occasional stirring, cooled to 0-5° C. in 2 hours, stirred gently at 0-5° C. for 2 hours and then filtered. The filter cake was washed with ice water (2×2.50 L) and dried at maximum 40° C. to a constant weight. 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt (1.09 kg, 90%) was obtained as beige crystalline solid. mp=183-185° C. ¹H NMR (DMSO-d₆): 7.87(2H, d, J=8.1 Hz), 7.61 (1H, m), 7.40 (2H, d, J=8.1 Hz), 6.68 (2H, m), 4.17 (1H, m), 3.85 (2H, m), 3.76 (2H, m), 3.43 (3H, s), 3.24(2H, s). ¹³C NMR (DMSO-d₆): 14 Carbons (170.84, 152.92, 137.35, 133.94, 132.87, 132.35, 128.01, 124.50, 118.12, 111.30, 71.42, 46.57, 45.11, 25.51). Anal. Calcd for C₂₀H₁₇Cl₃N₄O₂+1.3 H₂O: C, 50.51; H, 3.91; N, 11.79; Cl, 22.39. Found: C, 50.56; H, 3.86; N, 11.58; Cl, 21.98; KF, 5.12.

Example 2a4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt

To a suspension of 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt (1.00 kg, 2.21 mol) in dichloromethane (10.67 L) was added diispopropylethylamine (0.29 kg, 2.21 mol). The mixture was stirred to a clear solution, to which (+)-Di-p-toluoyl-D-tartaric acid (0.21 kg, 0.55 mol) was added. The resulting solution was warmed to 34-36° C. and seeded immediately. It was cooled to 20-25° C. in 1.5-2.0 hours. Crystallization occurred during cooling. TBME (2.75 L) was added in 0.5 hours. The suspension was stirred at 20-25° C. for 16 hours and then filtered. The filter cake was washed with dichloromethane/TBME (2/1, 1.00 L), TBME (1 L) and dried at maximum 35° C. to a constant weight. 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (0.47 kg, 35%) was obtained as a white crystalline solid. mp=175-177° C. ¹H NMR (DMSO-d₆): 7.86 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz), 7.61 (1H, m), 7.28 (2H, d, J=8.1 Hz), 7.22 (2H, 8.5 Hz), 6.68 (2H, m), 5.71 (1H, s), 3.81(1H, m), 3.50 (4H, m), 3.06 (3H, s), 2.34 (3H, s). ¹³C NMR (DMSO-d₆): 24 Carbons (171.45, 169.40, 165.04, 152.88, 143.61, 138.99, 133.88, 133.08, 132.16, 129.26, 129.20, 128.76, 127.84, 126.99, 124.51, 118.25, 110.78, 72.81, 73.38, 48.15, 47.51, 46.30, 24.90, 21.14). Anal. Calcd for C₃₀H₂₅Cl₂N₄O₆+0.5 H₂O: C, 58.40; H, 4.17; N, 9.08; Cl, 11.49. Found C, 58.58; H, 4.06; N, 8.94; Cl, 11.38; KF, 1.59.

Example 2b4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt

A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (10.0 g, 26.9 mmol), glycine (5.06 g, 67.4 mmol), hexamethylenetetramine (2.82 g, 20.1 mmol) in 50 mL N-methylpyrrolidinone and 25 mL of toluene under nitrogen was heated to 138° C. for approximately 12 h. Next, 25 mL toluene and 25 mL H₂O were added. The aqueous and nonaqueous layers were split, and the aqueous layer was washed with 25 mL of toluene, and the nonaqueous layers were combined to form a nonaqueous mixture. The nonaqueous mixture was heated to 45-50° C. and ethylene diamine (7.0 mL) was added. The nonaqueous mixture was stirred for 3 hours and then cooled to room temperature. Next, 50 mL H₂O was added, followed by the addition of 10 mL brine. The next addition was 25 mL toluene, which was followed by the addition of 125 mL CH₂Cl₂. The bottom layer of the mixture was removed through a filter. Next, (+)-Di-p-toluoyl-D-tartaric acid (2.59 g, 6.7 mmol) was added and the mixture was stirred for 18 h to form a slurry. Slowly 40 mL of MTBE was added to the slurry. A wash solution containing 7 mL of MTBE and 11 mL of CH₂Cl₂ was prepared. Filter paper was wetted with 1 mL of the wash solution. The slurry was filtered and then the filtered to form a cake. The filter, the wash reaction flask, and the cake were washed with the remaining 16 mL of the wash solution. Next, the cake was washed with 10 mL MTBE. 4-[(5S, 9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (4.0 g, 20% yield) was obtained as a white solid (98.7% HPLC AP and 98.3% ee).

Example 2c4-[(5S,9R)-3-3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]non-9-yl]-benzonitrile semi (+)-DTTA salt

A mixture of (E)-4-((1-(3,5)-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (40.0 g, 107.5 mmol), glycine (19.76 g, 263.2 mmol), hexamethylenetetramine (9.07 g, 64.7 mmol) in 200 mL N-methyl-2-pyrrolidinone and 100 mL of toluene was heated under nitrogen to 143° C. for approximately 5.5 h. Next, the mixture was cooled to 50° C. and a solution of 25 mL of ethylenediamine in 200 mL of tetrahydrofuran was added. The mixture was maintained at a temperature of 50° C. for 30 minutes and then was cooled to room temperature. Next, 520 mL of 20 wt % NaCl aqueous solution was added. The aqueous and nonaqueous layers were separated. The nonaqueous layer was transferred to a vacuum distillation apparatus and solvent was distilled off until the temperature of the residue in the flask reached 58° C. at a pressure of 60 torr. Next, 360 mL of methylene chloride was added, followed by the additions of 20 mL of methanol and 2 mL of water. The next addition was (+)-Di-p-toluoyl-D-tartaric acid (10.38 g, 26.9 mmol), followed by 120 mL of methylene chloride and 0.200 g of seeds of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]non-9-yl]-benzonitrile semi (+)-DTTA salt. A-slurry was formed and was stirred at room temperature for 24 hours. The slurry was filtered and the cake of crystals was washed with 200 mL of methylene chloride in two portions. The washed cake was then dried at 50° C. under vacuum for 24 hours. A total amount of 20.11 g (yield 31%) of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]non-9-yl]-benzonitrile semi (+)-DTTA salt, which was of greater than 99.5% area percent purity, 98.4% potency and 99.2% ee was obtained after drying.

Example 35-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt

To a suspension of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (7.50 kg, 12.30 mmol) and methyl 5-formylthiophene-3-carboxylate (2.2 kg, 13.10 mol) was added triethylamine (2.08 kg, 20.60 mol) at 20-25° C. The mixture was stirred to a clear solution, to which acetic acid (1.24 kg, 20.60 mol) was added. The resulting mixture was stirred at 20-25° C. for 1 hour and then cooled to 15° C. Solid sodium triacetoxyborohydride (1.31 kg, 6.17 mol) was added and the reaction mixture was stirred for 0.5 hours. The addition of sodium triacetoxyborohydride was repeated three more times. At the end, a total of 5.22 kg (24.7 mol) sodium triacetoxyborohydride was added in 2 hours. The reaction mixture was stirred at 20-25° C. for 16 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (48.1 L) was added to the resulting jelly reaction mixture. The mixture was washed with saturated sodium hydrogen carbonate solution (60.0 L×3). The combined aqueous phase was extracted with TBME (48.1 L). All organic layers were combined, washed with brine (48.1 L) and concentrated in vacuum to a volume of 10.6 L. Isopropanol (192.3 L) was added to the residue and the resulting oil precipitates were dissolved upon warming up to 70-75° C. The solvent volume was reduced to 160.0 L by distillation at 70-75° C. Concentrated HCl (1.5 L) was added at 75° C. in 10 minutes followed by the addition of seed crystals. Crystallization occurred upon cooling to 20-25° C. in 16 hours. The mixture was filtered. The cake was washed with isopropanol (9.6 L×2) and dried at maximum 40° C. to a constant weight. 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt (6.57 kg, 88.0%) was obtained as white crystalline solid. mp=204-207° C. ¹H NMR (CDCl₃): 14.22 (1H, b), 8.18 (1H, d, J=0.9 Hz), 7.86 (1H, m), 7.67 (2H, d, J=8.1 Hz), 7.24 (1H, m), 7.23 (2H, d, J=8.1 Hz), 6.67 (2H, m), 4.76 (2H, m), 4.46 (1H, m), 4.16 (1H, m), 4.02 (2H, m), 3.86 (3H, s), 3.75 (1H, m), 3.38 (3H, s). ¹³C NMR (CDCl₃): 18 Carbons (171.24, 162.32, 152.98, 136.05, 135.27, 134.03, 132.83, 131.94, 130.46, 128.85, 128.56, 123.92, 117.52, 113.43, 71.13, 52.43, 52.22, 46.73). Anal. Calcd for C₂₇H₂₃Cl₃N₄O₄S: C, 53.52; H, 3.83; N, 9.25; S, 5.29; Cl, 17.55. Found: C, 53.07; H, 3.69; N, 9.08; S, 5.23; Cl, 17.20.

Example 45-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid

To a solution of 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt (20.00 g, 33.00 mmol) and 1,2-propanediol (5.0 g) in tetrahydrofuran (200 mL) and water (100 mL) was added slowly potassium hydroxide solution (0.85M, 116 mL) at 8-12° C. in 0.5 hours. The resulting biphasic mixture was stirred at 8-12° C. for 20-27 hours until the reaction was complete. The reaction mixture was washed with n-heptane (200 mL). The pH was adjusted to 6.5 with addition of water (100 mL) and acetic acid (2.5 mL). Tetrahydrofuran was removed under reduced pressure at internal temperature <40° C. The pH was adjusted to 4.5 with addition of isopropyl acetate (400 mL) and acetic acid (11 mL). After 10 minutes of stirring, the aqueous layer was separated and was extracted with isopropylacetate (200 mL). The organic layers were combined, washed with water (100 mL) and concentrated under reduced pressure to a volume of 190 mL at bath temperature <40° C. Crystallization occurred during concentration. The crystal slurry was stirred at 20-25° C. for 16 hours and was then filtered. The cake was washed with cold isopropylacetate (15 mL×3) and dried in vacuum at 35-40° C. to a constant weight.

5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid (14.35 g, 78.3%) was obtained as white and sandy crystalline solid.

mp=209-230° C. ¹H NMR (Acetone-d₆): 8.19 (1H, d, J=1.3 Hz), 7.76 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.2 Hz), 7.43 (1H, d, J=1.0 Hz), 7.41 (1H, t, J=1.9 Hz), 6.87 (2H, d, J=1.9 Hz), 4.16 (1H, dd, J1=13.9 Hz J2=0.8 Hz), 4.10 (1H, dd, J1=11.7 Hz, J2=6.2 Hz), 3.99 (1H, d, J=14.0 Hz), 3.48(1H, d, J=10.6 Hz), 3.47 (1H, dd, J1=9.6 Hz, J2=6.2 Hz), 3.25 (3H, s), 3.24 (1H, dd, J1=9.6 Hz, J2=11.7 Hz), 3.01 (1H, d, J=11.3 Hz).

¹³C NMR (Acetone-d₆): 22 Carbons (172.69, 163.7, 153.98, 144.55, 142.23, 135.26, 135.09, 134.41, 133.89, 132.96, 130.33, 128.27, 126.98, 125.18, 119.07, 112.44, 74.28, 59.09, 56.45, 54.33, 50.73, 25.75).

Anal. Calcd for C₂₆H₂₀Cl₂N₄O₄S: C, 56.22; H, 3.62; N, 10.08; S, 5.77; Cl, 12.76. Found: C, 56.27; H, 3.20; N, 9.97; S, 5.65; Cl, 12.68.

................................

paper

J. Med. Chem. 2006, 49, 6946

http://pubs.acs.org/doi/abs/10.1021/jm0610806

LFA-1 (leukocyte function-associated antigen-1), is a member of the β2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

http://pubs.acs.org/doi/suppl/10.1021/jm0610806/suppl_file/jm0610806si20060913_101747.pdf synthesis as compd 8

says

a white solid: Anal.RP-HPLCtR= 3.09min (method D, purity 99%);

MS (ESI)m/z553 (M-H)-;

1H NMR(500 MHz, DMSO-d6)δ

8.17 (1 H, s), 7.62 (2 H, d,J=8.07 Hz), 7.44 (1 H, s), 7.27 (3 H, m), 6.64 (2 H, s),

4.11 (1 H, d,J=13.45 Hz), 3.96 (1 H, d,J=14.12 Hz), 3.88 (1 H, dd,J=11.76, 5.71 Hz), 3.43 (2 H, br. s.),

3.27 (1 H, br. s.), 3.23 (3 H, s), 3.06 (1 H, d,J=10.08 Hz);

Anal.(C26H20Cl2N4O4S)

Calcd.: C,56.22; H,3.63;Cl, 12.77; N,10.09; S,5.77;.

Found: C,55.95; H,3.59;Cl, 12.54; N,10.01; S,5.79;

ee =99.26±0.00 % [Chiralcel OJ-R, 150 x 4.6 mm, 5 um particle size, MeOH: CH3CN: 0.2% aq.H3PO4 (30:30:40)];

[α]D=-6.324 (c = 8.967 mg/mL, CHCl3);

......................

U.S. Patent 7,199,125 B2

http://www.google.com/patents/US7199125

.............................

.U.S. Patent 6,710,064 B2

http://www.google.com/patents/US6710064

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REFERENCES

• For a discussion on the inhibition of LFA-1/ICAM-1as an approach to treating autoimmune diseases see:

  
  

  Yusuf-Makagiansar, H.; Anderson, M. E.; Yakovleva, T. V.; Murray, J. S.; Siahaan, T. J. Medicinal Research Reviews 2002, 22, 146

• 2.

  For a discussion of therapeutic options for treatment of psoriasis, see:

  Gottlieb, A. B. J. Acad. Dermatol 2005, 53, S3

  
  

  Larson, R. S.; Davis, T.; Bologa, C.; Semenuk, G.; Vijayan, S.; Li, Y.; Oprea, T.; Chigaev, A.; Buranda, T.; Wagner, C. R.; Sklar, L. A.

  
  
• 3.

  For other small molecule LFA-1/ICAM-1 antagonists as potential drugs please see:

  (a) Pei, Z.; Xin, Z.; Liu, G.; Li, Y.; Reilly, E. B.; Lubbers, N. L.; Huth, J. R.; Link, J. T.; von Geldern, T. W.; Cox, B. F.; Leitza, S.; Gao, Y.; Marsh, K. C.; DeVries, P.; Okasinski, G. F. J. Med. Chem. 2001, 44, 2913

  
  

  (b) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries, P.; Leitza, S.; Reilly, E. B.; Olasinski, G. F.; Fesik, S. W.; von Geldern, T. W. J. Med. Chem. 2001, 44, 1202

  
  

  (c) Wu, J.-P.; Emeigh, J.; Gao, D. A.; Goldberg, D. R.; Kuzmich, D.; Miao, C.; Potocki, I.; Qian, K. C.; Sorcek, R. J.; Jeanfavre, D. D.; Kishimoto, K.; Mainolfi, E. A.; Nabozny, G.; Peng, C.; Reilly, P.; Rothlein, R.; Sellati, R. H.; Woska, J. R.; Chen, S.; Gunn, J. A.; O’Brien, D.; Norris, S. H.; Kelly, T. A. J. Med. Chem. 2004, 47, 5356

  
  

  (d) Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon, C. a.; Hopkins, J. L.; Jeanfavre, D. D.; Pav, S.; Qian, C.; Stevenson, J. M.; Tong, L.; Zindell, R.; Kelly, T. A. J. Am. Chem. Soc. 2001, 123, 5643

  
  

  (e) Wang, G. T.; Wang, S.; Gentles, R.; Sowin, T.; Leitza, S.; Reilly, E. B.; von Geldern, T. W. Bioorg. Med. Chem. Lett. 2005, 15, 195

  
  

  (f) Wattanasin, S.; Albert, R.; Ehrhardt, C.; Roche, D.; Savio, M.; Hommel, U.; Welzenbach, K.; Weitz-Schmidt, G. Bioorg. Med. Chem. Lett. 2003, 12, 499

  
  
• 4.

  The Discovery work towards this target compound BMS-587101 is described in:

  Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.; Fabreguettes, M.; Fouquet, A.; Maillet, M.; Nicolai, E.; Dorgeret, L.; Chevallier, F.; Besse, D.; Dufort, M.; Caussade, F.; Ahmad, S. Z.; Stetsko, D. K.; Skala, S.; Davis, P. M.; Balimane, P.; Patel, K.; Yang, Z.; Marathe, P.; Postelneck, J.; Townsend, R. M.; Goldfarb, V.; Sheriff, S.; Einspahr, H.; Kish, K.; Malley, M. F.; DiMarco, J. D.; Gougoutas, J. Z.; Kadiyala, P.; Cheney, D. L.; Tejwani, R. W.; Murphy, D. K.; Mcintyre, K. W.; Yang, X.; Chao, S.; Leith, L.; Xiao, Z.; Mathur, A.; Chen, B.-C.; Wu, D.-R.; Traeger, S. C.; McKinnon, M.; Barrish, J. C.; Robl, J. A.; Iwanowicz, E. J.; Suchard, S. J.; Dhar, M. T. G. J. Med. Chem. 2006, 49, 6946

  
  
• 5.

  For additional information related to this compound see:

  (a) Chen, B.-C.; DelMonte, A. J.; Dhar, T. G. M.; Fan, Y.; Gougoutas, J. Z.; Malley, M. F.; McLeod, D. D.; Waltermire, R.; Wei, C. Crystalline Forms and Process for Preparing Spiro-Hydantoin Compounds. (Bristol-Myers Squibb). U.S. Patent 7,381,737 B2 .

  
  

  (b) Dhar, T. G. M.; Potin, D.; Maillet, M.; Launay, M.; Nicolai, E.; Iwanowicz, E. Spiro-cyclic compounds useful as anti-inflammatory agents. Bristol-Myers Squibb and Cerep). U.S. Patent 7,199,125 B2.

  
  

  (c) Launay, M.; Potin, D.; Maillet, M.; Nicolai, E.; Dhar, T. G. M.; Iwanowicz, E. Hydantoin compounds useful as anti-inflammatory agents. (Bristol-Myers Squibb).U.S. Patent 6,710,064 B2.

  
  

  For the radiolabelled synthesis of BMS-587101 see:

  Tran, S. B.; Maxwell, B. D.; Chen, S.-Y.; Bonacorsi, S. J.; Leith, L.; Ogan, M.; Rinehart, J. K.; Balasubramanian, B. J. Labelled Compd. Radiopharm. 2009, 52, 236

  
  

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