RO 5114436

1220514-67-9  CAS OF FREE BASE

1220514-58-8 0F HCL SALT

Hoffmann La Roche,

3-​Furancarboxamide, N-​[(1S)​-​3-​[(3aR,​6aS)​-​5-​[(4,​6-​dimethyl-​5-​pyrimidinyl)​carbonyl]​hexahydropyrrolo[3,​4-​c]​pyrrol-​2(1H)​-​yl]​-​1-​(3-​fluorophenyl)​propyl]​tetrahydro-​, (3R)​-

(R)-Tetrahydrofuran-3-carboxylic acid [(S)-3-[5-(4,6-dimethylpyrimidine-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluorophenyl)propyl]amide

The chemokine receptor CCR5 is a clinically validated target for Human Immunodeficiency Virus (HIV) disease and a potentially interesting target for the inflammation therapy area. The first small-molecule CCR5 antagonist on the market, maraviroc (Selzentry), was approved by the FDA for treatment of HIV-1 infection.(1) Medicinal chemistry research at Roche led to the discovery of a series of 3,7-diazabicyclo[3.3.0]octane compounds,(2) represented by RO5114436 (1), that are potent CCR5 antagonists. Compound 1 also showed high potency in functional assays for inflammation. The PK properties of 1 were superior to those of maraviroc in preclinical species, including rat, dog, and monkey.

octahydro-pyrrolo[3,4-c]pyrrole derivatives useful in the treatment of a variety of disorders, including those in which the modulation of CCR5 receptors is implicated. More particularly, the present invention relates to 3-(hexahydro- pyrrolo[3,4-c]pyτrol-2-yl)-l-phenyl-propylamine and [3-(hexahydro-pyrrolo[3,4- c]pyτrol-2-yl)-propyl]-phenyl-amine compounds and related derivatives, to compositions containing, to uses of such derivatives and to processes for preparing said compoundsz. Disorders that may be treated or prevented by the present derivatives include HIV and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), diseases of the immune system and inflammatory diseases.

A-M. Vandamme et al. (Antiviral Chemistry & Chemotherapy, 1998 9:187-203) disclose current HAART clinical treatments of HIV- 1 infections in man including at least triple drug combinations. Highly active anti-retroviral therapy (HAART) has traditionally consisted of combination therapy with nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). These compounds inhibit biochemical processes required for viral replication. In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV- 1 to AIDS. While HAART has dramatically altered the prognosis for HIV infected persons, there remain many drawbacks to the current therapy including highly complex dosing regimes and side effects which can be very severe (A. Carr and D. A. Cooper, Lancet 2000356(9239):1423-1430). Moreover, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance, thus limiting their utility in long term therapy. Development of new drug therapies to provide better HIV-1 treatment remains a priority. Compounds of the present invention modulate the activity of the chemokine CCR5 receptors. The chemokines are a large family of pro-inflammatory peptides that exert their pharmacological effect through G-protein-coupled receptors. The name “chemokine”, is a contraction of “chemotactic cytokines”. The chemokines are a family of leukocyte chemotactic proteins capable of attracting leukocytes to various tissues, which is an essential response to inflammation and infection. Human chemokines include approximately 50 small proteins of 50-120 amino acids that are structurally homologous. (M. Baggiolini etal, Annu. Rev. Immunol. 1997 15:675-705)

Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV-1 and genetically related retroviruses. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body’s response to infection. Because chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonizing, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases. The chemokine receptor CCR5 is of particular importance in the context of treating inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MIP) designated MIP- la and MIP- lb, and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES).

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OPRD [PAPER

http://pubs.acs.org/doi/abs/10.1021/op100020z

A practical asymmetric synthesis of a 3,7-diazabicyclo[3.3.0]octane derivative (1), a representative of a new class of potent CCR5 receptor antagonists, is described. The benzylamine stereogenic center of 1 was introduced by a ruthenium-catalyzed asymmetric reductive amination using (R)-MeOBIPHEP as ligand. Aldehyde 4, prepared by Parikh−Doering oxidation, was used without workup in the reductive amination reaction, which not only simplified the process but also overcame the instability of 4. The 3,7-diazabicyclo[3.3.0]octane core was obtained by a [3 + 2] cycloaddition.

Oxalyl chloride (46.0 g, 36.2 mmol) was added over 1 h to a solution of (R)-tetrahydrofuran-3-carboxylic acid 3(16) (40.1 g, 34.5 mmol) in toluene (310 mL) containing DMF (0.5 mL) with stirring, while maintaining the temperature at 10 °C with an ice bath. …………DELETED…………………….The aqueous phase was extracted with Me-THF (20 mL), and the combined organic phase was evaporated at 40 °C to give the free base of 1 (11.44 g, 23.08 mmol) as a slightly tacky dry foam.

A solution of the free base of 1 (11.44 g, 23.08 mmol) in acetone (57.4 mL) and water (1.45 mL) was acidified with 12 N HCl (2.42 mL, 29.0 mmol). The clear solution was seeded with authentic product and stirred for 3.5 h, after which the resulting slurry was filtered and washed with ice-cold acetone (12 mL in two portions). Drying in a vacuum oven at 68 °C, 30−50 Torr gave 1·HCl as a dry, white powder (10.57 g, 86.1% theory, 97.8% purity by HPLC area).

Analytical data for 1·HCl salt:

mp 149−150 °C.

¹H NMR (300 MHz, D₂O) 1.73−1.91 (m, 1 H), 1.98−2.26 (m, 3 H), 2.34 (s, 3 H), 2.37 (s, 3 H), 2.82−3.37 (m, 8 H), 3.40−4.10 (m, 9 H), 4.81 (t, J = 7.54 Hz, 1 H), 6.93−7.13 (m, 3 H), 7.33 (td, J = 7.82, 5.84 Hz, 1 H), 8.83 (s, 1 H).

MS m/z 496.2 [M + H]⁺.

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WO/2005/121145

http://www.google.com/patents/WO2005121145A2?cl=en

CLOSEST EXAMPLE

Example 14

(S)-4,4-Difluoro-cyclohexanecarboxylic acid [3- [5-(4,6-dimethyl-pyrimidine-5- carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-l-(3-fluoro-phenyl)-propyl]-amide (I- 485)

 

56 step 2 I ^ 57a: R = Boc 57b: R = H

step 1 – To a solution of 56 (562 mg, 2.1 mmol, prepared as described in WO2004/018425) and 44 (518 mg, 2.1 mmol) in DCM (20mL) containing HOAc (0.31 mL) was added NaBH(OAc)₃ (579 mg, 2.73 mmol) in 1 portion and the reaction mixture was stirred for 18 hrs at RT. The reaction was quenched by the addition of 10% K₂CO₃ (20 mL) and stirring continued for 30 min. The product was twice extracted with DCM (25 mL). The combined extracts were dried (MgSO ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eiuting with DCM/ 5% MeOH (containing 2% NH₄OH) to afford 821 mg (79% theory) of 57a as a white foam: ms (ES+) m/z 498 (M+H)⁺. step 2 – A solution of 57a (821 mg, 1.65 mmol) dissolved in 10 M HCl in MeOH(40 mL) was heated at 65° C for 2 h. The MeOH was evaporated under reduced pressure and the residue cautiously partitioned between DCM (35 mL) and 20% K₂CO₃ solution. The aqueous layer was extracted with DCM (2 x 35 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo to afford 641 mg (98%) of 57b as a viscous liquid: ms (ES+) m/z 398 (M+H)⁺. step 3 – To a solution of 57b (98 mg, 0.25 mmol) in DCM (4 mL) at RT was added 4,4-difluorocyclohexanecarboxyιic acid (49 mg, 0.30mmol). To the resulting solution was added sequentially EDCI (61.4 mg, 0.32 mmol), HOBt (43 mg. 0.32 mmol) and DIPEA (0.13 mL, 0.74 mmol). The mixture was stirred for 4 h. The reaction mixture washed with brine and dried (Na₂SO₄), then concentrated in vacuo. The crude product was flash chromatographed on silica eiuting with DCM/ 7.5% MeOH (containing 2% NH OH) to afford 113 mg (84%) of 1-485 a white foam: ms (ES+) m/z 544 (M+H)⁺.

Example 13

Cyclopentanecarboxylic acid {3- [5-(4,6-dimethyl-pyrimidine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-l-phenyl-propyl}-amide (1-29)

 

To a solution of 12 (0.24 g, 0.70 mmol) in DCM (10 mL) were added 4,6-dimethyl- pyrimidine-5-carboxylic acid (55, 0.12 g, 0.84 mmol) , EDCI (0.17 g, 0.91 mmol), HOBt (0.12 g, 0.91 mmol) and DIPEA (0.36 mL, 2.10 mmol). The mixture was stirred at RT for 3 h. The reaction mixture was washed with saturated NaHCO₃ and the organic layer was dried (Na₂SO₄). The crude product was purified by SiO₂ column chromatography eiuting with DCM:MeOH:NH₄OH (150:10:1) to afford 0.27 g (81 %) of 1-29:: mp 48.0- 49.0 °C; ms (ES+) m/z 476 (M + H); Anal. (C₂₈H₃₇N₅O₂.0.2M CH₂C1₂) C; calcd, 68.76; found, 68.61; H; calcd, 7.65; found, 7.51; N; calcd, 14.22; found, 14.28

 

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REF

• 1   Haycock-Lewandowski, S. J.; Wilder, A.; Åhman, J. Org. Process Res. Dev. 2008, 12, 1094– 1103

  (b) Åhman, J.; Birch, M.; Haycock-Lewandowski, S. J.; Long, J.; Wilder, A. Org. Process Res. Dev. 2008, 12, 1104– 1113

  and references therein
• 2.

  Lee, E. K.; Melville, C. R.; Rotstein, D. M. Chem. Abstr. 2005, 144, 69821

  PCT Int. Publication Number WO/2005/121145 A2, 2005