Protease inhibiting succinic acid(cas:110-15-6) derivatives

Protease inhibiting succinic acid derivatives.Disclosed herein are compounds which inhibit human immunodeficiency virus (HIV) protease activity and inhibit HIV replication in human cells. Thus, the compounds are indicated for the treatment of HIV infections. The compounds can be represented by the formula ##STR1## wherein X is a terminal group, for example, an aryloxycarbonyl, an alkanoyl or an arylalkyl carbamoyl; A is absent or an amino acid or a derived amino acid, or succinic acid(cas:110-15-6); either R1 or R2 is hydrogen while the other is alkyl or R1 and R2 are joined to form a cyclohexane; Q is hydrogen, hydroxy, halo or lower alkoxy; and Y is a terminal group, for example, an alkylamino, alkoxy or an optionally substituted anilino.

The following examples illustrate further this invention. Solution percentages or ratios express a volume to volume relationship, unless stated otherwise. Temperatures are given in degrees Celsius. Proton nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 200 MHz or 400 MHz spectrometer (a 400 MHz spectrum being noted as such in the preamble of the spectrum). The chemical shifts of the NMR spectra are reported in parts per million relative to tetramethylsilane as the internal standard. Abbreviations or symbols used herein include Boc: tert-butyloxycarbonyl; tert-Bu: tert-butyl; Bzl: benzyl; DMF: dimethylformamide; HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; Et: ethyl; Et2 O: diethyl ether; EtOAc: ethyl acetate; HPLC: high performance liquid chromatography; Me: methyl; MeOH: methanol; Ph: phenyl; PhO: phenoxy; Pr: propyl; TBTU: 2-(1H-benzotriazol-1-yl)-N,N.N',N'-tetramethyluronium tetrafluoroborate; TFA: trifluoroacetic acid; Z: benzyloxycarbonyl.

A solution of 2(R)-tert-butyldihydro-2,5-furandione [10.0 g, 64 mmol; described by T. Polonski, J. Chem. Soc. Perkin Trans. I, 629 (1988)] in pyridine (230 mL) was cooled to -40° C. A solution of 1-ethylpropylamine (6.7 g, 77 mmol) in pyridine (20 mL) was added dropwise over a period of 20 min to the cooled solution. The reaction mixture was allowed to warm to room temperature (10°-22°) and stirred for 3.5 days. Removal of volatiles under reduced pressure gave an oily residue which was dissolved in EtOAc (200 mL) and washed with a 10% aqueous solution of citric acid or succinic acid(cas:110-15-6). The aqueous phase was back-extracted with EtOAc and the combined organic layers where washed with brine and dried over Na2 SO4. The solvent was removed under reduced pressure to give a semi-solid which was coevaporated twice with Et2 O (100 mL) to give a white solid (15.4 g, 99% yield). Mp: 104°-108°. [α]D24 -3.2° (c=1, MeOH). [α]Hg36524 -22.2° (c=1, MeOH). 1 H NMR (CDCl3, 400 MHz) δ 0.86 (t, J=7.6 Hz, 3H), 0.88 (t, J=7.3 Hz, 3H), 1.02 (s, 9H), 1.35 (m, J=7.0 Hz, 2H), 1.51 (m, J=7.0 Hz, 2H), 2.40 (dd, J=14.5, 3.3 Hz, 1H), 2.53 (dd, J=14.3, 11.4 Hz, 1H), 2.78 (dd, J=11.3, 3.3 Hz, 1H), 3.75 (m , 1H), 5.37 (d, J=8.9 Hz, 1H). FAB-MS (m/z): 243 (M+H)+.