Substituted pipecolinic acid derivatives as HIV protease inhibitors

• US 5,614,533 A
• Filed: 11/09/1994
• Issued: 03/25/1997
• Est. Priority Date: 03/13/1987
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Canada Ltd (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Bio-Mega/Boehringer Ingelheim Research Inc.
• Inventors: Anderson, Paul C., Beaulieu, Pierre L., Lavall ee, Pierre, Yoakim, Christiane, Soucy, Fran.cedilla.ois
• Primary Examiner(s): Springer, David B.
• Application Number:
  US08/336,637
• Time in Patent Office: 867 Days
• Field of Search: 546/168, 546/169, 514/314, 514/233.5, 514/256, 544/128, 544/333
• US Class Current: 514/314
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

Disclosed herein are compounds of formula 1 ##STR1## wherein X is a terminal group, for example, an aryloxycarbonyl, an alkanoyl or an optionally mono- or disubstituted carbamoyl; B is absent or an amino acid residue, for example, Val or Ash; R¹ is hydrogen or a ring substituent, for example, fluoro or methyl; R² is alkyl; and Y is a ring substituent, for example, phenoxy, 2-pyridinylmethoxy, phenylthio or 2-pyridinylthio. The compounds inhibit the activity of human immunodeficiency virus (HIV) protease and interfere with HIV induced cytopathogenic effects in human cells. These properties render the compounds useful for combating HIV infections.

Claims

1. A compound of formula 1 ##STR7## wherein X is R³ OC(O), R³ C(O) or R³ NR⁴ C(O) wherein R³ is 2-quinolinyl or 3-quinolinyl, and

R⁴ is hydrogen or lower alkyl;

B is absent or the divalent radical --NHCHR⁵ C(O)-- wherein R⁵ is lower alkyl;

lower cycloalkyl;

(lower cycloalkyl)-(lower alkyl);

phenylmethyl;

or lower alkyl monosubstituted with hydroxy, carboxy, lower alkoxycarbonyl, aminocarbonyl, (lower alkyl)aminocarbonyl or di(lower alkyl)aminocarbonyl;

R¹ is hydrogen, halo, hydroxy, lower alkyl or lower alkoxy;

R² is lower alkyl; and

Y is lower alkyl;

lower cycloalkyl;

phenyl or phenyl monosubstituted with halo, hydroxy, lower alkyl or lower alkoxy;

phenylmethyl or phenylmethyl monosubstituted with halo, hydroxy, lower alkyl or lower alkoxy;

or

Y is W(CH₂)_n Z wherein W is oxo, thio, sulfinyl or sulfonyl, Z is lower alkyl;

phenyl or phenyl monosubstituted with halo, hydroxy, lower alkyl or lower alkoxy;

or (Het); and

n is zero or one;

wherein the term "lower alkyl" as used herein, either alone or in combination with another radical, means a straight chain alkyl radical containing one to six carbon atoms or a branched chain alkyl radical containing three to four carbon atoms;

wherein the term "lower cycloalkyl" as used herein, either alone or in combination with another radical, means a saturated cyclic hydrocarbon radical containing from three to six carbon atoms;

wherein the term "lower alkoxy" as used herein means a straight chain alkoxy radical containing one to six carbon atoms or a branched chain alkoxy radical containing three to four carbon atoms;

wherein the term "halo" as used herein means a halo radical selected from bromo, chloro, fluoro and iodo; and

,

wherein (Het) as used herein means a monovalent radical derived by removal of a hydrogen from a five or six membered saturated or unsaturated heterocycle selected from the group consisting of furan, thiophene, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, 1H-imidazole, 1-methyl-1H-imidazole, isoxazole, thiazole, 2-methylthiazole, 2-aminothiazole, piperidine, 1,4-dioxane, morpholine, pyridine, 2-methylpyridine, pyrimidine, 4-methylpyrimidine, 2,4-dimethylpyrimidine, 2,6-dimethylpyrimidine and 4,6-dimethylpyrimidine;

or a therapeutically acceptable acid addition salt thereof.

2. A compound as defined in claim 1 wherein X is R³ OC(O), R³ C(O) or R³ NR⁴ C(O) wherein R³ is 2-quinolinyl, and R⁴ is hydrogen or lower alkyl;

B is absent or is the divalent radical --NHCHR⁵ C(O)-- wherein R⁵ is lower alkyl, or lower alkyl monsubstituted with hydroxy, lower alkoxycarbonyl, aminocarbonyl, (lower alkyl)aminocarbonyl or di(lower alkyl)aminocarbonyl;

R¹ is hydrogen, chloro, bromo or fluoro;

R² is 1-methylethyl, 2-methylpropyl or 1,1-dimethylethyl; and

Y is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, phenylmethyl, (4-fluorophenyl)methyl or (4-methylphenyl)methyl;

or

Y is W(CH₂)_n Z wherein W and n are as defined in claim 1 and Z is lower alkyl, phenyl, 2-furyl, 2-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 4-thiazolyl, 2-pyrimidinyl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl or 2,6-dimethyl-4-pyrimidinyl;

or a therapeutically acceptable acid addition salt thereof.

3. A compound as defined in claim 2 wherein X is 2-quinolinylcarbonyl;

B is absent or the divalent radical --NHCHR⁵ C(O)-- wherein R⁵ is 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 1-hydroxyethyl, (methoxycarbonyl)methyl, (ethoxycarbonyl)methyl, (aminocarbonyl)methyl or {(methylamino)carbonyl}-methyl;

R¹ is hydrogen or fluorine;

R² is 2-methylpropyl or 1,1-dimethylethyl; and

Y is phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, (4-methoxyphenyl)methyl, 2-methylpropoxy, phenoxy, 2-pyridinyloxy, 3-pyridinyloxy, 4-pyridinyloxy, 2-pyrimidinyloxy, (4-methyl-2-pyrimidinyl)oxy, (4,6-dimethyl-2-pyrimidinyl)oxy, (2,6-dimethyl-4-pyrimidinyl)oxy, benzyloxy, 2-pyridinylmethoxy, 3-pyridinylmethoxy, 4-pyridinylmethoxy, 4-thiazolylmethoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, 2-pyridinylthio, 3-pyridinylthio, 4-pyridinylthio, 2-pyrimidinylthio, (4-methyl-2-pyrimidinyl)thio, (2,6-dimethyl-4-pyrimidinyl)thio, (4,6-dimethyl-2-pyrimidinyl)thio, benzylthio, benzylsulfinyl, benzylsulfonyl, (2-pyridinylmethyl)thio, (3-pyridinylmethyl)thio or (4-pyridinylmethyl)thio;

or a therapeutically acceptable acid addition salt.

4. A compound as defined in claim 3 wherein X is 2-quinolinylcarbonyl;

B is valyl, tert-butylglycyl, isoleucyl, threonyl or asparaginyl;

R¹ is hydrogen or fluorine;

R² is 1,1-dimethylethyl; and

Y is phenyl, benzyl, phenoxy, 2-pyrimidinyloxy, (2,6-dimethyl-4-pyrimidinyl)oxy, 2-pyridinylmethoxy, 3-pyridin-ylmethoxy, 4-pyridinylmethoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, 2-pyridinylthio, 3-pyridinylthio, 4-pyridinylthio, 2-pyrimidinylthio (4,6-dimethyl-2-pyrimidinyl)thio, (2-pyridinylmeth-yl)thio, (3-pyridinylmethyl)thio or 4-(pyridinyl-methyl)thio;

or a therapeutically acceptable acid addition salt thereof.

6. A pharmaceutical composition comprising a compound as recited in claim 1, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method for treating HIV infections in a human comprising administering thereto an effective amount of a compound as defined in claim 1, or a therapeutically acceptable salt thereof.

5. A compound selected from the group consisting of:

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(phenylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)asparaginyl}amino}butyl}-4(R)-phenoxypiperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2quinolinylcarbonyl)asparaginyl}amino}butyl}-4(R)-(phenylsulfonyl)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)asparaginyl}amino}butyl}-4(R)-(phenylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(2-pyrimidinylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4-pyridinylmethyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(2-pyridinylmethoxy)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4,6-dimethyl-2-pyrimidinyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(4-pyridinylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(2-pyridinylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-phenoxypiperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(3-pyridinylmethyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(2-pyridinylmethyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(2-pyrimidinyloxy)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4,6-dimethyl-2pyrimidinyl)oxy}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4-methyl-2-pyrimidinyl)oxy}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(2,6-dimethyl-4-pyrimidinyl)oxy}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(phenylsulfonyl)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4- fluorophenyl)oxy}piperidine-2(S)carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(4-pyridinylmethoxy)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(2-pyridinylmethyl)sulfonyl}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(3-pyridinylmethyl)sulfonyl}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4-pyridinylmethyl)sulfonyl}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(2-pyridinylsulfonyl)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(4-pyridinylsulfonyl)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(2,6-dimethyl-4-pyrimidinyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-{(4-methyl-2-pyrimidinyl)thio}piperidine-2(S)-carboxamide

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)valyl}amino}butyl}-4(R)-(3-pyridinylmethoxy)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)-tert-butylglycyl}amino}butyl}-4(R)-(phenylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)asparaginyl}amino}butyl}-4(R)-{(4,6-dimethyl-2-pyrimidinyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)asparaginyl}amino}butyl}-4(R)-(2-pyrimidinylthio)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)-(N.sup.4 -methyl)asparaginyl}amino}-butyl}-4(R)-phenoxy-piperidine-2(S)-carboxamide

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)-tert-butylglycyl}amino}butyl}-4(R)-{(3-pyridinylmethyl)thio}piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)threonyl}amino}butyl}-4(R)-(phenylsulfonyl)piperidine-2(S)-carboxamide,

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)-tert-butylglycyl}amino}butyl}-4(R)-(4-pyridinylsulfonyl)piperidine-2(S)-carboxamide, and

N-tert-butyl-1-{2(R)-hydroxy-4-phenyl-3(S)-{{N-(2-quinolinylcarbonyl)-tert-butylglycyl}amino}butyl}-4(R)-(2-pyridinylsulfonyl)piperidine-2(S)-carboxamide.

8. A pharmaceutical composition comprising a compound as recited in claim 5, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The method for treating HIV infections in a human comprising administering thereto an effective amount of a compound as defined in claim 5, or a therapeutically acceptable salt thereof.