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WO1998009951B1 - Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors - Google Patents

Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors

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Publication number
WO1998009951B1
WO1998009951B1 PCT/US1997/015468 US9715468W WO9809951B1 WO 1998009951 B1 WO1998009951 B1 WO 1998009951B1 US 9715468 W US9715468 W US 9715468W WO 9809951 B1 WO9809951 B1 WO 9809951B1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
compound
aryl
alkyl
Prior art date
Application number
PCT/US1997/015468
Other languages
French (fr)
Other versions
WO1998009951A2 (en
WO1998009951A3 (en
Filing date
Publication date
Priority to UA99041906A priority Critical patent/UA67727C2/en
Priority to APAP/P/1999/001497A priority patent/AP1322A/en
Priority to SK90-2005A priority patent/SK285278B6/en
Priority to AU43317/97A priority patent/AU740369B2/en
Priority to EA199900257A priority patent/EA002051B1/en
Priority to JP51283198A priority patent/JP4149000B2/en
Priority to SK282-99A priority patent/SK284899B6/en
Priority to NZ334909A priority patent/NZ334909A/en
Priority to DK97941402T priority patent/DK0927165T3/en
Priority to PL331801A priority patent/PL198408B1/en
Priority to SI9730719T priority patent/SI1361216T1/en
Priority to EEP199900109A priority patent/EE04465B1/en
Priority to DE69726298T priority patent/DE69726298T2/en
Priority to EP97941402A priority patent/EP0927165B1/en
Application filed filed Critical
Priority to CA002264756A priority patent/CA2264756A1/en
Priority to BR9713192-0A priority patent/BR9713192A/en
Priority to APAP/P/2003/002938A priority patent/AP2003002938A0/en
Priority to IL12856797A priority patent/IL128567A/en
Priority to AT97941402T priority patent/ATE254603T1/en
Priority to SI9730605T priority patent/SI0927165T1/en
Publication of WO1998009951A2 publication Critical patent/WO1998009951A2/en
Publication of WO1998009951A3 publication Critical patent/WO1998009951A3/en
Publication of WO1998009951B1 publication Critical patent/WO1998009951B1/en
Priority to IS4982A priority patent/IS2030B/en
Priority to NO19991072A priority patent/NO313287B1/en
Priority to BG103305A priority patent/BG64793B1/en
Priority to AU14736/02A priority patent/AU766155B2/en
Priority to JP2007280974A priority patent/JP2008056693A/en

Links

Abstract

HIV-protease inhibitors inhibit or block the biological activity of the HIV-protease enzyme, causing the replication of the HIV virus to terminate. These compounds can be prepared by the novel methods of the present invention using the novel inventive compounds and intermediates of formula (3). R1 and X are defined in the claims

Claims

AMENDED CLAIMS [received by the International Bureau on 20 May 1998 (20.05.98); original claim 1, 5-7, 11, 13, 17, 21, 31 and 33 amended; remaining claims unchanged (17 pages)]
1. A compound of formula 3:
Figure imgf000003_0001
wherein R, is heteroaryl; or a group of formula 8
Figure imgf000003_0002
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R, is a group of formula 9
Figure imgf000003_0003
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R1 is a group of formula 10.
R40
^
R5 -R5
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyi or aryl; heteroaryl bonded through the heteroatom; or - -
N-hydroxyheterocyclic bonded through the-oxygen, with the proviso that when R^ is CH3C(O)-, X cannot be -OH; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1 , wherein R1 is -C(O)CH3.
3. A compound according to claim 2, wherein X is Cl.
4. A compound according to claim 1 , wherein X is Cl.
5. A compound of formula 2:
Figure imgf000004_0001
wherein R1 is a heteroaryl group; or a group of formula 8
Figure imgf000004_0002
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R1 is a group of formula 9
Figure imgf000004_0003
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R1 is a group of formula 10 -67-
RR0 ^ R«
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or a pharmaceutically acceptable salt or solvate thereof.
6. A method of making a compound of formula 2:
Figure imgf000005_0001
comprising: adding under sufficient conditions a suitable protecting group R, to a compound of formula 1
Figure imgf000005_0002
wherein R., is a heteroaryl group; or a group of formula 8
Figure imgf000005_0003
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; ■ or further wherein R1 is a group of formula 9
Figure imgf000005_0004
- -
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R^ is a group of formula 10
R40.
^
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; to form the compound of formula 2.
7. A method of making a compound of formula 3
Figure imgf000006_0001
comprising: adding under sufficient conditions a suitable protecting group R and a leaving group X to a compound of formula 1
Figure imgf000006_0002
wherein R1 is heteroaryl; or a group of formula 8
0
R.
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; - -
or further wherein R^ is a group of formula 9
Figure imgf000007_0001
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R., is a group of formula 10
R40. R ^
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is CH3C(O)- , X cannot be -OH; to form the compound of formula 3.
8. A method according to claim 7, wherein R, is -C(O)CH3.
9. A method according to claim 7, wherein X is Cl.
10. A method according to claim 9, wherein R1 is -C(O)CH3.
11. A method of making a compound of formula 3
Figure imgf000007_0002
-70- comprising: adding under sufficient conditions a leaving group X to a compound of formula 2
Figure imgf000008_0001
wherein R^ is heteroaryl; or a group of formula 8
0
R,
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R is a group of formula 9
Figure imgf000008_0002
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R., is a group of formula 10
RΛ
R ^, ϊ C
- *
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyi or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R., is CH3C(0)-, X cannot be -OH; to form the compound of formula 3.
12. A method according to claim 11 , wherein X is Cl.
13. A method of making a compound of formula 4
Figure imgf000009_0001
comprising: converting under sufficient conditions a compound of formula 3
Figure imgf000009_0002
wherein R1 is heteroaryl; or a group of formula 8
O
R.
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6 wherein R6 is an alkyl group, an aralkyl group, or an aryl group; - -
or further wherein R^ is a group of formula 9
Figure imgf000010_0001
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R1 is a group of formula 10
RR0 ^ R-.
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, to the compound of formula 4.
14. A method according to claim 13, wherein R., is -C(0)CH3.
15. A method according to claim 13, wherein X is Cl.
16. A method according to claim 15, wherein R1 is -C(0)CH3.
17. A method of making a compound of 'formula 4
-73-
comprising: deprotecting a compound of formula 5
Figure imgf000011_0001
and adding to the deprotected compound of formula 5, under sufficient conditions, a compound of formula 3:
Figure imgf000011_0002
wherein R1 is heteroaryl; or a group of formula 8
Figure imgf000011_0003
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R1 is a group of formula 9
Figure imgf000011_0004
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R1 is a group of formula 10 R40. R, ^
Rfi
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, to form the compound of formula 4.
18. A method according to claim 17, wherein R^ is -C(O)CH3.
19. A method according to claim 17, wherein X is Cl.
20. A method according to claim 19, wherein R1 is -C(O)CH3.
21. A method of making a compound of formula 4
Figure imgf000012_0001
comprising: combining under sufficient conditions a compound of formula 3:
Figure imgf000012_0002
wherein R1 is heteroaryl; or a group of formula 8
Figure imgf000013_0001
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R1 is a group of formula 9
Figure imgf000013_0002
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R., is a group of formula 10
Figure imgf000013_0003
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8 wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with a compound of formula 6
Figure imgf000013_0004
to obtain the compound of formula 4. - -
22. A method according to claim 21 , wherein R^ is -C(O)CH3.
23. A method according to claim 21 , wherein X is Cl.
24. A method according to claim 23, wherein R is -C(O)CH3.
25. A method of making a compound of formula 7
Figure imgf000014_0001
comprising: converting under sufficient conditions a compound of formula 4
Figure imgf000014_0002
to the compound of formu a 7 y:
(a) contacting the compound of formula 4 with an organic solvent;
(b) contacting the compound of formula 4 with methanesulfonic acid under conditions sufficient to form a compound of formula 7; and
(c) spray drying the compound of formula 7.
26. A method according to claim 25, wherein the organic solvent is ethanol. - -
27. A method of making a compound of formula 7
Figure imgf000015_0001
comprising: converting under sufficient conditions a compound of formula 4
Figure imgf000015_0002
to the compound of formula 7 by:
(a) combining the compound of formula 4, a suitable solvent, and methanesulfonic acid to form the compound of formula 7, the compound of formula 7 being dissolved in solution;
(b) adding a first antisolvent to the solution containing the compound of formula 7; (c) agitating the compound of formula 7 and the first antisolvent to form a product having a solid phase and a liquid phase; and
(d) filtering and washing the product with a second antisolvent, the second antisolvent being the same as or different from the first antisolvent, to obtain a solid.
28. A method according to claim 27, the method additionally comprising:
(e) drying the solid.
29. A method according to claim 27, wherein the suitable solvent is tetrahydrofuran.
30. A method according to claim 27, wherein the first antisolvent is diethyl ether.
31. A method of making a compound of formula 4
Figure imgf000016_0001
comprising: converting under sufficient conditions a compound of formula 2
Figure imgf000016_0002
wherein R is heteroaryl; or a group of formula 8
Figure imgf000016_0003
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R^ is a group of formula 9
Figure imgf000017_0001
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R is a group of formula 10
R40. R.
*R«
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; to the compound of formula 4.
32. A method according to claim 31 , wherein R is -C(O)CH3.
33. A method of making a compound of formula 7
Figure imgf000017_0002
comprising: deprotecting a compound of formula 5
Figure imgf000018_0001
adding to the deprotected compound of formula 5, under sufficient conditions, a compound of formula 3:
Figure imgf000018_0002
wherein R1 is heteroaryl; or a group of formula 8
Figure imgf000018_0003
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, or O-R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group; or further wherein R1 is a group of formula 9
Figure imgf000018_0004
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; or further wherein R., is a group of formula 10
Figure imgf000019_0001
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloaikyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, to form a compound of formula 4:
Figure imgf000019_0002
and converting the compound of formula 4 to the compound of formula 7.
PCT/US1997/015468 1995-09-26 1997-09-04 Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors WO1998009951A2 (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
UA99041906A UA67727C2 (en) 1996-09-05 1997-04-09 Intermediate compounds for preparation of hiv-protease inhibitors and methods for the preparation of hiv-protease inhibitors
EP97941402A EP0927165B1 (en) 1996-09-05 1997-09-04 Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors
AU43317/97A AU740369B2 (en) 1995-09-26 1997-09-04 Intermediates for making HIV-protease inhibitors and methods of making HIV-protease inhibitors
EA199900257A EA002051B1 (en) 1996-09-05 1997-09-04 Methods of making hiv-protease inhibitors
CA002264756A CA2264756A1 (en) 1996-09-05 1997-09-04 Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors
SK282-99A SK284899B6 (en) 1996-09-05 1997-09-04 Intermediates for preparing HIV-protease inhibitors and process for preparing the HIV-protease inhibitors
NZ334909A NZ334909A (en) 1996-09-05 1997-09-04 Intermediates for making HIV protease inhibitors
DK97941402T DK0927165T3 (en) 1996-09-05 1997-09-04 Intermediates for the preparation of HIV protease inhibitors and method for producing HIV protease inhibitors
PL331801A PL198408B1 (en) 1996-09-05 1997-09-04 Intermediate compounds for use in production of hiv protease inhibitors and method of obtaining such inhibitors
SI9730719T SI1361216T1 (en) 1996-09-05 1997-09-04 Method of making a HIV-Protease inhibitor
EEP199900109A EE04465B1 (en) 1996-09-05 1997-09-04 Intermediates for the preparation of HIV protease inhibitors and methods for the preparation of HIV protease inhibitors
DE69726298T DE69726298T2 (en) 1996-09-05 1997-09-04 INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF HIV PROTEASE INHIBITORS AND METHOD FOR THE PRODUCTION OF HIV PROTEASE INHIBITORS
SI9730605T SI0927165T1 (en) 1996-09-05 1997-09-04 Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors
APAP/P/1999/001497A AP1322A (en) 1996-09-05 1997-09-04 Intermediates for making HIV- protease inhibitors and methods of making HIV protease inhibitors.
JP51283198A JP4149000B2 (en) 1996-09-05 1997-09-04 Intermediate for producing HIV-protease inhibitor and method for producing HIV-protease inhibitor
BR9713192-0A BR9713192A (en) 1996-09-05 1997-09-04 Intermediates for making HIV protease inhibitors and methods of making HIV protease inhibitors
APAP/P/2003/002938A AP2003002938A0 (en) 1996-09-05 1997-09-04 Intermediates for making HIV- protease inhibitors and methods of making HIV protease inhibitors.
IL12856797A IL128567A (en) 1996-09-05 1997-09-04 Intermediates for preparing hiv-protease inhibitor nelfinavir, process for their preparation and methods of preparing nelfinavir
AT97941402T ATE254603T1 (en) 1996-09-05 1997-09-04 INTERMEDIATE PRODUCTS FOR PRODUCING HIV PROTEASE INHIBITORS AND METHOD FOR PRODUCING HIV PROTEASE INHIBITORS
SK90-2005A SK285278B6 (en) 1996-09-05 1997-09-04 Method of making HIV-Protease inhibitor
IS4982A IS2030B (en) 1996-09-05 1999-02-19 Intermediates for the construction of HIV protease inhibitors and methods for the construction of HIV protease inhibitors
NO19991072A NO313287B1 (en) 1996-09-05 1999-03-04 Methods for Preparing HIV Protease Inhibitors
BG103305A BG64793B1 (en) 1996-09-05 1999-04-02 Intermediate compounds for the preparation of hiv protease inhibitors and methods for the preparation of hiv protease inhibitors
AU14736/02A AU766155B2 (en) 1995-09-26 2002-01-31 Intermediates for making HIV-protease inhibitors and methods of making HIV-protease inhibitors
JP2007280974A JP2008056693A (en) 1996-09-05 2007-10-29 Intermediate for production of hiv-protease inhibitor, and method for producing hiv-protease inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70841196A 1996-09-05 1996-09-05
US08/708,411 1996-09-05

Publications (3)

Publication Number Publication Date
WO1998009951A2 WO1998009951A2 (en) 1998-03-12
WO1998009951A3 WO1998009951A3 (en) 1998-07-09
WO1998009951B1 true WO1998009951B1 (en) 1998-08-13

Family

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PCT/US1997/015468 WO1998009951A2 (en) 1995-09-26 1997-09-04 Intermediates for making hiv-protease inhibitors and methods of making hiv-protease inhibitors

Country Status (32)

Country Link
EP (2) EP0927165B1 (en)
JP (3) JP4149000B2 (en)
KR (1) KR100563289B1 (en)
CN (2) CN1305854C (en)
AP (2) AP2003002938A0 (en)
AT (2) ATE254603T1 (en)
AU (2) AU740369B2 (en)
BG (2) BG64793B1 (en)
BR (1) BR9713192A (en)
CA (1) CA2264756A1 (en)
CZ (2) CZ298175B6 (en)
DE (2) DE69734689T2 (en)
DK (2) DK0927165T3 (en)
EA (1) EA002051B1 (en)
EE (1) EE04465B1 (en)
ES (2) ES2252586T3 (en)
GE (1) GEP20022799B (en)
HU (1) HUP0000028A3 (en)
IL (1) IL128567A (en)
IS (1) IS2030B (en)
NO (1) NO313287B1 (en)
NZ (1) NZ334909A (en)
OA (1) OA10988A (en)
PL (2) PL198408B1 (en)
PT (1) PT927165E (en)
SG (1) SG94780A1 (en)
SI (2) SI1361216T1 (en)
SK (2) SK284899B6 (en)
TR (1) TR199900473T2 (en)
UA (1) UA67727C2 (en)
WO (1) WO1998009951A2 (en)
YU (1) YU11599A (en)

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641038A (en) * 1992-07-17 1994-02-15 Mitsubishi Kasei Corp Carboxylic acid derivative
US5484926A (en) * 1993-10-07 1996-01-16 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
JPH07248183A (en) * 1994-03-11 1995-09-26 Osaka Gas Co Ltd Bathroom and clothing drying room
JP3298293B2 (en) * 1994-03-14 2002-07-02 松下電器産業株式会社 Garbage processing machine
WO1996028423A1 (en) * 1995-03-15 1996-09-19 Sankyo Company, Limited Dipeptide compounds having ahpba structure
AU717710B2 (en) * 1995-09-26 2000-03-30 Agouron Pharmaceuticals, Inc. Production of amide derivatives and intermediate compounds therefor
US5962704A (en) * 1995-09-26 1999-10-05 Japan Tobacco Inc. Production of amide derivatives and intermediate compounds therefor
JP3566968B2 (en) * 1995-09-26 2004-09-15 日本たばこ産業株式会社 Method for producing amide derivative and intermediate
BR9707635A (en) * 1996-02-24 1999-07-27 Basf Ag Compound derived from pyrazol-4-IL-hetaroyl process for the preparation of the same herbicidal composition and process to control undesirable vegetation

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