SULFONAMIDE INHIBITORS OF ASPARTYL PROTEASE

Title:

SULFONAMIDE INHIBITORS OF ASPARTYL PROTEASE

Document Type and Number:

WIPO Patent Application WO/1999/065870

Kind Code:

A2

Abstract:

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

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Inventors:

SHERRILL RONALD GEORGE (US)
HALE MICHAEL R (US)
SPALTENSTEIN ANDREW (US)
FURFINE ERIC STEVEN (US)
ANDREWS CLARENCE WEBSTER III (US)
LOWEN GREGORY THOMAS (US)

Application Number:

PCT/US1999/013744

Publication Date:

December 23, 1999

Filing Date:

June 17, 1999

Export Citation:

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Assignee:

VERTEX PHARMA (US)
SHERRILL RONALD GEORGE (US)
HALE MICHAEL R (US)
SPALTENSTEIN ANDREW (US)
FURFINE ERIC STEVEN (US)
ANDREWS CLARENCE WEBSTER III (US)
LOWEN GREGORY THOMAS (US)

International Classes:

A61P31/18; C07C303/00; C07C311/48; C07C311/49; C07D213/30; C07D235/06; C07D235/26; C07D235/30; C07D235/32; C07D241/42; C07D243/04; C07D265/02; C07D277/30; C07D307/20; C07D309/06; C07D309/12; C07D319/06; C07D405/12; C07D407/12; C07D413/06; C07D417/12; C07D493/04; C07F9/6561; (IPC1-7): C07C303/00

Domestic Patent References:

WO1994005639A1	1994-03-17
WO1996033187A1	1996-10-24
WO1996033184A1	1996-10-24

Attorney, Agent or Firm:

Haley Jr., James F. (1251 Avenue of the Americas New York, NY, US)
VOSSIUS& PARTENER (Nr,31) (Munchen, GERMANY, DE)

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Claims:

Claims We claim:

1.

A compound of formula (I): wherein: A is selected from H; Ht;RlHt ; R1C1C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, ClC4 alkoxy, Ht,0 Ht,NR2CON (R2) 2 orCON (R2)2; R1C2C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, Ht,OHt,NR2COalkoxy, N (R2)2 or CON(R2)2; or R7; each Ru ils independently selected fromC (O), S (O) 2,C (O)C (0),0C (O), OS (0) 2,NR2S (0) 2,NR2 C(0)orNR2C (0)C (0) ; each Ht is independently selected from C3C7 cycloalkyl; C5C7 cycloalkenyl; C6Clo aryl; or a 57 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N (R2), O, S and S (0) n; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from SR2,R2,N(R2)(R2),R2OH,CN,OR2, S(O)2N(R2)2,N(R2)C(O)R2,C(O)R2,CO2R2,C(O)N(R2)2, S (0) 2,OCF3,S (O)nQ, methylenedioxy, N(R2)S(O) 2 (R2), NO2,halo,CF3, OR7,SR7,R7,N(R2)(R7)orOQ, N (R') 2 ; each Rt is independently selected from H, Ht or C1C6 alkyl optionally substituted with Q or Rl° ; B, when present, isN (R2)C (R3) 2C (O); each x is independently 0 or 1; each R3 is independently selected from H, Ht, ClC6 alkyl, C2C6 alkenyl, CsCc cycloalkyl or C5C6 cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from S(O)nN(R2)(R2),Ht,OR2,C(O)NHR2, CO2R2,CN,SR2, NR2C(O)R2; each n is independently 1 or 2; G, when present, is selected from H, R7 or C1C4 alkyl, or, when G is ClC4 alkyl, G and R7 are bound to one another either directly or through a C1C3 linker to form a heterocyclic ring; or when G is not present, the nitrogen to which G is attached is bound directly to the R7 group in OR7 with the concomitant displacement of oneZM group from R D is selected from Q; CiCe alkyl or C2C4 alkenyl, which is optionally substituted with one or more groups selected from C3C6 cycloalkyl,OR2,SHt,R3,0Q or Q; C3C6 cycloalkyl or C5C6 cycloalkenyl, which is optionally substituted with or fused to Q; each Q is independently selected from a 37 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 57 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from 0, N, S, S (0), or N (R2) ; wherein Q is optionally substituted with one or more groups selected from oxo,ORz,R2,N (R2) 2,N (R2) C (O)R2, R2OH, CN, CO2R2, C(O)N(R2)2, halo orCF3; D'D'is selected N=R10orN(R10)R1R3;OR10, E is selected from Ht; 0Ht; HtHt;0R3; N (R)(R);CiCgalkyi, which is optionally substituted with one or more groups selected from R4 or Ht; C2C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C ;CE saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or C5C¢, unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 orHt; each R4 is independently selected fromOR, SR2, halo,NR2C(O)R2,N(R2)2orS(O)2NH2, CN; each Ris independently selected from hydrogen, wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba,N (R2) 4, C1C12alkyl, C2C12 alkenyl, orR6; wherein 1 to 4 CH2 radicals of the alkyl or alkenyl group, other than theCH2 that is bound to Z, is optionally replaced by a heteroatom group selected from 0, S, S (0), S (O2), or N (R 2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from R2,N(R2)z,N(R2)3,OR2, ROH,CN,CO2Rz,C (0)N (RZ) 2, S (0) 2N (R2) 2, N (R2)C (O)R2, C (O) R",S (O)nR2, OCF3, S(O)nR6, N(R2)S(O)2(R2), halo, CF3, orN02; M'is H, ClCl2alkyl, C2Cl2alkenyl, orR6; wherein 1 to 4CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from 0, S, S (0), S (02), or N (R 2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, OR2, R2, N(R2)2, N(R2)3, CO2R2,C(O)N(R2)2,S(O)2N(R2)2,R2OH,CN, S(O)nR2,OCF3,S(O)nR6,N(R2)C(O)R2,C(O)R2, CF3,orNO2;N(R2)S(O)2(R2),halo, Z is 0, S, N (R2)2, or, when M is not present, H. Y is P or S; X is O or S; R9 is C (R 2, 0 or N (R2); and wherein when Y is S, Z is not S; R6 is a 56 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 810 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S (0) n or N (R2) ; and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, ClC4 alkyl, OC1C4 alkyl or OC (O)C1C4 alkyl; R is selected from ClC8 alkyl, C3C7 alkyl or cyano substituted C2C6 alkenyl; and R10 is selected from CiCs alkyl, C2C6 alkenyl, C6Cl4 aryl or Ht, wherein R10 optionally contains up to three substituents independently selected fromR,CN,SR SRNR5C(O)R6,NR5(SO2)R5,C(O)N(R5)2,SOR5,SO2R5, C(O)R6,C(S)R6,N(R5)2,NR5 C(S)N(R5)2,S(O)2N(R5)2, C (0) R5,NR5C (0) OR5, NR5C(O) N (R5)2, NR5C (S) R5,NR5 C (S) OR5,NR5C (S) N (R5) 2,NR5C [=N (R5)]N (R5) 2,NHC [=NNO2] NH2,NHC [=NN02]OR',N (R") 2C (O) R",NHC [=NNO2]NH2,NH OC(O)R6,OC(O)N(R5)2,C[=NNO2]OR5,N(R8)2C(O)R8, OC (S) N (R5)2, wherein any one of theCH2 groups of said alkyl or alkenyl chains of R10 may be optionally replaced by O, S, SO, SO2, C (0) or NR5 ; wherein each R5 is independently selected from hydrogen, ClC8 alkyl, C2C8 alkenyl, C2C8 alkynyl or Ht, wherein each R5, except for hydrogen, is optionally substituted withCF3,P03R3, azido or halo; or a pharmaceutically acceptable derivative thereof.

2.

The compound according to claim 1, wherein at least one R7 is selected from: , o 0 CH3 o N Jp H2CO N 0" CHL 0'0 (L)lysine,PO ; Na2,pNMe2, (L)tyrosine, PO3Mg, PO3(NH4)2,CH2OPO3Na2, (L)serine, SO3Na2, SO3Mg,SO3(NH4)2, CH2OSO3Na2,CH2OSO3(NH4)2, O H O N ONH2, OMe, ONH2 acetyl, (L)valine, (L)glutamic acid, (L)aspartic acid, (L)ytbutylaspartic acid, (L) (L)3pyridylalanine, (L)histidine,CHO, PO3spermine, P03 (spermidine): or P0 ; (meglamine) 2.

3.	A compound of formula (II): wherein A, R7, D'and E are as defined in claim 1; or a pharmaceutically acceptable derivative thereof.

4.	A compound of formula (III): wherein Ht, x, R, R, D'and E are as defined in claim 1; or a pharmaceutically acceptable derivative thereof.

5.	A compound of formula (IV): wherein A, R, R, D'and E are as defined in claim 1; or a pharmaceutically acceptable derivative thereof.

6.

The compound according to claim 3, wherein: A isC (O) Ht ; D'is0Rlo ; E is C6Clo aryl optionally substituted with one or more substituents selected from oxo, OR2, SR2, R2, N(R2)2, R2OH,CN,CO2R2,C (O)N (R2) 2,S (0) 2N (R2)2, N(R2)C(O) R2,C (0)R2,S (0) nRz,OCF3,S (O) nQ, methylenedioxy, CF3,NO2,Q,OQ,OR7,SR7,R7,N(R2)S(O)2(R2),halo, N (R (R) orN (R) 2; or a 5membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected fromCH3, R4, or Ht.

7.	The compound according to claim 3, wherein: E is a 5membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted <BR> <BR> <BR> with one to two groups independently selected fromCH3, R4, or Ht.

8.

The compound according to claim 3, wherein: R'inOR'group shown in formula II isPO (OM) 2 or C (O) CH20CH2CH20CH2CH20CH3 and both R7inN (R7) 2 are H; or R7 in OR 7group shown in formula II is C(O)CH3OCH2CH2OCH3, one R7 inN (R7) 2 is C (0) CH20CHCH20CH3 and the other is H; and wherein M is H, Li, Na, K or ClC4 alkyl.

9.	A compound according to claim 1, having formula (V): wherein A, R7, R10 and E are as defined in claim 1; or a pharmaceutically acceptable derivative thereof.

10.

A compound of formula (VI): wherein: R10 and R7 are as defined in claim 1; E is C6Cl4 aryl, optionally substituted with one or more groups selected from the group consisting of nitro, oxo, alkoxy, amino, hydroxyamino; heterocyclcyl, optionally substituted with one or more groups selected from the group consisting of nitro, oxo, alkoxy, amino, hydroxyamino or N (CO) OCH3; or a pharmaceutically acceptable derivative thereof.

11.	A compound of formula (VII): wherein A, E, R and R10 are as defined in claim, 1; or a pharmaceutically acceptable derivative thereof.

12.	A compound of formula (VIII): wherein A, R, R3, R7 and E are as defined in claim 1; or a pharmaceutically acceptable salt thereof.

13.	A compound selected from: wherein Rl° is selected from isopropyl or cyclopentyl; Rll is selected from NHR7 or OR7 ; x, R7 and G are as defined in claim 1; and Xis a pharmaceutically acceptable counterion.

14.

A compound selected from: (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N ( (1S, 2R) 1benzyl3 (cyclopentyloxy) [ (3 [2 (dimethylamino) ethyl] aminophenyl) sulfonyl] amino2hydroxypropyl) carbamate ; (3S, 3aR, 6aS) hexahydrofuro [2,3b] furan3yl N ( (1S, 2R) 1benzyl3 (cyclopentyloxy) [ (3 [2 (dimethylamino) ethyl] aminophenyl) sulfonyl] amino2hydroxypropyl) carbamate; (3R, 3aS, 6aR) Hexahydrofuro [2, 3b]fjuran3ylN((1S,2R) 1benzyl3(cyclopentyloxy) (2[(methylsulfonyl) amino] benzimidazol5ylsulfonyl) amino2hydroxypropyl) carbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N (1S, 2R)3 [[(3Nmethylaminophenyl) sulfonyl] (cyclopentylOxy) amino]1 benzyl2hydroxypropylcarbamate; 1,3Dioxan5ylN(1S,2R)1benzyl3[(cyclopentyloxy) (2{(methoxycarbonyl)amino]1Hbenzimidazol5ylsulfonyl) amino]2hydroxypropylcarbamate; (3R, 3aS, 6aR) hexahydrofuro [2, 3b]furan3yl N(1S,2R)1 benzyl2hydroxy3[[(4methoxyphenyl)sulfonyl](tetrahydro 2Hpyran4yloxy) amino] propylcarbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N (1S, 2R)3 [[(3aminophenyl)sulfonyl](cyclopentyloxy)amino]1benzyl2 hydroxypropylcarbamate ; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N [ (1S, 2R) 1benzyl3((cyclopentyloxy)[3(2[methoxy(methyl)amino]2 oxoethylamino) phenyl] sulfonylamino)2hydroxypropyl] carbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N [ (1S, 2R) 1benzyl4 (cyclopentyloxy)2hydroxy4 (6quinoxalinyl sulfonyl) butyl] carbamate; (3R, 3aS, 6aR) hexahydrofuro [2, 3b]furan3yl N((1S,2R) 1benzyl3 (cyclopentyloxy) [ (4methoxyphenyl) sulfonyl] amino 2hydroxypropyl) carbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N [ (1S, 2R) 1benzyl3((cyclopentyloxy) [3(2[(methylsulfonyl) amino] ethylamino) phenyl] sulfonylamino)2hydroxypropyl] carbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N (1S, 2R)3 [[(3Nmethylaminophenyl) sulfonyl] (cyclopentylOxy) amino]1 benzyl2hydroxypropylcarbamate, phosphate ester; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N (1S, 2R)3 [[(3aminophenyl)sulfonyl](cyclopentyloxy)amino]1benzyl2 hydroxypropylcarbamate phosphate ester; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N (1S, 2R) 3[[(4aminophenyl)sulfonyl](cyclopentyloxy)amino]1benzyl 2hydroxypropyl carbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl (1S, 2R)1 benzyl3{(1ethylpropoxy) [(4hydroxyphenyl) sulfonyl] amino} 2hydroxypropylcarbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl (1S, 2R)3 [ (1, 3benzodioxol5ylsulfonyl) (1ethylpropoxy) amino]1 benzyl2hydroxypropylcarbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N [ (1S, 2R) 3[(1, 3benzOdioxol5ylsulfonyl) (cyclopentylOxy) amino]1 benzyl2 (phosphonooxy) propyl] carbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl (1S, 2R)3 [ (1, 3benzodioxol5ylsulfonyl) (cyclohexyloxy) amino]1 benzyl2hydroxypropylcarbamate; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl 3 [ (1,3 benzodioxol5ylsulfonyl) (tetrahydro2Hpyran4 yloxy) amino]1benzyl2hydroxypropylcarbamate ; (3R, 3aS, 6aR) hexahydrofuro [2,3b] furan3yl N [ (1S, 2R) 3 [ (1, 3benzodioxol5ylsulfonyl) (cyclopentyloxy) amino]1 benzyl2(phosphonooxy) propyl] carbamate ; or a pharmaceutically acceptable derivative thereof.

15.	The compound according to claim 1 wherein said compound has a molecular weight less than or equal to about 700 g/mol.

16.	The compound according to claim 15 wherein said compound has a molecular weight less than or equal to about 600 g/mol.

17.	A pharmaceutical composition comprising an effective antiviral amount of a compound according to any one of claims 114 or a pharmaceutically acceptable derivative thereof together with a pharmaceutically acceptable carrier therefore.

18.	The pharmaceutical composition according to claim 17, further comprising an antiviral agent other than a compound according to claims 114.

19.	A pharmaceutical composition according to claim 17 or 18 in the form of a tablet or capsule.

20.	A method of treating a virus infection in a human comprising administering to said human an effective antiviral treatment amount of a compound according to any one of claims 113 or a pharmaceutically acceptable derivative thereof.

21.	The method according to claim 20 wherein the virus infection is an HIV infection.

22.	The method according to claim 20 or 21 wherein said step of administering comprises oral administration or administration by injection.

23.	Use of a compound according to any of claims 114 for the manufacture of a medicament for the treatment or prophylaxis of a viral infection.

24.	Use of a compound according to any of claims 114 or a formulation according to claim 17 for use in medical therapy.

Description:

FURTHERINFORMATIONCONTINUEDFROMPCT/ISA/210 ContinuationofBox1.2 Claim13relatesto9differentstructuralentitiesofwhichonlyoneis coveredbygeneralformulaIofclaim1.Thestructuresthatarenot coveredbyformulaIarealsonotsupportedbythedescription. Consequentlythesearchhasnotbeenpertinenttothestructuresin question. Theapplicant'sattentionisdrawntothefactthatclaims,orpartsof claims,relatingtoinventionsinrespectofwhichnointernational searchreporthasbeenestablishedneednotbethesubjectofan internationalpreliminaryexamination(Rule66.1(e)PCT).Theappli cant isadvisedthattheEPOpolicywhenactingasanInternational PreliminaryExaminingAuthorityisnormallynottocarryouta preliminaryexaminationonmatterwhichhasnotbeensearched.Thisis thecaseirrespectiveofwhetherornottheclaimsareamendedfollowin g receiptofthesearchreportorduringanyChapterIIprocedure. INTERNATIONALSEARCHREPORT !------------------ ! 'rnatlonal AppilcatlonNo Intormatlon on patent family memtmers PatentdocumentPublicationPatentfamilyPublication citedinsearchreportdate member(s)date WO9405639A17-03-1994AP 390 A 02-08-1995 AT 178598 T 15-04-1999 AU 691160 B 14-05-1998 AU 4852093 A 29-03-1994 BG 62488 B 30-12-1999 BG 99540 A 30-11-1995 BR 1100824 A 31-08-1999 CA 2143208 A 17-03-1994 CN 1087347 A 01-06-1994 CZ 9500587 A 13-12-1995 DE 69324369 D 12-05-1999 DE 69324369 T 26-08-1999 EP 0659181 A 28-06-1995 EP 0885887 A 23-12-1998 ES 2131589 T 01-08-1999 FI 951059 A 18-04-1995 GR 3030719 T 30-11-1999 HU 71892 A 28-02-1996 JP 3012002 B 21-02-2000 JP 8501299 T 13-02-1996 LT 917A,B 25-11-1994 NO 950876 A 08-05-1995 NZ 256238 A 24-04-1997 NZ 314376 A 28-10-1998 PL 307858 A 26-06-1995 RU 2135496 C 27-08-1999 SG 43862 A 14-11-1997 SK 29395 A 13-09-1995 US 5977137 A 02-11-1999 US 5585397 A 17-12-1996 US 5783701 A 21-07-1998 US 5723490 A 03-03-1998 US 5856353 A 05-01-1999US 5856353 A 05-01-1999 WO9633187A24-10-1996US 5691372 A 25-11-1997 AU 712913 B 18-11-1999 AU 5665596 A 07-11-1996 BG 102041 A 30-09-1998 BR 9608033 A 12-01-1999 CA 2217745 A 24-10-1996 CN 1184474 A 10-06-1998 CZ 9703294 A 18-03-1998 EA 970330 A 30-04-1998 EP 0833826 A 08-04-1998 HU 9801948 A 28-09-1999 JP 11504628 T 27-04-1999 NO 974744 A 14-10-1997 NZ 307342 A 29-04-1999 PL 322904 A 02-03-1998 SK 143097 A 04-03-1998 US 5990155 A 23-11-1999 ZA 9602891 A 15-10-1996ZA 9602891 A 15-10-1996 WO9633184A24-10-1996US 5723490 A 03-03-1998 AU 706732 B 24-06-1999 AU 5559696 A 07-11-1996 BG 102048 A 31-08-1998 BR 9608032 A 12-01-1999 INTERNATIONALSEARCHREPORT vsrnatlonal AppilcatlonNo Infortnation on patent tamlly membera PCT/US99/13744 PatentdocumentPublication Patent family Publication citedinsearchreportdatemember(s)date WO9633184ACA2217737A 24-10-1996 CN1181755A 13-05-1998 CZ9703293A 18-03-1998 EA970331A 30-04-1998 EP0846110A 10-06-1998 HU9801877A 28-09-1999 JP3046357B 29-05-2000 JP10509739T 22-09-1998 NO974722A 13-10-1997 PL322877A 02-03-1998 SK 143197 A 08-04-1998SK 143197 A 08-04-1998

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