AU681342B2 - Amine derivatives of oxo- and hydroxy-substitued hydrocarbons - Google Patents

Amine derivatives of oxo- and hydroxy-substitued hydrocarbons Download PDF

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AU681342B2
AU681342B2 AU37391/93A AU3739193A AU681342B2 AU 681342 B2 AU681342 B2 AU 681342B2 AU 37391/93 A AU37391/93 A AU 37391/93A AU 3739193 A AU3739193 A AU 3739193A AU 681342 B2 AU681342 B2 AU 681342B2
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Prior art keywords
alkyl
independently
previously defined
group
cycloalkyl
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AU37391/93A
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AU3739193A (en
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Damian Wojciech Grobelny
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Narhex Ltd
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Narhex Ltd
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Priority claimed from PCT/AU1993/000103 external-priority patent/WO1993018006A1/en
Priority to APAP/P/1993/000504A priority Critical patent/AP395A/en
Priority claimed from APAP/P/1993/000504A external-priority patent/AP395A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Description

OPI DATE 05/10/93 AOJP DATE 09/12/93 APPLN. ID 37391/93 II111II li Il III PCT NUMBER PCT/AU93/00103 I I1111 Nf IIIii AU9337391
X-C)
(51) International Patent Classification 5 International Publication Number: WO 93/18006 C07D 213/81, 213/30, 237/08 C07D 237/26, 215/48, 401/12 Al effe~? 10904, 07,; l33mo (43) International Publication Date: 16 September 1993 (16.09.93) C07C 243/14, 243/28, 281/02 (21) International Aliplication Number: PCT/AU93/00103 Designated States: AT, AU, BB, BG, BR, CA, CH, CZ, DE, DK, ES, Fl, GB, HU, JP, KP, KR, KZ, LK, LU, (22) International Filing Date: I I March 1993 (11.03.93) MG, MN, MW, NL, NO, N, PL, PT, RO, RU, SD, SE, SK, UA, US, VN, European patent (AT, BE, CHi, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), Priority data: OAPI patent (BF, 133, CF, CG, CI, CM, GA, GN, ML, PL 1304 11 March 1992 (11.03.92) AU MR, SN, TD, TG).
(71) Applicant (for all designated States except US): NARHEX Published LIMITED [GB/GB]; 11th Floor, 3A Charter Road, With international search report.
Hong Kong (72) Inventor; and Inventor/Applicant (for US only) GROBELNY, Damian, Wojciech [PL/AU]; 43 llrassey Avenue, Rosanna, VIC 3084
A
(74) Agent: SPRUSON FERGUSON; GPO Box 3898, Sydney, NSW 2001 (AU).
(54)Title: AMINE DERIVATIVES OF OXO- AND H-YDROXY-SUBSTITUED HYDR~OCARBONS N (57) Abstract The compounds of general formula wherein RI, R 2
R
3 are optionally substituted carbonyl and amide derivatives which are useful as inhibitors of retroviral proteases, and are effective in treating conditions characterized by unwanted activity of these enzymes, such as acquired immune deficiency syndrome.
WO 93/18006 PCT/AU93/00103 AMINE DERIVATIVES OF OXO- AND HYDROXY- SUBSTITUTED
HYDROCARBONS
TECHNICAL FIELD The invention relates to certain amine derivatives and their use in the inhibition of human immunodeficiency virus (HIV) proteases and thus in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS).
BACKGROUND ART Human immunodeficiency virus (HIV) is a pathogenic retrovirus causing AIDS and its related disorders. The development of antiviral chemotherapy against AIDS has been the subject of an intense research effort since the discovery of HIV. (For a recent review on molecular targets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533-1544). The HIV Proteases (HIV PR), and aspartyl proteases, were first suggested as a potential target for AIDS therapy by Kramer et al. (Science, 231, 1580, 1986). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al. Chimica .ggj, May 1991, pp 6-27 and Huff J.Med.Chem, 1991, 34, 2314- 2327). Of the classical transition state mimics for aspartyl proteases, the hydroxyethylene, dihydroxyethylene, hydroxyethylamine and phosphinic acid isosteres appear to provide the greatest affinity for HIV PR. Many inhibitors of HIV PR have been shown to have an antiviral activity at concentrations in the nanomolar range in the different cell systems and are described as such in the patent literature.
SUMMARY OF THE INVENTION The invention provides a new class of compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome.
A first embodiment of the invention is directed to compounds of the general formula R N 2 R 3 or pharmaceutically acceptable salts thereof, wherein:
R
1 is a group R, wherein R is selected from the group consisting of hydrogen, -R'H,
-R'C(O)NH
2 -R'C(O)NR' -R'NHC(O)R'', or where and are independently optionally substituted (C 1
-C
1 8 )alkyl, typically (C 1
-C
1 2 )alkyl; (0- 3
-C
1 gcycloalkyl, typically (C 3 -C 12 )cycloalkyl; (C 3
-C
1 8 )cycloalkyl(C 1
-C
1 8 )alkyl, typically
(C
3 -C 12 )cycloalkyl(C 1
-C
6 )alkyl; (C 6
-C
24 )aryl, typically (C 6
-C
1 6 )aryl;
(C
7
-C
25 )aralkyl, typically (C 7
-C
1 6 )aralkyl; (C 2
-C
18 )alkenyl, typically (C 2 -C2 2)alkenyl; (CB-C 26 )aralkenyl, typically (C 8
-C
16 )aralkenyl; (C 2
-C
1 8 )alkynyl, typically (C 2 -C 12 )alkynyl; (C 8
-C
26 )aralkynyl, typically (C 8
-C
1 6 )aralkynyl; or heterocyclic, and where R' is an optionalIly substituted divalent radical derived from (C -C 1 8 )alkyl, typically (C 1
-C
1 2 )alkyl; (C 3
-C
1 8 )cycloalkyl, typically
(C
3
-C
1 9cycloalkyl; (C 3
-C
1 8 )cycloalkyl(C 1
-C
1 8 )alkyl, typically (C 3
-C
12 )cycIoalkyl(C 1
-C
6 )alkyl; (C 6
-C
24 )aryl, typically (C 6
-C
1 6 )aryl; (C 7
-C
25 )aralkyl, typically (C 7 -C 16 )aralkyl; (C 2
-C
18 )alkenyl, typically (C 2
-C
1 2 )alkenyl; (C 8
-C
26 aralkenyl, typically (C 8
-C
1 6 )aralkenyl; (C 2
-C
1 8 )alkynyl, typically (C 2 -C 12)alkynyl; (C8-C 26 )aralkynyl, typically (C 8 -C 16 )aralkynyl; or heterocyclic, or R 1 is 0 000* 0* 0* *0 0*0 0* *0 0 0 ~0 0* *00* 0* 00 *000 C R where R 4
R
5 and R 6 are independently a group R as defined above, or R 4 has the meaning of R as defined above and R 5 and R 6 taken together are =S, =NH or =NR; and R 2 is R7 D 1 11
-N-B-C-Y
where R 7 is R is as previously defined; D is 0 or S; Y is hydrogen, -R or -OR, where R is as previously defined, or is an amino acid, aza-amino acid or peptide residue in which any functional group present is optionally protected; and B is optionally absent or is (C 1
-C
6 )alkylidenie, wherein any one or more -CH 2 groups may be replaced by or provided that the compound of Formula does not contain a chain of three or more atoms which are not carbon, and wherein any H atom may be substituted by a group R as previously [N:\LII3Z]205790AU:SAK 3 defined; and optionally N, RI and R 7 taken together form a cyclic diazaalkane of the formula: (CHR)p N N (CHR)p RHC CHR or RCH CHR
IN
N N where p is 1 to 3, each R is independently as defined above and R 8 is R, -NH 2 -NHR, -NR 2 -COOH, -COOL, -CHO, -CN, halo, -CF 3 -OL, -SR, -S(0) 2 R, -CONH2, -CONHR, -CONR 2 -NHOH, -NHOL, -NO 2
=O,
=S or -NHNH 2 wherein each R is independently as defined above and each L is independently R or a hydroxyl protecting group which is labile in vivo and which prevents premature metabolism of the compound of formula after administration to a patient; or R 2 N* and R 4 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinafter which may be additionally substituted by where Y is as previously defined and R 3 is X- W A' Q A wherein: A' and A independently are absent or (CI-C 8 )alkylidene, typically (Ci-C 4 )alkylidene which may be substituted with one or more substituents R as previously defined; Q is .9 9* 9 9 99 .9 .9 9 .99 C CR 2
O
o CR CR 2 or
OL
where L and each R, independently of the others, are as previously defined, and optionally Q and A together, or Q and A' together, or Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinafter; W is absent or is O or S, wherein R is as previously defined; and X is hydrogen, or XI, where X I is Ra- or RbC(O)- or RbS(O)z-, where z is 1 or 2 and Ra and Rb are independently (Ci-C 1 g)alkyl, typically (Ci-Cl2)alkyl;
(C
3 -C 8 )cycloalkyl, typically (C 3 -C 2 )cycloalkyl; (C 3 -Cg )cycloalkyl(C 1
-C
1 8 )alkyl, typically (C 3 -C 2 )cycloalkyl(C 1
-C
6 )alkyl; heterocyclic; (C -C 18 )alkylheterocyclic, typically (C -C 2 )alkylheterocyclic; heterocyclic(C 6
-C
24 )aryloxy, typically heterocyclic(C 6 -Ci 6 )aryloxy; (Ci-Cl 8 )alkoxy, typically (Ci-Cl 2 )alkoxy; (Ci-C 1 i)alkoxy(Ci-Cig)alkyl, typically (CI-C12)- IN:\LIBZ205790AU:SAK 4 alkoxy(C 1 -C 12 )alkyl; (C 6
-C
24 )aryloxy(C 1
-C
1 8 )alkyl, typically (C 6
-C
16 )aryloxy- (C i-c 2 )alkyl; (C 6
-C
24 )aryloxy(C 1
-C
1 8 )alkoxy, typically (C 6 -C 16 )aryloxy-
(C
1
-C
1 9alkoxy; (C 6
-C
24 )aryl, typically (C 6
-C
16 )aryl; (C 6
-C
24 )aryl(C 1
-C
1 8 )alkyl, typically (C 6 -C 16)aryl(C 1
-C
1 2 )alkyl; (C 6
-C
24 )aryl(C 1
-C
1 8 )alkylheterocyclic, typically (C 6 -CI 6)aryl(C 1 -C 2 )alkylheter-ocyclic; heterocyclicoxy(C 1
-C
1 8 )alkyl, typically heterocyclicoxy(C 1 -C 2 )alkyl; (C 1
-C
1 g)alkylamino, typically (C 1 -C 12)alkylamino; di(C 1
-C
1 galkylarnino, typically di(C 1 -C 12 )alkylamino; (C 6
-C
24 )arylamino, typically (C 6 -C 16 )arylamino; di (C 6
-C
24 )arylIamino, typically di(Cb-C 1 6 )arylamino; (C 7 -C2 5 )aralkylamino, typically (C 7
-C
1 2 )aralkylamino or di(C 7
-C
2 5 )aralkylamirio, typically di(C 7
-C
12 )aralkylamino; any of which may be optionally substituted as hereinbelow defined or substituted with a group Re, where Re is a group of the formula: Rf 0 Z NH OH C where Z has the meaning of Ra or Rb or is an acylated amino acid, azaamino 1: i acid or peptide residue, and Rf is the side-chain of a natural amino acid in which any functional group present is optionally protected; or X is Re as previously defined, or X is an optionally protected amino acid, azaamino acid or peptide residue; or when W is then X, N and the substituent R on N together may form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbelow or N, A' and the substituent R on N together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbelow.
So to :Also included within thle scope of the invention are compounds wherein two R.
substituents, not necessarily vicinal, taken together are optionally substituted
(C
2
-CI
8 )aikylidene, typically (C 2
-C
1 8)alkyl idene.
Also included within the scope of the invention are compounds lN:\L113Z]205790AU:CB WO 93/18006 PCT/AU93/00103 wherein the Z-NH bond shown is replaced by a m'odified isosteric bond, such as CH 3 -NRa-, RaCH 2 -NRa-, CH 3 -rHRa-, HCH =CRa-, RaCH =CRa-, HCOCHRa-, RaCOCHRa-, HCHOHCHRa-, RaCHOHCHRa-, HNRaCO-, HCF=CRa-, RaCF =CRa-, RaS(O)-, RaS(O) 2 RaP(O)ORa-, RaP(O)(ORa)CH 2 RaP(O)(ORa)O-, RaP(0)(ORa)S-, wherein each Ra is independently as previously defined, As used herein, the term "optionally substituted" means that one or more hydrogen atoms may be replaced by a group or groups selected from: -Cl, -Br, -CF 3 -OH, -ORlV, -NH 2 -NHRlV, -NRlVRV, -CN, -NO 2
-SH,
io -SRlV, -SORlV, SO 2 RIV, =NOH, =NORIV, -NHOH, -NHORlV, -CHO, where RIV and RV are independently (Cl-C 1 8)alkyl, typically
(C
1
-C
1 2 )alkyl; (C 3
-C
1 8 )cycloalkyl, typically (C 3
-C
1 2)cycloalkyl; (C 3
-C
1 8)cycloalkyl(C 1
-C
1 8 )alkyl, typically (C 3
-C
1 2 )cycioalkyl(C 1
-C
6 )alkyl; (C 6
-C
2 4 aryl, typically (C 6
-C
1 6)aryl; (C 7 -C2 5 )aralkyl, typically (C7-C 1 6 )aralkyl;
(C
2 -Cl 8 )alkenyl, typically (C2-C 1 2)aikenyl; (C8-C26)aralkenyl, typically (C8-C16)aralkenyl; (C 2
-C
1 8 )aikynyl, typically (C 2
-C
1 2)alkynyl; (C 8
-C
26 aralkynyl, typically (C8-Cl 6 )aralkynyl; or heterocyclic.
As used herein, the term "alkyl" includes within its meaning straight and branched chain alkyl groups. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, secamyl, 1 ,2-dimethylpropyl, 1 ,1 -dimethyl-propyl, hexyl, 4-methylpentyl, 1methylpentyl, 2-methylpentyl, 3-methylpentyl, 1 1 -dimethylbutyl, 2,2dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, I ,3-dimethylbutyi, 1,2,2trimethyipropyl, 1 ,1 ,2-trimethylpropyl, heptyl, 5-methylhexyl, 1 -methylhexyl, 2, 2-dimethylpentyl, 3, 3-dimethylpentyl, 4, 4-dimethylpentyl, 1,2dimethylpentyl, 1 ,3-dlmethylpentyl, 1 ,4-dimethyl-pentyl, 1 ,2,3-trimethylbutyl, 1 ,1 ,2-trimethylbutyl, 1, 1,3-trimethylbutyl, octyl, 6-methylheptyl, 1 methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 6- or 7methyl-octyl, 4- or 5-ethylheptyl, 2- or 3-propylhexyl, decyl, 1 7- or 8-methylnonyl, 5- or 6-ethyloctyl, 2-, 3- or 4-propylheptyl, undecyl, 8- or 9-methyldecyl, 1 5, 6- or 7-ethylnonyl, 4- or 5-propyloctyl, 2- or 3butylheptyl, 1-pentylhexyl, dodecyl, 9- or methylundecyl, 7- or 8-ethyldecyl, 5- or 6propylnonyl, 3- or 4-butyloctyl, 1- or 2-pentylheptyl, and the like.
A used herein, the term "cycloalkyl" refers to mono- or polycyclic alkyl groups, or alkyl substituted cyclic alkyl groups. Examples of such groups include cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, WO 93/18006 PCT/AU93/00103 6 cyclopentyl, methylcyc lope ntyl1, ethylcyclopentyl, cyclohexyl, methylcyclohexyl, ethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, decahydronaphthyl, bicyclo[2.2. 1Iheptanyl, bicyclo[2.2.2loctanyl and the like.
As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group as defined above.
As used herein, the term "alkenyl" includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined. Examples of such alkenyl groups are vinyl, allyl, 1methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1 -pentenyl, cyclopentenyl, 1 -methyl-cyclopentenyl, 1 -hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3nonenyl, 1 -decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3cyclo pentadilenyl, 1 .3-headlenyl, 1 ,4-hexadlenyl, 1 ,3-cyclohexadienyl, 1,4cyclohexadienyl, 1,3 cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7cyclooctatetraenyl.
As used herein, the term "alkynyl" includes within its meaning acetylenically unsaturated alkyl groups as previously defined. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-ibutynyl, n-hexynyl, methyl-pentynyl, (C 7
-C
12 )alkynyl and (C 7
-C
1 2 )cYCIOalkynyl.
As used herein, the term "alkylidene" refers to optionally unsaturated divalent alkyl radicals. Examples of such radicals are -CH 2
-CH
2
CH
2 -CH=CH-, -CH 2
CH
2
CH
2
-C(=CH
2
)CH
2
-CH
2 CH=CH-, -(CH 2 4
*CH
2
CH
2 CH -CH 2 CH =CHCH 2 and -(CH2)r- where r Is 5-8. The term also refers to such radicals In which one or more of the bonds of the radical from part of a cyclic system. Examples of such radicals are groups of the structure WO 93/18006 PCT/ U93/00 103 7 9 9 I I NoN N
NN
N -1-9 '3hi O
NN
0 N c ooo 0 N and similar groups wherein any N or 0 atom is replaced by S.
As used herein, the term "aryl" refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of such groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, 1o thlazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula WO 93/18006 PC~/AU93/00103 8 As used herein, the term "aralkyl" refers to alkyl groups substituted with one or more aryl groups as previously defined. Examples of such groups are benzyl, 2-phenylethyl and 1-phenylethyl.
As used herein, the terms "aralkenyl" and "aralkynyl" refer to alkenyl and alkynyl groups respectively, substituted with one or more aryl groups as previously defined. Examples of such groups are styryl, phenylacetylenyl and 2-phenyl-2-butenyi.
As used herein the term "saturated or unsaturated cyclic, bicyclic or fused ring system" refers to a cyclic system of up to 16 carbon atoms, up to o1 3 of which may be replaced by O, S or N, which ring system may be substituted with one or more of R, -NH 2 -NHR, -NR 2 -COOH, -COOL, -CHO, -CN, halo, -CF 3 -OL, -SR, -S(0) 2 R, -CONH 2
-CONHR,
-CONR
2 -NHOH, -NHOL, -NO 2 =S or -NHNH 2 wherein each L and R are independently as previously defined. Examples of such ring systems are those cyclic alkylidene groups exemplified above and -N K S N 'N
N-
-N N As used herein, the term "heterocyclic" refers to any 3- to 16-membered monocyclic, bicyclic or polycyclic ring containing, for 3- and 4membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur. The term "heterocyclic" includes any group in which a heterocyclic ring is fused to a benzene ring. Examples of heterocyclics are pyrryl, pyrimidinyl, quinolinyl, isoquinolinyl, Indolyl, piperidinyl, pyridinyl, WO 93/18006 PCT/A U93/00103 9 furyl, thiophenyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolyl, pyrenyl, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, furfuryl, thienyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, azanorbornyl, isoquinuclidinyl and the like. Nitrogen-containing heterocyclics may be substituted at nitrogen with an oxygen atom. Sulfurcontaining heterocyclics may be substituted at sulfur with one or two oxygen atoms.
Configurations which result in unstable heterocyclics are not included within the scope of the definition of "heterocyclic" or "saturated or unsaturated cyclic, bicyclic or fused ring system".
As used herein, the term "alkylheterocyclic" refers to a heterocyclic group as defined above, which is substituted with an alkyl group as defined above.
As used herein, the term "heterocyclic-oxy-alkyl" refers to a group of the formula heterocyclic-0-alkyl, wherein the heterocyclic and alkyl are as defined above.
As used herein, the term "alkoxy" refers to a group of the formula alkyl-O-, wherein the alkyl group is as defined above.
As used herein, the term "aryloxy" refers to a group of the formula aryl-0-, wherein the aryl group is as defined above.
As used herein, the term "alkanoyloxy" refers to a group of the formula alkyl-C(0)O-, wherein the alkyl group is as defined above.
As used herein, the t3rm "amino acid" refers to a synthetic or naturally occurring compound of the formula H 2 NCH(R)COOH, wherein R is as defined above.
As used herein, the term "azaamino acid" refers to an amino acid in which the CH(R) group has been replaced by a group wherein R is as defined above.
Suitable pharmaceutically acceptable salts of the compound of formula are salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, hydrobromic or hydriodic, or with pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic or valeric, The expression "protected" as used herein is intended to mean that a reactive group such as hydroxyl or amino is substituted by replacing a hydrogen atom of the reactive group in order to protect such groups during synthesis and/or to prevent premature metabolism of the compound of formula after administration to a patient before the compound can reach the desired site of action. Suitable protecting groups for hydroxyl substituents include substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl and the like, vinyl, acyl and carbonate groups. Suitable protecting groups for amino substituents include acyl groups such as acetyl, t-butylacetyl, o1 t-butyloxycarbonyl, benzoyl or carbobenzyloxycarbonyl, phenylmethoxycarbonyl, pyridinemethoxycarbonyl, quinoline-2-carbonyl or an aminoacyl residue. Protecting groups which are included in the compound ot formula must be amenable to hydrolytic or metabolic cleavage in vivo.
Usually, the compound of the general formula will have the structure represented by formula (IA): R R R 0 NI X -N Y (IA) *I I I 'b W c
*C
S* where X, Q, Y and each R is independently as previously defined, a and b are independently 0 to 4 and c is 0 to 6, or where two R groups, not necessarily vicinal, taken together are -(CHR1 8 m where m is 2-8 and R 18 has the meaning of R.
More usually, the compound of the general formula will have the structure represented by formula (IB): R R19i I I II N ,Qs N C XN A' A N Y (IB) where X, R, Q, A and Y are as previously defined or either or both of A and A' are absent, and R 19 and R 20 have the meaning of R or where R 1 9 N and R 20 together form a cyclic diazaalkane as previously defined.
Most usually, the compound of the general formula will have the structure represented by formula (IC) or (ID): 'if" IN LDZj205790AU.-SA 11 R 21 R 22 R 2A ,x N 7 Y (IC) R OH R23 0 R 21 R 22 R 24 N NN, Y
(ID)
R 0 R 23 0o wherein: P. is as defined above;
IZ
2 1 is hydrogen, optionally substituted (Cl-C 12 )alkyl; optionaP:... substituted
(C
6 -C 1 2)aryl; optionally substituted (C 7
-C
1 6)aralkyl;
R
22 is hydrogen, (Cl-C8)alkyl; (G 7
-C
1 6)aralkyl, or when R 2 1 and R 2 2 taken together are -(CH2) 11 wherein n is 2 to 8; R 2 2 is hydrogen, Cl-C~alkyl; C 7 C16aralky1, or wherein R 2 1 and R 2 2 taken together are -(CH 2 11 wherein n is 2-8;
R
2 3 is hydrogen; optionally substituted (Cl-C 12 )alkyl; (C 6 -Cl2)aryl; (C 7 Cl6)aralkyl; or wherein R 2 2 and R 2 3 taken together are -(CHR 2 5 wherein mn is 3-6 and R 25 has the meaning of RIO;
R
2 4 is hydrogen; optionally substituted (C 1 -Cl 2 )alkyl; optionally substituted 0 1(C 7
-C
16 )aralkyl; or optionally substituted (C6-C12)aryl; wherein NR 2 3 and NR 24 taken together may be a cyclic diazaalkane as previously defined; and X and Y are as previously defined.
Representative compounds in accordance with the invention are: t-butyl 3-isopropyl-3-[(2R or S ,3S)-2-liydroxy-3-(phenylmiethoxycarbonyl)amino-4-phenylbutyllcarbazate, 00i t-butyl 3-isopropyl-3-1(2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L-valyl)amino- 4-phenylbutylicarbazate, (iii) t-butyl 3-isopropyl-3-[(2R or S 3S)-2 -hydroxy-3-(N -quina Idyl -L-asparaginyl)amino-4-phenylbutyllcarbazate, 26 (iV) t-butyl 3-isopropyl-3-[(3S)-2-oxo-3-(N-quinaldy!-L-asparaginyl)amino-4phenylbutylicarbazate, t-butyl 1-methyl-3-phienylpropen-3-yl)-3-[(2R or S ,M3)-2-hydroxy-3- (phienylmethioxycarbonyl)amino-4-phenylbutyllcarbazate, (vi) t-butyl 1-methyl-3-phenylpropyl)-3-[(2R or S ,3S)-2-hydroxy-3-(Nao quinaldyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (vii) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2R or S ,3S)-2-hiydroxy-3-amino-4-phenylbutyl]- 3,4-diaz.abicyclo[4.4.O]decane, IN:\LI11Z)205790AU:SAK 12 (Viii) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2R or S ,3 S)-2-hydroxy-3-(phenylmethoxycarboniyl)amino-4-phenylbutyl]-diazabicyclo[4 O]decane, (ix) cis- 1, 6-3-t-butoxycarbonyl-4-[(2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L-valyl)amino-4-phenylbutyl] 4-diazabicyclo[4. cis- I ,6-3-t-butoxycarbonyl-4-[(2R or S ,3S)-2-hydroxy-3-[N-.(2-pyridyl)methoxycarbonyl)-L-valyl)amino-4-phenylbutyl1-3 ,4-diaza-bicyclo[4 O]decane (xi) cis- 1 ,6-3-t-butoxycarbonyl-4+[2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyvl]-3 ,4-diazabicyclo[4.4.O]decane, (xii) cis- 1 ,6-3-t-butoxycartionyl-4-[(2R or S ,3S)-2-hiydroxy-3-(N-quinaldyl-Lglutaminyl)amino-4-phenylbutyl] -3 ,4-diazabicyclo[4. 4. O]decane, (xiii) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2R or S ,3S)-2-hydroxy-3-(N-quinialclyl-Lthireonyl)amino-4-phenylbutyll-3 ,4-diazabicyclo[4 Oldecane, (xiv) 2-t-butoxycarbonyl-3-[(2R or S ,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2 ,3-diazabicyclo[2 is (xv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-h ydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2 ,3-diaza-bicyclo72.2. 1]heptane, (xvi) 2-t-butoxycarbony!-3-[(2R or S ,3S)-2-hydroxy-3-(N-(2-pyridyl)r~nethoxy-Lvalyl)arnino-4-phenylbutyl]-2 ,3-diaza-bicyclo[2 1.]heptane, 9. (xvii) 1S)(2-methyl-l1-methoxycarbonylpropyl)carbamoyl]-3 or S ,3S)-2- 20 hydroxy-3-IIN-(2-pyridyl)methoxy-L-valyl]amino-4-phenylbutyl] 3-diazabicyclo[2 .2.1t]heptane, (xviii) 2-t-butoxycarbonyl-3+[2R or S,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]-2 ,3-diazabicyclo[2 .2.1 hjleptane, 25(ixx) 1 -[2-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2R or S ,3S)-2-hydroxy-3- 2(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropyl-hydrazine, (xx) 2-t-butoxycarbonyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyll-1 ,2 ,3,4-tetrahydrophthalazine, (xxi) 1 -trimethylacetyl-2-[(2R or S ,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- 99 9 amino-4-phyenylbutyll-2-isopropylhydrazine, (xxii) 1 -trimethylacetyl-2-[2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl) amino-4-phenylbutyl]-2-isopropylhydrazine, (xxiii) 1 -(t-butylarnino)carbonyl-2II2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-Lasparagiriyl)arnino-4-phenyibutyll-2-isopropylhiydrazine, (xxiv) t-butyl 3-isopropyl-3-[(2R or 5, 3S)-2-hydroxy-3-(N-picol inoyl-L-asparaginyl)arnino-4-phenylbutyl]carbazate, (xxv) t-butyl 3-isopropyl-3-[2R or S ,3S)-2-hiydroxy-3-(N-(2-pyridyl)-methoxycarbonyl-anthranilyl)amino-4-phenylbutyllcarbazate.
(xxvi) t-butyl 3-benzyl-3-[(2R or S ,3S)-2-hydroxy-3-(phenylrnethoxycarbonyl)aniino- 4-phienylbutyllcarbazate, IN:\LfIBZ)20S790AU:SAK 13 (xxvii) t-butyl 3-benzyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyllcarbazate, (xxviii) t-butyl 3-cyclohexy?,-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methioxycarbonyl)amino-4-phenylbutyl]carbazate, (xxix) t-butyl 3-cyclohexyl-3-[(2R or S ,3 S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (xxx) t-butyl 3-isopropyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-( I-carbamoyl-methyl)acrylyl)amino-4-phenylbutyl]carbazate, (xxxi) t-butyl 3-isopropyl-3.-[2R or S ,3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio-2carbamoyl-methylpropionyl)amino-4-phenylbutyl]carbazate, (xxxii) t-butyl 3-isopropyl-3-[2R or S ,3S)-2-hydroxy-3-(N-( 1-benzoyl-L-asparaginyl)ainino-4-phenylbutylljcarbazate, (xxxiii) 1 -t-butyloxycarbonyl-2.-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyljhexahydropyridazine, (xxxiv) 1-t-butyloxycarbonyl-2-[2R or S,3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]hexahydropyridazine, (xxxv) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-3cyano-L-alanyl)amino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4 ,4 ,O]decane.
:The structures of representative compounds of the invention are as follows:
NH
2 *0 H OH 0 *N NN)JOBut H O 6H 2 Ph H
NH
2 0 IH 0 0 N N N,N N 'J 0Bu IN:\L111Z]205790AU:SAK 0 0 H OH H od 0 NCH 2 Ph 0 -Jl, But 0 #5 0 0 0S 0
NH
2 0 0 H OH N N
N
CO &6 H0 CH 2 Ph 000 0 ut The compound of formula (IC) or (ID) can exist in optically isomeric forms and the present invention includes within its scope all these forms in all proportions including all diastereoisomers and racemic mixtures, The compounds of formula may be prepared by known methods for the synthesis of substituted amines. For example, a compound of the formula
R
4 R D NN BOCY R6 R2 may be prepared by reaction of an amine of the formiula
'I
t~t [N:\L113Z1205790AU:SAK WO 93/18006 PCr/A U93/00103 R D I II
HN-N--B-C-Y
R
2 with a substituted alkyl halide of the formula
R
4 RS-C--Hal
R
6 Compounds of formula (IA) may be prepared by reacting an amine of formula RR 0 N-N
HY
with a halide of formula Compounds of formula (IB) may be prepared by reacting an amine of formula Ri1 O I II H NC \y Rz with a halide of formula
I
N' cs of f (AHal The compounds of formula (IC) can compound of formula (II)
R
21
O
1 \C-R22
X-N--C-C-C-R
22 I I I R H H be prepared by reacting a
(II)
wherein X, R 2 1
R
2 2 and R have the significance given earlier, with a compound of formula (111) WO 93/18006 PCr/U93/0103 16
R
23
O
I II H-N-N-C-Y (Ill)
R
2 4 wherein R 2 3
R
2 4 and Y have the significance given earlier.
A compound of formula (ID) may be obtained from a compound of formula (IC) by oxidation in accordance with known methods of oxidative transformations of alcohols to ketones.
A compound of formula (ID) may be also be obtained by reacting a compound of formula (lla) R O x,N Hal (Ila)
R
2 1 R2 wherein X, R, R21 and R22 are as previously defined and Hal is a group selected from -Cl, -Br, -1 or -OS(0) 2 R, with a compound of formula (III).
The methods of preparation of compounds of formula (IC) and (ID) may be represented by the following general Schemes I to 3. In the Schemes presented herein, the following abbreviations are made: AA refers to amino acid or amino acid residue; AcCN refers to acetonitrile; BOP refers to benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate; CBZ refers to carbobenzoxy; CDI refers to N,N'carbonyldiimidazole; DMF refers to dimethylformamide; DMSO refers to dimethylsulfoxide; HPT refers to 1-hydroxybenzotriazole; Py refers to pyridine; Py.xSO 3 refers to the pyridine complex of sulfur trioxide; RT refers to room temperature and L-Val refers to L-valine.
17 SCHEME I
R
21 0
R
23 0 X-N-C-C-C-R22
H-N-N--C-Y
I I I II
R
21
R
22 R24 N NL/'N AlC I I I K 0HlR 2 3 0 SCHEME 2
R
21
R
22
R
23 0 X-NC--C-CHaI+ H--N--N-C-Y R Fl s* a.
a. *6 a, a a a a a a a a. a .a.a a a a.
a.
a a a.
a.
a a a a
R
21
R
22
R
24 N Alc I I I K OH R 2 3 0 [N :\L113Z]205790AU:SAK WO 93/18006 WO 9318006PCT/AU93/00103 18 SCHEME 3 0 Z OH CDI, dioxane (iii) acid 0 Z'J AA 01- R OH R23 0 N N I CBZN NWN>Y R21 R22 R24
H
2 Pd/C R OH R23 0 H' N Y R21 RZ2 K24 SOP, HBT,(iPr) 2 NEtIDMF O OH R23 0 R21 R22 R24 DMSO, PYYxSO 3 Et 3
N
O R 0 R23 0 Zj~ N N R21 R2-1 2 The reaction schemes illustrated can be carried out by generally known methods as exemplified hereinafter. The amino acids or peptide mimics for use in the synthesis of compounds of this Invention are generally commercially available or may be prepared by conventional methods of organic chemistry.
Synthetic routes to the Intermediates (Ila) and (1ll) are readily WO 93/18006 PCTr/AU93/0103 19 available. The chiral aminoalkylepoxides of formula (11) can be obtained using methods described in the following: Evans, et al., J. Org. Chem., .50, 4615-4625 (1985); Luly, et al., J. Org. Chem., 52, 1487-1492 (1987); Handa, et al., European Patent Application No. 346,847-A2 (1989) and Marshall, et al., International Patent Application No W091/08221.
The N-protected aminoalkyl halomethylketones (lla) are commercially o1 available or can be prepared using methods described in: Rich, et al., J. Med. Chem., 33, 1285-1288 (1990) and Reference above.
The hydrazide intermediates (III) can be obtained using known methods such as those described in the following: Dutta, et al., J. Chem. Soc. Perkin Trans. I, (1975) 1712- 1720, Ghali, et al., J. O._rgChem., 46, 5413-5414 (1981), Gante, Synthesis (1989) 405-413 and Houben-Weyl's Methoden der Organische Chemie, vol. 16a, Part 1, pp 421-855; Georg Thieme Verlag, Stuttgart (1990) A second embodiment of the invention is directed to pharmaceutical compositions comprising a compound of formula together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients.
In a third embodiment of the invention there is provided a method for inhibiting retroviral proteases in a mammal in need of such inhibition, comprising administering to the mammal an effective amount of a compound of the first embodiment or of a composition of the second embodiment. In one form of the third embodiment, there is provided a method for the treatment or prophylaxis of HIV viral infections such as AIDS.
For inhibiting retroviral proteases or the treatment of HIV viral infections, a composition of the second embodiment may be administered orally, topically, parenterally, e.g. by injection and by intra-arterial infusion, rectally or by inhalation spray.
For oral administration, the pharmaceutical composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, granules, suspensions, emulsions, syrups and tinctures. Slow-release, or delayedrelease, forms may also be prepared, for example in the form of coated WO 93/18006 PC/AU93/00103 particles, multi-layer tablets or microgranules.
Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable o0 diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitabie coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
The emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.
For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion.
WO 93/18006 PCT/AU93/00103 21 The pharmaceutical composition may contain pharmaceutically acceptable binders, diluents, disintegrating agents, preservatives, lubricants, dispersing agents, suspending agents and/or emulsifying agents as exemplified above, For parenteral administration, the compound of formula I or its salt may be prepared in sterile aqueous or oleaginous solution or suspension.
Suitable mono-toxic parenterally acceptable diluents or solvents include water, Ringer's solution, Isotonic salt solution, 1,3-butanediol, ethanol, propylene glycol or polyethylene glycols In mixtures with water. Aqueous solutions or suspensions may further comprise one or more buffering agents.
Suitable buffering agents include sodium acetate, sodium citrate, sodium borate or sodium tartrate, for example.
For rectal administration, the compound of formula I is suitably administered in the form of an enema or suppository. A suitable suppository may be prepared by mixing the active substance with a non-irritating excipient which is solid at ordinary temperatures but which will melt in the rectum. Suitable such materials are cocoa butter and polyethylene glycols.
Suitable enemas may comprise agents as exemplified above with reference to forms for topical administration.
Suitably, an inhalation spray comprising a compound of formula I will be in the form of a solution, suspension or emulsion as exemplified above.
The inhalation spray composition may further comprise an inhalable propellant of low toxicity. Suitable propellants include carbon dioxide or nitrous oxide.
The dosage form of the ,ompound of formula I will comprise from 0.01% to 99% by weight of the active substance. Usually, dosage forms according to the Invention will comprise from 0.1% to about 10% by weight of the active substance.
The compound of formula I may be administered together or sequentially with 1 or more other active substances known or believed to be effective for the treatment of HIV viral infections. Examples of such other active substances include AZT and acyclovir.
BEST MODE OF CARRYING OUT THE INVFNTQIO Methods for the preparation of compounds of formula (IC) are described In the following Schemes la and 2a: SCHEM~Aa PhCH 2 0
X-N-C-C-C-H
I I II H H HH
R
27 0 1 1
H-N-N-C-Y
J(i) iPrOH; 60-90'C;12 hr Yield 70-90%, or (ii) A1 2 0 3 ether; RT; 12-24hr; Yield 30-45%
CH
2 Ph R 2 8 I I i H OH R 2 7 0 0 0000 0* 0* *0 OS 00 0 0 0 0 00 0 000 00 00 0 0 0 0 00 0 0@ 0 0000 0*00 0* 00 00** 0* 0 00 0 0 0 0000
CH
2 Ph HNCC0Hwa R2 7 0 1 1
H-N-N-C-Y
S(i) Nal/OMP or AcCUN; I hr; RT; (Hi) NaHCO 3 or tertiary arn~ne: 2-12 hr; RT (111) NaBH 4 30 min; RT
CH
2 Ph R 28 X\N N c,Y I 1 1 H OH R27 Q IN \t.IfB7120579OAU:SAK WO 93/18006 PCT/AU93/00103 23 Scheme 3a presents an alternative method of preparation of compounds of formula (IC) and (ID): SCHEME 3a
OH
ICDI, dioxane; RT; 30 min LICH, L-Val In water (iii) pH=2; Yield 72% 0 N Va'0H QQ0 H OH Pri 0 I I I
CH
2 Ph H
H
2 10% Pd/C,methanol RT; Yield -100% H OH Pr' 0 N N> H'W I'N' 01ut
CH
2 Ph H BOP, HBT, TPr) 2 Et In DMF RT, 12 Hrs;, Yield 79% 0 H OH Pri0 0 6 Val. N N) OBut DMSO, PY-XSO 3 Et 3
N
min; RT Yield 72% Compositions of the second embodiment may be prepared by means WO 93/18006 PC/AU93/00103 24 known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and mixing of the compound of formula together with the selected excipient(s), carrier(s), adjuvant(s) and/or diluent(s).
In the method for the treatment of HIV viral infections in accordance with the third embodiment of the invention, a compound of the first embodiment will usually be administered orally or by injection. A suitable treatment may consist of the administration of a single dose or multiple doses of the compound of formula or of a composition of the second embodiment. Usually, the treatment will consist of administering from one to five doses daily of the compound of formula for a period of from one day to several years, up to the lifetime of the patient. Most usually, the treatment will consist of the administration of the compound of formula for a period of from one day to one year.
The administered dosage of the compound of formula I can vary and depends on several factors, such as the condition of the patient. Dosages will range from 0.01mg to 200 mg per kg. Usually, the dose of the active substance will be from 0.01mg to 10mg per kg of body weight.
Examples of dosage forms in accordance with the invention are as follows: 1. Tablet Compound of formula I Starch Lactose Gelatin Magnesium stearate 2. Ca2sule Compound of formula I Glycerol Distilled water Saccharin Methyl Paraben Polyvinylpyrrolidone 0.01 to 20 mg, generally 0.1 to 10 to 20 mg 100 to 250 mg 0 to 5 mg 0 to 5 mg 0.01 to 20 mg, generally 0.1 to 100 to 200 mg 100 to 200 mg 0 to 2 mg 1 to 2 mg 0 to 2 mg WO 93/18006 PCT/AU93/00103 3. Injectable solution Compound of formula I Sodium chloride Potassium chloride Calcium chloride Water for injection, q.s. to 4. Elixir Compound of formula I 0.01 to 20 mg, generally 0.1 to 8.5 mg 3 mg 4.8 mg 10 ml 0.
1 Sucrose 1 Glycerol 2r Carboxymethylcellulose 2( Cherry flavour 2 Water q.
EXAMPLES
Examples of compounds of formula formula (IV) presented in Table 1: 01 to 20 mg, generally 0.1 to )mg )0 mg il )mg mg s. to 10 ml are those compounds of
CH
2 Ph R 28 X N ^N Y X I I Y H OH R 27
O
TABLE 1 X R27
CBZ-
Example No.
(8) (23) t-BuJ- QC-Asnti t-BuO- QC-Asn- t-BuO- 2b.A. (23A) QC-Asn- t-BuO- PC-r/AU93/00103 WO 93/18006 PTA9/00 (9) (12) (13) 011) (3) (4) (2) (16) (18) QC-Val- QC-Gln- QC-Thr- PC-Vat- QC-Asn- QC-Asn- 0t-Asn- OC-Val- PC-Val- QC-Asnt-BuOt-BuOt-BuOt-BuOt-BuOt-Buo- (2-PCNH)Pht-BuOt-BuOt-BuOi-Pri-Pri-Pri-Pr- 0 QC-Asn- QC-Asn- (26) QC-Asn- (27) PIC-Asn- QC-Asn- (32) QC-Asn- BZ-Asn- (37) QC-Asn- (38) CC-CNAla-
CH,
P h i-Pri-Pri-Pr- BzIcyclohexyl i-Prt-BuOt-But-BuN Ht-Buot-BuOt-BuOt-BuOt-BuOt-BuO- -(CF1 2 4 27 In the above Table, CBZ refers to benzyloxycarbonyl (phenylmethoxycarbonyl); QC refers to quinoline-2-carbonyl; PC refers to 2-pyridinemethoxycarbonyl; Asn refers to asparagine; Val refers to valine; Gin refers to glutamine and Thr refers to threonine, BZ refers to benzoyl, PIC refers to picolinyl and CNAla refers to 3-cyano-L-alanine.
These compounds have the ability to inhibit HIV-1 and HIV-2 proteases and anti- HIV antiviral properties at the concentration from 10 nM to 100 M in acutely infected MT 2 and peripheral blood lymphocytes. Compounds No. 2, 7B, 8 and 17 have shown a similar or increased ability to inhibit HIV to AZT (azidothymidine), with lower toxicity to the cells.
The HIV protease-inhibiting activity of representative compounds of the present invention has been tested by known methods (Brinkworth, et al., Biochem. Biophys.
Res. Commun. 176, 241, (1991); McLeod, et al., Bioorganic Medicinal Chemistry Letters (1991) 653-658). In this test, a number of compounds described in the examples hereinabove have been found to inhibit HIV-1 protease with half-maximal inhibition occurring at inhibitor concentrations (IC 50 of from sub nanomolar range to micromolar range, more typically, 3nM to The results of the above test compounds are presented in Table 2: TABLE IV Protease-inhibiting Activity of Compounds of Formula (IV) Compound No ICso (nM) 2a 5.4 0.54 7A 7.3 ±0.7 7B 10 3300 650 11 12.5 3.2 20 The antiviral activity of representative compounds of the present invention has been determined at the Antivirals Laboratory, Fairfield Hospital, Fairfield, Victoria, Australia. In this test a stock solution of each compound was made in DMSO, then diluted in culture medium (RF 10) to 2x the final concentration required for test.
The final concentration of DMSO was 1% or below. Approximately 250,000 continuous lymphocytes of human origin (MT2 cells) or 750,000 human peripheral blood lymphocytes (PBLs) were exposed to dilutions of each test compound, then immediately infected with Human Immunodeficiency Virus type 1 (HIV) strain 237228 (a clinical isolate obtained from a human source). The infectivity titers were expressed as tissue culture 50% infective dose (TCID 5 0 per ml) with 1 TCID 5 0 tK v h^ !N:\LIBZ]205790AU:SAK WO 93/18006 PCr~/A U93/0103 28 corresponding to the amount of supernatant required to infect 50% of the replicate cell cultures. The 250 and 200 TCID 5 0 were used for MT2 and PBL cells respectively. The cell/drug/virus mixture was then incubated at 37 0
C/CO
2 in a 24-well microtitre plate. Fresh amounts of the appropriate dilution of each drug were added to both MT2 and PBL cultures at day 3. At day 6, the extent of HIV-specific cytopathic effects (CPE) associated with each concentration of test compound in each of the cultures was rated accordi'o to the following scale: MT2 cells PBLs 75-100% of cells showing good CPE
CPE
50-75% of cells showing moderate CPE
CPE
25-50% of cells showing 1 low CPE
CPE
1 5-25% of cells showing trace: minimal CPE
CPE
less than 5% CPE Negative: no CPE Negative: no CPE The activity of the compounds at each concentration was also assessed by their ability to inhibit viron-associated reverse transcriptase (RT) activity in the culture supernates. At the time of rating of CPE, supernatant fluids from each well were removed and RT activity measured using a standard assay. CPE ratings of negative, (in MT2 cells) or trace (in PBLs), with greater than 95% inhibition of RT activity, was considered to represent IC 1 0 0 (the concentration of compound at which the virus replication is inhibited). Control cultures included in each test were: HIV-infected cells in the absence of test compound.
Uninfected cells in the absence of tested compound.
Cell toxicity control consisting of uninfected cells treated with dilutions of test compound.
At the conclusion of each experiment, viable cells in these cultures, WO 93/18006 PCr/AU93/00103 29 is determined by tryptan blue exclusion, were compared with the counts obtained in above. Only concentrations which were non-toxic (not resulting in viable cell counts significantly reduced to those found in were used in determining the antiviral index (Al) of each test compound. The ability of compounds 1-20 to block the spread of acute HIV infection in lymphocytic cell lines is shown in Table 3 Table 3: Anti-HIV-1 Antiviral Properties of Compounds 1-20.
No.
1.
2a.
2b.
2b.A.
3.
4.
6.
7A.
7B.
8.
9: 11.
12.
13.
14.
16.
17.
18.
19.
MT2 Cells
IC
1 0 0 (pM) Al 10(a) 1 0.1 50 0.1 50 0.01(b) 100 1 5 1 10 1 10 1 5 1 50 0.1 200 0.1 100 5 4 25 1 1 >10 1 10 1 50 1 50 1 100 1 100 0.1 100 1 10 1 10 1 10 PBL Cells
IC
1 0 0 (pM) nd 0.1 0.1 0.01 1 1 1 1 1 1 0.1 0.1 nd nd nd nd 1 1 1 1 0.1 1 0.1 1 Al 100 100 1000 200 100 200 1 200 150 200
IC
5 0
IC
8 0 nd not done.
In order to further illustrate the present invention, the following specific examples are given, it being understood that these are intended as illustrative only and are in no way limitative of the invention.
WO 93/18006 PCT/U93/00103 In these examples, melting points were taken on a hot stage apparatus and are uncorrected. Proton NMR spectra were recorded at 100 MHz or 300MHz on Perkin Elmer R32 or Bruker EM 300 spectrometers, respectively.
Chemical shifts are ppm downfield from tetramethylsilane. Molecular weights of the compounds presented in Examples 1 to 23 were confirmed by electrospray mass spectrometry analysis, performed in the Department of Chemistry at La Trobe University, Melbourne. Thin layer chromotography (TLC) was performed on silica gel 60-F254 plates (Merck). Compounds were visualized by ultraviolet light and/or 2% aqueous potassium permanganate solution. The compositions (by volume) of the TLC solvent system were as follows: hexane/ethyl acetate 4:1; hexane/ethyl acetate 3:2; (C) ethyl acetate; chloroform/methanol 23:2.
EXAMPLE 1 t-Butyl 3-isoproDvl-[(2R.3S)-2-hvdroxy-3-(Dhenvlmethoxvcarbonyl)amino-4ohenvlbutvllcabazate Step A: t-Butyl 3-isopropyl carbazate: The title compound can be prepared by method of Dutta et al., J.C.S. Perkin 1975, 1712-1720 or by the following procedure: A mixture of 13.2 g (0.1 mol) of t-butyl carbazate and 6 g (0.103 mol) of acetone and 12.5 g (0.1 mol) of anhydrous magnesium sulfate in 100 ml of methylene chloride was stirred for 12 hr. at room temperature. After removal of the drying agent by filtration the filtrate was evaporated to dryness under reduced pressure to give 16.9 g (98% yield) of corresponding hydrazone melting 104-105°C after crystallization from cyclohexane. To a suspension of 2.04 g (0.094 mol) of lithium borohydride in 100 ml of dry THF, 12 ml (0.094 mol) of chlorotrimethylsilane was added under nitrogen at room temperature. After 30 min. of stirring, 13.45 g (0.078 mol) of hydrazone was slowly added at room temperature and stirring was continued for 2 hr. Then 50 ml of methanol was carefully added and the mixture was evaporated to dryness under reduced pressure.
The residue was partitioned between ether (150 ml) and water (50 ml), The organic phase was dried over anhydrous magnesium sulfate and filtered off.
Dry hydrogen chloride was passed through the filtrate and the white solid formed was removed by filtration, washed with a fresh portion of ether and dried to give 10.5 g of hydrochloride salt of the title compound. This was transformed into a free base by partition between hexane (150 ml) and aqueous potassiun hydroxide. Yield 8.3 g Step, t-Buty. 3-Isopropyl-[(2R,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutylicarbazate: A mixture of 0.15 g (0.45 mmol) N-CBZ-L-phenylalanine chloromethyl ketone (1(S)-(phenylmethoxycarbonylamino)-2-' phenylethyl chloromethyl ketone) and 1 ml of a saturated solution of sodium iodide in dry DMF was stirred for 15 min. at room temperature. To this, 0.074 g (0.47 mmol) of tbutyl 3-isopropyl carbazate was added followed by 0.095 g (1.13 mmol) of sodium bicarbonate. After 6 hours of stirring at room temperature, 0.051 g (1.3 mmol) of sodium borohydride was added and stirring was continued for an additional 30 min. The solution was diluted to 30 ml with ethyl acetate and washed with 2% aqueous potassium bisulfate solution, water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purificaton of the residue by flash chromatography (silica gel; hexane/ethyl acetate 20:5) gave the title compound, melting at 118 119.5°C, in 49% yield; R(A)=0.11; R =0.47; NMR (CDC1 3 1.0 6H, isopropyl CH 3 1.44 9H, t-butyl CH3); 2.62 2H, butyl CH 2 2.75 3.2 3H, butyl CH-3, CH2-4; 3.47 1H, isopropyl CH); 3.89 1H, butyl CH-2); 4.44 (broad s, 1H, OH); 4.6 (broad m, 1H, NH); 5.03 2H, methoxy CH 2 5.3 (broad s, 1H, carbazate NH); 7.23 aromatic).
EXAMPLE2 t-Butyl 3-isopropyl-3-[(2R.3S)-2-hydroxy-3-(N-quinaldyl-L-valvy)amio-4-phenylbutyllearbazate 20 Step A: N-Quinaldyl-L-Valine: A mixture of 0.62 g (3.6 mmol) of quinaldic acid and 0.61 g (3.76 mmol) of 1,1'-carbonyldiimidazole in 1 ml of dry 1,4-dioxane was stirred Sfor 30 min at room temperature. To this, a solution of 0.43 g (3.7 mmol) of L-valine and 0.155g (3.7 mmol) of lithium hydroxide in 1 ml of water was added and the resulting mixture was stirred vigorously at room temperature for about 4 hours The mixture was diluted to 10 ml with water, cooled (ice-water bath), then acidified with IN hydrochloric acid to pH about 3 and allowed to stand for 2 hours at 4°C. The crystals which formed were removed by filtration, washed three times with 5 ml of cold water and dried under high vacuum over phosphorus pentoxide to give 0.75 g of the product. Yield 76%, melting point 134 -136 0 C, NMR (DMSO-d 6 1.03 6H, val CH3); 2.3 1H, val CH-P); 3.35 (broad s, 1H, OH); 4.49 1H, val CH-a); 7.5 8.3 5H, aromatic); 8.5 8.76 2H, aromatic, NH).
Step B: t-Butyl 3-isopropyl-3-[(2R,3S)-3-amino-2-hydroxy-4-pheniylbutyl]carbazate: To a chilled solution of 0.113 g (0.24 nmmol) of the product of Example 1 in 2 ml of methanol was added 0.1 g of 10% palladium on activated carbon under nitrogen, followed by 0.1 g of sodium borohydride. The reaction was allowed to warm to room temperature and stir for 1 hour, then catalyst was removed by filtration and washed with fresh portion of methanol. The combined filtrates were treated with 1 ml of 0.1 N aqueous solution of hydrochloric acid and evaporated to dryness under reduced pressure.
The residue was treated with 5 ml of 0.1 N potassium hydroxide and the product was S '740 taken up with 30 ml of diethyl ether. The organic phase was washed with saturated
\V
IN:%LIfZ]205790AU:CB 999**9 9 9* 99 .9 99 9* 9 9 *9 9 9..
.9 9.
9 9 9 9 9.
9 9 9 9 9.9.
99 9* 9.
99..
9 9, .9 9.
9.
9 9 9 9.9.
V.
32 aqueous sodium chloride solutio.-i, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 0.0797 g (99% yield) of thle Step B product, which was used in the next step without further purification.
~Step t-Butyl 3-isopropyl-3-[(2R,3S)-2-hydroxy-3-(N-quinaldyl-L-vaiyl)amino-4phenylbutyllcarbazate: To a mixture of 0.0643 g (0.24 inmol) of the acid from Step A, 0.0797 g (0.236 minol) of the the amine from Step 13, 0.032 g (0.24 minol) of 1-hydroxybenzotriazole in 0.5 ml of anhydrous DMF was added 0.071 g (0.24 minol) of 1. -(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide. After stirring overnight at r~mtemperature thle mixture was diluted to 30 ml with ethyl acetate and washed successively with water, 5 aqueous sodium bicarbonate, 2% aqueous potassium bisulfate solution, and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, hexane/ethyl acetate 3:2) gave 0.091 g yield) of the title compound, melting at 186 189'C: Rf (13) =0.19; Rf 16 0.83; NMR (CDCI 3 1.0 (in, 12H-, val and isopropyl CH- 3 1.71 9H1, t-butyl CH 3 2.3 (in, 111, val CH-B); 2.5 3.27 (in, 3H1, butyl CH-3, CH 2 3.5 (in, 1H1, isopropyl 4.31 (mn, 211, val CH-cx, 5.43 (broad s, 1H, carbazate NHl); 6.22 (broad d, 1H, butyl NH); 6.7 -8.73 (in, 1211, aromatic, NH).
EXAMPLE 3 20 utyl 3-ispropy-3{(2R, 3S)-2-ltydroxy-3-N-giinaidYl-L-a prgnlamino-4yllcaazate Stp.A N-Quinaidyl-L-asparagine: When L-asparagine was substituted for L-valine in Step A of Example 2, the identical process afforded the title compound, melting at 200 2031 0 C, in 85% yield, NMR (DMSO-d 6 3.0 (in, 2H1, asn CU 2 5.0 (in, 1H-, asn CH-C*C 25 6.3 (broad s, 1H-, 6.55 (broad s, 1H1, NI- 2 7.3 (broad s, 114, NH 2 7.55 8.6 (in, 61-, aromatic); 9.22 1H1, NI-).
Step.B: t-Butyl 3-isopropyl-3+{2R, 3S)-2-htydroxy-3-(N-quinaldyl-L-asparaginlyl)anuino-4-phienylbutyllcarbazatc: To a stirred solution of the product of Step A 111 g; 0.386 mmol), the product of Example 2, Step B3(0. 13022 g; 0.386 inmol), benzotriazol-1- .30 yloxytris(diinethyl-ainino)phosphoniuin hexafluorophosphate (0.205 g; 0.46 miol) and Ihydroxybenzotriazole (0.052 g; 0.384 minol) in 1 ml of anhydrous DMF was added, N,N-diisopropylethiylamine (0.24 ml; 1.38 inmol). After stirring for 12 hours at room temperature thle reaction was diluted to 30 ml with ethyl acetate and washed with water, 2% potassium bisulfate, 5% sodium bicarbonate and saturated aqueous sodium chloride 36 solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, ethyl acetate) gave 0. 152 g (65 yield) of the title product melting at 109 I 14*C; Rf(C) 0.36; Rf(D) 0.37; NMR (CDCI 3 1.0 (in, 61-I, val, isopropyl Cl1I 3 1.42 911, tbutyl C113); 2.5 3.1 (mn, 7H1, asn C! 2 buOy C14 2 CH-3); 3.44 (in, 111, isopropyl IN:\LIBZ]205790AU:SAK 33 4.21 (in, 1H, butyl 4.55 1H-, OH); 4.94 (in, 111, asn 5.4 -6.
(in, 3 H, amidle); 6.7 8.4 (in, IllIH, aromatic); 9.25 (in, lI H, NH).
EXAMP~LE 6 asparaginyl~amino-4-phnybuvl-2ispropyl-hydrazine S-tp..A: (2-Pyridyl)methoxycarbonylanthraniilic acid: Phosgene was bubbled thr~ough a solution of 10 g (66 inmol) of methylanthranilate in 15 ml of anhydrous toluene for 2 hours at reflux. Then the solvent was distilled off under reduced pressure to give 11.7 g (100%) of 2-methioxycarboniylphenylisocvanate; NMR (CDCI 3 3.89 3H1, l0 CH1 3 7.0 7.63 (in, 3H, phenyl 8.0 (dd, 1H1, phenyl 11-6). This was converted to the title compound, in 34% overall yield, by condensation with an equimolar amount of 2-pyridylcarbinol followed by saponification of the resulting ester with 1 N sodium hydroxide and acidification of the reaction mixture to pH 4. The crude product was purified by crystallization from ethyl acetate; melting point 172 175'C; NMR 1(DMSO-d 6 5.2 211, methoxy Gi4 2 6.8 8.8 (nm, 911, aromatic, NH); 10.8 (broad s, 114, OH-).
&pI: 2-[(2R,3S)-2-liydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]- 2-isopropyl-liydrazine: Hydrogen chloride gas was bubbled through the solution of 0. 1 g 165 mmiol) of product of Example 3 in 10 ml of 1% solution of methanol in methylene 20 chloride for 30 min at room temperature. After washing the excess of HG! with nitrogen the solvent was removed under reduced pressure to give 0.089 g (100%) of the title .9 compound as a whitc solid.
1-(2-pyridyl)rncthoxycarboiiylantliranilyl-2-[(2R,3S)-2-lhydroxy3..(Nquiinaldyl-L-asparaginyl)arniio-4-phenylbujtyl]-2-isopropyl-liydraziiie: Coupling the products of Step A and B, using the general procedure outlined in Example 3, Step B, gave the title compound in 24% yield, after purification by column chromatography (silica :gel, ethyl acetate); melting point 96 112 Rf 13 Rr 36; NMR
(CDCI
3 1.18 (mn, 614I, isopropyl Cl- 3 1.8 3.4 (mn, 8H, asn CH- 2 butyl CH 2 CH-3, 3.6 (mn, 114, isopropyl 4.2 (mn, lH, butyl CH-3); 4.5 5.18 (in, 211, 30 asn CH-cx, hydrazide NH); 5.35 2H-, inethoxy Cl- 2 5.3 6.5 (broad mn, 2H-, asn
NH
2 6.8 8.8 (in, 20H-, aromatic, butyl 9.14 (in, IH, asn NH); 10.36 111' anthr. NI-I).
EXAMPLE t-Btyl3-ioprpyl3-r2-oo~3S)-N-qina~jyL ptainyl)ainino-4- plienylbutylabzt To a mixture of 0,0533 g (0.088 ininol) of the product of Example 3 and 0.049 g (0.31 inmol) of sulfur trioxide pyridine complex in I mal of anhydrous DMS0 0.043 ml (0.31 inmol) of triethylainine was added. After stirring for 45 min at room temperature the reaction mixture was poured on ice and allowed to wvarm to room temperature. The precipitate which formed was removed by filtration, washed with wvater and dried IN:ALIBI1205790AUXC1 34 overnight in2 vacuo to give 0.044 g (83% yield) of the title compound which was further purified by crystallization from the aqueous methanol; melting point =146 150'C; Rt 0.32; NMR (CDCI 3 1.0 6H, isopropyl Cl- 3 1.38 9H-, t-butyl Cl- 3 2.5 3.3 (in, 511, asn Gil 2 butyl Gil 2 isopropyl CHI); 3.7 2H, butyl Gil 2 4.6 5.3 (in, 6 2H1, asn GCH, butyl CH-3); 5.6 (broad s, 1H-, NH); 6.09 (broad mn, 2H1, 2 x NH); 6.9 8.4 (in, 12 H1, aromatic, 9.2 (broad d, 1H-, asn NiH).
EXAMPLE-6 t-Butyl -3-(-Inetdhyl-3-phenyl-Propcn-3-yl)-3-[(2R and S, 3S')-2-iydroxy-3-(PheY-L niethoxycarbonyl)ainino hnylbuyllerazate Stp.A: ,2-Epoxy-3-phiyliniethioxycarbonylarnino-4-pheinylbutanc: To the solution of 6 g (18 minol) of N-CBZ-L-phenylalanine chlorornethyl. ketone (phienylmethioxycarbonylamino)-2-phenylethiyI chioromethyl ketone) in 30 ml of methanolic tetrahydrofuran was added 0.68 g of sodium borohydride. After stirring for min at room temperature the mixture was carefully acidified with IN hydrochloric acid 16 and evaporated to dryness under reduced pressure. The residue was diluted to 50 ml with methylene chloride, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, Evaporation gave 6.02 g (100%) of chloro-2-hydroxy-3-phenylmethioxycarbonylamiino-4-phenylbutane, as a white solid. This was dissolved in 50 ml of isopropanol and 9 ml of 2N methanolic potassium hydroxide S: 20 was added at room temperature. After stirring for I hour at room temperature tle solvent was removed under reduced pressure and the residue was partitioned between 50 mlI of ethyl acetate and 20 ml of water, The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness to give 5.3 g (99% yield) of the title compound as thle predominantly 2(S) stereoisomer as 26 determined from relative integration of erythro-NCH1 (3.74 ppm; 72%) and threo-NCH NMR (GDCI 3 2.42 3.17 (in, 5H-, butane GI-2-1,-4, CH-2); 3.74 (mn, 0,72H1, butane 4.2 (mn, 0.28H, butane 4.73 (broad inl, lIH, NH); 5.08 (s, 7: 2H1, methoxy CI-2); 7.3 (mn, 101-, aromatic).
Sep.LB: t-Butyl 3-(1-rncthyl-3-phenylpropcn-2-yl)carbazatc: This compound was 30 prepared by the method of Ghali et al. Org. Chemn., 1981, 4-6, 5413 5414) in about overall yield, from trans-4-phienyl-3-buten-2-one and t-butyl carbazate, after crystallization of the crude product from hexane; melting point 76 79*C; NMR
(CDCI
3 1.24 (dI, 3H1, Cl-I 3 1.45 9H-, t-butyl Cl-I 3 3.78 (inl, 2H-, propenyl Cl--, carbazate 5.8 6.29 (in, 2H1, carbazate NH-2, propenyl GH-2); 6.53 111, 36 propenyl 7.3 (mn, 511, aromatic).
Stop...: t-Butyl 3-(l-inietliyl-3-phcenylpropcni-3-yl1)-3-[(2R and S, 3S)-2- hydroxy-3- (plhenyhnetlioxycarbonyl)ainino-4-plicinylb~utyllcarbazates: 0.57 g of epoxide from Step A in about 15 ml of anhydrous ether was added at room temperature to a vigorously stirred suspension of 8 g of alumina Merck 1) impregnatedl with 1 g (3.81 inmol) of 46 the product of Step B. The stirring was continued for 16 hours and the catalyst was I N: \L1ZI2057W)AU:SAK removed by filtration and washed with ethyl acetate (3 x 25 ml). The combined filtrates were evaporated to dryness under reduced pressure and thle residue was separated and purified by column chromatography (silica gel, hexane/ethyl acetate The product fractions were evaporated in yamll to give the 2R,3S isomer (0.298 g; 28%) and the 2S,3S isomer 1 g; 9 of the title compoun~d as a white solid.
Isomer 2R,3S: mneiting point 101 104'C; Rf 0.19; NMR (CDCI 3 1.27 (dd, 3H, Cl- 3 1.42 9H, t-butyl Cl- 3 2.67 (in, 2H-, butyl CI- 2 3.0 (in, 2H-, butyl
CI-
2 3.5 (in, 2H, propenyl butyl 3.91 (in, 1H-, butyl CH-2); 4.4, 4.82, 5.38 (broad multiplets, 3 x amnide NH-, OH- 5.0 214, miethoxy CU 2 6.09 (dd, 1H, propenyl CH-2); 6.5 1H, propenyl CH-3); 7.22 (in, 1511, aromatic).
Isomer 2S,3S: inelting point 128 130*C; Rf 0.26; NMR (CDCl3) 1.22 (in, 3H-, CH 3 1.4 9H-, t-butyl CI-3); 2.55 (broad mn, 2H, butyl C112-1); 2.95 2H1, butyl CI- 2 3.5 (in, 311, propenyl CH-2, butyl 4.44 (in, 1H-, OH); 5.05 (in, 2H-, methoxy C12); 5.34 (in, 2H-, NH); 6.08 (dd, 1-1, propenyl CH-2); 6.5 (di, 1H, propenyl CH-3); 7.3 (in, 15H-, aromatic).
EXAMLEL -7 t-Butyl 3-(1 -jtlY (R3)2lyrQy--(-uu~y-L a~aainylhimino-4-phenylhuybiiriz see**: Step t-Butyl 3-(1-niethyl-3-phcniylpropyl)-3-[(2R,3S)-2-hydroxy-3-amino-4- 20 phciiylbutyllcarbazate: This was prepared in 98% yield by hydrogenolysis of the isomer 2R,3S of the product of Example 6, Step C, performed as described in Example 2, Step B, as white solid.
0 :6060 Ste t-Butyl 3-(1 -iznthiyl-3-phicnylpropyl)-3-[(2R,3S)-2-liydroxy-3-(N-qulinaldyl- L-asparaginyl)amnino-4- phenylbutyll-carbazate: Thle condensation of the amine from Step A (0.0835 g; 0.195 ininol) withi N-quinaldyl-L.-asparaginc (Example 3, Step A) (0.0563 g; 0.196 minlol), under condition given in Step B of Example 3, gave 0.11 g (81% yield) of the title compound after purification by column chromatography (silica ft S ft gel, chloroformi/methanol 23:2); inciting point 141 143*C; Rf 0.53, Rf 0.38; NMR (CDCI 3 0.7 2.1 (in, 15H-, CU 3 t-butyl Cl-I 3 propyl CU1 2 01H); 2.4 30 3.26 (in, 8H-, butyl CI-2-1, asn Cl- 2 propyl CH2-3); 3.5 (in, 111I, lpropyl 4.22 (in, 1H-, butyl CH-3); 4.7 (in, 111I, carbazate NH); 4.95 (in, 1H-, asn 5.24 6.4 (in, 31-1, NH 2 NI-I); 6.5 8.5 (in, 16H-, aromatic). 9.14 11-1, asn NI-I).
EXAMP~LE 8 cis-1LU -t-Jlutoxycarbon1A4[(2 he2lidox-4pin.neloxycaronvI1 inio4pinl~iyl34-n IC SIQ)p..A: cis- I ,6-3-t-Butoxycarbonyl-3,4-diaza-bicyclo[4.41-dccanic: Cis- 1 .2-cyclohiexanediinethanol was converted quantitatively to cis- 1 ,2-cyclohexanediinethyliodide by the general method (Vogel's Textbook of Practical Organic ChIemnistry, 4th Ed. p. 393, Longman Group Limited, London 1978). An alkylation of 1 -pheniylnetioxycarbonyl-2-t-butoxycarbonyllhydrazine (Dutta et al., J Perkin I, IN, U iZI 205790A U:SAK 36 1975, 1712 1720) with cis- 1,2-cyclohexaned iiethyl iodide, in the presence of two equivalents of sodium hydride by the method of Dutta et al Perkin I, 1975, 1712 1720) gave cis- I ,6-4-phenylinethoxycarbonyl-3-t-butoxycarbonyl-3 ,4-diazahicyclo[4 .4.01decane in 24% yield, after purification on column chromatography (silica gel, hexane); melting point 68 69.5 NMR (CDCI 3 JLO 2.2 (mn, 191H, CH 2 10, CI--1,6); 3.15 (in, 2H-, CH- 2 3.82 (in, 2H-, CH 2 5.11 (in, 2H, benzyl CI-2);7.3 aromatic). This was converted to the title compound in 95% yield by hydrogenolysis, performed as described in Example 2, Step B; melting point 55 63'C; NMR (CDCI 3 2.05 (mn, 19H1, CH- 2 -7,8,9,10, C14-1,6); 2.82 (in, 2H-, CH2-5); 3.33 (in, 2H-, l0 CH2-2), 4.0 (broad s, 1H-, NH).
sw'p D: cis- 1 ,6-3-t-Butoxycarboiiyl-4-[(2RS,3S)-2-iydroxy-3-(plicnylnietlioxycaribonyl)anmino-4-p)licnylbutyl]-3,4-diaza,-bicyclo-[4.4.0]dccance: When the product of Step A was substituted for t-butyl 3-(1-inethiyl-3-phienylpropen-2-yl)carbazate in Example 6, Step C, the identical process afforded the title compound, melting at 98 103' 0 C, in 42% yield, after purification on column chromatography (silica gel, hexane/ethyl acetate 4: Rf 0.2, 0.3; Rf 0.63; NMR (CDCI 3 1.0 -2.18 19H-, decane
CH
2 10, CH-1,6, t-butoxy C143); 2.42 (in, 2111, decane CH- 2 2.78 4.5 (in, 9H-, butyl CI- 2 CI--2,3, decane CH-2-2, 01-I); 4.8 (broad mn, 114I, NH); 5.0 2H1, rnethoxy Gil 2 7.22 (mn, 10H-, aromatic).
20 E XAMPLE 9 cls-1 .6-3-t-Bitoxycarbonvyl-4-r(2RS.3S)-2-hiydro- tdn-gildyl-L-valvl)-ainino-!- Iknylbityll-3,4-diaza-bicyclo4.4.Oidecanne fr1btl3iorpl3(R3) hydroxy-3 -(pheniy liethoxycarbonyl)ainio-4- phoeny IbutylI carbazate in Example 2, thc 25 identical process afforded thle title compound in 52% yield, after purification by column chromatography (silica gel, hexane/ethyl acetate melting point 95 101 Rr (B) -0,32; Rf 0.85; NMR (CDCI 3 0.64 1.93 2511I, val C171 3 decane CT-12-7,8,9,10, GI-I-1,6, t-butoxy C113), 2.38 (mn, 31-, decane CI 2 val 2.73 3.82 (mn, 7H-, decane C11 2 butyl CI-1 2 CI-I-3); 3.82 5.35 (in, 3H1, val Gil-a, butyl CI--2, OH1); 6.0 9.0 (in, 1311, aromnatic, NI-I).
XkMPLEI cis-1 .6-3-t-flutoxvcarbony-4-[(2RS.3S-2--lyroxv-3-(N-nijnhM1i91ptnDij-I amlnio-4-p)lieuylbtityl l-.4iaza--hkydio44.Oldikcnue According to Example 2, Step B, thle product of Example 8 was converted qluantitatively to cis- I ,6-3-t-butoxycarbonyl-4-f (2RS ,3S)-2-lhydroxy-3-ainto-4pheniylbutyll-3 ,4-dia-za-bicyclo[4 .4.Ojdccane. This material was coupled with N-quinaldyl-L-asparagine (Example 3, Step A) by process identical to Example 3, Step B to give the title compound in 52 yield melting point I111 I 14T.; Rf =0.44; Rf 0.46; NMR (CDCI3) 1.0 2.2 (mn, 191.1, decane C0-12-7489,10, GH-1A6 t-butoxy CH 3 2.2 3.83 (in, 11H-, decane CI-1 2 butyl C1-12-1,4, 4.13 (mn, IN \l.I1BZI205790AL1:SAK 37 211, butyl CH-2, OH); 4.95 (in, 1H, asn CH); 5.73, 6.24 s, 211, NH 2 6.7 7.33 fm, 6H1, aromatic, NH); 7.4 8.42 (in, 6H1, aromatic); 9.2 (broad in, 111, NH).
EXAMPLEI1I cis- 6-3-t-Butoxygarbonl-4-U(RS 3S) i-y rx-3-[N-(2-pyridy1-mthoxycrbony 6 L-yalyllami o4-phenylbutyl-3 1 a-b4icyco[4.4,Qjdecum Step N-(2-Pyridyl)inethoxycarbonyl-L-valine: An equiinolar mixture of (2-pyridyl)carbinol (3 g) and methyl L-2-isocyanato-3-inethylbutanoate (4.32 g) (Fankhauser P. et al., I-elv. Chum. Acta, 1970, 2298 2313) was stirred for 12 hours at 90'C under nitrogen to give 7.32 g (100%) of N-(2-pyridyl)inethoxycarbonyl-L-valine methyl ester as a colorless syrup; NMR (CDCI 3 0.94 (in, 3H-, val Cl- 3 2.17 (in, 1H1, val CH-P); 3.71 311, OCFI 3 4.27 (in, 1H1, val CH-cL); 5.18 (s, 2H-, Cl- 2 5.43 (in, 111, NH); 6.85 -7.82 (in, 311, aromatic); 8.45 (in, 1H1, aromatic).
This was diluted to 25 ml with methanol and 6.04 ml of 5 M aqueous potassium hydroxide was added. The resulting mixture was stirred for 1 hour at reflux, then cooled 16 to room temperature and evaporated to dryness in vaguo. The residue was diluted to ml with water and wvashed with ether. The aqueous phasc was cooled in an ice bath and acidified to pH 5 and allowed to stay overnight at 4'C. The resultant precipitate was filtered off, washed with small portions of cold water (3 x 15 ml) and dried in yamj over phosphorous pentoxide to give 4.92 g (71 yield) of the title compound melting at 116 118*C; NMR (DMSO-d6) 0.93 6H-, val Cl- 3 2.1 (in, 1H-, val 3.4 (broad s, lI, 0OH); 3.93 (in, 1H-, val CH-cx); 5.13 2H-, CH 2 7.17 8.0 (in, 411, aromatic, 8.5 (in, 111, aromatic).
StepJB: cis- 1 ,6-3-t-Butoxycarbonyl-4-[(2RS,3S)-2-hiydroxy-3-[N-(2-p~yridlyl)- 25incetlioxycarbonyl-L-valyllaniiio-4-plienylbutyl]-3,4-diaza-bicyclo[4 When the product of Step A is substituted for N-quinaldyl-.L-asparagine in Example the identical process afforded the title compound, melting at 82 87'C, in 38% yield after purification under the conditions given in Example 9; Rf 0.08; Rf 0.64; Rf 0.66; NMR (CDCI 3 Ci.2 (in, 61-I, val CH-3); 1.05 2.73 (in, 221-, ~decane CI-1 2 -5 ,7,8,9,10, Cl--I,6, t-butoxy Cl- 3 val CI-4); 2.73 4.6 (in, 91-I, butyl
CH-
2 CH--2,3, decane CI- 2 val CI--ct); 5.05 5.5 (in, 311, Cl- 2 5.5 6.78 (in, 7.0 7.9 (mn, 8H-, aromatic); 8.57 (in, 1H-, aromatic).
.cis- I .6-3-t-Buitoxycarbonlyl-4-[(2RS. 3S)-2-hvydr-ox'- (-nd l L-grtiUiin 36 Step N-Quinaldyl-L-Glutaminc: When L-glutainine was substituted for L-v'aline in Step A of Example 2, the idekical process afforded the title compound, melting at 188 190'C, in 72% yield; NMR (CDCI 3 /DMSO-d 6 1:1) 2.34 (in, 41-, gin Cl- 2 4.7 (in, lIH, gin CH-c); 6.3, 7.15 (broad ss, 21-1, NI- 2 7.4 8.51 (in, 71-, aromatic OH); 8.82(d, 11-I, NI-).
IN HI20~Z~57')AU:CB 38 Stlp1R: cis-1,6-3-t-ButoxycarbonyI-4-((2RS,3S)-2-hydroxy-3-[N-quinaldyILgltmnlaio4peybtl-34daabcco440dcpe When the product of Step A is substituted for N-quinaldyl-L-asparagine in Example 10, the identical process afforded the title compound, melting at 106 115T 0 in 18% yield; Rf =0,27; R f =0.30; NMR (CDC1 3 0.8 2.7 (in, 26WI, decane CH1 2 10, CH-1,6, gin CH 2 t-butoxy CH 3 butyl 2.7-3.8 (mn, 6H, decane C2-2,5, butyl CW 2 4.36 (in, III, butyl 4.6 (mn, 1W, gin 5.1 (broad s, IIW, 5.4 (mn, III, 6.07, 6.6 d, 2H, NH 2 6.8 8.5 (mn, 111-H, aromatic); 8.8 (in, I1H, gin NH).
EXAMPLE 13 phnybtylr-3,4-daza-bicyclo[4.4.Q]dean~ Stei2 A: N-Quinaldyl-L-threunine: When L-threonine was substituted for L-valine in Step A of Example 2, the identical process afforded the title compound, melting at 184 185 0 C, in 74% yield; NMR (CDC1 3 /DMSO-d 6 1:1) 1.29 3W, CW 3 4.5 (mn, 1W1, thr CHI3); 4.68 (dd, 1II, thr CW-c); 7.4 -9.27 (mn, 9H, aromatic, acid OW, 2-OH, NW).
SIpM: cis-1,6-3-t-Butoxycarbonyl-4.{(2RS,3S)-2-hydroxy-3-(N-quinaldyl-1tlireonyl)amino-4-phenylbutyl-3,4-diaza-bicyclo[4.4.O]decane: When the product of Step A is substituted for N-quinaldyl-L-asparagine in Example 10, the identical process afforded the title compound, melting at 102 1 12 0 C, in 36% yield, Rf 0.72; Rf 20 0.61, 0.7; NMR (CDCI 3 1.0 2.75 25H-, t-butoxy CW 3 decane
CW
2 -7,8,9,10, CW-1,6, butyl CW 2 OH); 2.75 4.0 (mn, 8W, decane CW 2 butyl
CH
2 OW); 4.0 4.7 (in, 3H-, thr CH-cx, butyl CW-3); 6.5 7.4 (in, 6H, aromatic, NW); 7.4 8.5 (in, 6H, aromatic); 8.8 (im, I1H, thr NH).
E XAMPLEJ14 2--Btoxycarb nyl-3-[(2rot3S-liyypylhlyej phlbuttyll-2,3-diaza-bicyclo[2.2. 0 Skp-A: 2-t-Butoxycarbonyl-3-phenylmcthoxycarbonyl-2,3-diza-bicyclo-[2.2.
I]-
rct5ce o a stirred mixture of 1 g (4.34 iniol) of 1-phenylinethoxycarbonyl-2t-butoxycarbonylhiydrazine (Dutta et al., J.C.S, Perkin 1, 1975, 1712 1720) in 30 ml of anhydrous inethylene chloride 1.55 g (8.7 iniol) of N-bromosucciniinide was added at 0OT and the stirring was continued for I hour with external cooling in an ice bath. The reaction mixture was washed with 10% aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, drind over anhydrous magnesium sulfate and evaporated to dryness in nw The residue was redissolved in 15 ml of anhydrous 36 ether, 0.57 g (8.7 iniol) of freshly distilled cyclopentadiene was added and the mixture was allowed to stay r-1 1 hour at room temperature. Evaporation to dryness under reduced pressure gave 1')17g (54% yield) of the title product as a colorless syrup; NMR
(CDCI
3 1.44 9H, t-butoxy Cl- 3 1.7 (mn, 2H-, C11 2 5.06 (in, 2H, CH-i,4); 5.15 2H-, inethoxy CH 2 6.4 (in, 2H-, CW-5,6); 7.24 (mn, 5H-, aromatic).
IN:\LIBZ]205790AU:CB 39 SLQpD: 2-t-Butoxycarboinyl-3{(2RS,3S)-2-hydroxy-3-(plhdnyinethoxycarbony)amino-4-phenylbutyll-2,3-diaza-bicyclo[2.2.1]-hept-5-ene: A mixture of 0.2 g (0.6 inmol) of the product of Step A and 0.8 ml] of iN aqueous solution of potassium hydroxide in 5 ml of methanol was refluxed under nitrogen for 4 hours. The resulting Smixture was partially evaporated, diluted to 10 ml with water and extracted with diethyl ether (3 x 10 ml). The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography (sili-a fyel; hexane/ethyl acetate 3:2) to give 0.05 g (42% yield) of 2-t-butoxycarbonyl-2 *n icyclo[2.2.1]hept-5-ene. This material (0.049 g, 0.25 mmol) was dissolved h, of isopropanol containing 0.0744 g (0.25 mmol) of 2(R,S)-3(S)-1,2-epoxy-3..phenylmethoxycarbonylamino-4-phenylbutane (Step A of Example 6) and the resulting mixture was stirred for 15 hours at 80 5*C under nitrogen. The mixture was cooled to room temnperature, evaporated to dryness in vacuoi and purified by column chromatography (silica gel hexane/ethyl acetate 4:1) to give 0.054 g (44% yield) of title product; melting point 1.11 113*C; Rf 0.07; Rf 0.31; NMR (GDCI 3 1.43 s, 9Hl, t-butoxy CH 3 1.8 (in, 2H, GH 2 2.4 3.15 (in, 4H, butyl CI- 2 3.2 4.2 (iii, 3H, butyl, CI--2,3, OH); 4.5 5.33 (in, 5Hl, CH-1,4, methoxy Gil 2 Nil); 6.2 6.6 (in, 2H, CH-5,6); 7.2 (in, 10H-, aromatic).
EXAMPLE :2-tBtyarboyl-3-(2RS,3S)-2-ydrxy-(phenylmethoxycaronyliain-4phgnylkz.,ty1-23-diaza-j c19I22114ptane When the product of Step A of Example 14 is substituted for cis- 1 6-4-phienylmethoxy-carbonyl-3-t-butoxycarbonyl-3-4-diaza-bicyclo[4 Oldecane in Example 8, a 25 similar procesv afforded the title compound in 31 yield; melting point 119 126*C; Rf 0. 12; Rf 0. 34, 0.39; NMR (CDCl 3 1.2 2.1 (in, 1511, t-butoxy Gil 3
H
2 2.5 3.2 (in, 4H, butyl CI- 2 3.2 4.4 (in, 4H, butyl Cil-2,3, CH-1,6); 4.7 5.5 (in, 4H-, inethoxy Gil 2 NH, Oil); 7.26 (in, 101-1, aromatic).
1~EXAMIPLEI?16~ 2-:tdhitxycrbonlyl-3-[(2RS. 3 )-2-blydroxy-3-[N-(2-pyridylJ-netlio varbonyl-L a mlliaiiino4-phnylbtyl-2,3-diaza-hicyclof D t =J-hcp According to Example 2, Step B the product of Example 15 was converted quantitatively to 2-t-butoxycarbonyl-3-[(2RS, 3S)-3-aiinino-2- hydroxy-4-plienylbutyl]- 2, 3-diaza-bicyclo[2 .2.1 Iheptanie. This material was coupled to N-(2-pyridyl)methoxycarbonyl-L-valine (Example 11, Step A) by process identical to Example 3, Step B to give the title compound in 5~1 yield: melting point 73 77'C; Rf 0.45; Rf 0.49; NMR (GDCI 3 0.7 1.0 (mn, 6H-, val Gil 3 1.25 2.15 (in, 1611, t-butoxy Gil 3 val Cil-, Ci1 2 2.55 3.1 (in, 4Hl, butyl Cil 2 3.3 3.7 (butyl CH-2,3); 3.91 (in, 111, val Gil-a); 4.1 4.4 (in, 2H1, 4.9 5.4 [in, 4H1, inethoxy d4 2 (s, 40 5.26), OH, NI; 6.6 (mn, I-I NIH); 7.26, 7.7, 8.57 (in, 71H, I-I, 1I, aromatic).
IN:\L3Z20579OMS~AK EXAMPLE I [N-(2-pyridyl)niethoxy-L-valyllaino-4-phenylbi 11l-2,3-diaza-bicy-clo[2.2. Iheptanle According to Example 4, Step B, the product of Example 16 was converted quantitatively to the hydrochloride salt of 3-[(2RS, 3S)-2-hydroxy-3-[N-(2-pyridyl)methoxy -L-valyl] amino-4-phenylbutyl]-2 ,3-diaza-bicyclo[2 .2.1 ]heptane. This material (0.06 g; 0.113 mmol) and an equimolar amount of methyl L-2-isocyanato-3-methyl.
butanoate were dissolved in 0.4 ml of ethanol free chloroform and to it was added 0.031 ml of diisopropylethylamine. The resulting mixture was allowed to stay for 12 hours at room temperature, under nitrogen, then diluted to 15 ml with ethyl acetate and washed with water and dried over magnesium sulfate. Evaporation in vacuo .and purification by coiumnrn chromatography (silica gel, ethyl acetate) gave 0.051 g of the title v.-mpound; melting point 79 84*C, Rf(C 0.2; Rf(D) 0.46; NMR(CDCl 3 (in, 12H-, val CH 3 1.0 2.5 (in, 1011, val CH-P3, butyl CH 2
CH
2 2.5 3.33 (in, 3H, butyl CH2-4, CHI-3); 3.33 4.05 (in, 6H, val CH-ca, CH-4, OCH 3 4.05 (in, 611, butyl CH-3, OH, CFH-1, NH, methoxy CH 2 5.82 6.7 (in, 2H1, val NH); 6.9 7.9, 8.6 (in, mn, 811,111, aromatic).
EXAMME 18 2-t-jutnxyctbny-3-r(2RS, 3S)-2-hiydroxy-3-(N-guiahdI-LspIaginYIamnQ-4- 20 Phe~ulluyI I i 2 3,4-tetrahydroplithal zone I=p A: 2-t-Butoxyearbonyl-34(2RS, 3S)-2-hydroxy-3-(phenylmetlioxycarbonlyl)- :amino-4-phenylbutyll-1,2,3,4-tctrahydrophtalaziine: To a mixture of 0. 19 g 11 L mmol) of hydrochloride salt of 1 ,2,3,4-tetrahydrophtlialazine [Groszkowski and Wesolowska, Arch. Pharm. (Weinhleim) 314, 880 (1981)] and 0.23 g (1.05 inmol) of di-tert-butyl dicarbonate in 5 ml of chloroform was added 0.147 ml (1.05 inmol) of triethylainine under nitrogen. After stirring for 5 hours at room temperature the mixture was diluted to 30 ml with ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent in xac.uo and puification of the residue by chromatography on silica gel (hexane/ethyl acetate 4:1) gave 0.0921 g of 2-t-butoxycarbonyl-1 ,2,3,4-tetrahydrophithalazine; NMR (CDCI 3 9H-, t-butoxy CH3); 4.0 2H-, CH 2 4.47 (broad s, 114, NI-I); 4.64 2H1,
CI-
2 6.95 (in, 411, aromatic). When this material was substituted for 2-t-butoxycarbonyl-2,3-diazabicyclo[2.2. llhept-5-ene in Step B of Example 14 a similar process afforded the title compound in 24% yield after purification on column chromatography (alumina, chloroforinlethyl acetate 95:5); melting point 68 71 0 C; NMR (CDCl 3 9H-, t-butoxy CU 3 2.18 3.15 (in, 4H-, buty! CH2-l,4); 3.3 5.5 (in, 101-, butyl CH-2,3, CH2-1,4, methoxy CH 2 014, NH); 7.22 (in, 14H1, aromatic).
Step a: 2-t-ButoxycarbonyI-3+[21S, 3S)-2-hiydroxy-3-(N-quinaldyl-L-asparaginyl)aniiino-4-phcnylbutyl]-1,2,3,4-tctrahiydroplitlialazinie: When the product of Step A is substituted for cis- 1,6-3 -t-Butoxycarboniyl-4-[(2RS ,3S)-2-hiydroxy-3-(phienylmcthioxy- IN: \LIBIIZ257iuA U: SAK 41 carbonyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane in Example 10 the identical process afforded the title compound in 70% yield; melting point 108 112 0 C; Rf (C) 0.44; Rf 0.39; NMR (CDCl 3 1.47 9H, t-butyl CH 3 2.3 3.11 6H, asn CH 2 butyl CH 2 3.2 5.14 8H, butyl CH-2,3, asn CH-a, CH2-1,4, OH); 5.14 6.1 2H, NH); 6.6 7.4 10H, aromatic, NH); 7.62, 7.77, 7.87 (3 x m, 1H, 1H, 1H, aromatic); 8.1 8.4 3H, aromatic); 9.11 1H, asn NH).
EXAMPLE 19 t-Butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)-amino-4phenylbutyllcarbazate Stel A: 2(R)-3(S)-1,2-Epoxy-3-phenylmethoxycarbonylamino-4-phenylbutane: To a stirred solution of 6.02 g (40 mmol) of sodium iodide in 50 ml of anhydrous acetonitrile was added 2.6 ml (22 mmol) of chlorotrimethylsilane under nitrogen. After 10 minutes of stirring, 6 g (20.1 mmol) of the predominantly erythro isomer of 2(R,S)-3(S)-1,2-Epoxy -3-phenylmethoxycarbonylamino-4-phenylbutane (Example 6, Step A) was added and stirring was continued for additional 1 hour. To this mixture was added 4g (61.2 mmol) of zinc dust followed by 6 ml of acetic acid. The resulting mixture was vigorously stirred for about 5 hours at room temperature and the solid material was removed by filtration. The filtrate was evaporated to dryness in vacuo and the residue was diluted to 75 ml with ether, washed with water and 5N aqueous sodium thiosulfate 20 and dried over anhydrous magnesium sulfate. Evaporation in vacuo and purification by S chromatography on silica gel (hexane/ethyl acetate 4:1) gave 5.1 g of (S)-2-(phenylmethoxycarbonyl)amino -1-phenylbut-3-ene; Rf 0.5; melting point S87 88 0 C (hexane); NMR (CDCl 3 2.87 2H, butene CH 2 4.77 2H, butene
CH
2 5.0 1H, NCH); 5.06 2H, methoxy CH2); 5.18 (broad d, 1H, NH); 5.55 2 6 1H, butene CH-3); 7.19, 7.27 s, 5H, 5H, aromatic). This material (2.23 g; 7.93 rmnol) was dissolved in 25 ml of dry methylene chloride and 4.5 g (22.1 mmol) of 85% 3-chloroperoxybenzoic acid was added at The resulting mixture was stirred for two days at the above temperature, then diluted to 50 ml with ether, washed sequentially with 0 C 10% aqueous sodium sulfite solution, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate.
After evaporation of the solvent the crude product was purified by crystallization from a mixture of hexane/methylene chloride to give 2.1 g (89% yield) of the title epoxide with the predominant threo stereochemistry; melting point 83 84°C; NMR (CDC1 3 2.47 5H, butane CH2-1,4, CH-2); 3.74 0.15H, NCH); 4.2 0.85H-, NCH); 4.53 36 (broad d, 1H, NH); 5.03 2H, methoxy CH2); 7.3 10H, aromatic).
Step B: t-Butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(phlnylmethoxycarbonyl)amino-4phenylbutyl]carbazate: A mixture of 2.03 g (6.83 mmol) of the product of Step A and 1.2 g (7.6 mmol) of t-butyl 3-isopropylcarbazate in 8 ml of isopropanol was stirred for 12 hours at 70 5°C under nitrogen. After evaporation of the solvent in Yacn~ the solid residue was recrystallised from hexane to give 2,6 g (80% yield) of the title compound (N:\LIZ)205790AU:SAK 42 melting at 114 Ild"C; Rf 0.2; Rf 0.61; NMR (GDCI 3 0.95 (in, 6H-, isopropyl Gil 3 1.42 9H1, t-butyl Gil 3 2.44 (in, 2H-, butyl CH 2 2,94 (mn, 311, butyl CI- 2 CH-3); 3.33 -3.93 (in, 2H1, isopropyl CH, butyl C11-2); 4.4 (broad mn, IH, OH); 5.05 211, methoxy Gil 2 5.33 (broad m, 211, NII); 7.18, 7.27 (in, s, 511, 5H1, aromatic).
EXAMfLE t Butyl 3-isopropyl-4-(25, 35)-Z-hydroxy- -(N-ginaldyl-L-asparaginy)amn-4phenylbutyljcarbazate When the product of Example 19 was substituted for t-butyl 3-isopropyl+[2R, 3S)- 2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate in Example 3, the identical process afforded the title compound in 66% yield; melting point 203 204'C (chloroform); Rf 0.36; Rf 0.37; NMR CD 3 0D in CDCl 3 1.0 (in, 611, isopropyl Gil 3 1.4 911, t-butyl Gil 3 2.53 2H-, butyl CH 2 2.87 (in, 411, asn CH 2 butyl C1 2 3.13 611, CD 3 OH); 3.42 (mn, 2H1, isopropyl CH, butyl 4.0 (in, 1H1, butyl CH-2); 4.89 (mn, 1H1, asn CH-cc); 7.11 (mn, 511, phenyl); 7.41, 8.47 (in, 6H-, quinaldyl).
EXAMPLE21 gcj&sl ?-3-t-Butoxycarbn-4[S 3S-2-hydroxy-3-(phienylmethoxycarbonylLamno-QA4 Phenylbtyll-3,4-diaza-bicydco4.4O~decan 20 When the product of Step A, Example 8, is substituted for t-butyl 3-isopropylcarbazate in Example 19, Step B, the identical process afforded the titled compound in 78%; melting point 110 HITC (hexane); Rf 0.28; Rf 0.63; NMR (CC3 1. eaeC27891,C-,,tbtx H) m H goo 3 21 i,11,deaeC1-,,,0 H16 tbtx U) i,21 :0.asdecane CH 2 2.75 4.1 (mn, 8H-, decane C11 2 butyl G112-1,4, CH-2,3); 4.93 (broad 25 s, 1H1, 011); 5.07 2H1, methoxy CH-2); 5.31 (broad m, 1H1, NH); 7.22, 7.32 (mn, s, 511, 511, aromatic).
0600EXAMPLE 22 IV 0 0 cis-1 6-3-t-Bvitoxycarbony-4-(2S, 35 2 byrowy-3ain.4p-hnylbityll-3,4-diaza- According to the method of Example 2, step B, the product of Example 21 (2 g; 0.037 inol) was converted quantitatively to the title compound (1.5 g of a heavy syrup); NMR (CDCI 3 :1.0 2.32 (mn, 19H1, decane CI-2-7,8,9,10, CH-1,6, t-butoxy Cl- 3 2.32 4.54 (in, 131H, butyl CH2-1,4, C11-2,3, decane CH 2
NH
2 011); 7.28 (mn, 511, aromatic).
A fractional crystallisation of the above product from hexane gave 0.74 g of isomer A as a colorless solid melting at 123 -124CG; NMR (CDCI 3 1.0 2.25 (in, 2111, decane CI-2-7,8,9,10, CH-1,6, t-butoxy CH 3
NH
2 2.35 3.0 (mn, 5H-, butyl Cil 2 CII-3); 3.05 3.4 (mn, 3H1, butyl CH--2, decane CH2-5); 3.5 (mn, 2H1, decane C11 2 3.82 (d, 1H-, 7.27 (in, 511, aromatic).
IN:\LIi3Z1205790AU-SAK 43 xane fraction gave 0.76 g of isomer B, after evaporation of the solvent. This was p, 'le y column chromatography (silica gel, 8% methanol in methylene chloride; Rf =JC zo give 0.72 g of pure isomer B as a colorless syrup: NMR (CDCI 3 1.0 -2.4 (in, 21H1, decane CH2-7,8,9,10, CH-l,6, t-butoxy CU 3
NH
2 2.4 3.1 (in, 611, butyl
CH
2 CH-2,3); 3.22 3.4 (in, 2H, decane CH 2 3.52 (mn, 2H-, decane C11 2 3.76 1H1, OH); 7.27 (in, 511I, aromatic).
EXAMPIU3 cis-1 ,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-lhydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutylj-3,4-diaza-bicyclo[4.4.Ojdecane When the product of Example 22 (mixture of isomers A and B) was substituted for cis- 1, 6-3-t-butoxycarbonyl-4-[(2RS, 3S)-2-hydroxy-3 -amino-4-phenylbuty] -3 ,4-diazabicyclo[4.4.0]decane in Example 10, the identical process afforded the title compound in 72% yield; melting point 108 110'C, Rf 0.44; Rf 0.46; NMR (CDCJ 3 0.71 2.18 (in, 19H1, decane CH 2 -7,8,9,10, CI--1,6, t-butoxy C11 3 2.18 4.48 (in, 16 1211, asn CH 2 decane CH 2 butyl CH- 2 CH-2,3); 4.95 (in, 211, asn CU, OH); 5.55, 6.13 (broad in,m, 2H, NH); 6.84 7.4 (in, 6H, aromatic, NH); 7.4 8.39 (in, 6H1, aromatic); 9.22 (in, 111, NH).
A sample of this product was separated to two isomers by reverse phase (Whatman
C
8 seinipreparative column) high pressure liquid chromatography, using 37% of 0.1% 20 aqueous solution of trifluoroacetic acid in acetonitrile containing 0.07% of trifluoroacetic acid and 10% of water, for the elution: Isomer A,Rf 16.8 min.; Isomer 1,Rf 18.3 min.
0 When the isoirners A and B of the product of Example 22 were used instead of :0 fe mixture, the respective isomers of the title compound were obtained.
Isomer A: 69% yield; melting point 110 116'C; NMR (CDCI 3 1.0 1.8 (in, 19H-, t-butyl CU 3 decane C11 2 -7,8,9,10, CH-1,6); 2.2 2.6 (in, 211, butyl CI- 2 2.7 64. 113.3 (in, 711, anCH2, butyl C11 2 C11-3, decane C11 2 3.56 (in, 211, decane CU 2 4.07 (in, 1H1, butyl CH-2); 5.0 (im, 111, asn CH), 5.4 5.75 (in, 2H1, NH, 0OH); 6.1 (in, 114, NH); 7.14 (in, 611, aromatic, NH); 7.63, 7.8, 8.22 (in, in, III, 1H1, 2H-, 311, aromatic); 9.21 (in, 111, asn NH).
Isomer B: 78% yield; melting pont 122 126'C; NMR (CDC1 3 1.1 1.71 (in, 19H-, t-butyl C11I 3 decane CH 2 -7,8,9,10, CH-l,6); 2.2 -2.6 (in, 2H, butyl CI4 2 2.7 3.15 (in, 6H-, asn CH 2 butyl CI- 2 -4 decane CH-I '3.43 (mn, 3H-, butyl CH-3, dcane Cl- 2 4.1 (in, 111, butyl CH-2); 4.94 (in, lH, OH); 5.0 (in, 1H1, asn 5.55, 6.2 (in, InI, 111, 11-1, NH 2 7.14 (mn, 61.1, aromatic, NH); 7.63, 7.8, 8.22 (111, 111, in, 1H, 211, 31-, aromatic); 9.27 (mn, 111, asn NH).
JN:\LI13Z)205790AU:SAX 44 EXAMPLE 24 1-TrimthyIacjyI-2-[(2S,3S'I-2- yrx--peny mtoyabony)amino-4-pheny.butylJ-2-isopropylhydrazine Step A: 1-ihn-ethylacetyl-2-isopropylhydrazine: A mixture of 10 g (0.086 mol) of methyl trimethylac-tate and 3.2 g (0.1 mol) of anhydrous hydrazine was refluxed for 12 hr. then evaporated to dryness under reduced pressure. The residue was purified by crystallization from an ether/hexane mixture to give 9g (90% yield) of trimethylacetyihydrazide, melting at 190 191' 0 C. When this product is substituted for tbutyl carbazate in Step A of Example 1 the identical process afforded the title compound lo in 67 yield, as colorless crystals; NMR (CDCI 3 1.03 6H-, isopropyl CH-3); 1. 18 (s, 9H, trimethyl CH 3 3.07 (in, 1H, isopropyl CH); 4,62 (broad s, 1H, NH); 7.4 (broad s, 1H1, NH amide).
SIMp..: 1-trimethylacetyl-2-[(2S,3S)-2-hydroxy-3-(phenylmethoxy-carbonyI)amino- 4-phienylbutyl]-2-isopropyl-hydrazine: When the product of Step A was substituted for 16 t-butyl 3-isopropylcarbazate in Step 13 of Example 19, the identical process afforded the title compound in 69% yield; melting point 132 134'C: Rf 0.07; Rf 0.33; NMR (CDCI 3 0,72 1.3 (in, 15H-, isopropyl Cl- 3 t-butyl Cl- 3 2.1 3.16 (mn, 511, butyl CH 2 3.16 4.0 (mn, 211, butyl CI--2, isopropyl CHI); 4.86 111, 5.08 2H, methoxy Gil 2 5.4 111, NIH); 6.1 1H1, 7.2, 7.31 (mn, s, 1IThjimclyltyl-2-(2S,3S)-2-hydroxy-3-(N-guiinaldyl-L-asparaginyl)arniino-4phenylblitylJ-2-isoliroplyrz :0 04 When the product of Example 24 was substituted for t-butyl-3-isopropyl-[(2R,3S)-2- 26 hydroxy-3-(phenylinethoxycarbonyl)amino-4-phenylbutyllcarbazate in Example 3, the 00 ~identical process afforded the title compound in 65 yield; melting point =222 a 223.5'C; Rf 0. 1; Rf 0.49; NMR (10 CD 3 0D in CDCI 3 0.7 1.31 (in, 15H, trimethyl Gil 3 isopropyl CH 3 2.0 3.6 (in, 9H1, asn CH 2 butyl CH 2
C-
2,3, isopropyl CHI); 4.05 CD 3 OH), 5.0 (mn, asn CHI); 6.64 8.5 (mn, 1111, aromatic).
E.XAMlPLE 26 1-(t-Biitylarnino' earbontyl-2-f(2S.3S)-2-hydrox-3-(N-gatiinaldv1-L-ipaa Ity)amino- To a vigorously stirred mixture of 0.33 g (0.0103 mol) of anhydrous hydrazine in 50 ml of dry ether was added I g (0.01 mol) of t-butyl isocyanate. The resulting mixture was stirred for 2 hr. at room temperature then was kept overnight at V 0 C. The crystals formed were filtered off, washed with a small portion of ether and dried to give 0.94 g (72% yield) of (t-butylainino)carboniylhydrazine melting at 192-193*C. When this was substituted for t-butyl carbazate in Step A of Example 1, the identical process afforded 1-(t-butylamnino)carbonyl-2-isopropylhiydrazine in 58% yield as a white solid; NMR I N:\LIB1205790AU:SAK
(CDCI
3 1.03 6H1, isopropyl CU 3 1.33 9H, t-butyl CH 3 3.9 (broad s. 1H, NH); 6.02 (broad s, 2H, NH amide). When this was substituted for t-butyl 3-isopropylcarbazate in Step B of Example 19 the identical process afforded 1-(t-butylamino)carbonyl-2-[(2S ,3S)-2-hiydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2isopropyihydrazine in 68% yield, as a white solid; NMR (CDCI 3 1.0 (in, 611, isopropyl
CU
3 1.3 911, t-butyl Cl- 3 2.33-4.22 (in, 8H1, butyl CH 2 CH-2,3, OH, isopropyl CH); 5.05 2H-, rnethoxy CT- 2 5.3 (mn, 211, NH); 5.91(m 111, NH); 7.2, 7.35 (mn, s, 511, 511, aromatic). When this was substituted for t-butyl 3-isopropyl-[(2R, 3S)-2-hydroxy-3-(plienylmethioxycarbonyl)amino-4-plhenylbutyljcarbazate in Example 3, the identical process afforded the title compound in 67% yield; melting point 119 125'C; Rf 0.06; Rf 0.43; NMR(CDCl 3 1.0 (mn, 6H1, isopropyl CU 3 1.32 9H1, t-butyl CU 3 2.24 3.38 (mn, 7H1, butyl CI-1-1,4, CH-3, asn Cl- 2 3.38 4.63 (mn, 311, butyl CI--2, OH, isopropyl CH); 5.09 (mn, 1H1, asn CIH); 5.63 8.4 (in, 16P., aromatic, NH); 9.0 111, asn NH).
EXAMPLE27 t-BIutyl -iorop- -f(2S, 3S)-2-iycX-3-(N-picoinoy-L-asparainflamino-4phenylbutylcarbazate STEPLA: N-picolinoyl-L-asparagine: When picolinic acid was substituted for quinaldic acid in Step A of Example 3, the identical process afforded the title compound melting at 20 171 172'C, in 68% yield, NMR(DMSO-d 6 2.75 (in, 211, asn C112); 4.8 (in, 1H1, asn 6.7 8.8 (in, 611, aromatic, NH 2 9.0 111, NH); 12.7 (broad s, Ili, 011).
SIEB: t-Butyl 3-isopr-opyl-3-[2S,3S)-2-hydrox y-3-(N-picolinoyl-L-asparaginyl)arnino-4-plhenylbutyl]carbazate; When thle product of Step A was substituted for Nquinaldyl-L-aspargine in Example 20, the identical process afforded the title compuund in 25 58 yield; melting point 10 1 108 Rf(C) 0. 16; Rf 0.48; NMR (CDCI 3 1.0 (in, 6H-, isopropyl C113); 1.4 9H, t-butyl CH 3 2.15 3.23(m 711, butyl CH- 2 -1,4, C14I-3, asn Cl- 2 3.23 4.53 (mn, 31-1, butyl CH--2, isopropyl Cl-I, 01-1); 4.94 (in, 11-1, asn CHI); 5.1 6.41 (in, 311, NH); 6.7 8.7 (mn, 101-1, aromatic, NH); 9.05 (mn, 1I, asn NH-).
3o t-Butyl 3-isoprapyl-3-I(2, 3S)-2-liydroxy-3-(N(2pyrtidyI)mgtlijxycarbonylm anlbrauilyl~hrniino-4-phienylbutyllcarbazat& When the product of Step A of Example 4 was substituted for N-quinaldyl-Lasparagine in Example 20, the identical process afforded the title compound in 61 yield; melting point 155 157'C; Rf 0.79; Rf 0.78; NMR (CDCI 3 1.0 (mn, 36 61-1, isopropyl CI-3); .1.42 9H-, t-butyl Cl- 3 2.33 3.22 (mn, 511, butyl CI- 2 -1,4 C- 3.62 (in, 111, butyl C11-3); 4.25 (mn, 111, isopropyl 4.67 (broad s, 1I, 0OH); 5.3 211, inethoxy CH 2 6.52 8.44 (in, 15H-, aromatic, NH); 8.55 (mn, lI-, NH).
IN:\L113Z1205790AU:SAK 46 EXAMILE29 t-Butyl 3-benzyl-3-(2S. 3S)-2-hydroxy-3-(phenylmethoxycrh- yamno-4-phenylbutllarbazatk S.TEP A: t-Butyl 3-benzylcarbazate: When benzaldehyde was substituted for acetone in Step A of Example 1, the identical process afforded the title compound in 69% yield as a heavy colorless syrup; NMR (CDC13): 1.44 9H1, t-butyl CH- 3 3.63 (broad s, 1H1, NHl); 4.0 2H, CH 2 6.08 1H, NH); 7.3 5H-, aromatic).
t-Butyl 3-benzyl-3-[(2S,3S)-2-hydroxy-3-(phenylmethoxy-carbonyl)arnino- 4-phenylbutylicarbazate: When the product of Step A was substituted for t-butyl 3isopropyl carbazate in Step B of Example 19, the identical process afforded the title compound in 71'% yield; melting point 142 143 0 C; Rf Rf 0.59; NMR (CDC1 3 1.31 9H1, t-butyl CH 3 2.12 3.12 (in, 5H1, butyl CH 2 CH-3); 3.35 4.11 (mn, 3H-, benzyl CH 2 butyl CH-2); 4.41 (broad s, 1H1, OH); 5.05 211, methoxy CH 2 5.2 (in, 211, NHl); 7.22 (mn, 15H, aromatic).
EAMPLEIII
t utyL3mbezy4f21S2iydny3-N inadyl-L-a no-4-y~aim pheuyh butlUarbazt When the product of Example 29 was substituted for t-butyl 3-ispropyl-[(2S, 3S)-2hiydroxy-3-(phenylrnethoxycarbonyl)amino-4-phienylbutyl]carbazate in Example 20, the 20 identical process afforded the title compound in 71% yield; melting point 150-153'C; Rf(CP 0.38; Rf 0.53; NMR (CDCI 3 1.3 9H-, t-butyl CH 3 2.13 -3.2 (mn, 711, butyl C11 2 CH-3, asn CH 2 3.2 4.73 (in, 4H-, benzyl CH 2 butyl CH-2, OH); L 5.0 (in, 111I, asn CIH); 5.14 6.7 (mn, 4H, NH); 6.7 8.35 (mn, 16H aromatic); 9.25 (broad mn, 1H-, asn NiH).
25 ExAIX'PLIL31t tL-Duy-LLy=1ocxy-3-[(2S, 3S)-2-lhydroxy-3-(pheniylniethiosycarbonyl)amijA- Step A: t-Butyl 3-cycloliexylcarbazatc: When cyclohexanone was substituted for acetone in Step I. of Example 1, the identical process aforded the title compound in 59% yield as a colorless solid; NMR (CDCI 3 0.75 2.2 (in, 19H, t-butyl CR 3 cyclohexyl
CH
2 2.75 (in, lH-, cyclohexyl 3.75 (broad s, 11-1, NIH); 6.27 (broad s, 111, NH).
,9kp..f: t-Butyl 3-cyclohcxyl-3-[(2S ,3S)-2-hy droxy-3-(phienylicitlioxycarbonyl)aimino-4-plicnylbuityl]carbazatc: When the product of Step A was subsituted for t-butyl 3-isopropyl carbazate in Step B of Example 19, the identical process ;ifforded the title compound in 76% yield; meliting point 142 143 0 C; Rf 0.28; Rf (1B) 0.7; NMR (CDCI 3 0.73 2.0 (in, 19H-, t-butyl C11 3 cyclohexyl Cl- 2 2.53 (in, 311, butyl CI-2-1, 3.0 211, butyl CH-2-4); 3.35 4.0 (in, 21-1, butyl CH-2, cyclohexyl 4.49 (broad s, 114, OH); 5.13 2H1, methoxy CH- 2 5.35 (mn, 2H-, 7.3, 7.4 (in, s, 51-I, 5H-, aromatic).
IN: \LIIIZ120571MALKC11 47 EXAMPLE 32 t-Butyl 3-cyclohexyl-3-4(2S 3S)-2-hydroxy-3-(JN-guinaldy-asaiainvflamino-4 phemylbutyllcarbazate When the product of Example 31 was substituted for t-butyl 3-isopropyl-3-(2S, 3S)-2hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyllcarbazate in Example 20, the identical process afforded the title compound in 75% yield: melting point 140 144 0
C;
Rf 0.42; Rf 0.56; NMR (CDCI 3 0.7 2.17 (in, 19H-, t-bi tyl CR3, cyclohexyl CH 2 2.17 3.29 (mn, 7H, butyl CH 2 CH-3 asn CR 2 3.3 4.87 (mn, 3H, butyl CH-2, cyclohexyl CR, 01-1): 4.95 (in, 114I, asn 5.14 6.4 (in, 311, NH); l0 6.62 8.3 (in, 12H, aromatic, NH); 9.15(d, 1H1, asn NH).
EXAMPLE 3 t-Blityl -isopropyl-3-[(S3S)-2-hydroxy-3-N-sI-crbaoylctylacryyiaino-m4A SIE1LA: (1-Carbanioylmethyl) acr~ylic acid: To a mixture of 3g (0.O27inol) of itaconic 19 anhydride in 30 ml of tetrahydrofuran, 3 ml of 28% ammnonium hydroxide was added.
After 1 hr. the reaction mixture was evaporated to dryness under reduced pressure. Thle residue was dissolved in 15 ml of water, then acidified to pH 2 with concentrated hydrochloric acid and allowed to stay overnight at The precipitate formed was filtered off, washed with a small portion of cold water and dried to give 1.4 g (40% yield) of the title compound melting at 153 154*C; NMR (DMSO-d 6 3.11 211, CR 2 5.67,6.13 s, 1H-, 114I, CR); 6.7, 7.9 (broad s, s 111I, IH, NH); 12.15 (broad s, 11-1,
OR).
TEP 13: t-Biityl 3-isopropyl-3-[(2S,3S)-2-lhydroxy-3-(N-(1-carbaioylmnethlyl)- 25acrylyl)ainino-4-plhenylbuityljcarbazatc: When the product of Step A was substituted for in Example 20, the identical process afforded the title compound in 61% yield; melting point =118 122 0 C; Rf 0.27; Rf 0.49; 04. 1 NMR (CDCI 3 1.0 (in, 6H1, isopropyl CR 3 1.4 91-1, t-butyl Cl- 3 2.49 (in, 2H1, butyl CH1 2 3.0 (in, 314, butyl CH 2 3.2 211, methyl CH 2 3.6 (in, 1H, isopropyl 4.07 (in, 111I, butyl CH1-2); 4.6 (broad s, 1I-I, 01-1); 5.2-5.8 (mn, 411, 3o acryl CH-, NH); 6.4 -7.0 (in, NH2); 7.2 (in, 51-I, aromatic).
-Bl I, ~spropyl-IZS..J31-Iiydroxy-3-(N-2-(RS)-3-ter-t-buitylhio-2-carbamioy.L methiylpropinnyl)anino- lcabaat To a mixture of 0.057 g (0.127 minol) of the product of Example 33 and 0.0172 ml (0.152 mmiol) of tert-butyl mercaptan in 0.5 ml of anhydrous methanol, I drop of a freshly prepared 20% solution of sodium methoxide in methanol was added. After stirring for 12 hr. at room temperature the mixture was evaporated to dryness, then diluted to l0mI with ether and wvashed with water and saturated sodium chloride solution, After drying over anhydirous magnesium sulfate, the ether was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel; ethyl acetate), [N XLIB1Z120S790AIJ:SAK 48 to give 0.032 g (47% yield) of the title compound; melting point 116 120'C; Rf (C) 0.42; Rf =0.56; NMR (CDCI 3 0.6 1.63 (in, 24H, t-butyl CH 3 isopropyl Cl-I 3 2.0 4.47 (mn, 13H-, butyl CH 2 C11-2,3, isopropyl CH, methyl C11 2 propionyl CH- 2 CH, OH); 4.82 6.78 (in, 4H1, NH 2 NH); 7.11 (in, 51-I, aromatic) E XAMPLE t-Butyl 3-isopropyl-3.{(2S 3S)-2 hyroxy 3 (N benzoyl-L-asprinIanoplienylbutyllearbazatc Step A: N-Benzoyl-L-asparagine: To a vigorously stirred solution of 2 g (0.013 mol) of L-asparagine monohydrate and 2.02 g (0.014 inol) of potassium carbonate in 15 ml of water, 1.51 ml (0.013 mol) of benzoyl chloride was added dropwise, over a period of mmi., at room temperature. The stirring was continued for 2 hour, then the mixture was extracted with 10 ml of ether and the aqueous phase was acidified to pl-I 2 with concentrated hydrochloric acid. The white precipitate was filtered off, washed with water and purified by crystallization from isopropyl alcohol to give 2.1 g (68% yield) of the title compound at 190-192'C; NMR (DMSO-d 6 2.62 (in, 211, Cl-I 2 3.32 (broad s, MH, 4.72 (mn, 1I-I, CHI); 6.64 8.0(m. 7H, aromatic, NI- 2 8.6 1H-, NH).
skpM t-Butyl 3-isopropyl-3-[(2S,3S)-2-liydroxy-3-(N-beinzoyl-L-asparaginyl)aiiiio-4-plienylbuityl]carbazate: When the product of Step A was substituted for Nquinaldyl-L-asparagine in Example 20, thle identical process afforded the title compound 0 0 20 in 65% yield; melting point 182 185 0 C; Rf(C) 0.22; Rf 0.51; NMR
(CDCI
3 /DMSO-d 6 0.92 (mn, 61I, isopropyl Cl- 3 1.38 9H-, t-butyl Cl- 3 2.19 3. 11 (im, 7H-, butyl CI- 2 4, CI--3, asa, Cl- 2 3.11 4.57 (mn, 3H, isopropyl CH-, butyl CI--2, 4.83 (in, l-I, asn 6.5 8.17 (mn, 14H-, aromatic NH); 8.56 (mn, 1H1, asn NI-).
'26 EXAMPLE23 phcnQiylbitityllliexaliydropyridazinc Step..A: 1-t-butyloxycairboniylliexalhydropyridazinc: When 1 ,4-dibromobutane was substituted for cis- 1,2-cyclohexanediinethyl iodide in Step A of Example 8, the identical process afforded 1 -t-butoxycarbony 1-2-pheniylmethioxycarbonylhecxahydropyridazinie in 65% yield; melting point 71-72'C; NMR (CDCI 3 1.15 1.9 (in, 13H-, t-butyl CH- 3 CI-2-4,5); 3.0, 4.15 (broad mn, mn, 2H1, 2H-, CH 2 5.2 (in, 21-1, ilethloxy Cl- 2 7.35 5H-, aromatic). This was converted to thle title compound in 93% yield by hydrogenolysis, performed as described in Example 2. The product was isolated as a colorless syrup.
Sijfl: I-t-butyloxycarboinyl-2-[(2S,3S)-2-hiydroxy-3-(phiciylmtehoxycarboinyl)ainiino-4-pheniylbutyllhcxaliydropyridazine: When the product of Step A was substituted for t-butyl 3-isopropylcarbazate in Step B of Example 19 thle identical process afforded the title compound in 71 yield, as a heavy colorless syrup; NMR (CDC1 3 1.0 1.87 (mn, 13H-, t-butyl C11I 3 pyridazine C1-12-4,5); IN \L11112057'X)AViSAK 49 4.0 (in, 11H, butyl CI- 2 CI--2,3, pyridazine CI- 2 5.05 2H-, methoxy Cl- 2 5,47(d, 1H-, NI-I); 7.19 (in, 10H-, aromatic).
EXAMPLE 37 1tBityoyabnlf-(S3)2lyrx--Ni dnly--s in1ajo phienylbityllhexahydropyridazine When the product of Example 36 was substituted for t-butyl 3. isopropyl-[(2S,3S)-2hiydiroxy-3-(phlenylinethioxycarbonyl)anino-4-phienylbuty Ijcarbhzate in Example 20, the identical process afforded the title compound in 65% yield; melting puint 104 110'C; Rf 0.3; Rf 0.62; NMR (CDCI 3 1.0 2.04 (in, 13H-, t-butyl CU 3 lo pyridazine CH 2 2,15 4.31 (in, 13H-, butyl CH 2 CI--2,3, asn CU 2 pyridazine CI- 2 4.95 (in, 11-, asn 5.14 6.6 (in, 3H-, NI); 6.8 8.4 (mn, 1111, aromatic); 9.21 I H, asn NIH), LXAMPLE 38 cis-.6~--Ditoxycar~onyl-4-[(2S3S)-2-iyroxy-3-(N-gi ady 3 cya oL-aanI',amino-4-plienylbutvl1-3.4-diaza-bicyclo[4.4,0dcclane Step..A: N-Qtiinalclyl-3-cyaino-L-alaniine: To a mixture of 0.198 g (0.69 miunol) of Nquinaldyl-L-asparagine and 0.24 ml (1.38 mmol) of N, N-diisopropylethylamine in 1 ml of chloroform was added 0. 146 8 (0.71 minol) of dicyclohiexylcai-bodiimide. The reaction mixture was stirred for 24 hr. at room terperature, then partitioned between 101ilI of sodium bicarbonate d 10 nil of ether. The aqueous phase was acidiied to pH2 and the acid was taken up by extraction with chloroform (3xlOnil). Thc organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give 0.101 g of crude product. This was recrystallized from a small portion of' mrethylene chloride to give 0.06 g of the title compound melting at 144 146*C; NMR DMSO-d 6 in CDCI 3 3.22 ~25 2H-, ala Cl- 2 4.95 (in, lI-, ala CH); 7.2 8.57 7H-, aromatic, 01-I); 9. 19(d, 1I-I,
NH-).
0::0 alanyl)aiinio-4-phcnylbutyl]-3,4-diaza-biylo[4.4.O]dccanc: When the proutofSe was substituted for N-quinaldyi-L-asparagine in Example 22 (isomer A) the identical process afforded the title compound with 67% yield, melting at 106-1 12*C; Rf 0.87; Rf 0.89; NMR (CDCI 3 0.7 2.84 (in, 241-I, t-butyl Cl-I 3 decane CU 2 7,8,9,10, CI--1,6, butyl CH 2 CI--3, cyanoalanyl CH- 2 2.85 4.65 (in, 81-I, butyl CI-b-4, C.1-1-2, decyl CI- 2 O1H); 4.7 5.6 (broad in, 21-I. cyanoalanyl CII, NI-1); 6.9 (in, I I H, aromatic); 8.9 (bioad in, 11-1, NI-I).
IN \H13II.20i7%OAL1:SAt(

Claims (10)

1. A compound of the general formula (IX): RiN* 2 3 (IX) or a pharmaceutically acceptable salt thereof, wherein: 6 R 2 is R7 D 1 1 -N--B-C-Y wherein D is 0 or S; Y is hydrogen, -R or -OR, where R is selected from the 2 F, 0 00 group consisting of hydrogen, -R'C(O)N- 2 -R'NR and where and are independently optionally substituted (C 1 -C 1 )alkyl, (C 3 -C 1 8 )CYCloalkyl, (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 18 )alkenyl, (C 8 -C 26 )aralkenyl, (C 2 -C 18 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, and R' is an optionally substituted divalent radical derived from (Cl-C 18 )alkyl, (C 3 -C, 8 )cycloalkyl, (C 3 -C 1 I )cycloalkyl(C 1 -C I 8 )alkyl, (C 6 -C 24 )aIrYl, (C 7 -C 24 )aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 26 )aralkenyl, (C 2 -C 1 8 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, or Y is an amnino acid, aza-amino acid or peptide residue in wvhich any functional group present is optionally protected; and B3 is optionally absent or is (CI-C 6 )alkylidene, wherein any one or more -CI'1 2 groups may be replaced by or provided that the compound of Formula (IX) does not contain a chain of three or more atoms which are not carbon. andl wherein any H- atom may be substituted by a group R as previously defined; and wherein N, RI and R 7 taken together form a cyclic diazaalkane of the formiula: (CHR)p N N (CHR)p RHO CHR N N RCH CHR N N where p is I to 3, each R is independently as defined above and R 8 is R, -NH 2 -NU-R, -NR 2 -COOH, -COOL, -CHO. -CN, halo, -CF 3 -OL, -SR, -S(O) 2 R, -CON14 2 -CONHR, -CONR2, -NHOII, -NHOL, -NO 2 =0, or -NtHN1 2 wherein each R is independently as defined above and each L is independently R or a hydroxyl protecting group which is labile in vivo and which IN kiItZNAflHEXICLAIMS COl 51 prevents p-emature metabolism of the compound of formula (IX) after administration to a patient; and R 3 is X- W A' Q A wherein: A' and A independently are absent or (Cl 8 )alkylidene which may be 6 substituted with one or more substituents R as previously defined; Q is R R R R I II I or I OL O R OL R where L and each R, independently of the others, are as previously defined, and optionally Q and A together, or Q and A' together, or Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; W is absent or is 0 or S, wherein R is as previously d ~ined; and X is hydrogen, or- X I, where X 1 I is Ra- or RbC(O)- or where z is l or 2 and Ra and Rb are independently (C 1 -C 18 )alkyl, (C 3 -C, 8 )cycloalkyl, 16 (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, heterocycl ic, (C 1 -C 1 8 )alkylheterocyclic, hieterocycliC(C 6 -C 24 )aryloxy, (C 1 -C 1 8 alkoxy, (C 1 I -C 1 8 )alkoxy(C I -C 1 S)alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkoxy, (C 6 '-C 24 )ar-yl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )ar-yl(C 1 -C 18 )alkyllheterocyclic, heterocyclic- OXY(C 1 -C 1 8 alkyl, (C 1 -C 1 8 alkylamino, (C 6 -C 24 )arylIamino, (C 7 -C 1 8 )aralkyl- amino; any of which may be optionally substituted as hereinbef-ore defined or :substituted with a group Re, where Re is a group of the formula: *Rf 0 Z NH OH C wvhere Z has the meaning of Ra or Rb or is an acylated amino acid, azaamino acid or peptide residue, and Rf is the side-chain of a natural amino acid in which 26 any functional group present is optionally protected, or wherein thle Z-NI- bond shown is replaced by a modified isosteric bond, such as CH 3 -NRa-, a. ~RaCI- 2 -NRa-, CI-1 3 -CI-TRa--, FICH =CRa-, RaCHI= CRa-, HCOCI-Ra-, RaCOCFIRa-, IICI-OI-CHRa-, RaCI-IQIICI-Ra-, IN RaCO-, I-CF =CRa-, ::RaCF CRa-, RaS(O)-, RaiS(O) 2 RaP(O)ORa-, RaP(O)(ORa)CH 2 RaP(O)(ORa)O-, RaP(0)(ORa)S-, wherein each Ra is independently as previously defined, or X is Re as previously defined, or X is an optionally protected amino acid, azaamino acid or peptide residue; or when W is then X, N and the substituenit R on N together may form a as saturated or unsaturated cyclic, biryclic or fused ring systemn as defined IN LIUZ'NAMtXICLAIMS COI 52 hereinbefore or N, A' and the substituent R on N together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; and wherein any two R substituents, not necessarily vicinal, taken together are optionally substituted (C 2 -C 1 8 )alkylidene.
2. A compound of the general formula (IY): R2 or a pharmaceutically acceptable salt thereof, wherein: RI is a group R, wherein R is selected from the group consisting of hydrogen, -R'H, -R'C(0)NH 2 -R'C(0)NHR", -R'C(O)NR' -R'NHC(0)R" and -R'NR where R" and are independently optionally substituted (C 1 -C 1 8 )alkyl, (C 3 -C 1 8 )cycloalkyl, (C 3 -C 1 8 )cycloalkyl(C 1 18 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 18 )alkenyl, (C 8 -C 26 )aralkenyl, (C 2 -C 18 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, and R' is an optionally substituted divalent radical derived from (Cf-C 18 )alky), (C 3 -C 1 8 )cycloalkyl, (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 g)alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, 1 8g)alkenyl, (C 8 -C 26 )aralkenyl, (C 2 -C 1 8 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, provided that any substitutent present on (CI-C 1 8 )alkyl is other than hydroxyl or carbonyl, or RI is CR R 6 where R 4 R 5 and R 6 are independently a group R, wherein R is as previously defined; or R 4 has the meaning of R as previously defined and R 5 and R 6 taken together are 0, S, NH or NR; and R 2 is ft ft... S ft ft. ft. ft ft. ft ft.. ft ft. ft. ft ft ft ft ft. ft ft.. ft ft... ft. ft ft ft. ft. ft ft ft ft ft... ft. ft ft ft ft ft... 3 R7 D where R 7 is a group R as previously defined; D is 0 or S; Y is hydrogen, -R or -OR, where R is as previously defined, or is an amino acid, aza-amino acid or peptide residue in which any functional group present is optionally protected; and B is optionally absent or is (CI-C 6 )alkylidene, wherein any one or more -CH1 2 groups may be replaced by or provided that the compound of Formula (IY) does not contain a chain of three or more atoms which are not carbon; and wherein any F-I atom may be substituted by a group R as previously defined, provided that when B is -CH 2 and D is 0, Y is a group R 9 wherein R 9 is selected from the group consisting of hydrogen, -RIO1-, -RIOC(O)0RI 1 -R 1 OCikS)NII 2 -RIOC(O)NIIRI 1, -RI0C(O)NRI 1 R 12 and -RIOC(O)Rl 1, where IN ALIBM\AftI4XICLAIMCD 53 R 1 1 and R 12 are independently optionally substituted (C 1 -C 18 )alkyl, (C 3 -C 1 8 cycloalkyl, (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 26 )aralkeniyl, (CI-C 1 8 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, and RIO is a divalent radical derived from (Cj-C, 8 )aikyl, (C 3 -C 1 8 )cycloalkyl, (C 3 -C 1 B)cycloalkyl(C I I )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 1 8 )alkenyl, (Cg-C 26 )aralkenyl, (C 2 -C 1 8 )alkynyl, (Cg-C 26 aralkynyl or heterocYclic; and optionally N, RI and R 7 taken together form a cyclic diazaalkane of the formula: R 8 CHRI RHQ CHR or N N NN RCH H N N where p is I to 3, eachi R is independently as defined above and R 8 is R, -Nil 2 -NI-R, -NR 2 -COOH, -COOL, -CHO, -CN, hialo, -CF 3 -OL, -SR, -S(O) 2 R, -CONH 2 -CONHR, -CONR 2 -NFIOH, -NHOL, -NO 2 =O, =S or -NI-NH 2 wherein each R is independently as defined above and each L is independently R or a hydroxyl protecting group which is labile in vivo; Stott:or R 2 N* and R 4 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore which may be additionally substituted by where Y is as previously defined .0 and R 3 is X- W- A' -Q -A wherein: to 20 one of A' and A is (C 1 -C 8 )alkylidene optionally substituted with one or more substituents R as previously defined, and the other of A' and A is (C 2 -C 8 )alkylidene optionally substituted with one or more substituents R as 9::previously defined; too:% Qis 0 oR R R R or1 I I 0OL O R OL R where L and each R, independently of the others, are as previously defined, and optionally Q and A together, or Q and A' together, or A' Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hiereinbefore; W is absent or is 0 or S, wherein R is as previously defined; IN %UIDZkNAflHEXICLA1MS:CD and X is hydrogen, or X1, where X 1 is Ra- or RbC(O)- or RbS(O)z-, where z is 1 or 2 and Ra and Rb are independently (CI-C 1 8 )alkyl, (C 3 -C 18 )cycloallcyl, (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, heterocyclic, (C I-C 18 )alkylheterocyclic, heterocyclic(C 6 -C 24 )aryloxy, (C 1 -C 1 8 alkoxy, (C 1 -C 1 8 )alkoxy(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 g)alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkoxy, 24 )aryl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkylheterocyclic, heterocyclic- oxy(C 1 -C 1 8 )alkyl, (C 1 -C 1 8 alkylamino, (C 6 -C 24 )arylamino, (C 7 -C 1 8 )aralkyl- amino: any of which may be optionally substituted as hereinbefore defined or substituted with a group Re, where Re is a group of the formula: Rf 0 Z NH OH C where Z has the meaning of Ra or Rb or is an acylated amino acid, azaamino acid or peptide residue, and Rf is the side-chain of a natural amino acid in which any functional group present is optionally protected, or wherein the Z-NH bond shown is replaced by a modified isosteric bond, such as CH 3 -NRa-, RaCH 2 NRa-, CH 3 -CHRa-, HCII=CRa-, RaCH=CRa-, HCOCHRa-, RaCOCHRa-, HCNOHCHRa-, RaCHOHCI-Ra-, HNRaCO-, H-CF:=CRa-, RaCF=CRa-, RaS(O)-, RaS(0) 2 RaP(O)ORa-, RaP(0)(ORa)CH 2 RaP(0)(ORa)0-, RaP(0)(ORa)S-, wherein each Ra is independently as previously defined. or X is Re as previously defined, or X is an optionally protected amino acid, azaamino acid or peptide residue; or when W is then X, N and the substituent R on N together may form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore or N, A' and the substituent R on N together form a saturated or L unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; 25 or wherein any two R substituents, not necessarily vicinal, taken together are optionally substituted (C 2 -C 18 )alkylidene.
3. A compound of the general formula (1Z): N*R 3 (IZ) 0 0 0 or a pharmaceutically acceptable salt threoween R 1 is a group R, wherein R is selected from the group consisting of hydrogen, -R'fI, and -R'NR where R" and are independently optionally substituted (C 1 -C 1 8 alkyl, (C 3 -,Cj 8 )cycloalkyl, (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 26 )aralk yl, (C 2 -C, 8 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, and R' is an optionally substituted divalent radical derived from (C 1 -C, 8 )alkyl, (C 3 -C 18 )cycloalkyl, (C )CycolklC 18 )alkyl, (C 6 -C 24 )arYl, (7C4aay, IN WOMZ~AflHfXICLAIMCfl (C 2 -C 1 8 )alkenyl, (C 8 -C 2 6 )aralkenyl, (C 2 -C 1 8 )alkynyl, (C8-C 2 6 )aralkynyl or heterocyclic, provided that any substitutent present on (C 1 -C] 8 )alkyl is other than hydroxyl or carbonyl, or RI is C R R 6 where R 4 R 5 and R 6 are independently a group R, wherein R is as previously defined; or R 4 has the meaning of R as previously defined and R 5 and R 6 taken together are 0, S, NH or NR; and R 2 is R7 D 1 1 -N-B-C-Y where R 7 is a group R as previously defined; D is 0 or S; Y is hydrogen, -R or -OR, where R is as previously defined, or is an amino acid, aza-amino acid or peptide residue in which any functional group present is optionally protected; and B is optionally absent or is (C 1 -C 6 )alkylidene, wherein any one or more -Gil 2 groups may be replaced by or provided that the compound of Formula (IZ) does not contain a chain of three or more atoms which are not carbon and wherein any H- atom may be substituted by a group R as previously defined, provided that when 13 is -CH 2 and D is 0, Y is a group R 9 wherein R 9 is selected from the group consisting of hydrogen, RIOH, -RIOC(O)0R 1 1 -RIOC(O)NH- 2 -RIOC(0)NI I, -RIOC(0)NR 11 RI 2 and -RIOC(O)R 11 where R 1 1 and R 12 are independently optionally substituted (CI-C 18 )alkyl, (C 3 -C 1 8 ccoky,(C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl, 7 C 4 aakl (C 2 -C 1 8 )alkenyl, (C8-C 26 )aralkenyl, (C 2 -C 18 )alkynyl, (C 8 -C 26 )aralkyniyl or heterocyclic, and RIO is a divalent radical derived fror' (C 1 -C 1 8 )alkyl, 25 (C 3 -C 1 8 )cycloalkyl, (C-C 1 8 )cycloalkyl(C 1 -C I 8 )alkYl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 26 )ar-alkeny I, (C 2 -C 1 8 )alkynyl, (C 8 -C 26 aralkynyl or heterocyclic; and optionally N, RI and R 7 taken together form a cyclic diazaalkane of the formula: IN \LIBZ\NARHEXICLAIMS:C3 NN- RH9; CHR o N, N f N N orRCH CHR N N where p is 1 to 3, each R is independently as d6fined above and R 8 is R, -NH 2 -NHR, -NR 2 -COOH, -COOL, -CHO, -CN, halo, -CF 3 -OL, -SR, -S(O) 2 R, -CONH 2 -CONHR, -CONR 2 -NH-Oll, -NHOL, -NO 2 =0, 6 =S or -NHNH 2 wherein each R is independently as definied above and each L is independently R or a hydroxyl protecting group which is labile in vivo; or R 2 N* and R 4 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore which may be additionally substituted by where Y is as previously defined and R 3 is X- W- A' -Q wherein: A' is (C 1 -C 8 )alkylidene which may be substituted with one or more substituents R as previously defined; Q and A taken together are R. R R Ii I or I I R. OL R 16 wherein L and each R, independently of the others, are as previously defined, provided that at least one of the groups R is other than hydrogen; *5*and optionally Q and A together, or Q and.A' together, or Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; 20 W is absent or is 0 or S, wherein R is as previously defined; to 00:94,and X is hydrogen, or X1, wbh.'re X1 is Ra- or RbC(O)- or RbS(O)z-, where z is 0 0 1 or 2 and Ra and Rb are independently (C 1 -C 18 )alkyl, (C 3 -C 18 )cycloalkyl, *(C 3 -C 18 )cycloalkyl(C I -C 18 )alkyl, heterocyclic, (C 1 I 8 )alkylhieterocyclic, lieterocyclic(C 6 -C 24 )aryloxy, (C 1 -C 1 g)alkoxy, (C 1 I -C 18 )alkoxy(C I -C 1 8)aIllyl, 0 .:66 25 (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkoxy, (C 6 -C 24 )aryl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkylheterocyclic, heterocyclic- OXY(C 1 -C 18 )alkyl, (C 1 -C 1 8 )alkylatiino, (C 6 -C 24 )arylamino, (C 7 -C 1 8 )aralkyl- amino; any of which may be optionally substituted as hereinbefore defined or substituted with a group Re, where Re is a group of the formula: IN \LUM\NAIIHEXICLAIMSICU Rf 0 Z NH CH C where Z has the meaning of Ra or Rb or is an acylated amino acid, azaamino acid or peptide residue, and Rf is the side-chain of a natural amino acid in which any functional group present is optionally protected, or wherein the Z-NH bond shown is replaced by a modified isosteric bond, such as CH 3 -NRa-, RaCH 2 NRa-, CH 3 -CHRa-, HCH=CRa-, RaCH=CRa-, HCOCHRa-, RaCOCHRa-, HCHOHCHRa-, RaCHOHCHRa-, HNRaCO-, HCF=CRa-, RaCF=CRa-, RaS(O)-, RaS(0) 2 RaP(0)ORa-, RaP(O)(ORa)CH 2 RaP(0)(ORa)O-, RaP(0)(ORa)S-, wherein each Ra is independently as previously defined. or X is Re as previously defined, or X is an optionally protected amino acid, azaamino acid or peptide residue; or when W is then X, N and the substituent R on N together may form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore or N, A' and the substituent R on N together form a saturated or 16 unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; or wherein any two R substituents, not necessarily vicinal, taken together are optionally substituted (C 2 -Cl 8 )alkylidene.
4. A compound of the general formula (IE) or (IF) R 21 R22 R 24 X'N N N Y X N I I Y R OL R23 R21 R22 R24 X,N/ N,,N Y 1 I I R O R23 O wherein: ,"lR 21 is hydrogen, optionally substituted (Ci-Ci2)alkyl; optionally substituted (C 6 Cl2)aryl; or optionally substituted (C7-Cl6)aralkyl; 26 R 22 is (Ci-C8)alkyl or (C7-Ci6)aralkyl, or wherein R 2 1 and R 22 taken together are wherein n is 2-8; R 23 is hydrogen; optionally substituted (Ci-CI2)alkyl; (CG-Cl2)aryl; (C7-C16)aralkyl; or wherein R 22 and R 23 taken together are wherein m is 3-6 and R 25 has the meaning of R; R 24 is hydrogen; optionally substituted (Ci-Cl 2 )alkyl; optionally substituted (C7-Cl6)aralkyl; or optionally substituted (C6-CI2)aryl; IN LIOZ\NAfHEXICLAIMS:CD 58 or wherein NR 23 and NR 24 taken together may be a cyclic diazaalkane as hereinbefore defined; X and Y are as defined in claim 1; and L is H or a protecting group that protects the hydroxyl group during synthesis and/or prevents premature metabolism of the compound. S. A compound according to claim 4 wherein Y is different to X.
6. A compound selected from the group consisting of: cis- 1, 6-3-t-butoxycarbonyl-4-[(2RS, 3S)-2-hydroxy-3-(phenylmethoxy- carbonyl)amino-4-phenylbutyl] -3 ,4-diaza-bicyclo[4 O]decane; (ii) cis- 1 ,6-3-t-butoxycarbonyl-4-I(2S, 3S)-2-hlydroxy-3-(phenylmethloxycarbonyl)- amino-4-phenylbutylJ-3 ,4-diaza-bicyclo[4. 4. O]decane; (iii) cis- 1, 6-3-t-butoxycarbonyl-4jj2RS, 3S)-2-hydroxy-3-(N-quinaldyl-L-valyl)- amino-4-phenylbutyl] -3 ,4-diaza-bicyclo[4 Qldecane; (iv) cis- 1 ,6-3-t-butoxycarbonyl-4-[2RS, 3S)-2-hiydroxy-3-(N-quinaldyl-L- asparaginyl)ainino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4 Oldecane; cis- 1 ,6-3-t-butoxycarbonyl-4-[(2S, 3S)-2-hiydroxy-3-(N-quinaldyl-L- asparaginyl)amino-4-phenylbutyll-3 ,4-diaza-bicyclo[4 Oldecane; (vi) cis- 1, 6-3-t-butoxycarbonyl-4-[(2RS, 3S)-2-hiydroxy-34[N-(2-pyridyl)-methoxy- carbonyl-L-valyllamino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4 O]decane; o 20 (Vii) cis- 1 ,6-3-t-butoxycarboniyl-4-[(2RS, 3S)-2-liydroxy-3-(N-quinaldyl-L- a glutam.inyl)amino-4-pheniylbutyl]-3 ,4-diaza-bicyclo[4 Oldecane; (viii) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2RS, 3S)-2-hiydroxy-3-(N-quinaldyl-L- threonyl)amino-4-phenylbutyl[-3 ,4-diaza-bicyclo[4 Qidecane; 00,0 (ix) 2-t-butoxycarbonyl-3-[(2RS, 3S)-2-hydrox-3 -(phenylmethioxycarbonyl)amino- 0 0: 24-phienylbutyl]-2,3-diaza-bicyclo[2.2. Wx 2-t-butoxycarbonyl-3-[(2RS, 3S)-2-hIydroxy-3-(phienyl miethioxycarbonyl)amino- *Soo*:4-plienylbutylj-2,3-diaza-bicyclo[2 1Iheptane; (xi) 2-t-butoxycarbonyl-3-[(2RS, 3S)-2-hiydr-oxy-3-[N-(2-pyridy 1)-methoxy- carbonyl-L-valyllaniino-4-phenylbutyl]-2 ,3-diaza,-bicyclo[2 1 1-heptane; (xii 1S)(2-metliyl-l1-rnethoxycarbonylpropyl)carbamoyll-3-1(2RS, 3S)-2- hydr-oxy-3-[N-(2-pyridyl)methoxy-L-valyllanilino-4-pheniylbutyll -2 ,3-diaza-bicyclo[2 .2.1]l- heptane; (xiii) 2-t-butoxycarbonyl-3-[(2RS, 3S)-2-lhydroxy-3-(N-quinialdyl-L-asparaginiyl)- amino-4-phenylbutyl] -1 ,2 ,3,4-tetrahydrophithalazinie; (xiv) 1 -t-butyloxycarbonyl-2-I(2S, 3S)-2-hiydroxy-3-(plienylmetlioxycarbonyl)amino- 4-phenylbutyllhexahiydropyridazine; (xv) 1-t-buty~oxycarbonyl-2-[(2S, 3S)-2-hiydroxy-3-(N-quinaldyl-L-asparaginyl)- aininio-4-phienylbutyllhexahydropyridazine; and (Xvi) cis-1I,6-3-t-butoxycarboniyl-4-[(2S ,3S)-2-hiydroxy-3-(N-quinaldyl-3-cya no-L- alanyl)ainino-4-phenylbutyl]-3 ,4-diaza-bicyclol4 .4 .O]dccane, IN XLrnZ\NARIIEXICLAIMS:SAK 59 or a pharmaceutically acceptable salt thereof.
7. A compound of the general formula (IG): or a pharmaceutically acceptable salt thereof, wherein: 6 RI is a group R, wherein R. is selected from the group consisting of hydrogen, -R'H, -R'NR" and where and are independently optionally substituted (C 1 -C 1 8 )alkyl, (C 3 -Cj 8)cycloalkyl, (C 3 -C 1 8)cyclo- alkyl(C i-Ci 8 )alkyl, (C 6 -C2 4 )aryl, (C 7 -C 2 4)aralkyl, (C 2 -C 1 8)alkeiiy1, (C 8 -C 2 6 aralkenyl, (C 2 -C1 8 )alkynyl, (C 8 -C 2 6)aralkynyl or heterocyclic, and R' is an optionally substituted divalent radical derived from (C 1 -C 1 8 )alkyl, (C 3 -C 1 8 )cycloalkyl, (C 3 -C 1 8 )cycloalkyi (C 1 -C 1 8)alkyl, (C6-C24)a'ryl, (C7-C 2 4)aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 2 6)aralkenyl, (C 2 -C 1 8 )alkynyl, (C8-C 2 6)aralkynyl or heterocyclic, 16 or RI is C R R6 R 4 R 5 and R 6 are independently a group R. as previously defined, or R has the meaning of R as previously defined and R 5 and R 6 taken together are 0, S, NH or NR; 00 20 and R 2 is R7 D S -N-B-C-Y 0 where R 7 is a group R. as previously defined; D is 0 or S; Y is hydrogen, or 5 -OR, where R. is as previously defined, or is an amino acid, aza-amino acid or peptide residue in which any functional group present is optionally protected; and 13 is optionally absent or is (C 1 -C 6 )alkyliclcnc, wherein any one or more -CEU 2 groups may be replaced by or provided that the compound of Formula (IG) does not contain a chain of three or more atoms which are !lot carbon, and wherein any 14 atom may be substituted by a group R as previously defined; and optionally N, R. 1 and R 7 taken together form a cyclic diazaalkane of the formula: (N %LWDZNARI4tXICLAIMSAK (CHR)p (CHR4., NN1\ 'N N orRICH, CHR N N where p is I to 3, each R is independently as defined above and R 8 is R, -NI- 2 -NHR, -NR 2 -COOH, -COOL, -CH-O, -CN, halo, -CF 3 -OL, -SR, -S(O) 2 R, -CONFI 2 -CONHR, -CONR2, -NHOI-, -NHOL, -NO 2 =O, 6 =S or -NI-NH 2 wherein each R is independently as defined above and each L is independently R or a hydroxyl protecting group which is labile in vivo and which prevents premature metabolism of the compound of formula (IG) after administration to a patient; or R 2 N* and R 4 together form a saturated or unsaturated cyclic, bicyclic or 10 fused ring system as defined hereinbefore which may be additionally substituted by where Y is as previously defined and R 3 isX- W -Q -A -,wherein: A' and A independently are absent or (C 1 -CS)alkylideile which may be 16substituted with one or more substituents R as previously defined; Q is R R R or c OL OL R where each R, independently of the others, are as previously defined, and L is R too*&:or a hydroxyl protecting group Which is labile in vivo and which prevents premature metabolism of the compound of formula (IG) after administration to a patient, provided that L is other than hydrogen; and optionaly Q and A together, or Q and A' together, or Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinibefore; W is absent or is 0 or S, wherein R is as previously defined; 26 and X is hydrogen, or X I, where X I is Ra- or RbC(O)- or- RbS(O)z-, where z is I. or 2 and Ra and Rb are independently (C 1 -C 18 )alkyl, (C 3 -C 18 )cycloalkyl, (C 3 -C 1 8 )CYCloalkyl(C 1 -C 1 g)alkyl, heterocycl ic, (C-C, 8 )alkyllheterocyclie, heterocycliC(C 6 -C 24 )aryloxy, (C -C 18 )alkoxy, (CI-C 18 )alkoxy(C 1 -C 1 I )alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryloxy(C 1 -C, 8 )ailkoxy, (C 6 -C 24 )aryl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkylhieterocyclic, heterocyclic- OXY(C 1 -C 1 8 )alkyl, (C 1 -C 18 )alkylamino, (C 6 -C 24 )ary lainto, (C 7 -C 1 8 )aralkyl- IN WIZNARHEXICLAIM9:SAK 61 amino; any of which may be optionally substituted as hereinbefore defined or substituted with a group Re, where Re is a group of the formula: Rf 0 Z NH CH C wihere Z has the meaning of Ra or Rb or is an acylated amino acid, azaamino acid or peptide residue, and Rf is the side-chain of a natural amino acid in which any functional group present is optionally protected, or wherein the Z-NH bond shown is replaced by a modified isosteric b)ond, such as CH- 3 -NRa-, RaCH 2 -NRa-, CH 3 -CHRa-, FICII= CRa-, RaCH =CRa-, I-COCHRa-, RaCOCI-Ra-, I-CFIOI-CI-Ra-, RaCI-OFICH[Ra-, HNRaCO-, HCF =CRa-, RaCF=CRa-, RaS(O)-, RaS(0) 2 RaP(O)QRa-, RaP(O)(ORa)CH 2 RaP(O)(ORa)0-, RaP(O)(ORa,)S-, wherein each Ra is independently as previously defined, or X is Re as previously defined, or X is an optionally protected amino acid, azaamino acid 01. peptide residue; or 16i when W is then X, N and the substituent R on N together may form a 0 0 saturated or unsaturated cyclic, bicyclic or fvjsed ring system as defined hereinbefore or N, A' and the substituent R on N together form a saturated or sea0 unsaturated cyclic, bicyclic or fused r-ing systenm as defined here inbe fore; 0 or wherein any two R substituents, not necessarily vicinal, taken together are optionally substituted (C 2 -C 1 8 )alkyl idene.
8. A compound of the formula (LIH) R'NZKR 3 (LI-) R'R 2 or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group R, wherein R is selected from the group consisting of hydrogen, -R'H, 25 -R'C(O)NI4 2 -R'C(O)NR' -R'NH-C(0)R'' and -R'NR where and are independently optionally substituted (C 1 18 )alkyl, (C 3 -C 1 8 )cyeloalkyl, (C 3 -C 1 8 )cycloalkyl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 26 )aralkcniyl, (C 2 -C, 8 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, and R' is an optionally substituted divalent radical derived from (C 1 -C 1 8 )alkyl, (C 3 -Ct 8 )cycloa'lkyl, (C 3 -C 1 8 )cycloalkyl(C -C 18 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, (C 2 -C 18 )alkenyl, (C 8 -C 26 )aralkenyl, (C 2 -C 18 )alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, provided that any substitutent present on (C I-C 18 )alkyl Is other than hydroxyl or carbonyl, IN WOINAfII4XICLAIMSAK or R 1 is C R where R 4 R 5 and R 6 are independently a group R, wherein R is as previously defined; or R 4 has the meaning of R as previously defined and R 5 and R 6 takei,, together are 0, S, NH or NR, and R 2 is R7 D -N-B-C-Y where R 7 is a group R as previously defined; D is 0 or S; Y is hydrogen, -R or -OR, where R is as previously defined, or is an amiino acid, aza-arnino acid or peptide residue in which any functional group present is optionally protected; and B is optionally absent or is (C 1 -C 6 )alkylidene, wherein any one or more -Cl-I 2 groups may be replaced by or provided that the compound 'P *of Formula (IY) does not contain a chain of three or more atomis which are not carbon and wherein any H- atom may be substituted by a group R as previously 16 i defined, provided that when B is -C11I 2 and D is 0, Y is a group R9 wherein R 9 too* 0 0 is selected from the group .onsisting of hydrogen, -RIOH-, -RIOC(O)OR 1 1 -R 10 )C(O)NH 2 -RIOC(O)NH-R 1 I, -RIOC(O)NR' 1 RI 2 and -RI')C(0)R 1 I, where R 1 I and R 12 are independently optionally substituted (C 1 -C, 8 )alkyl, (C 3 -C 1 8 cycloalkyl, (C 3 -C 1 8 )cycloalkyl(C -C 1 8 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 24 )aralkyl, 20 (C 2 -C 18 )alkenyl, (C 8 -C 26 )aralkenyl, (C 2 -C, 8 )alkynyl, (C 8 -C 26 )aralkynyl or :heterocyclic, and RIO is a divalent radical derived from (C I 8 )alkyl, (C 3 -C 1 8 )cycloalkyl, (C 3 -C 18 )cycloalkyl(C I -C 18 )alkyl, (C 6 -C 24 )aryl, (C 7 -C 2 4)aralkyl, (C 2 -C 1 8 )alkenyl, (C 8 -C 26 )ar1alkenyl, (C 2 -C 1 8 )alkynYl, (C 8 -C 26 aralkynyl or heterocyclic; 26 and optionally N, R' and R 7 taken together form a cyclic diazaalkane of the fornmula: (CHR)p (CHR)o N N RHC N N CHR o C H N N where p is I to 3, cachi R is independently as defined above and R 8 is R, -NH- 2 -NHR, -NR 2 -COOH, -COOL, -CHO, -CN, halo, -CF 3 -OL, -SR, IN tI1ttNAFlItXCAIM4 SAK 63 -S(O) 2 R, -CONH 2 -CONI-R, -CONR 2 -NHOH, -NI-OL, -NO 2 =0, =S or -NHNH 2 wherein each R is independently as defined above and each L is independently R or a hydroxyl protecting group which is labile in vivo; or R 2 N* and R 4 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore which may be additionally substituted by where Y is as previously defined and R 3 is X- W A' Q A wherein: A' and A independently arc absent or (C 1 -C 8 )alkylidenc which may be substituted with one or more substituents R. as previously defined; Q is R.R R R OL 0 R Ol'R whbere L and each R, independently of thle others, are as previously defined, and optionally Q and A together, or Q and A' together, or Q and A together form part of a saturated or unsaturated cyclic, bicyclic o- fuscd ring system as defined hereinbefore; W is 0 or S, wherein R is as previously defined; fee. and X is hydrogen, or X 1 where X I is Rn- or RbC(O)- or RbS(O)z-, where z is 9~*I or 2 and Ra and Rb are independently (C 1 -C 18 )alkyl, (C 3 -C, 8 )cycloalkyl, (C 3 -C 1 8 )cycloalkyl(C I-C 1 8 )alkyl, heterocycl ic, (C I -C 18 )alkylhecter-oeyclic, 20 hecterocycliC(C 6 -C 24 )aryloxy, (C I -C 18 )alkoxy, (C I -C 1 8 )alkoxy(C I -C 18 )alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkoxy, (C 6 -C 2 1 )aryl, :(C6-C24)aryl(Cp-Cj8)aky, (C6-C24)aryi(C -CI)alkylhecterocyclic, heterocyclic- amino; any of which may be optionally substituted as hercinbefore dcfined or substituted with a group Re, where Re is a group of the formula: P ~:Rf 0 Z NH CH C where Z has the meaning of Rn or Rb or is an acylated amino acid, azaarnio acid or peptide residue, and Rf is the side-chain of a natural amino acid in which any functional group present is optionally protected, or wherein the Z-NI- bond shown is replaced by a modified isosteric bond, such as C[1 3 -NRa-, RaCH4 2 -NRa-, CI- 3 -CiTRa-, HCHl C Ra-, RaCI1-1 CRa-, HCOCI-Ra-, RaCOCf Ra-, H-CI-OflCH Ra-, RaCI OHCIIRa-, [-NRaCO-, UHCF=CRa-, RaCF =CRa-, RaS(O)-, RaS(O) 2 RaPOOM-, RaP(O)(O11a)C11 2 RaP(O)(ORa)O-, RaP(O)(ORa)S-. wvherein each Rn is independently as as~ previously defined, IN %ItNARI~tXtAIM9 OAK or X is Re as previously defined, or X is an optionally protected amnino acid, azaarnino acid or peptde residue; or wherein any two R substituents, not necessarily vicinal, taken together are optionally substituted (C 2 -C 18 )alkylidene. 6 9. A pharmaceutical composition comprising a compound according to any one of claims 1-8 together with one or more pharmaceutically acceptable carriers. A method for inhibiting an H-IV protease in a mnammal in need of such protease inhibition, comprising administering to said mammal an effective amount of a compound according to any one of claims 1-8 or of a pharmaceutical composition io according to claim 9. It. A method for the treatment or prophylaxis of acquired immune deficiency syndrome in a mamimal in need or' such treatmcnt or prophylaxis, comprising administering to said mammal an effective amount of a compound according to any one of claims 1-8 or of a pharmaceutical composition according to claim 9.
12. A method for the treatment or prophylaxis of' acquired immune deficiency Soso*: syndrome in a mamimal in nieed of such treatment or prophylaxis, comprising administering to said mammal an effective amount of one or more active substances effective for the treatment of H-IV viral infections, together with an effective amount of a compound of' the formula (1K) C Ri' (1K) or pharmaceutically acceptable salts thereof, wherein: RI is a group R, wherein R is selected from the group consisting of hydrogen, -WI-I, -R'C(O)NI-1 2 -R'C(O)NF11V, -R'C(O)NR'R -R'NHC(O)R', and where and are independently 25 optionally substituted (C 1 -C 1 8)alkyl, (C 3 -C 1 8)cycloalkyl, (C 3 -C 1 8)cyclo- 0 :alkyl(C j-C 1 8)alkyl, (C 6 -C2 4 )aryl, (C7-C 2 4)aralkyl, (C 2 -Cj 8)alkeniyl, (C8-C 26 4:696:aralkenyl, (C2-C 1 8)alkyniyl, (C8-C2 6 )aralkynyI or heterocyclic, and R' is an optionally substituted divalent radical derived from (C 1 -C 1 8 )alkyl, (C 3 -C 1 8)cycloalkyl, (C 3 -C 1 8)cycloalkyl(C j-C 1 8)alkyl. (C6-C24)aryl, (C7-C24)aralkyl, (C 2 -C 1 8 )alkcnyl, (C8-C26)aralkenyl, (C2-C 1 8)alkynyl, (C 8 -C 26 )aralkynyl or heterocyclic, or RI is C R INA'Lit NARMEIXICLAIMS O3AK where R 4 R 5 and R 6 are independently a group R as previously defined, or R 4 has the meaning of R as previously defined and R 5 and R 6 taken together are =NH or =NR; and R 2 is R 7 D I II -N-B--C-Y where R 7 is a group R as previously defined; D is O or S; Y is hydrogen, -R or -OR, where R is as previously defined, or is an amino acid, aza-amino acid or peptide residue in which any functional group present is optionally protected; and B is optionally absent or is (Ci-C 6 )alkylidene, wherein any one or more -CH2- groups may be replaced by or provided that the compound of Formula (IK) does not contain a chain of three or more atoms which are not carbon, and wherein any H atom may be substituted by a group R as previously defined; and optionally N, R 1 and R 7 taken together form a cyclic diazaalkane of the formula: R8 q(CHR)p ;(CHR)p (CHR)p RHC CHR or NN NN N RCH CHR N N V. where p is 1 to 3, each R is independently as defined above and R 8 is R, -NH 2 -NHR, -NR 2 -COOH, -COOL, -CHO, -CN, halo, -CF 3 -OL, -SR, -S(0) 2 R, -CONH 2 -CONHR, -CONR 2 -NHOH, -NHOL, -NO 2 =O, =S or -NHNH 2 wherein each R is independently as defined above and each L is 20 independently R or a hydroxyl protecting group which is labile in vivo and which prevents premature metabolism of the compound of formula (IK) after administration to a patient; or R 2 N* and R 4 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore which may be additionally substituted 26 by where Y is as previously defined and R 3 is X- W A' Q A wherein: A' and A independently are absent or (CI-C)alkylidene which may be substituted with one or more substituents R as previously defined; IN ,LIDZ\NARHEXICLAIMS SAK Q is R R R R OL 0OR OLRI where L and each R, independently of the others, are as previously defined, and optionally Q and A together, or Q and A' together, or Q and A together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; W is absent or is 0 or S, wherein R is as previously defined; and X is hydrogen, or X1, where X 1 is Ra- or RbC(O)- or RbS(O)z-, where z iF 1 or 2 and Ra and Rb are independently (C 1 -C,8)alkyl, (C 3 -C 18 )cycloalkyl, (C-C I 8 )cycloalkyl(C I -C 1 8 )alkyl, heterocycl ic, (C 1 I -C 18 )alkylheterocyclic, heterocyclic(C 6 -C 24 )aryloxy, (C 1 1 I 8 )alkoxy, (C]I -C 1 I )alkoxy(C I -C 1 I 8 )alkyl, (C 6 -C 24 )aryloxy(C -C ,,)alkyl, (C 6 -C 24 )aryloxy(C 1 -C 1 8 )alkoxy, (C 6 -C 24 )aryl, (C 6 -C 24 )aryl(C 1 -C 1 8 )alkyl, (C 6 -C 24 )aryl(C 1 I 8 ,,)alkyllheterocyc] ic, hieterocyclic- oxy(C 1 -C 1 8 )alkyl, (C 1 -C 1 8 )alkylamino, (C 6 -C 24 )arylamino, (C 7 -C 1 8 )aralkyl- *to. amino; any of which may be optionally substituted as her-einbefore defined or substituted with a group Re, where Re is a group of the formula: ZNH Rf 0 Z H CH C where Z has thle meaning of Ra or Rb or is an acylated amino acid, azaamino acid or peptide residue, and Rf is thle side-chiain of a natural amino acid in which 20 any functional group present is optionally protected, or wherein the Z-NI- bond shown is replacrd by a modified isosteric bond, such as CH 3 -NRa-, RaCi- 2 -NRa-, CH 3 -CI-Ra-, HCH =CRa-, RaCH =CRa-, HCOCHRa-, RaCOCI-Ra-, HCHOI-CHRa-, RaCHOHCI-Ra-, HNRaCO-, HCF =CRa-, RaCF =CRa-, RaS(O)-, RaS(0) 2 RaP(0)ORa-, RaP(O)(ORa)CIW2.-, RaP(O)(ORa)O-, RaP(0)(ORa)S-, wherein each Ra is independently as previously defined, or X is Re as previously defined, or X is an optionally protected amino acid, azaamino acid or peptide residue; or when W is thent X, N and the substituent R onl N together maiy form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore or N, A' and the substituent R onl N together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined hereinbefore; or wherein any two R substituents, not necessarily vicinal, taken together are op~tionally substituted (C 2 -C 18 )alkylidene. IN XLOlZ\A!QEXICLAIMS:SAK 4,,7
13. A method according to claim 12 wherein said active substance effective for the treatment of HIV viral infections is AZT and/or acyclovir.
14. A process for preparing a compound according to claim 4, comprising reacting a compound of formula (HI) R 21 0 X N CC C R 2 2 R H with a compound of formula (III) R 23 0 H NN C Y (ll wherein R, X, R 21 R 22 R 23 R 24 and Y are as defined in claim 4. Dated 11 June, 1997 Narhex Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON IN 1LI9ZkNAnHUXICLAI.MS:SAK r INTERNATIONAL SEARCH P 'ORT litternational application No, PCr/AU93/00103 A. CLASSIFICATION OF SUBJECT MATTER Int. CLS C07D 213/81; 213/30; 237/08; 237/26; 215/48; C07D 401/12; C07C 109/04; 109/087; 133/00; 243/14; C07C 243/28; 281/02 According to International Patent Clasaficatin (IPC) or to both national clasification and IPC B. FIELDS SEARCRED M'vuzu? documntation serched (classification system followed by clasification symbols) lat. Cl- C07D 213/81; 213/30; 237/08; 237t26; 215/48; 401/12 CO7C 109/04; 109/087; 133/00; 243/14; 243/28; 281/02 Documentation searched other than minimum documentation to the exten that such documents are included in the fields searched AU:IPCuasabove Electronic data basn consulted during the international search (name of data base, and where practicable, search terms used) Chemical Abstracts -"ON LINE' database for substructure search based on sub-structure (MV on page 25 of specificationt. C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* A A XtP A Citation of document, with indication, where appropriate, of the relevant passages AU,B,63221/90 (Hoechs Aktiengeaelsnfi) I11 April 1991 (11.04.9 1) AU,A,55711/90 (Abbott Laboratories) 29 November 1990 (29.11.90) AU,A,19373/92 (Ciba-Geigy AG) 7 January 1993 (70.3 US,A,3330857 (Huma-Jurgen et al) 11 July 1967 (11.07.67) see formlas colium 2 line Relevant to Claim No. 1-5 and 13 1-5 and 13 1-5 and 13 [IFuther documents arm listed in tecontinuation of Box C. See patent family Annex. Special categories of cited documents 14T" later document pub~lished after the international filing date or prioritydate and not in conflict document defining the jencral state of the ant which is with the apl~dn but cited to understand the not considered tobeA ~atioular relevance picpeo hoyudryn h neto "EN ealier document buto pulse on or after the "X is ou~n fpriua rfvne lie international RIing aeinvenion cat be considere novel or cat be document wich may throw doubts on prioritconsider)ea to involve an inventve ste whnthe or which is cited to establish "h publition daue of document Is taken alone another citation or other spxal ron (as specified) fly" dloacu nt of particular relevance; the claimed docutytent referring to an oral disclosure, use, lvent~on cannot be considered to kivolve n exhibition or other mean inventive step when the document is combtned NPII document published prior die *4trnawinal Mahi date wh ne or aroe other such documents, juch but late thian the priority 4at claimed, combinatin bng obvious to a person skiCk in "A doumn member of the same patent faily Date of the actual completion of the international search Dute of miling of the international search report 28 May 1993 (28.05.93) $3 ,79 .q Name and mailing address of the ISA/AU Authorized officer AUSTRALIAN PATENT OFFICEIB i P0 BOX 200 WODEN ACT 2606cA ICK1CM' AUSTRALIA C .MC Facsimile No. 06 2153929 Telephone No. (06) 283245 Form PCT11SAM20 (continuation of first sheod (Jutly 199) copgil InTERNATIONAL S CH R ORT Information on paenat famiy manix. Inlternsonal application No. PCTIAU93/00103 This Annex lists the known publication level patent family members relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent ocumannt Cited in Search Patent Family Member Repud& EP 217640 AU 63221/90 CA 2026382 DE 4030350 AU 55711/90 AU 55711/90 CA 2017252 EP 402646 US 5142056 US 5151438 WO 9217176 AU 19373/92 EP 521827 END OF ANNEX Form PCTISA/210(ptc t famuily anneXuly 1992) copgil
AU37391/93A 1992-03-11 1993-03-11 Amine derivatives of oxo- and hydroxy-substitued hydrocarbons Ceased AU681342B2 (en)

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Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AUPL1304 1992-03-11
AUPL130492 1992-03-11
PCT/AU1993/000103 WO1993018006A1 (en) 1992-03-11 1993-03-11 Amine derivatives of oxo- and hydroxy-substitued hydrocarbons
APAP/P/1993/000504A AP395A (en) 1992-03-11 1993-03-29 Amine derivatives of oxo- and hydroxy-substituted hydrocarbons.

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Families Citing this family (3)

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Publication number Priority date Publication date Assignee Title
EP0604368B1 (en) * 1992-12-23 1996-09-18 Ciba-Geigy Ag Anti retroviral hydrazine derivatives
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
AU697662B2 (en) * 1993-09-10 1998-10-15 Narhex Limited Polar-substituted hydrocarbons

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU660469B2 (en) * 1991-07-03 1995-06-29 Novartis Ag Pharmacologically active hydrazine derivatives and processes for the preparation thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU660469B2 (en) * 1991-07-03 1995-06-29 Novartis Ag Pharmacologically active hydrazine derivatives and processes for the preparation thereof

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