United States Patent [19J
`Jenkins et al.
`
`[54]
`
`[75]
`
`INHIBITORS OF DP-MEDIATED
`PROCESSES, COMPOSITIONS AND
`THERAPEUTIC METHODS THEREOF
`
`Inventors: Paul D. Jenkins, Ramsey; D. Michael
`Jones, Nr. Ramsey; Michael Szelke,
`Ramsey, all of United Kingdom
`
`[73] Assignee: Ferring B.V., KC Hoofdorp,
`Netherlands
`
`[21] Appl. No.:
`
`08/647,887
`
`[22] PCT Filed:
`
`Nov. 30, 1994
`
`[86] PCTNo.:
`
`PCT/GB94/02615
`
`§ 371 Date:
`
`Aug. 27, 1996
`
`§ 102(e) Date: Aug. 27, 1996
`
`[87] PCT Pub. No.: W095/15309
`
`PCT Pub. Date: Jun. 8, 1995
`
`[30]
`
`Foreign Application Priority Data
`
`Dec. 3, 1993
`Dec. 6, 1993
`
`[GB]
`[GB]
`
`United Kingdom ................... 9324803
`United Kingdom ................... 9324981
`
`Int. Cl.6
`..................................................... A61K 38/05
`[51]
`[52] U.S. Cl. ............................ 548/535; 514/19; 548/400;
`548/405
`[58] Field of Search ............................... 514/19; 548/535,
`548/400, 405
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,200,412
`
`4/1993 Whittaker ................................ 514/293
`
`FOREIGN PATENT DOCUMENTS
`
`2/1971 United Kingdom .
`1221238
`W091!16339 10/1991 WIPO .
`W093/08259
`4/1993 WIPO .
`
`OTHER PUBLICATIONS
`
`Demuth et al., Federation of European Biochemical Societ(cid:173)
`ies, 320(1): 23-27 (Mar. 1993).
`Patents Abstracts of Japan, 1(120): 2929 C 77 (Oct. 12,
`1977).
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005939560A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,939,560
`Aug. 17, 1999
`
`Lotti et al., European Journal of Pharmacology, 162:
`273-280 (1989).
`
`Primary Examiner-Cecilia J. Tsang
`Assistant Examiner-David Lukton
`Attorney, Agent, or Firm-Foley & Lardner
`
`[57]
`
`ABSTRACT
`
`A-B (Groups I and II)
`
`e-A-B
`
`/
`
`())
`
`' \ -A -B
`
`e-A-B
`
`I e-A-B
`
`(Group III)
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`Compounds selected from those of general formula [A-B
`(Groups I and II)] and (group III), (1, 2 and 3) where B is
`(4) and A is selected from specified aminoacyl compounds
`are inhibitors of DP-IV mediated processes.
`
`8 Claims, No Drawings
`
`SAXA-DEF-00023
`
`Page 1 of 23
`
`AstraZeneca Exhibit 2011
` Mylan v. AstraZeneca
` IPR2015-01340
`
`

`
`5,939,560
`
`1
`INHIBITORS OF DP-MEDIATED
`PROCESSES, COMPOSITIONS AND
`THERAPEUTIC METHODS THEREOF
`
`BACKGROUND
`
`DP-IV (EC 3.4.14.5) is a membrane-bound serine pro(cid:173)
`tease first identified in rat kidney by its ability to cleave
`dipeptides from the N-terminus of certain peptides (Hopsu(cid:173)
`Havu, V. K. and Glenner, G. G., Histochernie, 1966, 7, 197).
`The dipeptides must be of the type X-Pro or X-Ala where
`X=any amino acid. X-Proline is more efficiently cleaved
`than X-Ala.
`DP-IV is widely distributed in mammalian tissues and is
`found in great abundance in the kidney, intestinal epithelium
`and placenta (Yaron, A and Naider, F., Critical Reviews in
`Biochern. Mol. Bioi. 1993,28 (1), 31). In the human immune
`system the enzyme is expressed almost exclusively by
`activated T-lymphocytes of the CD4+ type where the 20
`enzyme has been shown to be synonymous with the cell(cid:173)
`surface antigen CD26.
`The exact role of DP-IV in human physiology is not
`completely understood but recent research has shown that
`the enzyme clearly has a major role in human physiology
`and pathophysiology, eg.
`(a) The immune response: DP-IV expression is increased
`in T-cells upon mitogenic or antigenic stimulation (Mattern,
`T. et al., Scand. J. Irnrnunol. 1991, 33, 737). It has been 30
`reported that inhibitors of DP-IV and antibodies to DP-IV
`suppress the proliferation of mitogen- and antigen(cid:173)
`stimulated T-cells in a dose-dependant manner (Schon, E. et
`al., Bioi. Chern. Hoppe-Seyler, 1991, 372, 305 and refs. 35
`within).
`Various other functions ofT-lymphocytes such as cytok(cid:173)
`ine production, IL-2 mediated cell proliferation and B-cell
`helper activity have been shown to be dependant on DP-IV
`activity (Schon, E. et al., Scand. J. Irnrnunol. 1989, 29, 127).
`Recently, DP-IV inhibitors based on boroproline where
`reported (Flentke, G. R. et al., Proc. Natl. Acad. Sci. USA,
`1991, 88, 1556) which, although unstable, were effective in
`inhibiting antigen-induced lymphocyte proliferation and 45
`IL-2 production in murine CD4+ T-helper cells. Such
`boronic acid inhibitors have been shown to have an effect in
`vivo in mice causing suppression of antibody production
`induced by immune challenge (Kubota, T. et al., Clin. Exp.
`Irnrnunol. 1992, 89 192). Other recent papers also provide 50
`evidence for the involvement of DP-IV in the immune
`response (eg. Tanaka, T. et al., Proc. Natl. Acad. Sci. NY,
`1993, 90, 4586; Regen, M. et al., Cell Irnrnun. 1993, 146
`249; Subramanyan, M. et al., J. Irnrnunol. 1993, 150, 2544). 55
`The importance of DP-IV is attributed by some investi(cid:173)
`gators to its cell-surface association with the transmembrane
`phosphatase CD45 (Torimoto, Y. et al., J. Irnrnunol. 1991,
`147, 2514). The CD45-DP-IV association is possibly dis(cid:173)
`rupted by DP-IV inhibitors or non-active site ligands. CD45 60
`is known to be an integral component of T-cell signalling.
`(b) Recently, a press release from the Pasteur Institute in
`Paris (and subsequently a presentation by A G. Hovanessian
`at the 8th Cent. Gardes Meeting, Paris, Oct. 25-27th 1993) 65
`reported that DP-IV was essential for the penetration and
`infectivity of HIV-1 and HIV-2 viruses in CD4+ T-cells. The
`
`15
`
`2
`French group claimed that DP-IV interacted with and may
`have cleaved the V3 loop of the gp120 envelope glyco(cid:173)
`protein of the virus. They also reported that inhibitors or
`antibodies to DP-IV successfully prevented entry of the
`5 virus into cells. It was known previously that there is a
`selective decrease of CD26 expression in T-cells from HIV-1
`infected individuals (Valle-Blazquez, M. et al., J. Irnrnunol.
`1992, 149, 3073), and that HIV-1 Tat protein binds to DP-IV
`10 (Subramanyam, M. et al., J. Irnrnunol. 1993, 150, 2544).
`(c) It has been shown recently that lung endothelial DP-IV
`is an adhesion molecule for lung -metastatic rat breast and
`prostate carcinoma cells (Johnson, R. C. et al., J. Cell. Bioi.
`1993, 121, 1423). DP-IVis known to bind to fibronectin and
`some metastatic tumour cells are known to carry large
`amounts of fibronectin on their surface.
`(d) DP-IV has been shown to associate with the enzyme
`adenosine deaminase (ADA) on the surface of T-cells
`(Kameoka, J. et al., Science, 1993, 261, 466). ADA defi(cid:173)
`ciency causes severe combined immunodeficiency disease
`(SCID) in humans. This ADA-CD26 interaction may pro(cid:173)
`vide clues to the pathophysiology of scm.
`(e) High levels of DP-IV expression have been found in
`human skin fibroblast cells from patients with psoriasis,
`rheumatoid arthritis (RA) and lichen planus (Raynaud, F. et
`al., J. Cell. Physiol. 1992, 151, 378).
`(t) High DP-IV activity has been found in tissue homo(cid:173)
`genates from patients with benign prostate hypertrophy and
`in prostatosomes. These are prostate derived organelles
`important for the enhancement of sperm forward motility
`(Vanhoof, G. et al.,Eur. J. Clin. Chern. Clin. Biochern. 1992,
`30, 333).
`(g) DP-IV has been shown to be responsible for the
`degradation and inactivation of circulating peptides with
`penultimate proline or alanine at the N-terminus, eg. sub-
`40 stance P, growth hormone releasing factor and members of
`the glucagon/vasoactive intestinal peptide family
`(Menthein, R. et al., Eur. J. Biochern. 1993, 214, 829).
`
`25
`
`(h) Raised levels of DP-IV have been observed in the
`gingiva of patients with periodontitis (Cox, S. W. et al.,
`Arch. Oral. Bioi. 1992, 37, 167).
`(i) There are also a number of other reports of raised (or
`sometimes lowered) levels of DP-IV in various pathological
`conditions.
`It follows from the above that potent inhibitors of DP-IV
`may be useful as drugs for the treatment of human disease.
`Such inhibitors could be useful as:
`
`(a) Immunosuppressants, eg. in organ transplantation;
`cytokine release suppressants eg. in various autoim(cid:173)
`mune diseases such as inflammatory bowel disease,
`multiple sclerosis, RA
`(b) Drugs for the prevention of HIV entry into T-cells and
`therefore useful in the prophylaxis and treatment of
`AIDS.
`(c) Drugs for the prevention of metastases, particularly of
`breast and prostate tumours to the lungs.
`(d) Agents to treat dermatological diseases, eg. psoriasis,
`lichen planus.
`(e) Drugs to suppress sperm motility and therefore act as
`male contraceptive agents.
`
`SAXA-DEF-00024
`
`Page 2 of 23
`
`

`
`5,939,560
`
`15
`
`20
`
`35
`
`40
`
`3
`(t) Agents beneficial in benign prostate hypertrophy.
`Inhibitors of DP-IV
`The only competitive inhibitors ofDP-IV enzyme activity
`reported so far are the unstable boronic acids (t¥2 30-90 min 5
`at pH 7) mentioned above. (Bachovchin et al., WO
`91!16339, October 1991) having K; values in the nanomolar
`range for DP-IV, and simple amino-acid pyrrolidides or
`thiazolides (Neubert et al., DD 296 075 AS, November
`1991) which have only modest potency (K;>0.1 ,uM). 10
`Amino-acyl praline aldehydes claimed in the same German
`patent cannot be synthesised due to a facile intramolecular
`condensation of the N-terminal amino group with the alde-
`hyde function.
`We now disclose highly potent competitive inhibitors of
`DP-IV (with K; values in the 10- 6-10- 10 range) which are
`also chemically stable (t¥2>24 h). They fall into three broad
`groups of compounds (Groups I, II and III).
`GROUP I
`These are molecules designed to bind tightly in the active
`site of DP-IV and to inhibit its proteolytic activity without
`interfering with attachment of any accessory ligands which 25
`may bind to the surface of DP-IV (i.e. not at its active site).
`Such Group I compounds could be useful as immunosup(cid:173)
`pressants; anti-HIV infectivity agents; agents to suppress
`release of certain cytokines (eg. IL-2, IL-6, y-INF) from
`activated T-cells. The boronic acids and pyrrolidides 30
`referred to earlier also fall into this category.
`GROUP II
`These are evolved from Group I compounds; however
`they contain long -chain extensions to the side-chains of the
`amino-acid defined as A in the general structure. The result(cid:173)
`ing compounds bind tightly to the active-site of DP-IV but
`the long-chain extensions protrude from the enzyme active
`site and serve to prevent the attachment of any other ligand
`which may bind to the surface of DP-IV. Such compounds
`could have the same uses as Group I compounds but in
`addition could block the interaction of DP-IV with (i) CD45
`(ii) the gp 120 V3 loop of HIV-1 (iii) tumour cell surface
`fibronectin (iv) any other ligand important for T-cell 45
`activation, virus entry into T-cells or tumour cell adhesion.
`GROUP III
`This group comprises novel dimers in which two active(cid:173)
`site directed inhibitors of DP-IV are linked via the side- 50
`chains of their amino-acid residues designated A in the
`general structure by a long chain. Such dimers can inhibit
`two molecules of DP-IV concurrently and also prevent
`accessory ligands binding to the surface of DP-IV. These
`dimers would have the same uses as Group II compounds 55
`but may be more effective.
`The invention provides inhibitors of DP-IV mediated
`processes, the inhibitors being of general formula:
`A-B (Groups I and II) or
`
`60
`
`e-A-B
`/
`"\,
`e-A-B
`
`(Group II)
`
`65
`
`where B is
`
`4
`
`n=1 or 2;
`m=O, 1 or 2;
`X=CH2 , 0, S, SO, S02 ,
`NH or NR1 where R1 =lower alkyl (C1 to C6);
`A is attached to Y;
`- Y =-N, -CH or =C (when the -CO group of A is
`replaced with CH=or CF=);
`R=H, CN, CHO, B(OH)2 , C==C-R7 , or CH=N-R8 ;
`R7 =H, F, lower alkyl (C1 to C6 ), CN, N0 2 , OR9 , C0 2 R9
`or COR9 ;
`R8 =Ph, OH, OR9 , OCOR9 , or OBn;
`R9 =lower alkyl (CcC6 ); and either w or both E's may be
`absent.
`The structure of A is dependent on the nature of R in
`moiety B and on the nature of the group to which the
`resulting compound belongs.
`Group I Compounds
`(a) R=H
`A is an a-amino-acyl group derived from an a-amino-acid
`bearing a cycloaliphatic side-chain (e.g. c4 to c10' mono or
`bicyclic) whose ring may contain one or more heteroatoms
`e.g. L-cyclohexylglycine, L-cyclopentylglycine,
`L-decahydronaphthylglycine, L-piperidylglycine;
`or
`A is a ~-amino-acyl group of general formula
`
`/CH-NH2
`
`(CH2)p I
`
`'cH-CO-
`
`where p=1-6 and the ring may also contain one or more
`heteroatoms replacing CH2 unit(s).
`Both a and ~-amino acyl groups in (a) above may contain
`unsaturation in their rings e.g.
`
`also may contain one or more heteroatoms.
`(b) R=CN: C-C-R7 or CH=N-R8
`A is as defined in (a) above but in addition may be derived
`from any L-a-amino acid bearing a lipophilic side-chain, eg.
`Ile.
`(c) R=CHO or B(OH)2
`A is a ~-amino-acyl group as defined in (a) above. The
`resulting A-B compounds are stable, unlike a-aminoacyl
`
`SAXA-DEF-00025
`
`Page 3 of 23
`
`

`
`5
`derivatives of the same type which undergo a facile intramo(cid:173)
`lecular cyclisation. In compounds (c) B(OH)2 may be
`present as a boronate ester eg.
`
`5,939,560
`
`-B::r.o ::
`
`0
`
`Me
`Me
`
`/:mo
`
`Me Me
`
`- -B \
`
`or
`
`0
`
`'
`
`Me
`
`these being labile in water giving the free boronic acids.
`In a preferred embodiment, A is selected from the group
`consisting of T1, T2 and T3, wherein
`T1 is a ~-amino-acyl group of the formula
`
`5
`
`10
`
`15
`
`20
`
`6
`(or ester thereof e.g. as defined under C02H); S03H;
`S02NH2; S02NR5R6; OH; OR5 ; aryl or heteroaryl (e.g.
`5 or 6-membered rings, monocyclic or bicyclic)
`[including substituted aryl or heteroaryl with substitu(cid:173)
`ents preferably chosen from F, Cl, I, Br, OH, OR5 , N02,
`S03H, S02NH2, S02NR5R6, NH2, NR5R6 , C02R5 ,
`CF3, CN, CONH2, CONR5R6 , NHC02R5 , CH(:NR5 )
`NR5R6 , NH-CH(:NR5)NR5R6 and R5 ]; NH2; NR5R6 ;
`NHC02R5 ; NHS02NR5R6 ; NHCOR5 ; NH-S02R5 ;
`NH-CH(:NR5)NR5R6; NHCONR5R6 ; sugar (which
`may be attached via an ether or a glycosidic bond);
`CO-aminosugar (attached via the -NH2) eg. glu(cid:173)
`cosamine or galactosamine; NHCO-aminosugar, or
`NHCS-aminosugar. In the above definition of R3
`"sugar" refers to any carbohydrate or oligosaccharide,
`and R5 and R6 are independently selected from H and
`alkyl, fiuoroalkyl and cycloalkyl groups (of up to 8
`atoms), aryl, heteroaryl and alkylheteroaryl groups (of
`up to 11 atoms) or R5 and R6 together comprise a chain
`and (C3 to C8 ).
`
`(ii)
`
`where R1=H, Me; the ring may also contain more heteroa-
`30 toms;
`E=J-(CH2h---(R4)q-R3; l=CO, CH2 or S02; and a, b,
`q, R3 and R4 as defined under (i)
`
`wherein p is an integer of 1-6, and wherein the ring present
`in T1 optionally contains one or more heteroatoms, and
`wherein the ring present in T1 optionally has one or two sites 25
`of unsaturation and wherein the carbonyl group of T1 is
`optionally replaced with CH= or CF=;
`T2 is an a-amino acyl group bearing a cycloaliphatic side
`chain, wherein the ring present in T2 optionally con(cid:173)
`tains one or more heteroatoms, and wherein the ring
`present in T2 optionally has one or two sites of
`unsaturation, and wherein the carbonyl group of T2 is
`optionally replaced with CH= or CF=;
`T3 is an L-a-amino acid bearing a lipophilic side chain,
`wherein the carbonyl group of T3 is optionally replaced 35
`with CH= or CF=;
`with the provisos that,
`(a) A is T1 only if R is H, -CHO or -B(OH)2;
`(b) A is T2 only if R isH; and
`(c) A is T3 only if R is CN, C-C-R7 , or CH=N-R8 .
`Group II Compounds
`Where R=H, CN, C-C-R7 or CH=N-R8 , A is an
`a-amino acid derivative whose side-chain carries a func(cid:173)
`tional group which is derivatised to produce a long chain 45
`terminating in various groups R3. A may be of the following
`three types of structure:
`
`40
`
`(iii)
`
`or
`
`where R2=H or Me; the ring may also contain one or more
`heteroatoms;
`L=(CH2)a-[CO]r-(CH2h-(R4)q-R3 or (CH2)e(cid:173)
`NR1-(CH2h---(R4)q-R3; r=O or 1; d=0-4; e=2-4;
`and b, q, R3 and R4 as defined under (i).
`Group III
`Group m compounds are defined by the general formula:
`
`(i) 50
`
`where a=1-5; D=G---(CH2h-(R4)q-R3; G=O, NH, or
`NMe;
`b=0--12; q=0--5;
`D1=D with G >'0;
`R4=Z-NH-(CH2)c- or NH-Z-(CH2)c- where
`c=1-12 and Z=CO, CH2 or S02; and
`R3=C02H or ester [e.g. any lower alkyl, fiuoroalkyl or
`cycloalkyl (C1 to C8 ), or aromatic or heteroaromatic (5
`or 6-membered rings, mono- or bicylic) ester] thereof;
`CONH2; CONHNH2; CONR5R6 ; CONNR5R6 ; P03H
`
`55 where w=CH2, 0, NH, CO, S, S02, Ph or NMe and,
`independently, E=CH2, 0, NH, CO, S, S02, Ph or NMe.
`These compounds are symmetrical dimers. They may
`have any B structure as defined previously. A may be chosen
`from any group II structure [ (i), (ii) or (iii)], but in this case
`60 the terminal group R3 in each A residue is deleted and
`replaced with a shared symmetrical group [E-•-E] which
`connects the two halves of the dimer, • may be absent, in
`which case both E's are joined together to constitute the
`65 chain linking the two A-B moieties; alternatively both E's
`may be absent in which case • solely joins the two A-B
`moieties.
`
`SAXA-DEF-00026
`
`Page 4 of 23
`
`

`
`5,939,560
`
`7
`The structure of E-•-E must of course be chemically
`feasible eg. NH-CO-NH, CO-NH-CO-, S02-
`NMe-S02; it will be obvious to those skilled in the art
`which structures are not feasible, eg. -NH-NH-NH-. A
`specific possible example is shown in Table 7.
`In such compounds as described under Groups II and III
`groups present in the long chains could be
`certain -CH2-
`replaced with known bioisosteres eg. -0 - without affect(cid:173)
`ing inhibitory or binding activity towards DP-IV. Also such
`groupings as -CONHCH2CH2NHCO if they occur could
`be replaced by eg.
`
`-CO-N
`N-CO-.
`\__/
`
`Further, for compounds in Groups I, II and III any amide
`bond connecting A and B or any amide in the side-chains of
`A (in Groups II and III) may be replaced by known bioi(cid:173)
`sosteres of amides eg.
`
`I
`
`I
`
`I
`
`- co -N \ replacedby - c o - c \ ; CF=C\;
`
`8
`-continued
`
`5
`
`See Table 8 for examples of such replacements.
`Biochemistry
`All compounds were tested in vitro against pure human
`10 DP-IV (purchased from M & E, Copenhagen, Denmark).
`Inhibition of DP-IV was determined using the fluorescent
`substrate Ala-Pro-AFC (!(, 0.8 ,uM) at three concentrations
`for each inhibitor. A typical assay (total volume 0.4 ml)
`comprised sodium Hepes 83.3 mM, EDTA 1.67 mM, BSA
`15 1.5 mg ml- 1 pH 7.8, DP-IV 25 ,uU ml-1, inhibitor (in 10 mM
`acetate pH 4.0). The reaction was started by the addition of
`substrate and readings taken every 30 s for 7.5 min, exci(cid:173)
`tation at 395 nm, emission 450 nm. K; values were deter(cid:173)
`mined using Dixon plots.
`20 Chemistry
`152 Examples of compounds synthesised are shown in
`Tables 1-8 followed by schemes and experimental details
`for the preparation of different structural types. All final
`25 products were characterised by FAB mass spectrometry and
`purity assessed by reverse phase hplc; all intermediates were
`characterised by 1H NMR.
`Table 9 shows selected K; values against DP-IV deter(cid:173)
`mined for inhibitors of different structural types.
`
`TABLE 1
`
`Examples of Group I (a)
`
`x,
`()n
`
`(
`
`/--{
`
`A
`
`R
`
`No.
`
`A
`
`X
`
`R
`
`n Formula
`
`Mol.Wt.
`
`Calculated
`
`FAB Mass
`spec. [M + H]+
`
`CH2 H
`
`1 C 11H20N2 0
`
`196.2
`
`197.2
`
`n,N~
`
`0
`
`2
`
`CH2 H
`
`1 C 12H22N2 0
`
`210.2
`
`211.2
`
`0
`
`SAXA-DEF-00027
`
`Page 5 of 23
`
`

`
`5,939,560
`
`10
`
`9
`
`TABLE 1-continued
`
`Examples of Group I (a)
`
`x,
`()n
`
`(
`
`l-{
`
`A
`
`R
`
`No.
`
`3
`
`A
`
`X
`
`R
`
`n Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]+
`
`CH2 H
`
`CwH2oN20
`
`184.2
`
`185.2
`
`n,~ 0
`
`4
`
`CH2 H
`
`1 C 12H20N20
`
`208.2
`
`209.2
`
`0
`
`5
`cis
`
`trans
`
`7
`trans
`
`8
`trans
`
`196.1
`
`197.2
`
`196.1
`
`197.2
`
`194.1
`
`195.2
`
`182.1
`
`183.2
`
`SAXA-DEF-00028
`
`Page 6 of 23
`
`

`
`5,939,560
`
`12
`
`11
`
`TABLE 1-continued
`
`Examples of Group I (a)
`
`x,
`()n
`
`(
`
`l--{
`
`A
`
`R
`
`A
`
`X
`
`R
`
`n Formula
`
`Mol. Wt.
`
`Calculated
`
`FAB Mass
`spec. [M + H]+
`
`190.1
`
`191.2
`
`224.2
`
`225.2
`
`No.
`
`9
`
`10
`trans
`
`TABLE 2
`
`Examples of Group I (b)
`
`RJ\x,
`( )n
`
`l--{
`
`A
`
`R
`
`n R' R
`
`Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]+
`
`H CN
`H CN
`H CN
`
`C"H,9N30
`C19H26N403
`C,oHrsN30
`
`209.3
`358.2
`193.1
`
`H CN
`
`C9H 13N30S
`
`211.1
`
`210.2
`359.2
`194.1
`
`212.2
`
`H CN
`
`C9H 13N30S
`
`211.1
`
`212.2
`
`No. A
`
`11 H-Ile
`12 H-Lys(Z)
`13 H-Pro
`
`X
`
`CH2
`CH2
`CH2
`
`0
`
`14 '~~ CH2
`<rn-y
`
`15
`
`~s
`
`CH2
`
`0
`
`SAXA-DEF-00029
`
`Page 7 of 23
`
`

`
`5,939,560
`
`14
`
`13
`
`TABLE 2-continued
`
`Examples of Group I (b)
`
`No. A
`
`16
`
`X
`
`n R1
`
`R
`
`Formula
`
`Calculated
`Mol. Wt.
`
`FAB Mass
`spec. [M + H]+
`
`H CN
`
`235.2
`
`236.3
`
`0
`
`CH2
`
`H CN
`
`c,2H,9N30
`
`221.2
`
`222.2
`
`CH2
`
`H CN
`
`C11H,9N30
`
`209.2
`
`210.2
`
`17
`
`18
`
`n,N~
`n,~
`
`0
`
`0
`
`H CN
`CN H
`
`C10H17N30S
`C10H17N30S
`
`227.1
`227.1
`
`H CN
`
`C12H19N30S
`
`253.1
`
`228.1
`228.1
`
`254.1
`
`H CN C,sH24N403S
`
`376.2
`
`H CN
`
`C11H 17N30S
`
`239.1
`
`377.2
`
`240.2
`
`s
`s
`
`s
`
`s
`
`s
`
`19 H-Ile
`20 H-Ile
`
`21
`
`0
`
`22 H-Lys(Z)
`
`23
`
`n~~
`
`0
`
`24 H-Ile
`25 H-Ile
`26 H-Ile
`27 H-Ile
`
`28 H-Ile
`
`0
`CH2
`s
`so2
`
`H CN
`C10H17N302
`C12H21N30
`2 H CN
`C11H19N30S
`2 H CN
`H CN CwH,7N303S
`
`211.1
`223.2
`241.1
`259.1
`
`s+·,llo·
`
`H CN CwH,7N302S
`
`243.1
`
`212.2
`224.2
`242.1
`260.1
`
`244.1
`
`SAXA-DEF-00030
`
`Page 8 of 23
`
`

`
`5,939,560
`
`16
`
`15
`
`TABLE 2-continued
`
`Examples of Group I (b)
`
`R 1 \X ' ( )n
`
`/-{
`
`A
`
`R
`
`No. A
`
`X
`
`n R'
`
`R
`
`Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + Hj+
`
`29 H-Ile
`
`s+ ..... o·
`
`30 y,,,,( CH2
`31 Qy CH2
`
`NH2
`
`0
`
`H CN C10H17N30 2S
`
`243.1
`
`244.2
`
`H CN
`
`c,2H,9N30
`
`221.2
`
`222.2
`
`H CN
`
`c,2H,9N30
`
`221.2
`
`222.2
`
`NH2
`
`0
`
`32
`
`0
`
`CH2
`
`H CN
`
`C 11H 17N30
`
`207.2
`
`208.2
`
`NH2
`
`0
`
`CH2
`
`33
`
`C('~
`«' NH2
`34 Qy CH2
`35 y,,,,( CH2
`36 Qy CH2
`
`NH2
`
`0
`
`NH2
`
`0
`
`NH2
`
`0
`
`H CN
`
`C 11H 17N30
`
`207.2
`
`208.2
`
`H CN
`
`c,2H,7N30
`
`219.1
`
`220.1
`
`H CN
`
`c,2H,7N30
`
`219.1
`
`220.1
`
`H CN
`
`c,2H,9N30
`
`221.2
`
`222.2
`
`SAXA-DEF-00031
`
`Page 9 of 23
`
`

`
`5,939,560
`
`18
`
`17
`
`TABLE 2-continued
`
`Examples of Group I (b)
`
`RJ\x,
`( )n
`
`l-{
`
`A
`
`R
`
`No. A
`
`37
`
`X
`
`n R' R
`
`Formula
`
`Mol.Wt.
`
`spec. [M + H]*
`
`Calculated
`
`FAB Mass
`
`H CN
`
`219.1
`
`220.1
`
`TABLE 3
`
`Examples of Group I (c)
`
`x,
`()n
`
`(
`
`l-{
`
`A
`
`R
`
`No.
`
`A
`
`X
`
`R
`
`NH2
`
`0
`
`38 y,,,,( CH2 CHO
`39 p,,,( CH2 CHO
`Py
`41 p,,,( CH2 B*
`
`n
`
`Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + Hj+
`
`C12H2aN202
`
`224.2
`
`225.2
`
`C11HlsN202
`
`210.2
`
`211.2
`
`C11HlsN202
`
`210.2
`
`211.2
`
`C2oH33BN203
`
`360.3
`
`361.3
`
`40
`
`CH2 CHO
`
`H2N
`
`H2N'
`
`H2N
`
`I
`
`0
`
`0
`
`I
`
`0
`
`SAXA-DEF-00032
`
`Page 10 of 23
`
`

`
`5,939,560
`
`20
`
`19
`
`TABLE 3-continued
`
`Examples of Group I (c)
`
`X
`
`(
`
`'( )n
`
`l-{
`
`A
`
`R
`
`No.
`
`A
`
`X
`
`R
`
`CH2 B*
`
`NH2
`
`0
`
`NH2
`
`42 y .. ,,,(
`43 Qy CH2 B*
`0 am,,
`0 ex;: CH2 B*
`
`CH2 B*
`
`I(
`
`44
`
`45
`
`I
`
`\
`
`0
`
`n
`
`Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]*
`
`C2,H3sBN203
`
`374.3
`
`375.1
`
`C2,H3sBN203
`
`374.3
`
`375.1
`
`C2,H33BN203
`
`372.3
`
`373.3
`
`C2,H33BN203
`
`372.3
`
`373.3
`
`TABLE 4
`
`Examples of Group II (i)
`
`0
`
`No.
`
`n Q
`
`X
`
`m
`
`R Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]*
`
`46
`47
`48
`49
`50
`51
`
`--CONHCH2C02Bn
`--CONHCH2C02H
`--CONH(CHo)3C02H
`--CONH(CH2)2C02Bn
`--CONH(CH2)2C02H
`--CONH(CH2)5 C02Bn
`
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`
`H C17H23N304
`H C10H17N304
`H C12H21N304
`H C1sH2sN304
`H C11H19N304
`H C21H31N304
`
`333.2
`243.1
`271.2
`347.2
`257.1
`389.3
`
`334.2
`244.2
`272.2
`348.2
`258.2
`390.3
`
`SAXA-DEF-00033
`
`Page 11 of 23
`
`

`
`21
`
`22
`
`5,939,560
`
`TABLE 4-continued
`
`Examples of Group II (i)
`
`No.
`
`n Q
`
`X
`
`m
`
`R Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]+
`
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`98
`99
`100
`101
`102
`103
`
`--CONH(CH2)5C02H
`--CONH(CH2)3C02Bn
`2 --CONHCH2C02Bn
`2 --CONHCH2C02H
`2 --CONH(CH2)2C02Bn
`2 --CONH(CH2)3C02Bn
`2 --CONH(CH2)3C02H
`2 --CONH(CH2)5C02Bn
`2 --CONH(CH2)5C02H
`2 --CONH(CH2)2C02H
`2 --CONH(CH2)7C02Bn
`2 --CONH(CH2)7C02H
`2 --CONH(CH2)7CONH-(CH2)3NHZ
`2 --CONH(CH2)6 CONH-(CH2)5C02Bn
`2 --CONH(CH2)6 CONH-(CH2)5C02H
`2 --CONH(CH2)7CONH-(CH2)3NH2
`2 --CONH(CH2)11C02Bn
`2 --CONH(CH2)11C02H
`2 --CONH(CH2)6 C02Bn
`2 --CONH(CH2)6 C02H
`2 --CONH(CH2)5CONH--CH2CF3
`2 --CONH(CH2)5CONH--CH2(CF2)2CF3
`2 --CONH(CH2)5CONH-(CH2) 60H
`2 --CONH(CH2)5CONH-(CH2)3Ph
`2 --CONH(CH2)5CONH-(CH2)4Ph
`2 --CONH(CH2)5CON-("Bu)2
`2 --CONH(CH2)5CON-("Hx)2
`2 --CONH(CH2)5CONH--CH2Ph
`2 --CONH(CH2)4C02Bn
`2 --CONH(CH2)4C02H
`2 --CONH(CH2)5CONH--CH2CH3
`2 --CONH(CH2)6 0H
`2 --CONH(CH2)5C0-1-Pip
`2 --CONH(CH2)5CONH2
`2 --CONH(CH2)5CONH-(CH2)9CH3
`2 --CONH(CH2)5CONH-(CH2) 6CH3
`2 --CONH(CH2)5CONH--CH2Ch
`2 --CONH(CH2)5CONH-(CH2)3NHZ
`2 --CONH(CH2)5CONH-(CH2)3NH2
`2 --CONH(CH2)5CONH-(CH2)3-Gua
`2 --CONH(CH2)5CONH-Ph( 4-S03H)
`2 --CONH(CH2)5CONH-4-Pip(1-Bn)
`2 --CONH(CH2)5CONH-4-Pip
`2 --CONH(CH2)4N(Z)-(CH2)3NHZ
`2 --CONH(CH2)4NH-(CH2)3NH2
`2 --CONH(CH2)5C02Bn
`3 --CONH(CH2)6 CONH-(CH2)5C02Bn
`3 --CONH(CH2)6 CONH-(CH2)5C02H
`3 --CONH(CH2)5C02Bn
`3 --CONH(CH2)5C02H
`2 -S02NH(CH2)5C02H
`2 --CONH(CH2)8NH-{J+
`
`H C14H25N304
`H C19H 27N 3 0 4
`H C18H25N3 04
`H C"H,9N304
`H C19H27N3 04
`H C20H29N30 4
`H C 13H 23N 3 0 4
`H C22H33N304
`H C15H27N3 04
`H C 12H 21N 3 0 4
`H C24H37N304
`H C 17H31N30 4
`H C2sH4sNsOs
`H C29H4oN40s
`H C22H40N40 5
`H C2oH39Ns03
`H C2sH4sN304
`H C21H39N304
`H C 23H35N30 4
`H C 16H 29N 3 0 4
`H C 17H29F3N 40 3
`H C19H29F 7N40 3
`H C21H40N404
`H C24H3sN403
`H C 25H40N40 3
`H C 23H44N40 3
`H C27H52N 4 0 3
`H C22H34N40 3
`H C21H31N304
`H C14H25N304
`H C 17H32N40 3
`H C15H 29N 3 0 3
`H C2oH3oN403
`H C15H 28N 4 0 3
`H C 25H48N40 3
`H C22H42N40 3
`H C22H40N40 3
`H C26H 41N 5 0 5
`H C18H35N50 3
`H C19H37N70 3
`H C21H32N40 6S
`H C 27H43N50 3
`H C2oH37Ns03
`H C32H4sNsOo
`H C 16H 33N 5 0 2
`CN C 23H32N40 4
`H C3oH4sN40s
`H C 23H42N40 5
`H C 23H35N30 4
`H C 16H 29N 3 0 4
`H C14H27N3 0 5 S
`H C24H4sNs07S
`
`299.2
`361.2
`347.2
`257.1
`361.2
`375.2
`265.2
`403.3
`313.2
`271.2
`431.3
`341.3
`531.3
`530.4
`440.3
`397.3
`487.3
`397.3
`417.3
`327.2
`394.2
`494.2
`412.3
`430.3
`444.3
`424.3
`480.4
`402.3
`389.2
`299.2
`340.3
`299.2
`380.3
`312.2
`452.4
`410.3
`408.3
`503.3
`369.3
`411.3
`468.2
`485.3
`395.3
`595.3
`327.2
`428.3
`544.4
`454.3
`417.3
`327.2
`349.2
`547.4
`
`300.2
`362.2
`348.2
`258.1
`362.3
`376.3
`266.2
`404.3
`314.2
`272.2
`432.4
`342.5
`532.3
`531.2
`441.3
`398.3
`488.4
`398.3
`418.3
`328.2
`395.3
`495.2
`413.2
`431.2
`445.2
`425.3
`481.4
`403.4
`390.3
`300.3
`341.3
`300.3
`381.4
`313.3
`453.5
`411.4
`409.4
`504.4
`370.3
`412.4
`469.2
`486.3
`396.3
`596.3
`328.2
`429.3
`545.2
`455.3
`418.2
`328.2
`350.2
`548.5
`
`SAXA-DEF-00034
`
`Page 12 of 23
`
`

`
`23
`
`24
`
`5,939,560
`
`TABLE 4-continued
`
`Examples of Group II (i)
`
`No.
`
`n Q
`
`OH
`
`0
`
`X
`
`m
`
`R Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]+
`
`G*=
`
`HO~OH
`n~~~OH
`As
`
`NH
`
`0
`
`TABLE 5
`
`Examples of Group II (ii)
`
`NHQ
`I
`(CH2)n
`
`(
`
`X...._
`( )m
`
`n,)yN~R
`
`0
`
`No.
`
`n Q
`
`X
`
`m
`
`R
`
`Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]+
`
`104
`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`115
`116
`117
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
`128
`129
`130
`131
`132
`133
`134
`135
`
`--CO(CH2) 6C02H
`CH2
`--CO(CH2) 6C02Bn
`CH2
`CH2
`3 --CO(CHo)4C02H
`3 --CO(CH2)4C02Me
`CH2
`4 --CO(CH2)5 NH2
`CH2
`4 --CO(CH2)3NH2
`CH2
`4 --CO(CHo)3NHS02Pip
`CH2
`4 --CO(CH2)3NHCOPip
`CH2
`4 --CO(CH2)3NHS02--CH2CF3
`CH2
`4 --CO(CH2) 11 NHCO-(CH2) 6NHZ
`CH2
`4 --CO(CHo) 11 NH--CO(CH2) 6NH2
`CH2
`4 --CO(CH2)5 NHCO-(CH2)5 NHCO(CH2)5-NHZ CH2
`4 --CO(CH2)5 NHCO-(CH2)5 NHCO(CH2)5-NH2 CH2
`4 --CO(CH2)3C02H
`CH2
`4 --CO(CHo)3C02Bn
`CH2
`4 --CO(CH2) 6NH2
`CH2
`4 --CO(CH2) 7NH2
`CH2
`4 --CO(CH2) 16Me
`CH2
`4 --CO(CHo) 6-Gua
`CH2
`4 -S02(CH2) 7CH3
`CH2
`4 --CO(CH2) 11 NH2
`CH2
`4 --COCH2NHZ
`CH2
`4 --CO(CH2)2NHZ
`CH2
`4 --CO(CH2)3NHZ
`CH2
`4 --CO(CH2)2NH2
`CH2
`4 --CO(CHo)5 NHZ
`CH2
`4 --COCH2-Gua
`CH2
`4 --CO(CH2)2NH2
`CH2
`4 --CO(CH2)2-Gua
`CH2
`4 --CO(CHo)3-Gua
`CH2
`4 --CO(CH2)5 -Gua
`CH2
`4 --CO(CH2) 6NH2
`CH2
`
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`CN
`
`C1sH27N304
`C22H33N304
`C1sH27N304
`C16H29N304
`C16H32N402
`C14H2sN402
`C2oH27FsN404S
`C21H27FsN403
`C,oH29F3N404S
`C37H63Ns0s
`C29Hs7Ns03
`C36H60N606
`C2sHs4N604
`C1sH27N304
`C22H33N304
`C17H34N402
`ClsH36N402
`C2sHssN302
`ClsH36N602
`C,sH37N303S
`C22H44N402
`C2aH3aN404
`C21H32N404
`C22H34N404
`C12H24N402
`C24H3sN404
`C13H26N602
`C13H26N402
`C14H2sN602
`ClsH3aN602
`C17H34N602
`C1sH33Ns02
`
`313.2
`403.3
`313.2
`327.2
`312.3
`284.2
`514.2
`478.2
`430.2
`657.5
`523.4
`672.5
`538.4
`313.2
`403.3
`326.3
`340.3
`465.4
`368.3
`375.3
`396.4
`390.2
`404.2
`418.3
`256.2
`446.3
`298.2
`270.2
`312.2
`326.3
`354.3
`351.3
`
`314.3
`404.3
`314.3
`328.3
`313.3
`285.2
`515.2
`479.2
`431.3
`658.6
`524.4
`673.6
`539.4
`314.3
`404.3
`327.3
`341.3
`466.4
`369.3
`376.3
`397.4
`391.3
`405.3
`419.3
`257.2
`447.4
`299.3
`271.3
`313.3
`327.3
`355.3
`352.4
`
`SAXA-DEF-00035
`
`Page 13 of 23
`
`

`
`25
`
`26
`
`5,939,560
`
`TABLE 5-continued
`
`Examples of Group II (ii)
`
`No.
`
`n Q
`
`X
`
`m
`
`R Formula
`
`Calculated
`Mol. Wt.
`
`FAB Mass
`spec. [M + H]+
`
`365.3
`
`366.3
`
`TABLE 6
`
`Examples of Group II (iii)
`
`R~(' ( )n
`N~y
`
`H2N
`
`0
`
`No.
`
`n Q
`
`X
`
`m R Formula
`
`Calculated
`Mol.Wt.
`
`FAB Mass
`spec. [M + H]+
`
`--OCH2CONH(CH2)5 --C02H
`H
`137
`--OCH2CONH(CH2)5 --C02Bn
`H
`138
`H
`139
`--OCH2CONH(CH2)4--C02Bn
`--OCH2CONH(CH2)4--C02H
`H
`140
`141 CH3 --OCH3
`142 CH3 --OC2Hs
`143 CH3 --O(CHo)5 CH3
`144 CH3 --OCH2CONH(CH2)5 --C02Bn
`145 CH3 --CCH2CONH(CH2)5--C02H
`146 CH3 --OCH2CONH(CH2)4--C02Bn
`147 CH3 --OCH2CONH(CH2)4--C02H
`
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`CH2
`
`H ClsH27N30s
`H C22H33N30s
`H C21H31N30s
`H C14H2sN30s
`H C9HrsN202
`H C10H2aN202
`H C14H2sN202
`H C23H3sN30s
`H Cl6H29N30s
`H C22H33N30s
`H C1sH27N30s
`
`329.2
`419.3
`405.2
`315.2
`186.1
`200.1
`256.2
`433.3
`343.2
`419.2
`329.2
`
`330.3
`420.3
`406.3
`316.3
`187.2
`201.2
`257.3
`434.3
`344.3
`420.3
`330.3
`
`TABLE 7
`
`Example of Group III
`
`No. Structure
`
`148
`
`Formula
`
`Calculated
`Mol. Wt.
`
`FAB Mass
`spec. [M + H]+
`
`614.4
`
`615.4
`
`0
`
`0
`
`SAXA-DEF-00036
`
`Page 14 of 23
`
`

`
`No.
`
`149
`
`150
`
`151
`
`152
`
`5,939,560
`
`28
`
`27
`
`TABLE 8
`
`Specific examples of compounds A-B, containing amide bond bioisosteres.
`
`A-B
`
`Formula
`
`Calculated
`Mol. Wt.
`
`FAB Mass
`spec. [M + Hj+
`
`167.2
`
`168.2
`
`192.2
`
`193.2
`
`192.2
`
`193.2
`
`200.1
`
`201.2
`
`s
`
`TABLE 9
`
`TABLE 2
`
`Selected K values against DP-IV
`
`45 (a) R: --CN
`
`No.
`
`2
`7
`11
`20
`23
`35
`38
`44
`59
`66
`97
`110
`136
`143
`150
`
`K; (M)
`
`6.4 X 10-8
`7.6 X 10-6
`2.2 X 10-9
`1.7 X 10-9
`5.0 X 10-10
`3.7 X 10-8
`9.8 X 10-9
`2.0 X 10-9
`1.5 X 10-7
`1.8 X 10-7
`5.0 X 10-10
`2.5 X 10-7
`1.7 X 10-8
`9.4 X 10-7
`1.7 X 10-6
`
`50
`
`55
`
`60
`
`Schematic Representations for General Preparation of all
`Classes of Compounds
`Table 1
`Compounds can be made by an adaption of the general 65
`route described by E. Schon et al., Bioi. Chern. Hoppe(cid:173)
`Seyler, 1991, 372, 305-311.
`
`Boc-A-OH +
`
`x,
`( )n
`(
`Boc-A-N~NH2
`
`pyridine,
`imidazole
`
`0
`
`(
`
`x,
`x,
`()n
`()n
`I
`I
`Boc-A-N
`H+ H-A-N
`~eN-
`~CN
`X=S!mCPBA
`
`(
`
`SAXA-DEF-00037
`
`Page 15 of 23
`
`

`
`29
`
`30
`
`5,939,560
`
`TABLE 2-continued
`
`TABLE 2-continued
`
`(O)y
`I
`X...._
`()n
`I
`Boc-A-N
`~CN
`
`(
`
`(O)y
`I
`X...._
`()n
`I
`H-A-N
`~CN y=1,2
`
`(
`
`(b) R: ---CH~NPh
`
`Boc-A-ONSu +
`
`X
`
`PhNH2
`(I) Toluene, I'J.
`
`'()n
`I
`H+
`Boc-A-N~NPh-
`
`(
`
`X...._
`()n
`
`(
`
`H-A-N~NPh
`
`_....oR!
`R:CH=N
`
`R10NH2•HCl
`(I) pyridine, DMF
`
`ForRl=-Ac
`
`x,
`()n
`H-A-N~N-ORl
`
`(
`
`Py, Ac20
`(II) CH2Cl2
`
`5
`
`10
`
`15 (d) R = ---C==CR
`
`20
`
`Ph3P, CBr4
`(I) Zn, CH2Cl2
`
`25
`
`30
`
`(a)
`
`35
`
`x,
`()n
`I
`(
`Boc-A-N~N-OAc -
`x,
`()n
`I
`H-A-N
`~N-OAc
`
`H+
`
`(
`
`x,
`()n
`-------L
`
`(
`
`/ Br
`
`(i) "BuLi
`Boc-A-N ~
`(ii) "R+"
`(iii)H+
`
`Br
`
`x,
`()n
`I
`H-A-N
`~-C-R
`
`(
`
`TABLE 3
`
`Prepared by method of: W. W.
`Bachovchin et al., J. Bwl. Chern.,
`1990, 265, 3738-3743.
`
`(b)
`
`R=CHO (I)
`
`X
`
`(
`
`'()n
`I
`H-A-N
`~CHO
`
`40
`
`45
`
`50
`
`55
`
`60
`
`SAXA-DEF-00038
`
`Page 16 of 23
`
`

`
`5,939,560
`
`32
`
`31
`
`TABLE 4
`
`(a) R ~ CN
`
`0
`
`H
`
`0
`
`0
`
`! (i) remove P
`
`(ii) HONSu, WSCD
`
`(i) H2N(CH2)mP1
`(ii) modify P1 ~ P2
`
`if required
`
`0
`
`(III)
`
`0
`
`!POC13
`
`pyridine, imidazole
`
`H
`
`0
`
`0
`
`(b)
`
`(i) H2N(CH2)mP1
`(ii) modify P 1~P 2
`
`H
`
`0
`
`H
`
`0
`(IV)
`
`complete synthesis as above.
`
`(W, P ~ Protecting groups; P', P2 ~ Groups as described in corresponding tables)
`
`(IV) was prepared via method of G. Luisi et al., Tet. Lert.,
`1993,34,2391-2392. (c) For R=H, modify above procedure
`as described for Table 1 examples.
`
`SAXA-DEF-00039
`
`Page 17 of 23
`
`

`
`33
`
`TABLE 5
`
`(a)