peT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 95/15309
`
`WORLD INTELLEcruAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`C07D 207/16,295/18, C07C 211125,
`255/46, A61K 31140
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`8 June 1995 (08.06.95)
`
`(21) International Application Number:
`
`PCT/GB94102615
`
`(22) International Filing Date:
`
`30 November 1994 (30.11.94)
`
`(30) Priority Data:
`9324803.7
`9324981.1
`
`3 December 1993 (03.12.93)
`6 December 1993 (06.12.93)
`
`GB
`GB
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, JP, KE, KG,
`KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW,
`NL, NO, NZ, PL, PT, RO, RU, SD, SE, SI, SK, TJ, TT,
`UA, US, UZ, VN, European patent (AT, BE, CH, DE, DK,
`ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE,
`SN, TD, TG), ARIPO patent (KE, MW, SD, SZ).
`
`(71) Applicant (for all designated States except US): FERRING Published
`With international search report.
`B.V. [NUNL]; Maarstraat 9, P.O. Box 3129, NL-2130 KC
`Hoofdorp (NL).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only):
`JENKINS, Paul, D.
`[GB/GB]; 8 Petty Close, Tadburn Gardens, Romsey S051
`8UY (GB). JONES, D., Michael [GB/GB]; Sundew, Slab
`Lane, West Wellow, Nr.
`Romsey S051 6BY (GB).
`[GB/GB];
`"Southview", Braishfield,
`SZELKE, Michael
`Romsey S051 OPN (GB).
`
`(74) Agent: GEERING, Keith, Edwin; Reddie & Grose, 16
`Theobalds Road, London WCIX 8PL (GB).
`
`(54) Title: DP-IV-SERINE PROTEASE INHIBITORS
`
`A·B (Groups I andm
`
`(1)
`
`(2)
`
`-,-A-B
`
`l-A-B
`
`(3)
`
`(Groupm)
`
`(4)
`
`-..
`
`(57) Abstract
`
`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.
`
`SAXA-DEF-00046
`
`Page 1 of 57
`
`AstraZeneca Exhibit 2022
` Mylan v. AstraZeneca
` IPR2015-01340
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COle d'ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`DenlllllJk
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`TT
`UA
`US
`UZ
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`Viet Nam
`
`SAXA-DEF-00047
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`Page 2 of 57
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`

`
`W095/15309
`
`Background
`
`- 1 -
`DP-IV-SERINE PROl'EASE INHIBITORS
`
`PCT/GB94/02615
`
`DP-N (BC 3.4.14.5) is a membrane-bound serine protease fIrst identified in rat kidney by
`its ability to cleave dipeptides from the N-terminus of certain peptides (Hopsu-Havu, V.K.
`and Glenner, G.G., Histochemie, 1966,1, 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-N 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
`In the human immune system the enzyme is
`Biochem. Mol. Bioi. 1993, 28 (1), 31).
`expressed almost exclusively by activated T-lymphocytes of the CD4+ type where the
`enzyme has been shown to be synonymous with the cell-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, ego
`
`(a)
`
`The immune response: DP-IV expression is increased in T-cells upon mitogenic or
`antigenic stimulation (Mattern, T. et al., Scand. J. Immunol. 1991, 33, 737).
`It has
`inhibitors of DP-N and antibodies to DP-N suppress the
`been reponed that
`proliferation of mitogen- and antigen-stimulated T-cells in a dose-dependant manner
`(Schon, E. et al., Bioi. Chem. Hoppe-Seyler, 1991, 372, 305 and refs. within).
`
`IL-2
`Various other functions of T-lymphocytes such as cytokine production,
`mediated cell proliferation and B-cell helper activity have been shown to be
`dependant on DP-IV activity (Schon, E. et al., Scand. J. Immunol. 1989, 29, 127).
`Recently, DP-IV inhibitors based on boroproline where reponed (Flentke, G.R. et
`al., Proc. Natl. Acad. Sci. US.4, 1991, 88, 1556) which, although unstable, were
`effective in inhibiting antigen-induced lymphocyte proliferation and ll..-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. Immunol. 1992, 89, 192). Other
`recent papers also provide evidence for the involvement of DP-N in the immune
`response (eg. Tanaka, T. et al., Proc. Natl. Acad. Sci. NY, 1993, 90, 4586; Hegen, M.
`et al., Cell Immun. 1993, 146, 249; Subramanyan, M. et al., J. Immunol. 1993, 150,
`2544).
`
`.'
`
`t
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`

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`W095/15309
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`PCT/GB94/02615
`
`- 2 -
`
`The importance of DP-IV is attributed by some investigators to its cell-surface
`association with the transmembrane phosphatase CD45 (TorimOto, Y. et al., J.
`Immunol. 1991, 147,2514). The CD45 - DP-IV association is possibly disrupted by
`DP-IV inhibitors or non-active site ligands. CD45 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, 25-27th
`October 1993) reponed that DP-IV was essential for the penetration and infectivity
`of HIV-1 and HIV-2 viruses in CD4+ T-cells. The French group claimed that DP-IV
`interacted with and may have cleaved the V3 loop of the gp 120 envelope
`glyco-protein of the virus. They also reported that inhibitors or antibodies to DP-IV
`successfully prevented entry of the 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. Im.mun.ol. 1992, 149,3073), and that HIV-1
`Tat prOtein binds to DP-IV (Subramanyam, M. et al., 1. Immunoi. 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., 1. Ceil.
`Bioi. 1993, 121, 1423). DP-IV is known to bind to fibronecrin and some metastatic
`tumour cells are known to carry large amountS of fibronecrin 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
`deficiency causes severe combined immunodeficiency disease (SCID) in humans.
`This ADA-CD26 interaction may provide clues to the pathophysiology of SOD.
`
`(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).
`
`(f)
`
`High DP-IV activity has been found in tissue homogenates 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. Chem. Clin. Biochem. 1992, ~ 333).
`
`.
`
`f
`
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`

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`W095/15309
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`PCT/GB94/02615
`
`- 3 -
`
`(g) DP-N has been shown to be responsible for the degradation and inactivation of
`the N-terminus, ego
`circulating peptides with penultimate proline or alanine at
`substance
`P,
`growth
`hormone
`releasing
`factor
`and members
`of
`the
`glucagon/vasoactive intestinal peptide family (Menthein, R. et al., Eur. J. Biochem.
`1993, 214,829).
`
`(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-N 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, ego in organ transplantation; cytokine release suppressants ego
`in various autoimmune diseases such as inflammatory bowel disease, multiple
`sclerosis, RA.
`
`(b) Drugs for the prevention of mv 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, ego psoriasis, lichen planus.
`
`(e) Drugs· to suppress sperm motility and therefore act as male contraceptive agents.
`
`(f)
`
`Agents beneficial in benign prostate hypertrophy.
`
`Inhibitors of DP-IV
`
`The only competitive inhibitors of DP-N enzyme activity reported so far are the unstable
`boronic acids (tt 30 - 90 min at pH 7) mentioned above.
`(Bachovchin et al., WO
`91/16339, October 1991) having Ki values in the nanomolar range for DP-N, and simple
`amino-acid pyrrolidides or thiazolides (Neubert et al., DD 296075 AS, November 1991)
`which have only modest potency (Ki > 0.1 J,LM). Amino-acyl proline aldehydes claimed in
`the same German patent cannot be synthesised due to a facile intramolecular condensation
`of the N-terminal amino group with the aldehyde function.
`
`SAXA-DEF-00050
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`

`
`WO 95/15309
`
`PCT/GB94/02615
`
`- 4 -
`
`We now disclose highly potent competitive inhibitors of DP-IV (with Ki values in the 10-6
`- 10-10 range) which are also chemically stable (tt > 24 h). They fall into three broad
`groups of compounds (Groups I, II and IIl).
`
`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
`may bind to the surface of DP-IV (Le. not at its active site). Such Group I compounds
`could be useful as immunosuppressants; 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 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 resulting
`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 activation, virus entry into T-cells or tumour cell adhesion.
`
`GROUP ill
`
`This group comprises novel dimers in which two active-site directed inhibitors of DP-IV
`are linked via the side-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 but may be more effective.
`
`SAXA-DEF-00051
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`

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`W095/15309
`
`PCT/GB94/02615
`
`- 5 -
`
`The invention provides inhibitors of DP-IV mediated processes, the inhibitors being of
`general formula:
`
`A-B (Groups I and II) or
`
`/E-A-B
`ro
`
`~E-A-B
`
`(Group III)
`
`n = 1 or 2;
`m = 0,1 or 2;
`X = CH2, 0, S, SO, S02
`NH or NR1 where R1 = lower alkyl (C1 to C~;
`
`)
`
`(CH2r.:.
`nX
`
`I
`(CHVm
`
`CH-
`
`IR
`
`where B is
`
`/
`
`-y
`\
`
`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(OHh, C=C-R7, or CH=N-R8;
`R7 = H, F, lower alkyl (C1 to C6), CN, N02, O~, C02~ or COR9;
`
`Rg = Ph, OH, O~, OCO~, or OBn;
`~ = lower alkyl (C1 - C6); and either CJ) 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 ClO, mono or bicyclic) whose ring may contain one or more
`heteroatoms
`e.g.
`L-cyclohexylglycine,
`L-cyclopentylglycine,
`L-decahydro(cid:173)
`naphthylglycine, L-piperidylglycine;
`
`A is a 13-amino-acyl group of general formula
`
`/CH-NH2
`
`(CH2~ I
`
`CH-CO-
`
`where p = 1 - 6 and the ring may also contain
`one or more heteroatoms replacing CH2 unit(s).
`
`SAXA-DEF-00052
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`

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`W095/15309
`
`PCT/GB94/02615
`
`- 6 -
`
`Both a and ~-amino acyl groups in (a) above may contain unsaturation in their rings
`e.g.
`
`ce NH2
`
`I
`
`co-
`
`and also may contain one or more heteroatoms.
`
`(b)
`
`R = CN: C=C-R1 or CH=N-Rg
`
`A is as defined in (a) above but in addition may be derived from any L-a-amino acid
`bearing a lipophilic side-chain, ego lie.
`
`(c)
`
`R = CHO or B(OHh
`
`A is a ~-amino-acyl group as defined in (a) above. The resulting A-B compounds
`are stable, unlike a-aminoacyl derivatives of the same type which undergo a facile
`intramolecular cyc1isation.
`In compounds (c) B(OHh may be present as a boronate
`
`ester ego /:t-0
`
`-B
`\
`o
`
`Me
`Me
`
`Me
`
`or
`
`Me
`
`Me
`
`these being labile in water giving the free boronic acids.
`
`SAXA-DEF-00053
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`Page 8 of 57
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`

`
`W095/15309
`
`PCT/GB94/02615
`
`Group II Compounds
`
`- 7 -
`
`Where R = H, CN, C=C-R7 or CH=N-Rg, A is an a.-amino acid derivative whose
`side-chain carries a functional group which is derivatised to produce a long chain
`terminating in various groups R3. A may be of the following three types of structure:
`
`(i)
`
`or
`
`where a = 1 - 5; D = G-(CH2)b-(R4)q-R3; G = 0, NH, or NMe;
`b =0-12; q =0-5;
`
`Dl = D with G 't:- 0;
`
`R4 = Z-NH-(CH2)c- or NH-Z-(CH0c- where c = 1-12 and Z = CO, CH2or S02;
`and
`
`R3 = C02H or ester [e.g. any lower alkyl, fluoroalkyl or cycloalkyl (C 1 to Cg),
`or aromatic or heteroaromatic (5 or 6-membered rings, mono- or bicylic)
`ester] thereof; CONH2; CONHNH2; CONRsR6; CONHNRSR6; P03H
`thereof e.g. as defIned under C02H); S03H; S02NH2;
`(or ester
`S02NRs~; OH; ORs; aryl or heteroaryl (e.g. 5 or 6-membered rings,
`monocyclic or bicyclic) [including substituted aryl or heteroaryl with
`substituents preferably chosen from F, Cl,
`I, Br, OH, ORs, N02,
`S03H, S02NH2' S02NRSR6, NH2, NRsR6, C02Rs, CF3, CN,
`CONH2,
`NHC02Rs,
`CONRs~,
`CH(:NRs)NRs~,
`NH-CH(:NRs)NRsR6 and Rs]; NH2; NRsR6; NHC02Rs; NHS02NRsR6;
`sugar
`NHCORs; NH-S02Rs; NH-CH(:NRs)NRs.~; NHCONRsR6;
`(which may be attached via
`an ether or a glycosidic bond);
`CO-aminosugar
`(attached
`via
`the
`-NH2)
`ego
`glueosamine
`or
`galactosamine; NHCO-aminosugar; or NHCS-aminosugar.
`In the above definition of R3 "sugar" refers to any carbohydrate or
`oligosaccharide, and Rs and R6 are independently selected from H and
`alkyl, fluoroalkyl and cycloalkyl groups (of up to 8 atoms), aryl,
`heteroaryl and alkylheteroaryl groups (of up to 11 atoms) or Rs and ~
`together comprise a chain and (C3 to Cg).
`
`SAXA-DEF-00054
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`- 8 -
`
`or
`
`where Rl = H, Me; the ring may also contain more heteroatoms;
`E = J-(CHVb-(R4)q-R3; J = CO, CH2 or S02; and a, b, q, R3 and R4
`as defIned under (i)
`
`HN
`
`2>-<
`
`CO
`I
`
`R2
`
`OL
`
`or
`
`OL
`
`(ii)
`
`(iii)
`
`where R2 = H or Me; the ring may also contain one or more heteroatoms;
`
`L = (CH2)d-[CO]r-(CHVb-(R4)q-R3 or (CH2)e-NRl_(CH2)b-(R4)q-R3;
`r = 0 or 1; d = 0 - 4; e = 2 - 4; and b, q, R3 and R4
`as defined under (i).
`
`Group III
`
`Group ill compounds are defined by the general formula:
`
`o/E-A-B
`
`~E-A-B
`
`where Cl) = 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 defmed
`previously. A may be chosen from any group II structure [(i), (li) or (iii)], but in this case
`the terminal group R3 in each A residue is deleted and replaced with a shared symmetrical
`group [E-<.o-E] which connects the two halves of the dimer, Cl) may be absent, in which case
`both E'S are joined together to constitute the chain linking the two A-B moieties;
`alternatively both E'S may be absent in which case Cl) solely joins the two A-B moieties.
`
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`

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`PCT/GB94/02615
`
`- 9 -
`
`e-CJ)-e must of course be chemically feasible ego NH-CO-NH,
`The structure of
`CO-NH-CO-, S02-NMe-S02; it will be obvious to those skilled in the an which structures
`are not feasible, ego -NH-NH-NH-. A specific possible example is shown in Table 7.
`
`In such compounds as described under Groups II and ill certain -CH2- groups present in
`the long chains could be replaced with known bioisosteres ego -0- without affecting
`inhibitory
`or
`binding
`activity
`towards DP-IV.
`Also
`such
`groupings
`as
`-CONHCH2CH2NHCO if they occur could be replaced by ego
`
`r-\
`-CO-N
`N-CO-
`"---.J
`
`Further, for compounds in Groups I, II and ill any amide bond connecting A and B or any
`amide in the side-chains of A (in Groups II and ill) may be replaced by known
`bioisosteres of amides ego
`
`/
`
`replaced by
`
`See Table 8 for examples of such replacements.
`
`Biochemistrv
`
`All compounds were t.ested in vitro against pure human DP-IV (purchased from M & E,
`Copenhagen, Denmark).
`Inhibition of DP-IV was determined using the fluorescent
`substrate Ala-Pro-AFC (Km 0.8 ~) at three concentrations for each inhibitor. A typical
`assay (total volume 0.4 ml) comprised sodium Hepes 83.3 roM, EDTA 1.67 roM, BSA 1.5
`mg ml-1 pH 7.8, DP-IV 25 IlU 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, excitation at
`395 nm, emission 450 nm. ~ values were determined using Dixon plots.
`
`/
`
`-CO-C-""
`
`/
`
`CF=C'"
`
`-CO-N'"/
`.""
`
`CH=C
`
`/
`
`-CS-N'"
`
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`W095/15309
`
`Chemistry
`
`- 10 -
`
`PCT/GB94/02615
`
`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
`products were characterised by FAB mass spectrometry and purity assessed by reverse
`phase hplc; all intermediates were characterised by IH NMR.
`
`Table 9 shows selected ~ values against DP-IV determined for inhibitors of different
`structural types.
`
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`

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`WO 95/15309
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`PCT/GB94/02615
`
`Table 1
`Examples of Group I (a)
`
`No.
`
`A
`
`x
`
`- 11 -
`
`R
`
`H
`
`n
`
`1
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+HJ~
`
`196.2
`
`197.2
`
`o
`
`1
`
`2
`
`3 H,:t
`
`°
`
`°
`
`CH 2
`
`H
`
`1
`
`C12H22N2O
`
`210.2
`
`211.2
`
`CH 2
`
`H
`
`1
`
`C10H2QN2O
`
`184.2
`
`185.2
`
`4
`
`CH2
`
`H
`
`1
`
`C'2H2QN2O
`
`208.2
`
`209.2
`
`0
`
`5 Qy CH2
`
`NH2
`
`0
`
`cis
`
`H
`
`1
`
`C11 H2QN2O
`
`196.1
`
`197.2
`
`SAXA-DEF-00058
`
`Page 13 of 57
`
`

`
`WO 95/15309
`
`PCT/GB94/02615
`
`6 O·",l
`NH2 °
`6""~
`8 O·",l
`9 ~ CH 2
`ONH,
`
`No.
`
`A
`
`trans
`
`7
`trans
`
`trans
`
`10
`trans
`
`- 12 -
`
`R
`
`H
`
`n
`
`1
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`soec. ~
`
`Cl1 H20N2O
`
`196.1
`
`197.2
`
`H
`
`1
`
`C11H1SN20
`
`194.1
`
`195.2
`
`H
`
`C10H1SN20
`
`182.1
`
`183.2
`
`H
`
`1
`
`Cll H14N2O
`
`190.1
`
`191.2
`
`H
`
`C13H24N20
`
`224.2
`
`225.2
`
`X
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`""f]
`°
`
`SAXA-DEF-00059
`
`Page 14 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 1'3 -
`
`Table 2
`Examples of Group I (b)
`
`No.
`
`A
`
`X
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`H-lle
`
`H-Lys(Z)
`
`H-Pro
`
`(~
`
`HN
`
`a
`
`( "S
`
`HN-Zy
`a
`
`a
`
`a
`
`Rl
`
`R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. WI.
`
`spec. [M+H}+
`
`H
`
`CN
`
`C11H1gN30
`
`209.3
`
`210.2
`
`H
`
`CN
`
`C1gH26N403
`
`358.2
`
`359.2
`
`H
`
`CN
`
`C1oH1sN30
`
`193.1
`
`194.1
`
`n
`
`1
`
`1
`
`1
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`1
`
`H
`
`CN
`
`CgH13N3OS
`
`211.1
`
`212.2
`
`CH2
`
`1
`
`H
`
`CN
`
`C9H13N3OS
`
`211.1
`
`212.2
`
`1
`
`1
`
`235.2
`
`236.3
`
`221.2
`
`222.2
`
`SAXA-DEF-00060
`
`Page 15 of 57
`
`

`
`W095/15309
`
`- 14 -
`
`No.
`
`A
`
`X
`
`n
`
`R1
`
`R
`
`Formula
`
`PCT/GB94/02615
`
`Calculated
`
`FAB Mass
`
`Mol. WI.
`
`soec. IM+HJ+
`
`18 H~~ CH 2
`°
`
`H-lle
`
`H-lle
`
`19
`
`20
`
`21
`
`°
`
`22
`
`H-Lys(Z)
`
`S
`
`S
`
`S
`
`S
`
`S
`
`1
`
`H
`
`CN
`
`C11H19N30
`
`209.2
`
`210.2
`
`1
`
`1
`
`1
`
`1
`
`H
`
`CN
`
`C10H17N30S
`
`227.1
`
`CN
`
`H
`
`C1oH17N30S
`
`227.1
`
`228.1
`
`228.1
`
`253.1
`
`254.1
`
`376.2
`
`377.2
`
`1
`
`H
`
`CN
`
`239.1
`
`240.2
`
`23
`
`24
`
`25
`
`26
`
`28
`
`29
`
`°
`
`H-lle
`
`H-lle
`
`H-lle
`
`H-lle
`
`H-lle
`
`H-lle
`
`C 11 H17N3OS
`
`°
`
`CH 2
`
`S
`
`S02
`
`+
`S "110
`
`-
`
`2
`
`2
`
`1
`
`1
`
`S+~O- 1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CN
`
`C1oH17N302
`
`211.1
`
`CN
`
`C12H21N30
`
`223.2
`
`CN
`
`C11H19N30S
`
`241.1
`
`CN
`
`C10H17N303S
`
`259.1
`
`CN
`
`C10H17N302S
`
`243.1
`
`212.2
`
`224.2
`
`242.1
`
`260.1
`
`244.1
`
`CN
`
`C10H17N302S
`
`243.1
`
`244.2
`
`"
`
`SAXA-DEF-00061
`
`Page 16 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 15 -
`
`Rl
`
`R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`H
`
`CN
`
`C12H19N30
`
`221.2
`
`222.2
`
`n
`
`1
`
`No.
`
`A
`
`X
`
`30 Q.."rr"
`
`NH2
`
`0
`
`CH2
`
`31
`
`1
`
`H
`
`CN
`
`221.2
`
`222.2
`
`NH2
`
`°
`
`°
`32 o:~ CH 2
`33 cf CH2
`34 Qy CH2
`
`NH2
`
`NH 2
`
`0
`
`1
`
`H
`
`CN
`
`C11 H17N3O
`
`207.2
`
`208.2
`
`1
`
`H
`
`CN
`
`C 11 H17N3O
`
`207.2
`
`208.2
`
`1
`
`H
`
`CN
`
`C12H17N30
`
`219.1
`
`220.1
`
`35
`
`1
`
`H
`
`CN
`
`219.1
`
`220.1
`
`SAXA-DEF-00062
`
`Page 17 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 16 -
`
`No.
`
`A
`
`X
`
`n
`
`Rl
`
`R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`36 Qy CH 2
`
`NH2
`
`0
`
`1
`
`H
`
`CN
`
`C12H1gN30
`
`221.2
`
`222.2
`
`37 Qy CH2
`
`NH2 a
`
`1
`
`H
`
`CN
`
`C12H17N30
`
`219.1
`
`220.1
`
`SAXA-DEF-00063
`
`Page 18 of 57
`
`

`
`WO 95/15309
`
`PCT/GB94/02615
`
`Table 3
`Examples of Group I (c)
`
`- 17 -
`
`X
`
`'()n
`
`(
`
`,N-\
`A
`R
`
`No.
`
`A
`
`X
`
`R
`
`n
`
`Fonnula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+HJ+
`
`38 Q.",(
`NH 2 °
`39 0,( CH2
`40 ~ CH2
`°
`Q '1f
`42 Q""f(
`NH 2 °
`43 Qy CH 2
`
`H N
`2
`
`H2N
`
`41
`
`H,N
`
`'L
`
`Ia
`
`a
`
`CH 2
`
`CH2
`
`CHz
`
`CHO
`
`1
`
`C12H20N202
`
`224.2
`
`225.2
`
`CHO
`
`1
`
`C11H1SN202
`
`210.2
`
`211.2
`
`CHO
`
`1
`
`C11H1SNzOz
`
`210.2
`
`211.2
`
`8·
`
`1
`
`C2QH33 8NZ0 3
`
`360.3
`
`361.3
`
`8·
`
`1
`
`C21 Has8Nz0 3
`
`374.3
`
`375.1
`
`8·
`
`1
`
`CZ1 Has8Nz0 3
`
`374.3
`
`375.1
`
`0
`
`NH2
`(XNH'
`""r(
`I
`a
`
`44
`
`CH2
`
`8·
`
`1
`
`C21 H338N20 3
`
`372.3
`
`373.3
`
`SAXA-DEF-00064
`
`Page 19 of 57
`
`

`
`W095115309
`
`PCT/GB94/02615
`
`- 18 -
`
`No.
`
`A
`
`X
`
`R
`
`n
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+HL-.
`
`45 0:; CH2
`
`0
`
`8* =
`
`8*
`
`C21 H338N 20 3
`
`372.3
`
`373.3
`
`SAXA-DEF-00065
`
`Page 20 of 57
`
`

`
`W095/15309
`Table 4
`Examples of Group" (i)
`
`- 19 -
`
`PCT/GB94/02615
`
`Q
`
`/
`(CH2 )n(X"( )m
`
`H,NJ-YN~R
`°
`
`No.
`
`46
`
`47
`
`48
`
`49
`
`50
`
`n
`
`1
`
`1
`
`1
`
`1
`
`1
`
`Q
`
`X
`
`m
`
`R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`-CONHCH2C02Bn
`
`CH2
`
`-CONHCH2C02H
`
`CH2
`
`-CONH(CH2h C02H
`
`CH2
`
`-CONH(CH2hC02Bn CH2
`
`-CONH(CH2hC02H
`
`CH2
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C17H23N304
`
`333.2
`
`C1oH17N304
`
`243.1
`
`C12H21N304
`
`271.2
`
`ClsH25N304
`
`347.2
`
`C11H1gN304
`
`257.1
`
`334.2
`
`244.2
`
`272.2
`
`348.2
`
`258.2
`
`389.3
`
`390.3
`
`51
`
`52
`
`53
`
`54
`
`55
`
`56
`
`57
`
`58
`
`1
`
`1
`
`1
`
`2
`
`2
`
`2
`
`2
`
`2
`
`-CONH(CH2)sC02Bn CH2
`
`C21H31N304
`
`-CONH(CH2)sC02H
`
`CH2
`
`-CONH(CH2bC02Bn CH2
`
`-CONHCH2C02Bn
`
`CH2
`
`-CONHCH2C02H
`
`CH2
`
`-CONH(CH2hC02Bn CH2
`
`-CONH(CH2hC02Bn CH2
`
`-CONH(CH2h C02H
`
`CHz
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C14H25N304
`
`299.2
`
`C19H27N304
`
`361.2
`
`C1sH25N304
`
`347.2
`
`C11H1gN304
`
`257.1
`
`C19H27N304
`
`361.2
`
`C2QH29N30 4
`
`375.2
`
`C13H23N304
`
`285.2
`
`300.2
`
`362.2
`
`348.2
`
`258.1
`
`362.3
`
`376.3
`
`286.2
`
`SAXA-DEF-00066
`
`Page 21 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 20 -
`
`No.
`
`n
`
`Q
`
`X m R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+HJ+
`
`59
`
`60
`
`61
`
`62
`
`63
`
`64
`
`2
`
`2
`
`2
`
`2
`
`2
`
`2
`
`1
`
`1
`
`1
`
`1
`
`1
`
`-CONH(CH2)sC028n
`
`CH2
`
`-CONH(CH2)5C02H
`
`CH2
`
`-CONH(CH2hC02H
`
`-CONH(CH2hC028n
`
`CH2
`
`CH2
`
`-CONH(CH2h C02H
`
`CH 2
`
`-CONH(CH2hCONH-
`(CH2hNHZ
`
`CH2
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C22H33N30 4
`
`403.3
`
`C1sH27N304
`
`313.2
`
`C12H21N304
`
`271.2
`
`C24H37N304
`
`431.3
`
`C17H31N304
`
`341.3
`
`C29H45NsOs
`
`531.3
`
`1
`
`H
`
`530.4
`
`404.3
`
`314.2
`
`272.2
`
`432.4
`
`342.5
`
`532.3
`
`65
`
`2
`
`-CONH(CH2)sCONH-
`(CH2)sC028n
`
`66
`
`2
`
`-CONH(CH2)sCONH-
`(CH2)sC02H
`
`67
`
`2
`
`-CONH(CH2hCONH-
`(CH2hNH2
`
`CH2
`
`C29H46N4OS
`
`531.2
`
`CH2
`
`1
`
`H
`
`C22H40N4OS
`
`440.3
`
`441.3
`
`CH2
`
`1
`
`H
`
`C2QH3QNS0 3
`
`397.3
`
`398.3
`
`68
`
`69
`
`70
`
`71
`
`72
`
`2
`
`2
`
`2
`
`2
`
`2
`
`-CONH(CH2)11 C02Bn
`
`CH2
`
`-CONH(CH2)11 C02H
`
`CH2
`
`-CONH(CH2)sC028n
`
`CH2
`
`-CONH(CH2)6C02H
`
`CH2
`
`1
`
`1
`
`1
`
`-CONH(CH2)sCONH-
`CH2CF3
`
`CH2
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C29H45N30 4
`
`487.3
`
`C21 H3QN30 4
`
`397.3
`
`C23H35N30 4
`
`417.3
`
`C16H29N304
`
`327.2
`
`C17H29F3N403
`
`394.2
`
`488.4
`
`398.3
`
`418.3
`
`328.2
`
`395.3
`
`SAXA-DEF-00067
`
`Page 22 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 21 -
`
`No.
`
`n
`
`Q
`
`X m R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`73
`
`2
`
`-CONH(CH2)sCONH-
`CH2(CF2)2CF3
`
`74
`
`2
`
`-CONH(CH 2)sCONH-
`(CH2)sOH
`
`75
`
`2
`
`-CONH(CH2)sCONH-
`(CH2bPh
`
`76
`
`2
`
`-CONH(CH 2)sCONH-
`(CH2)4Ph
`
`T7
`
`2
`
`-CONH(CH2)sCON-
`("Suh
`
`CH2
`
`1
`
`H
`
`C19H29F7N403
`
`494.2
`
`495.2
`
`CH2
`
`1
`
`H
`
`C21 H4QN40 4
`
`412.3
`
`413.2
`
`CH2
`
`1
`
`H
`
`C24H38N403
`
`430.3
`
`431.2
`
`CH2
`
`1
`
`H
`
`C25H4QN40 3
`
`444.3
`
`445.2
`
`CH2
`
`1
`
`H
`
`C23H44N40 3
`
`424.3
`
`425.3
`
`78
`
`2
`
`1
`
`H
`
`C27Hs2N403
`
`480.4
`
`481.4
`
`-CONH(CH2)sCON-
`("Hxh
`
`CH2
`
`79
`
`2
`
`-CONH(CH2)sCONH-
`CH2Ph
`
`CH 2
`
`1
`
`H
`
`C22H34N40 3
`
`402.3
`
`403.4
`
`80
`
`81
`
`2
`
`2
`
`82
`
`2
`
`-CONH(CH2)4C02Bn
`
`-CONH(CH2)4C02H
`
`-CONH(CH2)sCONH-
`CH2CH3
`
`CH2
`
`CH2
`
`CH2
`
`83
`
`2
`
`-CONH(CH2)sOH
`
`CH2
`
`84
`
`85
`
`2
`
`2
`
`-CONH(CH2)sCO-1-Pip CH2
`
`-CONH(CH2)sCONH2
`
`CH2
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C21H31N304
`
`389.2
`
`C14H25N304
`
`299.2
`
`C17H32N403
`
`340.3
`
`C1sH29N303
`
`299.2
`
`CzoH36N40 3
`
`380.3
`
`C1sH28N403
`
`312.2
`
`390.3
`
`300.3
`
`341.3
`
`300.3
`
`381.4
`
`313.3
`
`SAXA-DEF-00068
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`Page 23 of 57
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`W095/15309
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`PCT/GB94/02615
`
`- 22 -
`
`No.
`
`n
`
`Q
`
`X m R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec [M+H]+
`
`86
`
`2
`
`-CONH(CH 2)sCONH-
`(CH 2)gCH 3
`
`87
`
`2
`
`88
`
`2
`
`-CONH(CH2)sCONH-
`(CH2)sCH3
`
`-CONH(CH2)sCONH-
`CH2Ch
`
`89
`
`2
`
`-CONH(CH2)sCONH-
`(CH2bNHZ
`
`CH 2
`
`H
`
`C25H48N40 3
`
`452.4
`
`453.5
`
`CH2
`
`1
`
`H
`
`C22H42N403
`
`410.3
`
`411.4
`
`CH2
`
`1
`
`H
`
`C22H4QN40 3
`
`408.3
`
`409.4
`
`CH2
`
`1
`
`H
`
`C26H41 NsOs
`
`503.3
`
`504.4
`
`90
`
`2
`
`H
`
`ClsH35Ns03
`
`369.3
`
`370.3
`
`-CONH(CH2)sCONH-
`(CH2bNH2
`
`91
`
`2
`
`-CONH(CH2)sCONH-
`(CH2k Gua
`
`92
`
`2
`
`-CONH(CH2)sCONH-
`Ph(4-S03H)
`
`CH2
`
`CH2
`
`H
`
`C1gH37N703
`
`411.3
`
`412.4
`
`CH2
`
`1
`
`H
`
`C21 H32N4OSS
`
`468.2
`
`469.2
`
`93
`
`2
`
`-CONH(CH2)sCONH-4- CH2
`Pip(1-Bn)
`
`H
`
`C27H43Ns03
`
`485.3
`
`486.3
`
`94
`
`2
`
`-CONH(CH2)sCONH-
`4-Pip
`
`95
`
`2
`
`96
`
`2
`
`-CONH(CH2)4N(Z)-
`(CH2bNHZ
`
`-CONH(CH2)4NH-
`(CH2bNH2
`
`CH2
`
`1
`
`H
`
`C2QH37NS0 3
`
`395.3
`
`396.3
`
`CH2
`
`1
`
`H
`
`C32H45NsOs
`
`595.3
`
`596.3
`
`CH2
`
`1
`
`H
`
`C1sH33Ns02
`
`327.2
`
`328.2
`
`SAXA-DEF-00069
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`Page 24 of 57
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`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 23 -
`
`No.
`
`97
`
`98
`
`n
`
`2
`
`3
`
`Q
`
`X m R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`-CONH(CH2)sC02Bn
`
`CH2
`
`-CONH(CH2)6CONH-
`(CH2)sC02Bn
`
`CH2
`
`1
`
`1
`
`CN
`
`C23H32N40 4
`
`428.3
`
`H
`
`C3JH48N4OS
`
`544.4
`
`429.3
`
`545.2
`
`99
`
`3
`
`-CONH(CH2)6CONH-
`(CH2)sC02H
`
`CH2
`
`1
`
`H
`
`C23H42N4OS
`
`454.3
`
`455.3
`
`100
`
`3
`
`-CONH(CH2)sC02Bn
`
`CH2
`
`1
`
`101
`
`102
`
`3
`
`2
`
`-CONH(CH2)sC02H
`
`CH2
`
`-S02NH(CH2)sC02H
`
`CH2
`
`103
`
`2
`
`-CONH(CH2)eNH-G"
`
`CH 2
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`C23H35N30 4
`
`417.3
`
`C16H29N304
`
`327.2
`
`C14H27N30SS
`
`349.2
`
`418.2
`
`328.2
`
`350.2
`
`C24H45N50~
`
`547.4
`
`548.5
`
`OHH°te
`
`NH
`
`~s
`
`OH
`
`0
`
`G*=
`
`SAXA-DEF-00070
`
`Page 25 of 57
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`

`
`WO 95/15309
`
`PCT/GB94/02615
`
`- 24 -
`
`Table 5
`Examples of Group II (ii)
`
`No.
`
`n
`
`Q
`
`X m R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+HJ~
`
`104
`
`105
`
`106
`
`107
`
`1
`
`1
`
`3
`
`3
`
`108
`
`4
`
`-CO(CH2)6C02H
`
`CH2
`
`-CO(CH2)sC02Bn
`
`CH2
`
`-CO(CH2)4C02H
`
`CH2
`
`-CO(CH2)4C02Me
`
`CH2
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C1sH27N304
`
`313.2
`
`C22H33N30 4
`
`403.3
`
`314.3
`
`404.3
`
`C1sH27N304
`
`313.2
`
`314.3
`
`C16H29N304
`
`327.2
`
`328.3
`
`C16H32N402
`
`312.3
`
`313.3
`
`-CO(CH2)sNH2
`
`-CO(CH2bNH2
`
`CH2
`
`CH2
`
`-CO(CH2hNHS02Pfp CH2
`
`-CO(CH2hNHCOPfp
`
`-CO(CH2bNHS02-
`CH2CF3
`
`CH2
`
`CH2
`
`CH 2
`
`109
`
`110
`
`111
`
`112
`
`4
`
`4
`
`4
`
`4
`
`113
`
`4
`
`-CO(CH2)11 NHCO-
`(CH2)6NHZ
`
`114
`
`4
`
`-CO(CH2)11 NH-
`
`CH2
`
`CO(CH 2)sNH2
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C14H28N402
`
`284.2
`
`285.2
`
`C2QH27FSN404S
`
`514.2
`
`515.2
`
`C21H27FsN403
`
`478.2
`
`479.2
`
`C1sH29F3N404S
`
`430.2
`
`431.3
`
`C37H63NsOs
`
`657.5
`
`658.6
`
`C29H57Ns0 3
`
`523.4
`
`524.4
`
`SAXA-DEF-00071
`
`Page 26 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 25 -
`
`No.
`
`n
`
`Q
`
`X m R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`soec. [M+H]+
`
`115
`
`4
`
`-CO(CH2)5NHCO-
`
`CH2
`
`1
`
`H
`
`C36HsoNsOs
`
`672.5
`
`673.6
`
`(CH2)5NHCO(CH2)5_
`NHZ
`
`116
`
`4
`
`-CO(CH2)5NHCO-
`
`CH2
`
`1
`
`H
`
`C28H54Ns0 4
`
`538.4
`
`539.4
`
`(CH2)5NHCO(CH2k
`NH2
`
`117
`
`4
`
`-CO(CH2hC02H
`
`118
`
`119
`
`120
`
`4
`
`4
`
`4
`
`-CO(CH2bC028n
`
`-CO(CH2)sNH2
`
`-CO(CH2hNH2
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C15H27N304
`
`313.2
`
`314.3
`
`C22H33N30 4
`
`403.3
`
`C17H34N402
`
`326.3
`
`C1sH36N402
`
`340.3
`
`465.4
`
`404.3
`
`327.3
`
`341.3
`
`121
`
`122
`
`123
`
`124
`
`125
`
`126
`
`127
`
`128
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`-CO(CH2)16Me
`
`-CO(CH2k Gua
`
`-S02(CH2hCH3
`
`-CO(CH2)11 NH2
`
`-COCH2NHZ
`
`-CO(CH2hNHZ
`
`-CO(CH2hNHZ
`
`-CO(CH2hNH2
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`CH 2
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`C28H55N30 2
`
`466.4
`
`C1sH36Ns02
`
`368.3
`
`369.3
`
`C1sH37N303S
`
`375.3
`
`376.3
`
`C22H44N40 2
`
`396.4
`
`397.4
`
`C20H30N40 4
`
`390.2
`
`C21H32N404
`
`C22H34N40 4
`
`404.2
`
`418.3
`
`391.3
`
`405.3
`
`419.3
`
`C12H24N402
`
`256.2
`
`257.2
`
`SAXA-DEF-00072
`
`Page 27 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 26 -
`
`No.
`
`n
`
`Q
`
`X
`
`m
`
`R
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`129
`
`130
`
`131
`
`132
`
`4
`
`4
`
`4
`
`4
`
`-CO(CH2)sNHZ
`
`-COCH2-Gua
`
`CH2
`
`CH 2
`
`-CO(CH2)2NH2
`
`CH2
`
`-CO(CH2h-Gua
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CN
`
`CN
`
`C24H38N404
`
`446.3
`
`447.4
`
`C13H26Ns02
`
`298.2
`
`C13H26N402
`
`270.2
`
`C14H2BNS02
`
`312.2
`
`299.3
`
`271.3
`
`313.3
`
`C1sH~Ns02
`
`326.3
`
`327.3
`
`C17H34Ns02
`
`354.3
`
`355.3
`
`C1sH33Ns02
`
`351.3
`
`352.4
`
`C19H35Ns02
`
`365.3
`
`366.3
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`CH2
`
`133
`
`4
`
`-CO(CH2k Gua
`
`134
`
`135
`
`136
`
`4
`
`4
`
`4
`
`-CO{CH2k Gua
`
`-CO(CH 2)sNH z
`
`-CO(CH2hNH z
`
`SAXA-DEF-00073
`
`Page 28 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 27 -
`
`Table 6
`Examples of Group II (iii)
`
`No.
`
`137
`
`R
`
`H
`
`138
`
`H
`
`139
`
`H
`
`R1
`
`-OCH2CONH(CH2k
`C02H
`
`-OCH2CONH(CH2k
`C02Bn
`
`-OCH2CONH(CH2k
`C02Bn
`
`140
`
`H
`
`-OCH2CONH(CH2k
`C02H
`
`X
`
`CH2
`
`n
`
`1
`
`y
`
`H
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`C1sH27N30S
`
`329.2
`
`330.3
`
`CH2
`
`1
`
`H
`
`C22H33N3OS
`
`419.3
`
`420.3
`
`CH2
`
`1
`
`H
`
`C21H31N30S
`
`405.2
`
`406.3
`
`CH2
`
`1
`
`H
`
`C14H25N30S
`
`315.2
`
`316.3
`
`141
`
`CH3
`
`-OCH3
`
`CH2
`
`1
`
`H
`
`C9H1SN202
`
`186.1
`
`142
`
`CH3
`
`-OC2Hs
`
`143
`
`CH3
`
`-O(CH2)sCH 3
`
`144
`
`CH3
`
`-OCH2CONH(CH2k
`C02Bn
`
`145
`
`CH3
`
`-OCH2CONH(CH 2k
`C02H
`
`CH2
`
`CH2
`
`CH2
`
`1
`
`1
`
`1
`
`H
`
`H
`
`C10H2QN20 2
`
`200.1
`
`C14H28N202
`
`256.2
`
`H
`
`C23H35N3OS
`
`433.3
`
`187.2
`
`201.2
`
`257.3
`
`434.3
`
`CH2
`
`1
`
`H
`
`C16H29N30S
`
`343.2
`
`344.3
`
`SAXA-DEF-00074
`
`Page 29 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 28 -
`
`No.
`
`R
`
`R1
`
`X
`
`n
`
`Y
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt. spec.~
`
`146
`
`CH3
`
`-OCH 2CONH(CH 2k
`C02Bn
`
`147
`
`CH3
`
`-OCH2CONH(CH 2k
`C02H
`
`CH2
`
`H C22H33N3OS
`
`419.2
`
`420.3
`
`CH 2
`
`1
`
`H C1sH27N30S
`
`329.2
`
`330.3
`
`SAXA-DEF-00075
`
`Page 30 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 29 -
`
`Table 7
`Example of Group III
`
`No.
`
`148
`
`Structure
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`614.4
`
`615.4
`
`SAXA-DEF-00076
`
`Page 31 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 30 -
`
`Table 8
`Specific examples of compounds A-B, containing amide bond bioisosteres.
`
`No.
`
`149
`
`150
`
`151
`
`152
`
`A-B
`
`Formula
`
`Calculated
`
`FAB Mass
`
`Mol. Wt.
`
`spec. [M+H]+
`
`167.2
`
`168.2
`
`192.2
`
`193.2
`
`192.2
`
`193.2
`
`200.1
`
`201.2
`
`CN
`
`"/ CN
`
`s
`
`SAXA-DEF-00077
`
`Page 32 of 57
`
`

`
`WO 95/15309
`
`PCT/GB94/02615
`
`- 31 -
`
`Table 9
`Selected Kj values against DP-IV.
`
`No.
`
`Kj (M)
`
`2
`
`7
`
`11
`
`20
`
`23
`
`35
`
`38
`
`44
`
`59
`
`66
`
`97
`
`110
`
`136
`
`143
`
`150
`
`6.4 x 10-3
`
`7.6x10-6
`
`2.2 x 10-9
`
`1.7 X 10-9
`
`5.0 X 10-10
`
`3.7 X 10-3
`
`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 10-3
`
`9.4 x 10-7
`
`1.7 x 10-6
`
`SAXA-DEF-00078
`
`Page 33 of 57
`
`

`
`WO 95/15309
`
`PCT/GB94/02615
`
`- 32 -
`
`Schematic Representations for General Preparation of all Classes of Compounds
`
`Table 1
`
`Compounds can be made by an adaption of the general route described by E. Schon et al.,
`BioI. Chern. Hoppe-Seyler, 1991,372,305-311.
`
`Table 2
`
`(a) R:
`
`-CN
`
`Boc-A-OH. +
`
`pyridine,
`imidazole
`
`x
`
`'On
`(
`Boc-A-N~
`
`CN
`
`x-s1mCPBA
`
`x
`
`"()n
`(
`Boc-A-N ~NH2
`
`PyBop •
`
`°
`
`X
`
`'( ~
`(
`H+
`- - -... H-A-N~
`CN
`
`CN
`
`(0\
`
`IX
`
`'On
`(
`Boc-A-N~
`
`y = 1,2
`
`(G)y
`
`IX
`
`'()n
`(
`H-A-N~
`CN
`
`SAXA-DEF-00079
`
`Page 34 of 57
`
`

`
`W095/15309
`
`(b) R:
`
`-CH=NPh
`
`'()n
`(
`Boc-A-ONSu + ~N~OH
`
`X
`
`- 33 -
`
`PCT/GB94/02615
`
`CH2Cl2
`
`X
`
`'()n
`(
`~ BOC-A-N~OH
`
`DMP
`CH2C12
`
`~
`
`X
`
`'On
`(
`BOC-A-N-Y0
`
`H
`
`(I)
`
`(I)
`
`PhNH2
`Toluene, ~
`
`.. Boc-A-N~
`
`X
`
`(
`
`'On
`
`-NPh
`
`H+
`
`X
`
`'On
`(
`~ H-A-N~
`-NPh
`
`(c) R: CH=N.......
`
`ORI
`
`(1)
`
`R IONH2·HCl
`~
`pyridine, DMF
`
`ForRI = -Ac
`
`(II)
`
`Py, AC20
`CH2C12 ~
`(RI = H)
`
`(d) R= -C=CR
`
`(1)
`
`X
`
`'On
`(
`H-A-N-l
`"=N-ORI
`
`(ll)
`
`X(
`'(~
`BOC-A-N~Br
`
`Br
`
`~
`
`(i) nBuLi
`(ii) "R+"
`(iii) H+
`
`X
`
`'()n
`(
`H-A-N-l
`~C-R
`
`Table 3
`
`(a) R= -<fiJ
`
`(b) R=CHO
`
`(I)
`
`Prepared by method of: W.W. Bachovchin et aI.,
`J. BioI. Chern., 1990,265,3738-3743.
`
`x
`
`'()n
`(
`H-A-N~
`CHO
`
`SAXA-DEF-00080
`
`Page 35 of 57
`
`

`
`W095/15309
`
`PCT/GB94/02615
`
`- 34 -
`
`Table 4
`
`CW, P = Protecting gro