INTERNATIONAL SEARCH REPORT Inte'ional Applieation No PC1/US 00/06837 A. CLASSIFICATION OF SUBJECT MATTER IPC 7 A61P37/00 A61P25/00 A61P29/00 C07D277/30 C07D295/20 C07D417/04 C07D211/58 C07D207/14 C07D211/72 C07D417/12 C07D277/38 C07D417/06 C07C255/29 According to International Patent Classification (IPC) or to both national classification and IPC B.FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X WO 95 15309 A (FERRING BV; JENKINS PAUL D 1-7 (GB); JONES D MICHAEL (GB); SZELKE MICH) 8 June 1995 (1995-06-08) page 13-page 16; table 2 X WO 95 13069 A (MORRIELLO GREGORI J 1-7 ; PATCHETT ARTHUR A (US); CHEN MENG H (US); YAN) 18 May 1995 (1995-05-18) claim 1 X WO 90 13561 A (BOOTS CO PLC) 1-7 15 November 1990 (1990-11-15) page 27 X EP 0 754 454 A (ZERIA PHARM CO LTD) 1-7 22 January 1997 (1997-01-22) page 12, line 35-line 50 ___ Further documents are listed in the continuation of box C. JY Patent family members are listed in annex. LJ L-I Special categories of cited documents : 'T'later document published after the international fiting date 'A'document defining the general state of the art which is not or priority date and not in conflict with the application but consideredto be of particular relevance invention invention 'E'earlier document but published on or after the international X document of particular relevance the claimed invention filing date cannot be considered novel or cannot be considered to 'L'document which may throw doubts on priority claim (s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another-y. document of particular relevance ; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the '0'document referring to an oraf disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled 'P'document published prior to the international filing date but in the art. later than the priority date claimed'&'document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 24 November 2000 Name and mailing address of the ISA Authorized officer European Patent Office, P. B. 5818 Patentlaan 2 NL-2280 HV Rijswijk 6 Tel. (+31-70) 340-2040, Tx. 31 651 epo nl, Fax : (+31-70) 340-3016 INTERNATIONAL SEARCH REPORT Intc'ional Application No PCT/US 00/06837 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category 0 Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP 0 536 399 A (ZERIA PHARM CO LTD) 1-7 14 April 1993 (1993-04-14) page 27-page 28; table 2 X EP 0 419 683 A (JAPAN TOBACCO INC 1-7,19, ; YOSHITOMI PHARMACEUTICAL (JP)) 24 3 April 1991 (1991-04-03) page 25; table 1 X EP 0 355 572 A (BEHRINGWERKE AG) 1-7 28 February 1990 (1990-02-28) page 5 X PATENT ABSTRACTS OF JAPAN 1-7 vol. 013, no. 137 (C-582), 5 April 1989 (1989-04-05) &JP 63 301868 A (NIPPON KAYAKU CO LTD), 8 December 1988 (1988-12-08) abstract X JINGRONG LI ET AL.: 1-7 "Aminoacylpyrrolidine-2-nitriles : Potent and stable Inhibitors of Dipeptidyl-Peptidase IV (CD 26)" ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, vol. 323, no. 1,1995, pages 148-154, XP000965067 page 150-page 151 X SUZUE ET AL:"Hepatic agents. I. 1-7 Synthesis of aminoacyl (and hydroxyacyl)aminoacetonitriles" CHEMICAL AND PHARMACEUTICAL BULLETIN, TOKYO, JP, vol. 16, no. 8, August 1968 (1968-08), pages 1417-1432, XP002108053 ISSN: 0009-2363 page 1429-page 1432 X HANZLIK R P ET AL:"REVERSIBLE COVALENT 1-7 BINDING OF PEPTIDE NITRILES TO PAPAIN" BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES, AMSTERDAM, NL, vol. 1035, no. 1,1990, pages 62-70, XP000929836 ISSN: 0005-2736 page 69 X PICKEN, PAULA P. ET AL:"Inhibition of 1-7 bovine cathepsin B by amino acid-derived nitriles" BIOCHEM. SOC. TRANS., vol. 18, no. 2,1990, page 3016 XP000929783 page 316 6 INTERNATIONAL SEARCH REPORT Inte tional Application No PCI/US 00/06837 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X MCMATH, ANDREW R. ET AL:"Direct 1-7 dialkylation of peptide nitriles. Application to the synthesis of 1-aminocyclopropane-1-carboxylic acid (Acc)-containing dipeptides" BULL. SOC. CHIM. FR. (1997), 134 (1), 105-110, vol. 134, no. 1,1997, pages 105-110, XP000960770 page 106 page 108-page 109 X DATABASE CHEMABS'Online ! 1-7 CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO,US; YAMADA, TAKASHI ET AL:"Studies of unusual amino acids and their peptides. IX. The synthetic study of bottromycins B1 and B2" retrieved from STN Database accession no. 89: 129910 XP002153760 abstract &BULL. CHEM. SOC. JPN. (1978), 51 (3), 878-83, X ASHWORTH D M ET AL:"4-Cyanothiazolidides 1-7 as very potent, stable inhibitors of dipeptidyl peptidase IV" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, GB, OXFORD, vol. 6, no. 22, 19 November 1996 (1996-11-19), pages 2745-2748, XP004135888 ISSN: 0960-894X page 2746 X MOSER H ET AL :"130. 1-7 POLY (DIPEPTAMIDINIUM)-SALZE: DEFINITION UND METHODEN ZUR PRAPARATIVEN HERSTELLUNG. POLY (DIPEPTAMIDINIUM) SALTS: DEFINITION AND METHODS OF PREPARATION" HELVETICA CHIMICA ACTA, CH, VERLAG HELVETICA CHIMICA ACTA. BASEL, vol. 69,1986, pages 1224-1262, XP002049723 ISSN : 0018-019X the whole document 6 6 INTERNATIONAL SEARCH REPORT t' ! ional Application No PCT/US 00/06837 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X LIPSHUTZ, BRUCE H. ET AL:"Oxazolophanes 1-7 as masked cyclopeptide alkaloid equivalents : cyclic peptide chemistry without peptide couplings" J. AM. CHEM. SOC., vol. 112, no. 19,1990, pages 7032-7041, XP002153754 page 7035 X NORTH, MICHAEL ET AL:"Synthetic studies 1-7 towards cyclic peptides. Concise synthesis of thiazoline and thiazole containing amino acids" TETRAHEDRON, vol. 46, no. 24,1990, pages 8267-8290, XP002153755 page 8271 X KATRITZKY, ALAN R. ET AL: 1-7 "Benzotriazole-assisted synthesis of. alpha.- (acylamino) nitriles and a conceptually novel method for peptide elongation" J. CHEM. SOC., PERKIN TRANS. 1, no. 7,1990, pages 1853-1857, XP002153756 scheme 1 page 1853 Scheme 2 page 1856 X THOMPSON, STEWART A. ET AL: 1-7 "Carboxyl-modified amino acids and peptides as protease inhibitors" J. MED. CHEM., vol. 29, no. 1,1986, pages 104-111, XP002153757 page 109 X VARUGHESE, K. A. ET AL:"The structure 1-7 and resonance Raman spectra-structure correlations for methyloxycarbonyl-L-phenylalanyl-L-alanine ethyl dithioester" CAN. J. CHEM., vol. 64, no. 8,1986, pages 1668-1673, XP002153758 page 1669 ___ 6 INTERNATIONAL SEARCH REPORT lnt, lional Application No PCT/US 00/06837 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X LIPSHUTZ, BRUCE H. ET AL:"Heterocycles 1-7 as masked diamide/dipeptide equivalents. Formation and reactions of substituted 5- (acylamino) oxazoles as intermediates en route to the cyclopeptide alkaloids" J. AM. CHEM. SOC., vol. 105, no. 26,1983, pages 7703-7713, XP002153759 page 7706 X DATABASE CHEMABS'Online ! 1-7 CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO,US; LIPSHUTZ, BRUCE H. ET AL:"Chiral induction in originally racemic amino acids via 5-acyl and 5-acyloxyaminooxazoles" retrieved from STN Database accession no. 108: 222080 XP002153761 abstract &ISR. J. CHEM. (1986), 27 (1), 49-55, X DATABASE CHEMABS'Online ! 1-7 CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO,US; VARGHA, EUGEN:"Peptide derivatives. VI. N-protected di-and peptide nitriles" retrieved from STN Database accession no. 71: 39374 XP002153762 abstract &STUD. UNIV. BABES-BOLYAI, SER. CHEM. (1968), 13 (2), 31-5, X GOUR-SALIN B J ET AL:"INHIBITION OF 1-7 PAPAIN BY PEPTIDE NITRILES: CONVERSION OF THE NITRILEGROUP INTO OTHER FUNCTIONALITIES VIA THE PAPAIN: NITRILE THIOMIDATE ESTER ADDUCT" CANADIAN JOURNAL OF CHEMISTRY, CA, NATIONAL RESEARCH COUNCIL. OTTAWA, vol. 69, no. 8,1991, pages 1288-1297, XP002049724 ISSN: 0008-4042 page 1289-page 1291 6 INTERNATIONAL SEARCH REPORT Inte ional Application No PC1/US 00/06837 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X DUFOUR ET AL:"Engineering nitrile 1-7 hydratase activity into a cysteine protease by a single mutation" BIOCHEMISTRY, US, AMERICAN CHEMICAL SOCIETY. EASTON, PA, vol. 34, no. 50,1995, pages 16382-16388, XP002129204 ISSN: 0006-2960 page 16385 P, X BERGEMANN, MARCO ET AL:"Studies on the 1-28 reactivity of. alpha.-cyano. alpha.-isocyano alkanoates. Versatile synthons for the assembly of imidazoles" HELV. CHIM. ACTA, vol. 82, no. 6,1999, pages 909-918, XP002144357 page 912 P, X WO 99 24460 A (NOVARTIS AG, 1-28 SWITZ. ; NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT MBH) 20 May 1999 (1999-05-20) examples 1-419 E WO 00 51998 A (BOEHRINGER INGELHEIM 1-28 PHARMA) 8 September 2000 (2000-09-08) the whole document E WO 00 55124 A (VENKATRAMAN SHANKAR; AXYS 1-28 PHARM INC (US); BUYSSE ANN M (US); PALME) 21 September 2000 (2000-09-21) the whole document 6 xnational application No. INTERNATIONAL SEARCH REPORT PCT/US 00/06837 Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet) This International Search Report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons: 1. 3 Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely : Although claims 19-28 are directed to a method of treatment of the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. ClaimsNos. : claims 1-28 (partially not searched) because they relate to parts of the International Application that do not comply with the prescribed requirements to such an extent that no meaningful International Search can be carried out, specifically : see FURTHER INFORMATION sheet PCT/ISA/210 3. Claims Nos. : because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4 (a). Box 11 Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows : see additional sheet 1. As all required additional search fees were timely paid by the applicant, this International Search Report covers all searchable claims. 2. As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. As only some of the required additional search fees were timely paid by the applicant, this International Search Report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is restricted to the invention first mentioned in the claims ; it is covered by claims Nos.: Remark on Protest ! The additional search fees were accompanied by the applicant's protest. u v No protest accompanied the payment of additional search fees. I-J International Application No. PCTAJS 00/) 6837 FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 Continuation of Box 1. 2 Claims Nos.: claims 1-28 (partially not searched) The initial phase of the search revealed a very large number of documents relevant to the issue of novelty. So many documents were retrieved that it is impossible to determine which parts of the claim (s) may be said to define subject-matter for which protection might legitimately be sought (Article 6 PCT). For these reasons it appears impossible to execute a meaningful search and/or to issue a complete search report over the whole breadth of the above mentiones claims in a far as invention 2 of the previous invitation to pay additional fees is concerned. The search and the report for above mentioned claims with respect to the content of invention 2 can only be considered complete for compounds according to the definition of invention 2 as they have been mentioned in the specific embodiments (see the examples) by chemical name and for which physico-chemical data have been provided in the description. The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure. International Application No. PCTAJS 00 t6837 FURTHER INFORMATION CONTINUED FROM PCTiiSA/210 This International Searching Authority found multiple (groups of) inventions in this international application, as follows: 1. Claims: 1,2,4,9-13,19-23 (all partially) Compounds of formula I, wherein X1=C (O) and R4 either beeing -CN or-C (O) OR12. 2. Claims: 1, 2,5,6,9-28 (all partially) Compounds of formula I, wherein X1=C (O) ; R4= (C1-6) Alkyl (optionally substituted) or R4=H and R3=H or R4=H and R3=C (1-6) Alykl. 3. Claims: 1,5,9-13,19-23 (all partially) Compounds of formula I, wherein X1=C (O), R4 is a (poly) cycloalkyl or a (poly) cycloaryl moiety. 4. Claims: 1,2,3,4,5,6,7,8,9-28 (all partially) Compounds of formula I, wherein X1=C (O) and R4 taken together with R2 or R3 forms a cyclic structure. 5. Claims: 1, 9-13, 19-23 (all partially); 6,14-18, 24-28 (all partially) Compounds according to formula I, claim 1 with X1=CH2S02 or according to formula II claim 6 with X1 beeing either S (O) or C (S) or S (0) 2 or P (0) 2. INTERNATIONAL SEARCH REPORT Intf ional Application No Information on patentfamily members PCT/US 00/06837 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9801133 A 15-01-1998 AU 3359697 A 02-02-1998 WO 9808867 A 05-03-1998 AU 713133 B 25-11-1999 AU 3868097 A 19-03-1998 BR 9712081 A 24-08-1999 CN 1235610 A 17-11-1999 EP 0933379 A 04-08-1999 WO 9524382 A 14-09-1995 AT 195933 T 15-09-2000 AU 2115695 A 25-09-1995 CA 2184691 A 14-09-1995 DE 69518631 D 05-10-2000 EP 0749418 A 27-12-1996 WO 9515309 A 08-06-1995 AU 1113395 A 19-06-1995 AU 8421998 A 12-11-1998 CA 2178066 A 08-06-1995 CN 1141033 A 22-01-1997 CZ 9601595 A 15-01-1997 EP 0731789 A 18-09-1996 FI 962315 A 05-08-1996 HU 76274 A 28-07-1997 JP 9509921 T 07-10-1997 NO 962269 A 30-07-1996 PL 314838 A 30-09-1996 US 5939560 A 17-08-1999 ZA 9409525 A 02-08-1995 WO 9513069 A 18-05-1995 US 5494919 A 27-02-1996 US 5492916 A 20-02-1996 US 5492920 A 20-02-1996 AU 1172995 A 29-05-1995 BG 100555 A 31-10-1996 BR 9408019 A 26-08-1997 CA 2175218 A 18-05-1995 CN 1174504 A 25-02-1998 CZ 9601342 A 11-12-1996 EP 0739204 A 30-10-1996 FI 961951 A 08-05-1996 HU 74733 A 28-02-1997 JP 10506091 T 16-06-1998 LV 11525 A 20-10-1996 LV 11525 B 20-02-1997 NO 961865 A 08-07-1996 PL 322706 A 16-02-1998 SK 56296 A 05-02-1997 US 5622973 A 22-04-1997 US 5721250 A 24-02-1998 US 5721251 A 24-02-1998 WO 9013561 A 15-11-1990 AT 107660 T 15-07-1994 AU 631641 B 03-12-1992 AU 5547290 A 29-11-1990 BG 60916 B 28-06-1996 CA 2056402 A 29-10-1990 CN 1047340 A 28-11-1990 DD 296960 A 19-12-1991 DE 69010199 D 28-07-1994 INTERNATIONAL SEARCH REPORT Inte ional Application No ! ntf ona! App! <cat! on No . nformation on patent family members PCT/US 00/06837 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9013561 A DE 69010199 T 13-10-1994 DK 470136 T 01-08-1994 EG 19583 A 30-09-1995 EP 0470136 A 12-02-1992 ES 2055427 T 16-08-1994 GR 90100315 A, B 27-09-1991 HR 930700 A 30-06-1995 HU 58345 A 28-02-1992 HU 9500687 A 28-12-1995 IE 64351 B 26-07-1995 IL 94227 A 29-12-1994 IN 170683 A 02-05-1992 IN 173230 A 12-03-1994 JP 4506003 T 22-10-1992 LT 1645 A, B 25-07-1995 Lav 10200 A, B 20-10-1994 MX 20503 A 01-12-1993 NO 914206 A 17-12-1991 NZ 233475 A 25-10-1991 PL 166810 B 30-06-1995 PT 93921 A, B 20-11-1990 RO 112032 B 30-04-1997 RU 2074891 C 10-03-1997 US 5468480 A 21-11-1995 US 5380656 A 10-01-1995 ZA 9003228 A 28-12-1990 ZA 9003228 A 28-12-1990 EP 0754454 A 22-01-1997 JP 7228529 A 29-08-1995 AU 681251 B 21-08-1997 AU 1718195 A 04-09-1995 US 6017929 A 25-01-2000 WO 9522326 A 24-08-1995 EP 0536399 A 14-04-1993 DE 69116692 D 07-03-1996 DE 69116692 T 05-09-1996 US 5407950 A 18-04-1995 AT 133407 T 15-02-1996 AU 643300 B 11-11-1993 AU 7986691 A 31-12-1991 CA 2084204 A 08-12-1991 DK 536399 T 03-06-1996 WO 9118877 A 12-12-1991 EP 0419683 A 03-04-1991 WO 9012005 A 18-10-1990 US 5118811 A 02-06-1992 EP 0355572 A 28-02-1990 DE 3827415 A 15-02-1990 AT 87006 T 15-04-1993 AU 617507 B 28-11-1991 AU 3951589 A 15-02-1990 CA 1336080 A 27-06-1995 DE 58903791 D 22-04-1993 JP 2111788 A 24-04-1990 US 5202416 A 13-04-1993 JP 63301868 A 08-12-1988 NONE WO 9924460 A 20-05-1999 AU 1487399 A 31-05-1999 INTERNATIONAL SEARCH REPORT,". tional Application No Information on patent family members PCT/US 00/06837 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9924460 A BR 9813197 A 29-08-2000 EP 1028942 A 23-08-2000 NO 20002320 A 04-07-2000 ZA 9810073 A 05-05-1999 WO 0051998 A 08-09-2000 NONE WO 0055124 A 21-09-2000 NONE