(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date PCT (10) International Publication Number 2 August 2007 (02.08.2007) WO 2007/085557 A3

(51) International Patent Classification: (74) Agent: POPPE, Regina; Grenzacherstrasse 124, A61K 31/4164 (2006.01) C07D 401/04 (2006.01) CH-4070 Basel (CH). A61K 31/4174 (2006.01) C07D 405/06 (2006.01) C07D 233/06 (2006.01) C07D 409/06 (2006.01) (81) Designated States (unless otherwise indicated, for every C07D 233/54 (2006.01) A61P 25/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (21) International Application Number: CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, PCT/EP2007/050443 GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV,LY, MA, MD, MG, MK, MN, MW, MX, MY, (22) International Filing Date: 17 January 2007 (17.01.2007) MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW

(26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 06100955.1 27 January 2006 (27.01.2006) EP ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (71) Applicant (for all designated States except US): F. HOFF¬ FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, MANN-LA ROCHE AG [CWCH]; Grenzacherstrasse RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, 124, CH-4070 Basel (CH). GN, GQ, GW, ML, MR, NE, SN, TD, TG).

(72) Inventors; and Published: (75) Inventors/Applicants (for US only): GALLEY, Guido — with international search report [DE/DE]; Katzenbuckelweg 14, 79618 Rheinfelden — before the expiration of the time limit for amending the (DE). GROEBKE ZBINDEN, Katrin [CWCH]; claims and to be republished in the event of receipt of Laubibergstrasse 61, CH-4410 Liestal (CH). HOENER, amendments Marius [CWCH]; Alemannengasse 103, CH-4058 Basel (88) Date of publication of the international search report: (CH). KOLCZEWSKI, Sabine [DE/DE]; Minna Vor- 20 September 2007 tisch Strasse 12d, 79540 Loerrach (DE). NORCROSS, Roger [GB/CH]; Maetteli 244, CH-4305 Olsberg (CH). For two-letter codes and other abbreviations, refer to the "G uid STALDER, Henri [CH/CH]; Strassburgerallee 83, ance Notes on Codes and Abbreviations" appearing at the beg in CH-4055 Basel (CH). ning of each regular issue of the PCT Gazette.

(54) Title: USE OF SUBSTITUTED 2-IMIDAZOLE OF IMIDAZOLINE DERIVATIVES

(57) Abstract: The present invention relates to the use of compounds of Formula (I), wherein R is hydrogen, tritium, hydroxy, amino, lower alkyl, cycloalkyl, lower alkoxy, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halo gen, phenyl, O-phenyl, -S-phenyl, optionally substituted by halogen, or is benzyl, benzyloxy, NHC(O)-lower alkyl or pyridin-2,3 or 4-yl; R is hydrogen, hydroxy or lower alkyl; R is hydrogen or lower alkyl; aryl is an aromatic group, selected from phenyl, naphthalen-1-yl or naphthalen-2-yl; hetaryl is an aromatic group, containing at least one O, N or S ring atom, selected from the group consisting of pyridine-3-yl, pyrazolyl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, thiophen-2-yl, thiophen-3-yl, benzo[b]thiophen-3-yl or indol-3-yl; n is 1, 2, 3, 4 or 5; when n is 2, 3, 4 or 5, R may be the same or not; the dotted line may be a bond or not; and to their pharmaceutically active salts for the preparation of medicaments for the treat ment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic com plications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders. a p c PCT/EP2007/050443

A. CLASSIFICATION OF SUBJECT MATTER INV. A61K31/4164 A61K31/4174 C07D233/06 C07D233/54 C07D401/04 C07D405/06 C07D409/06 A61P25/00

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) A61K C07D

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) EPO-Internal , BIOSIS, EMBASE, BEILSTEIN Data, CHEMABS Data, WPI Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category * Citation of document with indication, where appropriate of the relevant passages Relevant to claim No

X ,Y WO 02/22801 A2 (OREGON HEALTH & SCIENCE 1-26 UNIVER [US]; BUNZOW JAMES R [US]; GRANDY DAVID) 21 March 2002 (2002-03-21) claims 41-54

X BUNZOW J R ET AL: "AMPHETAMINE, 1-26 3 ,4-METHYLENEDIOXYMETHAMPHETAMINE , LYSERGIC ACID DIETHYLAMIDE, AND METABOLITES OF THE CATECHOLAMINE NEUROTRANSMITTERS ARE AGONISTS OF A RAT TRACE AMINE RECEPTOR" MOLECULAR PHARMACOLOGY, BALTIMORE, MD, US, vol. 60, no. 6 , December 2001 (2001-12), pages 1181-1188, XP008008060 ISSN: 0026-895X page 1186

Further documents are listed in the continuation of Box C See patent family annex

* Special categories of cited documents "T" later document published after the international filing date or priority date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention 1 "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 cla ιm(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another "Y 1 document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve a n inventive step when the 1O" document referring to an oral 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 in the art 1P1 document published prior to the international filing date but 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

16 July 2007 06/08/2007

Name and mailing address of the ISA/ Authorized officer European Patent Office, P B 5818 Patentlaan 2 NL -228O HV RlJSWlJk TeI (+31-70) 340-2040, Tx 3 1 651 epo nl, Fax (+31-70) 340-3016 Steendijk, Martin

Form PCT/ISA/21 0 (second sheet) (April 2O05) C(Continuatlon). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, whsre appropriate, of the relevant passages Relevant to claim No.

Y HOLT ANDREW: "Imidazol ine binding sites 1-26 on receptors and enzymes : emerging targets for novel antidepressant drugs?" JOURNAL OF PSYCHIATRY & NEUROSCIENCE : JPN NOV 2003, vol . 28, no. 6 , November 2003 (2003-11), pages 409-414, XP002438693 ISSN: 1180-4882 page 411 , right-hand column

A LINDEMANN L ET AL: "Trace 1-26 ami ne-associ ated receptors form structural l y and function al l y distinct subfami l ies of novel 6 protein-coupled receptors" GENOMICS, ACADEMIC PRESS, SAN DIEGO, US, vol . 85, no. 3 , March 2005 (2005-03), pages 372-385, XP004779696 ISSN: 0888-7543 page 382

X, Y WENTLAND M P ET AL: "SYNTHESIS AND 1-26 ANTIDEPRESSANT PROPERTIES OF NOVEL 2-SUBSTITUTED 4,5-DIHYDRO-lH-IMIDAZOLE DERIVATIVES" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol . 30, 1987, pages 1482-1489 , XP000939021 ISSN: 0022-2623 table 1

X, Y EP 0 125 410 A (STERLING DRUG INC [US]) 1-26 21 November 1984 (1984-11-21) pages 1-2

X , Y US 3 377 247 A (EBLE JOHN N) 1-26 9 Apri l 1968 (1968-04-09) column 1 , l ines 17-23

X , Y US 3 586 695 A (WYSONG DON V ET AL) 1-26 22 June 1971 (1971-06-22) column 1 , l ines 40-55 column 2 , lines 3-15

XJ US 4 146 647 A (LAFON LOUIS) 1-26 27 March 1979 (1979-03-27) column 4 , l ines 35-40 table 1

X, Y US 3 660 423 A (WYSONG DON V ET AL) 1-26 2 May 1972 (1972-05-02) column 1 , lines 20-56

-/-

Form POT/ISA/210 (continuation of second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

X, Y YOSHIYA AMEMIYA ET AL: "Synthesis and 1-26 alpha-adrenergic activities of 2- and 4-substituted imidazol ine and imidazole analogues" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol . 35, no. 4 , 1992, pages 750-755, XP002151512 ISSN: 0022-2623 page 750

X, Y CA 2 246 027 Al (ALLELIX BIOPHARMA [CA]; 1-26 UNIV VIRGINIA COMMONWEALTH [US]) 27 February 2000 (2000-02-27) abstract

X1Y WO 98/12183 A (ALLELIX BIOPHARMA [CA]; 1-26 UNIV VIRGINIA COMMONWEALTH [US]) 26 March 1998 (1998-03-26) pages 1-2 page 7

X , Y US 2 161 938 A (ADOLF SONN) 1-26 13 June 1939 (1939-06-13) col umn 2 , l ines 19-24 c l aim 1

X, Y US 2 744 910 A (EUGENE SPEETER MERRILL) 1-26 8 May 1956 (1956-05-08) the whole document

X, Y US 2 457 047 A (KYRIDES LUCAS P) 1-26 21 December 1948 (1948-12-21) column 1, l ines 40-53

X, Y FAUST, J . A . ET AL: "Antihypertensi ve 1-26 agents : derivatives of 2-imidazol ine and 1,4,5, 6-tetrahydropyr imi d i ne" JOURNAL OF ORGANIC CHEMISTRY , 26, 4044 - 7 CODEN: JOCEAH; ISSN: 0022-3263, 1961 , XP002442336 page 4044, left-hand col umn the whole document

x,Y SAVOLA J-M ET AL: "CARDIOVASCULAR AND 1-26 SEDATIVE ALPHA-ADRENOCEPTOR EFFECTS OF DETOMIDINE-LIKE ARYLALKYL IMIDAZOLES AND ASSOCIATED DERIVATIVES" ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, ECV EDITIO CANTOR VERLAG , AULENDORF, DE , vol . 38, no. 1 , January 1988 (1988-01) , pages 29-35, XP002033085 ISSN: 0004-4172 table 1

Form PCT/ISA/210 (continuation of second sheet) (April 2005) o PCT/EP2007/050443

C(Continuatlon). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relavant to claim No.

X, Y US 2 778 836 A (HENRI MORREN) 1-26 22 January 1957 (1957-01-22) column 1, l ines 6-8 c l aim 1

X Y US 2 744 909 A (EUGENE SPEETER MERRILL) 1-26 8 May 1956 (1956-05-08) col umn 1

X, Y US 3 161 653 A (WOLFGANG FRUHSTORFER ET 1-26 AL) 15 December 1964 (1964-12-15) column 1 , l ines 15-35

X, Y DE 22 03 373 Al (LABAZ) 1-26 17 August 1972 (1972-08-17) c l aim 1 page 4

X, Y US 2 919 274 A (FAUST JOHN A ET AL) 1-26 29 December 1959 (1959-12-29) column 1

X, Y US 4 665 095 A (WINN MARTIN [US] ET AL) 1-26 12 May 1987 (1987-05-12) column 1 , l ines 45-67

X ES 323 985 Al (BLADE PIQUE JUAN [ES]) 1-26 16 December 1966 (1966-12-16) page 2

X Y FR 6 551 M (MERCK AG) 1-26 16 December 1968 (1968-12-16) page 1 , left-hand col umn

X Y EP 0 924 209 Al (LILLY CO ELI [US]) 1-26 23 June 1999 (1999-06-23) c l aims 1 , 41

χ, γ WO 01/81334 A (SUNTORY LTD [JP] ; IMOTO 1-26 MASAHIRO [JP]; IWANAMI TATSUYA [JP] ; AKABANE M) 1 November 2001 (2001-11-01) page 1 , l ines 6-14 examples

χ ,γ EP 1 103 243 A2 (ESTEVE LABOR DR [ES]) 1-26 30 May 2001 (2001-05-30) c l aim 1 examples

Form PGT/1SA/210 (continuation of second sheet) (April 2005) C(Contlnuatlon). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document with indication where appropriate, of the relevant passages Relevant to claim No

NATHANSON J A : "PHENYLIMINOIMIDAZOLIDINES 1-26 CHARACTERIZATION OF A CLASS OF POTENT AGONISTS OF. OCTOPAMINE-SENSITIVE ADENYLATE CYCLASE AND THEIR USE IN UNDERSTANDING THE PHARMACOLOGY OF OCTOPAMINE RECEPTORS" MOLECULAR PHARMACOLOGY, BALTIMORE, MD, US, vol. 28, no. 3 , 1985, pages 254-268, XP009085722 ISSN: 0026-895X table 3

Form POT/ISA/210 (continuation of second sheet) (April 2005) Information on patent family members PCT/EP2007/050443

Patent document Publication Patent family Publication cited in search report date member(s) date

WO 0222801 A2 21-03-2002 AU 9261701 A 26-03-2002 CA 2422288 Al 21-03-2002 EP 1319070 A2 18-06-2003

EP 0125410 A 21-11-1984 AU 568839 B2 14-01-1988 AU 2487784 A 20-09-1984 CA 1215369 Al 16-12-1986 DK 112984 A 15-09-1984 ES 8601907 Al 01-03-1986 FI 840839 A 15-09-1984 GR 81813 Al 12-12-1984 I L 70966 A 31-08-1987 J P 59193875 A 02-11-1984 NO 840893 A 17-09-1984 NZ 207184 A 05-12-1986 PH 19715 A 17-06-1986 PT 78195 A 01-04-1984 US 4540705 A 10-09-1985 ZA 8401323 A 31-10-1984

US 3377247 A 09-04-1968 NONE

US 3586695 A 22-06-1971 NONE

US 4146647 A 27-03-1979 BE 850723 Al 16-05-1977 CA 1074797 Al 01-04-1980 CH 620901 A5 31-12-1980 DE 2702119 Al 28-07-1977 DK 30277 A 27-07-1977 ES 455294 Al 01-01-1978 FR 2338927 Al 19-08-1977 GB 1538097 A 10-01-1979 I E 44416 Bl 18-11-1981 J P 1279553 C 29-08-1985 J P 52105131 A 03-09-1977 J P 59053895 B 27-12-1984 LU 76641 Al 24-06-1977 NL 7700806 A 28-07-1977 SE 440501 B 05-08-1985 SE 7700777 A 27-07-1977

US 3660423 A 02-05-1972 NONE

CA 2246027 Al 27-02-2000 NONE

WO 9812183 A 26-03-1998 AU 4291897 A 14-04-1998 US 6048862 A 11-04-2000

US 2161938 A 13-06-1939 NONE

US 2744910 A 08-05-1956 NONE

US 2457047 A 21-12-1948 NONE

US 2778836 A 22-01-1957 NONE

US 2744909 A 08-05-1956 NONE

Form PGT/ISA/210 (patent family annex) (April 2005) Information on patent family members PCT/EP2007/050443

Patent document Publication Patent family Publication cited in search report date member(s) date

US 3161653 A 15-12-1964 CH 446353 A 15-11-1967 DE 1121054 B 04-01-1962 FR 1614 M GB 951989 A 11-03-1964 SE 305877 B 11-11-1968 US 3238101 A 01-03-1966

DE 2203373 Al 17-08-1972 AT 311336 B 12-11-1973 AU 3817772 A 26-07-1973 BE 777689 Al 05-07-1972 CA 962273 Al 04-02-1975 CH 535254 A 31-03-1973 DK 138496 B 18-09-1978 FI 55841 B 29-06-1979 GB 1333471 A 10-10-1973 HU 162823 B 28-04-1973 J P 49038273 B 16-10-1974 NL 7201121 A 31-07-1972 NO 134115 B 10-05-1976 SE 378426 B 01-09-1975 SU 474145 A3 14-06-1975 US 3818035 A 18-06-1974 YU 18172 A 10-07-1979 ZA 7200286 A 27-09-1972

US 2919274 A 29-12-1959 NONE

US 4665095 A 12-05-1987 AU 591740 B2 14-12-1989 AU 6631986 A 18-06-1987 CA 1282334 C 02-04-1991 DE 3674569 Dl 31-10-1990 EP 0230532 Al 05-08-1987 FI 865025 A 12-06-1987 J P 2089414 C 02-09-1996 J P 7116038 B 13-12-1995 J P 62145067 A 29-06-1987 NO 864993 A 12-06-1987 NZ 218334 A 29-03-1989

ES 323985 Al 16-12-1966 NONE

FR 6551 M 16-12-1968 BE 700032 A 18-12-1967 DE 1617618 Al 25-03-1971 I L 28047 A 30-11-1970

EP 0924209 Al 23-06-1999 AT 239013 T 15-05-2003 AU 2003099 A 12-07-1999 AU 2201699 A 12-07-1999 CA 2315226 Al 01-07-1999 DE 69814012 Dl 05-06-2003 DE 69814012 T2 01-04-2004 DK 924209 T3 25-08-2003 ES 2198033 T3 16-01-2004 J P 2001526286 T 18-12-2001 PT 924209 T 29-08-2003 WO 9932112 Al 01-07-1999 WO 9932482 Al 01-07-1999

Form PCT7ISA/210 (patent family annex) (April 2005) Information on patent family members PCT/EP2007/050443 Patent document Publication Patent family Publication cited in search report date member(s) date

ZA 9811672 A 19-06-2000

WO 0181334 01-11-2001 AU 782763 B2 25-08-2005 AU 4879901 A 07-11-2001 CA 2372673 A l 01-11-2001 CN 1392874 A 22-01-2003 EP 1280793 A2 05-02-2003 JP 2001302643 A 31-10-2001 US 2003100769 A l 29-05-2003

EP 1103243 A2 30-05-2001 AT 257379 T 15-01-2004 AU 754124 B2 07-11-2002 AU 5422999 A 28-02-2000 BR 9912807 A 16-10-2001 CA 2339661 A l 17-02-2000 CN 1317966 A 17-10-2001 CZ 20010412 A3 15-08-2001 DE 69914085 D l 12-02-2004 DE 69914085 T2 25-11-2004 DK 1103243 T3 03-05-2004 ES 2150378 A l 16-11-2000 O 0007542 A2 17-02-2000 HU 0105428 A2 29-05-2002 JP 2002522359 T 23-07-2002 NO 20010634 A 06-04-2001 NZ 509645 A 31-01-2003 PL 346221 A l 28-01-2002 PT 1103243 T 31-05-2004 RU 2223116 C2 10-02-2004 TR 200100378 T2 21-06-2001 TW 445259 B 11-07-2001 us 6518295 B l 11-02-2003 ZA 200100867 A 16-08-2001

Form POT/ISA/210 (patent family annex) (April 2005)