Title:
IMIDAZOLINDERIVATIVES THEIR PREPARATION AND THEIR PHARMACEUTICAL USE
Document Type and Number:
WIPO Patent Application WO/2000/078724
Kind Code:
A2
Abstract:
This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.
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Inventors:
AMMENN JOCHEN (DE)
PAAL MICHAEL (DE)
RUEHTER GERD (DE)
SCHOTTEN THEO (DE)
STENZEL WOLFGANG (DE)
PAAL MICHAEL (DE)
RUEHTER GERD (DE)
SCHOTTEN THEO (DE)
STENZEL WOLFGANG (DE)
Application Number:
PCT/US2000/011882
Publication Date:
December 28, 2000
Filing Date:
June 19, 2000
Export Citation:
Assignee:
LILLY CO ELI (US)
AMMENN JOCHEN (DE)
PAAL MICHAEL (DE)
RUEHTER GERD (DE)
SCHOTTEN THEO (DE)
STENZEL WOLFGANG (DE)
AMMENN JOCHEN (DE)
PAAL MICHAEL (DE)
RUEHTER GERD (DE)
SCHOTTEN THEO (DE)
STENZEL WOLFGANG (DE)
International Classes:
C07D233/10; C07D233/22; C07D317/72; C07D401/04; C07D405/04; C07D405/14; C07D451/02; C07D491/08; C07D493/10; (IPC1-7): C07D233/00
Domestic Patent References:
| WO1997042179A1 | 1997-11-13 |
Foreign References:
| EP0924209A1 | 1999-06-23 | |||
| EP0882718A1 | 1998-12-09 | |||
| EP0846688A1 | 1998-06-10 | |||
| EP0491525A1 | 1992-06-24 |
Attorney, Agent or Firm:
Vorndran-jones, Macharri (IN, US)
Download PDF:
Claims:
We claim
| 1. | A compound of Formula (I) compounds of the following wherein Rl, R2, R3, and R9 are each independently hydrogen or C1 8 alkyl; or R1 and R3, together with the carbon atoms to which they are attached, combine to form a C37 carbocyclic ring and R2 and R9 are each independently hydrogen or C1 8 alkyl; or R and R, together optionally form a bond and R2 and R9 are each independently hydrogen or C18 alkyl ; or R'and R, together with the carbon atom to which they are attached combine to form a C3 7 spirocarbocyclic ring and R3 and R9 are each independently hydrogen or C1 8 alkyl; or R3 and R9, together with the carbon atom to which they are attached, combine to form a C3 7 spirocarbocyclic ring and R'and R2are each independently hydrogen or C1 8 alkyl; X S,orNR5;O, R5 is independently selected from the group consisting of hydrogen, C18 alkyl, optionally substituted aryl, and an amino protecting group; n is 0, 1, or 2; R4 is a group of the formula: Q'and Q"are each independently selected from the group consisting of C, N, and NO, provided that if one of Q'or Q"is N or NO, then the other of Q'or Q"must be C, such that Q'and Q"cannot each simultaneously be selected from the group consisting of N and NO; YZ is (CH2) n'wherein n'is 3,4,5, or 6; such that a 5to 8membered ring is formed to provide a bicyclic ring along with the benzene or pyrimidine group to which it is fused, which 5to 8membered ring is saturated, partially saturated or unsaturated and may optionally contain up to two atoms each independently selected from the group consisting ofO,S, andNR, wherein each such optionalO,S, atom or NR12groups replacing any one of theCH2groups comprising Y, provided that the resulting benzofused bicyclic ring is not an indole, and in which any of theCH2groups which comprise y2 may be substituted by R6, R7, R8 or R16 provided that no more than four H atoms in Y2 are replaced by said substitution and that the resulting benzofused bicyclic is not naphthalene or quinoline; and any two selected from the group consisting of R6, R, R8, Rl6 and R12 may optionally combine to form a bridge which is comprised of up to four carbon atoms provided that such bridgeforming two of R6, R7, R8, Rl6 and Rl2 are not bound to adjacent atoms, or together with the carbon atom to which they are attached may form a ¬37 spirocarbocyclic ring, in which one or two carbon atoms are optionally replaced by oxygen, sulfur, or NR, or together with the two adjacent carbon atoms to which they are attached R6, R7, R8, Rl6 and Rl2 may form a C19 carbocyclic ring, in which one or two of the carbon atoms is optionally replaced by oxygen, sulfur or NR5, and further provided that at least one of the group consisting of R6, R7, R8, Rl6 and R is not hydrogen when X is NH, n is 0, and R', R, R3, and R9 are each hydrogen and Q' and Q" are each C; R12 is selected from the group consisting of hydrogen, C18 alkyl, optionally substituted aryl, and an amino protecting group; R6 is selected from the group consisting of hydrogen, C18 alkyl, C37 cycloalkyl, Ci. g alkoxy, C1 8 alkylthio, halo CI8 alkylthio, C1 8 alkylsulfinyl, C1 8 alkylsulfonyl, arylC18alkoxy,halo,haloC18alkyl,haloC18cycloalkoxy, alkoxy, nitro, NR14R15, CONR14R15, aryl C18 alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, C 18 acylamino, haloCi. g acylamino, cyano, hydroxy, COR, COOR, halo C1 8 alkylsulfinyl, halo C1 8 alkylsulfonyl, and alkoxyalkyloxy of the formula CH3 (CH2) pO (CH2) qO ; R7, R8, and R16 are each independently selected from the group consisting of hydrogen, C18alkoxy,C37cycloalkyl,C37cycloalkoxy,halo,alkyl, haloC1 8 alkyl, haloC1 8 alkoxy, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heteroaryl; Rl° is selected from the group consisting of hydrogen, halo, C1 8 alkyl, C3 7 cycloalkyl, C37 cycloalkoxy, alkoxy,haloC18alkyl,cycloalkylC18 haloC1 8 alkoxy, C1 8 alkoxy, carboC1 8 alkoxy, optionally substituted aryl, and optionally substituted heteroaryl; Rl is selected from the group consisting of hydrogen, halo, C 18 alkoxy, C3 7 cycloalkyl,alkoxy,C18alkyl,C37cycloalkoxy,hydroxy,halocycloalkylC18 C18 alkoxy, carboC1 8 alkoxy, optionally substituted phenyl, optionally substituted phenylCl8 alkyl, optionally substituted phenyloxy, optionally substituted phenylC18 alkoxy, (tetrahydropyran2yl) methoxy, C1 8 alkylS (O) m, optionally substituted CH3(CH2)p'Z1(CH2)q'Z2,andZ3(CH2)q''alkylS(O)m', Z2; where Z1 and Z2 are each independently a bond,O,S, sulphoximino, or NR"', Z3 is hydroxy, protected hydroxy, NR14'R15', protected amino, SH, or protected SH; R13 is hydrogen, C18 alkyl, or optionally substituted phenyl; Ri4 Rl4 Rl5 and R15' are each independently selected from the group consisting of hydrogen, C1 8 alkyl, optionally substituted aryl C1 8 alkyl, optionally substituted phenyl, or R14 and R15 or R14' and R15', respectively, together with the nitrogen atom to which they are attached may combine to form a heterocyclic ring comprising the nitrogen and C26 alkyl, wherein C26alkyl is optionally substituted with one or two C1 8 alkyl groups or one carbon atom of the heterocyclic ring is optionally replaced by0orS ; p and p'are each independently selected from the group consisting of 3, and 4; q, q', and q"'are each independently selected from the group consisting of 1,2,3,4, and5; m, m', and m"are each independently selected from the group consisting of 0,1 and 2; provided that when Rl, R2, R3, and R9 are each hydrogen, X is NH, n is 0, then R4 is not 4 (benzothiazol2yl) benzyl or a group of the formula: and pharmaceutically acceptable salts and esters thereof. |
| 2. | A compound according to Claim 1 wherein Rl and R2 are each hydrogen and R3 and R9 are each hydrogen or methyl. |
| 3. | A compound according to Claim 2 wherein X isNH. |
| 4. | A compound according to Claim 2 wherein X is S and n is 1. |
| 5. | A compound according to either of Claims 2 and 3 wherein n is 0. |
| 6. | A compound according to Claim 5 wherein R"is H3C (CH) p ~O~ (CH) q' 0. |
| 7. | A compound according to any one of the preceding claims wherein Q and Q2 are each C. |
| 8. | A compound according to either of Claims 2 or 5 in which R4 is a coumarin group or a quinolone group. |
| 9. | A pharmaceutical formulation comprising a compound according to any of Claims 1 to 8 or a pharmaceutically acceptable salt or ester thereof, together with a pharmaceutically acceptable carrier or diluent therefor. |
| 10. | A compound according to Claim 1 or a pharmaceutically acceptable salt or ester thereof, for use as a pharmaceutical. |
| 11. | A compound according to Claim 1 or a pharmaceutically acceptable salt or ester thereof, for use in the manufacture of a medicament for the treatment of a mammal for diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present. |
Description:
INTERNATIONAL SEARCH REPORT Internat 1 Application No PCT/US 00/11882 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication. where appropriate, of the relevant passages Relevant to claim No. A WO 97 42179 A (MERCK & CO.) 1-11 13 November 1997 (1997-11-13) page1W 1 International Application No. PCTAJS 00 A 1882 FURTHER INFORMATION CONTINUED FROM PCTASA/210 Continuation of Box 1. 2 Claims Nos.: 1-7 Present claims 1-7 relate to an extremely large number of possible compounds. Support within the meaning of Article 6 PCT and/or disclosure within the meaning of Article 5 PCT is to be found, however, for only a very small proportion of the compounds claimed. In the present case, the claims so lack support, and the application so lacks disclosure, that a meaningful search over the whole of the claimed scope is impossible. Consequently, the search has been carried out for those parts of the claims which appear to be supported and disclosed, namely those parts relating to the compounds prepared in the examples and closely related homologous compounds 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 SEARCH REPORT Interna: I Application No Information on patent family members | PCT/US 00/11882 Patent document Publication Patent family Publication cited in search report date member (s) date EP 924209 A 23-06-1999 AU 2003099 A 12-07-1999 AU 2201699 A 12-07-1999 WO 9932112 A 01-07-1999 WO 9932482 A 01-07-1999 EP 882718 A 09-12-1998 AU 722514 B 03-08-2000 AU 1209597 A 28-07-1997 BR 9612434 A 28-12-1999 JP 3063162 B 12-07-2000 CA 2241186 A 28-06-1997 CN 1211238 A 17-03-1999 HU 9900625 A 28-06-1999 WO 9724334 A 10-07-1997 AU 4400597 A 05-05-1998 WO 9815530 A 16-04-1998 EP 846688 A 10-06-1998 FR 2756560 A 05-06-1998 AT 189816 T 15-03-2000 AU 719145 B 04-05-2000 AU 4765297 A 11-06-1998 BR 9706126 A 18-05-1999 CA 2223541 A 04-06-1998 CN 1186074 A 01-07-1998 DE 69701307 D 23-03-2000 DE 69701307 T 14-09-2000 DK 846688 T 17-07-2000 ES 2145563 T 01-07-2000 GR 3032715 T 30-06-2000 HU 9702341 A 28-07-1998 JP 10168065 A 23-06-1998 NO 975591 A 05-06-1998 NZ 329312 A 28-07-1998 PL 323515 A 08-06-1998 PT 846688 T 31-05-2000 US 5925665 A 20-07-1999 EP 491525 A 24-06-1992 CA 2057324 A 19-06-1992 JP 4308560 A 30-10-1992 US 5397798 A 14-03-1995 WO 9742179 A 13-11-1997 AU 3057797 A 26-11-1997 US 5925659 A 20-07-1999
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