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Title:
IMMUNOPOTENTIATOR AGENTS
Document Type and Number:
WIPO Patent Application WO/2000/071519
Kind Code:
A2
Abstract:
Novel compounds and methods for preparing same, immunopotentiating compositions, and a method for potentiating the immune system of a host animal. The method comprises administering to the animal an effective amount of an immunopotentiating compound of Formula (I) or Formula (II), or a physiologically acceptable salt.

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Inventors:
CREEMER LAWRENCE CAMILLO (US)
HERRING JANICE RHEA (US)
MCGRUDER EDWARD DEORSEY (US)
Application Number:
PCT/US2000/006710
Publication Date:
November 30, 2000
Filing Date:
May 11, 2000
Export Citation:
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Assignee:
LILLY CO ELI (US)
CREEMER LAWRENCE CAMILLO (US)
HERRING JANICE RHEA (US)
MCGRUDER EDWARD DEORSEY (US)
International Classes:
C07D211/32; C07D211/60; C07D211/78; C07D409/06; C07D451/06; (IPC1-7): C07D211/00
Foreign References:
US5741800A1998-04-21
US4528294A1985-07-09
US5561146A1996-10-01
US5407943A1995-04-18
US4402961A1983-09-06
EP0623595A11994-11-09
Other References:
DATABASE WPI Section Ch, Week 199851 Derwent Publications Ltd., London, GB; Class B05, AN 1998-609909 XP002154637 & WO 98 46569 A (SUMITOMO PHARM CO LTD), 22 October 1998 (1998-10-22)
Attorney, Agent or Firm:
Demeter, John C. (IN, US)
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Claims:
We claim:
1. An immunopotentiating composition which comprises a physiologically acceptable carrier and an effective immunopotentiating amount of a compound defined by the following Formula I: wherein: Ri is H, ClC4 alkyl or (=O); R2 is C (O) R8, CH2C (O) R8, CN, CH20H, OH, OC (O) R9 or OS (O) 2R9 R3, R4 and R5 are each independently H or ClC4 alkyl; R6 is C (O) OCH2Ar3, C (O) NHCH2Ar3, C (O) Ar1, C (O) CH (R3) Ar2, C (O) CH (R3) CH2Ar2, C (O) CH (R3) CH2CH2Ar4 or C (O) NHR9; R7 is H or CH2C (O) R8; R8 is H, ClC4 alkyl, OR10, NHR11 or OH (when R6 is C (O) Arl or C (O) CH (R3) Ar2); C1C4alkyl;R9is Rlo is C2C8 alkyl, CH2CH2N (CH3) 2 or CH3 (when R6 is C (O) Arl and Arl is phenyl); Rn is C2C6 alkyl, CH2CH2N (CH3) 2 or C7C9 alkyl (when R6 is C (O) Arl); Ar1 is phenyl, 4fluorophenyl, 2thienyl, 3thienyl or 1,4biphenyl; Ar2 is phenyl or 2thienyl; Ar3 is phenyl; Ar4 is 2thienyl; Ars is phenyl or 2halophenyl; halo is Cl, Br or F; and Ar6 is phenyl or 4fluorophenyl; with the proviso that when R7 is CH2C (O) R8, then R2 and R3 are H, R4 and Rs are H or ClC4 alkyl; R6 is C (O) CH (R3) Ar4; Rg is H, ClC4 alkyl, OR9 or NHRIO; R9 is ClC8 alkyl and R10 is C2C8 alkyl ; and with the further proviso that when R, is (=O), then R2 is C (O) R8 or CH2C (O) R8; R3, R4 and Rs are H or CtC4 alkyl; R6 is C (O) OCH2Ar3, C (O) Ar6 or C (O) NHR9; R7 is H or, together with R5, CH2CH2: R8 is H, C1C4 alkyl, OR10 or NHR11 ; R9 is C1C4 alkyl ; Rlo is ClC8 alkyl and Ri 1 is C2Cg alkyl; or Formula II: wherein: R12 is C (O) RI8 or CH2C (O) RIS ; R13, R14, R15 and Rl6 are each independently H or ClC4 alkyl; R! ky ! ; R18 is H, ClC4 alkyl; OR ; NHR20 or N (CH3) 2; C1C8alkyl;R19is C2C8alkyl;R20is Ar7 is phenyl, 4fluorophenyl or 1,3thiazol2yl; X is I, Cl, Br, O (SO2) R2l; and R21 is CH3, CF3, phenyl or pmethylphenyl; or a physiologically acceptable salt of the compound of Formula I or Formula II.
2. The composition of claim 1, wherein the compound comprises ethyl 1 benzoyl3piperidinecarboxylate ; ethyl 1 (3thlophenecarbonyl)3piperidinecarboxylate; ethyl1benzyloxycarbonyl3ethyl1benzoyl4oxo3piperidinecarboxylate; piperidinecarboxylate; ethyl 1phenylacetyl3piperidinecarboxylate; ethyl 1 (4 (2thiophenecarbonyl)3fluorobenzoyl)3piperidinecarboxylate;ethyl piperidinecarboxylate ; ethyl 1 (2thiopheneacetyl)3piperidinecarboxylate; ethyl 1 benzyloxycarbonyl4oxo3piperidinecarboxylate; ethyl 1 (Nmethylaminocarbonyl)4 oxo3piperidinecarboxylate; ethyl 1 (4fluorobenzoyl)4oxo3piperidinecarboxylate; n butyl 1benzoyl3piperidinecarboxylate; (S)ethyl 1benzoyl3piperidinecarboxylate; N ethyl 1benzoyl3piperidinecarboxamide; N(noctyl) 1benzoyl3 piperidinecarboxamide; Nethyl 1 (2thiopheneacetyl)3piperidinecarboxamide; ethyl 1 (3 (2thienyl) propionyl)3piperidinecarboxylate; 2dimethylaminoethyl 1 (2 thiopheneacetyl)3piperidinecarboxamide; ethyl 1 (2thiopheneacetyl)3 piperidinylacetate; ethyl 1 (2thiopheneacetyl)2piperidinylacetate ; 1benzoyl3 butyrylpiperidine; (S)ethyl 1 (2thiopheneacetyl)3piperidinecarboxylate; ethyl 1 (2 thiopheneacetyl)6methyl3piperidinecarboxylate; ethyl 1benzyl3 piperidinecarboxylate 1methiodide; ethyl 1 (4phenylbenzoyl)3piperidinecarboxylate; (S)1(2thiopheneacetyl)3piperidine carboxylic acid; methyl 1benzyloxycarbonyl4 oxo3piperidinecarboxylate; ethyl 1benzoyl3methyl3piperidinecarboxylate; 8 [(methylamino)carbonyl]3oxo8azabicyclo [3.2.1] octane2carboxylic acid, methyl ester; (S)1(2thiopheneacetyl)3 piperidinecarboxylic acid ammonium salt; ethyl 1 (lphenylpropionyl)3 ethyl1piperidinecarboxylate;1(2thiopheneacetyl)3(Omethanesulfonhyl)piperidine; (2bromobenzoyl)2acetylpiperidinecarboxylate; 1 (2thiopheneacetyl)3 (O propionyl) piperidine; (S)ethyl 1 (Nbenzylurea)3piperidinecarboxylate; (S)ethyl 1 (N methylurea)3piperidinecarboxylate; (S)1benzoyl3piperidinecarboxylic acid; (S) methyl 1benzoyl3piperidinecarboxylate; (S)propyl 1benzoyl3piperidinecarboxylate; (S)ethyl 1 (2thienylpropyl)3piperidinecarboxylate; ethyl 1 (2thiopheneacetyl)5 methyl3piperidinecarboxylate; (S) ethyl 1 (2phenylpropionyl)3 piperidinecarboxylate; (S)ethyl 1(2thiopheneacetyl)3hydroxymethylpiperidine ; ethyl 1(2thiopheneacetyl)4methyl3piperidinecarboxylate; (S)1(2thiopheneacetyl)3 piperidinecarboxaldehyde; (S)1(2thiopheneacetyl)3piperidinonitrile ; (S)ethyl 1 benzyl3piperidinecarboxylate 1methiodide; (S)N, Ndimethyl 1benzyl3 piperidinecarboxamide 1methiodide; or (S)ethyl 1(2thiazyl)3piperidinecarboxylate 1methiodide; or a physiologically acceptable salt of one of the foregoing.
3. The composition of claim 1, wherein the compound comprises ethyl 1 (2 thiopheneacetyl)3piperidinecarboxylate; ethyl 1 (Nmethylaminocarbonyl)4oxo3 piperidinecarboxylate; (S)ethyl 1benzoyl3piperidinecarboxylate; 1benzoyl3 butyrylpiperidine; (S)ethyl 1(2thiopheneacetyl)3piperidinecarboxylate; (S)1(2 thiopheneacetyl)3piperidine carboxylic acid; or (S)ethyl 1benzyl3 piperidinecarboxylate 1methiodide; or a physiologically acceptable salt of one of the foregoing.
4. The composition of claim 3, wherein the compound comprises (S)ethyl 1 (2thiopheneacetyl)3piperidinecarboxylate or (S)1(2thiopheneacetyl)3piperidine carboxylic acid.
5. A method for potentiating the immune system of a host animal, comprising administering to the host the composition of claim 1.
6. The method of claim 5, wherein the host animal is a member of the avian, bovine or porcine species.
7. The method of claim 5, wherein the host animal is a mammal.
8. A method for protecting a host animal against infection, comprising administering to a host animal in need of such protection the composition of claim 1.
9. The method of claim 8, wherein the method is for protecting the host animal against infection by E. coli.
10. The method of claim 9, wherein the host animal is a member of the avian species.
11. The method of claim 8, wherein the host animal is a member of the porcine species, and wherein the method is for protecting the host animal against infection by Actinobacillus pleuropneumoniae.
12. The composition of claim 1, or a physiologically acceptable salt thereof, for medicinal use in humans.
13. The composition of claim 1, or a physiologically acceptable salt thereof, for veterinary use.
14. A compound of Formula I, or Formula II wherein: R, is H, ClC4 alkyl or (=O); R2 is C (O) R8, CH2C (O) R8, CN, CH20H, OH, OC (O) R9 or OS (O) 2R9 R3, R4 and R5 are each independently H or ClC4 alkyl; R6 is C (O) OCH2Ar3, C (O) NHCH2Ar3, C (O) Arl, C (O) CH (R3) Ar2, C (O) CH (R3) CH2Ar2, C (O) CH (R3) CH2CH2Ar4 or C (O) NHR9; R7 is H or CH2C (O) R8; R8 is H, C1C4 alkyl, ORlo NHR or OH (when R6is C (O) Arl or C (O) CH (R3) Ar2); C1C4alkyl;R9is Rio is C2C8 alkyl, CH2CH2N (CH3) 2 or CH3 (when R6 is C (O) Arl and Arl is phenyl); Rn 1 is C2C6 alkyl, CH2CH2N (CH3) 2 OR C7C9 alkyl (when R6 is C (O) Ar); Ar1 is phenyl, 4fluorophenyl, 2thienyl, 3thienyl or 1,4biphenyl; Ar2 is phenyl or 2thienyl; Ar3 is phenyl; Ar4 is 2thienyl; Ar5 is phenyl or 2halophenyl; halo is Cl, Br or F; and Ar6 is phenyl or 4fluorophenyl; with the proviso that when R7 is CH2C (O) R8, then R2 and R3 are H, R4 and R5 are H or C1C4 alkyl; R6 is C (O) CH (R3) Ar4; R8 is H, ClC4 alkyl, OR9 or NHR10 ; Rg is ClCg alkyl and Rlo is C2C8 alkyl; and with the further proviso that when Rl is (=O), then R2 is C (O) R8 or CH2C (O) R8; R3, R4 and R5 are H or C1C4 alkyl ; R6 is C (O) OCH2Ar3, C (O) Ar6 or C (O) NHR9; R7 is H or, together with R5, CH2CH2: H,C1C4alkyl,OR10orNHR11;R9isC1C4alkyl;R10isC1C8alkylandR11R8is is C2C8 alkyl; R, 2 is C (O) R, or CH2C (O) Rl8; Ri3, Ri4, Ris and R16 are each independently H or ClC4 alkyl; RI is ClC4 alkyl; R, 8 is H, CC4 alkyl; OR,; NHR20 or N (CH3) 2; Rl9 is ClC8 alkyl; R20 is C2C8 alkyl; Ar7 is phenyl, 4fluorophenyl or 1,3thiazol2yl; X is I, Cl, Br, O (SO2) RZ,; and R2 is CH3, CF3, phenyl or pmethylphenyl; or a physiologically acceptable salt thereof; with the further provisos that when R1, R4, R5 and R7 are H, R is C (O) R8, R6 is C (O) Ar3 and R8 is Orin. then R3 is not Cl alkyl and Rlois is not ClC2 alkyl; when R1 is (=O), R2 is C (O) R8, R4, R5 and R7 are H, R6 is C (O) Ar6, Rg is ORIO and Ar6 is phenyl, then R3 is not C2 alkyl or C4 alkyl and Rlois is not ClC2 alkyl; when R, is (=O), R2 is C (O) Rg, R3, R4, R5 and R7 are H, R6 is C (O) OCH2Ar6, R8 is OR) and Ar6 is phenyl, then R10 is not ClC2 alkyl; when R1, R3, R4, R5 and R7 are H, R2 is C (O) R8, R6 is C (O) CH2Ar3 and R8 is ORIO, then R10 is not ClC2 alkyl; and when R1, R2, R3, R4 and R5 are H, R6 is C (O) Ar5, R7 is CH2C(O)R8 and Ar5 = phenyl, then R8 is not C1 alkyl or NHRIO (when Rio is C, alkyl).
15. The compound as claimed in claim 14 which is ethyl 1 (2 thiopheneacetyl)3piperidinecarboxylate; ethyl 1 (Nmethylaminocarbonyl)4oxo3 piperidinecarboxylate; 1benzoyl3butyrylpiperidine; (S)ethyl 1 (2thiopheneacetyl)3 carboxylicacid;or(S)piperidinecarboxylate;(S)1(2thiopheneacetyl)3piperidine ethyl 1benzyl3piperidinecarboxylate 1methiodide; or a physiologically acceptable salt thereof.
16. The compound as claimed in claim 14 which is (S)ethyl 1 (2 thiopheneacetyl)3piperidinecarboxylate or (S)1(2thiopheneacetyl)3piperidine carboxylic acid.
17. A process for the preparation of a compound of Formula I, as claimed in claim 14, which comprises: acylating an amine compound of Formula ni with a compound of Formula IV R6Y IV wherein Rl, R2, R3, R4, R5, R6 and R7 are as previously defined, and Y is Cl, Br, or OH; whereafter if desired, forming a physiologically acceptable salt.
18. The process of claim 17, further comprising the step of hydrolyzing, alkylating, acylating, reducing or oxidizing the compound resulting from the process of claim 17.
19. The process of claim 18, further comprising the step of resolving the compound to its (S)enantiomer.
20. A process for the preparation of a compound of Formula II, as claimed in claim 14, which comprises: alkylating an amine compound of Formula VII with a compound of Formula V Ar7CH2X V or, reductively aminating the amine compound of Formula VII with a compound of Formula VI Ar7CHO VI and, quaternizing the resulting amine compound with a compound of Formula vm Rl7X VIII wherein R12, Rl3, Rl4, Rl5 Rl6, Rl7, Ar7 and X are as previously defined; whereafter if desired, forming a physiologically acceptable salt.
21. The process of claim 20, further comprising the step of hydrolyzing, alkylating, acylating, reducing or oxidizing the compound resulting from the process of claim 20.
22. The process of claim 21, further comprising the step of resolving the compound to its (S)enantiomer.
23. A compound of Formula I of a physiologically acceptable salt thereof, whenever prepared by the process of any one of claims 17,18 and 19.
24. A compound of Formula II of a physiologically acceptable salt thereof, whenever prepared by the process of any one of claims 20,21 and 22.
25. A compound of Formula I or Formula II, substantially as described herein with reference to any one of Examples 1 to 73.
26. A compound of Formula I or Formula II, as claimed in claim 1, or a physiologically acceptable salt thereof, for use as an immunopotentiating agent.
Description:
INTERNATIONAL SEARCH !----------------. ยง Intern lal Application No PCT/US00/06710 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation ot document. with indication. where appropriate, of the relevant passages Relevant to claim No. X US 5 561 146 A (KIM KYOUNG S ET AL) 14 1 October 1996 (1996-10-01) page 39, left-hand column, line 56-page 40, right-hand column, line 31 X US 5 407 943 A (YANG BINGWEI V) 14 18 April 1995 (1995-04-18) page 20, line 56-69 X US 4 402 961 A (DUBROEUCQ MARIE-CHRISTINE 14 ET AL) 6 September 1983 (1983-09-06) page 10, line 31 X EP 0 623 595 A (SQUIBB BRISTOL MYERS CO) 14 9 November 1994 (1994-11-09) example13 International Application No. PCTAJS 00 p6710 FURTHER INFORMATION CONTINUE FROM PCT/FSA/210 Continuation of Box 1. 2 Claims Nos.: 1,12-14,17-19,23 (all partially) Present claims 1,12-14,17-19,23 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 according to the examples and claims2-4,15,16. 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 ! nterr, ia ! Apphcation No Information on patent family members PCT/US 00/06710 Patent document Publication Patent family Publication cited in search report date member (s) date US 5741800 A 21-04-1998 AU 7185094 A 17-01-1995 DE 69415672 D 11-02-1999 DE 69415672 T 20-05-1999 WO 9500507 A 05-01-1995 EP 0705258 A 10-04-1996 JP 8511548 T 03-12-1996 US 4528294 A 09-07-1985 FR 2508445 A 31-12-1982 AR 230048 A 29-02-1984 AT 9795 T 15-10-1984 AU 550320 B 20-03-1986 AU 8542982 A 06-01-1983 CA 1187501 A 21-05-1985 CS 235542 B 15-05-1985 DD 202557 A 21-09-1983 DE 3260949 D 15-11-1984 DK 289382 A, B, 30-12-1982 EP 0069012 A 05-01-1983 ES 513565 D 16-03-1983 ES 8304936 A 16-06-1983 FI 822215 A, B, 30-12-1982 GR 76401 A 10-08-1984 HU 189150 B 30-06-1986 IE 53189 B 17-08-1988 IL 66123 A 28-02-1986 JP 1027062 B 26-05-1989 JP 1545492 C 15-02-1990 JP 58008061 A 18-01-1983 KR 8801298 B 22-07-1988 NO 822185 A, B, 30-12-1982 OA 7133 A 31-03-1984 PH 17368 A 06-08-1984 PT 75135 A, B 01-07-1982 SU 1147251 A 23-03-1985 US 4680402 A 14-07-1987 YU 141582 A 20-03-1985 ZA 8204536 A 27-04-1983 WO 9846569 A 22-10-1998 AU 6747498 A 11-11-1998 US 5561146 A 01-10-1996 AU 2162095 A 21-12-1995 CA 2151412 A 11-12-1995 EP 0686642 A 13-12-1995 JP 8053492 A 27-02-1996 US 5407943 A 18-04-1995 AT 184603 T 15-10-1999 CA 2111463 A, C 23-12-1992 DE 69230005 D 21-10-1999 DE 69230005 T 05-01-2000 DK 641339 T 20-12-1999 EP 0641339 A 08-03-1995 ES 2136086 T 16-11-1999 FI 935700 A 17-12-1993 FI 982097 A 29-09-1998 GR 3031701 T 29-02-2000 JP 1943950 C 23-06-1995 JP 6078335 B 05-10-1994 JP 6503355 T 14-04-1994 INTERNATIONAL SEARCH REPORT | Intern lalApplicationNo Information on patent family members | PCT/US 00/06710 Patent document Publicatio cited in search report date member (s) date US 5407943 A PT 100597 A, B 30-09-1993 WO 9222550 A 23-12-1992 US 4402961 A 06-09-1983 FR 2485014 A 24-12-1981 AR 227731 A 30-11-1982 AT 377518 B 25-03-1985 AT 37784 A 15-08-1984 AT 377519 B 25-03-1985 AT 37884 A 15-08-1984 AT 377517 B 25-03-1985 AT 275281 A 15-08-1984 AU 537379 B 21-06-1984 AU 7198381 A 24-12-1981 CA 1184180 A 19-03-1985 DE 3169169 D 11-04-1985 DK 271981 A 21-12-1981 EP 0042781 A 30-12-1981 ES 503166 D 01-11-1982 ES 8300748 A 01-02-1983 ES 513448 D 01-04-1983 ES 8305353 A 01-07-1983 ES 513449 D 01-04-1983 ES 8305354 A 01-07-1983 GR 75685 A 02-08-1984 JP 57102885 A 26-06-1982 NO 812105 A 21-12-1981 PT 73232 A, B 01-07-1981 ZA 8104126 A 30-06-1982 EP 0623595 A 09-11-1994 AU 6183494 A 10-11-1994 CA 2122397 A 04-11-1994 JP 6329627 A 29-11-1994 US 5583146 A 10-12-1996 US 5741792 A 21-04-1998 US 5741799 A 21-04-1998



 
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