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Title:
COMPOUNDS AND METHODS FOR TREATMENT OF ASTHMA, ALLERGY AND INFLAMMATORY DISORDERS
Document Type and Number:
WIPO Patent Application WO/2000/058295
Kind Code:
A2
Abstract:
The present invention provides 1,4 substituted piperazines, 1,4 substituted piperidines, and 1-substituted,4-alkylidenyl piperidines compounds. The compounds of the invention are dual acting molecules having both leukotriene inhibition properties as well as antihistaminergic properties. The compounds of the invention are useful for treating conditions in which there is likely to be a histamine and/or leukotriene component. These conditions include preferably asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media. Also provided are methods of treating asthma and rhinitis by administering an effective asthma and rhinitis-relieving amount of the compounds to a subject in need thereof.

Inventors:
SCANNEL RALPH (US)
CHATELAIN PIERRE (BE)
TOY-PALMER ANNA (US)
DIFFERDING EDMOND (BE)
ELLIS JAMES (US)
LASSOIE MARIE-AGNES (BE)
YOUNG MICHELLE (US)
CAI XIONG (US)
HUSSOIN SAJJAT (US)
GREWAL GURMIT (US)
LEWIS TIMOTHY (US)
Application Number:
PCT/BE2000/000026
Publication Date:
October 05, 2000
Filing Date:
March 23, 2000
Export Citation:
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Assignee:
UCB SA (BE)
SCANNEL RALPH (US)
CHATELAIN PIERRE (BE)
TOY PALMER ANNA (US)
DIFFERDING EDMOND (BE)
ELLIS JAMES (US)
LASSOIE MARIE AGNES (BE)
YOUNG MICHELLE (US)
CAI XIONG (US)
HUSSOIN SAJJAT (US)
GREWAL GURMIT (US)
LEWIS TIMOTHY (US)
International Classes:
A61K31/435; C07D295/08; A61K31/4545; A61K31/473; A61K31/495; A61K31/496; A61P1/00; A61P1/04; A61P7/02; A61P11/00; A61P11/02; A61P11/06; A61P17/00; A61P17/04; A61P17/06; A61P19/02; A61P27/02; A61P27/14; A61P27/16; A61P29/00; A61P37/00; A61P37/08; A61P39/02; A61P43/00; C07C275/64; C07D295/00; C07D295/084; C07D295/088; C07D295/092; C07D295/096; C07D295/12; C07D295/125; C07D295/13; C07D295/135; C07D295/14; C07D295/15; C07D307/14; C07D307/52; C07D401/04; C07D401/06; C07D401/08; C07D403/06; C07D405/06; (IPC1-7): C07D295/00
Foreign References:
US5616596A1997-04-01
US4525358A1985-06-25
US4282233A1981-08-04
US5066658A1991-11-19
US5438062A1995-08-01
Attorney, Agent or Firm:
Lechien, Monique (Allée de la Recherche 60, Brussels, BE)
Download PDF:
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Claims:
We Claim:
1. A compound of formula I: and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein: X and X'independently are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, trifluoromethyl (Y')m'W'; G and G'together form CH=or=N;Dis R1 and R2 independently are hydrogen or together are (CH2) n in which n is equal to 0,1,2, or 3; m and m'are independently 0 or 1; Y and Y'areLlorL2V (Z) tL3in which t is 0 or 1; L1 is alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced byO,S,S (O),S (O) 2,N (Q), orN (R3); L2 is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced byO,S,S (O),S (O) 2,N (Q'), orN (R4), or (b)L4 C (O)N (Q') or L4(Q'), or (c) a direct bond; L3 is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced byO,S,S (O),S (O) 2,N (Q"), orN (R5), or (b) a direct bond; L4 is (a) alkylene; alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced byO,S,S (O),S (O) 2,N (Q"), orN (R5), or (b) a direct bond; V is (a) a divalent arene, a divalent heteroarene, or a divalent saturated heterocycle when t is 0, or (b) a trivalent arene or trivalent heteroarene when t is 1; Q, Q', and Q"independently are hydrogen,AC (O) OR6, orAC (O) NR6R7; W and W'independently areN (OM) C (O) N (R8) R9,N (R8) C (O) N (OM) R9, N (OM) C (O) R8, C (O) NR8R9, orC (O) OR8, provided that at least one of W and W'is N (OM) C (O) N (R8)R9, N(R8) C (O) N (OM) R9, orN (OM) C (O) R8. Z isA"N (OM') C (O) N (R'°) R11, A"N(R10) C (O) N (OM') R11, A"N(OM') C (O) RI l, A'C C(O)N(OM')R11, A'C(O)NR10R11, A'C(O)OR10, halo, CH3, NR3R4, NR3C (O) R4, NO2, CN, CF3, S (0) 2NR3R4, S (0) 2R3, SR3, or S (O) R3. A, A'and A"independently are a direct bond, alkylene, alkenylene, alkynylene, yloalkylaryl, yloarylalkyl, or diyloalkylarene or one of the foregoing in which one or more methylenes are replaced withO,NH,S,S (O), orS (O) 2 and/or one or more methylidenes are replaced by =N ; M and M'independently are hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable group; and R3, R4, R5, R6, R7, R8, R9, Rl°, and Rll are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, or one of the foregoing in which one or more methylenes are replaced byO,NH,S,S (O), orS (O) 2 and/or one or more methylidenes are replaced by =N ; provided that, other than the oxygens bound to the sulfurs inS (O) andS (O) 2, when one or more methylenes are replaced withO,NH,S,S (O), orS (O) 2 and when one or more methylidenes are replaced with =N, such replacement does not result in two heteroatoms being covalently bound to each other; and further provided that when m is 0, W is notC (O) NRR9, orC (O) OR8, and further provided that in the substituentAC (O) OOR6, R6 cannot be hydrogen when A is a direct bond.
2. The compound of claim 1 having the formula I" : wherein the substituents are as defined in claim 1, and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
3. The compound according to claim 1 having the formula II: wherein the substituents are as defined in claim 1, and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
4. The compound according to claim 1 having the formula III: wherein the substituents are as defined in claim 1, and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
5. The compound according to either of claims 3 or 4 wherein X isCl, X'is hydrogen, m is 1 and W isN (OH) C (O) NH2.
6. The compound according to either of claims 3 or 4 wherein X isCl, X'is hydrogen, m is 1, Y isLl, wherein Ll is alkynylene, yloalkoxy, or yloalkoxyalkyl.
7. The compound according to either of claims 3 or 4 wherein X isCl, X'is hydrogen, m is 1, Y isL2V (Z) tL3, t is 0, V is 1,4phenylene or 1,3phenylene, L2 is yloalkoxy, and L3 is alkylene, alkenylene, or alkynylene.
8. The compound according to either of claims 3 or 4 wherein X isCl, X'is hydrogen, m is 1, Y isL 2_V (Z) tL3, t is 0, V is 2,5furylene, L2 is alkylene, and L3 is alkylene, alkenylene, or alkynylene.
9. The compound according to either of claims 3 or 4 wherein X isCl, X'is hydrogen, m is 1, Y isL2V (Z) tL3, t is 1, L2 is yloalkoxy, V is trivalent heteroarene, Z is A'C (O) NR10R11 orA'C (O) OR'°, and W isN (OH) C (0) NH2.
10. The compound according to either of claims 3 or 4 wherein X and X'are F, m is 1, Y is L2V (Z) tL3, t is 0, V is 1,4phenylene or 1,3phenylene, L2 is yloalkoxy, and L3 is alkylene, alkenylene, or alkynylene;.
11. A compound selected from the group consisting of compounds 1,5,11,12,13,17,23, 24,31,32,33,34,35,36,37,40,41,42,43,44,45,46,48,49,50,52,53,54,55,56,57, 58,59,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,82,83, 84,85,86,87,88,89,90,91,92,93, and 94.
12. A compound selected from the group consisting of compounds 17,32,34,35,46,52 and 80.
13. A compound according to claim 1 wherein X and X'independently are hydrogen, halo or(Y) mW; G and G'together form D isCH= or =N ; Rl and R2 independently are hydrogen or together are (CH2) 2 ; m and m'are independently 0 or 1; Y and Y'areLlorL2V (Z) tL3in which t is 0 or 1; L1 is alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by O; L2 is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced byOorN (Q') or (b) L4C(O)N(Q'); L3 is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced byOorN (Q") ; L4 is alkylene; V is (a) a divalent arene, a divalent heteroarene, or a divalent saturated heterocycle when t is 0, or (b) a trivalent arene or trivalent heteroarene when t is 1; Q is hydrogen; Q', and Q"independently areAC (O) OR6, orAC (O) NR6R7; W and W' independently areN (OM) C (O) N (R8) R9, N (R8) C (O) N (OM) R9, N (OM) C (O) R8,C (O) NR8R9, orC (O) OR8, provided that at least one of W and W'is N (OM) C (O) N (R8)R9, N(R8) C (O) N (OM) R9, orN (OM) C (O) R8. Z isA'C (O) NR10R11, A'C(O)OR10, halo, NR3C (O) R4, NO2, CN or CF3; A and A'independently are a direct bond, alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced with O; M and M'independently are hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable group; and R3, R4, R5, R6, R7, R8, R9, Rl°, and Rll, if present, are independently hydrogen or alkyl in which one or more methylenes may be replaced by O; provided that, other than the oxygens bound to the sulfurs inS (O) andS (0) 2, when one or more methylenes are replaced with O, NH, S, S (O), orS (O) 2 and when one or more methylidenes are replaced with =N, such replacement does not result in two heteroatoms being covalently bound to each other; and further provided that when m is 0, W is notC (O) NR8R9, orC (O) OR8, and further provided that in the substituentAC (O) OOR6, R6 cannot be hydrogen when A is a direct bond.
14. A compound according to claim 13 wherein X and X'independently areH or halo; G and G'together form Y isL2V (Z)tL3 in which t is 0 or 1; L2 is Cl to C6 alkylene in which one or more methylenes may be replaced by O V (Z) t is phenylene optionally substituted byA'C (O) NR10R11, A'C(O)OR10, halo, NR3C (O) R4, NO2, CN or CF3 or furylene or oxolanylene; L3 is Cl to C6 alkylene in which one or more methylenes may be replaced byOor C2 to C6 alkynylene; W isN (OM) C (O) N (R8)R9, N(R8) C (O) N (OM) R9 orN (OM) C (O) R8 A'is methylene, vinylene or a direct bond. R3, R4, R5, R6, R7, R8, R9, Rl°, and R", if present, are independently hydrogen or Ci to C6 alkyl in which one or more methylenes may be replaced by O.
15. A compound according to claim 14 wherein X is fluorine or chlorine; X'is hydrogen or fluorine; Y isL2V (Z) tL3in which t is 0 or 1; L2 is Cl to C6 alkylene in which one methylene may be replaced by O V(Z)t is phenylene optionally substituted by halo,A'C(O)OR10, NR3C(O)R4, NO2, CN or CF3 orfurylene or oxolanylene; L3 is Cl to C6 alkylene in which one methylene may be replaced byOor C2 to C6 alkynylene; W isN (OH) C (O) NH2; A'is methylene, vinylene or a direct bond R3, R4, R5, R6, R7, R8, R9, Rl°, and R11, if present, are independently hydrogen or Ci to C6 alkyl in which one methylene may be replaced by O.
16. A compound according to claim 1 wherein X and X'independently are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy or trifluoromethyl; W isN (OM) C (O) N (R8) R9,N (R8) C (O) N (OM) R9 orN (OM) C (O) R8;.
17. A compound according to claim 1 wherein L4 is alkylene Z isN (OM') C (O) N (R10)R11, N(R10) C (O) N (OM') R",N (OM') C (O) R", A'C (O) N (OM') R11, A'C(O)NR10R11 or A'C(O)OR10.
18. A compound according to claim 1 wherein X and X'independently areH, halo, alkyl, alkenyl, alkynyl, alkoxy or trifluoromethyl; L4 is alkylene W isN (OM) C (O) N (R8) R9,N (R8) C (O) N (OM) R9 orN (OM) C (O) R8; Z isN (OM') C (O) N (RI°) Rl l,N (RI°) C (O) N (OM') Rll,N (OM') C (O) R11, A'C (O) N (OM') R",A'C (O) NRl°R" orA'C (O) ORIO.
19. A compound according to claim 1 wherein when M or M'is a metabolically cleavable group this is selected from an organic or inorganic anion, a pharmaceutically acceptable cation, acyl, alkyl, phosphate, sulfate and sulfonate, NH2C (O) or (alkyl) OC (O).
20. A compound according to claim 19 wherein acyl is (alkyl) C (O), including acetyl, propionyl and butyryl.
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 120.
22. A method of simultaneously inhibiting both leukotrieneand histaminemediated biological processes, the method comprising administering an effective leukotrieneand histamineinhibiting amount of a compound according to any one of claims 120 to a subject in need of such inhibition.
23. A method of treating asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media, the method comprising administering to a patient suffering from asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media, an amount of a compound according to any one of claims 120 sufficient to reduce or eliminate the asthma.
24. A method according to claim 23 wherein the disease to be treated is selected from asthma and seasonal and perennial rhinitis.
Description:
INTERNATIONALSEARCH REPORT | Intf alAppiloatlonNo PCT/BE00/00026 C.(Continuation) DOCUMENTS CONSIDEREDTOBERELEVANT Category I Cftationofdocument,withindication,whereappropriate,oftherele vantpassagesRelevanttodaimNo. AUS5438062A(GANGULYASHITKETAL)23,24 1August1995(1995-08-01) example11 1 INTERNATIONALSEARCHREPORT Informationonpatentfamilymembers PCT/BE 00/00026 PCT/BE00/00026 PatentdocumentPublication Patent family Publication citedinsearchreportdate member (s) date US5616596A01-04-1997US 5288751 A 22-02-1994 AT 178049 T 15-04-1999 AU 673040 B 24-10-1996 AU 5666094 A 08-06-1994 CA 2136077 A 26-05-1994 DE 69324152 D 29-04-1999 DE 69324152 T 28-10-1999 EP 0667855 A 23-08-1995 ES 2131185 T 16-07-1999 GR 3030354 T 30-09-1999 JP 8503200 T 09-04-1996 WO 9411342 A 26-05-1994 US4525358A25-06-1985AT 8140 T 15-07-1984 AU 544066 B 16-05-1985 AU 8023182 A 12-08-1982 BA 97198 B 02-08-1999 BA 97199 B 02-08-1999 CA 1199918 A 28-01-1986 CY 1307 A 06-12-1985 DE 3260282 D 02-08-1984 DK 5388A,B,07-01-1988 DK 44082A,B,07-08-1982 EP 0058146 A 18-08-1982 ES 509358 D 01-08-1983 ES 8307776 A 01-11-1983 ES 521548 D 01-08-1984 ES 8406455 A 01-11-1984 FI 820318A,B,07-08-1982 GR 75407 A 13-07-1984 HK 86485 A 15-11-1985 JP 1463099 C 28-10-1988 JP 57149282 A 14-09-1982 JP 63011353 B 14-03-1988 LT 2553 R 28-02-1994 LV 5494 A 10-03-1994 MY 27987 A 31-12-1987 NO 820297A,B,09-08-1982 NZ 199650 A 06-07-1984 PL 234935 A 09-05-1983 PL 239687 A 18-07-1983 PT 74390A,B 01-03-1982 SU 1227113 A 23-04-1986 SU 1310397 A 15-05-1987 SU 1287749 A 30-01-1987 YU 23782 A 30-06-1985 YU 223584 A 30-06-1985 ZA 8200752 A 29-12-1982 HU 184989 B 28-11-1984HU 184989 B 28-11-1984 US4282233A04-08-1981AT 9695 T 15-10-1984 AU 543054 B 28-03-1985 AU 7186281 A 24-12-1981 CA 1160230 A 10-01-1984 CY 1405 A 22-04-1988 DE 3166441 D 08-11-1984 DK 263481 A 20-12-1981 EP 0042544 A 30-12-1981 INTERNATIONAL SEARCH REPORT Ith bonal dpplicationNo fnfonMttononpxtentfamitymombeft,, PCT/BE00/00026 PatentdocumentPublication Patent citedinsearchreportdatemembers)date US4282233AES 503085 D 01-11-1982 ES 8300779 A 01-02-1983 FI 811878A,B,20-12-1981 HK 94387 A 18-12-1987 HU 186774 B 30-09-1985 IE 51303 B 26-11-1986 IL 63122 A 30-06-1985 JP 1506964 C 13-07-1989 JP 57035586 A 26-02-1982 JP 63055513 B 02-11-1988 KE 3758 A 02-10-1987 KR 8500744 B 24-05-1985 LU 88359 A 04-05-1994 MY 76187 A 31-12-1987 NZ 197435 A 30-03-1984 PH 19252 A 17-02-1986 PT 73200A,B 01-07-1981 SG 70587 G 19-02-1988 US 4355036 A 19-10-1982 US 4560688 A 24-12-1985 US 4831042 A 16-05-1989 ZA 8104062 A 28-07-1982 US5066658A19-11-1991NONE US5438062A01-08-1995US 5089496 A 18-02-1992 US 4826853 A 02-05-1989 US 5665726 A 09-09-1997 EP 0685476 A 06-12-1995 AT 114650 T 15-12-1994 AU 643946 B 02-12-1993 AU 5642090 A 29-11-1990 CA 2053903A,C 02-11-1990 CZ 9104144 A 12-05-1993 DE 69014393 D 12-01-1995 DE 69014393 T 01-06-1995 DK 396083 T 06-02-1995 EP 0396083 A 07-11-1990 EP 0471750 A 26-02-1992 ES 2064520 T 01-02-1995 FI 102609 B 15-01-1999 IE 66392 B 27-12-1995 IL 94258 A 07-10-1994 JP 2863629 B 03-03-1999 JP 4504724 T 20-08-1992 KR 9509859 B 29-08-1995 NO 179674 B 19-08-1996 NZ 233495 A 25-11-1992 OA 9521A 15-11-1992 WO 9013548 A 15-11-1990 US 5151423 A 29-09-1992 ZA 9003303 A 30-01-1991 AT 116310 T 15-01-1995 AU 635400 B 18-03-1993 AU 7285991 A 30-05-1991 AU 604285 B 13-12-1990 AU 8336287 A 25-05-1988 CA 1305147 A 14-07-1992 INTERNATIONAL SEARCH REPORT Int Uonal AppileationNo Intormatlon on patent tamily memben PatentdocumentPublication Patent family Publication citedinsearchreportdate member (s)date US5438062ACA 1321589 A 24-08-1993 CS 9104143 A 16-09-1992 DE 3750929 D 09-02-1995 DE 3750929 T 01-06-1995 DK 73193 A 21-06-1993 DK 354688 A 28-06-1988 EP 0270818 A 15-06-1988 EP 0330673 A 06-09-1989 ES 2068179 T 16-04-1995 FI 891806A,B,17-04-1989 HK 186396 A 11-10-1996 IE 65174 B 04-10-1995 JP 6078316 B 05-10-1994 JP 2500910 T 29-03-1990 KR 9302489 B 02-04-1993 NO 882907A,B,29-06-1988 NZ 222347 A 27-03-1990NZ 222347 A 27-03-1990



 
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