U.S. patent application number 10/637163 was filed with the patent office on 2004-03-11 for compounds and methods for treatment of asthma, allergy and inflammatory disorders.
This patent application is currently assigned to UCB S.A.. Invention is credited to Cai, Xiong, Chatelain, Pierre, Differding, Edmond, Ellis, James, Grewal, Gurmit, Hussoin, Sajjat, Lassoie, Marie-Agnes, Lewis, Timothy, Scannell, Ralph, Toy-Palmer, Anna, Young, Michelle.
Application Number | 20040048875 10/637163 |
Document ID | / |
Family ID | 22425273 |
Filed Date | 2004-03-11 |
United States Patent
Application |
20040048875 |
Kind Code |
A1 |
Scannell, Ralph ; et
al. |
March 11, 2004 |
Compounds and methods for treatment of asthma, allergy and
inflammatory disorders
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: |
Scannell, Ralph; (Hopkinson,
MA) ; Chatelain, Pierre; (Woluwe Saint Pierre,
BE) ; Toy-Palmer, Anna; (Arlington, MA) ;
Differding, Edmond; (Louvain-La-Neuve, BE) ; Ellis,
James; (Boxford, MA) ; Lassoie, Marie-Agnes;
(Braine-Le-Chateau, BE) ; Young, Michelle;
(Belmont, MA) ; Cai, Xiong; (Belmont, MA) ;
Hussoin, Sajjat; (Lexington, MA) ; Grewal,
Gurmit; (Natick, MA) ; Lewis, Timothy;
(Marlborough, MA) |
Correspondence
Address: |
Michael S. Greenfield
McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Assignee: |
UCB S.A.
|
Family ID: |
22425273 |
Appl. No.: |
10/637163 |
Filed: |
August 8, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10637163 |
Aug 8, 2003 |
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10242346 |
Sep 12, 2002 |
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10242346 |
Sep 12, 2002 |
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09534947 |
Mar 24, 2000 |
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6451801 |
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60126521 |
Mar 26, 1999 |
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Current U.S.
Class: |
514/253.01 ;
514/253.03; 514/255.04; 514/290; 514/316; 514/317; 544/360;
544/361; 546/93 |
Current CPC
Class: |
A61P 19/02 20180101;
C07D 295/135 20130101; A61P 27/16 20180101; C07D 295/096 20130101;
C07D 401/04 20130101; A61P 11/06 20180101; A61P 1/00 20180101; C07D
295/088 20130101; A61P 1/04 20180101; A61P 17/04 20180101; A61P
29/00 20180101; A61P 17/06 20180101; A61P 39/02 20180101; A61P
37/00 20180101; A61P 37/08 20180101; A61P 11/00 20180101; C07D
295/125 20130101; C07D 307/52 20130101; A61P 11/02 20180101; A61P
43/00 20180101; A61P 7/02 20180101; A61P 27/14 20180101; C07D
295/13 20130101; C07D 295/084 20130101; C07D 295/15 20130101; A61P
17/00 20180101; C07D 307/14 20130101; A61P 27/02 20180101 |
Class at
Publication: |
514/253.01 ;
514/253.03; 514/255.04; 514/290; 514/317; 514/316; 544/360;
544/361; 546/093 |
International
Class: |
A61K 031/496; A61K
031/495; A61K 031/473; A61K 031/4545 |
Claims
We claim:
1. A compound of formula I: 103and the geometrical isomers,
enantiomers, diastereomers, and pharmaceutically acceptable salts
thereof, wherein: X and X' independently are hydrogen, halo, alkyl,
alkenyl, alkynyl, alkoxy, trifluoromethyl or --(Y').sub.m--W'; G
and G' together form 104D is --CH.dbd. or .dbd.N--; R.sup.1 and
R.sup.2 independently are hydrogen or together are
--(CH.sub.2).sub.n- in which n is equal to 0, 1, 2, or 3; m and m'
are independently 0 or 1; Y and Y' are -L.sup.1- or
-L.sup.2-V(Z).sub.t-L.sup.3- in which t is 0 or 1; L.sup.1 is
alkylene, alkenylene, alkynylene, or one of the foregoing in which
one or more methylenes are replaced by --O--, --S--, --S(O)--,
--S(O).sub.2--, --N(Q")-, or --N(R.sup.3)--; L.sup.2 is (a)
alkylene, alkenylene, alkynylene, or one of the foregoing in which
one or more methylenes are replaced by --O--, --S--, --S(O)--,
--S(O).sub.2--, --N(Q')-, or --N(R.sup.4)--, or (b)
-L.sup.4-C(O)--N(Q')- or -L.sup.4(Q')-, or (c) a direct bond;
L.sup.3 is (a) alkylene, alkenylene, alkynylene, or one of the
foregoing in which one or more methylenes are replaced by --O--,
--S--, --S(O)--, --S(O).sub.2--, --N(Q")-, or --N(R.sup.5)--, or
(b) a direct bond; L.sup.4 is (a) alkylene; alkenylene, alkynylene,
or one of the foregoing in which one or more methylenes are
replaced by --O--, --S--, --S(O)--, --S(O).sub.2--, --N(Q")-, or
--N(R.sup.5)--, 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)OR.sup.6, or
-AC(O)NR.sup.6R.sup.7; W and W' independently are
--N(OM)C(O)N(R.sup.8)R.sup.9, --N(R.sup.8)C(O)N(OM)R.su- p.9,
--N(OM)C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, or C(O)OR.sup.8,
provided that at least one of W and W' is
--N(OM)C(O)N(R.sup.8)R.sup.9, --N(R.sup.8)C(O)N(OM)R.sup.9, or
--N(OM)C(O)R.sup.8. Z is -A"N(OM')C(O)N(R.sup.10)R.sup.11,
-A"N(R.sup.10)C(O)N(OM')R.sup.11, -A"N(OM')C(O)R.sup.11,
-A'C(O)N(OM')R.sup.11, -A'C(O)NR.sup.10R.sup.11, -A'C(O)OR.sup.10,
halo, CH.sub.3, NR.sup.3R.sup.4, NR.sup.3C(O)R.sup.4, NO.sub.2, CN,
CF.sub.3, S(O).sub.2NR.sup.3R.sup.4, S(O).sub.2R.sup.3, SR.sup.3,
or S(O)R.sup.3. 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 with --O--, --NH--, --S--, --S(O)--, or
--S(O).sub.2-- and/or one or more methylidenes are replaced by
.dbd.N--; M and M' independently are hydrogen, a pharmaceutically
acceptable cation, or a metabolically cleavable group; and R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and
R.sup.11 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkyl, alkylaryl, alkylarylalkyl, or one of the foregoing in
which one or more methylenes are replaced by --O--, --NH--, --S--,
--S(O)--, or --S(O).sub.2-- and/or one or more methylidenes are
replaced by .dbd.N--; provided that, other than the oxygens bound
to the sulfurs in --S(O)-- and --S(O).sub.2--, when one or more
methylenes are replaced with --O--, --NH--, --S--, --S(O)--, or
--S(O).sub.2-- and when one or more methylidenes are replaced with
.dbd.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 not --C(O)NR.sup.8R.sup.9, or --C(O)OR.sup.8, and further
provided that in the substituent -AC(O)OOR.sup.6, R.sup.6 cannot be
hydrogen when A is a direct bond.
2. The compound of claim 1 having the formula I": 105wherein 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:
106wherein 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:
107wherein the substituents are as defined in claim 1, and the
geometrical isomers, enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
5. The compound according to claim 3 wherein X is --Cl, X' is
hydrogen, m is 1 and W is --N(OH)C(O)NH.sub.2.
6. The compound according to claim 4 wherein X is --Cl, X' is
hydrogen, m is 1 and W is --N(OH)C(O)NH.sub.2.
7. The compound according to claim 3 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.1-, wherein L.sup.1 is alkynylene,
yloalkoxy, or yloalkoxyalkyl.
8. The compound according to claim 4 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.1-, wherein L.sup.1 is alkynylene,
yloalkoxy, or yloalkoxyalkyl.
9. The compound according to claim 3 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is
1,4-phenylene or 1,3-phenylene, L.sup.2 is yloalkoxy, and L.sup.3
is alkylene, alkenylene, or alkynylene.
10. The compound according to claim 4 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is
1,4-phenylene or 1,3-phenylene, L.sup.2 is yloalkoxy, and L.sup.3
is alkylene, alkenylene, or alkynylene.
11. The compound according to claim 3 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is
2,5-furylene, L.sup.2 is alkylene, and L.sup.3 is alkylene,
alkenylene, or alkynylene.
12. The compound according to claim 4 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is
2,5-furylene, L.sup.2 is alkylene, and L.sup.3 is alkylene,
alkenylene, or alkynylene.
13. The compound according to claim 3 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 1,
L.sup.2 is yloalkoxy, V is trivalent heteroarene, Z is
-A'C(O)NR.sup.10R.sup.11 or -A'C(O)OR.sup.10, and W is
--N(OH)C(O)NH.sub.2.
14. The compound according to claim 4 wherein X is --Cl, X' is
hydrogen, m is 1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 1,
L.sup.2 is yloalkoxy, V is trivalent heteroarene, Z is
-A'C(O)NR.sup.10R.sup.11 or -A'C(O)OR.sup.10, and W is
--N(OH)C(O)NH.sub.2.
15. The compound according to claim 3 wherein X and X' are F, m is
1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is 1,4-phenylene or
1,3-phenylene, L.sup.2 is yloalkoxy, and L.sup.3 is alkylene,
alkenylene, or alkynylene.
16. The compound according to claim 4 wherein X and X' are F, m is
1, Y is -L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is 1,4-phenylene or
1,3-phenylene, L.sup.2 is yloalkoxy, and L.sup.3 is alkylene,
alkenylene, or alkynylene.
17. 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.
18. A compound selected from the group consisting of compounds 17,
32, 34, 35, 46, 52 and 80.
19. A compound according to claim 1 wherein X and X' independently
are hydrogen, halo or --(Y').sub.m--W; G and G together form 108D
is --CH.dbd. or .dbd.N--; R.sup.1 and R.sup.2 independently are
hydrogen or together are --(CH.sub.2).sub.2--; m and m' are
independently 0 or 1; Y and Y' are -L.sup.1- or
-L.sup.2-V(Z).sub.t-L.sup.3- in which t is 0 or 1; L.sup.1 is
alkylene, alkenylene, alkynylene, or one of the foregoing in which
one or more methylenes are replaced by --O--; L.sup.2 is (a)
alkylene, alkenylene, alkynylene, or one of the foregoing in which
one or more methylenes are replaced by --O-- or --N(Q')- or (b)
-L.sup.4-C(O)--N(Q')-; L.sup.3 is (a) alkylene, alkenylene,
alkynylene, or one of the foregoing in which one or more methylenes
are replaced by --O-- or --N(Q")-; L.sup.4 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
are -AC(O)OR.sup.6, or -AC(O)NR.sup.6R.sup.7; W and W'
independently are --N(OM)C(O)N(R.sup.8)R.- sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9, --N(OM)C(O)R.sup.8,
--C(O)NR.sup.8R.sup.9, or --C(O)OR.sup.8, provided that at least
one of W and W' is --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9, or --N(OM)C(O)R.sup.8. Z is
-A'C(O)NR.sup.10R.sup.11, -A'C(O)OR.sup.10, halo,
NR.sup.3C(O)R.sup.4, NO.sub.2, CN or CF.sub.3; 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 R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, and R.sup.11, 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 in --S(O)-- and --S(O).sub.2--, when one or more methylenes
are replaced with --O--, --NH--, --S--, --S(O)--, or --S(O).sub.2--
and when one or more methylidenes are replaced with .dbd.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
not --C(O)NR.sup.8R.sup.9, or --C(O)OR.sup.8, and further provided
that in the substituent -AC(O)OOR.sup.6, R.sup.6 cannot be hydrogen
when A is a direct bond.
20. A compound according to claim 19 wherein X and X' independently
are --H or halo; G and G together form 109Y is
-L.sup.2-V(Z).sub.t-L.sup.3- in which t is 0 or 1; L.sup.2 is
C.sub.1 to C.sub.6 alkylene in which one or more methylenes may be
replaced by --O--V(Z).sub.t is phenylene optionally substituted by
-A'C(O)NR.sup.10R.sup.11, -A'C(O)OR.sup.10, halo,
NR.sup.3C(O)R.sup.4, NO.sub.2, CN or CF.sub.3 or furylene or
oxolanylene; L.sup.3 is C.sub.1 to C.sub.6 alkylene in which one or
more methylenes may be replaced by --O-- or C.sub.2 to C.sub.6
alkynylene; W is --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9 or --N(OM)C(O)R.sup.8 A' is methylene,
vinylene or a direct bond. R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11, if present, are
independently hydrogen or C.sub.1 to C.sub.6 alkyl in which one or
more methylenes may be replaced by --O--.
21. A compound according to claim 20 wherein X is fluorine or
chlorine; X' is hydrogen or fluorine; Y is
-L.sup.2-V(Z).sub.t-L.sup.3- in which t is 0 or 1; L.sup.2 is
C.sub.1 to C.sub.6 alkylene in which one methylene may be replaced
by --O--V(Z).sub.t is phenylene optionally substituted by
-A'C(O)NR.sup.10R.sup.11, -A'C(O)OR.sup.10, halo,
NR.sup.3C(O)R.sup.4, NO.sub.2, CN or CF.sub.3 or furylene or
oxolanylene; L.sup.3 is C.sub.1 to C.sub.6 alkylene in which one
methylene may be replaced by --O-- or C.sub.2 to C.sub.6
alkynylene; W is --N(OH)C(O)NH.sub.2; A' is methylene , vinylene or
a direct bond R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, and R.sup.11, if present, are independently
hydrogen or C.sub.1 to C.sub.6 alkyl in which one methylene may be
replaced by --O--.
22. A compound according to claim 1 wherein X and X' independently
are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy or
trifluoromethyl; W is --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9 or --N(OM)C(O)R.sup.8;
23. A compound according to claim 1 wherein L.sup.4 is alkylene Z
is --N(OM')C(O)N(R.sup.10)R.sup.11,
--N(R.sup.10)C(O)N(OM')R.sup.11, --N(OM')C(O)R.sup.11,
-A'C(O)N(OM')R.sup.11, -A'C(O)NR.sup.10R.sup.11 or
-A'C(O)OR.sup.10.
24. A compound according to claim 1 wherein X and X' independently
are --H, halo, alkyl, alkenyl, alkynyl, alkoxy or trifluoromethyl;
L.sup.4 is alkylene W is --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9 or --N(OM)C(O)R.sup.8; Z is
--N(OM')C(O)N(R.sup.10)R.sup.11, --N(R.sup.10)C(O)N(OM')R.sup.11,
--N(OM')C(O)R.sup.11, -A'C(O)N(OM')R.sup.11,
-A'C(O)NR.sup.10R.sup.11 or -A'C(O)OR.sup.10.
25. 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, NH.sub.2C(O)-- or
(alkyl)OC(O)--.
26. A compound according to claim 25 wherein acyl is (alkyl)C(O),
including acetyl, propionyl and butyryl.
27. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound according to claims 1.
28. A method of simultaneously inhibiting both leukotriene- and
histamine- mediated biological processes, the method comprising
administering an effective leukotriene- and histamine- inhibiting
amount of a compound according to claim 1 to a subject in need of
such inhibition.
29. 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
claim 1 sufficient to reduce or eliminate the asthma.
30. A method according to claim 29 wherein the disease to be
treated is selected from asthma and seasonal and perennial
rhinitis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a application is a divisional of U.S. Ser. No.
10/242,346, filed Sep. 12, 2002, which is a continuation of
application Ser. No. 09/534,947, filed Mar. 24, 2000, now U.S. Pat.
No. 6,451,801 issued Sep. 17, 2002, which claims the benefit of
U.S. Provisional Application No. 60/126,521 filed Mar. 26,
1999.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to the field of 1,4 substituted
piperazines, 1,4 substituted piperidines, and 1-substituted,
4-alkylidenyl piperidines.
[0004] 2. Summary of the Related Art
[0005] Leukotrienes are potent local mediators, playing a major
role in inflammatory and allergic responses including arthritis,
asthma, psoriasis, and thrombotic disease. Leukotrienes are
straight chain eicosanoids produced by the oxidation of arachidonic
acid by lipoxygenases. Arachidonic acid is oxidized by
5-lipoxygenase and ultimately converted to leukotrienes A4, B4, C4,
D4 or E4. 15-Lipoxygenase is responsible for the conversion of
arachidonic acid to various biologically active metabolites
including 15-hydroxy-5,8,11,13-ei- cosatetraenoic acid (15-HETE).
Both of these mediators have been implicated in the pathogenesis of
airway and allergic diseases such as asthma by contributing to
bronchoconstriction, mucus secretion, and eosinophil migration. A
mixture of one or more of such leukotrienes are known to be potent
bronchoconstrictors. Thus, leukotrienes have been shown to play an
important role in the pathology of asthma. Rigorous proof for the
role of leukotrienes in asthma has been provided by several pivotal
clinical trials in which orally administered 5-lipoxygenase (5-LO)
inhibitors (or LTD4 receptor antagonists) produce clear therapeutic
benefit in asthma patients. These benefits include reduction in the
use of classic asthma therapies such as beta agonists and
corticosteroids.
[0006] It is well known in the art that certain hydroxyurea- and
hydroxyamide- substituted aromatic compounds can function as 5-LO
inhibitors. For example, WO 92/09567 and WO 92/09566 disclose a
wide variety of N-hydroxyurea and hydroxamic acid compounds as
inhibitors of the lipoxygenase enzyme.
[0007] Histamine has been established to play a role in
inflammation in general. Antihistamines are well established most
notably for allergy control. Furthermore, histamine is believed to
play a role in asthma. For example, histamine and cysteinyl
leukotrienes (cLT's) are both known to be key mediators in airway
tone. Clinical studies have shown that a combination therapy of a
cLT receptor antagonist and an antihistamine administered to twelve
asthma patients, reduced early asthmatic responses (EAR) and late
asthmatic responses (LAR) to a greater extent than either
single-acting agent alone (A. Roquet, et al., Am. J. Respir Crit.
Care Med, 155, 1856 (1997)). This indicates that histamine plays a
role in asthma.
[0008] It is well known that certain [bis(substituted and/or
unsubstituted aryl) methyl- and methylene]-1-piperidyl compounds
possess antihistaminergic activity, and numerous publications
disclose such. For example, Yanni et al. (U.S. Pat. No. 4,810,713
and 4,950,674) disclose [[bis(aryl)methyl- or
methylene-]-1-piperidinyl]alkoxy -aryl and -heteroaryl compounds
for the treatment of allergic phenomena, including asthma and
rhinitis. Teng et al. (U.S. Pat. No. 5,070,087) disclose
[bis(aryl)methyl- and methylene]-N-[(phenoxy and
phenylthio)alkyl]piperid- ines for countering effects of histamine
in allergies.
[0009] Others have shown [bis(aryl)methyl]piperazin-1-yl compounds
for use as antiasthmatics and antiallergics that inhibit
leukotriene release (e.g., JP 97077754). U.S. Pat. No. 4,525,358
teaches 2-[4-(diphenylmethyl)-1-piperazinyl]-acetic acid and its
amides as antiallergic, spasmolytic, and antihistamine agents. JP
7138230 discloses 4-aralkyl-1-piperazinyl-unsaturated carboxylic
acid derivatives useful an antiallergic agents for the treatment
of, for example, asthma and rhinitis. WO 97/23466 describes the
preparation of N-diarylmethylpiperazines as analgesics.
[0010] None of the art, however, teaches, suggests, or contemplates
combining the 5-LO and 15-LO inhibiting functionality of
hydroxyurea moieties with the antihistaminergic properties of
[bis(substituted and/or unsubstituted aryl) methyl- and
methylene]-1-piperidyl or -1-piperazinyl moieties in a single
entity to yield a compound possessing the dual functions as an
antihistaminergic and a 5-LO/15-LO inhibitor.
SUMMARY OF THE INVENTION
[0011] The present invention provides novel compounds having dual
properties, each compound possessing both lipoxygenase inhibition
properties as well as antihistaminergic properties. In a preferred
embodiment, each of the novel compounds of the invention functions
as both a 5-LO and/or 15-LO inhibitor as well as a histamine H1
receptor antagonist.
[0012] 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. Accordingly, the invention also provides
pharmaceutical compositions comprising the compounds of the
invention and methods of treating asthma and rhinitis with the
pharmaceutical compositions.
[0013] The compounds disclosed herein can also be used as research
tools to study biological pathways involving both leukotrienes and
histamine and, in particular, further elucidate the role histamine
plays in bronchoconstriction.
[0014] All patent applications, patents, and other publications
recited herein are hereby incorporated by reference in their
entirety.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 displays the synthesis of compound 1.
[0016] FIG. 2 displays the synthesis of compound 12.
[0017] FIG. 3 displays the synthesis of compound 17.
[0018] FIG. 4 displays the synthesis of compound 35 and 36.
[0019] FIG. 5 displays the synthesis of compound 37.
[0020] FIG. 6 displays the synthesis of compound 80.
[0021] FIG. 7 displays the synthesis of compound 32.
[0022] FIG. 8 displays the synthesis of compound 46.
[0023] FIG. 9 displays the synthesis of compound 27.
DETAILED DESCRIPTION OF THE INVENTION
The Compounds
[0024] In one aspect, the present invention comprises compounds of
formula I, including geometrical isomers, enantiomers,
diastereomers, racemates, and pharmaceutically acceptable salts
thereof: 1
[0025] wherein:
[0026] X and X' independently are hydrogen, halo, alkyl, alkenyl,
alkynyl, alkoxy, trifluoromethyl or --(Y').sub.m--W';
[0027] G and G' together form 2
[0028] D is --CH.dbd. or .dbd.N--;
[0029] R.sup.1 and R.sup.2 independently are hydrogen or together
are --(CH.sub.2).sub.n-- in which n is equal to 0, 1, 2, or 3;
[0030] m and m' are independently 0 or 1;
[0031] Y and Y' are -L.sup.1- or -L.sup.2-V(Z).sub.t-L.sup.3- in
which t is 0 or 1;
[0032] L.sup.1 is alkylene, alkenylene, alkynylene, or one of the
foregoing in which one or more methylenes are replaced by --O--,
--S--, --S(O)--, --S(O).sub.2--, --N(Q)-, or --N(R.sup.3)--;
[0033] L.sup.2 is (a) alkylene, alkenylene, alkynylene, or one of
the foregoing in which one or more methylenes are replaced by
--O--, --S--, --S(O)--, --S(O).sub.2--, --N(Q')-, or
--N(R.sup.4)--, or (b) -L.sup.4-C(O)--N(Q')- or -L.sup.4(Q')-, or
(c) a direct bond;
[0034] L.sup.3 is (a) alkylene, alkenylene, alkynylene, or one of
the foregoing in which one or more methylenes are replaced by
--O--, --S--, --S(O)--, --S(O).sub.2--, --N(Q")-, or
--N(R.sup.5)--, or (b) a direct bond;
[0035] L.sup.4 is (a) alkylene, alkenylene, alkynylene, or one of
the foregoing in which one or more methylenes are replaced by
--O--, --S--, --S(O)--, --S(O).sub.2--, --N(Q")-, or
--N(R.sup.5)--, or (b) a direct bond;
[0036] 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;
[0037] Q, Q', and Q" independently are hydrogen, -AC(O)OR.sup.6, or
-AC(O)NR.sup.6R.sup.7;
[0038] W and W' independently are --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9, --N(OM)C(O)R.sup.8,
--C(O)NR.sup.8R.sup.9, or --C(O)OR.sup.8, provided that at least
one of W and W' is --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9, or --N(OM)C(O)R.sup.8.
[0039] Z is -A"N(OM')C(O)N(R.sup.10)R.sup.11,
-A"N(R.sup.10)C(O)N(OM')R.su- p.11, -A"N(OM')C(O)R",
-A'C(O)N(OM')R.sup.11, -A'C(O)NR.sup.10R.sup.11, -A'C(O)OR.sup.10,
halo, CH.sub.3, NR.sup.3R.sup.4, NR.sup.3C(O)R.sup.4, NO.sub.2, CN,
CF.sub.3, S(O).sub.2NR.sup.3R.sup.4, S(O).sub.2R.sup.3, SR.sup.3,
or S(O)R.sup.3.
[0040] 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 by --O--, --NH--, --S--, --S(O)--, or
--S(O).sub.2-- and/or one or more methylidenes are replaced by
.dbd.N--;
[0041] M and M' independently are hydrogen, a pharmaceutically
acceptable cation, or a metabolically cleavable group; and
[0042] R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, and R.sup.11 are independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, or
one of the foregoing in which one or more methylenes are replaced
by --O--, --NH--, --S--, --S(O)--, or --S(O).sub.2-- and/or one or
more methylidenes are replaced by .dbd.N--;
[0043] provided that, other than the oxygens bound to the sulfurs
in --S(O)-- and --S(O).sub.2--, when one or more methylenes are
replaced with --O--, --NH--, --S--, --S(O)--, or --S(O).sub.2-- and
when one or more methylidenes are replaced with .dbd.N--, such
replacement does not result in two heteroatoms being covalently
bound to each other;
[0044] and further provided that when m is 0, W is not
--C(O)NR.sup.8R.sup.9, or --C(O)OR.sup.8,
[0045] and further provided that in the substituent -AC(O)OR.sub.6,
R.sub.6 cannot be hydrogen when A is a direct bond.
[0046] Preferably, compounds of the present invention are those
having formula I': 3
[0047] and the geometrical isomers, enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof, wherein each of the
variables is as defined above, except that:
[0048] X and X' independently are hydrogen, halo, alkyl, alkenyl,
alkynyl, alkoxy, or trifluoromethyl; and
[0049] W is --N(OM)C(O)N(R.sup.8)R.sup.9,
--N(R.sup.8)C(O)N(OM)R.sup.9, or --N(OM)C(O)R.sup.8.
[0050] In another preferred embodiment, the compounds of the
present invention are given by formula I": 4
[0051] and the geometrical isomers, enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof, wherein each of the
variables is as defined above.
[0052] In other preferred embodiments, compounds of formula I are
represented by the following formulas, II and III: 5
[0053] and the geometrical isomers, enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof, wherein each of the
variables is as defined above.
[0054] More preferred embodiments of the compounds of formula II
and III and the geometrical isomers, enantiomers, diastereomers,
and pharmaceutically acceptable salts thereof, are those wherein
each of the variables is as defined above except that:
[0055] 1. X is --Cl, X' is hydrogen, m is 1 and W is
--N(OH)C(O)NH.sub.2;
[0056] 2. X is --Cl, X' is hydrogen, m is 1, Y is -L.sup.1-,
wherein L.sup.1 is alkynylene, yloalkoxy, or yloalkoxyalkyl;
[0057] 3. X is --Cl, X' is hydrogen, m is 1, Y is
-L.sup.2-V(Z).sub.t-L.su- p.3-, t is 0, V is 1,4-phenylene or
1,3-phenylene, L.sup.2 is yloalkoxy, and L.sup.3 is alkylene,
alkenylene, or alkynylene;
[0058] 4. X is --Cl, X' is hydrogen, m is 1, Y is
-L.sup.2-V(Z).sub.t-L.su- p.3-, t is 0, V is 2,5-furylene, L.sup.2
is alkylene, and L.sup.3 is alkylene, alkenylene, or alkynylene;
or
[0059] 5. X is --Cl, X' is hydrogen, m is 1, Y is
-L.sup.2-V(Z).sub.t-L.su- p.2-, t is 1, L.sup.2 is yloalkoxy, V is
trivalent heteroarene, Z is -A'C(O)NR.sup.10R.sup.11 or
-A'C(O)OR.sup.10 and W is --N(OH)C(O)NH.sub.2.
[0060] 6. X and X' are F, m is 1, Y is
-L.sup.2-V(Z).sub.t-L.sup.3-, t is 0, V is 1,4-phenylene or
1,3-phenylene, L.sup.2 is yloalkoxy, and L.sup.3 is alkylene,
alkenylene, or alkynylene;
[0061] Compounds of the invention include those shown in TABLE I as
follows:
1 MS CPD Stereo- Melt. Obs # Structure Chem.sup.1 Salt Temp Mass
LogP Name 1 6 CR 3.07 N-{{4-(2-[4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}
amino-N-hydroxyamide 2 7 CR 2.72 N-{{4-(2-[4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}amino aminooate 3 8
CR 3.62 N-{[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]
piperazinyl}prop-1-ynyl) phenyl] methyl}amino-N-hydroxyamide 4 9 CR
3.27 N-{[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]
piperazinyl}prop-2-ynyl) phenyl]methyl}aminocarbonylamino aminooate
5 10 CR 3.18 N-{[3-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl)piperazinyl}ethoxy) phenyl]methyl]amino-N-hydroxyamide
6 11 CR 2.82 N-{[3-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}aminocarbonylamino
amiooate 7 12 CR 3.08 N-{[2-(2-{4-[(1R)(4-chlorophenyl- )
phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}amino-N-hydroxyamide
8 13 CR 3.62 N-{[3-(3-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}prop-2-ynyl)
phenyl]methyl]amino-N-hydroxyamide 9 14 CR 1.76
N-(4-{4-[(1R)(4-chlorophenyl)phenyl methyl]piperazinyl}but-2-ynyl)
amino-N- hydroxyamide 10 15 3.65
amino-N-{4-[4-(8-chloro(5,6-dihydro benzo[f]pyridino[2,3-b][7-
]annulen-11- ylidene))piperidyl]but-2-ynyl}-N- hydroxyamide 11 16 R
3.18 amino-N-{[4-(2-{4-[bis(4-fluorophenyl)
methyl]piperazinyl}ethoxy)phenyl]ethyl}-N-hydroxyamide 12 17 CR
533.3 4.19 N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]but-3-ynyl}amino-N-
hydroxyamide 13 18 CR 3.98 N-{[4-(3-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}propyl) phenyl]methyl}amino-N-hydroxyamide
14 19 R 1.65 tert-butyl2-{2-[4-({4-[(aminohydroxy
carbonylamino)methyl]phenyl}phenylmethyl)piperazinyl]ethoxy}acetate
15 20 R 2.77 tert-butyl2-{2-[4-({4-[4-(aminohydroxy
carbonylamino)but-1-ynyl]phenyl}phenylmethyl)piperazinyl]ethoxy}acetate
16 21 1.33 amino-N-(4-{4-[bis(4-fluorophenyl)
methyl]piperazinyl}but-2-ynyl)-N- hydroxyamide 17 22 CR 148-150
536.64 4.55 N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]butyl}amino-N-hydroxamide
18 23 R 1.05 amino-N-[2-(2-{4-[(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)ethyl]- N-hydroxyamide 19 24 CR
2.37 N-(4-[4-[(1R)(4-chlorophenyl)phenyl methyl]piperazinyl}buty-
l)amino-N- hydroxyamide 20 25 R 2 HCl -0.04
2-{2-[4-({4-[(aminohydroxycarbonyl
amino)methyl]phenyl}phenylmethyl) piperazinyl]ethoxy}acetic acid 21
26 R 2 HCl 1.08 2-{2-[4-({4-[4-aminohydroxycarbonyl
amino)but-1-ynyl]phenyl}phenyl methyl)piperazinyl]ethoxy}acetic
acid 22 27 CR 1.34 N-[2-(2-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)ethyl]amino- -N-hydroxyamide 23 28
CR 533.2 4.19 N-{4-[3-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]but-3-ynyl}amino-N-
hydroxyamide 24 29 CR 509.2 3.82 N-{[3-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)
phenyl]methyl}(methyl{hydroxyamino)) carboxamide 25 30 Chiral S
1.34 N-[2-(2-{4-[(1S)(4-chlorophenyl) phenylmethyl]piperaziny-
l}ethoxy)ethyl]amin-N-hydroxyamide 26 31 CR 455 2.44
N-{[5-({4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}methyl)(2-
furyl)}methyl]amino-N-hydroxyamide 27 32 CR 493.2 3.45
N-{4-[5-({4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}methyl)(2- furyl)]but-3-ynyl}amino-N-
hydroxyamide 28 33 R 2 TFA 480.2 1.08
2-{2-[4-({4-[4-(aminohydroxycarbonyl amino)but-1-ynyl}phenyl}p-
henyl methyl)piperazinyl]ethoxy}acetic acid 29 34 R 2 TFA 442.2
-0.04 2-{2-[4-({4-[(aminohydroxycarbonyl
amino)mthyl]phenyl}phenylm- ethyl) piperazinyl]ethoxy}acetic acid
30 35 503.4 3.93 amin-N-[4-(3-{2-[4-(diphenylmethyl)
piperazinyl]ethoxy}phenyl)butyl]-N- hydroxyamide 31 36 CR 537.1
4.64 N-{4-[3-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]butyl}amino-N-hydroxyamide
32 37 557.14 6.08 amino-N-[4-(4-{2-[4-(8-chloro[5,6-
dihydrobenzo[f]pyridino[2,3-b][7]annul-
en-11-ylidene))piperidyl]ethoxy}phenyl)but-3-ynyl]-N-hydroxyamide
33 38 M 493.2 3.48 N-{3-[5-({4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}methyl)(2-
furyl)]-1-methylprop-2-ynyl}amino-N- hydroxyamide 34 39 494 3.03
amino-N-{4-[5-({4-[bis(4-f- luorophenyl)
methyl]piperazinyl}methyl)(2-furyl)] but- 3-ynyl}-N-hydroxyamide 35
40 CR 156-158 575.45 3.14 2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]benzamide 36 41 CR 591.1
4.33 methyl2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl-
}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]benzoate 37
42 CR 577.1 3.89 2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]benzoic acid 38 43 CR 616.1
3.64 ethyl2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}-N-{4-[4-
(aminohydroxycarbonylamino)but-1- ynyl]phenyl}acetylamino)acetate
39 44 CR 672.1 7.37 methyl2-(2-{4-[(1R)(4-chlorophenyl)
(phenyl)methyl]-1-piperazinyl}ethoxy)-5-
{4-[hydroxy(phenoxycarbonyl) amino]butyl}benzoate 40 45 CR 595.2
4.83 methyl2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4- -
(aminohydroxycarbonylamino)butyl]benzoate 41 46 CR 581.2 4.39
2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-
-5-[4- (aminohydroxycarbonylamino)butyl]benzoic acid 42 47 CR 580.2
3.64 2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}et-
hoxy)-5-[4- (aminohydroxycarbonylamino)butyl]benzamide 43 48 CR 2
HCl 581.2 4.39 2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino)butyl]b- enzoic acid 44 49 CR 2 HCl 577
3.89 2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]benzoic acid 45 50 593.3
3.91 methyl5-[4-(aminohydroxycarbonyl amino)but-1-ynyl]-2-(2-{4--
[bis(4- fluorophenyl)methyl]piperazinyl}ethoxy)benzoate 46 51
Chiral 497 2.75 N-{4-[5-({4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}methyl)(2S,
5S)oxolan-2-yn]but-3-ynyl}amino-N- hydroxyamide 47 52 M 633 4.8
ethyl3-[({4-[4-(aminohydro- xycarbonyl
amino)but-1-ynyl]phenyl)methyl) amino]-4-{4-[(4-chlorophenyl)
phenylmethyl]piperazinyl}butanoate 48 53 CR 621.2 4.97
methyl(2E)-3-[2-(2-{4-[(1R)(4-chloro
phenyl)phenylmethyl]piperazinyl}etho-
xy)-5-[4-(aminohydroxycarbonyl amino)butyl]phenyl]prop-2-enoate 49
54 CR 617.1 4.63 methyl(2E)-3-[2-(2-{4-[(1R)(4-chloro
phenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4-(aminohydroxycarbonyl
amino)but-1-ynyl]phenyl]prop-2-enoate 50 55 2 HCl 579 3.47
5-[4-(aminohydroxycarbonylamino)but-
1-ynyl]-2-(2-{4-[bis(4-fluoroph- enyl)
methyl]piperazinyl}ethoxy)benzoic acid 51 56 R 517.1 2.94
methyl3-{[4-({5-[4-(aminohydroxy carbonylamino)but-1-ynyl)(2-f-
uryl)}methyl)piperazinyl]phenylmethyl}benzoate 52 57 CR 547.07 4.54
N-{4-[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}-
propoxy) phenyl]but-3-ynyl}amino-N- hydroxyamide 53 58 R 559.1 5.42
amino-N-[4-(4-{2-[4-(8-chloro(5,6,11- trihydroxybenzo[b]pyridi-
no[3,2-f][7]annulen-11-yl))piperidyl]ethoxy}phenyl)but-3-ynyl]-N-hydroxyam-
ide 54 59 571.14 6.44 amino-N-[4-(4-{3-[5-(8-chloro(5,6- -
dihydroxybenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl]propoxy-
}phenyl)but-3-ynyl]-N-hydroxyamide 55 60 CR 2 HCl 603.2 4.19
(2E)-3-[2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethox- y)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]phenyl]prop-2-enoic acid 56
61 CR 602 3.44 N-{4-[3-((1E)-2-carbamoylvinyl)-4-(2-{4- -
[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]but-3-ynyl}a-
mino-N-hydroxyamide 57 62 CR 551.64 4.35
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-3-
fluorophenyl]but-3-ynyl}amino-N- hydroxyamide 58 63 578.02 2.71
5-[4-(aminohydroxycarbonylamino)but- 1-ynyl]-2-(2-{4-[bis(4-f-
luorophenyl) methyl]piperazinyl}ethoxy)benzoamide 59 64 552.96 3.92
amino-N-{4-[4-(2-{4-[bis(4-fluoro phenyl)methyl]piperazinyl}e-
thoxy)-3- fluorophenyl]but-3-ynyl}-N- hydroxyamide 60 65 Chiral
Trans 499 2.33 N-{4-[(2S,5S)-5-({4-[bis(4-fluoro
phenyl)methyl]piperazinyl}methyl) oxolan-2-yl]but-3-ynyl}amino-N-
hydroxyamide 61 66 599.82 5.03 5-[4-(aminohydroxycarbo-
nylamino)but- 1-ynyl]-2-{2-[4-(8-chloro(5,6-
dihydroxybenzo[f]pyridino[2,3-
-b][7]annulen-11-ylidene))piperidyl]ethoxy}benzamide 62 67 CR
153-155 589.21 3.49 2-(3-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}propoxy)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]benzamide 63 68 CR 590.06
3.65 2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[5-
(aminohydroxycarbonylamino)pent-1-ynyl]benzamide 64 69 CR 2 HCl 208
576.2 3.14 2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino]but-1- ynyl]benzamide 65 70 CR 5.34
N-{4-[4-(2-{4-[(1R)(4-chl- orophenyl)
phenylmethyl]piperazinyl}ethoxy)-3- (trifluoromethyl)phenyl]but-
-3- ynyl}amino-N-hydroxyamide 66 71 CR 2 HCl 600.36 5.34
N-{4-[4-(2-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-3-
(trifluoromethyl)phenyl;]but-3-ynyl}amin-N-hydroxyamide 67 72 CR
557.5 4.1 N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-3- cyanophenyl]but-3-ynyl}amino-N-
hydroxyamide 68 73 CR 560.59 5.05
N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}butoxy)pheny-
l]but-3-ynyl}amino-N-hydroxyamide 69 74 CR 561.57 2.63
2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-(3-
(aminohydroxycarbonylamino)prop-1- ynyl]benzamide 70 75 CR 564.56
5.41 N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)
phenylmethyl)piperazinyl}butoxy)phenyl]butyl}amino-N-hydroxyamide
71 76 CR 604.56 5.84 N-{4-[4-(2-{4-[(1S)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-3-
(trifluoromethyl)phenyl]butyl}amino-N- - hydroxyamide 72 77 CR 2
HCl 604.44 5.84 N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-3-
(trifluoromethyl)phenyl]butyl}amino-N- hydroxyamide 73 78 6.95
amino-N-[4-(4-{4-[4-(8-chloro(5,6- dihydroxbenzo[f]pyridino[2,3--
b][7]annulen-11-ylidene))piperidyl]butoxy}phenyl)but-3-ynyl]-N-hydroxyamid-
e 74 79 7.31 amino-N-[4-(4-{4-[4-(8-chloro(5,6-
dihydrobenzo[f]puridino[2,3-b][7]annulen-11-ylidene))piperidyl]butoxy}phe-
nyl)butyl]-N-hydroxyamide 75 80 CR 561.57 5.4
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy) phenyl]but-3-ynyl}ethoxy-N-
hydroxycarboxamide 76 81 CR 2 HCl 121-123 564.64 5.41
N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}butoxy) phenyl]butyl}amino-N-hydroxyamide
77 82 CR 90-95 589.45 3.19 N-[2-(2-{4-[(1R)(4-chloophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]phenyl]acetamide 78 83 CR 2
HCl 400 589.7 3.19 N-[2-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}ethoxy)-5-[4-
(aminohydroxycarbonylamino)but-1- ynyl]phenyl]acetamide 79 84 CR
60-65 550.49 4.9 N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)
phenylmethyl)piperazinyl}propoxy) phenyl]butyl}amino-N-hydroxyamide
80 85 64-68 562.5 4.63 amino-N-{4-[4-(4-{4-[bis(4-fluoro
phenyl)methyl]piperazinyl}butoxy) phenyl]but-3-ynyl}-N-hydroxyamide
81 86 Chiral (R,R,R) 42 496.57 4.39 N-{4-[(2R)-5-({4-[(1R)(4-c-
hlorophenyl) phenylmethyl]piperazinyl}methyl)
oxolan-2-yl]but-3-ynyl}amino- -N- hydroxyamide 82 87 CR 52-90
536.52 2.75 N-{3-[4-(3-{4-[(1R)(4-chlorophenyl)
phenylmethyl)piperazinyl}propxy) phenyl]propyl}amino-N-hydroxyamide
83 88 78 549.1 4.12 amino-N-{4-[4-(3-{4-[bis(4-fluoro
phenyl)methyl]piperazinyl}propoxy)
phenyl]but-3-ynyl}-N-hydroxyamide 84 89 CR 123-125 594.3 4
2-(3-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}propoxy)-5-[4- (aminohydroxycarbonylamino)
butyl]benzamide 85 90 138-140 582.5 3.22
5-{4-[(aminocarbonyl)(hydroxy)amino]butyl}-2-(2-{4-[bi-
s(4-fluorophenyl) methyl]-1-piperazinyl}ethoxy) benzamide 86 91
30-80 539.4 3.97 N-{3-[4-(3-{4-[bis(4-fluorophenyl)
methyl]-1-piperazinyl}propoxy)phenyl]propyl}-N-hydroxyurea 87 92
65-70 580.1 3.74 N-{4-[4-(2-{4-[bis(4-fluorophenyl)
methyl]-1-piperazinyl}ethoxy)-2-
nitrophenyl]-4-butynyl}-N-hydroxyurea 88 93 140-145 539.2 4.12
N-{4-[4-(2-{4-[bis(4-fluorophenyl- )
methyl]-1-piperazinyl)ethoxy)phenyl]butyl}-N-hydroxyurea 89 94 CR
Fumarate 162-165 576.2 3.14 5-{4-[(aminocarbonyl)(hydroxy)amino]- -
1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1-
piperazinyl)ethoxy)benzamide 90 95 CR 70-75 577.9 4.17
N-{4-[4-(2-[(R)-(4-chlorophenyl)
(phenyl)methyl]-1-piperazinyl}ethoxy)-2-
nitrophenyl]-3-butynyl}-N-hydroxyurea 91 96 CR Maleate 169-172
576.2 3.14 5-{4-[(aminocarbonyl)(hydroxy)amino]-
1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1-
piperazinyl}ethoxy)benzamide 92 97 CR L-tartrate 155-158 576.2 3.14
5-{4-[(aminocarbonyl)(hydroxy)amino]- 1-butynyl}-2-(2-{4-[(R)-- (4-
chlorophenyl)(phenyl)methyl]-1- piperazinyl}ethoxy)benzamide 93 98
CR Citrate 153-156 576 3.14 5-{4-[(aminocarbonyl)(hydroxy)am- ino]-
1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1-
piperazinyl}ethoxy)benzamide 94 99 CR 64-66 538 4.39
N-{3-[4-(3-{4-[(R)-(4-chlorophenyl)
(phenyl)methyl]-1-piperazinyl}propyl) phenoxy]propyl}-N-hydroxyurea
95 100 CR 127-130 557 4.44 N-(4-{4-[(4-{4-[(R)-(4-chlorophenyl)
(phenyl)methyl]-1-piperazinyl}-2- butynyl)oxy]phenyl}-3-butynyl)-N-
hydroxyurea .sup.1R = Racemate; CR = Chiral R; M '2 Mixture
[0062] Particularly preferred compounds are those listed in Table
I, infra.
[0063] More preferred are 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. The most preferred compounds are
17, 32, 34, 35, 46, 52 and 80.
Definitions
[0064] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds of the invention and
are intended to apply uniformly throughout the specification and
claims unless expressly stated otherwise.
[0065] The term alkyl refers to a univalent C.sub.1 to C.sub.6
saturated straight, branched, or cyclic alkane moiety and
specifically includes methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl,
hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl. The alkyl group can be optionally substituted
with any appropriate group, including but not limited to R.sup.3 or
one or more moieties selected from the group consisting of halo,
hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,
cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or
phosphonate, either unprotected, or protected as necessary, as
known to those skilled in the art or as taught, for example, in
Greene, et al., "Protective Groups in Organic Synthesis," John
Wiley and Sons, Third Edition, 1999.
[0066] The term alkoxy refers to an alkyl moiety having a terminal
--O-- with free a valence, e.g., CH.sub.3CH.sub.2--O--;
[0067] The term yloalkoxy is an alkoxy (as defined above) in which
a hydrogen atom has been removed from the alkyl moiety to yield a
divalent radical, .e.g., --CH.sub.2CH.sub.2O-- or
--CH(CH.sub.3)O--.
[0068] The term yloalkoxyalkyl refers to a divalent, dialkyl ether
moiety having one free valence on each of the alkyl moieties, which
alkyl moieties are the same or different, e.g.,
--CH.sub.2CH.sub.2CH.sub.2--O--- CH.sub.2--.
[0069] The term alkylene refers to an alkyl moiety (as defined
above) in which a hydrogen atom has been removed to yield a
divalent radical, e.g.,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--.
[0070] The term alkenyl refers to a univalent C.sub.2-C.sub.6
straight, branched, or in the case of C.sub.5-6, cyclic hydrocarbon
with at least one double bond, optionally substituted as described
above.
[0071] The term alkenylene refers to an alkenyl moiety (as defined
above) in which a hydrogen atom has been removed to yield a
divalent radical, e.g., --CH.sub.2CH.dbd.CHCH.sub.2--.
[0072] The term alkynyl refers to a univalent C.sub.2 to C.sub.6
straight or branched hydrocarbon with at least one triple bond
(optionally substituted as described above) and specifically
includes acetylenyl, propynyl, and --C.ident.C--CH.sub.2(alkyl),
including --C.ident.C--CH.sub.2(CH.sub.3).
[0073] The term alkynylene refers to an alkynyl moiety (as defined
above) in which a hydrogen atom has been removed to yield a
divalent radical, e.g., --C.ident.C--CH(CH.sub.3)--.
[0074] The term aryl refers to a univalent phenyl (preferably),
biphenyl, or napthyl. The aryl group can be optionally substituted
with any suitable group, including but not limited to one or more
moieties selected from the group consisting of halo, hydroxyl,
amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,
sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
either unprotected, or protected as necessary, as known to those
skilled in the art, for example, as taught in Greene, et al.,
"Protective Groups in Organic Synthesis," John Wiley and Sons,
Third Edition, 1999, and preferably with halo (including but not
limited to fluoro), alkoxy (including methoxy), aryloxy (including
phenoxy), W, cyano, or R.sup.3.
[0075] The terms arylene and divalent arene refer to an aryl moiety
(as defined above) in which a hydrogen atom has been removed to
yield a divalent radical, e.g., --C.sub.6H.sub.4--.
[0076] The term trivalent arene refers to an arylene moiety (as
defined above) in which a hydrogen atom has been removed to yield a
trivalent radical, e.g., 101
[0077] The term yloalkylaryl refers to a divalent alkyl-substituted
aryl moiety in which one open valence is on the alkyl moiety and
one is on the aryl moiety, e.g.,
--CH.sub.2--CH.sub.2--C.sub.6H.sub.4--.
[0078] The term yloarylalkyl refers to a divalent aryl-substituted
alkyl moiety in which one open valence is on the alkyl moiety and
one is on the aryl moiety, e.g.,
--C.sub.6H.sub.4--CH.sub.2--CH.sub.2--.
[0079] The term diylodialkylarene refers to a divalent,
dialkyl-substituted arene in which there is one open valence on
each of the alkyl moieties (which may be the same or different),
e.g., --CH.sub.2--C.sub.6H.sub.4--CH.sub.2CH.sub.2--
[0080] The term heteroatom means O, S, or N.
[0081] The term heterocycle refers to a cyclic alkyl, alkenyl, or
alkynyl moiety as defined above wherein one or more ring carbon
atoms is replaced with a heteroatom.
[0082] The terms heteroarylene and divalent heteroarene refer to an
arylene (or divalent heteroarene) that includes at least one
sulfur, oxygen, or nitrogen in the aromatic ring, which can
optionally be substituted as described above for the aryl groups.
Non-limiting examples are, furylene, pyridylene,
1,2,4-thiadiazolylene, pyrimidylene, thienylene, isothiazolylene,
imidazolylene, tetrazolylene, pyrazinylene, pyrimidylene,
quinolylene, isoquinolylene, benzothienylene, isobenzofurylene,
pyrazolylene, indolylene, purinylene, carbazolylene,
benzimidazolylene, and isoxazolylene.
[0083] The term trivalent heteroarene refers to a heteroarylene
moiety (as defined above) in which a hydrogen atom has been removed
to yield a trivalent radical, e.g., 102
[0084] The term halo refers to chloro, fluoro, iodo, or bromo.
[0085] When a methylene of an alkyl, alkenyl, or alkynyl (or their
divalent radical counterparts) is replaced by O, --NH--, --S--,
--S(O)--, or --S(O).sub.2--, it may be at any suitable position in
the moiety, either at the terminal or internal positions, e.g.,
CH.sub.3CH.sub.2--O--, CH.sub.3--O--CH.sub.2--,
CH.sub.3CH.sub.2NH--, and CH.sub.3NHCH.sub.2--.
[0086] Open valences on the radical moieties described herein can
occur on any one (or more for divalent radicals) of the atoms
within the moiety. For example, the monovalent C.sub.3 alkyl moiety
includes both propyl and isopropyl. As another example, the
divalent C.sub.4 alkylene moiety includes both tetramethylene
(--CH.sub.2(CH.sub.2).sub.2CH.sub.2--) and ethylethylene
(--CH(CH.sub.2CH.sub.3)CH.sub.2--).
[0087] The term organic or inorganic anion refers to an organic or
inorganic moiety that carries a negative charge and can be used as
the negative portion of a salt.
[0088] The term "pharmaceutically acceptable cation" refers to an
organic or inorganic moiety that carries a positive charge and that
can be administered in association with a pharmaceutical agent, for
example, as a countercation in a salt. Pharmaceutically acceptable
cations are known to those of skill in the art, and include but are
not limited to sodium, potassium, and quaternary ammonium.
[0089] The term "metabolically cleavable group" refers to a moiety
that can be cleaved in vivo from the molecule to which it is
attached, and includes but is not limited to an organic or
inorganic anion, a pharmaceutically acceptable cation, acyl (for
example (alkyl)C(O), including acetyl, propionyl, and butyryl),
alkyl, phosphate, sulfate and sulfonate, NH.sub.2C(O)-- or
(alkyl)OC(O)--.
[0090] The term 5-lipoxygenase inhibitor refers to a compound that
inhibits the enzyme at 30 .mu.M or lower. The term 15-lipoxygenase
inhibitor refers to a compound that inhibits the enzyme at 30 .mu.M
or lower.
[0091] As used herein, the term pharmaceutically acceptable salts
or complexes refers to salts or complexes that retain the desired
biological activity of the above-identified compounds and exhibit
minimal or no undesired toxicological effects. Examples of such
salts include, but are not limited to acid addition salts formed
with inorganic acids (for example, hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, nitric acid, and the like),
and salts formed with organic acids such as fumaric acid, maleic
acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic
acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,
alginic acid, polyglutamic acid, naphthalenesulfonic acid,
naphthalenedisulfonic acid, and polygalacturonic acid. The
compounds can also be administered as pharmaceutically acceptable
quaternary salts known by those skilled in the art, which
specifically include, but are not limited to the quaternary
ammonium salt of the formula --NR.sup.+Z.sup.-, wherein R is
hydrogen, alkyl, or benzyl, and Z is a counterion, including
chloride, bromide, iodide, --O-alkyl, toluenesulfonate,
methylsulfonate, sulfonate, phosphate, or carboxylate (such as
fumarate, benzoate, succinate, acetate, glycolate, maleate, malate,
citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,
benzyloate, and diphenylacetate).
[0092] The term pharmaceutically active derivative refers to any
compound that upon administration to the recipient, is capable of
providing directly or indirectly, the compounds disclosed
herein.
Synthetic Schemes
[0093] The synthetic schemes displayed in FIGS. 1-9 and Examples
1-7 illustrate how compounds according to the invention can be
made. Those skilled in the art will be able to routinely modify
and/or adapt these schemes and descriptions to synthesize any
compound of the invention.
Pharmaceutical Compositions, Methods of Treatment and
Administration
[0094] 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. The compounds exhibit this biological
activity by acting as histamine H1 receptor antagonists, by
inhibiting the lipoxygenase enzymes such as 5-lipoxygenase, or by
exhibiting dual activity, i.e., by acting as both a histamine H1
receptor antagonist and inhibitor of lipoxygenase such as
5-lipoxygenase.
[0095] Subjects in need of treatment for a leukotriene-mediated
and/or histamine-mediated condition (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)
can be treated by administering to the patient an effective amount
of one or more of the above-identified compounds or a
pharmaceutically acceptable derivative or salt thereof in a
pharmaceutically acceptable carrier or diluent to reduce formation
of oxygen radicals. The active materials can be administered by any
appropriate route, for example, orally, parenterally,
intravenously, intradermally, subcutaneously, intramuscularly or
topically, in liquid, cream, gel or solid form, via a buccal or
nasal spray, or aerosol.
[0096] The invention further concerns the use of the compounds of
formula I for the manufacture of a medicament for therapeutic
application. In particular, the invention concerns the use of the
compounds of formula 1 for the manufacture of a medicament useful
for treating conditions in which there is likely to be a histamine
and/or leukotriene component. The invention concerns the use of the
compound of formula 1 for the manufacture of a medicament useful
for 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, and preferably asthma,
seasonal and perennial allergic rhinitis.
[0097] The invention further concerns the compounds of formula I
for use as medicaments. The invention concerns the compounds of
formula I for use as a medicament for treating asthma, seasonal and
perennial allergic rhinitis, sinusitis, conjunctivitis, food
allergy, scombroid poisoning, psoriasis, urticaria, pruritus,
eczema, rheumatoid arthritis, inflammatory bowel disease, chronic
obstructive pulmonary disease, thrombotic disease and otitis media,
and preferably asthma, seasonal and perennial allergic
rhinitis.
[0098] The active compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to
a patient a therapeutically effective amount without causing
serious toxic effects in the patient treated. A preferred dose of
the active compound for all of the above-mentioned conditions is in
the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg
per day, more generally 0.5 to about 25 mg per kilogram body weight
of the recipient per day. A typical topical dosage will range from
0.01-3% wt/wt in a suitable carrier. The effective dosage range of
the pharmaceutically acceptable derivatives can be calculated based
on the weight of the parent compound to be delivered. If the
derivative exhibits activity in itself, the effective dosage can be
estimated as above using the weight of the derivative, or by other
means known to those skilled in the art.
[0099] The methods of the invention comprise administration to a
mammal (preferably human) suffering from a leukotriene-mediated
and/or histamine-mediated condition (preferably, asthma and
rhinitis) a pharmaceutical composition according to the invention
in an amount sufficient to alleviate the condition. The compound is
conveniently administered in any suitable unit dosage form,
including but not limited to one containing 1 to 3000 mg,
preferably 5 to 500 mg of active ingredient per unit dosage form. A
oral dosage of 1-500, preferably 10-250, more preferably 25-250 mg
is usually convenient.
[0100] The active ingredient should be administered to achieve peak
plasma concentrations of the active compound of about 0.001-30
.mu.M, preferably about 0.01-10 .mu.M. This may be achieved, for
example, by the intravenous injection of a solution or formulation
of the active ingredient, optionally in saline, or an aqueous
medium or administered as a bolus of the active ingredient.
[0101] The concentration of active compound in the drug composition
will depend on absorption, distribution, inactivation, and
excretion rates of the drug as well as other factors known to those
of skill in the art. It is to be noted that dosage values will also
vary with the severity of the condition to be alleviated. It is to
be further understood that for any particular subject, specific
dosage regimens should be adjusted over time according to the
individual need and the professional judgment of the person
administering or supervising the administration of the
compositions, and that the concentration ranges set forth herein
are exemplary only and are not intended to limit the scope or
practice of the claimed composition. The active ingredient may be
administered at once, or may be divided into a number of smaller
doses to be administered at varying intervals of time.
[0102] Oral compositions will generally include an inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches, or capsules.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition.
[0103] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a dispersing
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterores; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring. When the dosage unit form is a capsule, it can
contain, in addition to material of the above type, a liquid
carrier such as a fatty oil. In addition, dosage unit forms can
contain various other materials which modify the physical form of
the dosage unit, for example, coatings of sugar, shellac, or
enteric agents.
[0104] The active compound or pharmaceutically acceptable salt or
derivative thereof can be administered as a component of an elixir,
suspension, syrup, wafer, chewing gum or the like. A syrup may
contain, in addition to the active compounds, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
[0105] The active compound or pharmaceutically acceptable
derivatives or salts thereof can also be mixed with other active
materials that do not impair the desired action, or with materials
that supplement, the desired action, such as adrenergic agonists
like pseudoephedrine, antibiotics, antifungals, other
anti-inflammatories, or antiviral compounds.
[0106] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, intravenous, intramuscular or topical application can
include the following components: a sterile diluent such as water
for injection, saline solution, fixed oils, polyethylene glycols,
glycerin, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediaminetetraacetic acid; buffers such as
acetates, citrates or phosphates and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The parental
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic.
[0107] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[0108] In one embodiment, the active compounds are prepared with
carriers that will protect the compound against rapid elimination
from the body, such as a controlled release formulation, including
implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. The materials can also be
obtained commercially from Alza Corporation (CA) and Guilford
Pharmaceuticals (Baltimore, Md.). Liposomal suspensions may also be
pharmaceutically acceptable carriers. These may be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811 (which is
incorporated herein by reference in its entirety). For example,
liposome formulations may be prepared by dissolving appropriate
lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl
phosphatidylcholine, arachadoyl phosphatidylcholine, and
cholesterol) in an inorganic solvent that is then evaporated,
leaving behind a thin film of dried lipid on the surface of the
container. An aqueous solution of the active compound or its
monophosphate, diphosphate, and/or triphosphate derivatives are
then introduced into the container. The container is then swirled
by hand to free lipid material from the sides of the container and
to disperse lipid aggregates, thereby forming the liposomal
suspension.
[0109] The following Examples are provided for illustrative
purposes only and are not intended, nor should they be construed,
as limiting the invention in any manner. Those skilled in the art
will appreciate that routine variations and modifications of the
following Examples can be made without exceeding the spirit or
scope of the invention.
EXAMPLES
Example 1
Preparation of N-{[4-(2-{4-[(1R)(4-chlorophenyl)
phenylmethyl]piperazinyl}-
ethoxy)phenyl]methyl}-amino-N-hydroxyamide (compound 1, FIG. 1)
[0110] 4-(2-Bromoethoxy)benzylalcohol (compound 101)
[0111] To a solution of 4-hydroxybenzylalcohol (2.0 g, 16.11 mmol)
in DMF (10 mL) was added potassium carbonate (2.67 g, 19.32 mmol).
The reaction was stirred at room temperature for 30 minutes and
then 1,2-dibromoethane (3.03 g, 16.13 mmol) was added. The reaction
was stirred at room temperature for additional 20 hours and then
quenched with water, and extracted with ethyl acetate. The organic
layer was washed with water and brine, evaporated to yield an oil
which was purified by flash column chromatography (silica gel, 3:1
hexane/ethyl acetate) to yield 101 (1.7 g, 45.7%): .sup.1H NMR
(CDCl.sub.3) .delta. 3.64 (t, 2H), 4.29 (t, 2H), 4.62 (s, 2H), 6.91
(d, 2H), 7.30 (d, 2H).
[0112]
4-{12-[4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl]ethoxy}benzy-
lalcohol (compound 103)
[0113] To a solution of 101 (205 mg, 0.89 mmol),
[(1R)(4-chlorophenyl) phenylmethyl]-piperazine (102) (230 mg, 0.80
mmol) in dichloromethane (2.5 mL) was added triethylamine (122.0
mg, 1.21 mmol). The reaction was stirred at 50.degree. C. for 20
hours. The solvent was evaporated and the residue was purified by
flash column chromatography (silica gel, 3:1 hexane/ethyl acetate)
to yield 103 (330 mg, 94.1%): .sup.1H NMR (CDCl.sub.3) .delta. 2.45
(m, 4H), 2.62 (m, 4H), 2.81 (t, 2H), 4.08 (t, 2H), 4.22 (s, 1H),
4.51 (s, 2H), 6.87 (d, 2H), 7.28 (m, 6H), 7.39 (m, 5H).
[0114]
N-{[4-(2-{4-[(1R)(4-Chlorophenyl)phenylmethyl]piperazinyl}ethoxy)ph-
enyl]methyl}phenoxycarbonylaminophenoxyformate (compound 104)
[0115] To a stirred solution of 103 (330 mg, 0.76 mmol),
phenoxycarbonylaminophenoxyformate (251.6 mg, 0.92 mmol) and
triphenylphosphine (225.2 mg, 0.86 mmol) in THF (8 mL) at 0.degree.
C. was added diisopropylazodicarboxylate (174.1 mg, 0.86 mmol).
After addition, the reaction was warmed to room temperature and
stirred at room temperature for 2 hours. The solvent was evaporated
and the residue was purified by flash column chromatography (silica
gel, 2:1 hexane/ethyl acetate) to give 104 (410 mg, 78.4%): .sup.1H
NMR (CDCl.sub.3) .delta. 2.47 (m, 4H), 2.65 (m, 4H), 2.84 (t, 2H),
4.12 (t, 2H), 4.23 (s, 1H), 4.95 (s, 2H), 6.92 (d, 2H), 7.20 (m,
5H), 7.26 (m, 6H), 7.40 (m, 10H).
[0116] N-{[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}
ethoxy)phenyl]methyl}-amino-N-hydroxyamide (compound 1)
[0117] In a screw top vessel was placed a solution of 104 (410 mg,
0.59 mmol) in methanol (15 mL) and cooled to -78.degree. C. with
dry ice-acetone bath. To this vessel was added liquid NH3 (2-3 mL)
and sealed. The dry ice-acetone bath was then removed and the
reaction was stirred at room temperature for 16 hours. The reaction
was cooled again in a dry ice-acetone bath and the pressure
released. The vessel was opened and the solvent was evaporated.
Compound 1 was separated by flash column chromatography (silica
gel, 19:1 CH.sub.2Cl.sub.2/CH.sub.3OH) (215 mg, 73.2%): .sup.1H NMR
(CDCl.sub.3) .delta. 2.42 (m, 4H), 2.59 (m, 4H), 2.74 (t, 2H), 3.98
(t, 2H), 4.20 (s, 1H), 4.57 (s, 2H), 5.22 (bs, 2H), 6.77 (d, 2H),
7.25 (m, 6H), 7.36 (m, 5H).
Example 2
Preparation of
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl-
}ethoxy)phenyl]but-3-ynyl}-amino-N-hydroxyamide (compound 12, FIG.
2)
[0118] 4-(2-Bromoethoxy)-1-iodobenzene (compound 105)
[0119] To a solution of 4-iodophenol (10.0 g, 45.45 mmol) in DMF
(50 mL) was added potassium carbonate (12.6 g, 91.17 mmol). The
reaction was stirred at room temperature for 30 minutes and then
1,2-dibromoethane (17.07 g, 90.91 mmol) was added. The reaction was
stirred at room temperature for additional 16 hours and then
quenched with water and extracted with dichloromethane. The organic
layer was washed with water and brine, evaporated to yield an oil
which was purified by flash column chromatography (silica gel,
hexane) to yield 105 (2.7 g, 18.2%): .sup.1H NMR (CDCl.sub.3)
.delta. 3.63 (t, 2H), 4.26 (t, 2H), 6.70 (d, 2H), 7.58 (d, 2H).
[0120] 4-[4-(2-Bromoethoxy)phenyl]but-3-yn-1-ol (compound 106)
[0121] To a mixture of 105 (2.7 g, 8.26 mmol), 3-butyn-1-ol (696.3
mg, 9.94 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.15
g, 1.64 mmol) and cuprous iodide (317.1 mg, 1.67 mmol) was added
triethylamine (45 mL). The reaction was stirred at room temperature
for 16 hours. The solvent was evaporated and the residue purified
by flash column chromatography (silica gel, 3:1 hexane/ethyl
acetate) to yield 106 (1.3 g, 58.6%): .sup.1H NMR (CDCl.sub.3)
.delta. 2.70 (m, 4H), 3.65 (t, 2H), 3.82 (m, 2H), 4.30 (t, 2H),
6.83 (d, 2H), 7.37 (d, 2H).
[0122]
4-{4-[2-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy]phe-
nyl}but-3-yn-1-ol (compound 107)
[0123] To a solution of 106 (1.5 g, 5.58 mmol),
[(1R)(4-chlorophenyl)pheny- lmethyl]piperazine (102) (1.6 g, 5.59
mmol) in DMF (15 mL) was added triethylamine (871.2 mg, 8.63 mmol).
The reaction was stirred at 50.degree. C. for 20 hours, water was
added, and the reaction mixture was extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over
magnesium sulfate, filtered and evaporated to an oil which was
purified by flash column chromatography (silica gel, 1:1
hexane/ethyl acetate) to yield 107 (2.6 g, 98.1%): .sup.1H NMR
(CDCl.sub.3) .delta. 2.42 (m, 4H), 2.61 (m, 4H), 2.68 (t, 2H), 2.82
(t, 2H), 3.80 (t, 2H), 4.10 (t, 2H), 4.21 (s, 1H), 6.80 (d, 2H),
7.26 (m, 5H), 7.35 (m, 6H).
[0124]
N-{4-[4-(2-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy)-
phenyl]but-3-ynyl}phenoxycarbonylaminophenoxyformate (compound
108)
[0125] To a stirred solution of 107 (1.5 g, 3.16 mmol),
phenoxycarbonylaminophenoxyformate (1.05 g, 3.85 mmol) and
triphenylphosphine (937.1 mg, 3.57 mmol) in THF (35 mL) at
0.degree. C. was added diisopropylazodicarboxylate (721.4 mg, 3.57
mmol). After addition, the reaction was warmed to room temperature
and stirred at room temperature for 2 hours. The solvent was
evaporated and the residue was purified by flash column
chromatography (silica gel, 2:1 hexane/ethyl acetate) to give 108
(1.4 g, 60.6%): .sup.1H NMR (CDCl.sub.3) .delta. 2.44 (m, 4H), 2.62
(m, 4H), 2.82 (m, 2H), 2.91 (t, 2H), 4.10 (m, 4H), 4.21 (s, 1H),
6.80 (d, 2H), 7.18 (m, 5H), 7.30 (m, 8H), 7.37 (m, 8H).
[0126]
N-{4-[4-(2-[4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)-
phenyl]but-3-ynyl]-amino-N-hydroxyamide (compound 12)
[0127] In a screw top vessel was placed a solution of 108 (1.4 g,
1.92 mmol) in methanol (50 mL) and cooled to -78.degree. C. with
dry ice-acetone bath. To this vessel was added liquid NH.sub.3 (6
mL) and sealed. The dry ice-acetone bath was then removed and the
reaction was stirred at room temperature for 16 hours. The reaction
was cooled again in a dry ice-acetone bath and the pressure
released. The vessel was opened and the solvent evaporated.
Compound 12 was separated by flash column chromatography (silica
gel, 19:1 CH.sub.2Cl.sub.2/CH.sub.3OH) (580 mg, 56.9%): .sup.1H NMR
(CDCl.sub.3) .delta. 2.45 (m, 4H), 2.65 (m, 4H), 2.72 (t, 2H), 2.84
(t, 2H), 3.80 (t, 2H), 4.10 (t, 2H), 4.22 (s, 1H), 5.25 (bs, 2H),
6.80 (d, 2H), 7.25 (m, 5H), 7.36 (m, 6H).
Example 3
Preparation of
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl-
}ethoxy)phenyl]butyl}-amino-N-hydroxyamide (compound 17, FIG.
3)
[0128] 4-[4-(2-Bromoethoxy)phenyl]butan-1-ol (compound 109)
[0129] A solution of 106 (1.3 g, 4.83 mmol) in methanol (15 mL) was
hydrogenated over 10% palladium on charcoal (130 mg) at balloon
pressure for 7 hours. The catalyst was filtered off and the
filtrate was evaporated to give 109 (1.31 g, 99.2%): .sup.1H NMR
(CDCl.sub.3) .delta. 1.65 (m, 4H), 2.60 (t, 2H), 3.66 (m, 4H), 4.28
(m, 2H), 6.83 (d, 2H), 7.10 (d, 2H).
[0130]
4-{4-[2-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy]phe-
nyl}butan-1-ol (compound 110)
[0131] To a solution of 109 (1.3 g, 4.76 mmol) and
[(1R)(4-chlorophenyl)ph- enylmethyl]piperazine (102) (1.39 g, 4.86
mmol) in DMF (12 mL) was added triethylamine (762.3 mg, 7.55 mmol).
The reaction was stirred at 500 C for 16 hours, water was added,
and the reaction was extracted with dichloromethane. The organic
layer was washed with water and brine, dried over magnesium
sulfate, filtered, and evaporated to an oil, which was purified by
flash column chromatography (silica gel, 1:1 hexane/ethyl acetate)
to yield 110 (2.42 g, 104%): .sup.1H NMR (CDCl.sub.3) .delta. 1.65
(m, 4H), 2.45 (m, 4H), 2.62 (m, 6H), 2.81 (t, 2H), 3.66 (t, 2H),
4.08 (t, 2H), 4.21 (s, 1H), 6.81 (d, 2H), 7.08 (d, 2H), 7.25 (m,
4H), 7.36 (m, 5H), 8.02 (bs, 1H).
[0132]
N-{4-[4-(2-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy)-
phenyl]butan-1-ol}phenoxycarbonylaminophenoxyformate (compound
111)
[0133] To a stirred solution of 110 (1.5 g, 3.14 mmol),
phenoxycarbonylaminophenoxyformate (1.05 g, 3.85 mmol) and
triphenylphosphine (938.0 mg, 3.58 mmol) in THF (35 mL) at
0.degree. C. was added diisopropylazodicarboxylate (724.0 mg, 3.58
mmol). After addition, the reaction was warmed to room temperature
and stirred at room temperature for 2 hours. The solvent was
evaporated and the residue was purified by flash column
chromatography (silica gel, 2:1 hexane/ethyl acetate) to give 111
(1.58 g, 68.7%).
[0134]
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)
phenyl]butyl}-amino-N-hydroxyamide (compound 17)
[0135] In a screw top vessel was placed a solution of 111 (1.58 g,
2.16 mmol) in methanol (50 mL) and cooled to -78.degree. C. in a
dry ice-acetone bath. To this vessel was added liquid ammonia (6
mL) and sealed. The dry ice-acetone bath was then removed and the
reaction was stirred at room temperature for 16 hours. The reaction
was cooled again in a dry ice-acetone bath and the pressure was
released. The vessel was opened and the solvent was evaporated.
Compound 17 was separated by flash column chromatography (silica
gel, 19:1 CH.sub.2Cl.sub.2/CH.sub.3OH) and further purified by
recrystallization using ethyl acetate-hexane as a solvent (550 mg,
47.4%): .sup.1H NMR (CDCl.sub.3) .delta. 1.60 (m, 4H), 2.44 (m,
4H), 2.52 (t, 2H), 2.67 (m, 4H), 2.83 (t, 2H), 3.48 (t, 2H), 4.08
(t, 2H), 4.21 (s, 1H), 6.78 (d, 2H), 7.04 (d, 2H), 7.25 (m, 4H),
7.35 (m, 5H).
Example 4
Preparation of
methyl-2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperaziny-
l}ethoxy)-5-[4-(aminohydroxycarbonylamino)but-1-ynyl]benzoate
(compound 36, FIG. 4),
2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy-
)-5-[4-(aminohydroxyarbonylamino) but-1-ynyl]benzamide (compound
35, FIG. 4), and
2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazin-yl}ethoxy)-5--
[4-(aminohydroxycarbonylamino)but-1-ynyl]benzoic acid (compound 37,
FIG. 5)
[0136] 4-iodophenol, methyl acetate (compound 112)
[0137] To a solution of 5-iodosalicylic acid (5.0 g, 18.94 mmol) in
methanol (100 mL) was added a few drops of sulfuric acid. The
reaction was stirred at reflux for 24 hours. The reaction solvent
(methanol) was evaporated to small volume and water was added and
extracted with dichloromethane. The organic layer was washed with
10% NaHCO.sub.3 solution, water and brine, dried over magnesium
sulfate, filtered and evaporated to give the title compound (3.5 g,
66.5%): .sup.1H NMR (CDCl.sub.3) .delta. 3.96 (s, 3H), 6.78 (d,
1H), 7.70 (dd, 1H), 8.12 (d, 1H).
[0138] Methyl 2-hydroxy-5-(4-hydroxybut-1-ynyl)benzoate (compound
113)
[0139] To a mixture of 112 (2.0 g, 7.19 mmol), 3-butyn-1-ol (655.2
mg, 9.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.0
g, 1.42 mmol) and cuprous iodide (276.3 mg, 1.45 mmol) was added
triethylamine (40 mL). The reaction was stirred at room temperature
for 16 hours. The solvent was evaporated and the residue was
purified by flash column chromatography (silica gel, 2:1
hexane/ethyl acetate) to yield 113 (1.6 g, 101.3%): .sup.1H NMR
(CDCl.sub.3) .delta. 2.68 (t, 2H), 3.81 (m, 2H), 3.96 (s, 3H), 6.92
(d, 1H), 7.50 (dd, 1H), 7.93 (d, 1H).
[0140] Methyl 2-(2-bromoethoxy)-5-(4-hydroxybut-1-ynyl)benzoate
(compound 114)
[0141] To a solution of 113 (1.6 g, 7.27 mmol) in DMF (8 mL) was
added potassium carbonate (1.51 g, 10.91 mmol). The reaction was
stirred at room temperature for 30 minutes and then
1,2-dibromoethane (5.47 g, 29.09 mmol) was added. The reaction was
stirred at room temperature for additional 16 hours and then
quenched with water and extracted with dichloromethane. The organic
layer was washed with water and brine, evaporated to yield an oil
which was purified by flash column chromatography (silica gel, 2:1
hexane/ethyl acetate) to yield 114 (710 mg, 29.8%): .sup.1H NMR
(CDCl.sub.3) .delta. 2.70 (t, 2H), 3.68 (t, 2H), 3.82 (t, 2H), 3.90
(s, 3H), 4.35 (t, 2H), 6.90 (d, 1H), 7.50 (dd, 1H), 7.88 (d,
1H).
[0142] Methyl
2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy-
)-5-(4-hydroxybut-1-ynyl)benzoate (compound 115)
[0143] To a solution of 114 (300.0 mg, 0.92 mmol),
[(1R)(4-chlorophenyl) phenylmethyl]piperazine (102) (262.4 mg, 0.92
mmol) in DMF (2 mL) was added triethylamine (139.0 mg, 1.38 mmol).
The reaction was stirred at 50.degree. C. for 20 hours, water was
added, and the reaction was extracted with dichloromethane. The
organic layer was washed with water and brine, dried over magnesium
sulfate, filtered and evaporated to an oil which was purified by
flash column chromatography (silica gel, ethyl acetate) to yield
115 (510 mg, 102.4%): .sup.1H NMR (CDCl.sub.3) .delta. 2.44 (m,
4H), 2.68 (m, 6H), 2.90 (m, 2H), 3.81 (t, 2H), 3.84 (s, 3H), 4.08
(m, 2H), 4.21 (s, 1H), 6.90 (d, 1H), 7.25 (m, 4H), 7.38 (m, 5H),
7.49 (dd, 1H), 7.85 (d, 1H).
[0144]
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)-
-3-(methoxycarbonyl) phenyl] but-3-ynyl}phenoxycarbonylamino
phenoxylormate (compound 116)
[0145] To a stirred solution of 115 (320.0 mg, 0.60 mmol),
phenoxycarbonylaminophenoxyformate (198.4 mg, 0.73 mmol) and
triphenylphosphine (55.7 mg, 0.21 mmol) in THF (2 mL) at 0.degree.
C. was added diisopropylazodicarboxylate (78.2 mg, 0.68 mmol).
After addition, the reaction was warmed to room temperature and
stirred at room temperature for 2 hours. The solvent was evaporated
and the residue was purified by flash column chromatography (silica
gel, 1:1 hexane/ethyl acetate) to give 116 (350 mg, 73.9%): .sup.1H
NMR (CDCl.sub.3) .delta. 2.42 (m, 4H), 2.65 (m, 6H), 2.90 (m, 2H),
3.82 (s, 3H), 4.15 (m, 4H), 4.21 (s, 1H), 6.85 (d, 1H), 7.25 (m,
8H), 7.40 (m, 12H), 7.82 (s, 1H).
[0146] Methyl
2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy-
)-5-[4-(aminohydroxycarbonyl amino)but-1-ynyl]benzoate (compound
36) and
2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)-5-[4-(amino-
hydroxycarbonyl amino)but-1-ynyl]benzamide (compound 35)
[0147] In a screw top vessel was placed a solution of 116 (350 mg,
0.44 mmol) in methanol (20 mL) and cooled to -78.degree. C. in a
dry ice-acetone bath. To this vessel was added liquid ammonia (3
mL) and sealed. The dry ice-acetone bath was then removed and the
reaction was stirred at room temperature for 16 hours. The reaction
was cooled again in a dry ice-acetone bath and the pressure
released. The vessel was opened and the solvent was evaporated.
Compound 36 was separated by flash column chromatography (silica
gel, 9:1 CH.sub.2Cl.sub.2/CH.sub.3OH) as a white solid. The mixture
of compound 35 and 36 was further purified by flash column
chromatography (silica gel, 9:1 CH.sub.2Cl.sub.2/CH.sub.3OH) to
give additional compound 36 (total 31 mg) and compound 35
(containing about 5% compound 36). Compound 35 was further
separated from compound 36 by recrystallization using ethyl
acetate-hexane as a solvent (35 mg).
[0148] Compound 36: .sup.1H NMR (CDCl.sub.3) .delta. 2.45 (m, 4H),
2.70 (m, 6H), 2.90 (t, 2H), 3.75 (t, 2H), 3.83 (s, 3H), 4.18 (t,
2H), 4.21 (s, 1H), 5.34 (bs, 2H), 6.85 (d, 1H), 7.25 (m, 4H), 7.37
(m, 5H), 7.43 (dd, 1H), 7.80 (s, 1H).
[0149] Compound 35: .sup.1H NMR (CDCl.sub.3) .delta. 2.40 (m, 4H),
2.54 (m, 4H), 2.75 (t, 2H), 2.80 (t, 2H), 3.80 (t, 2H), 4.20 (m,
3H), 5.42 (bs, 2H), 5.80 (bs, 1H), 6.87 (d, 1H), 7.25 (m, 4H), 7.36
(m, 5H), 7.45 (dd, 1H), 8.14 (d, 1H), 8.75 (bs, 1H).
[0150]
2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)-5-[4--
(aminohydroxycarbonyl-amino)but-1-ynyl]benzoic acid (compound
37)
[0151] In a small round-bottomed flask was placed compound 36 (30
mg, 0.05 mmol). To this flask was added 1M KOH/CH.sub.3OH (0.30 mL,
0.30 mmol). The reaction was stirred at room temperature for 48
hours and then cooled in an ice bath. 1M HCl/ether (0.30 mL, 0.30
mmol) was added and the mixture was purified by flash column
chromatography (silica gel, 9:1 CH.sub.2Cl.sub.2/CH.sub.3OH) to
give 37 as a white solid (9 mg, 31.4%): .sup.1H NMR (CD.sub.3OD)
.delta. 2.56 (m, 4H), 2.66 (t, 2H), 2.96 (m, 4H), 3.10 (t, 2H),
3.68 (t, 2H), 4.32 (t, 2H), 4.34 (s, 1H), 6.98 (d, 1H), 7.20 (d,
1H), 7.30 (m, 4H), 7.44 (m, 6H).
Example 5
Preparation ofAmino
N-{4-[4-(2-{4-(8-chloro(5,6-dihydrobenzo[f]pyridino[2,-
3-b][7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl}-N-hydroxyam-
ide (compound 32, FIG. 7)
[0152] 4-(2-Bromoethoxy)-1-iodobenzene
[0153] To a stirring solution of 4-iodophenol (25 g, 110 mmol) and
K.sub.2CO.sub.3 (31 g, 220 mmol) in DMF (250 mL) was added
1,2-dibromoethane (5 mL, 55 mmol) over a period of 1 hr. The
solution was heated at 50.degree. C. and stirred overnight under
Ar. In order to complete the reaction additional reagents were
added: 1,2-dibromoethane (20 mL, 220 mmol) and K.sub.2CO.sub.3 (6
g, 43 mmol) and the mixture was heated at 50.degree. C. an
additional 12 hours under Ar. Water was added and the reaction
mixture was extracted with dichloromethane, dried over
Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced
pressure. The crude mixture was purified by silica gel
chromatography eluted with 10% ethyl acetate in hexanes to give the
title compound as a white solid (5.5 g, 17 mmol).
[0154] 4-[4-(2-Bromoethoxy)phenol]but-3-yn-1-ol
[0155] To a mixture of 4-(2-Bromoethoxy)-1-iodobenzene (5.5 g, 17
mmol), 3-butyn-1-ol (1.9 mL, 25 mmol), CuI (952 mg, 5 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (3.5 g, 5 mmol) in
dichloromethane (100 mL) was added dropwise Et.sub.3N (3.5 mL, 25
mmol). The reaction was stirred overnight at room temperature under
Ar. The solvent was evaporated under reduced pressure and ethyl
acetate was added to dissolve the reaction mixture, which was
filtered over celite to remove most of the Pd. The crude product
was purified by silica gel chromatography eluted with hexane/ethyl
acetate (2:1). 4 g of the title compound were obtained as a light
brown solid.
[0156]
4-[4-(2-{4-(8-chloro-5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-1-
1-yliden)piperidyl}ethoxy)but-3-yn-1 ol
[0157]
8-chloro-11-(4-piperidylidene)-5,6-dihydrobenzo[a]pyridino[2,3-d][7-
]annulene (2.5 g, 7.75 mmol) and
4-[4-(2-bromoethoxy)phenol]but-3-yn-1-ol (2.5 g, 9.2 mmol) were
disolved in dichloromethane. To this solution was added Et.sub.3N
(2.6 mL, 18.5 mmol) and the reaction was heated at reflux overnight
under Ar. The dichloromethane was evaporated under reduced
pressure. The unreacted starting materials were recovered after
purification by chromatography with 10% MeOH in dichloromethane.
The title compound was obtained as a white solid (1.9 g, 3.76
mmol).
[0158] Phenyl
{N-{4-[4-(2-{4-(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][-
7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl}phenoxycarbonylam-
inooxy}formate
[0159] A solution of
4-[4-(2-{4-(8-chloro-5,6-dihydrobenzo[f]pyridino[2,3--
b][7]annulen-11-yliden)piperidyl}ethoxy)but-3-yn-lol (1.9 g, 3.76
mmol), triphenylphosphine (1.2 g, 4.7 mmol) and
N,O-bis-(phenoxycarbonyl)hydroxy- lamine (1.3 g, 4.7 mmol) in THF
(20 mL) was cooled at 0.degree. C. with an ice bath.
Diisopropylazodicarboxlate (950 mg, 4.7 mmol) was added dropwise to
the stirring solution. The reaction was allowed to warm to room
temperature and stir for one hour. Once the reaction was complete,
the solvent was evaporated under vacuum. The product was purified
by silica gel chromatography using 10% MeOH in dichloromethane. 4;5
g of the title compound (slightly impure) were obtained.
[0160]
Amino-N-{4-[4-(2-{4-(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][7]-
annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl]-N-hydroxyamide
[0161] Phenyl
{N-{4-[4-(2-{4-(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][-
7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl}phenoxycarbonylam-
inooxy}formate (4.5 g) was disolved in MeOH saturated with NH3 (100
mL). The system was sealed with a rubber septum and the mixture was
stirred at room temperature overnight. The the solvent was
evaporated under vacuum and the crude compound was purified by
chromatography on silica gel, eluted with 10% MeOH saturated with
NH.sub.3 in dichloromethane to give the title compound, compound 32
(800 mg) [Alternatively, the reaction may be run in a pressure
tube].
Example 6
Preparation of
N-(4-[4-(3-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl-
}propoxy)phenyl]but-3-ynyl}-amino-N-hydroxyamide (compound 52)
[0162] 4-(2-Bromopropoxy)-1-iodobenzene
[0163] To a stirring solution of 4-iodophenol (15 g, 70 mmol) and
K.sub.2CO.sub.3 (12.4 g, 90 mmol) in DMF (30 mL) was added
1,2-dibromopropane (7.8 mL, 90 mmol) over a period of 1 hr. The
solution was heated at 50.degree. C. and stirred overnight under
Ar. Water (500 mL) was added and the reaction mixture was extracted
with dichloromethane, dried over Na.sub.2SO.sub.4, filtered and the
solvent evaporated under reduced pressure. Purified on silica gel
chromatography, eluted with 10% ethyl acetate in hexanes to give
the title compound as a white solid (10 g, 29 mmol).
[0164] 4-[4-(2-Bromopropoxy)phenyl]but-3-yn-1-ol
[0165] To a solution of 4-(2-Bromopropoxy)-1-iodobenzene (10 g, 29
mmol), 3-butyn-1-ol (2.6 mL, 37 mmol), CuI (980 mg, 5.2 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (3.6 g, 5.2 mmol) in
dichloromethane (40 mL) was added Et.sub.3N (6.0 mL, 44 mmol)
dropwise. The reaction was stirred overnight at room temperature
under Ar. The solvent was evaporated under reduced pressure and
ethyl acetate was added to dissolve the compound, the solution was
filtered over celite to remove most of the Pd. The crude product
was purified by silica gel chromatography, eluted with hexane/ethyl
acetate (2:1). 2.6 g of the title compound were obtained as a light
brown solid
[0166]
4-{4-[3-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)propoxy]ph-
enyl}but-3-yn-1-ol
[0167] [(1R)(4-chlorophenyl)phenylmethyl]piperazine (1.6 g, 5.6
mmol) and 4-[4-(2-bromopropoxy)phenyl]but-3-yn-1-ol (2.0 g, 7.04
mmol) were dissolved in dichloromethane (10 mL). Et.sub.3N (1 mL,
7.04 mmol) was added dropwise, the solution was heated at reflux
under Ar overnight. The solvent was evaporated and the compound was
purified by silica gel chromatography, eluted with ethyl acetate.
2.0 g of the title compound were obtained as a white solid.
[0168] N-{4-[4-(3-(4-((1R)(4-chlorophenyl) phenylmethyl)
piperazinyl) propoxy)
phenyl]but-3-ynyl}phenoxycarbonylaminophenoxyformate
[0169] A solution of 4-{4-[3-(4-((1R) (4-chlorophenyl)
phenylmethyl) piperazinyl) propoxy]phenyl}but-3-yn-1-ol (1.6 g, 5.6
mmol), triphenylphosphine (1.3 g, 5.1 mmol) and
N,O-bis-(phenoxycarbonyl)hydroxy- lamine (1.4 g, 5.1 mmol) in THF
(20 mL) was cooled at 0.degree. C. with an ice bath.
Diisopropylazodicarboxlate (1.0 g, 5.1 mmol) was added dropwise to
the stirring solution. Then the reaction was allowed to warm to
room temperature and stir for one hour. After completion of the
reaction, the solvent was evaporated under vacuum. No further
purification of the compound was done.
[0170]
N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}propoxy-
)phenyl]but-3-ynyl}-Amino-N-hydroxyamide (compound 52)
[0171]
N-{4-[4-(3-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinyl)propoxy-
)phenyl] but-3-ynyl}phenoxycarbonylaminophenoxyformate was
dissolved in MeOH and added to 20 mL of condensed (dry ice/acetone)
NH3 in a pressure tube. The pressure tube was closed, allowed to
warm at room temperature. After stirring overnight, the pressure
was released slowly and the cap removed opening the system to the
air, then the solvent was evaporated under vacuum. Purification by
silica gel chromatography, eluted with 10% MeOH saturated with NH3
in dichloromethane afforded the title compound, compound 52 (1.05
g)
Example 7
[0172] Preparation of Amino-N-{4-[4-(4-{4-[bis(4
fluorophenyl)methyl]piper- azinyl}butoxy)
phenyl]but-3-ynyl}-N-hydroxyamide (compound 80, FIG. 6)
[0173] 1-(4-bromobutoxy)-4-iodobenzene (117). To a stirring
solution of 4-iodophenol (100 g, 0.5 mol) and K.sub.2CO.sub.3 (70
g, 0.5 mol) in DMF (400 mL) was added 1,4 dibromobutane (100 mL,
0.84 mol) over a period of 1 hr. The solution was stirred overnight
at room temperature under Ar. H.sub.2O (1000 mL) was added and the
reaction mixture was extracted with CH.sub.2Cl.sub.2. The organic
layer was then washed with 1000 mL of brine, dried over MgSO.sub.4,
concentrated to gave a white solid (100 g); .sup.1H NMR
(CD.sub.3Cl): .delta. 2.15-1.87 (m, 6H), 3.50-3.20 (m, 4H), 3.94
(t, 2H), 6.85 (d, 2H), 7.55 (d, 2H).
[0174] 4-[4-(4-bromobutoxy)phenol]but-3-yn-1-ol (118). A solution
of 117 (100 g, 0.3 mol), 3-butyn-1-ol (45 mL, 0.6 mol), CuI (800
mg, 4.2 mmol) and dichlorobis (triphenylphosphine) palladium (II)
(2.9 g, 4.2 mmol) in dichloromethane (400 mL) was cooled at 0 C
(ice bath). Et.sub.3N (84 mL, 0.6 mol) was added dropwise while
maintaining the low temperature. Then the mixture was warmed at
room temperature and stirred overnight under Ar. The
dichloromethane was removed under vacuum. The semi-solid obtained,
was dissolved in a minimum of CH.sub.2Cl.sub.2 and passed over a
large plug of silica gel eluting with 10% EtOAc in hexane, followed
by 50% EtOAc: 50% hexane. 75 g of a light tan solid were obtained;
.sup.1H NMR (CD.sub.3CI) .delta. 2.10-1.80 (m, 4H), 2.66 (t, 2H),
3.25 (t, 1H), 3.50 (t, 2H), 3.80 (t, 2H), 3.94 (t, 2H), 6.85 (d,
2H), 7.55 (d, 2H).
[0175] Compound 119: 4-bis(4-fluorophenyl methyl piperazine (58 g,
0.2 mol) and 118 (74 g, 0.25 mol) were dissolved in
CH.sub.2Cl.sub.2 (500 mL). To this solution was added NEt.sub.3 (43
mL, 0.31 mol). The mixture was allowed to stir for 48 hr at room
temperature under Ar. After evaporation of the solvent under
vacuum, the semi-solid obtained was dissolved in a minimum amount
of CH.sub.2Cl.sub.2 and passed over a large plug of silica gel
eluting with 50% EtOAc:50% hexane, followed by EtOAc to remove the
desired compound. Concentration of the solution gave an off-white
foam (70 g) 90% pure; .sup.1H NMR (CD.sub.3CI) .delta. 1.78-1.75
(m, 6H), 2.72-2.45 (m, 12H), 3.78 (t, 2H), 3.94 (t, 2H), 4.23 (s,
1H), 6.76 (d, 2H), 6.97 (t, 4H), 7.37-7.25 (m, 6H).
[0176] Compound 80: A solution of 119 (70 g, 0.14 mol),
triphenylphosphine (45 g, 0,17 mol) and
N,O-bis-(phenoxycarbonyl)hydroxylamine (46 g, 0.17 mol) in THF (500
mL) was cooled at 0.degree. C. with an ice bath.
Diisopropylazodicarboxylate (34 mL, 0.17 mol) was added dropwise to
the stirring solution. The ice bath was removed, the reaction was
allowed to warm at room temperature and stir for 1 hr. The reaction
was checked by TLC for completion. The solvent was removed under
vacuum, the crude material was dissolved in 700 mL of MeOH
saturated with ammonia. The mixture was stirred overnight in a
round bottom flask sealed with a rubber septa. The reaction was
worked up by an acid/base extraction, concentrated and passed over
a large plug of silica gel (45 g), eluted with 10% MeOH in
dichloromethane. The product was recrystallized with 500 mL of
refluxing EtOAc, and cooled at room temperature overnight to gave
20 g pure compound; .sup.1H NMR (CD.sub.3Cl) .delta. 1.78-1.75 (m,
6H), 2.57-2.45 (m, 10H), 2.72 (t, 2H), 3.78 (t, 2H), 3.94 (t, 2H),
4.23 (s, 1H), 5.34 (s br, 2H), 6.76 (d, 2H), 6.97 (t, 4H),
7.37-7.25 (m, 6H). The following Table II provides illustrative NMR
data for the especially preferred compounds.
2TABLE II COMPOUND # .sup.1H-NMR (CDCl.sub.3) .delta. (ppm) 17 1.60
(m, 4 H), 2.44 (m, 4 H), 2.52 (t, 2 H), 2.67 (m, 4 H), 2.83 (t, 2
H), 3.48 (t, 2 H), 4.08 (t, 2 H), 4.21 (s, 1 H), 6.78 (d, 2 H),
7.04 (d, 2 H), 7.25 (m, 4 H), 7.35 (m, 5 H). 32 2.20-2.95 (m, 14
H), 3.35 (m, 2 H), 3.72 (t, 2 H), 4.05 (t, 2 H), 5.62 (brs, 2 H),
6.72 (d, 2 H), 7.10 (m, 4 H), 7.25 (d, 2 H), 7.45 (d, 1 H), 8.35
(d, 1 H). 34 2.45 (br d, 8 H); 2.75 (t, 2 H); 3.50 (s, 2 H); 3.70
(t, 2 H); 4.20 (s, 1 H); 5.57 (br s, 2 H); 6.15 (d, 1 H); 6.39 (d,
1 H); 6.95 (t, 4 H); 7.33 (dd, 4 H). 35 2.40 (m, 4 H), 2.54 (m, 4
H), 2.75 (t, 2 H), 2.80 (t, 2 H), 3.80 (t, 2 H), 4.20 (m, 3 H),
5.42 (br s, 2 H), 5.80 (br s, 1 H), 6.87 (d, 1 H), 7.25 (m, 4 H),
7.36 (m, 5 H), 7.45 (dd, 1 H), 8.14 (d, 1 H), 8.75 (br s, 1 H). 46
1.40-1.55 (m, 1 H); 1.85-1.96 (m, 1 H); 2.05-2.20 (m, 2 H);
2.30-2.70 (m, 12 H); 3.62 (ddd, 2 H); 4.18 (s, 1 H); 4.27 (br d, 1
H); 4.63 (br t, 1 H); 5.58 (br s, 2 H); 7.15-7.35 (m, 9 H). 52 1.95
(m, 2 H), 2.65-2.35 (m, 10 H), 2.72 (t, 2 H), 3.78 (t, 2 H), 3.93
(t, 2 H), 4.20 (s, 1 H), 5.25 (brs, 2 H), 6.75 (d, 2 H), 7.15-7.40
(m, 11 H). 80 1.78-1.75 (m, 6 H), 2.57-2.45 (m, 10 H), 2.72 (t, 2
H), 3.78 (t, 2 H), 3.94 (t, 2 H), 4.23 (s, 1 H), 5.34 (s br, 2 H),
6.76 (d, 2 H), 6.97 (t, 4 H), 7.37-7.25 (m, 6 H).
Example 8
CHO-K1 H1R Binding Assay Protocol
[0177] This assay is commonly used to measure the ability of a
compound to act as a histamine H1 receptor binding ligand. As this
assay employs human cloned H1 receptors it can provide a good
approximation of what can be expected when a compound is
administered to humans.
[0178] Details of the assay procedure are as follows. CHO-K1 cells
expressing the human cloned H1 receptor are grown to confluence in
tissue culture dishes. Cells are harvested using D-PBS buffer (JRH
Biosciences), kept at 4.degree. C., centrifuging to pellet cells
(4.degree. C., 500 g, 10 min). The final cell pellet is homogenized
and resuspended using Tris/sucrose buffer (20 mM Tris, 250 mM
sucrose, pH 7.4 at 4.degree. C.). Aliquots of the membrane
preparation are stored at -70.degree. C.
[0179] On the day of assay, the membrane preparation is thawed and
centrifuged (TLA100.3 rotor, 4.degree. C., 15 min, 23,000 rpm). The
pellet is resuspended in Tris/sucrose buffer initially and then
diluted further as necessary using assay buffer A (50 mM
Na/KPO.sub.4, 2 mM MgCl.sub.2, 0.5% (w/v) BSA, pH 7.5).
[0180] For the binding assay, the membrane preparation, test
compound and .sup.3H-pyrilamine (2 nM final) in buffer A with 1%
(v/v) DMSO final are incubated in a 96-well polypropylene plate for
3 hours at 37.degree. C. Non-specific binding is determined in the
presence of 10 .mu.M pyrilamine. A 96-well harvester (Packard) is
used to harvest the 96-well plate onto a GF/B filter plate
pre-treated with 0.1% (v/v) PEI. The plate is counted in a Packard
Topcounter after adding Microscint 20 (Packard) scintillation
fluid. The K.sub.i for each compound at the histamine H1 receptor
is then calculated from these counts. The results are displayed in
Table 1, infra.
Example 9
Inhibition of LTB.sub.4 Production in Human Whole Blood
[0181] This assay examines the ability of a compound to inhibit
leukotriene B.sub.4 production from human blood stimulated with
calcium ionophore. As this production of leukotriene B.sub.4 is
mediated via the activation of the 5-lipoxygenase enzyme, this
assay is predictive of a compound's ability to inhibit the human
5-lipoxygenase enzyme.
[0182] The procedure for the assay is as follows. Blood is drawn
from normal human volunteers into tubes containing heparin. 1 ml of
the heparinized blood is pipetted into a 1.5 ml polypropylene tube.
To this sample is added either different concentrations of the test
compound (5 .mu.l) dissolved in DMSO or 5 .mu.l of DMSO as a
vehicle control. These samples are incubated in a water bath, at
37.degree. C. for 15 min. 5 .mu.l of the calcium ionophore A23187
(at a final concentration of 50 .mu.M) is then added to each
sample, which is vortexed and placed back in the water bath for 30
min. The samples are then centrifuged at 2500 rpm for 10 min. at
4.degree. C. 50 .mu.l of the supernatant is transferred into
pre-cooled Eppendorf tubes containing 950 .mu.l of enzyme
immunoassay (EIA) buffer. A commercially available EIA kit (Cayman
Chemical Co., Ann Arbor, Mich., USA) is used to subsequently
measure the LTB4 production in the samples. The LTB.sub.4 levels
produced in the vehicle control sample is then compared to those in
which the test compound has been added. From this a percent
inhibition of LTB.sub.4 production by each concentration of test
compound is calculated and the IC.sub.50 for inhibition of
LTB.sub.4 production for each test compound is determined. The
results are displayed in Table 1, infra.
3TABLE 1 CHOH1 HWB Cpd # K.sub.1 (nM) IC.sub.50 (nM) 1 24 1515 3
260 1681 5 23 2041 46 133 313 8 220 5768 9 12 4222 11 130 3626 12
380 267 80 27 78 13 10 2444 16 94 2657 87 58 251 18 15 2101 22 8
1473 23 10 287 24 7 253 26 4 1714 27 150 650 30 36 412 17 15 254 32
7 263 34 550 142 35 135 85 36 420 94 37 4 6589 40 120 122 42 35 106
52 6 105 43 2 2742
Example 10
Antihistaminergic Activity In Vivo
[0183] Male, Hartley guinea pigs are obtained from Charles River
Labs at a body weight of 350-400 grams. Inhibition of histamine
activity is measured by the method of Konzett and Rossler
(Naonyn-Schmiedebergs Arch. Exp. Path. Pharmakol. 195, 71-74
(1940). Aneasthetized guinea pigs are subjected to artificial
ventilation. The endotracheal pressure is recorded.
Bronchoconstriction is induced by successive intravenous injections
of histamine. The test compounds are administered orally in a 1%
methocellulose suspension at set timepoints prior to the
administration of histamine.
[0184] The results (Table 2) show the percent inhibition of
histamine-induced bronchoconstriction by selected compounds at
multiple time points post oral dosing. 50% inhibition or greater is
considered significant.
4 TABLE 2 Cpd # Dose of test cpd Time (in hours) % inhibition 1 5
mg/kg 3 hrs 56% 12 2 mg/kg 3 hrs 62% 12 2 mg/kg 6 hrs 66% 87 2
mg/kg 3 hrs 66% 87 2 mg/kg 6 hrs 73% 23 2 mg/kg 3 hrs 80% 23 2
mg/kg 6 hrs 92% 27 2 mg/kg 3 hrs 86% 27 2 mg/kg 6 hrs 91% 32 2
mg/kg 3 hrs 65% 34 2 mg/kg 3 hrs 81% 34 2 mg/kg 6 hrs 89% 17 2
mg/kg 3 hrs 66% 17 2 mg/kg 6 hrs 73% 35 2 mg/kg 3 hrs 72% 35 2
mg/kg 6 hrs 88% 52 2 mg/kg 3 hrs 69% 80 2 mg/kg 3 hrs 98%
[0185] It can be seen from this Table that compounds of the present
invention possess good activity with regard to their ability to
inhibit histamine-induced bronchoconstriction. Furthermore, several
of the compounds administered at a single dose possess
antihistaminergic activity of long duration. For example, 27, at a
dose of 2 mg/kg, still inhibits histamine-induced
bronchoconstriction by 91% at 6 hours post oral dosing.
[0186] These experiments also indicate that the compounds tested
are orally bioavailable.
Example 11
5-Lipoxygenase Inhibitory Activity In Vivo
[0187] Male, Hartley guinea pigs are obtained from Charles River
Labs at a body weight of 350-400 grams. Compounds are prepared at a
volume of [1-2 mg/ml] in 1% methocellulose for oral dosing. Animals
are separated into groups of five (5). Each assay includes a
control group dosed with vehicle. Each group of animals is dosed
with either vehicle or compound by oral gavage. Animals are allowed
to rest for one, three, or six hours after dosing. Control animals
are allowed to rest for three hours. At the appropriate times, the
animals are anesthetized with Urethane at 1.5 g/kg, ip. Blood is
drawn into a heparinized syringe via cardiac puncture.
[0188] Blood (0.5 ml) is aliquoted into separately-labeled 1.5 ml
eppendorf tubes. Each sample is loaded with 5 .mu.l of [15 mM]
Arachidonic Acid, and placed in a 37.degree. C. water bath for five
minutes. After five minutes, the blood is stimulated with 5 .mu.l
of [5 mM] A23187 (Calcium lonophore) and retained in the water bath
for an additional 30 minutes. After the thirty minutes, the blood
samples are removed from the water bath and centrifuged at 14,000
rpm for 2 minutes. Plasma is diluted to EIA buffer and an EIA is
performed following manufacturer instructions (Cayman Chemical Co.,
Ann Arbor, Mich., USA).
[0189] The results (Table 3) show the percent inhibition of
5-lipoxygenase by selected compounds at multiple time points post
oral dosing. 50% inhibition or greater is considered
significant.
5 TABLE 3 Cpd # Dose Time in hours % inhibition 1 2 mg/kg 1
hour.sup. 62% 12 2 mg/kg 6 hours 80% 87 2 mg/kg 1 hour.sup. 70% 87
2 mg/kg 6 hours 94% 23 2 mg/kg 1 hour.sup. 80% 27 2 mg/kg 1
hour.sup. 88% 32 2 mg/kg 1 hour.sup. 88% 17 2 mg/kg 3 hours 70% 17
2 mg/kg 6 hours 94% 35 2 mg/kg 1 hour.sup. 87% 35 2 mg/kg 3 hours
97% 52 2 mg/kg 3 hours 61% 80 2 mg/kg 3 hours 73% 80 2 mg/kg 6
hours 88% 34 2 mg/kg 3 hours 38%
[0190] It can be seen from this Table that compounds of the present
invention possess good activity with regard to their ability to
inhibit the 5-lipoxygenase enzyme. Furthermore, several of the
compounds administered at a single dose possess 5-lipoxygenase
inhibitory activity of long duration. For example, 87 at a dose of
2 mg/kg, still inhibits 5-lipoxygenase activity by 94% at 6 hours
post oral dosing.
[0191] These experiments also indicate that the compounds tested
are orally bioavailable.
Example 12
Inhibition of 15-Lipoxygenase
[0192] This assay examines the ability of a compound to inhibit
production of 15-hydroxy-5, 8, 11, 13-eicosateraenoic acid
(15-HETE) via the action of 15-lipoxygenase on arachidonic acid.
15-lipoxygenase was purified from rabbit peritoneal
polymorphonuclear leukocytes. The enzyme is responsible for the
conversion of arachidonic acid (via oxygenation at carbon 15 of
arachidonic acid) to 15-hydroperoxy-5, 8, 11, 13-eicosatetraenoic
acid (15-HPETE), which then reduced to 15-hydroxy-5, 8, 11,
13-eicosatetraenoic acid (15-HETE).
[0193] The procedure for the assay is as follows. Arachidonic acid
is co-incubated with 15-HETE for 5 min at 37.degree. C. in the
presence or absence of different concentrations of test compound
(10.sup.-8 to 10.sup.-5 M). Production of 15-HETE in each sample is
then measured by radioimmunoassay. The 15-HETE levels produced in
the vehicle control sample are then compared to those in which the
test compound has been added. From this a percent inhibition of
15-HETE production by each concentration of test compound is
calculated and the IC.sub.50 for inhibition of 15-HETE production
for each test compound is determined. The IC.sub.50 s (nM) are
1300, 170, 46, 61, and 110 for compounds 1, 32, 35, 52 and 80,
respectively.
* * * * *