U.S. patent application number 09/547941 was filed with the patent office on 2002-11-28 for compounds and methods for the treatment of inflammatory and immune disorders.
Invention is credited to Cai, Xiong, Hussoin, Sajjat, Hwang, San-Bao, Killian, David, Shen, T.Y..
Application Number | 20020177723 09/547941 |
Document ID | / |
Family ID | 27129612 |
Filed Date | 2002-11-28 |
United States Patent
Application |
20020177723 |
Kind Code |
A1 |
Cai, Xiong ; et al. |
November 28, 2002 |
Compounds and methods for the treatment of inflammatory and immune
disorders
Abstract
2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes,
2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes,
1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl
pyrrolidines are disclosed that reduce the chemotaxis and
respiratory burst leading to the formation of damaging oxygen
radicals of polymorphonuclear leukocytes during an inflammatory or
immune response. The compounds exhibit this biological activity by
acting as PAF receptor antagonists, by inhibiting the enzyme
5-lipoxygenase, or by exhibiting dual activity, i. e., by acting as
both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. A
method to treat disorders mediated by PAF or leukotrienes is also
disclosed, that includes administering an effective amount of one
or more of the above-identified compounds or a pharmaceutically
acceptable salt thereof, optionally in a pharmaceutically
acceptable carrier.
Inventors: |
Cai, Xiong; (Allston,
MA) ; Hussoin, Sajjat; (Lexington, MA) ;
Hwang, San-Bao; (Wayland, MA) ; Killian, David;
(Cambridge, MA) ; Shen, T.Y.; (Charlottesville,
VA) |
Correspondence
Address: |
Christine C O'Day
130 Water Street
Boston
MA
02109
US
|
Family ID: |
27129612 |
Appl. No.: |
09/547941 |
Filed: |
April 11, 2000 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09547941 |
Apr 11, 2000 |
|
|
|
08469073 |
Jun 6, 1995 |
|
|
|
6294574 |
|
|
|
|
08469073 |
Jun 6, 1995 |
|
|
|
08062391 |
May 12, 1993 |
|
|
|
5648486 |
|
|
|
|
08062391 |
May 12, 1993 |
|
|
|
07933991 |
Aug 24, 1992 |
|
|
|
5434151 |
|
|
|
|
07933991 |
Aug 24, 1992 |
|
|
|
07912788 |
Jul 13, 1992 |
|
|
|
5358938 |
|
|
|
|
Current U.S.
Class: |
549/491 ;
546/152; 546/283.4; 549/414; 549/493; 549/494 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 407/12 20130101; C07D 405/04 20130101; C07D 207/09 20130101;
C07D 307/12 20130101; C07D 333/18 20130101; C07D 333/20 20130101;
C07D 333/16 20130101; C07D 307/14 20130101; A61P 29/00 20180101;
A61P 37/00 20180101; A61P 43/00 20180101; C07D 405/12 20130101 |
Class at
Publication: |
549/491 ;
549/493; 549/494; 549/414; 546/152; 546/283.4; 514/471; 514/459;
514/314; 514/336 |
International
Class: |
A61K 031/353; A61K
031/4709; C07D 45/02; A61K 031/34 |
Claims
We claim:
1. A compound of the formula: 39wherein: X is O, S, S(O),
S(O).sub.2, CR.sup.9, or NR.sup.10; W is independently: (1)
--AN(OM)C(O)N(R.sup.3)R.s- up.4, --AN(R.sup.3)C(O)N(OM)R.sup.4,
--AN(OM)C(O)R.sup.4, --AC(O)N(OM)R.sup.4,
--N(OM)C(O)N(R.sup.3)R.sup.4, --N(R.sup.3)C(O)N(OM)R.sup.4,
--N(OM)C(O)R.sup.4, --C(O)N(OM)R.sup.4,
--OR.sup.6N(R.sup.5)R.sup.6--(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--OR.sup.6N(COR.sup.5)R.sup.6--(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--OR.sup.6OC(O)N(COR.sup.5)R.sup.6--(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--OR.sup.6O(CO)N(CO.sub.2R.sup.6)R.sup.6(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--A(C.sub.5H.sub.4N)R.sup.6R.sup.7, or
--OR.sup.6N(CO.sub.2R.sup.5)R.sup.-
6--(C.sub.5H.sub.4N)R.sup.6R.sup.7; (2) an amidohydroxyurea of the
formula: --N(R.sup.19)C(O)C(R.sup.19).sub.2N(OM)C(O)NHR.sup.20,
--C(O)N(R.sup.19)C(R.sup.19).sub.2N(OM)C(O)NHR.sup.20,
--AN(R.sup.19)C(O)C(R.sup.19).sub.2N(OM)C(O)NHR.sup.20,
--AC(O)N(R.sup.19)C(R.sup.19).sub.2N(OM)C(O)NHR.sup.20,
--NHC(O)N(OM)C(R.sup.19).sub.2C(O)N(R.sup.19).sub.2; or
--NHC(O)N(OM)C(R.sup.19).sub.2N(R.sup.19)C(O)R.sup.19; (3) an
oxalkane of the structure: 40 wherein n and m are independently
1-4; (4) a thioalkane of the structure: 41 or (5) a
quinolylinethoxy of the structure: 42n is 1 or 2; m is 1, 2 or 3; p
is 0 or 1; A is alkyl, alkenyl, alkynyl, alkyaryl, aralkyl, halo
lower alkyl, halo lower alkenyl, halo lower alkynyl,
--C.sub.1-10alkyl(oxy)C.sub.1-10alkyl,
--C.sub.1-10alkyl(thio)C.sub.1-10alkyl, --N(R.sup.3)C(O)alkyl,
--N(R.sup.3)C(O)alkenyl, --N(R.sup.3)C(O)alkynyl,
--N(R.sup.3)C(O)(alkyl)- oxy(alkyl),
--N(R.sup.3)C(O)(alkyl)thio(alkyl), --N(R.sup.3)C(O)N(alkyl),
--N(R.sup.3)C(O)N(alkenyl), --N(R.sup.3)C(O)N(alkynyl),
--N(R.sup.3)C(O)N(alkyl)oxy(alkyl),
--N(R.sup.3)C(O)N(alkyl)thio(alkyl), --N(R.sup.3)C(O.sub.2)alkyl,
--N(R.sup.3)C(O.sub.2)alkenyl, --N(R.sup.3)C(O.sub.2)alkynyl,
--N(R.sup.3)C(O.sub.2)(alkyl)oxy(alkyl),
--N(R.sup.3)C(O.sub.2)(alkyl)thio(alkyl), --OC(O.sub.2)alkyl,
--OC(O.sub.2)alkenyl, --OC(O.sub.2)alkynyl,
--OC(O.sub.2)(alkyl)oxy(alkyl- ), --OC(O.sub.2)(alkyl)thio(alkyl),
--N(R.sup.3)C(S)alkyl, --N(R.sup.3)C(S)alkenyl,
--N(R.sup.3)C(S)alkynyl, --N(R.sup.3)C(S)(alkyl)- oxy(alkyl),
--N(R.sup.3)C(S)(alkyl)thio(alkyl), --N(R.sup.3)C(S)N(alkyl),
--N(R.sup.3)C(S)N(alkenyl), --N(R.sup.3)C(S)N(alkynyl),
--N(R.sup.3)C(S)N(alkyl)oxy(alkyl),
--N(R.sup.3)C(S)N(alkyl)thio(alkyl), --N(R.sup.3)C(S)S(alkyl),
--N(R.sup.3)C(S)S(alkenyl), --N(R.sup.3)C(S)S(alkynyl),
--N(R.sup.3)C(S)S(alkyl)oxy(alkyl),
--N(R.sup.3)C(S)S(alkyl)thio(alkyl), --SC(S)S(alkyl),
--SC(S)S(alkenyl), --SC(S)S(alkynyl), --SC(S)S(alkyl)oxy(alkyl),
and --SC(S)S(alkyl)thio(alk- yl); M is hydrogen, a pharmaceutically
acceptable cation, or a metabolically cleavable leaving group; Y is
independently; (a) hydrogen; (b) R.sup.1-6, R.sup.8, R.sup.10,
--OR.sup.3, --OR.sup.11, --OR.sup.12, R.sup.3S--, R.sup.5S,
R.sup.3SO--, R.sup.5SO--, R.sup.3SO.sub.2--, R.sup.5SO.sub.2--,
CF.sub.3O--, CF.sub.3S--, CF.sub.3SO--, --CF.sub.3SO.sub.2,
--OCH.sub.2oxycyclopropyl, --OCH.sub.2C(O)OR.sup.3,
--OCH.sub.2OR.sup.3, --OCH.sub.2C(O)R.sup.3,
--OCH.sub.2C.sub.3-8cycloalk- yl, --OCH.sub.2CH(R)R.sup.3,
--OCH.sub.2cyclopropyl, --OCH.sub.2-aryl,
--OCH.sub.2CH(OH)CH.sub.2OH, aryl-CH.sub.2--SO.sub.2--,
(R.sup.3).sub.2CHCH.sub.2SO.sub.2--, --CH.sub.2CH(OH)CH.sub.2OH,
CF.sub.3SO.sub.2--, R.sup.3R.sup.4N--, --OCH.sub.2CO.sub.2R.sup.3,
--NR.sup.3COR.sup.3, --OCONH.sub.2, --OCONR.sup.3R.sup.4,
--CONH.sub.2, --CONR.sup.3R.sup.4, --CR.sup.3R.sup.3R.sup.4,
--SO.sub.2NR.sup.3R.sup.4, --SONR.sup.3R.sup.4,
CH.sub.3OCH.sub.2ONR.sup.3R.sup.6, --SNR.sup.3R.sup.4,
--CO.sub.2R.sup.3, --NR.sup.3R.sup.4SO.sub.2R.sup.3,
--NR.sup.3R.sup.4SOR, --COR.sup.3, --CONR.sup.3, --NO.sub.2, --CN,
--N(R.sup.5)CONR.sup.3R.sup.4,
--CH.sub.2N(R.sup.5)CONR.sup.3R.sup.4, --R.sup.6NR.sup.3R.sup.4,
--OR.sup.6NR.sup.3R.sup.4, --O(O)CR.sup.5, --O(O)CNR.sup.3R.sup.4,
43 --SR.sup.6NR.sup.3R.sup.4, --S(O)R.sup.6NR.sup.3R.sup.4,
--SO.sub.2R.sup.6NR.sup.3R.sup.4, 44 --SR.sup.6OH; --S(O)R.sup.6OH;
--SO.sub.2R.sup.6OH; --OR.sup.6OC(O)N(CO.sub.2R.sup.6)R.sup.6;
O-alkyl-N-(aryl)-C(O)-heterocyc- le; 45(c) a heterocycle, including
but not limited to, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl,
pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl,
pyrazinyl, pyrinidyl, quinolyl, isoquinolyl, benzothienyl,
isobenzofuryl, pyrazolyl, indolyl, purinyl, carbozolyl,
benzamidazolyl, and isoxazolyl, optionally substituted with a group
described in Y section (b); (d) 46 wherein X' is halo, --C(O)aryl,
CF.sub.3, or OR.sup.3; --NR.sub.3C(O)R.sup.3; --OC(O)NH.sub.2;
--CR.sup.3R.sup.3R.sup.4; --C(O)R.sup.3; --CH.sub.2OR.sup.3;
--CH.sub.2CO.sub.2R.sup.3; --CH.sub.2OC(O)R.sup.3;
R.sup.3CH(R.sup.3)CH.sub.2SO.sub.3--; --NHCH.sub.2COOR.sup.3; halo
such as F, Cl, Br and I; N+R.sup.3R.sup.3R.sup.4R.sup.7;
--NR.sup.3SO.sub.2R.sup.3; --C(O)R.sup.3; NO.sub.2; or CN; or 47 48
wherein R.sup.13, R.sup.14 and R.sup.15 independently represents:
BO-- wherein B is --CH.sub.2-oxacyclopropyl, --CH.sub.2OR.sup.3,
--CH.sub.2C(O)R.sup.3, --CH.sub.2CH(R.sup.3)R.sup.3,
--CH.sub.2Aryl, --CH.sub.2CH(OH)--CH.sub.2OH;
R.sup.3C(R.sup.3).sub.2CH.sub.2SO.sub.2; or R.sup.13--R.sup.14 or
R.sup.14--R.sup.15 are joined together to form a bridge such as
--OCHR.sup.2CHR.sup.2--S(O).sub.2-- wherein n is 0 to 3; or 49where
X' is halo, --C(O)aryl, CF.sub.3, or OR.sup.3; --CH.sub.2OR.sup.3;
--CH.sub.2CO.sub.2R.sup.3; --CH.sub.2C(O)R.sup.3;
--NHCH.sub.2COOR.sup.3; --N+R.sup.3R.sup.3R.sup.4R.sup.7. R.sup.1
and R.sup.2 are independently hydrogen, halogen, or lower alkyl,
halo lower alkyl, halo, --COOH, --CONR.sup.16R.sup.17 wherein
R.sup.16 and R.sup.17 independently represent C.sub.1-6 alkyl and
hydrogen, --COOR.sup.3, alkenyl, --C(O)R.sup.3; --CH.sub.2OR.sup.3;
lower alkynyl, CH.sub.2NR.sup.4R.sup.3; --CH.sub.2SR.sup.3; .dbd.O;
--OR.sup.3; or --NR.sup.3R.sup.3; R.sup.3 and R.sup.4 are
independently cyclic and acyclic alkyl, alkenyl, alkynyl, aryl,
aralkyl, alkyaryl, hydrogen, C.sub.1-6 alkoxy-C.sub.1-10 alkyl,
C.sub.1-6 alkylthio-C.sub.1-10 alkyl, and C.sub.1-10 substituted
alkyl (wherein the substituent is independently hydroxy or
carbonyl, located on any of C.sub.1-10); R.sup.5 is cyclic and
acyclic lower alkyl, lower alkenyl, lower alkynyl, halo lower
alkyl, halo lower alkenyl, halo lower alkynyl, aralkyl, or aryl;
R.sup.6 is cyclic and acyclic lower alkyl, lower alkenyl, lower
alkynyl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower
alkynyl, or aryl; R.sup.7 is an organic or inorganic anion; R.sup.8
is halo alkyl, halo lower alkyl, halo lower alkenyl, halo lower
alkynyl, lower alkenyl, lower alkynyl, aralkyl, or aryl; R.sup.9 is
independently hydrogen, halogen, lower alkyl, halo lower alkyl,
lower alkenyl, lower alkynyl, --CONR.sup.3R.sup.4, --C(O)R.sup.5,
--CO.sub.2R.sup.5, --CH.sub.2OR.sup.5, --CH.sub.2NR.sup.5R.sup.5,
--CH.sub.2SR.sup.5, .dbd.O, .dbd.NR.sup.5, --NR.sup.3R.sup.4,
--NR.sup.3R.sup.4R.sup.7, or --OR.sup.5; R.sup.10 is --R.sup.3,
--R.sup.8, --C(O)N(OR.sup.3)R.sup.3, or --OR.sup.3; R.sup.11 is
phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3O).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(CN).sub.d-phenyl-S(O).s- ub.g-lower alkyl-;
(halo).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3COO).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3OCO).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3CO).sub.d-phenyl-S(O).sub.g-lower alkyl-; phenyl-O-lower
alkyl-; (R.sup.3O).sub.d-phenyl-O-lower alkyl-;
(CN).sub.d-phenyl-O-lower alkyl-; (halo).sub.d-phenyl-O-lower
alkyl-; (R.sup.3COO).sub.d-phenyl-O-lower alkyl-;
(R.sup.3OCO).sub.d-phenyl-O-lower alkyl-; (R.sup.3R.sup.3N).sub.d-
-phenyl-S(O).sub.g-lower alkyl-; or
(R.sup.3CO).sub.d-phenyl-O-lower alkyl- where d is 1, 2, 3, 4 or 5;
and g is 0, 1, or 2; R.sup.12 is selected from the group consisting
of: alkyl; substituted alkyl wherein the substituent is selected
from the group consisting of hydroxy and amino; -lower
alkyl-O-R.sup.18, wherein R.sup.18 is --PO.sub.2(OH)--M+ or
--PO.sub.3(M+).sub.2, wherein M+ is a pharmaceutically acceptable
cation; --C(O)(CH.sub.2).sub.2CO.sub.2--M+, or --SO.sub.3--M+;
-lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower
alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-,
wherein the substituents each independently represent lower alkyl;
pyridyl-lower alkyl; imidazolyl-lower alkyl; imidazolyl-Y-lower
alkyl wherein Y is thio or amino; morpholinyl-lower alkyl;
pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl;
piperidinyl-lower alkyl; morpholinyl-lower hydroxyalkyl; N-pyrryl;
piperazinyl-lower alkyl; N-substituted piperazinyl-lower alkyl,
wherein the substituent is lower alkyl; triazolyl-lower alkyl;
tetrazolyl-lower alkyl; tetrazolylamino-lower alkyl; or
thiazolyl-lower alkyl; R.sup.19 is H, lower alkyl, or lower
alkenyl; and R.sup.20 is H, halogen, lower alkoxy, or lower
alkyl.
2. A compound of the formula: 50wherein: X is O, S, S(O),
S(O).sub.2, or NR.sup.10; t is 1, 2, 3, or 4; m is 1, 2, or 3; Z is
independently W or Y; and all of the R groups are as defined in
claim 1.
3. A compound of the formula: 51wherein Ar.sup.5 is: 52wherein
Ar.sup.6 is: 53 wherein: v is 0, 1, or 2; all R groups, t, m, and n
are as defined in claims 1 and 2; and Q is selected from the group
consisting of substituted C.sub.1 to C.sub.12 alkyl wherein the
substituent is selected from the group consisting of hydroxy and
amino, alkylcarbonylalkyl, alkyl; lower alkyl S(O).sub.m-lower
alkyl in which m is 1 or 2; imidazolyl lower alkyl, morpholinyl
lower alkyl, thiazolinyl lower alkyl, piperidinyl ower alkyl,
imidazolylcarbonyl, morpholinyl carbonyl, amorpholinyl (lower
alkyl) aminocarbonyl, N-pyrrylpyridinyl-lower alkyl;
pyridylthio-lower alkyl; morpholinyl-lower alkyl;
hydroxyphenylthio-lower alkyl; cyanophenylthio-lower alkyl;
imidazolylthio-lower alkyl; triazolylthio-lower alkyl;
triazolylphenylthio-lower alkyl; tetrazolylthio-lower alkyl;
tetrazolylphenylthio-lower alkyl; aminophenylthio-lower alkyl;
N,N-di-substituted aminophenylthio-lower alkyl wherein the amine
substituents each independently represent lower alkyl
amidinophenylthio-lower alkyl; phenylsultinyl-lower alkyl; or
phenylsulfonyl lower alkyl; -lower alkyl-O-R.sup.18, wherein
R.sup.18 is --PO.sub.2(OH)--M+ or --PO.sub.3(M+).sub.2, wherein M+
is a pharmaceutically acceptable cation;
--C(O)(CH.sub.2).sub.2CO.sub.2--M+, or --SO.sub.3--M+; -lower
alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower
alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-,
wherein the substituents each independently represent lower alkyl;
pyridyl-lower alkyl; imidazolyl-lower alkyl; imidazolyl-Y-lower
alkyl wherein Y is thio or amino; morpholinyl-lower alkyl;
pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl;
piperidinyl-lower alkyl; morpholinyl-lower hydroxyalkyl; N-pyrryl;
piperazinyl-lower alkyl; N-substituted piperazinyl-lower alkyl,
wherein the amine substituent is lower alkyl; triazolyl-lower
alkyl; tetrazolyl-lower alkyl; tetrazolylamino-lower alkyl; or
thiazolyl-lower alkyl.
4. A pharmaceutical composition comprising an effective amount of
the compound of claim 1 in a pharmaceutically acceptable
carrier.
5. The compound of claim 2 further comprising a pharmaceutically
acceptable carrier.
6. The compound of claim 3 further comprising a pharmaceutically
acceptable carrier.
7. A method for the treatment of disorders mediated by platelet
activating factor or products of 5-lipoxygenase in an animal,
comprising administering an effective amount, to reduce formation
of oxygen radicals, of a compound of claim 1 in a pharmaceutically
acceptable carrier.
8. The method of claim 7, wherein the animal is a mammal.
9. The method of claim 8, wherein the mammal is a human.
10. The method of claim 8, wherein the mammal is equine.
11. The method of claim 8, wherein the mammal is canine.
12. The method of claim 8, wherein the mammal is bovine.
13. A method for the treatment of disorders mediated by platelet
activating factor or products of 5-lipoxygenase in an animal,
comprising administering an effective amount of a compound of claim
2 in a pharmaceutically acceptable carrier.
14. The method of claim 13, wherein the animal is a mammal.
15. The method of claim 14, wherein the mammal is a human.
16. The method of claim 14, wherein the mammal is equine.
17. The method of claim 14, wherein the mammal is canine.
18. The method of claim 14, wherein the mammal is bovine.
19. A method for the treatment of disorders mediated by platelet
activating factor or products of 5-lipoxygenase in an animal,
comprising administering an effective amount of a compound of claim
3 in a pharmaceutically acceptable carrier.
20. The method of claim 19, wherein the animal is a mammal.
21. The method of claim 20, wherein the mammal is a human.
22. The method of claim 20, wherein the mammal is equine.
23. The method of claim 20, wherein the mammal is canine.
24. The method of claim 20, wherein the mammal is bovine.
25.
trans-2-[5-N'-methyl-N'-hydroxyureidylmethyl)-3-methoxy-4-p-chlorophen-
ylthioethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
07/933,991. filed on Aug. 24, 1992, by Xiong Cai, Sajjat Hussoin,
San Bao Hwang, David Killian. and T. Y. Shen, which is a divisional
application of U.S. Ser. No. 07/912,788, filed Jul. 13, 1992, by
Xiong Cai, Sajjat Hussoin, San Bao Hwang, David Killian, and T. Y.
Shen.
BACKGROUND OF THE INVENTION
[0002] This invention is in the area of pharmaceutical compositions
and methods for the treatment of inflammatory and immune disorders,
and specifically provides novel compounds that reduce damage
arising from an inflammatory or immune response. The compounds
exhibit this biological activity by acting as PAF receptor
antagonists, by inhibiting the enzyme 5-lipoxygenase, or by
exhibiting dual activity, i. e., by acting as both a PAF receptor
antagonist and inhibitor of 5-lipoxygenase.
[0003] Platelet activating factor (PAF,
1-O-alkyl-2-acetyl-sn-glycerol-3-p- hosphorylcholine) is a potent
inflammatory phospholipid mediator with a wide variety of
biological activities. PAF was initially identified as a water
soluble compound released by immunoglobulin E (IgE)-sensitized
rabbit basophils. It is now known that PAF is also generated and
released by monocytes, macrophages, polymorphonuclear leukocytes
(PMNs), eosinophils, neutrophils, natural killer lymphocytes,
platelets and endothelial cells, as well as by renal and cardiac
tissues under appropriate immunological and non-immunological
stimulation. (Hwang, "Specific receptors of platelet-activating
factor, receptor heterogeneity, and signal transduction
mechanisms", Journal of Lipid Mediators 92, 123 (1990)). PAF causes
the aggregation and degranulation of platelets at very low
concentrations. The potency (active at 10.sup.-12 to 10.sup.-9M),
tissue level (picomoles) and short plasma half life (2-4 minutes)
of PAF are similar to those of other lipid mediators such as
thromboxane A.sub.2, prostaglandins, and leukotrienes. PAF mediates
biological responses by binding, to specific PAF receptors found in
a wide variety of cells and tissues. Structure-activity studies on
PAF and its analogs indicate that the ability of PAF to bind to
these receptors is highly structure specific and stereospecific.
(Shen. et al., "The Chemical and Biological Properties of PAF
Agonists, Antagonists, and Biosynthetic Inhibitors",
Platelet-Activating Factor and Related Lipid Mediators, F. Snyder,
Ed. Plenum Press, New York, N.Y. 153 (1987)).
[0004] While PAF mediates essential biological responses, it also
appears to play a role in pathological immune and inflammatory
responses. Many published studies have provided evidence for the
involvement of PAF in human diseases, including arthritis, acute
inflammation, asthma, endotoxic shock, pain, psoriasis, ophthalmic
inflammation, ischemia, gastrointestinal ulceration, myocardial
infarction, inflammatory bowel diseases, and acute respiratory
distress syndrome. Animal models also demonstrate that PAF is
produced or increased in certain pathological states.
[0005] The involvement of PAF in pathological inflammatory and
immune states has stimulated a substantial research effort to
identify PAF receptor antagonists. In 1983, a phospholipid analog
referred to as CV-3988
(rac-3-(N-n-octadecyl-carbamoyloxy-w-methoxypropy)-2-thiazolioeth-
yl phosphate) was reported to have PAF receptor antagonist
properties. (Terashita, et al., Life Sciences 32, 1975 (1983)). In
other early work in this area, Shen, et al., (in Proc. Natl. Acad.
Sci. USA 82, 672 (1985)), reported that kadsurenone, a neolignan
derivative isolated from Piper futokadsura Sieb et Zucc (a Chinese
herbal plant) was a potent, specific and competitive inhibitor of
PAF activity at the receptor level. Hwang, et al., disclosed in
1985 that trans-2,5-bis-(3,4,5-trimethoxyphen- yl) tetrahydrofuran
(L-652,731) inhibits the binding of tritiated PAF to PAF receptor
sites. (Hwang, et al., "Trans-2,5-bis-(3,4,5-trimethoxypheny-
l)tetrahydrofuran", Journal of Biological Chemistry 260, 15639
(1985).) L-652,731 was found to be orally active, and to inhibit
PAF-induced rat cutaneous vascular permeability at a dosage of 30
mg/kg body weight. The compound was found to have no effect on the
enzyme 5-lipoxygenase. Hwang, et al., also reported that
trans-L-652,731, wherein the aryl groups at the 2 and 5 positions
are on opposite sides of the plane of the tetrahydrofuran ring, is
approximately 1000 times more potent than cis-L-652,73 1, wherein
the 2 and 5 aryl substituents are on the same side of the plane of
the tetrahydrofuran ring.
[0006] In 1988, Hwang, et al., reported that L-659,989
(trans-2-(3-methoxy-4-propoxyphenyl-5-methylsulfonyl)-5-(3,4,5-trimethoxy-
phenyl)tetrahydrofuran) is an orally active, potent, competitive
PAF receptor antagonist, with an equilibrium inhibition constant 10
times greater than that of trans-L-652,731. (Hwang, et al.,
Pharmacol. Exp. Ther. 246, 534 (1988).)
[0007] U.S. Pat. Nos. 4,996,203, 5,001,123 and 4,539,332 to Biftu,
et al. and European Patent Application Nos. 89202593.3, 90306235.4,
and 90306234.7 disclose that a specific class of 2,5-diaryl
tetrahydrofurans are PAF receptor antagonists.
[0008] Leukotrienes, like PAF, 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 to the hydroperoxide 5-hydroperoxyeicosatetraenoic
acid (5-HPETE), which is converted to leukotriene A.sub.4, which in
turn can be converted to leukotriene B.sub.4, C.sub.4, or D.sub.4.
The slow-reacting substance of anaphylaxis is now known to be a
mixture of leukotrienes C.sub.4, D.sub.4, and E.sub.4, all of which
are potent bronchoconstrictors.
[0009] There has been a research effort to develop specific
receptor antagonists or inhibitors of leukotriene biosynthesis, to
prevent or minimize pathogenic inflammatory responses mediated by
these compounds.
[0010] Leukotrienes are released simultaneously from leukocytes
with PAF, possibly from a common phospholipid precursor such as
1-O-hexadecyl-2-arachidonyl-sn-glycero-phosphocholine, and upon
cellular activation, act synergistically with PAF in many
biological models. Recently, it was reported that the
tetrahydrothiophene derivative of L-652,731,
trans-2,5-bis-(3,4,5-trimethoxyphenyl)tetrahydrothiophene
(L-653,150), is a potent PAF antagonist and a moderate inhibitor of
5-lipoxygenase. It has been disclosed that certain 2,5-diaryl
tetrahydrothiophenes are PAF antagonists and leukotriene synthesis
inhibitors. (Biftu, et al., Abstr, of 6.sup.th Int. Conf. on
Prostaglandins and Related Compounds, Jun. 3-6, 1986, Florence,
Italy: U.S. Pat. No. 4,757,084 to Biftu). European Patent
Application Nos. 90117171.0 and 901170171.0 disclose indole,
benzofuran, and benzothiophene lipoxygenase inhibiting compounds.
Given the significant number of pathological immune and
inflammatory responses that are mediated by PAF and leukotrienes,
there remains a need to identify new compounds and compositions
that exhibit PAF receptor antagonistic activity or inhibit the
enzyme 5-lipoxygenase.
[0011] Therefore, it is an object of the present invention to
provide compounds that reduce the chemotaxis and respiratory burst
leading to the formation of damaging oxygen radicals during an
inflammatory or immune response.
[0012] It is another object of the present invention to provide
pharmaceutical compositions for the treatment of pathological
immune or inflammatory disorders mediated by PAF or products of
5-lipoxygenase.
[0013] It is another object of the present invention to provide
methods for the treatment of pathological immune or inflammatory
disorders mediated by PAF or products of 5-lipoxygenase.
SUMMARY OF THE INVENTION
[0014] 2,5-Diaryl tetrahydrothiophenes, tetrahydrofurans, and
pyrrolidines, 1,3-diaryl cyclopentanes, and 2,4-diaryl
tetrahydrothiophenes, tetrahydrofurans and pyrrolidines for the
treatment of pathological immune or inflammatory disorders are
disclosed of the structures: 1
[0015] wherein:
[0016] X is O, S, S(O), S(O).sub.2, CR.sup.9, or NR.sup. ;
[0017] W is independently:
[0018] (1) --AN(OM)C(O)N(R.sup.3)R.sup.4,
--AN(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4,
--AC(O)N(OM)R.sup.4, --N(OM)C(O)N(R.sup.3)R.sup.4.
--N(R.sup.3)C(O)N(OM)R.sup.4, --N(OM)C(O)R.sup.4, --C
(O)N(OM)R.sup.4,
--OR.sup.6N(R.sup.5)R.sup.6--(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--OR.sup.6N(COR.sup.5)R.sup.6--(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--OR.sup.6OC(O)N(COR.sup.5)R.sup.6--(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--OR.sup.6O(CO)N(CO.sub.2R.sup.6)R.sup.6(C.sub.5H.sub.4N)R.sup.6R.sup.7,
--A(C.sub.5H.sub.4N)R.sup.6R.sup.7, or
--OR.sup.6N(CO.sub.2R.sup.5)R.sup.-
6--(C.sub.5H.sub.4N)R.sup.6R.sup.7.
[0019] (2) an amidohydroxyurea of the formula:
--N(R.sup.19)C(O)C(R.sup.19- ).sub.2N(OM)C(O)NHR.sup.20,
--C(O)N(R.sup.19)C(R.sup.19).sub.2N(OM)C(O)NHR- .sup.20,
--AN(R.sup.19)C(O)C(R.sup.19).sub.2N(OM)C(O)NHR.sup.20,
--AC(O)N(R.sup.19)C(R.sup.19).sub.2N(OM)C(O)NHR.sup.20,
--NHC(O)N(OM)C(R.sup.19).sub.2C(O)N(R.sup.19).sub.2; or
--NHC(O)N(OM)C(R.sup.19).sub.2N(R.sup.19)C(O)R.sup.19;
[0020] (3) an oxalkane of the structure: 2
[0021] wherein n and m are independently 1-4;
[0022] (4) a thioalkane of the structure: 3
[0023] or (5) a quinolylmethoxy of the structure: 4
[0024] n is 1 or 2;
[0025] m is 1. 2or 3;
[0026] p is 0 or 1;
[0027] A is alkyl, alkenyl, alkynyl, alkaryl, aralkyl, halo lower
alkyl, halo lower alkenyl, halo lower alkynyl,
--C.sub.1-10alkyl(oxy)C.sub.1-10a- lkyl,
--C.sub.1-10alkyl(thio)C.sub.1-10alkyl, --N(R.sup.3)C(O)alkyl,
--N(R.sup.3)C(O)alkenyl, --N(R.sup.3)C(O)alkynyl,
--N(R.sup.3)C(O)(alkyl)- oxy(alkyl),
--N(R.sup.3)C(O)(alkyl)thio(alkyl), --N(R.sup.3)C(O)N(alkyl),
--N(R.sup.3)C(O)N(alkenyl), --N(R.sup.3)C(O)N(alkynyl),
--N(R.sup.3)C(O)N(alkyl)oxy(alkyl),
--N(R.sup.3)C(O)N(alkyl)thio(alkyl), --N(R.sup.3)C(O.sub.2)alkyl,
--N(R.sup.3)C(O.sub.2)alkenyl, --N(R.sup.3)C(O.sub.2)alkynyl,
--N(R.sup.3)C(O.sub.2)(alkyl)oxy(alkyl),
--N(R.sup.3)C(O.sub.2)(alkyl)thio(alkyl), --OC(O.sub.2)alkyl,
--OC(O.sub.2)alkenyl, --OC(O.sub.2)alkynyl,
--OC(O.sub.2)(alkyl)oxy(alkyl- ), --OC(O.sub.2)(alkyl)thio(alkyl),
--N(R.sup.3)C(S)alkyl, --N(R.sup.3)C(S)alkenyl,
--N(R.sup.3)C(S)alkynyl, --N(R.sup.3)C(S)(alkyl)- oxy(alkyl),
--N(R.sup.3)C(S)(alkyl)thio(alkyl), --N(R.sup.3)C (S)N(alkyl),
--N(R.sup.3)C(S)N(alkenyl), --N(R.sup.3)C(S)N(alkynyl),
--N(R.sup.3)C(S)N(alkyl)oxy(alkyl),
--N(R.sup.3)C(S)N(alkyl)thio(alkyl), --N(R.sup.3)C(S)S(alkyl),
--N(R.sup.3)C(S)S(alkenyl), --N(R.sup.3)C(S)S(alkynyl),
--N(R.sup.3)C(S)S(alkyl)oxy(alkyl),
--N(R.sup.3)C(S)S(alkyl)thio(alkyl), --SC(S)S(alkyl),
--SC(S)S(alkenyl), --SC(S)S(alkynyl), --SC(S)S(alkyl)oxy(alkyl),
and --SC(S)S(alkyl)thio(alk- yl);
[0028] M is hydrogen, a pharmaceutically acceptable cation, or a
metabolically cleavable leaving group;
[0029] Y is independently:
[0030] (a) hydrogen;
[0031] (b) R.sup.1-6, R.sup.8, R.sup.10, --OR.sup.3, --OR.sup.11,
--OR.sup.12, R.sup.3S--, R.sup.5S--, R.sup.3SO--, R.sup.5SO--,
R.sup.3SO.sub.2--, R.sup.5SO.sub.2--, CF.sub.3O--, CF.sub.3S--,
CF.sub.3SO--, --CF.sub.3SO.sub.2, --OCH.sub.2oxycyclopropyl,
--OCH.sub.2C(O)OR.sup.3, --OCH.sub.2OR.sup.3,
--OCH.sub.2C(O)R.sup.3, --OCH.sub.2C.sub.3-8cycloalkyl,
--OCH.sub.2CH(R.sup.3)R.sup.3, --OCH.sub.2cyclopropyl,
--OCH.sub.2-aryl, --OCH.sub.2CH(OH)CH.sub.2OH, aryl-CH.sub.2--SO--,
(R.sup.3).sub.2CHCH.sub.2SO.sub.2--, --CH.sub.2CH(OH)CH.sub.2OH,
CF.sub.3SO.sub.2--, R.sup.3R.sup.4N--, --OCH.sub.2CO.sub.2R.sup.3,
--NR.sup.3COR.sup.3, --OCONH.sub.2, --OCONR.sup.3R.sup.4,
--CONH.sub.2, --CONR.sup.3R.sup.4, --CR.sup.3R.sup.3R.sup.4,
--SO.sub.2NR.sup.3R.sup.4, --SONR.sup.3R.sup.4,
--CH.sub.3OCH.sub.2NR.sup.3R.sup.6, --SNR.sup.3R.sup.4,
--CO.sub.2R.sup.3, --NR.sup.3R.sup.4SO.sub.2R.sup.3,
--NR.sup.3R.sup.4SOR.sup.3, --COR.sup.3, --CONR.sup.3, --NO.sub.2,
--CN.sub.2N(R.sup.5)CONR.sup.3R.sup.4, --R.sup.6NR.sup.3R.sup.4,
--OR.sup.6NR.sup.3R.sup.4, --O(O)CR.sup.5, --O(O)CNR.sup.3R.sup.4,
5
[0032] --SR.sup.6NR.sup.3R.sup.4, --S(O)R.sup.6NR.sup.3R.sup.4,
--SO.sub.2R.sup.6NR.sup.3R.sup.4, 6
[0033] --SR.sup.6OH, --S(O)R.sup.6OH, --SO.sub.2R.sup.6OH,
--OR.sup.6OC(O)N(CO.sub.2R.sup.6)R.sup.6;
O-alkyl-N-(aryl)-C(O)-heterocyc- le; 7
[0034] (c) a heterocycle, including but not limited to, pyrryl,
furyl, pyridyl; 1,2,4-thiadiazolyl; pyrimidyl, thienyl,
isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,
indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl,
optionally substituted with a group described in Y section (b);
[0035] (d) 8
[0036] wherein X' is halo such as F, Cl, Br and I; --C(O)aryl;
CF.sub.3; OR.sup.3; --NR.sub.3COR.sup.3; --OC(O)NH.sub.2;
--CR.sup.3R.sup.3R.sup.4; --C(O)R.sup.3; --CH.sub.2OR.sup.3;
--CH.sub.2CO.sub.2R.sup.3; --CH.sub.2OC(O)R.sup.3;
R.sup.3CH(R.sup.3)CH.sub.2SO.sub.3; --NHCH.sub.2COOR.sup.3;
N+R.sup.3R.sup.3R.sup.4R.sup.7; --NR.sup.3SO.sub.2R.sup.3;
COR.sup.3; NO.sub.2; or CN; or 9
[0037] wherein R.sup.13, R.sup.14 and R.sup.15 independently
represents:
[0038] BO-- wherein B is --CH.sub.2-oxacyclopropyl,
--CH.sub.2OR.sup.3, --CH.sub.2C(O)R.sup.3,
--CH.sub.2CH(R.sup.3)R.sup.3, --CH.sub.2Aryl,
--CH.sub.2CH(OH)--CH.sub.2OH;
R.sup.3C(R.sup.3).sub.2CH.sub.2SO.sub.2;
[0039] or R.sup.13--R.sup.14 or R.sup.14--R.sup.5 are joined
together to form a bridge such as --OCHR.sup.2CHR.sup.2--S(O).sub.n
wherein n is 0 to 3; or 10
[0040] where X' is halo, --C(O)aryl, --CF.sub.3, or --OR.sup.3;
--CH.sub.2OR.sup.3; --CH.sub.2CO.sub.2R.sup.3;
--CH.sub.2C(O)R.sup.3; --NHCH.sub.2COOR.sup.3; or
--N+R.sup.3R.sup.3R.sup.4R.sup.7
[0041] R.sup.1 and R.sup.2 are independently hydrogen, or lower
alkyl, specifically including lower alkyl of 1-6 carbon atoms,
e.g., methyl, cyclopropylmethyl, ethyl, isopropyl, butyl, pentyl
and hexyl, as well as C.sub.3-8 cycloalkyl, for example,
cyclopentyl; halo lower alkyl, especially C.sub.1-6 haloalkyl, for
example, tritluoromethyl; halo, especially fluoro; --COOH;
--CONR.sup.16R.sup.17 wherein R.sup.16 and R.sup.17 independently
represent C.sub.1-6 alkyl and hydrogen, --COOR.sup.3, lower
alkenyl, especially C.sub.2-6 alkenyl, e.g., vinyl, allyl,
CH.sub.3CH.dbd.CH--CH.sub.2--CH.sub.2, and CH.sub.3CH.sub.2).sub.3-
--CH.dbd.CH--; --C(O)R.sup.3; --CH.sub.2OR.sup.3; lower alkynyl,
especially C.sub.2-6 alkynyl, e.g., --C.dbd.CH;
--CH.sub.2NR.sup.4R.sup.3- ; --CH.sub.2SR.sup.3; .dbd.O;
--OR.sup.3; or --NR.sup.3R.sup.4;
[0042] R.sup.3 and R.sup.4 are independently alkyl, alkenyl,
alkynyl, aryl, aralkyl, alkaryl, hydrogen, C.sub.1-6
alkoxy-C.sub.1-10 alkyl, C.sub.1-6 alkylthio-C.sub.1-10 alkyl, and
C.sub.1-10 substituted alkyl (wherein the substituent is
independently hydroxy or carbonyl, located on any of
C.sub.1-10);
[0043] R.sup.5 is lower alkyl, lower alkenyl, lower alkynyl,
hydroxyl, hydrogen, halo lower alkyl, halo lower alkenyl, halo
lower alkynyl, aralkyl, or aryl;
[0044] R.sup.6 is lower alkyl, lower alkenyl, lower alkynyl,
aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl,
or aryl;
[0045] R.sup.7 is an organic or inorganic anion;
[0046] R.sup.8 is halo alkyl, halo lower alkyl, halo lower alkenyl,
halo lower alkynyl, lower alkenyl, lower alkynyl, aralkyl, or
aryl;
[0047] R.sup.9 is independently hydrogen, halogen, lower alkyl,
halo lower alkyl, lower alkenyl, lower alkynyl,
--CONR.sup.3R.sup.4, --C(O)R.sup.5, --CO.sub.2R.sup.5,
--CH.sub.2OR.sup.5, --CH.sub.2NR.sup.5R.sup.5, --CH.sub.2SR.sup.5,
.dbd.O, .dbd.NR.sup.5, --NR.sup.3R.sup.4, --NR.sup.3R.sup.4R.sup.7,
or --OR.sup.5;
[0048] R.sup.10 is --R.sup.3, --R.sup.8, --C(O)N(OR.sup.3)R.sup.3,
or --OR.sup.3.
[0049] R.sup.11 is phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3O).sub.d-phenyl- -S(O)g-lower alkyl-;
(R.sup.3R.sup.3N).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(CNR).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(halo).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3COO).sub.d-phenyl-S(- O).sub.g-lower alkyl-;
(R.sup.3OCO).sub.d-phenyl-S(O).sub.g-lower alkyl-;
(R.sup.3CO).sub.d-phenyl-S(O).sub.g-lower alkyl-; phenyl-O-lower
alkyl-; (R.sup.3O).sub.d-phenyl-O-lower alkyl-;
(CN).sub.d-phenyl-O-lower alkyl-; (halo).sub.d-phenyl-O-lower
alkyl-; (R.sup.3COO).sub.d-phenyl-O-lower alkyl-;
(R.sup.3OCO).sub.d-phenyl-O-lower alkyl-; or
(R.sup.3CO).sub.d-phenyl-O-lower alkyl- where d is 1, 2, 3, 4 or 5;
and g is 0, 1, or 2.
[0050] R.sup.12 is alkyl; substituted alkyl wherein the substituent
is selected from the group consisting of hydroxy and amino; -lower
alkyl-O-R.sup.18, wherein R.sup.18 is --PO.sub.2(OH)-M+ or
--PO.sub.3(M+).sub.2, wherein M+ is a pharmaceutically acceptable
cation; --C(O)(CH.sub.2).sub.2CO.sub.2-- M+, or --SO.sub.3--M+;
-lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower
alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-,
wherein the substituents each independently represent lower alkyl;
pyridyl-lower alkyl; imnidazolyl-lower alkyl; imidazolyl-Y-lower
alkyl wherein Y is thio or amino; morpholinyl-lower alkyl;
pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl;
piperidinyl-lower alkyl; morpholinyl-lower hydroxyalkyl; N-pyrryl;
piperazinyl-lower alkyl; N-substituted piperazinyl-lower alkyl,
wherein the substituent is lower alkyl; triazolyl-lower alkyl;
tetrazolyl-lower alkyl; tetrazolylarnino-lower alkyl; or
thiazolyl-lower alkyl;
[0051] R.sup.19 is H, lower alkyl, or lower alkenyl; and
[0052] R.sup.20 is H, halogen, lower alkoxy, or lower alkyl; 11
[0053] wherein:
[0054] X is O, S, S(O), S(O).sub.2, or NR.sup.10;
[0055] m is 1, 2, or 3;
[0056] t is 1, 2, 3, or 4;
[0057] Z is independently W or Y; and 12
[0058] v is 0, 1, or 2; and
[0059] Q is selected from the group consisting of substituted
C.sub.1 to C.sub.12 alkyl wherein the substituent is selected from
the group consisting of hydroxy and amino, alkylcarbonylalkyl,
alkyl; lower alkyl S(O).sub.m-lower alkyl in which m is 1 or 2;
imidazolyl lower alkyl, morpholinyl lower alkyl, thiazolinyl lower
alkyl, piperidinyl lower alkyl, imidazolylcarbonyl, morpholinyl
carbonyl, amorpholinyl (lower alkyl) aminocarbonyl,
N-pyrrylpyridinyl-lower alkyl; pyridylthio-lower alkyl;
morpholinyl-lower alkyl; hydroxyphenylthio-lower alkyl;
cyanophenylthio-lower alkyl; imidazolylthio-lower alkyl;
triazolylthio-lower alkyl; triazolylphenylthio-lower alkyl;
tetrazolylthio-lower alkyl; tetrazolylphenylthio-lower alkyl;
aminophenylthio-lower alkyl; N,N-di-substituted
aminophenylthio-lower alkyl wherein the amine substituents each
independently represent lower alkyl; amidinophenylthio-lower alkyl;
phenylsulfinyl-lower alkyl; or phenylsulfonyl lower alkyl; -lower
alkyl-O--R.sup.18, wherein R.sup.18 is --PO.sub.2(OH)-M+ or
--PO.sub.3 (M+).sub.2, wherein M+ is a pharmaceutically acceptable
cation; --C(O)(CH.sub.2).sub.2CO.sub.2-- M+, or --SO.sub.3-M+;
-lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower
alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl,
wherein the amine substituents each independently represent lower
alkyl; pyridyl-lower alkyl; imidazolyl-lower alkyl;
imidazolyl-Y-lower alkyl wherein Y is thio or amino;
morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl;
thiazolinyl-lower alkyl; piperidinyl-lower alkyl; morpholinyl-lower
hydroxyalkyl; N-pyrryl: piperazinyl-lower alkyl; N-substituted
piperazinyl-lower alkyl, wherein the amine substituent is lower
alkyl; triazolyl-lower alkyl; tetrazolyl-lower alkyl;
tetrazolylamino-lower alkyl; or thiazolyl-lower alkyl.
[0060] These compounds in general reduce the chemotaxis and
respiratory burst leading to the formation of damaging oxygen
radicals of polymorphonuclear leukocytes during an inflammatory or
immune response. The compounds exhibit this biological activity by
acting as PAF receptor antagonists, by inhibiting the enzyme
5-lipoxygenase, or by exhibiting dual activity, i. e., by acting as
both a PAF receptor antagonist and inhibitor of 5-lipoxygenase.
[0061] A method to treat disorders mediated by PAF or leukotrienes
is also disclosed, that includes administering an effective amount
of one or more of the above-identified compounds or a
pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier, to reduce formation of oxygen
radicals.
[0062] The compounds disclosed herein can also be used as research
tools to study the structure and location of PAF receptors as well
as biological pathways involving leukotrienes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0063] FIGS. 1a and 1b provide a schematic illustration of a
process for the preparation of
trans-2-[5-(N'-methyl-N'-hydroxyureidylmethyl)-3-metho-
xy-4-p-chlorophenylthioethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrof-
uran.
DETAILED DESCRIPTION OF THE INVENTION
I. Description and Synthesis of the Compounds
[0064] A. Compounds
[0065] The term alkyl, as used herein, unless otherwise specified,
refers to a saturated straight, branched, or cyclic hydrocarbon of
C.sub.1 to C.sub.10, 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.
[0066] The term lower alkyl, as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.6 saturated straight,
branched, or cyclic (in the case of C.sub.5-6) hydrocarbon, 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.
[0067] The term alkenyl, as referred to herein, and unless
otherwise specified, refers to a straight, branched, or cyclic (in
the case of C.sub.5-6) hydrocarbon of C.sub.2 to C.sub.10 with at
least one double bond.
[0068] The term lower alkenyl, as referred to herein, and unless
otherwise specified, refers to an alkenyl group of C.sub.2 to
C.sub.6, and specifically includes vinyl and allyl.
[0069] The term lower alkylamino refers to an amino group that has
one or two lower alkyl substituents.
[0070] The term alkynyl, as referred to herein, and unless
otherwise specified, refers to a C.sub.2 to C.sub.10 straight or
branched hydrocarbon with at least one triple bond.
[0071] The term lower alkynyl, as referred to herein, and unless
otherwise specified, refers to a C.sub.2 to C.sub.6 alkynyl group,
specifically including acetylenyl and propynyl.
[0072] The term aryl, as used herein, and unless otherwise
specified, refers to phenyl or substituted phenyl, wherein the
substituent is halo or lower alkyl.
[0073] The term halo, as used herein, includes fluoro, chloro,
bromo, and iodo.
[0074] The term halo (alkyl, alkenyl, or alkynyl) refers to a
(alkyl, alkenyl, or alkynyl) group in which at least one of the
hydrogens in the group has been replaced with a halogen atom.
[0075] The term heterocycle or heteroaromatic, as used herein,
refers to an aromatic moiety that includes at least one sulfur,
oxygen, or nitrogen in the aromatic ring. Non-limiting examples are
pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl,
isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,
indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
[0076] The term aralkyl refers to an aryl group with an alkyl
substituent.
[0077] The term alkaryl refers to an alkyl group that has an aryl
substituent.
[0078] 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.
[0079] 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 quatemary amine.
[0080] The term "metabolically cleavable leaving 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.
[0081] The term "enantiomerically enriched composition or compound"
refers to a composition or compound that includes at least 95% by
weight of a single enantiomer of the compound.
[0082] The term PAF receptor antagonist refers to a compound that
binds to a PAF receptor with a binding constant of 30 .mu.M or
lower.
[0083] The term 5-lipoxygenase inhibitor refers to a compound that
inhibits the enzyme at 30 .mu.M or lower in a broken cell
system.
[0084] 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.
[0085] The 2,5-diaryl tetrahydrothiophenes, pyrrolidines, and
tetrahydrofurans, 1,3-diaryl cyclopentanes, and the 2,4-diaryl
tetrahydrothiophenes, pyrrolidines and tetrahydrofurans of the
above-defined formulas exhibit PAF receptor antagonist activity or
inhibit the enzyme 5-lipoxygenase, or have dual activity, and are
thus useful in the treatment of humans who have immune and allergic
disorders that are mediated by PAF or products of
5-lipoxygenase.
[0086] The following are nonlimiting examples of compounds that
fall within Formulas I, II, and III. These examples are merely
exemplary and are not intended to limit the scope of the
invention.
Formula I
Cis and Trans Isomers of the Following Compounds
[0087] N-Alkyl/arylhydroxyureas
[0088]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0089]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trirethoxyphenyl)-tetrahydrofuran
[0090]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(3-bromophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0091]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(3,4-dichlorophenylthioethoxy)--
3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0092]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-chlorophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0093]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trirnethoxyphenyl)-tetrahydrofuran
[0094]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2,3,5,6-tetrafluorophenylthioe-
thoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0095]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetralluorophenylethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0096]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-bromophenysulfonylethoxy)-3--
methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0097]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylsulfonylethoxy)-3-
-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0098]
2-[5-(N'-Hydroxy-N'-methylyureidyl)-4-(p-bromophenylthioethoxy)-3-m-
ethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0099]
2-[5-(N'-Hydroxy-N'-methylureidyl)-4-(2-bromophenylthioethoxy)-3-me-
thoxyphenyl]-5-( 3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0100]
2-[5-(N'-Hydroxy-N'-methylureidyl)-4-(3-bromophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trirnethoxyphenyl)tetrahydrofuran
[0101]
2-[5-(N'-Hydroxy-N'-methylureidyl)-4-(3,4-dichlorophenylthioethoxy)-
-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0102]
2-[5-(N'-Hydroxy-N'-methylureidyl)-4-(p-chlorophenylthioethoxy)-3-m-
ethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0103]
2-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-p-fluorophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0104]
2-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(2,3,5,6-tetrafluorophenylthioe-
thoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0105]
2-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenylethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0106]
2-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenylethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0107]
2-[5-(N'-p-Chlorophenyl-N'-hydroxyureidyl)-4-(2-bromophenylsulfonyl-
ethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0108]
2-[5-(N'-p-Chlorophenyl-N'-hydroxyureidyl)-4-(p-bromophenylthioetho-
xy)-3-methoxyphenyl]-5-(3,4,5-trinethoxyphenyl)-tetrahydrofuran
[0109]
2-[5-(N'-tert-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)--
3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0110]
2-[5-(N'-tert-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)--
3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0111]
2-[5-(N'-tert-Butyl-N'-hydroxyureidyl)-4-(3-bromophenylthioethoxy)--
3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0112]
2-[5-(N'-Cyclohexyl-N'-hydroxyureidyl)-4-(3,4-dichlorophenylthioeth-
oxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0113]
2-[5-(N'-Cyclohexyl-N'-hydroxyureidyl)-4-(p-chlorophenylthioethoxy)-
-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0114]
2-[5-(N'-Cyclohexyl-N'-hydroxyureidyl)-4-(p-fluorophenylthioethoxy)-
-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0115]
2-[5-(N'-Benzyl-N'-hydroxyureldyl)-4-(2,3,5,6-tetrafluorophenylthio-
ethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0116]
2-[5-(N'-Benzyl-N'-hydroxyureidyt)-4-(2,3,4,5-tetrafluorophenyletho-
xy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0117]
2-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(p-bromophenylsulfonylethoxy)--
3-methoxyphenyl]-5-(3,4,5-trethoxyphenyl)tetrahydrofuran
[0118]
2-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(2-bromophenylsulfonylethoxy)--
3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0119]
2-[5-(N'-Hydroxy-N'-i-propylureidyl)-4-(p-bromophenylthioethoxy)-3--
methoxyphenyl]-5-(3,4,5-trimnethoxyphenyl)-tetrahydrofuran
[0120]
2-[5-(N'-sec-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)-3-
-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0121]
2-[5-(N'-sec-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)-3-
-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0122]
2-[5-(N'-Hydroxy-N'-propylureidyl)-4-(3-bromophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0123]
2-[5-(N'-Hydroxy-N'-n-pentylureidyl)-4-(3,4-dichlorophenylthioethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0124]
2-[5-(N'-Hexyl-N'-hydroxyureldyl)-4-(p-chlorophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0125]
2-[5-(N'-Hydroxy-N'-octylureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0126]
2-[5-(N'-Hydroxy-methoxyethylureidyl)-4-(2,3,5,6-tetrafluorophenylt-
hioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0127]
2-[5-(N'-Decyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenylethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0128]
2-[5-(N'-Hydroxy-N'-methylureidylmethyl)-4-(p-chlorophenylthioethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0129]
2-[5-(N'-Hydroxy-N'-i-propylureidylmethyl)-4-(p-chlorophenylthioeth-
oxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0130]
2-[5-(N'-Butyl-N'-hydroxyureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0131]
2-[5-(N'-Hydroxy-N'-propylureidylmethyl)-4-(p-chlorophenylthioethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0132]
2-[5-(N'-Ethyl-N'-hydroxyureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0133]
2-[5-(N'-Hydroxy-N'-octylureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0134]
2-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(p-bromophenylsulfonylethoxy)--
3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0135]
2-[-(N'-Benzyl-N'-hydroxyureidyl)-4-(2-bromophenylsulfonylethoxy)-3-
-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0136]
2-[5-(N'-Hydroxy-N'-i-propylureidyl)-4-(p-bromophenylthioethoxy)-3--
methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0137]
2-[5-(N'-Hydroxyl-N'-otylureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0138]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0139]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0140]
2-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(3-bromophenylthioethoxy)-3-met-
hoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0141]
2-[5-(N'-Hydroxy-N'-methylureidylmethyl)-4-(p-chlorophenylthioethox-
y)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0142]
2-[5-(N'-Hydroxy-N'-i-propylureidylmethyl)-4-(p-chlorophenylthioeth-
oxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0143]
2-[5-(N'-Butyl-N'-hydroxyureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene
[0144] Triple Bonded Hydroxamates
[0145]
2-[5-[1-(N-Acetyl-N-hydroxyamino)propyn-3-yl]-4-(p-bromophenylthioe-
thoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0146]
2-[5-[1-(N-Hydroxy-N-propanoylamino)propyn-3-yl]-4-(p-chlorophenylt-
hioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0147]
2-[5-[1-(N-Butanoyl-N-hydroxyamino)propyn-3-yl]-4-(3,4-dichlorophen-
ylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0148]
2-[5-[1-(N-Hydroxy-N-cyclohexanecarbonylamino)propyn-3-yl]-4-(p-flu-
orophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydr-
ofuran
[0149]
2-[5-[1-(N-Hydroxy-N-3-phenoxybenzoylamino)propyn-3-yl]-4-(2,3,5,6--
tetrafluorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-t-
etrahydrofuran
[0150]
2-[5-[1-(N-Hydroxy-N-methoxybenzoylamino)propyn-3-yl]-4-(2-bromophe-
nylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0151]
2-[5-[1-(N-Hydroxy-N-hydroxybenzoylamino)propyn-3-yl]-4-(p-chloroph-
enylthioethoxy)
-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofur- an
[0152] Triple Bonded Ureas
[0153]
2-[5-[1-(N'-Hydroxy-N'-methylureidyl)propyn-3-yl]-4-(p-chlorophenyl-
thioethoxy)
-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0154]
2-[5-[1-(N'-Ethyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chlorophenylt-
hioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0155]
2-[5-[1-(N'-Hydroxy-N'-propylureidyl)propyn-3-yl]-4-(p-chlorophenyl-
thioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0156]
2-[5-[1-(N'-n-Butyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chloropheny-
lthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0157]
2-[5-[1-(N'-Hydroxy-N'-i-propylureidyl)propyn-3-yl]-4-(p-chlorophen-
ylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0158]
2-[5-[1-(N'-tert-Butyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chloroph-
enylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofura-
n
[0159]
2-[5-[1-(N'-Benzyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chlorophenyl-
thioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0160]
2-[5-[1-(N'-Cyclopropylmethyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-c-
hlorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahy-
drofuran
[0161]
2-[5-[1-(N-Allyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chlorophenylth-
ioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0162]
2-[5-[1-(N'-Hydroxy-N'-hydroxyethylureidyl)propyn-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0163] Double Bonded Hydroxamates: Both Cis and Trans Isomers at
the Tetrahydrofuran Ring
[0164]
2-[5-[trans-1-(N-Acetyl-N-hydroxyamino)propen-3-yl]-4-(p-bromopheny-
lthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0165]
2-[5-[trans-1-(N-Hydroxy-N-propanoylamino)propen-3-yl]-4-(p-chlorop-
henylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofur-
an
[0166]
2-[5-[trans-1-(N-Butanoyl-N-hydroxyamino)propen-3-yl]-4-(3,4-dichlo-
rophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydro-
furan
[0167]
2-[5-[trans-1-(N-Hydroxy-N-cyclohexanecarbonylamino)propen-3-yl]-4--
(p-fluorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tet-
rahydrofuran
[0168]
2-[5-[trans-1-(N-Hydroxy-N-phenoxybenzoylamino)propen-3-yl]-4-(2,3,-
5,6-tetrafluorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxypheny-
l)-tetrahydrofuran
[0169]
2-[5-[trans-1-(N-Hydroxy-N-methoxybenzoylamino)propen-3-yl]-4-(p-br-
omophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydr-
ofuran
[0170]
2-[5-[trans-1-(N-Hydroxy-N-hydroxybenzoylamino)propen-3-yl]-4-(p-ch-
lorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahyd-
rofuran
[0171] Double Bonded Ureas: Both Cis and Trans Isomers at the
Tetrahydrofuran Ring
[0172]
2-[5-[trans-1-(N'-Hydroxy-N'-methylureidyl)propen-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0173]
2-[5-[trans-1-(N'-Ethyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chlorop-
henylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofur-
an
[0174]
2-[5-[trans-1-(N'-Hydroxy-N'-propylureidyl)propen-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0175]
2-[5-[trans-1-(N'-n-Butyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chlor-
ophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrof-
uran
[0176]
2-[5-[trans-1-(N'-Hydroxy-N'-i-propylureidyl)propen-3-yl]-4-(p-chlo-
rophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydro-
furan
[0177]
2-[5-[trans-1-(N'-tert-Butyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-ch-
lorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahyd-
rofuran
[0178]
2-[5-[trans-1-(N'-Benzyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0179]
2-[5-[trans-1-(N'-Cyclopropylmethyl-N'-hydroxyureidyl)propen-3-yl]--
4-(p-chlorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-t-
etrahydrofuran
[0180]
2-[5-[trans-1-(N'-Allyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chlorop-
henylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofur-
an
[0181]
2-[5-[trans-1-(N'-Hydroxy-N'-hydroxyethylureidyl)propen-3-yl]-4-(p--
chlorophenylthioethoxy)-3-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrah-
ydrofuran
Formula II
Cis and Trans Isomers of the Following Compounds
N-Alkyl/arylhydroxyureas
[0182]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)-3-met-
hoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0183]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)-3-met-
hoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0184]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(3-bromophenylthioethoxy)-3-met-
hoxyphenyl]-2-(3,4,5-trimethoxypheny)-tetrahydrofuran
[0185]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(3,4,-dichlorophenylthioethoxy)-
-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0186]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-chlorophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0187]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0188]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-2,3,5,6-tetrafluorophenylthioet-
hoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0189]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenylethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0190]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylsulfonylethoxy)-3-
-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0191]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylsulfonylethoxy)-3-
-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0192]
4-[5-(N'-Hydroxy-N'-methylureidyl)-4-(p-bromophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0193]
4-[5-(N'-Hydroxy-N'-methylureidyl)-4-(2-bromophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimnethoxyphenyl)-tetrahydrofuran
[0194]
4-[5-(N'-Hydroxy-N'-methylureidyl)-4-(3-bromophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0195]
4-[5-(N'-Hydroxy-N'-methylureidyl)-4-(3,4-dichlorophenylthioethoxy)-
-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0196]
4-[5-(N'-Hydroxy-N'-methylureidyl)-4-(p-chlorophenylthioethoxy)-3-m-
ethoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0197]
4-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0198]
4-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(2,3,5,6-tetrafluorophenylthioe-
thoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0199]
4-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenylethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0200]
4-[5-(N'-Ethyl-N'-hydroxyureidyl)-4-(p-bromophenylsulfonylethoxy)-3-
-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0201]
4-[5-(N'-p-Chlorophenyl-N'-hydroxyureidyl)-4-(2-bromophenylsultonyl-
ethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0202]
4-[5-(N'-p-Chlorophenyl-N'-hydroxyureidyl)-4-(p-bromophenylthioetho-
xy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0203]
4-[5-(N'-tert-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0204]
4-[5-(N'-tert-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0205]
4-[5-(N'-tert-Butyl-N'-hydroxyureidyl)-4-(3-bromophenylthioethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0206]
4-[5-(N'-Cyclohexyl-N'-hydroxyureidyl)-4-(3,4-dichlorophenylthioeth-
oxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0207]
4-[5-(N'-Cyclohexyl-N'-hydroxyureidyl)-4-(p-chlorophenylthioethoxy)-
-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0208]
4-[5-(N'-Cyclohexyl-N'-hydroxyureidyl)-4-(p-fluorophenylthioethoxy)-
-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0209]
4-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(2,3,5,6-tetrafluorophenylthio-
ethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0210]
4-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenyletho-
xy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0211]
4-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(p-bromophenylsulfonylethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0212]
4-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(2-bromophenylsulfonylethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0213]
4-[5-(N'-Hydroxy-N'-i-propylureidyl)-4-(p-bromophenylthioethoxy)-3--
methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0214]
4-[5-(N'-sec-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)-3-
-methoxyphenyl]-2-(3,4,5-trinethoxyphenyl)-tetrahydrofuran
[0215]
4-[5-(N'-sec-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)-3-
-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0216]
4-[5-(N'-Hydroxy-N'-propylureidyl)-4-(3-bromophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0217]
4-[5-(N'-Hydroxy-N'-n-pentylureidyl)-4-(3,4-dichlorophenylthioethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0218]
4-[5-(N'-Hexyl-N'-hydroxyureidyl)-4-(p-chlorophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0219]
4-[5-(N'-Hydroxy-N'-octylureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0220]
4-[5-(N'-Hydroxy-N'-methoxyethylureidyl)-4-(2,3,5,6-tetrafluorophen-
ylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0221]
4-[5-(N'-Decyl-N'-hydroxyureidyl)-4-(2,3,4,5-tetrafluorophenylethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0222]
4-[5-(N'-Hydroxy-N'-methylureidylmethyl)-4-(p-chlorophenylthioethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0223]
4-[5-(N'-Hydroxy-N'-i-propylureidylmethyl)-4-(p-chlorophenylthioeth-
oxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0224]
4-[5-(N'-Butyl-N'-hydroxyureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0225]
4-[5-(N'-Hydroxy-N'-propylureidylmethyl)-4-(p-chlorophenylthioethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0226]
4-[5-(N-Ethyl-N-hydroxyureidylmethyl)-4-(p-chlorophenylthioethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0227]
4-[5-(N'-Hydroxy-N'-octylureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0228]
4-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(p-bromophenylsulfonylethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0229]
4-[5-(N'-Benzyl-N'-hydroxyureidyl)-4-(2-bromrophenyltsufonyethoxy)--
3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0230]
4-[5-(N'-Hydroxy-N'-i-propylureidyl)-4-(p-bromophenylthioethoxy)-3--
methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0231]
4-[5-(N'-Hydroxy-N'-octylureidyl)-4-(p-fluorophenylthioethoxy)-3-me-
thoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0232]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(p-bromophenylthioethoxy)-3-met-
hoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0233]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(2-bromophenylthioethoxy)-3-met-
hoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0234]
4-[5-(N'-Butyl-N'-hydroxyureidyl)-4-(3-bromophenylthioethoxy)-3-met-
hoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0235]
4-[5-(N'-Hydroxy-N'-methylureidylmethyl)-4-(p-chlorophenylthioethox-
y)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0236]
4-[5-(N'-Hydroxy-N'-i-propylureidylmethyl)-4-(p-chlorophenylthioeth-
oxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0237]
4-[5-(N'-Butyl-N'-hydroxyureidylmethyl)-4-(p-chlorophenylthioethoxy-
)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0238] Triple Bonded Hydroxamates
[0239]
4-[5-[1-(N-Acetyl-N-hydroxyamino)propyn-3-yl]-4-(p-bromophenylthioe-
thoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0240]
4-[5-[1-(N-Hydroxy-N-propanoylamino)propyn-3-yl]-4-(p-chlorophenylt-
hioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0241]
4-[5-[1-(N-Butanoyl-N-hydroxyamino)propyn-3-yl]-4-(3,4-dichlorophen-
ylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0242]
4-[5-[1-(N-Hydroxy-N-cyclohexanecarbonylamino)propyn-3-yl]-4-(p-flu-
orophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydr-
ofuran
[0243]
4-[5-[1-(N-Hydroxy-N-phenoxybenzoylamino)propyn-3-yl]-4-(2,3,5,6-te-
trafluorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tet-
rahydrofuran
[0244]
4-[5-[1-(N-Hydroxy-N-methoxybenzoylamino)propyn-3-yl]-4-(2-bromophe-
nylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0245]
4-[5-[1-(N-Hydroxy-N-hydroxybenzoylamino)propyn-3-yl]-4-(p-chloroph-
entylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofur-
an
[0246] Triple Bonded Ureas
[0247]
4-[5-[1-(N'-Hydroxy-N'-methylureidyl)propyn-3-yl]-4-(p-chlorophenyl-
thioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0248]
4-[5-[1-(N'-Ethyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chlorophenylt-
hioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0249]
4-[5-[1-(N'-Hydroxy-N'-propylureidyl)propyn-3-yl]-4-(p-chlorophenyl-
thioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0250]
4-[5-[1-(N'-n-Butyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chloropheny-
lthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0251]
4-[5-[1-(N'-Hydroxy-N'-i-propylureidyl)propyn-3-yl]-4-(p-chlorophen-
ylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0252]
4-[5-[1-(N'-tert-Butyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chloroph-
enylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofura-
n
[0253]
4-[5-[1-(N'-Benzyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chlorophenyl-
thioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0254]
4-[5-[1-(N'-Cyclopropylmethyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-c-
hlorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahy-
drofuran
[0255]
4-[5-[1-(N'-Allyl-N'-hydroxyureidyl)propyn-3-yl]-4-(p-chlorophenylt-
hioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0256]
4-[5-[1-(N'-Hydroxy-N'-hydroxyethylureidyl)propyn-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0257] Double Bonded Hydroxamates: Both Cis and Trans Isomers at
the Tetrahydrofuran Ring
[0258]
4-[5-[trans-1-(N-Acetyl-N-hydroxyamino)propen-3-yl]-4-(p-bromopheny-
lthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0259]
4-[5-[trans-1-(N-Hydroxy-N-propanoylamino)propen-3-yl]-4-(p-chlorop-
henylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofur-
an
[0260]
4-[5-[trans-1-(N-Butanoyl-N-hydroxyamino)propen-3-yl]-4-(3,4-dichlo-
rophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydro-
furan
[0261]
4-[5-[trans-1-(N-Hydroxy-N-cyclohexanecarbonylamino)propen-3-yl]-4--
(p-fluorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tet-
rahydrofuran
[0262]
4-[5-[trans-1-(N-Hydroxy-N-phenoxybenzoylamino)propen-3-yl]-4-(2,3,-
5,6-tetrafluorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxypheny-
l)-tetrahydrofuran
[0263]
4-[5-[trans-1-(N-Hydroxy-N-methoxybenzoylamino)propen-3-yl]-4-(2-br-
omophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydr-
ofuran
[0264]
4-[5-[trans-1-(N-Hydroxy-N-hydroxybenzoylamino)propen-3-yl]-4-(p-ch-
lorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahyd-
rofuran
[0265] Double Bonded Ureas: Both Cis and Trans Isomers at the
Tetrahydrofuran Ring
[0266]
4-[5-[trans-1-(N'-Hydroxy-N'-methylureidyl)propen-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0267]
4-[5-[trans-1-(N'-Ethyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chlorop-
henylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-tmethoxyphenyl)-tetrahydrofuran
[0268]
4-[5-[trans-1-(N'-Hydroxy-N'-propylureidyl)propen-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trinethoxyphenyl)-tetrahydrofu-
ran
[0269]
4-[5-[trans-1-(N'-n-Butyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chlor-
ophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrof-
uran
[0270]
4-[5-[trans-1-(N'-Hydroxy-N'-i-propylureidyl)propen-3-yl]-4-(p-chlo-
rophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydro-
furan
[0271]
4-[5-[trans-1-(N'-tert-Butyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-ch-
lorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahyd-
rofuran
[0272]
4-[5-[trans-1-(N'-Benzyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chloro-
phenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofu-
ran
[0273]
4-[5-[trans-1-(N'-Cyclopropyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-c-
hlorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahy-
drofuran
[0274]
4-[5-[trans-1-(N'-Allyl-N'-hydroxyureidyl)propen-3-yl]-4-(p-chlorop-
henylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrahydrofur-
an
[0275]
4-[5-[trans-1-(N'-Hydroxy-N'-hydroxyethylureidyl)propen-3-yl]-4-(p--
chlorophenylthioethoxy)-3-methoxyphenyl]-2-(3,4,5-trimethoxyphenyl)-tetrah-
ydrofuran
Formula III
Cis and Trans Isomers of the Following Compounds
[0276]
2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-N-methylaminophenyl)-5-(3-
,4,5-trimethoxyphenyl)-tetrahydrofuran
[0277]
2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-N-ethylaminophenyl)-5-(3,-
4,5-trimethoxyphenyl)-tetrahydrofuran
[0278]
2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-N,N-dipropylaminophenyl)--
5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0279]
2-(3-Methoxy-4-p-bromophenylthioethoxy-5-N,N-dipropylaminophenyl)-5-
-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0280]
2-(3-Methoxy-4-3,4-dichlorophenylthioethoxy-5-N,N-dipropylaminophen-
yl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0281]
2-(3-Methoxy-4-p-fluorophenylthioethoxy-5-N,N-dipropylaminophenyl)--
5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0282]
2-[3-Methoxy-4-(2,3,5,6-tetrafluorophenylthioethoxy)-5-N,N-dipropyl-
aminophenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0283]
2-[3-Methoxy-4-(2-bromophenylthioethoxy)-5-N,N-dipropylaminophenyl]-
-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0284]
2-[3-Methoxy-4-p-chlorophenylthioethoxy-5-(1-pyrrolidinyl)phenyl]-5-
-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0285]
2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-N,N-diethylaminophenyl)-5-
-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0286]
2-[3-Methoxy-4-p-chlorophenylthioethoxy-5-(4-morpholinyl)phenyl]-5--
(3,4,5-trimethoxyphenyl)-tetrahydrofuran
[0287]
2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-N,N-dibutylaminophenyl)-5-
-(3,4,5-trimethoxyphenyl)-tetrahydrofuran
B. Stereochemistry
[0288] The 2,5-diaryl tetrahydrofurans, tetrahydrothiophenes, and
pyrrolidines. 1,3-cyclopentanes, and the 2,4-diaryl
tetrahydrofurans, tetrahydrothiophenes, and pyrrolidines disclosed
herein exhibit a number of stereochemical configurations. Carbon
atoms 2 and 5 (or 2 and 4, in the compounds of Formula II) in the
center ring are chiral, and thus the center ring exists at a
minimum as a diastereomeric pair. Each diastereomer exists as a set
of enantiomers. Therefore, based on the chiral C.sub.2 and C.sub.5
(or C.sub.2 and C.sub.4, in Formula II) atoms alone, the compound
is a mixture of four enantiomers.
[0289] If nonhydrogen substituents are located on carbon atoms 3
and 4 in the center ring, (or carbon atoms 3 and 5, in Formula II
compounds) then the C.sub.3 and C.sub.4 atoms are also chiral, and
can also exist as a diastereomeric pair, that is also a mixture of
four enantiomers.
[0290] The R groups in the active compounds described herein can
likewise include chiral carbons, and thus, optically active
centers.
[0291] It is sometimes found that one or more enantiomers of a
biologically active compound is more active, and perhaps less
toxic, than other enantiomers of the same compound. Such
enantiomerically enriched compounds are often preferred for
pharmaceutical administration to humans. For example, it has been
discovered that trans-2,5-diaryl tetrahydrothiophene and
trans-2,5-diaryl tetrahydrofuran are often more active PAF receptor
antagonists than their cis counterparts.
[0292] One of ordinary skill in the art can easily synthesize and
separate the enantiomers of the disclosed compounds using chiral
reagents and known procedures, and can evaluate the biological
activity of the isolated enantiomer using methods disclosed herein
or otherwise known. Through the use of chiral NMR shift reagents,
polarimetry, or chiral HPLC, the optical enrichment of the compound
can be determined.
[0293] Classical methods of resolution include a variety of
physical and chemical techniques. Often the simplest and most
efficient technique is repeated recrystallization.
Recrystallization can be performed at any stage in the preparation
of the compound, or the final enantiomeric product. If successful,
this simple approach represents a method of choice.
[0294] When recrystallization fails to provide material of
acceptable optical purity, other methods can be evaluated. If the
compound is basic, one can use chiral acids that form
diastereomeric derivatives that may possess significantly different
solubility properties. Nonlimiting examples of chiral acids include
malic acid, mandelic acid, dibenzoyl tartaric acid,
3-bromocamphor-8-sulfonic acid, 10-camphorsulfonic acid, and
di-p-toluoyltartaric acid. Similarly, acylation of a free hydroxyl
group with a chiral acid also results in the formation of
diastereomeric derivatives whose physical properties may differ
sufficiently to permit separation.
[0295] Enantiomerically pure or enriched compounds can be obtained
by passing the racemic mixture through a chromatographic column
that has been designed for chiral separations, including
cyclodextrin bonded columns marketed by Rainin Corporation.
[0296] A variety of chemical reagents and experimental procedures
have been developed in recent years to produce enantiomerically
pure or enriched products. For example, individual 2S, 5S or 2R, 5R
enantiomers of 2,5-diaryl tetrahydrofurans can be prepared by the
method described by Corey et al. (Corey, E. J., et al., Tetrahedron
Letters 29, 2899 (1988)).
[0297] C. Syntheses of Active Compounds
[0298] The 2,5-diaryl tetrahydrofurans and tetrahydrothiophenes
disclosed herein can be prepared in a variety of ways known to
those skilled in the art, including by methods disclosed in or
obvious in view of methods disclosed in U.S. Pat. Nos. 4,539,332,
4,757,084, 4,996,203 and 5,001,123, and European Patent Application
Nos. 90306234.7, 90306235.4, and 89202593.3.
[0299] 1,3-Diaryl cyclopentanes can be prepared using the procedure
of Graham, et al. (1,3-Diaryl Cyclopentanes: A New Class of Potent
PAF Receptor Antagonists. 197.sup.th ACS National Meeting, Dallas,
Tex., Apr. 9-14, 1989, Division of Medicinal Chemistry, poster no.
25 (abstract)), or by other known methods.
[0300] 2,5-Diaryl pyrrolidines can be prepared by methods known to
those skilled in the art including that described by Boekvall, et
al. (J. Org. Chem. 55, 826 (1990)).
[0301] 2,4-Diaryl tetrahydrofurans and tetrahydrothiophenes and
2,4-diaryl pyrrolidines can also be prepared by adaptations of
methods described herein, or by other known methods.
[0302] A general procedure for preparing a hydroxyurea is: 13
[0303] wherein R is a 2,5-diaryl tetrahydrothiophene,
tetrahydrofuran, or pyrrolidine; 1,3-diaryl cyclopentane; or
2,4-diaryl tetrahydrothiophene, tetrahydrofuran or pyrrolidine;
with or without a linking moiety, and R' is a moiety as defined in
detail above.
[0304] General procedures for preparing reverse hydroxyureas are:
14
[0305] A general procedure for preparing a hydroxamic acid is:
15
[0306] A general procedure for preparing a reverse hydroxamic acid
is: 16
[0307] A general procedure for preparing amidohydroxyurea moieties
is: 17
[0308] Oxalkanes and thioalkanes can be prepared as described by
Crawley, et al., J. Med. Chem., 35, 2600-2609 (1992), and
illustrated below, by conversion of the desired moiety into a
Grignard reagent or lithium salt, followed by reaction with the
appropriate cyclic ketone. 18 19 20
[0309] Quinolylmethoxy moieties can be prepared as described by
Musser, et al., J. Med. Chem., 35, 2501-2524 (1992), and references
cited therein, as illustrated below. 21
[0310] A method for the preparation of
trans-2-[5-(N'-methyl-N'-hydroxyure-
idylmethyl)-3-methoxy-4-p-chlorophenylthioethoxyphenyl]-5-(3, 4,
5-trimethoxyphenyl)tetrahydrofuran is described in detail in the
working example below. This example is merely illustrative, and not
intended to limit the scope of the invention.
EXAMPLE 1
Preparation of
trans-2-[5-(N'-methyl-N'-hydroxyureidylmethyl)-3-methoxy-4--
p-chlorophenylthioethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
(29, FIGS. 1a and 1b)
[0311] 3-(N,N-Dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone
(compound 101, FIG. 1). 3,4,5-Trimethoxyacetophenone (50 g, 237.8
mmole), paraformaldehyde (9.75 g, 304.7 mmole), dimethylamine
hydrochloride (26.42 g, 324.0 mmole) and 5 mL conc. HCl were
dissolved in 200 mL absolute ethanol and refluxed for 10 hours.
Additional dimethylamine hydrochloride (13.21 g, 162.0 mmole) and
paraformaldehyde (9.75 g, 304.7 mmole) were added and the solution
returned to reflux. After 54 hours (total reaction time), 80 mL of
10% HCl and 500 mL of water were added and the solution was
extracted with ethyl ether. The acidic aqueous layer was adjusted
to pH 10 with 10% NaOH. The basic solution was extracted with ethyl
acetate, dried over MgSO.sub.4, filtered and evaporated in vacuo to
provide 57.5 g of a yellow oil (92%). .sup.1H NMR (CDCl.sub.3):
2.30 (s, 6H); 2,74 (t, 2H); 3.11 (t, 3H); 3.91 (s, 9H); 7.23 (s,
1H); 7.32 (s, 1H).
[0312]
3-(N,N,N-Trimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone
iodide (compound 102, FIG. 1).
3-(N,N-Dimethylamino)-1-(3,4,5-trimethoxyp- henyl)-1-propanone (57
g, 213.5 mmole) was dissolved in 200 mL of anhydrous diethyl ether.
To this solution was added methyl iodide (57.6 g, 405.7 mmole). A
white precipitate formed immediately, and the reaction mixture was
stirred at room temperature for an additional 2 hours. This product
was isolated by suction filtration (83.8 g, 96%)
[0313] 3,4,5-Trimethoxyphenylvinylketone (compound 103, FIG. 1).
3-(N,N,N-Trimethylamino) -1-(3,4,5-trimethoxyphenyl)-1-propanone
iodide (50 g, 120 mmole) was dissolved in H.sub.2O (500 mL) and
ethyl acetate (500 mL) was added. The mixture was vigorously
stirred at reflux for 3 hours. The reaction mixture was cooled and
the layers were separated. To the aqueous phase was added ethyl
acetate (400 mL). This was brought to reflux for 1.5 hours. The
reaction mixture was cooled and separated. The combined organic
layers were washed with saturated NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to an oil
which was purified by flash column cbromatography using 3:1
hexane/ethyl acetate as solvent (14.7 g, 54%). .sup.1H NMR
(CDCl.sub.3): 3.92 (s, 9H); 5.92 (d, 1H); 6.44 (d, 1H); 7.12 (m,
1H); 7.22 (s, 2H).
[0314] 3-Methoxy-4-hydoxyethoxy-5-iodobenzaldehyde (compound 104,
FIG. 1). 5-Iodovanillin (25 g, 90 mmol) in DMF (100 mL) was added
to potassium carbonate (18.6 g, 135 mmol). The mixture was heated
at 40.degree. C. for 16 hours. The reaction mixture was allowed to
cool to room temperature and quenched with water (500 mL) and
extracted with ethyl acetate. The organic layer was washed with
water and saturated NaCl solution, and dried over MgSO.sub.4,
filtered and evaporated in vacuo to an oil, and then purified by
column chromatography (silica, 2:1 hexane/ethyl acetate), to
provide the product (16.6 g, 57%). .sup.1H NMR (CDCl.sub.3): 2.70
(t, 1H); 3.92 (t, 2H); 3.92 (s, 3H); 3.94 (s, 3H); 4.29 (t, 2H);
7.44(s,1H); 7.87 (s, 1H); 9.85 (s, 1H).
[0315]
1-(3-Methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxypheny-
l)-1,4-butanedione (compound 105, FIG. 1).
3,4,5-Trimethoxyphenylvinylketo- ne (4.8 g, 21.6 mmol),
3-methoxy-4-hydroxyethoxy-5-iodobenzaldehyde (5.7 g, 17.8 mmol),
and 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (1.9 g,
7.0 mmol) were stirred in triethylamine (20 mL) at 60.degree. C.
for 16 hours. The reaction mixture was then acidified with 10% HCl,
and extracted with dichloromethane. The organic layer was dried
over MgSO.sub.4, filtered and evaporated in vacuo. The product was
purified in column chromatography (silica. 1:1 hexane/ethyl
acetate) as a solid (9.7 g, 51%). .sup.1H NMR (CDCl.sub.3): 3.41
(m, 4H); 3.90 (m, 2H); 3.92 (s, 3H); 3.93 (s, 9H); 4.26 (t, 2H);
7.29 (s, 2H); 7.57 (d, 1H); 8.08 (d, 1H).
[0316]
1-(3-Methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxypheny-
l) -1,4-butanediol (compound 106, FIG. 1).
1-(3-Methoxy-4-hydroxyethoxy-5--
iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione (11.6 g,
21.3 mmol), was added to 120 mL tetrahydrofuran and 240 mL
methanol. To this solution was added dropwise sodium borohydride
(1.45 g, 38.4 mmol), in 60 mL water. The reaction mixture was
stirred at room temperature for 2.5 hours, and then cooled,
quenched with water, and the aqueous layer extracted with ethyl
acetate. The organic layer was dried over MgSO.sub.4, filtered and
evaporated in vacuo to provide the product (11.8 g, 98.8%). .sup.1H
NMR (CDCl.sub.3): 1.84 (m, 4H); 3.84 (m, 2H); 3.86 (s, 3H); 3.87
(s, 9H); 4.15 (t, 2H); 4.68 (m, 2H); 6.57 (s, 2H); 6.91 (s, 1H);
7.32 (s, 1H).
[0317]
trans-2-(3-Methoxy-4-hydroxyethoxy-5-iodophenyl)-5-(3,4,5-trimethox-
yphenyl)tetrahydrofuran (compound 107, FIG. 1). To
1-(3-methoxy-4-hydroxye-
thoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol (11.8
g 21.5 mmol) in chloroform (100 mL) at 0.degree. C. was added
dropwise trifluoroacetic acid (9.82 g, 86.1 mmol) in chloroform
(100 mL) over 30 minutes. The solution was stirred at 0.degree. C.
for 2 hours and then at room temperature for 1 hour. The reaction
mixture was quenched with 1N NaOH and chloroform (100 mL) was
added. The organic layer was washed with 1N NaOH solution, water
and saturated NaCl solution, and then dried over MgSO.sub.4,
filtered and evaporated in vacuo to an oil which was a cis and
trans mixture. The trans isomer was isolated by column
chromatography (silica, 1:1 hexane/ethyl acetate) (4.7 g, 41.4%) as
the faster eluting isomer. .sup.1H NMR (CDCl.sub.3): 1.99 (m, 2H);
2.47 (m, 2H); 3.83 (t, 2H); 3.84 (s, 3H); 3.87 (s, 3H); 3.89 (s,
6H); 4.16 (t, 2H); 5.18 (m, 2H); 6.62 (s, 2H); 6.96 (d, 1H); 7.39
(d, 1H).
[0318]
trans-2-(3-Methoxy-4-methylsulfoxyethoxy-5-iodophenyl)-5-(3,4,5-tri-
methoxyphenyl)tetrahydrofuran (compound 108, FIG. 1). To the
solution of
trans-2-(3-methoxy-4hydroxyethoxy-5-iodophenyl)-5-(3,4,5-trimethoxyphenyl-
) tetrahydrofuran (4.7 g, 8.87 mmol) in dichloromethane (50 mL) at
0.degree. C. was added methylsulfonyl chloride (3.05 g, 26.6 mmole)
and triethylamine (2.69 g, 26.60 mmol). The reaction mixture was
stirred at 0.degree. C. for 2 hours and room temperature overnight.
The solvent was evaporated in vacuo and the residue purified by
column chromatography (silica, 1:1 hexanelethyl acetate) (4.17 g,
77.3%). .sup.1H NMR (CDCl.sub.3): 1.98 (m, 2H); 2.45 (m, 2H); 3.15
(s, 3H); 3.84 (s, 3H); 3.88 (s, 9H); 4.26 (t, 2H); 4.61 (t, 2H);
5.17 (m, 2H); 6.62 (s, 2H); 6.96 (d, 1H); 7.38 (d, 1H).
[0319]
trans-2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-iodophenyl)-5-(3,4,-
5-trimethoxyphenyl)tetrahydrofuran (compound 109, FIG. 1),
trans-2-(3-Methoxy-4-methylsulfoxyethoxy-5-iodophenyl)-5-(3,4,5-trimethox-
yphenyl) tetrahydrofuran (2.5 g, 4.11 mmol) was dissolved in 50 mL
ethanol. To this solution was added 4-chlorothiophenol (1.19 g,
8.22 mmol) and triethylamine (0.831 g, 8.22 mmol). The reaction
mixture was refluxed for 16 hours and then the solvent was removed
in vacuo. The residue was purified by column chromatography
(silica, 3:1 hexanelethyl acetate) (2.35 g, 87%). .sup.1H NMR
(CDCl.sub.3): 1.97 (m, 2H); 2.45 (m, 2H); 3.35 (t, 2H); 3.82 (s,
3H); 3.84 (s, 3H); 3.88 (s, 6H); 4.11 (t, 2H); 5.17 (m, 2H); 6.61
(s, 2H); 6.92 (s, 1H); 7.26 (d, 2H); 7.33 (d, 2H); 7.35 (s,
1H).
[0320]
trans-2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-cyanophenyl)-5-(3,4-
,5-trimethoxyphenyl)tetrahydrofuran (compound 110, FIG. 1),
trans-2-(3-Methoxy-4p-chlorophenylthioethoxy-5-iodophenyl)-5-(3,4,5-trime-
thoxyphenyl) tetrahydrofuran (2.35 g, 3.58 mmole) and CuCN (0.358
g, 4.30 mmole) in DMF (20 mL) were heated at 140.degree. C. for 16
hours. The reaction mixture was cooled and quenched with water and
extracted with ethyl acetate. The organic layer was washed with
water and saturated NaCl solution, dried over MgSO.sub.4, filtered
and evaporated in vacuo to oil which was purified by column
chromatography (silica, 2:1 hexanelethyl acetate) (1.79 g, 90.0%).
.sup.1H NMR (CDCl.sub.3): 1.99 (m, 2H); 2.47 (m, 2H); 3.32 (t, 2H);
3.85 (s, 6H), 3.89 (s, 6H); 4.27 (t, 2H); 5.17 (m, 2H); 6.61 (s,
2H); 7.16 (s, 2H); 7.28 (d, 2H); 7.32 (d, 2H).
[0321] trans
2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-aminomethylphenyl)--
5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (compound 111, FIG. 1).
To
trans-2-(3-methoxy-4-p-chlorophenylthioethoxy-5-cyanophenyl)-5-(3,4,5-tri-
methoxyphenyl tetrahydrofuran (300 mg, 0.5405 mmol) in THF (10 mL)
was added sodium borohydride (36.8 mg, 0.9729 mmol) and boron
trifluoride etherate (191.8 mg. 1.3512 mmol) dropwise. The reaction
mixture was refluxed for 1 hour, cooled, and then treated with a
few drops of 10% HCl. The reaction mixture was poured into 10%
K.sub.2CO.sub.3 and extracted with ethyl acetate. The organic layer
was washed with water and saturated NaCl solution, dried over
MgSO.sub.4, filtered and evaporated in vacuo to an oil which was
purified by column chromatography (silica, 93:7
CH.sub.2Cl.sub.2/MeOH) 64 mg, 21.2%). .sup.1H NMR (CDCl.sub.3):
1.99 (m, 2H); 2.46 (m, 2H); 3.28 (t, 2H); 3.84 (s, 6H); 3.88 (s,
6H); 4.26 (t, 2H); 5.19 (m, 2H); 6.71 (s, 2H); 6.90 (s, 2H); 7.25
(d, 2H); 7.32 (d, 2H).
[0322]
trans-2-[5-(N'-Methyl-N'-hydroxyureidylmethyl)-3-methoxy-4-p-chloro-
phenylthioethoxypenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
(29, FIG. 1),
trans-2-(3-methoxy-4-p-chlorophenylthioethoxy-5-aminomethylphenyl)
-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (54 mg, 0.0966 mmol)
was dissolved in 4 mL dry dichloromethane. To this solution was
added triphosgene (9.46 mg, 0.0319 mmol) and triethylamine (9.77
mg, 0.0966 mmol). The reaction mixture was refluxed for 2 hours and
then cooled to room temperature. To this solution was then added
triethylamine (35.2 mg, 0.3478 mmol) and methylhydroxyamine
hydrochloride (24.2 mg. 0.2898 mmol). The reaction mixture was
stirred at room temperature overnight, and then quenched with water
and extracted with dichloromethane. The organic layer was washed
with water and saturated NaCl solution, dried over MgSO.sub.4,
filtered and evaporated in vacuo. The product was purified by
column chromatography (silica, ethyl acetate) (49 mg, 80.1%).
.sup.1H NMR (CDCl.sub.3): 1.97 (m, 2H); 2.43 (m, 2H); 3.08 (s, 3H);
3.27 (t, 2H); 3.82 (s, 3H); 3.83 (s, 3H); 3.87 (s, 6H); 4.15 (t,
2H); 4.39 (d, 2H); 5.17 (m, 2H); 6.41 (t, 1H); 6.51 (s, 2H); 6.78
(broad s, 1H); 6.90 (s, 2H); 7.24 (d, 2H); 7.31 (d, 2H).
II. Pharmaceutical Compositions
[0323] Humans, equine, canine, bovine and other animals, and in
particular, mammals, suffering from inflammatory diseases, and in
particular, disorders mediated by PAF or products of 5-lipoxygenase
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, or topically, in
liquid, cream, gel or solid form.
[0324] 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 undesired toxicological effects. Nonlimiting examples of
such salts are (a) 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 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; (b) base addition salts formed with metal
cations such as zinc, calcium, bismuth, barium, magnesium,
aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and
the like, or with a cation formed from ammonia,
N,N-dibenzylethylene-diamine, D-glucosamine, tetraethylammonium, or
ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc
tannate salt or the like. The compounds can also be administered as
pharmaceutically acceptable quaternary salts known by those skilled
in the art, which specifically include the quaternary ammonium salt
of the formula --NR-Z--, wherein R is alkyl or benzyl, and Z is a
counterion, including chloride, bromide, iodide, --O-alkyl,
toluenesulfonate, methylsulfonate, sulfonate, phosphate, or
carboxylate (such as benzoate, succinate, acetate, glycolate,
maleate, malate, citrate, tartrate, ascorbate, benzoate,
cinnamoate, mandeloate, benzyloate, and diphenylacetate.
[0325] 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.
[0326] 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 25-250 mg is usually convenient.
[0327] The active ingredient should be administered to achieve peak
plasma concentrations of the active compound of about 0.01-30 mM,
preferably about 0.1-10 mM. 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.
[0328] 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.
[0329] 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.
[0330] 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 Sterotes; 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.
[0331] 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.
[0332] 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 antibiotics,
antifungals, other antiinflammatories, or antiviral compounds.
[0333] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, 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.
[0334] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[0335] 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 Scios Nova
(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
phosphatidyl choline, arachadoyl phosphatidyl choline, 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.
III. Biological Activity
[0336] A wide variety of biological assays have been used to
evaluate the ability of a compound to act as a PAF receptor
antagonist, including the ability of the compound to bind to PAF
receptors, and the effect of the compound on various PAF mediated
pathways. Any of these known assays can be used to evaluate the
ability of the compounds disclosed herein to act as PAF receptor
antagonists.
[0337] For example, PAF is known to induce hemoconcentration and
increased permeability of microcirculation leading to a decrease in
plasma volume. PAF mediated acute circulatory collapse can be used
as the basis of an assay to evaluate the ability of a compound to
act as a PAF antagonist, by analyzing the effect of the compound on
PAF induced decreased plasma volume in an animal model such as
mouse. Endotoxemia causes the release of chemical mediators
including eicosanoids, PAF, and tumor necrosis factor (TNF) that
stimulate a variety of physiologic responses including fever,
hypotension, leukocytosis, and disturbances in glucose and lipid
metabolism. Endotoxemia can result in severe shock and death.
Endotoxin-induced mouse mortality is a useful animal model to
evaluate the pharmacological effect of compounds on endotoxic
shock.
[0338] Two other common assays used to evaluate the ability of a
compound to act as a PAF receptor antagonist are platelet
aggregation in vitro and hypotension in rats (Shen, et al., "The
Chemical and Biological Properties of PAF Agonists, Antagonists,
and Biosynthetic Inhibitors", Platelet-Activating Factor and
Related Lipid Mediators, F. Snyder. Ed. Plenum Press, New York,
N.Y. 153 (1987)).
[0339] A wide variety of biological assays have also been used to
evaluate the ability of a compound to inhibit the enzyme
5-lipoxygenase. For example, a cytosol 5-lipoxygenase of rat
basophilic leukemia ceuls (RBL) has been widely utilized in studies
on leukotriene biosynthesis. Compounds that inhibit 5-lipoxygenase
decrease the levels of leukotrienes. Another biological assay used
to evaluate the ability of a compound to inhibit the enzyme
5-lipoxygenase is based on the classic pharmacological model of
inflammation induced by the topical application of arachidonic acid
to the mouse ear. On application, arachidonic acid is converted by
5-lipoxygenase to various leukotrienes (and other mediators), which
induce changes in blood flow, erythema, and increase vasodilation
and vasopermeability. The resulting edema is measured by comparing
the thickness of the treated ear to a control ear. Agents that
inhibit 5-lipoxygenase reduce the edematous response, by lowering
the amounts of biochemical mediators formed from arachidonic
acid.
EXAMPLE 2
Ability of Compound to Bind to PAF Receptors
[0340] a) Preparation of Human Platelet Membranes
[0341] Human platelet membranes were prepared from platelet
concentrates obtained from the American Red Cross Blood Services
(Dedham, Mass.). After several washes with platelet wash solution
(150 mM NaCl, 10 mM Tris, and 2 mM EDTA, pH 7.5), the platelet
pellets were resuspended in 5 mM MgCl. 10 mM Tris, and 2 mM EDTA at
pH 7.0. The cells were then quickly frozen with liquid nitrogen and
thawed slowly at room temperature. The freezing and thawing
procedure was repeated at least three times. For further
fractionation of membrane fragments, the lysed membrane suspension
was layered over the top of a discontinuous sucrose density
gradient of 0.25, 1.03, and 1.5 M sucrose prepared in 10 mM
MgCl.sub.2, 10 mM Tris and 2 mM EDTA, pH 7.0, and centrifuged at
63,500.times.g for 2 hr. The membrane fractions banding between
0.25 and 1.03 M (membrane A) and between 1.03 and 1.5 M (membrane
B) were collected separately. The protein concentration of the
membrane preparations was determined by Lowry's method with bovine
serum albumin (BSA) as the standard. The membranes were then
separated into smaller fractions (4 ml each) and stored at
-80.degree. C. and thawed before use.
[0342] b) [.sup.3H]PAF Binding inhibition
[0343] The ability of [.sup.3H]PAF to bind to specific receptors on
human platelet membranes was evaluated at optimal conditions at pH
7.0 and in the presence of 10 mM MgCl.sub.2. Membrane protein (100
.mu.g) was added to a final 0.5 ml solution containing 0.15 pmol
(0.3 nM concentration) of [.sup.3H]PAF and a known amount of
unlabeled PAF or PAF receptor antagonist in 10 mM MgCl.sub.2, 10 mM
Tris and 0.25% BSA at pH 7.0. After incubation for four hours at
0.degree. C., the bound and unbound [3H]PAF were separated through
a Whatman GF/C glass fiber filter under vacuum. No degradation of
filter bound [.sup.3H]PAF has been detected under this assay
condition. The nonspecific binding was defined as the total binding
in the presence of excess unlabeled PAF (1 mM) where no further
displacement was found with higher concentrations of either
unlabeled PAF or PAF analogs or PAF receptor antagonists. The
specific binding was defined as the difference between total
binding and nonspecific binding.
[0344] To determine the relative potency of tested compounds,
[3H]PAF binding in the presence of inhibitors was normalized in
terms of percent inhibition by assigning the total binding in the
absence of inhibitors as 0% inhibition and the total binding in the
presence of 1 mM unlabeled PAF as 100%. The percent inhibition by
the compound can be calculated by the formula expressed below: 1 %
inhibition = [ ( Total binding - total binding in the presence of
compound ) / nonspecific binding ] .times. 100 %
[0345] The IC.sub.50 was calculated as the concentration of the
inhibitor necessary to obtain 50% inhibition of the specific
[.sup.3H]PAF binding and was calculated by a nonlinear regression
computer software program, GraphPad Inplot, version 3.0 (GraphPad
software, San Diego, Calif.). Tables 1 and 2 provide IC.sub.50
values for a number of the disclosed compounds.
1TABLE 1 22 IC.sub.50(nM) Compounds A B PAF 5-LO 1 S--Ph-p-Br*
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 20.9 18.7 2 SO.sub.2--Ph-p-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 38.3 3 S--Ph-2-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 23.0 33.0 4 SO.sub.2--Ph-2-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 25.0 161.0 5 S--Ph-3-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 16.0 43.3 6 S--Ph-p-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 45.0 63.8 7 S--Ph-2,3,5,6-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 2.2 118.4 8 SO.sub.2--Ph-2,3,5,6-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 285.3 520.2 9 O--Ph-2,3,5,6-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 55.3 132.8 10 S--Ph-p-Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 10.0 58.5 11 S--Ph-3,4-Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 45.0 17.4 12 S--Ph-p-OH
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 5.53 180.0 13 S--Ph-p-OCH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 39.2 71.2 14 S--Ph-p-CN
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 62.6 62.3 15 SCH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 13.5 190.0 16 OCH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 195.2 17 23
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 281.0 87.0 18 24
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 390.6 19 25 CH.sub.3 321.2 719.0
20 26 CH.sub.2Ph 622.7 900.9 21 27 CH.sub.2CH.sub.2CH.sub.2CH.sub.3
321.8 366.3 22 28 CH.sub.2CH.sub.2CH.sub.2CH.sub.3 16.3 479.0 23 29
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 197.4 24 30 Ph-p-Cl 84.2 25 31
Ph-p-Cl 6285 670.0 26 CH.sub.3 Ph-p-Cl 217.6 533.0 27 S--Ph-p-OH
Ph-p-Cl 26.9 3000 28 SCH.sub.3 Ph-p-Cl 317.7 3000 *Ph = phenyl
[0346]
2TABLE 2 32 IC.sub.50(nM) Compounds A B PAF 5-LO 29 S--Ph-p-Cl
CH.sub.2NHCON(OH)CH.sub.3 7.60 22.2 30 S--Ph-p-Cl
CH.sub.2N(CH.sub.2CH.sub.2CH.sub.3)CON(OH)CH.sub.3 7.40 31
S--Ph-p-Cl CH.sub.2N(OH)CONH.sub.2 33.2 34.2 32 S--Ph-p-Cl
CH.sub.2N(OH)CON 06 185.0 33 S--Ph-p-Cl NHCOCH.sub.2N(OH) 318.0 34
S--Ph-p-Cl NHCOCH.sub.2N(OH)CONHCH.sub.3 3318.8 35 O--Ph-p-F
.ident.--CH.sub.2N(OH)CONH.sub.2 73.9 828.2 36 S--Ph-p-Cl
.ident.--CH.sub.2N(OH)CONH.sub.2 11.3
EXAMPLE 3
Effect of Compound on PAF-induced Hemoconcentration
[0347] a) Animals
[0348] Female CD-1 mice, weighing 16-20 grams, were obtained from
Charles River Laboratory (Wilmington, Mass.). Tap water and rodent
laboratory chow (5001, Purina Mills, St. Louis, Mo.) were provided
ad libitum. The mice were housed for an average of four days prior
to use.
[0349] b) Hematocrit Measurement
[0350] PAF (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine,
Sigma Chemical Co.) was dissolved in 0.25% bovine serum albumin
(BSA) in 0.9% NaCl solution. Except for dose-response studies, 10
.mu.g (10 ml/kg) of PAF solution was injected into the tail vein.
All test compounds were dissolved in 0.5 DMSO saline solution and
intravenously injected at 3 mg/kg body weight 15 minutes prior to
PAF challenge. Thirty to fifty .mu.L blood was collected by cutting
the tail end into a heparinized micro-hematocrit tube (O.D. 1.50
mm) 15 minutes after PAF administration. Table 2 provides the mouse
hematocrit response to varying concentration of PAF at 15 minutes
after injection of PAF. Tables 3 and 4 provide the effect of
various test compounds on PAF-induced mouse hemoconcentration; the
reference compound MK287 is
trans-2-(3,4,5-trimethoxy)-5-(3-methoxy-4-
-oxyallyl-(2-hydroxyethylsulfonyl))-tetrahydrofuran. (Sahoo, et
al., Bioorganic Medicinal Chem. Letters, (1991), 1, 327.)
EXAMPLE 4
Effect of 2,5-Diaryl Tetrahydrothiophenes and Tetrahydrofurans on
Arachidonic Acid-induced Mouse Ear Edema
[0351] a) Animals
[0352] The animals were obtained and treated as in Example 3
above.
[0353] b) Edema Measurement
[0354] Arachidonic acid was applied to both ears of mice in 0.025
ml of freshly prepared vehicle (acetone:pyridine:water) (97:2:1
v/v/v) and dried under a Sun-Lite Hitensity bulb. Except for
dose-response studies, 0.5 mg of arachidonic acid was used for all
applications. All test compounds were dissolved in 0.5% DMSO saline
solution and intravenously injected at 3 mg/kg body weight 15
minutes prior to arachidonic acid treatment. Animals were
sacrificed by cervical dislocation at 1 hour after topical
application of arachidonic acid. A 7 mm-diameter disc of tissue was
removed from each ear by means of a metal punch. Edema was measured
by the average wet weight of the both ear tissues.
[0355] Tables 3 and 4 provides the effect of various test compounds
on arachidonic acid induced mouse ear edema.
3TABLE 3 33 InH (%)* Compounds A B PAF-Htc AA-Ed 1 S--Ph-p-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 -10.5 -2.7 2 SO.sub.2--Ph-p-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 29.3 34.5 3 S--Ph-2-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 34.2 26.3 4 SO.sub.2--Ph-2-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 60.4 -9.1 5 S--Ph-3-Br
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 28.2 40.2 6 S--Ph-p-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 33.6 7 S--Ph-2,3,5,6-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 58.8 30.4 8 SO.sub.2--Ph-2,3,5,6-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 50.4 11.9 9 O--Ph-2,3,5,6-F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 59.1 29.2 10 S--Ph-p-Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 25.3 39.2 11 S--Ph-3,4-Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 26.1 26.3 12 S--Ph-p-OH
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 33.5 49.9 13 S--Ph-p-OCH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 23.6 2.7 14 S--Ph-p-CN
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 -12.4 46.5 15 SCH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 11.1 41.1 16 OCH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 11.2 17 34
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 26.1 57.0 19 35 CH.sub.3 49.6 47.8
20 36 CH.sub.2Ph 63.1 49.9 21 37 CH.sub.2CH.sub.2CH.sub.2CH.sub.3
70.4 57.0 26 CH.sub.3 Ph-p-Cl 23.7 *All test compounds were given
intravenously at 3 mg/kg 15 minutes before PAF (10 ug/kg,
intravenously) or AA (0.5 mg/ear) in mice.
[0356]
4TABLE 4 38 InH (%)* Compounds A B PAF-Htc AA-Ed 29 S--Ph-p-Cl
CH.sub.2NHCON(OH)CH.sub.3 55.7 45.6 31 S--Ph-p-Cl
CH.sub.2N(OH)CONH.sub.2 57.9 23.6 32 S--Ph-p-Cl
CH.sub.2N(OH)CONHCH.sub.3 41.1 10.3 33 S--Ph-p-Cl
NHCOCH.sub.2N(OH)CONH.sub.2 2.1 51.1 34 S--Ph-p-Cl
NHCOCH.sub.2N(OH)CONHCH.sub.3 -9.8 31.0 35 O--Ph-p-F
.ident.--CH.sub.2N(OH)CONH.sub.2 99.5 24.5 *All test compounds were
given intravenously at 3 mg/kg 15 minutes before PAF (10 ug/kg,
intravenously) or AA (0.5 mg/ear) in mice. Ph = phenyl
EXAMPLE 5
Effect of 2,5-Diaryl Tetrahydrothiophenes and Tetrahydrofurans on
Endotoxin-induced Mouse Mortality
[0357] a) Animals
[0358] The mice are obtained and treated as in Example 3 above.
[0359] b) Mortality Measurement
[0360] Endotoxin (E. coli serotype 0127:B8, lipopolysaccharide,
Sigma Chemical Co. (St. Louis, Mo.) are freshly dissolved in 0.9%
NaCl solution. Except for dose-response studies, endotoxin at 50
mg/kg is injected into the tail vein. All test compounds are
dissolved in 0.5% DMSO saline solution and intravenously injected
at 3 mg/kg body weight 15 minutes prior to PAF challenge. Death
occurs typically within 12-36 hours. Mortality is recorded 48 hours
after endotoxin challenge, as death rarely occurs after 48
hours.
EXAMPLE 6
Effect of Compounds on Cytosol 5-Lipoxygenase of Rat Basophile
Leukemia Cells
[0361] a) Enzyme Preparation
[0362] Washed rat RBL cells (4.times.108) are suspended in 20 ml of
50 M potassium phosphate buffer at pH 7.4 containing 10% ethylene
glycol/1 mM EDTA (Buffer A). The cell suspension is sonicated at 20
KHz for 30 seconds, and the sonicate is centrifuged at
10.000.times.g for 10 minutes, followed by further centrifugation
at 105,000.times.g for 1 hr. The supernatant solution (cytosol
fraction) containing 5-lipoxygenase is stored at -70.degree. C.
Protein concentration is determined according to the procedure of
Bradford (Bradford Dye Reagent) with bovine serum albumin as a
standard.
[0363] b) Enzyme Assay
[0364] For routine assay of 5-LO the mixture contains 50 mM
potassium phosphate buffer at pH 7.4, 2 mM CaCl.sub.2. 2 mM ATP, 25
M arachidonic acid (0.1 Ci) and enzyme (50-100 mg of protein) in a
final volume of 200 L. The reaction is carried out at 24.degree. C.
for 3 minutes. The mixture is extracted with 0.2 ml of an ice-cold
mixture of ethyl ether:methanol: 0.2 M citric acid (30:4:1). The
extract is subjected to thin-layer chromatography at -10.degree. C.
in a solvent system of petroleum ether:ethyl ether:acetic acid
(15:85:0.1) The silica gel zones corresponding to authentic
arachidonic acid and its metabolites are scraped into scintillation
vials for counting. The enzyme activity is expressed in terms of
the amount of arachidonic acid oxygenated for 3 minutes.
[0365] Modifications and variations of the present invention
relating to compounds that reduce the formation of oxygen radicals
during an inflammatory or immune response will be obvious to those
skilled in the art from the foregoing detailed description of the
invention. Such modifications and variations are intended to come
within the scope of the appended claims.
* * * * *