U.S. patent application number 10/292771 was filed with the patent office on 2003-10-02 for benoxazinones/benzothiazinones as serine protease inhibitors.
Invention is credited to Berryman, Kent Alan, Downing, Dennis Michael, Dudley, Danette Andrea, Edmunds, Jeremy John, Narasimhan, Lakshmi Sourirajan, Rapundalo, Stephen Taras.
Application Number | 20030187256 10/292771 |
Document ID | / |
Family ID | 22155527 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030187256 |
Kind Code |
A1 |
Berryman, Kent Alan ; et
al. |
October 2, 2003 |
Benoxazinones/benzothiazinones as serine protease inhibitors
Abstract
This invention discloses benzoxazinone and benzothiazinone
compounds which display inhibitory effects on serine proteases such
as factor Xa, thrombin, and/or factor VIIa. The invention also
discloses pharmaceutically acceptable salts of the compounds,
pharmaceutically acceptable compositions comprising the compounds
or their salts, and methods of using them as therapeutic agents for
treating or preventing disease states in mammals characterized by
abnormal thrombosis.
Inventors: |
Berryman, Kent Alan;
(Gunnison, CO) ; Downing, Dennis Michael; (Ann
Arbor, MI) ; Dudley, Danette Andrea; (Ann Arbor,
MI) ; Edmunds, Jeremy John; (Ypsilanti, MI) ;
Narasimhan, Lakshmi Sourirajan; (Canton, MI) ;
Rapundalo, Stephen Taras; (Ann Arbor, MI) |
Correspondence
Address: |
Cynthia M. Bott
Warner-Lambert Company
2800 Plymouth Road
Ann Arbor
MI
48105
US
|
Family ID: |
22155527 |
Appl. No.: |
10/292771 |
Filed: |
November 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10292771 |
Nov 12, 2002 |
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09622265 |
Aug 14, 2000 |
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6509335 |
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09622265 |
Aug 14, 2000 |
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PCT/US98/26708 |
Dec 15, 1998 |
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60080142 |
Mar 31, 1998 |
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Current U.S.
Class: |
544/51 ; 540/490;
544/105 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
43/00 20180101; A61P 9/00 20180101; C07D 279/16 20130101; C07D
265/36 20130101 |
Class at
Publication: |
544/51 ; 544/105;
540/490; 514/230.5; 514/211.06; 514/224.2 |
International
Class: |
C07D 417/02; C07D
413/02; A61K 031/553; A61K 031/554; A61K 031/542; A61K 031/538 |
Claims
What is claimed is:
1. A compound according to Formula 1 77or stereoisomers or
pharmaceutically acceptable salt forms or prodrugs thereof,
wherein: A is selected from O, S, S(.dbd.O), S(.dbd.O)(.dbd.O),
OCH.sub.2, CH.sub.2O, SCH.sub.2, S(.dbd.O)CH.sub.2,
S(.dbd.O)(.dbd.O)CH.sub.2, CH.sub.2S, CH.sub.2S(.dbd.O),
CH.sub.2S(.dbd.O)(.dbd.O); B is selected from cycloalkyl,
heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl,
heterocycle, heterocycloalkyl, each optionally substituted with
R.sub.1 and R.sub.2; D is selected from H, alkyl, cycloalkyl,
heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl,
heterocycle, heterocycloalkyl, each optionally substituted with
R.sub.1 and R.sub.2; E is absent or selected from O, S, NH; F is
selected from N, NCH.sub.2, CH.sub.2N; G is absent or selected from
alkyl, alkyl interrupted by one or more heteroatoms, cycloalkyl,
cycloalkyl interrupted by one or more heteroatoms; J is absent or
selected from aryl or heterocycle each optionally substituted with
R.sub.1 and R.sub.2; K is absent or selected from an alkyl, alkyl
interrupted by one or more heteroatoms, cycloalkyl interrupted by
one or more heteroatoms, cycloalkylalkyl interrupted by one or more
heteroatoms, each optionally substituted with R.sub.1 and R.sub.2;
L is selected from H, chlorine, fluorine, bromine, iodine, OH,
O(alkyl), amine, alkyl, fluoroalkyl, amide, NO.sub.2, SH,
S(O).sub.n(alkyl), SO.sub.3H, SO.sub.3alkyl, aldehyde, ketone,
acid, ester, urea, Oalkylamide, Oalkylester, Oalkylacid,
Nalkylacid, alkylamine, alkylamide, alkylketone, alkylacid,
alkylester, alkylurea, Nalkylamide, Nalkylester, NC(.dbd.O)alkyl,
NC(.dbd.O)aryl, NC(.dbd.O)cycloalkyl, NC(.dbd.O)cycloalkylalkyl,
NC(.dbd.O) alkylaryl, R.sub.1. R.sub.2, nitrile; R.sub.1 is
selected from H, amine, alkylamine, amide, C(.dbd.NH)NHNH.sub.2,
alkylC(.dbd.NH)NHNH.sub.2, C(.dbd.NH)NHOH, alkylC(.dbd.NH)NHOH,
NHC(.dbd.NH)NH.sub.2, alkylNHC(.dbd.NH)NH.sub.2, C(.dbd.S)NH.sub.2,
alkylC(.dbd.S)NH.sub.2, C(.dbd.NH)alkyl, alkylC(.dbd.NH)alkyl,
C(.dbd.NR.sub.3)N(R.sub.4)(R.sub.5),
alkylC(.dbd.NR.sub.3)N(R.sub.4)(R.su- b.5); R.sub.2 is selected
from H, chlorine, fluorine, bromine, iodine, OH, Oalkyl, amine,
alkylaldehyde, alkylamide, alkylester, alkylketone, alkylacid,
Oalkylamide, Oalkylacid, Oalkylester, aninealkylacid,
aminealkylamide, aminealkylester, NC(.dbd.O)alkyl, NC(.dbd.O)aryl,
NC(.dbd.O)cycloalkyl, NC(.dbd.O)alkylaryl, alkylamine, amide,
aldehyde, ester, ketone, NO.sub.2, SH, S(O).sub.n(C.sub.1-10alkyl),
SO.sub.3H, SO.sub.3alkyl, CHO, acid, alkyl, C(.dbd.NH)alkyl,
C(.dbd.NH)NHNH.sub.2, alkylC(.dbd.NH)NHNH.sub.2, C(.dbd.NH)NHOH,
alkylC(.dbd.NH)NHOH, NHC(.dbd.NH)NH.sub.2,
alkylNHC(.dbd.NH)NH.sub.2, C(.dbd.S)NH.sub.2,
alkylC(.dbd.S)NH.sub.2, alkylC(.dbd.NH)alkyl,
C(.dbd.NR.sub.3)N(R.sub.4)(- R.sub.5),
alkylC(.dbd.NR.sub.3)N(R.sub.4)(R.sub.5); R.sub.3, R.sub.4, and
R.sub.5 are a hydrogen atom, alkyl group having 1 to 4 carbon atoms
optionally interrupted by a heteroatom, or R.sub.4 and R.sub.5 are
bonded to form --(CH.sub.2).sub.p--W--(CH.sub.2).sub.q--, wherein p
and q are an integer of 2 or 3, a certain position on the methylene
chain is unsubstituted or substituted by an alkyl group having 1 to
4 carbon atoms, W is a direct bond, --CH.sub.2--, --O--,
--N(R.sub.6)--, or --S(O).sub.r-- wherein R.sub.6 is H or alkyl,
and r is 0 or 1 or 2; n is selected from 0, 1,2; X.sub.1 is C or N;
X.sub.2 is C or N; X.sub.3 is C or N; and X.sub.4 is C or N.
2. A compound according to claim 1 wherein the compound is
according to Formula 2 78or stereoisomers or pharmaceutically
acceptable salts, esters, amides or prodrugs thereof, wherein A, B,
E, G, J, K, and L are defined as above.
3. A compound according to claim 1 wherein the compound is
according to Formula 3 79or stereoisomers or pharmaceutically
acceptable salts, esters, amides or prodrugs thereof, wherein B, G,
J, K, and L are defined as above.
4. A compound according to claim 1 wherein the compound is
according to Formula 4 80or stereoisomers or pharmaceutically
acceptable salts, esters, amides or prodrugs thereof, wherein B, G,
J, K, and L are defined as above.
5. A compound according to claim 1 wherein the compound is
according to Formula 5 81or stereoisomers or pharmaceutically
acceptable salts, esters, amides or prodrugs thereof, wherein
R.sub.1, R.sub.2, G, J, K, and L are as defined above.
6. A compound according to claim 1 wherein the compound is
according to Formula 6 82or stereoisomers or pharmaceutically
acceptable salts, esters, amides or prodrugs thereof, wherein
R.sub.1, R.sub.2, G, J, K, and L are as defined above.
7. A compound according to Formulas 7 and 8 83or stereoisomers or
pharmaceutically acceptable salt forms or prodrugs thereof, wherein
R.sub.7 is (3-amidino)phenyl, (3-hydroxy)phenyl,
[3-hydroxylamino(imino)m- ethyl]-phenyl,
[3-hydrazino(imino)methyl]-phenyl, (3-aminomethyl)phenyl,
(3-amino)phenyl, (3-methylamino)phenyl, (3-dimethylamino)phenyl,
(5-amidino-2-hydroxy)phenyl, (5-amidino-2-methoxy)phenyl,
(1-amidino)piperid-3-yl, (1-amidino)pyrrolid-3-yl,
(5-amidino)thien-2-yl, (5-amidino)furan-2-yl,
(5-amidino)-1,3-oxazol-2-yl, (2-amidino)-1,3-oxazol-5-yl,
1H-pyrazol-5-yl, tetrahydro-1H-pyrazol-3-yl,
(1-amidino)tetrahydro-1H-pyrazol-3-yl,
(2-amidino)-1H-imidazol-4-yl, (2-amino)-1H-imidazol-4-yl,
(5-amidino)-1H-imidazol-2-yl, (5-amino)-1H-imidazol-2-yl,
pyridin-3-yl, (4-amino)pyridin-3-yl, (4-dimethylamino)pyridin-3-yl,
(6-amino)pyridin-2-yl, (6-amidino)pyridin-2-yl,
(2-amino)pyridin-4-yl, (2-amidino)pyridin-4-yl,
(2-amidino)pyrimid-4-yl, (2-amino)pyrimidin-4-yl,
(4-amidino)pyrimid-2-yl- , (4-amino)pyrimidin-2-yl,
(6-amidino)pyrazin-2-yl, (6-amino)pyrazin-2-yl,
(4-amidino)-1,3,5-triazin-2-yl, (4-amino)-1,3,5-triazin-2-yl,
(3-amidino)-1,2,4-triazin-5-yl, (3-amino)-1,2,4-triazin-5-yl,
(3-amidino)benzyl, (3-amino)benzyl, (3-aminomethyl)benzyl,
(1-amidino)piperid-3-ylmethyl, (1-amidino)pyrrolid-3-ylmethyl,
(5-amidino)thien-2-ylmethyl, (5-amidino)furan-2-ylmethyl,
(5-amidino)oxazol-2-ylmethyl, (2-amidino)imidazol-5-ylmethyl,
(5-amidino)imidazol-2-ylmethyl, (6-amidino)pyridin-2-ylmethyl,
(6-amino)pyridin-2-ylmethyl, (2-amidino)pyrimidin-4-ylmethyl,
(2-amino)pyrimidin-4-ylmethyl, (4-amidino)pyrimidin-2-ylmethyl,
(4-amino)pyrimidin-2-ylmethyl, (6-amidino)pyrazin-2-ylmethyl,
(6-amino)pyrazin-2-ylmethyl, 3-aminocyclohexyl,
3-amidinocyclohexyl, 3-aminocyclohexylmethyl,
3-amidinocyclohexylmethyl, 3-aminocyclopentyl,
3-amidinocyclopentyl, and 3-aminocyclopentylmethyl, and
3-amidinocyclopentylmethyl; R.sub.8 is Br, I, C.sub.2H.sub.5, H,
Cl, F, SH, SMe, CF.sub.3, CH.sub.3; CO.sub.2H, CO.sub.2Me, CN,
C(.dbd.NH)NH.sub.2, C(.dbd.NH)NHOH, C(.dbd.NH)NHNH.sub.2,
C(.dbd.O)NH.sub.2, CH.sub.2OH, CH.sub.2NH.sub.2, NO.sub.2, OH, OMe,
OCH.sub.2Ph, OCH.sub.2CO.sub.2H, O(CH.sub.2).sub.2CO.sub.2H,
O(CH.sub.2).sub.3CO.sub.2H, NHCH.sub.2CO.sub.2H,
NH(CH.sub.2).sub.2CO.sub- .2H, NH(CH.sub.2).sub.3CO.sub.2H,
OCH.sub.2CH.sub.2OH, OCH.sub.2(1H-tetrazol-5-yl), NH.sub.2,
NHButyl, NMe2, NHPh, NHCH.sub.2Ph, NHC(.dbd.O)Me,
NHC(.dbd.O)c-Hexyl, NHC(.dbd.O)CH.sub.2c-Hexyl, NHC(.dbd.O)Ph,
NHC(.dbd.O)CH.sub.2Ph, NHS(.dbd.O).sub.2Me,
NHS(.dbd.O).sub.2c-Hexyl, NHS(.dbd.O).sub.2CH.sub.2c-Hexyl,
NHS(.dbd.O).sub.2Ph, and NHS(.dbd.O).sub.2CH.sub.2Ph; R.sub.9 is
(CH.sub.2).sub.5, (CH.sub.2).sub.4, (CH.sub.2).sub.6,
CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NHC(.dbd.O)CH.sub.2,
(CH.sub.2).sub.2NH(CH.sub.2).sub.2,
(CH.sub.2).sub.2O(CH.sub.2).sub.2, C.sub.6H.sub.4,
CH.sub.2C.sub.6H.sub.4, C.sub.6H.sub.4CH.sub.2, C.sub.6H.sub.10,
CH.sub.2C.sub.6H.sub.10, C.sub.6H .sub.10CH.sub.2, C.sub.5H.sub.8,
CH.sub.2C.sub.5H.sub.8, C.sub.5H.sub.8CH.sub.2, and
CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2; and R.sub.10 is
2,6-dimethylpiperidinyl, 2,2,6,6-tetramethyl-piperidinyl-4-one,
piperidinyl, 2,2,6,6-tetramethylpiperidinyl,
(2-carboxy)piperidinyl, (3-carboxy)piperidinyl,
(4-carboxy)piperidinyl, 3,5-dimethylpiperidinyl,
(4-hydroxy)piperidinyl, (2-imino)piperidinyl, piperidin-4-one-yl,
(2-dimethylaminomethyl)-piperidinyl, (4-dimethylamino)-piperidinyl,
(4-sulphonyloxy)-piperidinyl, (2-phenyl)piperidinyl,
2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy)pyrrolidinyl,
(3-N-acetyl-N-methyl)pyrrolidinyl, (3-amino)pyrrolidinyl,
(2,5-bis-methoxymethyl)-pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl,
2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino,
diethylamino, methylamino, 1-methyl-4,5-dihydro-1H-imidazol-2-yl,
2,5-dimethyl-1H-1-imidazolyl, morpholinyl, 2,6-dimethylmorpholinyl,
piperazinyl, 2,6-dimethylpiperazinyl, 1H-pyrazolyl,
tetrahydro-1H-pyrazol yl, and
2,5-dimethyltetrahydro-1H-1-pyrazolyl.
8. A compound according to claim 7 wherein R.sub.7 is (2-hydroxy,
5-amidino)phenyl.
9. A compound according to claim 7 wherein R.sub.8 is H.
10. A compound according to claim 7 wherein R.sub.9 is
(CH.sub.2).sub.5.
11. a compound according to claim 7 wherein R.sub.10 is
2,6-dimethylpiperidinyl.
12. A compound according to claim 7 wherein R.sub.8 is H, R.sub.9
is (CH.sub.2).sub.5, and R.sub.10 is 2,6-dimethylpiperidinyl.
13. A compound according to claim 7 wherein R.sub.8 is H, R.sub.9
is (CH.sub.2).sub.5, and R.sub.10 is 2,5-dimethylpyrrolidinyl.
14. A compound which is:
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyri-
dinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-methoxybenzenec-
arboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pen-
tyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-hydroxyph-
enyl)-2H-1,4-benzothiazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydr-
o-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-N-hyd-
roxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-N-hydroxybenze-
necarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-
pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidohydraz-
ide;
2-[3-(Aminomethyl)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(3-Aminophenyl)-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiaz-
in-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-
-[3-(methylamino)phenyl]-2H-1,4-benzothiazin-3(4H)-one;
2-[3-(Dimethylamino)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyr-
idinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one; 3-(4-5
-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-
-2H-1,4-benzothiazin-2-yl)-4-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)tetrahydro-1(2H)-pyridinecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-1-pyrrolidinecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl
-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-thiophenecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-2-furancarboximidamide;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-1,3-oxazole-5-carboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-1,3-oxazole-2-carboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(
1H-pyrazol-5-yl )-2H-1,4-benzothiazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dime-
thyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazi-
n-2-yl)-1-pyrazolidinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1H--
imidazole-2-carboximidamide;
2-(2-Amino-1H-imidazol-4-yl)-4-5-[(2R,6S)-2,6-
-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-1H-imidazole-5-carboximidamide;
2-(5-Amino-1H-imidazol-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-py-
ridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-2-(3-pyridinyl)-2H-1,4-benzothiazin-3(4H)-o-
ne;
2-(4-Amino-3-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyri-
dinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-[4-(Dimethylamino)-3-pyridin-
yl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benz-
othiazin-3(4H)-one;
2-(6-Amino-2-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetra-
hydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-2-pyridinecarboximidamide;
2-(2-Amino-4-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetra-
hydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-
-pyridinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyr-
idinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyrimidinecarb-
oximidamide;
2-(2-Amino-4-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-4-pyrimidinecarboximidamide;
2-(4-Amino-2-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyrid-
inyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-
-2-pyrazinecarboximidamide;
2-(6-Amino-2-pyrazinyl)-4-5-[(2R,6S)-2,6-dimet-
hyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)-1,3,5-triazine-2-carboximidamide;
2-(4-Amino-1,3,5-triazin-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimeth-
yltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin--
2-yl)-1,2,4-triazine-3-carboximidamide;
2-(3-Amino-1,2,4-triazin-5-yl)-4-5-
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazi-
n-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]penty-
l-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]benzenecarboximidamide-
;
2-(3-Aminobenzyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pe-
ntyl-2H-1,4-benzothiazin-3(4H)-one;
2-[3-(Aminomethyl)benzyl]-4-5-[(2R,6S)-
-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-o-
ne;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3-
,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]tetrahydro-1(2H)-pyridinecarbox-
imidamide;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl--
3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1-pyrrolidinecarboximid-
amide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-thiophenecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-furancarboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1,3-oxazole-5-carboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1H-imidazole-2-carboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1H-imidazole-5-carboximidamide;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyridinecarboximidamide;
2-[(6-Amino-2-pyridinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-[(4-5-[(2R,6S)-2,6-Dime-
thyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazi-
n-2-yl)methyl]-2-pyrimidinecarboximidamide;
2-[(2-Amino-4-pyrimidinyl)meth-
yl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benz-
othiazin-3(4H)-one;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridiny-
l]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-4-pyrimidineca-
rboximidamide;
2-[(4-Amino-2-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyl-
tetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyrazinecarboximidamide;
2-[(6-Amino-2-pyrazinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(3-Aminocyclohexyl)-4-5-
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazi-
n-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-
-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)cyclohexanecarboximidamide;
2-[(3-Aminocyclohexyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimeth-
yltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin--
2-yl)methyl]cyclohexanecarboximidamide;
2-(3-Aminocyclopentyl)-4-5-[(2R,6S-
)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)--
one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3-
,4-dihydro-2H-1,4-benzothiazin-2-yl)cyclopentanecarboximidamide;
2-[(3-Aminocyclopentyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimet-
hyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-
-2-yl)methyl]cyclopentanecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetr-
ahydro-1(2H)-pyridinyl]butyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)be-
nzenecarboximidamide;
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridin-
yl]hexyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide-
;
2-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin--
4-yl)-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;
3-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-
-yl)-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethy-
l]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-3--
oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-3-o-
xo-3,4-dihydro-2H1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-oxo-3-
,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)-
-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclohexyl)-
-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-3-oxo--
3,4-dihydro-2H1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl-
)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl-
)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-3--
oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[3-Oxo-4-(5-piperidinopentyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benz-
enecarboximidamide;
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,-
4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazi-
n-4-yl)pentyl]-2-piperidinecarboxylic acid;
1-[5-(2-3-[Amino(imino)methyl]-
phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]-3-piperidinecarb-
oxylic acid;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-
-benzothiazin-4-yl)pentyl]-4-piperidinecarboxylic acid;
3-4-[5-(3,5-Dimethylpiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothia-
zin-2-ylbenzenecarboximidamide;
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo--
3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(2-Iminopiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-
-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihyd-
ro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[4-(5-2-[(Dimethylami-
no)methyl]piperidinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]ben-
zenecarboximidamide;
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazi-
n-4-yl)pentyl]-4-piperidinesulfonic acid;
3-3-Oxo-4-[5-(2-phenylpiperidino-
)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benz-
othiazin-2-ylbenzenecarboximidamide; 3-3-Oxo-4-[5-(
1-pyrrolidinyl)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboxi-
midamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-be-
nzothiazin-4-yl)pentyl]-2-pyrrolidinecarboxylic acid;
N-1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothia-
zin-4-yl)pentyl]tetrahydro-1H-pyrrol-3-yl-N-methylacetamide;
3-4-[5-(3-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothia-
zin-2-ylbenzenecarboximidamide;
3-(4-5-[2,5-Bis(methoxymethyl)-1-pyrrolidi-
nyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidami-
de;
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1-
,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-5-m-
ethyl-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)ben-
zenecarboximidamide;
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2H-
-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(Diethylamino)pentyl]-
-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylben-
zenecarboximidamide;
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-be-
nzothiazin-2-ylbenzenecarboximidamide;
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-
-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothia-
zin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydr-
o-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-4-[5-(2,6-Dimethylpip-
erazino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximi-
damide;
3-3-Oxo-4-[5-(1H-pyrazol-1-yl)pentyl]-3,4-dihydro-2H-1,4-benzothia-
zin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpe-
ntyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-3-oxo-3,4-dihydro--
2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-(6-Chloro-4-5-[(2R,6S)-2-
,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benz-
othiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-6-fluoro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-
-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benz-
enecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-
]pentyl-6-(methylsulfanyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benz-
enecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-
]pentyl-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]ben-
zenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridiny-
l]pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarbox-
imidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carbox-
ylic acid; Methyl
2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyl-
tetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-
-carboxylate;
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamid-
e;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H-
)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboximidamid-
e;
2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H-
)-pyridinyl]pentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carb-
oximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl--
6-[hydrazino(imino)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenze-
necarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethy-
ltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine--
6-carboxamide; 3-[4-5
-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pen-
tyl-6-(hydroxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzeneca-
rboximidamide; 3-(6-(Aminomethyl)-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2-
H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarb-
oximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-
-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide-
;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-hydroxy--
3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methoxy-3-
-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-(Benzyloxy)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]acetic
acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]-
propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimeth-
yltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin--
6-yl)oxy]butanoic acid;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,-
6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo-
thiazin-6-yl)amino]acetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2-
R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1-
,4-benzothiazin-6-yl)amino]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phe-
nyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzothiazin-6-yl)amino]butanoic acid;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(2-hydrox-
yethoxy)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide-
;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(2-
H-1,2,3,4-tetraazol-5-ylmethoxy)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benz-
enecarboximidamide;
3-(6-Amino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboxim-
idamide;
3-(6-(Butylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyrid-
inyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidam-
ide;
3-(6-(Dimethylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridi-
nyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidami-
de;
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]penty-
l-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-(Benzylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pe-
ntyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-
H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)acetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-
H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)cyclohexane-
carboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethylte-
trahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl-
)-2-cyclohexylacetamide; N-(2-3-[Amino(imino)methyl]phenyl
-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dih-
ydro-2H-1,4-benzothiazin-6-yl)benzenecarboxamide;
N-(2-3-[Amino(imino)meth-
yl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-phenylacetamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[(methylsu-
lfonyl)amino]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximida-
mide;
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzene-
carboximidamide;
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-d-
imethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothi-
azin-2-yl)benzenecarboximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-6-[(phenylsulfonyl)amino]-3,4-dihydro-2H-1,4-be-
nzothiazin-2-ylbenzenecarboximidamide; or
3-(6-[(Benzylsulfonyl)amino]-4-5-
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro--
2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
15. A compound which is:
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyri-
dinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-methoxybenzenecar-
boximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]penty-
l-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-hydroxyph-
enyl)-2H-1,4-benzoxazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-N-hydroxy-
benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyrid-
inyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidohyd-
razide;
2-[3-(Aminomethyl)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H-
)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(3-Aminophenyl)-4-5-[(2R-
,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-
-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-[3-(met-
hylamino)phenyl]-2H-1,4-benzoxazin-3(4H)-one;
2-[3-(Dimethylamino)phenyl]--
4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxaz-
in-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]penty-
l-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximidamid-
e;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-
-dihydro-2H-1,4-benzoxazin-2-yl)tetrahydro-1(2H)-pyridinecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H1,4-benzoxazin-2-yl)-1-pyrrolidinecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)-2-thiophenecarboximidamide; 5-(4-5
-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-
-2H-1,4-benzoxazin-2-yl)-2-furancarboximidamide;
2-(4-5-[(2R,6S)-2,6-Dimet-
hyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-
-yl)-1,3-oxazole-5-carboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H1,4-benzoxazin-2-yl)-1,3-oxazo-
le-2-carboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-
pentyl-2-(1H-pyrazol-5-yl)-2H-1,4-benzoxazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-tetrahydro-1-
H-pyrazol-3-yl-2H1,4-benzoxazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-
-pyrazolidinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1H-imidazole-2-
-carboximidamide; 2-(2-Amino-1H-imidazol-4-yl)-4-5
-[(2R,6S)-2,6-dimethylt-
etrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H1,4-benzoxazin-2-yl)-1H-imidazole-5-carboximidamide;
2-(5-Amino-1H-imidazol-2-yl)-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetr-
ahydro-1(2H)-pyridinyl]pentyl-2-(3-pyridinyl)-2H-1,4-benzoxazin-3(4H)-one;
2-(4-Amino-3-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-[4-(Dimethylamino)-3-pyridinyl]-4-
-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazi-
n-3(4H)-one;
2-(6-Amino-2-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1-
(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dim-
ethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-
-2-yl)-2-pyridinecarboximidamide;
2-(2-Amino-4-pyridinyl)-4-5-[(2R,6S)-2,6-
-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)-2-pyridinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)-2-pyrimidinecarboximidamide;
2-(2-Amino-4-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyrid-
inyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetra-
hydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-p-
yrimidinecarboximidamide;
2-(4-Amino-2-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimet-
hyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)-2-pyrazinecarboximidamide;
2-(6-Amino-2-pyrazinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3,5-
-triazine-2-carboximidamide;
2-(4-Amino-1,3,5-triazin-2-yl)-4-5-[(2R,6S)-2-
,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)-1,2,4-triazine-3-carboximidamide;
2-(3-Amino-1,2,4-triazin-5-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethy-
ltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-y-
l)methyl]benzenecarboximidamide;
2-(3-Aminobenzyl)-4-5-[(2R,6S)-2,6-dimeth-
yltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-[3-(Aminomethyl)benzyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyrid-
inyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetr-
ahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)met-
hyl]tetrahydro-1(2H)-pyridinecarboximidamide;
3-[(4-5-[(2R,6S)-2,6-dimethy-
ltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-y-
l)methyl]-1-pyrrolidinecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetra-
hydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)meth-
yl]-2-thiophenecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-fu-
rancarboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridiny-
l]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1,3-oxazole-5-ca-
rboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pen-
tyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1H-imidazole-2-carbox-
imidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl--
3-oxo-3,4-dihydro-2H1,4-benzoxazin-2-yl)methyl]-1H-imidazole-5-carboximida-
mide;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyridinecarboximidamide;
2-[(6-Amino-2-pyridinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-[(4-5-[(2R,6S)-2,6-Dimeth-
yltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2--
yl)methyl]-2-pyrimidinecarboximidamide;
2-[(2-Amino-4-pyrimidinyl)methyl]--
4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxaz-
in-3(4H)-one;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-4-pyrimidinecarboximid-
amide;
2-[(4-Amino-2-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H1,4-benzoxazin-2-yl)methyl]-2-pyrazinecarboximidamide;
2-[(6-Amino-2-pyrazinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(3-Aminocyclohexyl)-4-5-[-
(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(-
4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-o-
xo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)cyclohexanecarboximidamide;
2-[(3-Aminocyclohexyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyl-
tetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl-
)methyl]cyclohexanecarboximidamide;
2-(3-Aminocyclopentyl)-4-5-[(2R,6S)-2,-
6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)cyclopentanecarboximidamide;
2-[(3-Aminocyclopentyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethy-
ltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-y-
l)methyl]cyclopentanecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahyd-
ro-1(2H)-pyridinyl]butyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenec-
arboximidamide;
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hex-
yl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-y-
l)-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;
3-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-y-
l)-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethy-
l]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-3--
oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-3,4-d-
ihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-3-o-
xo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-oxo-3-
,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)-
-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclohexyl)-
-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-3-oxo--
3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl-
)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl-
)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-3--
oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[3-Oxo-4-(5-piperidinopentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzen-
ecarboximidamide;
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,4--
dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin--
4-yl)pentyl]-2-piperidinecarboxylic acid;
1-[5-(2-3-[Amino(imino)methyl]ph-
enyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]-3-piperidinecarboxyl-
ic acid;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-ben-
zoxazin-4-yl)pentyl]-4-piperidinecarboxylic acid;
3-4-[5-(3,5-Dimethylpipe-
ridino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidam-
ide;
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxaz-
in-2-ylbenzenecarboximidamide;
3-4-[5-(2-Iminopiperidino)pentyl)-3-oxo-3,4-
-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylb-
enzenecarboximidamide;
3-[4-(5-2-[(Dimethylamino)methyl]piperidinopentyl)--
3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo-
xazin-2-yl)benzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3--
oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]-4-piperidinesulfonic
acid;
3-3-Oxo-4-[5-(2-phenylpiperidino)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2--
ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1-pyrrolidinyl)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbe-
nzenecarboximidamide; 1-[5-(2-3
-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihy-
dro-4H-1,4-benzoxazin-4-yl)pentyl]-2-pyrrolidinecarboxylic acid;
N-1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazi-
n-4-yl)pentyl]tetrahydro-1H-pyrrol-3-yl-N-methylacetamide;
3-4-[5-(3
-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylben-
zenecarboximidamide;
3-(4-5-[2,5-Bis(methoxymethyl)-1-pyrrolidinyl]pentyl--
3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4--
benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-5-methyl-
-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecar-
boximidamide;
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-be-
nzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(Diethylamino)pentyl]-3-oxo-3,-
4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenze-
necarboximidamide;
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-dih-
ydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1H-
-imidazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarb-
oximidamide;
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-
-2-yl]benzenecarboximidamide;
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzen-
ecarboximidamide;
3-4-[5-(2,6-Dimethylpiperazino)pentyl]-3-oxo-3,4-dihydro-
-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1H-pyrazol-1--
yl)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpentyl)-3,4-dihydro-2H-1,4-benzox-
azin-2-yl]benzenecarboximidamide;
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazo-
l-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidam-
ide; 3-(6-Chloro-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-fluoro-3--
oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-sul-
fanyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(methylsu-
lfanyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(tr-
ifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methyl-3--
oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic
acid; Methyl
2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate-
;
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3--
oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)--
pyridinyl]pentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxim-
idamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[h-
ydrazino(imino)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarb-
oximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetra-
hydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbox-
amide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(hy-
droxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidami-
de;
3-(6-(Aminomethyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl-
]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-nitro-3-o-
xo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-hydroxy-3-
-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methoxy-3-
-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Benzyloxy)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]acetic
acid
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]pro-
panoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethylt-
etrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-
oxy]butanoic acid;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dim-
ethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-
-6-yl)amino]acetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2-
,6-dimethyltetrahydro-1
(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-ben-
zoxazin-6-yl)amino]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5--
[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-
H-1,4-benzoxazin-6-yl)amino]butanoic acid;
3-[4-5-[(2R,6S)-2,6-Dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-6-(2-hydroxyethoxy)-3-oxo-3,4-dihydro-2H-1,-
4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetr-
ahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(2H-1,2,3,4-tetraazol-5-ylmethoxy)-3-
,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(6-Amino-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-
-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Butylamino)-4-5-[(2R-
,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,-
4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Dimethylamino)-4-5-[(2R,6S-
)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-b-
enzoxazin-2-yl)benzenecarboximidamide;
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimet-
hyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-
-yl)benzenecarboximidamide; 3-(6-(Benzylamino)-4-5
-[(2R,6S)-2,6-dimethylt-
etrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-
benzenecarboximidamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-
-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzox-
azin-6-yl)acetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-di-
methyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazi-
n-6-yl)cyclohexanecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,-
6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-
-benzoxazin-6-yl)-2-cyclohexylacetamide;
N-(2-3-[Amino(imino)methyl]phenyl-
-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihy-
dro-2H-1,4-benzoxazin-6-yl)benzenecarboxamide;
N-(2-3-[Amino(imino)methyl]-
phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,-
4-dihydro-2H-1,4-benzoxazin-6-yl)-2-phenylacetamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[(methylsu-
lfonyl)amino]-3-oxo-3,4-dihydro-2H1,4-benzoxazin-2-ylbenzenecarboximidamid-
e;
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarbo-
ximidamide;
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-dimeth-
yltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2--
yl)benzenecarboximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyr-
idinyl]pentyl-3-oxo-6-[(phenyl
sulfonyl)amino]-3,4-dihydro-2H1,4-benzoxazi-
n-2-ylbenzenecarboximidamide; or
3-(6-[(Benzylsulfonyl)amino]-4-5-[(2R,6S)-
-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H1,4-ben-
zoxazin-2-yl)benzenecarboximidamide.
16. A compound which is:
3-((2R)-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-methoxybenze-
necarboximidamide;
3-((2S)-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyrid-
inyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-methoxybenzenecarb-
oximidamide;
3-((2R)-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]p-
entyl
-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximi-
damide;
3-((2S)-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-
-3-oxo-3,4-dihydro-2H1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximidamide;
3-((2R)-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo--
3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide; or
3-((2S)-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-I
(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide.
17. A compound which is: 3-((2S)-4-5
-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H-
)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenz-
enecarboximidamide.
18. A compound of which is: 2H-1,4-Benzoxazin-3(4H)-one,
4-[3-(2,6-dimethyl-1-piperidinyl)propyl]-2-phenyl-;
4-[5-(2,5-Dimethyl-pyrrolidin-1-yl)-pentyl]-2-phenyl-4H-benzo[1,4]oxazin--
3-one; 2H-1,4-Benzoxazin-3(4H)-one,
4-[5-[bis(1-methylethyl)amino]pentyl]-- 2-phenyl-;
2H-1,4-Benzoxazin-3(4H)-one, 4-[3-(2,5-dimethyl-1-pyrrolidinyl)-
propyl]-2-phenyl-; 2H-1,4-Benzoxazin-3(4H)-one,
4-[3-[bis(1-methylethyl)am- ino]propyl]-2-phenyl-;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-phenyl-
-4H-benzo[1,4]oxazin-3-one;
4-(5-Diethylamino-pentyl)-2-phenyl-4H-benzo[1,- 4]oxazin-3-one;
2-Phenyl-4-(5-pyrrolidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-- 3-one;
2-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-iso-
indole-1,3-dione;
4-(5-Imidazol-1-yl-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-- 3-one;
2-(4-Chloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-b-
enzo[1,4]oxazin-3-one;
2-(2-Chloro-phenyl)-4-[5-(2,5-dimethyl-pyrrolidin-1-
-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-(2-Chloro-phenyl)-4-[5-(2,6-dime-
thyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentanamidine;
2-Phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Chloro-phenyl)-4-[5-(2,5-dimethyl-pyrrolidin-1-yl)-pentyl]-4H-benzo[-
1,4]oxazin-3-one;
2-Phenyl-4-(5-pyrrolidin-1-yl-pentyl)-4H-benzo[1,4]oxazi- n-3-one;
compound with trifluoro-acetic acid; 3-(3-Oxo-2-phenyl-2,3-dihydr-
o-benzo[1,4]oxazin-4-ylmethyl)-benzonitrile;
4-[6-(2,5-Dimethyl-pyrrolidin-
-1-yl)-hexyl]-2-phenyl-4H-benzo[1,4]oxazin-3-one;
3-(3-Oxo-2-phenyl-2,3-di-
hydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
2-Naphthalen-2-yl-4-(5-pip-
eridin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
4-(5-Amino-pentyl)-2-phenyl- -4H-benzo[1,4]oxazin-3-one;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-p-
henyl-4H-benzo[1,4]oxazin-3-one;
6-Methyl-2-phenyl-4-(5-piperidin-1-yl-pen-
tyl)-4H-benzo[1,4]oxazin-3-one; 7-Methoxy-2-phenyl
-4-(5-piperidin-1-yl-pe- ntyl)-4H-benzo[1,4]oxazin-3-one;
8-Chloro-2-phenyl-4-(5-piperidin-1-yl-pen-
tyl)-4H-benzo[1,4]oxazin-3-one;
3-Oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-
-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile;
4-(3-Oxo-2-phenyl-2,3-di-
hydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
1-[5-(3-Oxo-2-phenyl-2,3-d-
ihydro-benzo[1,4]oxazin-4-yl)-pentyl]-piperidine-2,6-dione;
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionitrile;
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-butyronitrile;
5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentanenitrile;
N-[3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propyl]-guanidine-
;
N-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-guanidin-
e;
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
2-(4-Methoxy-phenyl)-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-on-
e;
7-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one-
;
5-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
6-Methoxy-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
N-Hydroxy-4-(3-oxo-2-phenyl-2,3-dihydro-benzo
[1,4]oxazin-4-ylmethyl)-ben- zamidine;
6-Chloro-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazi-
n-3-one;
2-(4-Methoxy-phenyl)-4-(5-piperazin-1-yl-pentyl)-4H-benzo[1,4]oxa-
zin-3-one; 2-(4-Hydroxy-phenyl)-4-(5
-piperidin-1-yl-pentyl)-4H-benzo[1,4]- oxazin-3-one;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-hydroxy-phen-
yl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Methoxy-phenyl)-4-[5-(4-methyl-piperaz-
in-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
4-{4-[5-(2,6-Dimethyl-piperidi-
n-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzonitrile;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[-
1,4]oxazin-2-yl}-benzamidine;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl-
]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-thiobenzamide;
[2-(4-Methoxy-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetic
acid;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-N-hydroxy-benzamidine; Benzenecarboximidic
acid,
4-[3,4-dihydro-4-[5-(2,6-dimethyl-1-piperidinyl)pentyl]-3-oxo-2H-1,4-benz-
oxazin-2-yl]-, hydrazide;
6-Amino-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H--
benzo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(3,4-dimethoxy-phenyl)-4H-ben-
zo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(3,4,5-trimethoxy-phenyl)-4H-ben-
zo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]-
oxazin-3-one;
N-[2-(2,6-Dimethyl-piperidin-1-yl)-ethyl]-2-[2-(4-methoxy-ph-
enyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(3,4,5-trimethoxy-phenyl)-4H-
-benzo[1,4]oxazin-3-one;
2-(3,4-Dimethoxy-phenyl)-4-[5-(2,6-dimethyl-piper-
idin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-(4-Bromo-phenyl)-4-[5-(2,6-
-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
8-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Benzylamino-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-be-
nzo[1,4]oxazin-3-one;
2-(4-Methoxy-phenyl)-4-[5-(2,2,6,6-tetramethyl-piper-
idin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
4-(2-Bromo-ethyl)-2-(4-metho-
xy-phenyl)-4H-benzo[1,4]oxazin-3-3-one;
4-(5-Bromo-pentyl)-2-(3,4-dichloro-
-phenyl)-4H-benzo[1,4]oxazin-3-one;
4-(2-Hydroxy-ethyl)-2-(4-methoxy-pheny-
l)-4H-benzo[1,4]oxazin-3-one;
2-(3,4-Dichloro-phenyl)-4-[5-(2,6-dimethyl-p-
iperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
4-[3-(2,6-Dimethyl-piper-
idin-1-ylmethyl)-benzyl]-2-(4-methoxy-phenyl)-4H-benzo
1,4]oxazin-3-one;
4-(2-Amino-ethyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-3-one;
2-(2,6-Dimethyl-piperidin-1-yl)-N-{2-[2-(4-methoxy-phenyl)-3-oxo-2,3-dihy-
dro-benzo[1,4]oxazin-4-yl]-ethyl}-acetamide;
4-[5-(2,6-Dimethyl-piperidin--
1-yl)-5-oxo-pentyl]-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
3-{4-[4-(2,6-Dimethyl-piperidin-1-yl)-butyl]-3-oxo-3,4-dihydro-2H-benzo[1-
,4]oxazin-2-yl}-benzamidine;
3-{4-[6-(2,6-Dimethyl-piperidin-1-yl)-hexyl]--
3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(5-Aminomethyl-2-hydroxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pen-
tyl]-4H-benzo[1,4]oxazin-3-one;
2-(3-Aminomethyl-phenyl)-4-[5-(2,6-dimethy-
l-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-7-methyl-3-oxo-3,4-dihydro--
2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-y-
l)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-4-methoxy-benzamidi-
ne;
2-(5-Aminomethyl-2-methoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)--
pentyl]-4H-benzo[1,4]oxazin-3-one;
3-(4-[5-(2,6-Dimethyl-piperidin-1-yl)-p-
entyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-N-hydroxy-4-methoxy-ben-
zamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro--
2H-benzo[1,4]oxazin-2-yl}-N-hydroxy-benzamidine;
3-{7-Chloro-4-[5-(2,6-dim-
ethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}--
benzamidine; 4-(5-Bromo-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
3-[3-Oxo-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-
]-benzamidine;
N-{2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin--
1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-acetamide;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-methyl-3-oxo-3,4-dihydro--
2H-benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
3-[4-(5-Diisopropylamino--
pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
3-(4-{4-[(Diisopropylamino)-methyl]-benzyl}-3-oxo-3,4-dihydro-2H-benzo[1,-
4]oxazin-2-yl)-benzamidine;
3-{4-[4-(2,6-Dimethyl-piperidin-1-ylmethyl)-be-
nzyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[-
1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1--
yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-N-methyl-benzamidi-
ne;
{2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-
-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-acetic acid;
3-(4-{3-[(Diisopropylamino)-methyl]-benzyl}-3-oxo-3,4-dihydro-2H-benzo[1,-
4]oxazin-2-yl)-benzamidine;
3-{4-[3-(2,6-Dimethyl-piperidin-1-ylmethyl)-be-
nzyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-o-
xo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid;
3-{3-Oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-benzo[1,4]oxazin--
2-yl}-benzamidine;
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-
-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic
acid methyl ester;
3-[4-(5-Dihexylamino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4-
]oxazin-2-yl]-benzamidine;
3-{4-[4-(Methyl-pyridin-2-yl-amino)-butyl]-3-ox-
o-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-[3-(imino-morpholin-4-yl-met-
hyl)-phenyl]-4H-benzo[1,4]oxazin-3-one;
3-{3-Oxo-4-[4-(pyrimidin-2-ylamino-
)-butyl]-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-[4-(4-Cyclohexylamino-butyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-
]-benzamidine;
3-{4-[5-(2,5-Dimethyl-pyrrolidin-1-yl)-pentyl]-3-oxo-3,4-di-
hydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-[4-(5-Morpholin-4-yl-pentyl-
)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-2,3-dihydroxy-pentyl]-3-oxo-3,4-dih-
ydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-[2-(3-Carbamimidoyl-phenyl)--
3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-N,N-dimethyl-benzamide;
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-o-
xo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid;
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmeth-
yl]-N,N-dimethyl-benzamide; 3-{4-[5-(2,6-Dimethyl
-piperidin-1-yl)-pent-2--
enyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-[4-(5-Amino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzami-
dine;
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl-
]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl
ester;
4-Methoxy-3-[4-(4-methoxy-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-
-yl]-benzonitrile;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pent-3-enyl]-3-ox-
o-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-[2-(3-Cyano-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-N,N--
dimethyl-benzamide; p1
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-ben-
zo[1,4]oxazin-4-ylmethyl]-5-(2,6-dimethyl-piperidin-1-ylmethyl)-benzoic
acid;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}1-4-hydroxy-benzamidine;
3-Acetyl-2-(2-methoxy-pheny- l)-thiazolidine-4-carboxylic acid
4-cyano-2-{4-[5-(2,6-dimethyl-piperidin--
1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-phenyl
ester;
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmeth-
yl]-5-(2,6-dimethyl-piperidin-1-ylmethyl)-N-hydroxy-benzamide;
4-(2-Dimethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-one;
4-(2-Diethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-one;
2H-1,4-Benzothiazin-3(4H)-one,
4-[2-(dimethylamino)ethyl]-7-nitro-2-pheny- l-, monohydrochloride;
2H-1,4-Benzothiazin-3(4H)-one,
4-[2-(diethylamino)ethyl]-7-nitro-2-phenyl-, monohydrochloride;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-4H-benzo[-
1,4]thiazin-3-one;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-
-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzonitrile;
4-{4-[5-(2,6-Dimethyl-pi-
peridin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-thioben-
zamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-4H-
-benzo[1,4]thiazin-3-one; compound with trifluoro-acetic acid;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[-
1,4]thiazin-2-yl}-benzonitrile;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pent-
yl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(3-methoxy-phenyl)-2-(4-meth-
oxy-phenyl)-4H-benzo[1,4]thiazin-3-one;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-
-pentyl]-2-(4-methoxy-phenyl)-1,1-dioxo-1,4-dihydro-2H-1l>6_-benzo[1,4]-
thiazin-3-one;
2-(4-Benzyloxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-p-
entyl]-4H-benzo[1,4]thiazin-3-one;
2-(4-Butoxy-phenyl)-4-[5-(2,6-dimethyl--
piperidin-1-yl)-pentyl]-4H-benzo[1,4]thiazin-3-one;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[-
1,4]thiazin-2-yl}-thiobenzamide;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pen-
tyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[-
1,4]thiazin-2-yl}-N-hydroxy-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-
-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamidine;
3-{4-[5-(2-Hydroxymethyl-pyrrolidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-be-
nzo[1,4]thiazin-2-yl}-benzamidine;
4-Allyl-2,2-diphenyl-4H-benzo[1,4]thiaz- in-3-one;
4-(2-Diethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-
-one;
2-(3-Diethylamino-propylamino)-4-methyl-2-phenyl-4H-benzo[1,4]thiazi-
n-3-one;
4-(2-Diethylamino-ethyl)-2,2-diphenyl-4H-benzo[1,4]thiazin-3-one;
2-Benzyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-Cyclohexyl-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]thia-
zin-3-one; 2H-1,4-Benzothiazin-3(4H)-one, 4-methyl-2,2-diphenyl-;
4-Ethyl-2-phenyl-2-piperidin-1-yl-4H-benzo[1,4]thiazin-3-one;
4-Methyl-2-phenyl-2-piperidin-1-yl-4H-benzo[1,4]thiazin-3-one;
3-{4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[-
1,4]oxazin-2-yl}-piperidine-1-carboxamidine;
4-[5-(2,6-Dimethyl-piperidin--
1-yl)-pentyl]-2-piperidin-3-yl-4H-benzo[1,4]oxazin-3-one;
3-Oxo-2-phenyl-2,4-bis-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-6-carbonitrile;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-pyri-
din-2-yl-4H-benzo[1,4]oxazin-3-one;
N-Hydroxy-3-oxo-2-phenyl-4-(5-piperidi-
n-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine;
3-Oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-6-carboxamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,-
4-dihydro-2H-benzo[1,4]oxazin-2-yl}-thiobenzamide;
3-{4-[5-(Adamantan-1-yl
amino)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(3-Diethylamino-propylamino)-4-methyl-2-phenyl-4H-benzo[1,4]oxazin-3-on-
e;
4-[3-(2,6-Dimethyl-1-piperidinyl)propyl]-2-phenyl-2H/-1,4-benzoxazin-3(-
4H/)-one; or 4-Methyl-2-phenyl-2H/-1,4-benzoxazin-3(4H/)-one.
19. A method for the treatment or prophylaxis of thrombotic
disorders in a mammal comprising administering to said mammal an
effective amount of a compound according to claim 1.
20. A method according to claim 19, wherein said disorder is venous
thrombosis.
21. A method according to claim 19, wherein said disorder is
arterial thrombosis.
22. A method according to claim 19, wherein said disorder is
pulmonary embolism.
23. A method according to claim 19, wherein said disorder is
myocardial infarction.
24. A method according to claim 19, wherein said disorder is
cerebral infarction.
25. A method according to claim 19, wherein said disorder is
restenosis.
26. A method according to claim 19, wherein said disorder is
cancer.
27. A method according to claim 19, wherein said disorder is
angina.
28. A method according to claim 19, wherein said disorder is
diabetes.
29. A method according to claim 19, wherein said disorder is atrial
fibrillation.
30. A method according to claim 19, wherein said disorder is heart
failure.
31. A pharmaceutical formulation comprising a compound of claim 1
admixed with a carrier, diluent or excipient.
32. A pharmaceutical formulation comprising a compound of claim 2
together with a carrier, diluent or excipient.
33. A pharmaceutical formulation comprising a compound of claim 14
together with a carrier, diluent or excipient.
34. A pharmaceutical formulation comprising a compound of claim 15
together with a carrier, diluent or excipient.
35. A method for inhibiting serine proteases comprising
administering to a mammal an effective amount of serine protease
inhibitor of claim 1.
36. A method according to claim 35, wherein said serine protease is
factor Xa.
Description
FIELD OF THE INVENTION
[0001] In one aspect, this invention discloses benzoxazinone and
benzothiazinone compounds which display inhibitory effects on
serine proteases such as factor Xa, thrombin, and/or factor VIIa.
The invention also discloses pharmaceutically acceptable salts of
the compounds, pharmaceutically acceptable compositions comprising
the compounds or their salts, and methods of using them as
therapeutic agents for treating or preventing disease states in
mammals characterized by abnormal thrombosis.
BACKGROUND OF THE INVENTION
[0002] In economically developed countries, cardiovascular disease
still represents a major cause of mortality. In particular,
abnormal coagulation and inappropriate thrombus formation within
blood vessels precipitates many acute cardiovascular disease
states. While it has long been recognized that a variety of plasma
proteins such as fibrinogen, serine proteases, and cellular
receptors are involved in hemostasis, it is the abnormal regulation
that has emerged as important contributing factors to
cardiovascular disease. Thrombin can be considered the key or
principal regulatory enzyme in the coagulation cascade; it serves a
pluralistic role as both a positive and negative feedback regulator
in normal hemostasis. However, in some pathologic conditions, the
former is amplified through catalytic activation of cofactors
required for thrombin generation such as factor Xa. Factor Xa, as
part of the prothrombinase complex composed of nonenzymatic
cofactor Va, calcium ions, and a phospholipid membrane surface
regulates the generation of thrombin from its zymogen prothrombin.
Furthermore, the location of the prothrombinase complex at the
convergence of both the intrinsic and extrinsic coagulation
pathways suggests that inhibition of factor Xa, and hence thrombin
generation, may be a viable approach to limiting the procoagulant
activity of thrombin.
[0003] Indeed, ample evidence exists for the role of factor Xa
inhibitors as anticoagulants. Antistasin, a potent inhibitor of
blood coagulation factor Xa from the Mexican leech: Haementeria
officinalis, displays antithrombotic activity in various models of
arterial and venous thrombosis (Lapatto et al., Embo. J.,
1997:5151-5161). Other protein or polypeptide factor Xa inhibitors
include recombinant tick anticoagulant peptide (rTAP), which is
known to accelerate the recombinant tissue plasminogen activator
mediated clot lysis and prevent acute reocclusion in the dog, hence
indicating factor Xa inhibitors may be useful as an adjunct to
thrombolytic therapy (Mellott et al., Fibrinolysis, 1993:195-202).
Furthermore, in a canine coronary artery electrolytic lesion model,
rTAP was demonstrated to reduce thrombus mass and time to occlusion
in the absence of dramatic hemodynamic or hemostatic changes
indicating the primary role for factor Xa in the process of
arterial thrombosis (Lynch et al., Thromb. Haemostasis,
1995:640-645; Schaffer et al., Circulation, 1991:1741-1748). On the
venous side, rTAP was also demonstrated to reduce fibrin deposition
in a rabbit model of venous thrombosis while having little affect
on systemic hemostatic parameters (Fioravanti et al., Thromb. Res.,
1993:317-324). In addition to these relatively high molecular
weight proteins that are not suitable as oral antithrombotic
agents, there also exist examples of low molecular weight factor Xa
inhibitors. In particular Dx9065a, a low molecular weight synthetic
factor Xa inhibitor, has also shown antithrombotic potential in
various experimental thrombosis rat models. In both arteriovenous
shunt and venous stasis models, inhibition of thrombus formation
was achieved at doses that had little effect on APTT, indicating
that DX9065a is effective in preventing thrombosis and hence has
therapeutic antithrombotic potential (Wong et al., Thromb. Res.,
1996:117-126).
[0004] The majority of factor Xa inhibitors known to date have been
previously summarized in two reviews (Edmunds et al., Annual
Reports in Medicinal Chemistry, 1996:51 and Kunitada and Nagahara,
Curr. Pharm. Des., 1996:531-542). However, it is readily apparent
that there still exists a need for more effective agents that
regulate factor Xa proteolytic activity.
[0005] Some benzoxazinones and benzothiazinones have been reported
and these compounds have displayed marked pharmacological
activity:
[0006] Moriyama et al., Biol. Pharm. Bull., 1997:701-703;
[0007] Gezginci et al., Farmaco, 1997:255-256;
[0008] Sastry et al., Indian J. Chem., Sect. B, 1989:882-884;
[0009] U.S. Pat. No. 680,718;
[0010] Bornschein et al., Pharmazie, 1977:695-697 and Pfeifer et
al., Pharmazie, 1977:587-592;
[0011] Japanese Application 60166674;
[0012] European Application 116368;
[0013] Japanese Application 01272524;
[0014] U.S. Pat. No. 4,786,635;
[0015] Fujita M. et al., J. Med. Chem., 1990:1898;
[0016] Japanese Application 03118380;
[0017] Japanese Application 09227561;
[0018] Shridhar et al., Indian J. Chem., Sect. B,
1985;24B(12):1263-1267;
[0019] Bornschein et al., Pharmazie, 1977;32(11):695-697 and
1977;32(10):587-592;
[0020] Thuillier et al., Eur. J. Med. Chem.-Chim. Ther.,
1975;10(1):37-42;
[0021] German Patent 2044530; and
[0022] U.S. Pat. No. 3,401,166.
[0023] None of the above articles set forth above, however,
disclose or suggest compounds set forth herein that are inhibitors
of serine proteases involved in the blood coagulation cascade.
SUMMARY OF THE INVENTION
[0024] One object of the present invention is to provide serine
protease inhibitors that display inhibitory activity towards
enzymes involved in the coagulation cascade and principally the
target enzymes, factor Xa, thrombin, and factor VIIa.
[0025] A further object of the present invention is to provide
serine protease inhibitors that display inhibitory activity towards
the target enzyme factor Xa and are provided for in a
pharmacologically acceptable state.
[0026] Still a further object of the present invention is to
provide for the use of these factor Xa inhibitors and formulations
thereof as anticoagulant and factor Xa inhibitory agents.
[0027] Yet a further object of the present invention is to provide
for the use of these factor Xa inhibitors and formulations thereof
for therapeutic treatment of various thrombotic maladies.
[0028] A further object of the present invention is a process for
the synthesis of these low molecular weight thrombin inhibitors.
The enzyme inhibitors of the present invention are encompassed by
the structure of general Formula 1 set forth below.
[0029] The present invention meets these objectives and provides
for novel compounds that display antithrombotic activity. More
specifically, the present invention provides for novel compounds
that display antithrombotic activity via the inhibition of factor
Xa as reflected in Formula 1, or pharmaceutically acceptable salts
or prodrug forms thereof. The present invention also provides
pharmaceutically acceptable compositions comprising the novel
compounds or their salts or prodrug forms, and methods of using
them as therapeutic agents for treating or preventing disease
states in mammals characterized by abnormal thrombosis.
[0030] Thus in a first embodiment, the present invention provides
novel compounds of Formula 1: 1
[0031] or stereoisomers or pharmaceutically acceptable salt forms
or prodrugs thereof, wherein:
[0032] A is selected from O, S, S(.dbd.O), S(.dbd.O)(.dbd.O),
OCH.sub.2, CH.sub.2O, SCH.sub.2, S(=O)CH.sub.2,
S(.dbd.O)(.dbd.O)CH.sub.2, CH.sub.2S, CH.sub.2S(.dbd.O),
CH.sub.2S(.dbd.O)(.dbd.O);
[0033] B is selected from hydrogen, cycloalkyl, heteroalkyl,
cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle,
heterocycloalkyl, each optionally substituted with R.sub.1 and
R.sub.2;
[0034] D is selected from H, (C.sub.3-20)alkyl, cycloalkyl,
heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl,
heterocycle, heterocycloalkyl, each optionally substituted with
R.sub.1 and R.sub.2;
[0035] E is absent or selected from O, S, NH;
[0036] F is selected from N, NCH.sub.2, CH.sub.2N;
[0037] G is absent or selected from alkyl, alkyl interrupted by one
or more heteroatoms, cycloalkyl, cycloalkyl interrupted by one or
more heteroatoms;
[0038] J is absent or selected from aryl or heterocycle each
optionally substituted with R.sub.1 and R.sub.2;
[0039] K is absent or selected from an alkyl, alkyl interrupted by
one or more heteroatoms, cycloalkyl interrupted by one or more
heteroatoms, cycloalkylalkyl interrupted by one or more
heteroatoms, each optionally substituted with R.sub.1 and
R.sub.2;
[0040] L is selected from H, chlorine, fluorine, bromine, iodine,
OH, O(alkyl), amine, alkyl, fluoroalkyl, amide, NO.sub.2, SH,
S(O).sub.n(alkyl), SO.sub.3H, SO.sub.3alkyl, nitrile aldehyde,
ketone, acid, ester, urea, Oalkylamide, Oalkylester, Oalkylacid,
Nalkylacid, alkylamine, alkylamide, alkylketone, alkylacid,
alkylester, alkylurea, Nalkylamide, Nalkylester, NC(.dbd.O)alkyl,
NC(.dbd.O)aryl, NC(.dbd.O)cycloalkyl, NC(.dbd.O)cycloalkylalkyl,
NC(.dbd.O) alkylaryl, R.sub.1. R.sub.2;
[0041] R.sub.1 is selected from H, amine, alkylamine, amide,
C(.dbd.NH)NHNH.sub.2, alkylC(.dbd.NH)NHNH.sub.2, C(.dbd.NH)NHOH,
alkylC(.dbd.NH)NHOH, NHC(.dbd.NH)NH.sub.2,
alkylNHC(.dbd.NH)NH.sub.2, C(.dbd.S)NH.sub.2,
alkylC(.dbd.S)NH.sub.2, C(.dbd.NH)alkyl, alkylC(.dbd.NH)alkyl,
C(.dbd.NR.sub.3)N(R.sub.4)(R.sub.5),
alkylC(.dbd.NR.sub.3)N(R.sub.4)(R.sub.5);
[0042] R.sub.2 is selected from H, chlorine, fluorine, bromine,
iodine, OH, Oalkyl, amine, alkylaldehyde, alkylamide, alkylester,
alkylketone, alkylacid, Oalkylamide, Oalkylacid, Oalkylester,
aninealkylacid, aminealkylamide, aminealkylester, NC(.dbd.O)alkyl,
NC(.dbd.O)aryl, NC(.dbd.O)cycloalkyl, NC(.dbd.O)alkylaryl,
alkylamine, amide, aldehyde, ester, ketone, NO.sub.2, SH,
S(O).sub.n(C.sub.1-10-alkyl), SO.sub.3H, SO.sub.3alkyl, CHO, acid,
alkyl, C(.dbd.NH)alkyl, C(.dbd.NH)NHNH.sub.2,
alkylC(.dbd.NH)NHNH.sub.2, C(.dbd.NH)NHOH, alkylC(.dbd.NH)NHOH,
NHC(.dbd.NH)NH.sub.2, alkylNHC(.dbd.NH)NH.sub.2, C(.dbd.S)NH.sub.2,
alkylC(.dbd.S)NH.sub.2, alkylC(.dbd.NH)alkyl,
C(.dbd.NR.sub.3)N(R.sub.4)(- R.sub.5),
alkylC(.dbd.NR.sub.3)N(R.sub.4)(R.sub.5);
[0043] R.sub.3, R.sub.4, and R.sub.5 are a hydrogen atom, alkyl
group having 1 to 4 carbon atoms optionally interrupted by a
heteroatom, or R.sub.4 and R.sub.5 are bonded to form
--(CH.sub.2).sub.p--W--(CH.sub.2).- sub.q--, wherein p and q are an
integer of 2 or 3, a certain position on the methylene chain is
unsubstituted or substituted by an alkyl group having I to 4 carbon
atoms, W is a direct bond, --CH.sub.2--, --O--, --N(R.sub.6)--, or
--S(O).sub.r-- wherein R.sub.6 is H or alkyl, and r is 0 or 1 or
2;
[0044] n is selected from 0, 1, 2;
[0045] X.sub.1 is C or N;
[0046] X.sub.2 is C or N;
[0047] X.sub.3 is C or N; and
[0048] X.sub.4 is C or N.
[0049] Preferred compounds according to this invention have the
Formula 2: 2
[0050] or stereoisomers or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, wherein A, B, E, G, J, K, and
L are defined as above.
[0051] Another preferred group of compounds have the Formula 3:
3
[0052] or stereoisomers or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, wherein B, G, J, K, and L are
defined as above.
[0053] Another preferred group of compounds have the Formula 4:
4
[0054] or stereoisomers or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, wherein B, G, J, K, and L are
defined as above.
[0055] Even more preferred compounds have the Formula 5: 5
[0056] or stereoisomers or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, wherein R.sub.1, R.sub.2, G,
J, K, and L are as defined above.
[0057] Another more preferred group of compounds have the Formula
6: 6
[0058] or stereoisomers or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, wherein R.sub.1, R.sub.2, G,
J, K, and L are as defined above.
[0059] The most preferred compounds provided by this invention are
compounds of Formulas 7 and 8: 7
[0060] or stereoisomers or pharmaceutically acceptable salts,
esters, amides, or prodrugs thereof, wherein
[0061] R.sub.7 is (3-amidino)phenyl, (3-hydroxy)phenyl,
[3-hydroxylamino(imino)methyl]-phenyl,
[3-hydrazino(imino)methyl]-phenyl, (3-aminomethyl)phenyl,
(3-amino)phenyl, (3-methylamino)phenyl, (3-dimethylamino)phenyl,
(5-amidino-2-hydroxy)phenyl, (1-amidino)piperid-3-yl,
(5-amidino-2-methoxy)phenyl, (1-amidino)pyrrolid-3-yl,
(5-amidino)thien-2-yl, (5-amidino)furan-2-yl,
(5-amidino)-1,3-oxazol-2-yl, (2-amidino)-1,3-oxazol-5-yl,
1H-pyrazol-5-yl, tetrahydro-1H-pyrazol-3-yl,
(1-amidino)tetrahydro-1H-pyr- azol-3-yl,
(2-amidino)-1H-imidazol-4-yl, (2-amino)-1H-imidazol-4-yl,
(5-amidino)-1H-imidazol-2-yl, (5-amino)-1H-imidazol-2-yl,
pyridin-3-yl, (4-amino)pyridin-3-yl, (4-dimethylamino)pyridin-3-yl,
(6-amino)pyridin-2-yl, (6-amidino)pyridin-2-yl,
(2-amino)pyridin-4-yl, (2-amidino)pyridin-4-yl,
(2-amidino)pyrimid-4-yl, (2-amino)pyrimidin-4-yl- ,
(4-amidino)pyrimid-2-yl, (4-amino)pyrimidin-2-yl,
(6-amidino)pyrazin-2-yl, (6-amino)pyrazin-2-yl,
(4-amidino)-1,3,5-triazin- -2-yl, (4-amino)-1,3,5-triazin-2-yl,
(3-amidino)-1,2,4-triazin-5-yl, (3-amino)-1,2,4-triazin-5-yl,
(3-amidino)benzyl, (3-amino)benzyl, (3-aminomethyl)benzyl,
(1-amidino)piperid-3-ylmethyl, (1-amidino)pyrrolid-3-ylmethyl,
(5-amidino)thien-2-ylmethyl, (5-amidino)furan-2-ylmethyl,
(5-amidino)oxazol-2-ylmethyl, (2-amidino)imidazol-5-ylmethyl,
(5-amidino)imidazol-2-yl methyl, (6-amidino)pyridin-2-ylmethyl,
(6-amino)pyridin-2-ylmethyl, (2-amidino)pyrimidin-4-ylmethyl,
(2-amino)pyrimidin-4-ylmethyl, (4-amidino)pyrimidin-2-ylmethyl,
(4-amino)pyrimidin-2-ylmethyl, (6-amidino)pyrazin-2-ylmethyl,
(6-amino)pyrazin-2-ylmethyl, 3-aminocyclohexyl,
3-amidinocyclohexyl, 3-aminocyclohexylmethyl,
3-amidinocyclohexylmethyl, 3-aminocyclopentyl,
3-amidinocyclopentyl, 3-aminocyclopentylmethyl, and
3-amidinocyclopentylmethyl;
[0062] R.sub.8 is Br, I, C.sub.2H.sub.5, H, Cl, F, SH, SMe,
CF.sub.3, CH.sub.3, CO.sub.2H, CO.sub.2Me, CN, C(.dbd.NH)NH.sub.2,
C(.dbd.NH)NHOH, C(.dbd.NH)NHNH.sub.2, C(.dbd.O)NH.sub.2,
CH.sub.2OH, CH.sub.2NH.sub.2, NO.sub.2, OH, OMe, OCH.sub.2Ph,
OCH.sub.2CO.sub.2H, O(CH.sub.2).sub.2CO.sub.2H,
O(CH.sub.2).sub.3CO.sub.2H, NHCH.sub.2CO.sub.2H,
NH(CH.sub.2).sub.2CO.sub.2H, NH(CH.sub.2).sub.3CO.su- b.2H,
OCH.sub.2CH.sub.2OH, OCH.sub.2(1H-tetrazol-5-yl), NH.sub.2,
NHButyl, NMe.sub.2, NHPh, NHCH.sub.2Ph, NHC(.dbd.O)Me,
NHC(.dbd.O)c-Hexyl, NHC(.dbd.O)CH.sub.2c-Hexyl, NHC(.dbd.O)Ph,
NHC(.dbd.O)CH.sub.2Ph, NHS(.dbd.O).sub.2Me,
NHS(.dbd.O).sub.2c-Hexyl, NHS(.dbd.O).sub.2CH.sub.2C- -Hexyl,
NHS(.dbd.O).sub.2Ph, and NHS(.dbd.O).sub.2CH.sub.2Ph;
[0063] R.sub.9 is (CH.sub.2).sub.5, (CH.sub.2).sub.4,
(CH.sub.2).sub.6, CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NHC(.dbd.O)CH.sub.2,
(CH.sub.2).sub.2NH(CH.sub.2).sub.2,
(CH.sub.2).sub.2O(CH.sub.2).sub.2, C.sub.6H.sub.4,
CH.sub.2C.sub.6H.sub.4, C.sub.6H.sub.4CH.sub.2, C.sub.6H.sub.10,
CH.sub.2C.sub.6H.sub.10, C.sub.6H.sub.10CH.sub.2, CH.sub.5H.sub.8,
CH.sub.2C.sub.5H.sub.8, C.sub.5H.sub.8CH.sub.2, and
CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2; and
[0064] R.sub.10 is piperidinyl, 2,6-dimethylpiperidinyl,
2,2,6,6-tetramethyl-piperidinyl-4-one, 2,2,6,6-tetramethyl
piperidinyl, (2-carboxy)piperidinyl, (3-carboxy)piperidinyl,
(4-carboxy)piperidinyl, 3,5-dimethylpiperidinyl,
(4-hydroxy)piperidinyl, (2-imino)piperidinyl, piperidin-4-one-yl,
(2-dimethylaminomethyl)-piperidinyl, (4-dimethylamino)-piperidinyl,
(4-sulphonyloxy)-piperidinyl, (2-phenyl)piperidinyl,
2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy)pyrrolidinyl,
(3-N-acetyl-N-methyl)pyrrolidinyl, (3-amino)pyrrolidinyl,
(2,5-bis-methoxymethyl)-pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl,
2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino,
diethylamino, methylamino, 1-methyl-4,5-dihydro-1H-imid- azol-2-yl,
2,5-dimethyl-1H-1-imidazolyl, morpholinyl, 2,6-dimethylmorpholinyl,
piperazinyl, 2,6-dimethylpiperazinyl, 1H-pyrazolyl,
tetrahydro-1H-pyrazolyl, and 2,5-dimethyltetrahydro-1H-1-py-
razolyl.
[0065] In one embodiment of Formulas 7 and 8, R.sub.8, R.sub.9, and
R .sub.10 are as above and R.sub.7 is (2-hydroxy, 5-amidino)phenyl.
In another embodiment of Formulas 7 and 8, R.sub.7, R.sub.9, and
R.sub.10 are as above and R.sub.8 is H. In another embodiment of
Formulas 7 and 8, R.sub.7, R.sub.8, and R.sub.10 are as above and
R.sub.9 is (CH.sub.2).sub.5. In another embodiment of Formulas 7
and 8, R.sub.7, R.sub.8, and R.sub.10 is 2,6-dimethylpiperidinyl.
In another embodiment of Formulas 7 and 8, R.sub.7 is as defined
above and R.sub.8 is H, R.sub.9 is (CH.sub.2).sub.5 and R.sub.10 is
2,6-dimethylpiperidinyl. In another embodiment of Formulas 7 and 8,
R.sub.7 is as defined above and R.sub.8 is H, R.sub.9 is
(CH.sub.2).sub.5 and R.sub.10 is 2,5-dimethylpyrrolidinyl.
[0066] Representative compounds of the present invention
include:
[0067]
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-methoxybenzenecarboximidamide;
[0068]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0069]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-hyd-
roxyphenyl)-2H-1,4-benzothiazin-3(4H)-one;
[0070]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-N-hydroxybenzenecarboximidamide;
[0071]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-N-hydroxybenzenecarboximidamide;
[0072]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidohydrazide;
[0073]
2-[3-(Aminomethyl)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0074]
2-(3-Aminophenyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0075]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-[3-(me-
thylamino)phenyl]-2H-1,4-benzothiazin-3(4H)-one;
[0076]
2-[3-(Dimethylamino)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-
H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0077]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-hydroxybenzenecarboximidamide;
[0078]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)tetrahydro-1(2H)-pyridinecarboximida-
mide;
[0079]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-pyrrolidinecarboximidamide;
[0080]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-thiophenecarboximidamide;
[0081]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-furancarboximidamide;
[0082]
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,3-oxazole-5-carboximidamide;
[0083]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,3-oxazole-2-carboximidamide;
[0084]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(1H-py-
razol-5-yl)-2H-1,4-benzothiazin-3(4H)-one;
[0085]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl
-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-pyrazolidinecarboximidamid-
e;
[0086]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1H-imidazole-2-carboximidamide;
[0087]
2-(2-Amino-1H-imidazol-4-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0088]
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1H-imidazole-5-carboximidamide;
[0089]
2-(5-Amino-1H-imidazol-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0090]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-pyr-
idinyl)-2H-1,4-benzothiazin-3(4H)-one;
[0091]
2-(4-Amino-3-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0092]
2-[4-(Dimethylamino)-3-pyridinyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0093]
2-(6-Amino-2-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0094]
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyridinecarboximidamide;
[0095]
2-(2-Amino-4-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0096]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyridinecarboximidamide;
[0097]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyrimidinecarboximidamide;
[0098]
2-(2-Amino-4-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0099]
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-pyrimidinecarboximidamide;
[0100]
2-(4-Amino-2-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0101]
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyrazinecarboximidamide;
[0102]
2-(6-Amino-2-pyrazinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0103]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,3,5-triazine-2-carboximidamide;
[0104]
2-(4-Amino-1,3,5-triazin-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0105]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,2,4-triazine-3-carboximidamide;
[0106]
2-(3-Amino-1,2,4-triazin-5-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0107]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]benzenecarboximidamide;
[0108]
2-(3-Aminobenzyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0109]
2-[3-(Aminomethyl)benzyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0110]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]tetrahydro-1(2H)-pyridinecar-
boximidamide;
[0111]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1-pyrrolidinecarboximidamid-
e;
[0112]
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-thiophenecarboximidamide;
[0113]
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-furancarboximidamide;
[0114]
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1,3-oxazole-5-carboximidami-
de;
[0115]
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1H-imidazole-2-carboximidam-
ide;
[0116]
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1H-imidazole-5-carboximidam-
ide;
[0117]
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyridinecarboximidamide;
[0118]
2-[(6-Amino-2-pyridinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0119]
4-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyrimidinecarboximidamide-
;
[0120]
2-[(2-Amino-4-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0121]
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-4-pyrimidinecarboximidamide-
;
[0122]
2-[(4-Amino-2-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0123]
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyrazinecarboximidamide;
[0124]
2-[(6-Amino-2-pyrazinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0125]
2-(3-Aminocyclohexyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyr-
idinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0126]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)cyclohexanecarboximidamide;
[0127]
2-[(3-Aminocyclohexyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1-
(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0128]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]cyclohexanecarboximidamide;
[0129]
2-(3-Aminocyclopentyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-py-
ridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0130]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)cyclopentanecarboximidamide;
[0131]
2-[(3-Aminocyclopentyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
[0132]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]cyclopentanecarboximidamide;
[0133]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]butyl-3-oxo--
3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0134]
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-3-oxo--
3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0135]
2-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothi-
azin-4-yl)-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetam-
ide;
[0136]
3-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothi-
azin-4-yl)-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropana-
mide;
[0137]
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamin-
o)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
[0138]
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyeth-
yl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0139]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0140]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-
-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0141]
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylpheny-
l)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0142]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-
-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0143]
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylm-
ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0144]
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclo-
hexyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0145]
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl--
3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0146]
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-
methyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0147]
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclo-
pentyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0148]
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pente-
nyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0149]
3-[3-Oxo-4-(5-piperidinopentyl)-3,4-dihydro-2H-1,4-benzothiazin-2-y-
l]benzenecarboximidamide;
[0150]
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,4-dihydro-2H--
1,4-benzothiazin-2-ylbenzenecarboximidamide;
[0151]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
thiazin-4-yl)pentyl]-2-piperidinecarboxylic acid;
[0152]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
thiazin-4-yl)pentyl]-3-piperidinecarboxylic acid;
[0153]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
thiazin-4-yl)pentyl]-4-piperidinecarboxylic acid;
[0154]
3-4-[5-(3,5-Dimethylpiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zothiazin-2-ylbenzenecarboximidamide;
[0155]
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzot-
hiazin-2-ylbenzenecarboximidamide;
[0156]
3-4-[5-(2-Iminopiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothi-
azin-2-ylbenzenecarboximidamide;
[0157]
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihydro-2H-1,4-benzothiaz-
in-2-ylbenzenecarboximidamide;
[0158]
3-[4-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-3-oxo-3,4-dihydr-
o-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
[0159]
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4-dihydro-2H-1,4-
-benzothiazin-2-yl)benzenecarboximidamide;
[0160]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
thiazin-4-yl)pentyl]-4-piperidinesulfonic acid;
[0161]
3-3-Oxo-4-[5-(2-phenylpiperidino)pentyl)-3,4-dihydro-2H-1,4-benzoth-
iazin-2-ylbenzenecarboximidamide;
[0162]
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,-
4-benzothiazin-2-ylbenzenecarboximidamide;
[0163]
3-3-Oxo-4-[5-(1-pyrrolidinyl)pentyl]-3,4-dihydro-2H-1,4-benzothiazi-
n-2-ylbenzenecarboximidamide;
[0164]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
thiazin-4-yl)pentyl]-2-pyrrolidinecarboxylic acid;
[0165]
N-1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-ben-
zothiazin-4-yl)pentyl]tetrahydro-1H-pyrrol-3-yl-N-methylacetamide;
[0166]
3-4-[5-(3-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zothiazin-2-ylbenzenecarboximidamide;
[0167]
3-(4-5-[2,5-Bis(methoxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihy-
dro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0168]
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2-
H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0169]
3-(4-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0170]
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothia-
zin-2-ylbenzenecarboximidamide;
[0171]
3-4-[5-(Diethylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin--
2-ylbenzenecarboximidamide;
[0172]
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-
-ylbenzenecarboximidamide;
[0173]
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4--
benzothiazin-2-ylbenzenecarboximidamide;
[0174]
3-4-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H--
1,4-benzothiazin-2-ylbenzenecarboximidamide;
[0175]
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-y-
l]benzenecarboximidamide;
[0176]
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zothiazin-2-ylbenzenecarboximidamide;
[0177]
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydro-2H-1,4-benzothiazin-2-y-
l]benzenecarboximidamide;
[0178]
3-4-[5-(2,6-Dimethylpiperazino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zothiazin-2-ylbenzenecarboximidamide;
[0179]
3-3-Oxo-4-[5-(1H-pyrazol-1-yl)pentyl]-3,4-dihydro-2H-1,4-benzothiaz-
in-2-ylbenzenecarboximidamide;
[0180]
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpentyl)-3,4-dihydro-2H-1,4--
benzothiazin-2-yl]benzenecarboximidamide;
[0181]
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-3-oxo-3,4-di-
hydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
[0182]
3-(6-Chloro-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pen-
tyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0183]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-flu-
oro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0184]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-6-sulfanyl-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0185]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(me-
thylsulfanyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximid-
amide;
[0186]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximi-
damide;
[0187]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-met-
hyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0188]
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic
acid;
[0189] Methyl
2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetr-
ahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-car-
boxylate;
[0190]
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0191]
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboximid-
amide;
[0192]
2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6--
carboximidamide;
[0193]
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[hyd-
razino(imino)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarb-
oximidamide;
[0194]
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxamid-
e;
[0195]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(hy-
droxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximida-
mide;
[0196]
3-(6-(Aminomethyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridi-
nyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidami-
de;
[0197]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-nit-
ro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0198]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-hyd-
roxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0199]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-met-
hoxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0200]
3-(6-(Benzyloxy)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridiny-
l]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide-
;
[0201]
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]-
acetic acid;
[0202]
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]-
propanoic acid;
[0203]
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]-
butanoic acid;
[0204]
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)amin-
o]acetic acid;
[0205]
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)amin-
o]propanoic acid;
[0206] 4-[(2-3-[Amino(imino)methyl]phenyl
-4-5-[(2R,6S)-2,6-dimethyltetrah-
ydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)ami-
no]butanoic acid;
[0207]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(2--
hydroxyethoxy)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximi-
damide;
[0208] 3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1
(2H)-pyridinyl]pentyl-3-ox-
o-6-(2H-1,2,3,4-tetraazol-5-ylmethoxy)-3,4-dihydro-2H-1,4-benzothiazin-2-y-
l]benzenecarboximidamide;
[0209] 3-(6-Amino-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pen-
tyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0210]
3-(6-(Butylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamid-
e;
[0211]
3-(6-(Dimethylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyri-
dinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximida-
mide;
[0212]
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pe-
ntyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
[0213]
3-(6-(Benzylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridi-
nyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidami-
de;
[0214]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)aceta-
mide;
[0215]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)cyclo-
hexanecarboxamide;
[0216]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-cy-
clohexylacetamide;
[0217]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)benze-
necarboxamide;
[0218]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-ph-
enylacetamide;
[0219]
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[(me-
thylsulfonyl)amino]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarbo-
ximidamide;
[0220]
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydr-
o-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzen-
ecarboximidamide;
[0221]
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-
benzenecarboximidamide;
[0222]
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo--
6-[(phenyl
sulfonyl)amino]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarb-
oximidamide;
[0223]
3-(6-[(Benzylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecar-
boximidamide;
[0224]
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-methoxybenzenecarboximidamide;
[0225]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0226]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-hyd-
roxyphenyl)-2H-1,4-benzoxazin-3(4H)-one;
[0227]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-N-hydroxybenzenecarboximidamide;
[0228]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidohydrazide;
[0229] 2-[3-(Aminomethyl)phenyl]-4-5
-[(2R,65)-2,6-dimethyltetrahydro-1(2H-
)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0230] 2-(3-Aminophenyl)-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridi-
nyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0231]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-[3-(me-
thylamino)phenyl]-2H-1,4-benzoxazin-3(4H)-one;
[0232]
2-[3-(Dimethylamino)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-
H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0233]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximidamide;
[0234]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)tetrahydro-1(2H)-pyridinecarboximidami-
de;
[0235]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-pyrrolidinecarboximidamide;
[0236]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-thiophenecarboximidamide;
[0237]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-furancarboximidamide;
[0238]
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3-oxazole-5-carboximidamide;
[0239]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3-oxazole-2-carboximidamide;
[0240]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(1H-py-
razol-5-yl)-2H-1,4-benzoxazin-3(4H)-one;
[0241]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-tetrah-
ydro-1H-pyrazol-3-yl-2H-1,4-benzoxazin-3(4H)-one;
[0242]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-pyrazolidinecarboximidamide;
[0243]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1H-imidazole-2-carboximidamide;
[0244]
2-(2-Amino-1H-imidazol-4-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0245]
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1H-imidazole-5-carboximidamide;
[0246]
2-(5-Amino-1H-imidazol-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0247]
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-pyr-
idinyl)-2H-1,4-benzoxazin-3(4H)-one;
[0248]
2-(4-Amino-3-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0249]
2-[4-(Dimethylamino)-3-pyridinyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0250]
2-(6-Amino-2-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0251]
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyridinecarboximidamide;
[0252]
2-(2-Amino-4-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0253]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyridinecarboximidamide;
[0254]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyrimidinecarboximidamide;
[0255]
2-(2-Amino-4-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0256]
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-pyrimidinecarboximidamide;
[0257]
2-(4-Amino-2-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0258]
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyrazinecarboximidamide;
[0259]
2-(6-Amino-2-pyrazinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-p-
yridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0260]
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3,5-triazine-2-carboximidamide;
[0261]
2-(4-Amino-1,3,5-triazin-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0262]
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,2,4-triazine-3-carboximidamide;
[0263]
2-(3-Amino-1,2,4-triazin-5-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0264]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]benzenecarboximidamide;
[0265]
2-(3-Aminobenzyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0266]
2-[3-(Aminomethyl)benzyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-
-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0267]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]tetrahydro-1(2H)-pyridinecarbo-
ximidamide;
[0268]
3-[(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-pyrrolidinecarboximidamide;
[0269]
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-thiophenecarboximidamide;
[0270]
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-furancarboximidamide;
[0271]
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1,3-oxazole-5-carboximidamide-
;
[0272]
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1H-imidazole-2-carboximidamid-
e;
[0273]
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1H-imidazole-5-carboximidamid-
e;
[0274]
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyridinecarboximidamide;
[0275]
2-[(6-Amino-2-pyridinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0276]
4-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyrimidinecarboximidamide;
[0277]
2-[(2-Amino-4-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0278]
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-4-pyrimidinecarboximidamide;
[0279]
2-[(4-Amino-2-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0280]
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyrazinecarboximidamide;
[0281]
2-[(6-Amino-2-pyrazinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0282]
2-(3-Aminocyclohexyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyr-
idinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0283]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)cyclohexanecarboximidamide;
[0284]
2-[(3-Aminocyclohexyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1-
(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0285]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]cyclohexanecarboximidamide;
[0286]
2-(3-Aminocyclopentyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-py-
ridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0287]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)cyclopentanecarboximidamide;
[0288]
2-[(3-Aminocyclopentyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
[0289]
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]cyclopentanecarboximidamide;
[0290]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]butyl-3-oxo--
3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0291]
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-3-oxo--
3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0292]
2-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxaz-
in-4-yl)-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamid-
e;
[0293]
3-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxaz-
in-4-yl)-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanami-
de;
[0294]
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamin-
o)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
[0295]
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyeth-
yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0296]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0297]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0298]
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylpheny-
l)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0299]
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-
-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0300]
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylm-
ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0301]
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclo-
hexyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0302]
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl--
3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0303]
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-
methyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0304]
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclo-
pentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0305]
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pente-
nyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0306]
3-[3-Oxo-4-(5-piperidinopentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]-
benzenecarboximidamide;
[0307]
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,4-dihydro-2H--
1,4-benzoxazin-2-ylbenzenecarboximidamide;
[0308]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
xazin-4-yl)pentyl]-2-piperidinecarboxylic acid;
[0309]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
xazin-4-yl)pentyl]-3-piperidinecarboxylic acid;
[0310]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
xazin-4-yl)pentyl]-4-piperidinecarboxylic acid;
[0311]
3-4-[5-(3,5-Dimethylpiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zoxazin-2-ylbenzenecarboximidamide;
[0312]
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzox-
azin-2-ylbenzenecarboximidamide;
[0313]
3-4-[5-(2-Iminopiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxaz-
in-2-ylbenzenecarboximidamide;
[0314]
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-
-2-ylbenzenecarboximidamide;
[0315]
3-[4-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-3-oxo-3,4-dihydr-
o-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
[0316]
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4-dihydro-2H-1,4-
-benzoxazin-2-yl)benzenecarboximidamide;
[0317]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
xazin-4-yl)pentyl]-4-piperidinesulfonic acid;
[0318]
3-3-Oxo-4-[5-(2-phenylpiperidino)pentyl]3,4-dihydro-2H-1,4-benzoxaz-
in-2-ylbenzenecarboximidamide;
[0319]
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,-
4-benzoxazin-2-ylbenzenecarboximidamide;
[0320] 3-3-Oxo-4-[5-(
1-pyrrolidinyl)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-
-2-ylbenzenecarboximidamide;
[0321]
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzo-
xazin-4-yl)pentyl]-2-pyrrolidinecarboxylic acid;
[0322]
N-1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-ben-
zoxazin-4-yl)pentyl]tetrahydro-1H-pyrrol-3-yl-N-methylacetamide;
[0323]
3-4-[5-(3-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zoxazin-2-ylbenzenecarboximidamide;
[0324]
3-(4-5-[2,5-Bis(methoxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihy-
dro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0325]
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2-
H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0326]
3-(4-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0327]
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazi-
n-2-ylbenzenecarboximidamide;
[0328]
3-4-[5-(Diethylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2--
ylbenzenecarboximidamide;
[0329]
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-y-
lbenzenecarboximidamide;
[0330]
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4--
benzoxazin-2-ylbenzenecarboximidamide;
[0331]
3-4-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H--
1,4-benzoxazin-2-ylbenzenecarboximidamide;
[0332]
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]-
benzenecarboximidamide;
[0333]
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zoxazin-2-ylbenzenecarboximidamide;
[0334]
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]-
benzenecarboximidamide;
[0335]
3-4-[5-(2,6-Dimethylpiperazino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-ben-
zoxazin-2-ylbenzenecarboximidamide;
[0336]
3-3-Oxo-4-[5-(1H-pyrazol-1-yl)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-
-2-ylbenzenecarboximidamide;
[0337]
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpentyl)-3,4-dihydro-2H-1,4--
benzoxazin-2-yl]benzenecarboximidamide;
[0338]
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-3-oxo-3,4-di-
hydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
[0339]
3-(6-Chloro-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pen-
tyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0340]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-flu-
oro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0341] 3-(4-5
-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-ox-
o-6-sulfanyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0342]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(me-
thylsulfanyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidam-
ide;
[0343]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximida-
mide;
[0344]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-met-
hyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0345]
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic
acid;
[0346] Methyl 2-3-[amino(imino)methyl]phenyl
-4-5-[(2R,6S)-2,6-dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carb-
oxylate;
[0347]
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0348] 2-3-[Amino(imino)methyl]phenyl-4-5
-[(2R,6S)-2,6-dimethyltetrahydro-
-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboximida-
mide;
[0349]
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro--
1(2H)-pyridinyl]pentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-ca-
rboximidamide;
[0350]
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[hyd-
razino(imino)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarbox-
imidamide;
[0351] 2-3-[Amino(imino)methyl]phenyl-4-5
-[(2R,6S)-2,6-dimethyltetrahydro- -1(2H)-pyridinyl]pentyl
-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamid- e;
[0352]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(hy-
droxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidami-
de;
[0353]
3-(6-(Aminomethyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridi-
nyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide-
;
[0354]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-nit-
ro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0355]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-hyd-
roxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0356]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-met-
hoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0357]
3-(6-(Benzyloxy)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridiny-
l]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0358] 2-[(2-3-[Amino(imino)methyl]phenyl
-4-5-[(2R,6S)-2,6-dimethyltetrah-
ydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]a-
cetic acid
[0359]
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]pr-
opanoic acid;
[0360]
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]bu-
tanoic acid;
[0361]
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]-
acetic acid;
[0362]
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]-
propanoic acid;
[0363]
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahy-
dro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]-
butanoic acid;
[0364]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(2--
hydroxyethoxy)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximida-
mide;
[0365]
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-6-(2H-1,2,3,4-tetraazol-5-ylmethoxy)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]b-
enzenecarboximidamide;
[0366]
3-(6-Amino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pent-
yl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0367]
3-(6-(Butylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridin-
yl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0368]
3-(6-(Dimethylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyri-
dinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidami-
de;
[0369]
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pe-
ntyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
[0370]
3-(6-(Benzylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridi-
nyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide-
;
[0371]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)acetami-
de;
[0372]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)cyclohe-
xanecarboxamide;
[0373]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-cycl-
ohexylacetamide;
[0374]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)benzene-
carboxamide;
[0375]
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahyd-
ro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-phen-
ylacetamide;
[0376] 3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl
-6-[(methylsulfonyl)amino]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzen-
ecarboximidamide;
[0377]
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydr-
o-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenec-
arboximidamide;
[0378]
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-dimethyltet-
rahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)be-
nzenecarboximidamide;
[0379]
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo--
6-[(phenyl
sulfonyl)amino]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarbox-
imidamide;
[0380]
3-(6-[(Benzylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(-
2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarbo-
ximidamide;
[0381] 2H-1,4-Benzoxazin-3(4H)-one,
4-[3-(2,6-dimethyl-1-piperidinyl)propy- l]-2-phenyl-;
[0382] 4-[5-(2,5-Dimethyl-pyrrolidin-1-yl)-pentyl]-2-phenyl
-4H-benzo[1,4]oxazin-3-one;
[0383] 2H-1,4-Benzoxazin-3(4H)-one,
4-[5-[bis(1-methylethyl)amino]pentyl]-- 2-phenyl-;
[0384] 2H-1,4-Benzoxazin-3(4H)-one,
4-[3-(2,5-dimethyl-1-pyrrolidinyl)prop- yl]-2-phenyl-;
[0385] 2H-1,4-Benzoxazin-3(4H)-one,
4-[3-[bis(1-methylethyl)amino]propyl]-- 2-phenyl-;
[0386]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-phenyl-4H-benzo[1,4]ox-
azin-3-one;
[0387]
4-(5-Diethylamino-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
[0388] 2-Phenyl-4-(5-pyrrolidin-1-yl-pentyl)-4H-benzo[
1,4]oxazin-3-one;
[0389] 2-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[
1,4]oxazin-4-yl)-pentyl]-is- oindole-1,3-dione;
[0390]
4-(5-Imidazol-1-yl-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
[0391]
2-(4-Chloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-b-
enzo[1,4]oxazin-3-one;
[0392]
2-(2-Chloro-phenyl)-4-[5-(2,5-dimethyl-pyrrolidin-1-yl)-pentyl]-4H--
benzo[1,4]oxazin-3-one;
[0393]
2-(2-Chloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-b-
enzo[1,4]oxazin-3-one;
[0394]
5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentanamidine;
[0395]
2-Phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
[0396]
2-(4-Chloro-phenyl)-4-[5-(2,5-dimethyl-pyrrolidin-1-yl)-pentyl]-4H--
benzo[1,4]oxazin-3-one;
[0397]
2-Phenyl-4-(5-pyrrolidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
compound with trifluoro-acetic acid;
[0398]
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzonit-
rile;
[0399]
4-[6-(2,5-Dimethyl-pyrrolidin-1-yl)-hexyl]-2-phenyl-4H-benzo[1,4]ox-
azin-3-one;
[0400]
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamid-
ine;
[0401]
2-Naphthalen-2-yl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0402] 4-(5-Amino-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
[0403]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-phenyl-4H-benzo[1,4]ox-
azin-3-one;
[0404]
6-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0405]
7-Methoxy-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin--
3-one;
[0406]
8-Chloro-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0407]
3-Oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-6-carbonitrile;
[0408]
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamid-
ine;
[0409]
1-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-pip-
eridine-2,6-dione;
[0410]
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionitrile;
[0411]
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-butyronitrile;
[0412]
5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentanenitrile-
;
[0413]
N-[3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propyl]-gua-
nidine;
[0414]
N-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-gua-
nidine;
[0415]
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamid-
ine;
[0416]
2-(4-Methoxy-phenyl)-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazi-
n-3-one;
[0417]
7-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0418]
5-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0419] 6-Methoxy-2-phenyl
-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin- -3-one;
[0420]
N-Hydroxy-4-(3-oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl-
)-benzamidine;
[0421]
6-Chloro-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0422]
2-(4-Methoxy-phenyl)-4-(5-piperazin-1-yl-pentyl)-4H-benzo[1,4]oxazi-
n-3-one;
[0423]
2-(4-Hydroxy-phenyl)-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazi-
n-3-one;
[0424]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-hydroxy-phenyl)-4H--
benzo[1,4]oxazin-3-one;
[0425]
2-(4-Methoxy-phenyl)-4-[5-(4-methyl-piperazin-1-yl)-pentyl]-4H-benz-
o[1,4]oxazin-3-one;
[0426]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl }-benzonitrile;
[0427]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl }-benzamidine;
[0428]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl }-thiobenzamide;
[0429]
[2-(4-Methoxy-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acet-
ic acid;
[0430]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl }-N-hydroxy-benzamidine;
[0431] Benzenecarboximidic acid,
4-[3,4-dihydro-4-[5-(2,6-dimethyl-1-piper-
idinyl)pentyl]-3-oxo-2H-1,4-benzoxazin-2-yl]-, hydrazide;
[0432]
6-Amino-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3--
one;
[0433]
4-(5-Bromo-pentyl)-2-(3,4-dimethoxy-phenyl)-4H-benzo[1,4]oxazin-3-o-
ne;
[0434]
4-(5-Bromo-pentyl)-2-(3,4,5-trimethoxy-phenyl)-4H-benzo[1,4]oxazin--
3-one;
[0435]
4-(5-Bromo-pentyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
[0436]
N-[2-(2,6-Dimethyl-piperidin-1-yl)-ethyl]-2-[2-(4-methoxy-phenyl)-3-
-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide;
[0437]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(3,4,5-trimethoxy-phen-
yl)-4H-benzo[1,4]oxazin-3-one;
[0438]
2-(3,4-Dimethoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-
-4H-benzo[1,4]oxazin-3-one;
[0439]
2-(4-Bromo-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-be-
nzo[1,4]oxazin-3-one;
[0440]
8-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-
-one;
[0441]
2-(4-Benzylamino-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-
-4H-benzo 1,4]oxazin-3-one;
[0442]
2-(4-Methoxy-phenyl)-4-[5-(2,2,6,6-tetramethyl-piperidin-1-yl)-pent-
yl]-4H-benzo[1,4]oxazin-3-one;
[0443]
4-(2-Bromo-ethyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
[0444]
4-(5-Bromo-pentyl)-2-(3,4-dichloro-phenyl)-4H-benzo[1,4]oxazin-3-on-
e;
[0445]
4-(2-Hydroxy-ethyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
[0446]
2-(3,4-Dichloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]--
4H-benzo[1,4]oxazin-3-one;
[0447]
4-[3-(2,6-Dimethyl-piperidin-1-ylmethyl)-benzyl]-2-(4-methoxy-pheny-
l)-4H-benzo[1,4]oxazin-3-one;
[0448]
4-(2-Amino-ethyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
[0449]
2-(2,6-Dimethyl-piperidin-1-yl)-N-{2-[2-(4-methoxy-phenyl)-3-oxo-2,-
3-dihydro-benzo[1,4]oxazin-4-yl]-ethyl }-acetamide;
[0450]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-5-oxo-pentyl]-2-(4-methoxy-pheny-
l)-4H-benzo[1,4]oxazin-3-one;
[0451]
3-{4-[4-(2,6-Dimethyl-piperidin-1-yl)-butyl]-3-oxo-3,4-dihydro-2H-b-
enzo[1,4]oxazin-2-yl}-benzamidine;
[0452]
3-{4-[6-(2,6-Dimethyl-piperidin-1-yl)-hexyl]-3-oxo-3,4-dihydro-2H-b-
enzo[1,4]oxazin-2-yl}-benzamidine;
[0453] 2-(5-Aminomethyl-2-hydroxy-phenyl
)-4-[5-(2,6-dimethyl-piperidin-1--
yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
[0454]
2-(3-Aminomethyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-
-4H-benzo[1,4]oxazin-3-one;
[0455]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-7-methyl-3-oxo-3,4-di-
hydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0456]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-4-methoxy-benzamidine;
[0457]
2-(5-Aminomethyl-2-methoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-y-
l)-pentyl]-4H-benzo[1,4]oxazin-3-one;
[0458]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-N-hydroxy-4-methoxy-benzamidine;
[0459]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-N-hydroxy-benzamidine;
[0460]
3-{7-Chloro-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-di-
hydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0461] 4-(5-Bromo-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
[0462]
3-[3-Oxo-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazi-
n-2-yl]-benzamidine;
[0463]
N-{2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pe-
ntyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-acetamide;
[0464]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-methyl-3-oxo-3,4-di-
hydro-2H-benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
[0465]
3-[4-(5-Diisopropylamino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxa-
zin-2-yl]-benzamidine;
[0466]
3-(4-{4-[(Diisopropylamino)-methyl]-benzyl}-3-oxo-3,4-dihydro-2H-be-
nzo[1,4]oxazin-2-yl)-benzamidine;
[0467] 3-{4-[4-(2,6-Dimethyl-piperidin-1-yl
methyl)-benzyl]-3-oxo-3,4-dihy-
dro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0468]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
[0469]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-N-methyl-benzamidine;
[0470]
{2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pent-
yl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-acetic acid;
[0471]
3-(4-{3-[(Diisopropylamino)-methyl]-benzyl}-3-oxo-3,4-dihydro-2H-be-
nzo[1,4]oxazin-2-yl)-benzamidine;
[0472]
3-{4-[3-(2,6-Dimethyl-piperidin-1-ylmethyl)-benzyl]-3-oxo-3,4-dihyd-
ro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0473]
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-penty-
l]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid;
[0474]
3-{3-Oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-benzo[1,4]o-
xazin-2-yl}-benzamidine;
[0475]
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-penty-
l]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methyl
ester;
[0476]
3-[4-(5-Dihexylamino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin--
2-yl]-benzamidine;
[0477]
3-{4-[4-(Methyl-pyridin-2-yl-amino)-butyl]-3-oxo-3,4-dihydro-2H-ben-
zo[1,4]oxazin-2-yl}-benzamidine;
[0478]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-[3-(imino-morpholin-4--
yl-methyl)-phenyl]-4H-benzo[1,4]oxazin-3-one;
[0479]
3-{3-Oxo-4-[4-(pyrimidin-2-ylamino)-butyl]-3,4-dihydro-2H-benzo[1,4-
]oxazin-2-yl}-benzamidine;
[0480]
3-[4-(4-Cyclohexylamino-butyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazi-
n-2-yl]-benzamidine;
[0481]
3-{4-[5-(2,5-Dimethyl-pyrrolidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-
-benzo[1,4]oxazin-2-yl}-benzamidine;
[0482]
3-[4-(5-Morpholin-4-yl-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazi-
n-2-yl]-benzamidine;
[0483]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-2,3-dihydroxy-pentyl]-3-oxo-3-
,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0484]
4-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4--
ylmethyl]-N,N-dimethyl-benzamide;
[0485]
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-penty-
l]-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazine-6-carboxylic acid;
[0486]
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4--
ylmethyl]-N,N-dimethyl-benzamide;
[0487]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pent-2-enyl]-3-oxo-3,4-dihydr-
o-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0488]
3-[4-(5-Amino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-b-
enzamidine;
[0489]
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-penty-
l]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl
ester;
[0490]
4-Methoxy-3-[4-(4-methoxy-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]ox-
azin-2-yl]-benzonitrile;
[0491]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pent-3-enyl]-3-oxo-3,4-dihydr-
o-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
[0492]
4-[2-(3-Cyano-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl-
]-N,N-dimethyl-benzamide;
[0493]
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4--
ylmethyl]-5-(2,6-dimethyl-piperidin-1-ylmethyl)-benzoic acid;
[0494]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
[0495] 3-Acetyl-2-(2-methoxy-phenyl)-thiazolidine-4-carboxylic acid
4-cyano-2-{4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2-
H-benzo[1,4]oxazin-2-yl}-phenyl ester;
[0496]
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4--
ylmethyl]-5-(2,6-dimethyl-piperidin-1-ylmethyl)-N-hydroxy-benzamide;
[0497]
4-(2-Dimethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-o-
ne;
[0498]
4-(2-Diethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-on-
e;
[0499] 2H-1,4-Benzothiazin-3(4H)-one,
4-[2-(dimethylamino)ethyl]-7-nitro-2- -phenyl-,
monohydrochloride;
[0500] 2H-1,4-Benzothiazin-3(4H)-one,
4-[2-(diethylamino)ethyl]-7-nitro-2-- phenyl-,
monohydrochloride;
[0501]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-4H--
benzo[1,4]thiazin-3-one;
[0502]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl) -benzonitrile;
[0503]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-thiobenzamide;
[0504]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-4H--
benzo[1,4]thiazin-3-one; compound with trifluoro-acetic acid;
[0505]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-benzonitrile;
[0506]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-benzamide;
[0507]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(3-methoxy-phenyl)-2-(-
4-methoxy-phenyl)-4H-benzo[1,4]thiazin-3-one;
[0508]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-1,1-
-dioxo-1,4-dihydro-2H-1>6_-benzo[1,4]thiazin-3-one;
[0509]
2-(4-Benzyloxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4-
H-benzo[1,4]thiazin-3-one;
[0510]
2-(4-Butoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-b-
enzo[1,4]thiazin-3-one;
[0511]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-thiobenzamide;
[0512]
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-benzamidine;
[0513]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-N-hydroxy-benzamidine;
[0514]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]thiazin-2-yl}-benzamidine;
[0515]
3-{4-[5-(2-Hydroxymethyl-pyrrolidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-
-2H-benzo[1,4]thiazin-2-yl}-benzamidine;
[0516] 4-Allyl-2,2-diphenyl-4H-benzo[1,4]thiazin-3-one;
[0517]
4-(2-Diethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-on-
e;
[0518]
2-(3-Diethylamino-propylamino)-4-methyl-2-phenyl-4H-benzo[1,4]thiaz-
in-3-one;
[0519]
4-(2-Diethylamino-ethyl)-2,2-diphenyl-4H-benzo[1,4]thiazin-3-one;
[0520]
2-Benzyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
[0521]
2-Cyclohexyl-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,-
4]thiazin-3-one;
[0522] 2H-1,4-Benzothiazin-3(4H)-one, 4-methyl-2,2-diphenyl-;
[0523]
4-Ethyl-2-phenyl-2-piperidin-1-yl-4H-benzo[1,4]thiazin-3-one;
[0524]
4-Methyl-2-phenyl-2-piperidin-1-yl-4H-benzo[1,4]thiazin-3-one;
[0525]
3-{4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-piperidine-1-carboxamidine;
[0526]
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-piperidin-3-yl-4H-benz-
o[1,4]oxazin-3-one;
[0527]
3-Oxo-2-phenyl-2,4-bis-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-6-carbonitrile;
[0528] 4-[5-(2,6-Dimethyl
-piperidin-1-yl)-pentyl]-2-pyridin-2-yl-4H-benzo-
[1,4]oxazin-3-one;
[0529]
N-Hydroxy-3-oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-
-benzo[1,4]oxazine-6-carboxamidine;
[0530]
3-Oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-6-carboxamidine;
[0531]
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H--
benzo[1,4]oxazin-2-yl}-thiobenzamide;
[0532]
3-{4-[5-(Adamantan-1-ylamino)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,-
4]oxazin-2-yl}-benzamidine;
[0533]
2-(3-Diethylamino-propylamino)-4-methyl-2-phenyl-4H-benzo[1,4]oxazi-
n-3-one;
[0534]
4-[3-(2,6-Dimethyl-1-piperidinyl)propyl]-2-phenyl-2H/-1,4-benzoxazi-
n-3(4H/)-one; and
[0535] 4-Methyl-2-phenyl-2H/-1,4-benzoxazin-3(4H/)-one.
DETAILED DESCRIPTION OF THE INVENTION
[0536] The term "alkyl" means a straight, branched, saturated or
unsaturated carbon chain having from 1 to 20 carbon atoms. Typical
alkyl groups include methyl, isobutyl, pentyl, 2-methyl-pentyl,
pent-1,4-dienyl, but-1-enyl and the like.
[0537] The term "cycloalkyl" means a saturated or unsaturated
carbon chain which forms a ring having from 3 to 20 carbon atoms.
Typical examples include cyclopropyl, cyclohexyl and the like.
[0538] The term "cycloalkylalkyl" means a cycloalkyl group attached
to an alkyl group wherein "cycloalkyl" and "alkyl" are as defined
above and includes, for example, cyclopropylmethyl,
cyclopentylethyl and the like.
[0539] The term "heteroalkyl" means a straight, branched, saturated
or unsaturated carbon chain having from 1 to 20 carbon atoms
wherein one or more carbon atoms is replaced by a heteroatom
selected from oxygen, nitrogen, sulfur, sulphoxide or sulphone.
Typical "heteroalkyl" groups include methoxymethyl,
3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl and the like.
[0540] The term "aryl" represents an unsaturated carbocyclic
ring(s) of 6 to 16 carbon atoms which is optionally substituted
with, OH, O(alkyl), SH, S(alkyl), amine, halogen, acid, ester,
amide, alkyl ketone, aldehyde, nitrile, fluoroalkyl, amidine,
nitro, sulphone, sulfoxide or (C.sub.1-6)alkyl, thioamide,
Oalkylaryl, benzylamino, C(NH)(NHNH.sub.2), N-hydroxyamidine,
N-methylamidine. Typical rings include phenyl, naphthyl,
phenanthryl, and anthracenyl. Preferred aryl rings are phenyl,
substituted phenyl, and naphthyl.
[0541] The term "arylalkyl" means an aromatic radical attached to
an alkyl radical wherein "aryl" and "alkyl" are as defined above
and includes, for example, benzyl, and naphthylmethyl.
[0542] The term "heterocycle" means a saturated or unsaturated
mono- or polycyclic (i.e. bicyclic) ring incorporating one or more
(i.e. 1-4) heteroatoms selected from N, O, and S. It is understood
that a heterocycle is optionally substituted with OH, O(alkyl), SH,
S(alkyl), amine, halogen, acid, ester, amide, amidine alkyl ketone,
aldehyde, nitrile, fluoroalkyl, nitro, sulphone, sulfoxide or
C.sub.1-6 alkyl. Examples of suitable monocyclic heterocycles
include, but are not limited to substituted or unsubstituted
thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl,
piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl,
oyetanyl. Preferred monoydicheterocycles include, but are not
limited to, 2- or 3-thienyl, 2- or 3-furanyl, 1-, 2-, or
3-pyrrolyl, 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or
5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-,
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 1,3-, or 5-triazolyl,
1-, 2-, or 3-tetrazolyl, 2, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-,
4-, or 5-pyrimidinyl, 1-, 2-, 3-, or 4-piperidinyl, 1-, 2-, or
3-pyrrolidinyl, 1- or 2-piperazinyl, 1-, 2-, or 3-azetidinyl, 1- or
2-aziridinyl, 2-, 3-, or 4-morpholinyl, 2- or 3-thietanyl, 2- or
3-oxetanyl. Examples of suitable bicyclic heterocycles include, but
are not limited to, indolizinyl, isoindolyl, benzothienyl,
benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, and
preferably 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 1-, 2-, 3-, 5-,
6-, 7-, or 8-indolizinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl,
2-, 3-, 4-, 5-, 6-, or 7-benzothienyl, 2-, 4-, 5-, 6-, or
7-benzoxazolyl, 1-, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 3-,
4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or
8-isoquinolinyl.
[0543] The term "heteroatom" as used herein represents oxygen,
nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl
(SO or SO2) unless otherwise indicated. It is understood that alkyl
chains interrupted by one or more heteroatoms means that a carbon
atom of the chain is replaced with a heteroatom having the
appropriate valency. Preferably, an alkyl chain is interrupted by 1
to 4 heteroatoms and that two adjacent carbon atoms are not both
replaced. Examples of such groups include methoxymethyl,
3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl.
[0544] The term "amine" refers to a group such as NH.sub.2,
NHalkyl, NH(cycloalkyl), NH(cycloalkylalkyl), NH(aryl),
NH(arylalkyl), NH(heteroaryl), NH(heteroarylalkyl),
N(alkyl)(alkyl), N(alkyl)(cycloalkyl), N(alkyl)(cycloalkylalkyl),
N(alkyl)(aryl), N(alkyl)(arylalkyl), N(alkyl)(heteroaryl),
N(alkyl)(heteroarylalkyl), N(cycloalkyl)(cycloalkyl),
N(cycloalkyl)(cycloalkylalkyl), N(cycloalkyl)(aryl),
N(cycloalkyl)(arylalkyl), N(cycloalkyl)(heteroaryl),
N(cycloalkyl)(heteroarylalkyl),
N(cycloalkylalkyl)(cycloalkylalkyl), N(cycloalkylalkyl)(aryl),
N(cycloalkylalkyl)(arylalkyl), N(cycloalkylalkyl)(heteroaryl),
N(cycloalkylalkyl)(heteroarylalkyl), N(aryl)(cycloalkylalkyl),
N(aryl)(aryl), N(aryl)(arylalkyl), N(aryl)(heteroaryl),
N(aryl)(heteroarylalkyl), N(arylalkyl)(arylalkyl),N(-
arylalkyl)(heteroaryl), N(arylalkyl)(heteroaryl alkyl),
N(heteroaryl)(heteroaryl), N(heteroaryl)(heteroarylalkyl),
N(heteroaryl alkyl)(heteroarylalkyl).
[0545] The term "acid" refers to C(.dbd.O)OH.
[0546] The term "ketone" refers to C(.dbd.O)alkyl,
C(.dbd.O)cycloalkyl, C(.dbd.O)cycloalkylalkyl, C(.dbd.O)aryl,
C(.dbd.O)arylalkyl, C(.dbd.O)heteroaryl,
C(.dbd.O)heteroarylalkyl.
[0547] The term "ester" refers to a group such as C(.dbd.O)Oalkyl,
C(.dbd.O)Ocycloalkyl, C(.dbd.O)Ocycloalkylalkyl, C(.dbd.O)Oaryl,
C(.dbd.O)Oarylalkyl, C(.dbd.O)Oheteroaryl,
C(.dbd.O)Oheteroarylalkyl.
[0548] The term "amide" refers to a group such as,
C(.dbd.O)NH.sub.2, C(.dbd.O)NHalkyl, C(.dbd.O)NH(cycloalkyl),
C(.dbd.O)NH(cycloalkylalkyl), C(.dbd.O)NH(aryl),
C(.dbd.O)NH(arylalkyl), C(.dbd.O)NH(heteroaryl),
C(.dbd.O)NH(heteroarylalkyl), C(.dbd.O)N(alkyl)(alkyl),
C(.dbd.O)N(alkyl)(cycloalkyl), C(.dbd.O)N(alkyl)(cycloalkylalkyl),
C(.dbd.O)N(alkyl)(aryl), C(.dbd.O)N(alkyl)(arylalkyl),
C(.dbd.O)N(alkyl)(heteroaryl), C(.dbd.O)N(alkyl)(heteroarylalkyl),
C(.dbd.O)N(cycloalkyl)(cycloalkyl),
C(.dbd.O)N(cycloalkyl)(cycloalkylalky- l),
C(.dbd.O)N(cycloalkyl)(aryl), C(.dbd.O)N(cycloalkyl)(arylalkyl),
C(.dbd.O)N(cycloalkyl)(heteroaryl),
C(.dbd.O)N(cycloalkyl)(heteroarylalky- l),
C(.dbd.O)N(cycloalkylalkyl)(cycloalkylalkyl),
C(.dbd.O)N(cycloalkylalk- yl)(aryl),
C(.dbd.O)N(cycloalkylalkyl)(arylalkyl), C(.dbd.O)N(cycloalkylal-
kyl)(heteroaryl), C(.dbd.O)N(cycloalkylalkyl)(heteroarylalkyl),
C(.dbd.O)N(aryl)(cycloalkylalkyl), C(.dbd.O)N(aryl)(aryl),
C(.dbd.O)N(aryl)(arylalkyl), C(.dbd.O)N(aryl)(heteroaryl),
C(.dbd.O)N(aryl)(heteroarylalkyl),
C(.dbd.O)N(arylalkyl)(arylalkyl),
C(.dbd.O)N(arylalkyl)(heteroaryl),
C(.dbd.O)N(arylalkyl)(heteroarylalkyl)- ,
C(.dbd.O)N(heteroaryl)(heteroaryl),
C(.dbd.O)N(heteroaryl)(heteroarylalk- yl),
C(.dbd.O)N(heteroarylalkyl)(heteroarylalkyl).
[0549] The term "urea" refers to a group such as
NHC(.dbd.O)N(alkyl)(alkyl- ), NHC(.dbd.O)N(alkyl)(cycloalkyl),
NHC(.dbd.O)N(alkyl)(cycloalkylalkyl), NHC(.dbd.O)N(alkyl)(aryl),
NHC(.dbd.O)N(alkyl)(arylalkyl), NHC(.dbd.O)N(alkyl)(heteroaryl),
NHC(.dbd.O)N(alkyl)(heteroarylalkyl),
NHC(.dbd.O)N(cycloalkyl)(cycloalkyl),
NHC(.dbd.O)N(cycloalkyl)(cycloalkyl- alkyl),
NHC(.dbd.O)N(cycloalkyl)(aryl), NHC(.dbd.O)N(cycloalkyl)(arylalkyl-
), NHC(.dbd.O)N(cycloalkyl)(heteroaryl),
NHC(.dbd.O)N(cycloalkyl)(heteroar- ylalkyl),
NHC(.dbd.O)N(cycloalkyl alkyl)(cycloalkylalkyl),
NHC(.dbd.O)N(cycloalkylalkyl)(aryl),
NHC(.dbd.O)N(cycloalkylalkyl)(arylal- kyl),
NHC(.dbd.O)N(cycloalkylalkyl)(heteroaryl),
NHC(.dbd.O)N(cycloalkylal- kyl)(heteroarylalkyl),
NHC(.dbd.O)N(aryl)(cycloalkylalkyl), NHC(.dbd.O)N(aryl)(aryl),
NHC(.dbd.O)N(aryl)(arylalkyl), NHC(.dbd.O)N(aryl)(heteroaryl),
NHC(.dbd.O)N(aryl)(heteroarylalkyl),
NHC(.dbd.O)N(arylalkyl)(arylalkyl),
NHC(.dbd.O)N(arylalkyl)(heteroaryl),
NHC(.dbd.O)N(arylalkyl)(heteroarylalkyl),
NHC(.dbd.O)N(heteroaryl)(hetero- aryl),
NHC(.dbd.O)N(heteroaryl)(heteroarylalkyl),
NHC(.dbd.O)N(heteroaryla- lkyl)(heteroarylalkyl).
[0550] The term "halogen" refers to chlorine, fluorine, bromine,
and iodine.
[0551] The wedge or hash is only one representation of a
stereochemical descriptor. All stereoisomers, including enantiomers
and diastereomers, are included within Formulas 1-8 and are
provided by this invention. When specific isomers are drawn, they
are the preferred isomers.
[0552] In some situations, compounds may exist as tautomers. All
tautomers are included within Formulas 1-8 and are provided by this
invention.
[0553] When compounds are administered, some metabolism may occur.
All metabolites are included within Formulas 1-8 and are provided
by this invention.
[0554] When a bond to a substituent is shown to cross the bond
connecting 2 atoms in a ring, then such substituent may be bonded
to any atom in the ring, provided the atom will accept the
substituent without violating its valency. When there appears to be
several atoms of the substituent that may bond to the ring atom,
then it is the first atom of the listed substituent that is
attached to the ring.
[0555] When a bond is represented by a line such as " _ _ _," this
is meant to represent that the bond may be absent or present
provided that the resultant compound is stable and of satisfactory
valency.
[0556] Compounds of the present invention are capable of forming
acid addition salts (see for example, Berge S. M., et al.,
"Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977:1
-10) with inorganic acids such as, for example, hydrochloric acid,
sulfuric acid and the like, as well as salts derived from organic
acids such as, for example, aliphatic mono and dicarboxylic acids
or aliphatic and aromatic sulphonic acids. The acid addition salts
are prepared by contacting the free base form with a sufficient
amount of the desired acid to produce the salt. The free base form
may be regenerated by contacting the salt form with a base. While
the free base more may differ from the salt form in terms of
physical properties, such as solubility, the salts are equivalent
to their respective free bases for the purposes of the present
invention.
[0557] Certain compounds of the present invention can exist in
unsolvated form as well as solvated form including hydrated form.
In general, the solvated form including hydrated form is equivalent
to unsolvated form and is intended to be encompassed within the
scope of the present invention.
[0558] "Prodrugs" are intended to include any covalently bonded
carrier which releases the active parent drug according to Formulas
1-8 in vivo. Examples of prodrugs include acetates, formates,
benzoate derivatives of alcohols and amines present in compounds of
Formulas 1-8. They also include derivatives of the amidine or
guanine functionality and would include C(.dbd.NR.sub.3)NH.sub.2
where R.sub.3 is selected from OH, NH.sub.2, C.sub.1-4 alkoxy,
C.sub.6-10 aryloxy, C.sub.1-10 alkoxycarbonyl, C.sub.6-10
aryloxycarbonyl. Preferred derivatives include examples wherein
R.sub.3 is OH, NH.sub.2, methoxy, and ethoxycarbonyl.
[0559] The following table provides a list of abbreviations and
definitions thereof used in the present invention.
1 Abbreviation Description AMC aminomethylcoumarin aPTT activated
partial thromboplastin time BOC tertiary-butyloxycarbonyl
BOP-reagent benzotriazol-1-yloxy-tris(dimethylamino) phosphonium
hexafluorophosphate Bz benzoate CDCl.sub.3 deuterochloroform DMF
dimethyl formamide DMSO dimethylsulfoxide .sup.1H-NMR proton
nuclear magnetic resonance HCl hydrogen chloride HF hydrogen
fluoride HMPA hexamethylphosphoramide HPLC high pressure liquid
chromatography MOT mean occlusion time MS(APCI) mass spectrometry
(atmospheric pressure CI) MS(CI) mass spectrometry (chemical
ionization) MS(ES) mass spectrometry (electro spray) NaOH sodium
hydroxide uBuLi n-butyl lithium NH.sub.4Cl ammonium chloride Pd/C
palladium on carbon PtO.sub.2 platinum oxide r.t. or RT room
temperature TFA trifluoroacetic acid THF tetrahydrofuran TT
thrombin time VAZO-52 2,2'-Azobis-2-methylvaleronitrile
[0560] Also provided by this invention is a method for preventing
and treating acute, subacute, and chronic thrombotic disorder in a
mammal comprising administering to such mammal an effective amount
of a compound of Formulas 1-8. The compounds are useful as
anticoagulants for the treatment and prophylaxis of disorders such
as venous and arterial thrombosis, pulmonary embolism, and ischemic
events such as myocardial infarction or cerebral infarction. These
compounds also have therapeutic utility for the prevention and
treatment of complications of indwelling vascular access ports and
arteriovenous shunts and coagulopathies associated with
cardiopulmonary bypass or other extracorporeal systems. These
compounds are useful for preventing or treating unstable angina,
refractory angina, intermittent claudication, disseminated
intravascular coagulation, and ocular buildup of fibrin. Since
thrombin and serine proteases have also been demonstrated to
activate a number of different cell types, these compounds are
useful for the treatment or prophylaxis of septic shock and other
inflammatory responses such as acute or chronic atherosclerosis.
The compounds also have utility in treating neoplasia/metastasis
and neurodegenerative diseases such as Alzheimer's and Parkinson's
disease. In a preferred method, the thrombotic disorder is selected
from venous thrombosis, arterial thrombosis, pulmonary embolism,
myocardial infarction, cerebral infarction, angina, cancer,
diabetes. A further embodiment of this invention is a
pharmaceutical formulation comprising a compound of Formulas 1-8
administered with a diluent, excipient, or carrier thereof.
PREPARATION OF COMPOUNDS OF THE INVENTION
[0561] The compounds of Formulas 1-8 can be prepared by any of
various methods known to those skilled in the art of organic
chemistry. The following general schemes represent preferred routes
to provide the compounds of this disclosure. The reactions are
typically performed in solvents appropriate to the reagents and
substrates employed. It is understood that functionality present in
the molecule must be compatible with the reagents and reaction
conditions proposed. Not all compounds of Formulas 1-8 falling into
a given class may be compatible with some of the reaction
conditions described. Such restrictions are readily apparent to
those skilled in the art of organic synthesis, and alternative
methods must then be used. 8
[0562] Step a:
[0563] The aldehyde is converted to the trichloromethyl carbinol by
treatment with carbon tetrachloride and aluminum/lead bromide DMF
at room temperature according to the procedure of Tanaka J., Org.
Chem., 1989:444. Alternative procedures include the addition of
trimethylsilyl trichloromethane and tetrabutylammonium fluoride or
more typically chloroform and potassium hydroxide as exemplified by
Galun, Org. Synth. Coll., 1973;V: 130. It should also be noted that
trimethylsilyl trichloroacetate in the presence of potassium
fluoride is an effective process for the preparation of
trichlormethylcarbinols as exemplified by Weissman, Org. Proced.
Int., 1995;27(5):590-592.
[0564] Step b:
[0565] Addition of o-aminophenol and base affords the benzoxazinone
in a manner similar to the procedure of Gukasyan et al., Arm. Khim.
Zh., 1988;41 (9):572-575. This typically involves treatment of the
trichloromethyl carbinol with a suitably substituted ortho-amino
phenol in a solvent such as DMF or DMSO in the presence of
potassium hydroxide or sodium hydride at room temperature to
100.degree. C. It is apparent that by employing chiral
trichloromethyl carbinol, the resulting benzoxazinone will be
obtained in chiral form.
[0566] Step c:
[0567] Alkylation is typically achieved by treatment with an
appropriate electrophile and by the addition of a base in a dipolar
aprotic solvent. Typical conditions include, for example, use of a
bis-electrophilic substrate such as 1,5-dibromopentane in a dipolar
aprotic solvent such as DMF or DMSO and addition of a base, such as
sodium hydride. Alternatively, alkylation can be achieved by the
addition of a phase transfer reagent such as an alkylammonium salt,
such as benzyltriethylammonium chloride, and employing a base such
as sodium ethoxide. Reaction rates are typically improved by the
application of heat, and hence, reactions are run at from 0.degree.
C. to 70.degree. C.
[0568] Step d:
[0569] Treatment with an amine, such as cis-2,6-dimethylpiperidine
at an elevated temperature such as 50.degree. C. affords the
expected N-alkylated piperidine. The amine may be used as solvent,
or alternatively, the amine may be added in stoichiometric
proportions and the reaction mixture refluxed in a solvent such as
ethanol, acetonitrile, or toluene. The product, as the appropriate
acid addition salt, is then neutralized by the addition of base
such as aqueous potassium hydroxide. In situations where the amine
is volatile, then the reaction mixture is heated, typically from
50.degree. C. to 150.degree. C., in a sealed tube.
[0570] Step e:
[0571] Conversion of the nitrile to the hydroxyamidine is achieved
by allowing the nitrile to react with hydroxylamine in methanol at
room temperature. Typically, hydroxylamine hydrochloride is added
to the nitrile containing substrate at room temperature, and the
reaction is initiated by the addition of base such as potassium
carbonate or diisopropylethylamine. The reaction is usually
monitored by HPLC to determine the absence of starting material,
the nitrile, and are typically complete within a 24-hour
period.
[0572] Step f:
[0573] The amidoxime is activated by the addition of acetic
anhydride of trifluoroacetic anhydride intermediate in a solvent
such as acetic acid or trifluoroacetic acid to afford the
O-acylated intermediate, which may be isolated or alternatively
used directly in the subsequent reduction step. This step and the
subsequent reduction may be combined, i.e., the reduction with Pd/C
is performed in acetic anhydride/acetic acid, or trifluoro acetic
anhydride/trifluoroacetic acid.
[0574] Step g:
[0575] The substrate is dissolved in methanol, or acetic acid, or
trifluoroacetic acid, and treated with a transition metal catalyst
such as Palladium dispersed on carbon and is then hydrogenated
briefly, typically for 1 to 12 hours. The product is then isolated,
typically by crystallization or via chromatography such as reverse
phase HPLC.
[0576] Alternative procedures for the synthesis of the parent
benzoxazinone include, for example in scheme 2: 9
[0577] Step a:
[0578] Treatment of the methyl alpha-bromo phenylacetate with
ortho-nitrophenol and base readily affords the phenolic ether. Of
course, it is realized that activation of the benzylic carbon as a
chloride or mesylate would also suffice to allow the initial
etherification to proceed. Typically, the potassium or sodium salt
of ortho-nitrophenol is added to the electrophile in a solvent,
such as DMF, and the mixture warmed, typically to 50.degree. C.,
until the reaction is judged complete by TLC. Use of a chiral
alpha-functionalized aryl acetate would afford the chiral
adduct.
[0579] Step b:
[0580] Reduction of the nitro group to the corresponding aniline is
readily achieved with a transition metal such as palladium on
carbon or Raney nickel and hydrogen or alternatively by treatment
with tin in aqueous hydrochloric acid. These anilines readily
cyclize to the corresponding benzoxazinone during the reduction or
upon warming in a solvent such as methanol.
[0581] Step c:
[0582] Alternatively upon addition of ortho-aminophenol according
to the procedure of Bull. Soc. Chim. Belg., 1987:473-480, the
benzoxazine-2-one is isolated directly.
[0583] A further alternative procedure for the preparation of the
requisite benzoxazinones requires the treatment of the substituted
amino phenol with the acid chloride as shown in Scheme 3 in a
manner similar to that described by Krapcho, Tawada et al., Chem.
Pharm. Bull., 1990:1238-1245. 10
[0584] Step a:
[0585] The ortho amino phenol is treated with the acid chloride in
a solvent such 5 as dichloromethane in the presence of a base such
as diisopropylethylamine to afford the N-acylated product.
[0586] Step b:
[0587] Treatment with a base such as potassium carbonate in a
solvent such as DMF then affords the parent benzoxazinone via an
intramolecular nucleophilic addition of the phenoxide to the
secondary bromide.
[0588] A further alternative procedure is outlined in Scheme 4
which is initiated by etherification of an ortho-halo phenol with
an alpha-bromo phenylacetamide.
[0589] Subsequent intramolecular nucleophilic substitution then
affords the N-alkylated benzoxazinone (Coutts and Southcott J.,
Chem. Soc., Perkin Trans. 1, 1990:767-771). 11
[0590] Step a:
[0591] The sodium salt of the phenol is treated with the
electrophile in a solvent such as methylene chloride or dioxane,
and then the reaction mixture is warmed to 100.degree. C. for 4
hours.
[0592] Step b:
[0593] Addition of sodium hydride in a solvent such as DMPU and
warming to 100.degree. C. affords the required benzoxazinone.
[0594] Scheme 5 demonstrates another alternative procedure that may
be employed. 1213
[0595] Step a:
[0596] 2-Hydroxy-2H-1,4-benzoxazin-3(4H)-one is prepared by the
procedures of Sahu A., Indian Journal of Chemistry, 1990;603-605,
or Matlin S A, JCS Perkin Trans I, 1979;2481-2487 and is then
treated with HBr in acetic acid/acetic anhydride to afford
2-bromo-2H-1,4-benzoxazin-3(4H)-one at room temperature for 24 to
48 hours, according to the procedure of Tietze L F, Synthesis,
1991; 1118-1120. The product precipitates from the reaction mixture
and due to its hydrolytic instability is used directly in the
subsequent reaction step. Alternatively the acetate may be prepared
by treating the alcohol with acetic anhydride in the presence of
pyridine and catalytic DMAP. Addition of HBr in acetic acid to this
acetate again affords the corresponding bromide.
[0597] Step b:
[0598] Addition of a phenol or phenolic ether, such as 4-bromo
anisole and a Lewis acid, such as tin (IV) chloride or aluminum
(III) chloride, affords after refluxing for several hours the
corresponding 2-aryl substituted benzoxazinone.
[0599] Steps c-f:
[0600] Performed in a manner similar to the previous schemes
[0601] The substituted alpha-bromo phenylacetates used in these
reactions are prepared by a number of standard procedures such as
those shown in Scheme 6. 14
[0602] Acetic acid derivatives are prepared by conversion of the
substituted benzoic acid to the corresponding acid chloride with,
for example, oxalyl chloride and catalytic DMF and is then treated
with ethereal diazomethane. Rearrangement with silver oxide in an
alcoholic solvent, such as methanol, affords the homologated acetic
acid methyl ester. Functionalisation of the alpha position is then
achieved by refluxing a solution of the ester in carbon
tetrachloride with N-bromosuccinimide in the presence of a radical
initiator such as AIBN. It is also readily apparent that treatment
of acetic acid derivatives with bromine in the presence of
phosphorus tribromide will afford the alpha-bromo phenyl acetate in
a manner similar to the named reaction Hell-Volhard-Zelinskii.
[0603] Alternatively, the intermediate alpha bromo ester may be
prepared by the procedure shown in Scheme 7 according to the
procedure of Robert A., Jaguelin S., Guinamant J. L. "Synthesis of
esters of .alpha.-halo acids from gem dicyano epoxides.
Tetrahedron, 1986;42(8):2275-2281. 15
[0604] In this situation the aldehyde, such as 3-bromobenzaldehyde
as a representative example, is reacted with malononitrile in the
presence of catalytic piperidine in a solvent such as dioxane to
afford the 2-[(3-bromophenyl)-methylene]malononitrile. Epoxide
formation proceeds readily with commercial bleach at a pH of 5 to
6. Treatment with hydrobromic acid in methanol then affords the
required methyl 2-bromo-2-(3-bromophenyl)acetate. Similarly
prepared was methyl 2-bromo-2-(3-cyanophenyl)acetate
[0605] Alternative procedures for the conversion of nitrites to
amidines are also available as shown in Scheme 8. The nitrile in
turn are available by, for example, a palladium catalyzed
cross-coupling reaction with Zn(CN).sub.2 or via treatment of the
aryl bromide at elevated temperatures with copper (I) cyanide.
Treatment of the nitrile with hydrogen chloride in an alcoholic
solvent affords the corresponding iminoether hydrochloride. These
intermediates are then treated with source of ammonia, for example
ammonia in methanol, or ammonium chloride, or ammonium acetate, and
the mixture is stirred, and warmed if necessary, to afford the
amidine. 16
[0606] The benzothiazinone of Formula 1 may also be prepared
according to Scheme 9. 1718
[0607] The reaction sequence is similar to that described in Scheme
1 except that 2-aminophenyl thiol replaces 2-aminophenol in the
initial reaction sequence.
[0608] Since some of the compounds of Formula 1 exist as a mixture
of enantiomers, it is often desirable to prepare the optically pure
material. In these situations, the addition salts with chiral acids
are prepared and the mixture separated by crystallization. The
parent compounds may then be liberated by treatment with base, such
as potassium hydroxide. Enantiomers may also be separated by chiral
HPLC. Suitable columns for separating enantiomers of intermediates
such as
3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarbonitrile
include beta-cyclodextrin (keystone chiral .beta.-PM) employing 50%
water and acetonitrile mixtures. Alternatively, an asymmetric
synthesis may be employed for the synthesis of a specific
enantiomer. In particular, a suitably substituted phenoxide (for
benzoxazinones) or thiophenoxide (for benzothiazinones) may be
added to a pentolactone derivative, as described by Koh, J. Org.
Chem., 1994;59:4683-4686 and outlined in Scheme 10. 19
[0609] Use of (R) pantolactone esters affords the (S) diastereomer.
In this scheme, Y is a substituent that may be elaborated to afford
an aniline which undergoes intramolecular cyclization to afford the
required chiral benzoxazinone. Examples of such substituents would
include a nitro functionality or N-acetyl group.
[0610] A further alternative procedure for the generation of chiral
benzoxazinone intermediates is available by application of
lactamide derived esters of racemic alpha-halo carboxylic acids
(Devine, Tetrahedron Letts., 1996:2683-2686) as outlined in Scheme
11. 20
[0611] The diastereoselectivity of this reaction is good, and the
products are of the (R) stereochemistry providing a complementary
approach to that of Scheme 10.
[0612] It should be noted that chiral alpha-trichloromethyl
carbinols afford optically active alpha-aryloxy acids upon
treatment with phenoxide providing yet another alternative method
to preparing chiral benzoxazinones or benzothiazinones (Corey,
Tetrahedron Lett., 1992:3431).
[0613] Another procedure for preparing chiral benzoxazinones is
outlined in Scheme 12 21
[0614] Step a:
[0615] The aldehyde is protected via the formation of a suitable
protecting group, which in the above scenario is a benzylether,
with for example potassium carbonate or sodium hydroxide and benzyl
bromide in a solvent such as DMF or ethanol.
[0616] Step b:
[0617] Addition of cyanide to the aldehyde readily forms the
intermediate cyano hydrin in a solvent such as methanol. It is
envisioned that this process may also be performed in an assymetric
manner by use of any one of the following general procedures Danda,
H et al., Chem Lett 1991, 731. Poly(quinidine-co-acrylonitrile)
Effenberger, F et al., Tetrahedron Lett 1990, 31 (9), 1249.
(Oxynitrilase) Mori, A. et al., Chem Lett 1989 (12), 2119.
Cyclo-(Leu-His) or Tanaka, K. et al., J Org Chem 1990, 55, 181.
cyclo((S)-Phe-(S)-His) Minamikawa, H. et al., Bull Chem Soc Jpn
1988, 61 (12), 4379.
1,1,4,4-Tetraphenylbutanetetraol-(2R,3R)--O,O-phenylethyliden- e
Ti(i-PrO)2C12 Harrington, K. J et al., Aust J Chem 1986, 39, 1135.
1) beta-Cyclodextrin
[0618] Steps c:
[0619] Conversion of the cyano functional group to a methyl ester
is readily achieved by treatment of the nitrile with HCl gas in an
alcoholic solvent such as methanol. Addition of water then readily
converts the intermediate imino ether to the ester.
[0620] Step d:
[0621] Oxidation of the alcohol to the keto-ester is readily
achieved with an oxidising agent such as oxalyl chloride and
dimethylsulfoxide or by heating with manganese dioxide in a solvent
such as toluene or methylene chloride.
[0622] Step e:
[0623] Chiral reduction of the keto-ester is best achieved with a
reducing agent like R-alpine borane. This reduction is typically
slow and takes several days to complete.
[0624] Step f:
[0625] A Mitsunobo coupling reaction is then performed on this
chiral alcohol employing nitro phenol (or possibly amino phenol),
diisopropylazodicarboxalate (or other alkylazodicarboxylate) and
triphenylphosphine in a solvent such as ethylacetate at a low
temperature such as -40 .degree. C.
[0626] Step g:
[0627] Reduction of the nitro group is best achieved with neutral
Raney Nickel and a hydrogen atmosphere in a solvent such as
methanol. It is important that the solution does not become basic
since a reduction in enantiomeric excess may be observed.
[0628] Compounds of the present invention are further characterized
by their ability to inhibit the catalytic activity of factor Xa,
which is demonstrated in the assay as follows. Compounds of the
present invention may be prepared for assay by dissolving them in
buffer to give solutions ranging in concentrations from 1 to 100
.mu.M. In an assay to determine the inhibitory dissociation
constant, K.sub.i, for a given compound, a chromogenic or
fluorogenic substrate of factor Xa would be added to a solution
containing a test compound and factor Xa; the resulting catalytic
activity of the enzyme is spectrophotometrically determined. This
assay is well-known to those skilled in the art and is commonly
used to determine antithrombotic activity.
[0629] The compounds of the present invention may be used as
anti-coagulants in vitro or ex vivo as in the case of contact
activation with foreign thrombogenic surfaces such as is found in
tubing used in extracorporeal shunts. The compounds of the
invention may also be used to coat the surface of such thrombogenic
conduits. To this end, the compounds of the invention can be
prepared as lyophilized powders, redissolved in isotonic saline or
similar diluent, and added in an amount sufficient to maintain
blood in an anticoagulated state.
[0630] The therapeutic agents of the present invention may be
administered alone or in combination with pharmaceutically
acceptable carriers. The proportion of each carrier is determined
by the solubility and chemical nature of the compound, the route of
administration, and standard pharmaceutical practice. For example,
the compounds may be injected parenterally; this being
intramuscularly, intravenously, or subcutaneously. For parenteral
administration, the compound may be used in the form of sterile
solutions containing other solutes, for example, sufficient saline
or glucose to make the solution isotonic. The compounds may be
administered orally in the form of tablets, capsules, or granules
containing suitable excipients such as starch, lactose, white sugar
and the like. The compounds may also be administered sublingually
in the form of troches or lozenges in which each active ingredient
is mixed with sugar or corn syrups, flavoring agents, and dyes, and
then dehydrated sufficiently to make the mixture suitable for
pressing into solid form. The compounds may be administered orally
in the form of solutions which may contain coloring and/or
flavoring agents. Typical formulations will contain from about 5%
to 95% by weight of an invention compound.
[0631] The amount of invention compound to be utilized to prevent
and treat thrombotic disorders is that amount which is effective to
prevent or treat the condition without causing unacceptable side
effects. Such effective amounts will be from about 0.01 mg/Kg to
about 500 mg/Kg, preferably from about 1 mg/Kg to about 100 mg/Kg.
Physicians will determine the precise dosage of the present
therapeutic agents which will be most suitable. Dosages may vary
with the mode of administration and the particular compound chosen.
In addition, the dosage may vary with the particular patient under
treatment.
[0632] When the composition is administered orally, a larger
quantity of the active agent will typically be required to produce
the same effect as caused with a smaller quantity given
parenterally.
[0633] To further assist in understanding the present invention,
the following non-limiting examples of such factor Xa inhibitory
compounds are provided. The following examples, of course, should
not be construed as specifically limiting the present invention,
variations presently known or later developed, which would be
within the purview of one skilled in the art and considered to fall
within the scope of the present invention as described herein. The
preferred compounds as of the present invention are synthesized
using conventional preparative steps and recovery methods known to
those skilled in the art of organic and bio-organic synthesis,
while providing a new and unique combination for the overall
synthesis of each compound. Preferred synthetic routes for
intermediates involved in the synthesis as well as the resulting
anti-thrombotic compounds of the present invention follow.
EXAMPLES
[0634] In general, evaporation of reaction mixtures were carried
out by rotary evaporation in vacuo at room temperature 18.degree.
C. to 25.degree. C. or at elevated temperatures up to 50.degree. C.
Chromatography, preferably by medium pressure liquid
chromatography, were generally performed on Merck Kieselgel.
Reverse phase purification via high pressure liquid chromatography
(HPLC), for particular polar compounds, was performed on C-18
reverse phase silica gel employing a gradient elution of water and
acetonitrile containing 0.1% trifluoroacetic acid. The final
products displayed nuclear magnetic resonance (NMR) spectra and
mass spectra consistent with their assigned structure.
Intermediates were not typically fully characterized and their
purity was routinely assessed by HPLC or thin layer
chromatography.
Example 1
[0635]
4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-pyridinyl]pentyl-2-(4-methoxyp-
henyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one
[0636] Step (a): Preparation of Methyl
2-bromo-2-(4-methoxyphenyl)acetate 22
[0637] To methyl 4-methoxyphenylacetate (1) (5.0 g, 27.7 mmol) in
carbon tetrachloride was added N-bromosuccinimide (5.92 g, 33.3
mmol) and VAZO52 (152 mg, 0.612 mmol). The reaction mixture was
stirred and heated at reflux for 3 hours. .sup.1H NMR indicated
complete bromination of the starting material. The mixture was
cooled in an ice-bath. The precipitate was filtered and washed with
carbon tetrachloride. The filtrate was evaporated in vacuo to give
(2) as a brown oil in quantitative yield, and sufficiently pure for
subsequent reactions.
[0638] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.7.44 (2H, d,
J=6.84 Hz), 6.84 (2H, d, J=6.71 Hz), 5.31 (1H, s), 3.77 (3H, s),
3.75 (3H, s).
[0639] Step (b): Preparation of Methyl
2-(4-methoxyphenyl)-2-(2-nitropheno- xy)acetate 23
[0640] To (3) (7.18 g, 27.7 mmol) in DMSO (20 mL) was added
o-nitrophenol sodium salt (7.32 g, 45.5 mmol). The reaction mixture
was stirred at 70.degree. C. for 24 hours. The reaction mixture was
cooled, diluted with water, and extracted with ethyl acetate
(3.times.300 mL). The combined organic extracts were washed with
brine (200 mL), dried with magnesium sulfate, filtered, and
evaporated in vacuo. The residue was purified on a silica gel
column eluted with 20% ethyl acetate in hexane. The product (4) was
isolated 2.90 g (33%) as an orange oily solid.
[0641] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.88 (1H, m),
7.54-7.44 (3H, m), 6.92-7.11 (4H, m), 5.70 (1H, s), 3.82 (3H, s),
3.72 (3H, s).
[0642] Step (c): Preparation of
2-(4-Methoxyphenyl)-3.4-dihydro-2H-1,4-ben- zoxazin-3-one 24
[0643] The phenolic ether (4) (2.88 g, 9.08 mmol) was hydrogenated
over Raney nickel (1 g) in THF (50 mL) and methanol (50 mL) for 23
hours at room temperature. The mixture was filtered and the filter
pad washed with methanol and THF. The combined filtrate and
washings were evaporated in vacuo to give the benzoxazinone (5) as
an orange solid in quantitative yield.
[0644] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.78 (1H, bs),
7.35 (2H, d, J=8.79 Hz), 7.00-6.76 (6H, m), 5.63 (1H, s), 3.77 (3H,
s).
[0645] Step (d): Preparation of
4-(5-Bromopentyl)-2-(4-methoxyphenyl)-3,4-- dihydro-2H-1
4-benzoxazin-3-one 25
[0646] To the benzoxazinone (5) (2.42 g, 9.48 mmol) in DMF (9 mL)
was added sodium hydride (0.433 g, 10.82 mmol), and the solution
was stirred at 70.degree. C. for 15 minutes until bubbling stopped.
To this solution was added 1,5-dibromopentane (8.66 g, 37.7 mmol),
and the solution was stirred at 70.degree. C. for additional 5
hours. The solution was cooled, diluted with water, and extracted
with ethyl acetate (5.times.200 mL). The combined organic extracts
were washed with brine (2.times.100 mL), dried with magnesium
sulfate, filtered, and evaporated in vacuo. The residue was
purified on a silica gel column eluted with 20% ethyl acetate in
hexane. The product (6) was isolated 1.85 g (48%) as a yellow
oil.
[0647] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.26 (2H, d,
J=4.49 Hz), 7.03-6.96 (4H, m), 6.84 (2H, d, J=6.68 Hz), 5.64 (1H,
s), 4.12 (2H, m), 3.80 (3H, s), 3.40 (2H, m), 1.96-1.87 (2H, m),
1.75-1.68 (2H, m), 1.61-1.51 (2H, m).
[0648] Step (e): Preparation of
4-5-[(2R.6S)-2,6-Dimethylhexahydro-1-pyrid-
inyl]pentyl-2-(4-methoxyphenyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one
26
[0649] To (6) (0.50 g, 1.23 mmol) was added
cis-2,6-dimethylpiperidine (2 mL, 14.8 mmol), and the solution was
stirred at 50.degree. C. for 16 hours. The solution was cooled,
diluted with water, and extracted with ethyl acetate (3.times.100
mL). The combined organic extracts were washed with saturated
sodium bicarbonate (2.times.100 mL), washed with brine (2.times.100
mL), dried with magnesium sulfate, filtered, and evaporated in
vacuo. The residue was purified by preparative HPLC (Vydac
218TP1022C-18, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 95:5 (i):(ii) to 60:40
(i):(ii) over 90 minutes, flow rate 20 mL/minute, .lambda.=214 nM)
and was lyophilized to give 27 mg (12%) of product (7) as a fluffy
white solid.
[0650] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.7.27 (2H, m),
7.03-6.95 (4H, m), 6.84 (2H, m), 5.63 (1H, s), 4.03 (2H, m), 3.77
(3H, s), 3.25 (2H, m), 3.00 (2H, s), 2.72 (2H, m), 2.41 (2H, bs),
2.04 (2H, m), 1.88-1.66 (6H, m), 1.48-1.32 (6H, m).
[0651] CI MS M+1=437.
[0652] HPLC: RT=17.28 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
Example 2
[0653]
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide
[0654] Step (a): Preparation of
3-(2,2,2-Trichloro-1-hydroxyethyl)benzonit- rile 27
[0655] Into a mixture of lead(II) bromide (1.69 g, 4.60 mmol) and
finely cut aluminum foil (1.25 g, 45.8 mmol) in DMF (226 mL) was
added 3-cyanobenzaldehyde (6.01 g, 45.8 mmol) and carbon
tetrachloride (8.84 mL, 91.7 mmol), and the mixture was stirred at
ambient temperature 3 hours. The reaction was quenched with aqueous
IN hydrochloric acid (100 mL), and the mixture was extracted with
ethyl acetate (3.times.300 mL). The combined organic extracts were
washed with brine (200 mL), dried with magnesium sulfate, filtered,
evaporated in vacuo, and dried under high vacuum to give the
trichloromethyl carbinol (9) as a brown oil in quantitative
yield.
[0656] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.94 (1H, m), 7.86
(1H, m), 7.66 (1H, m), 7.48 (1H, m), 5.24 (1H, s), 4.98 (1H,
bs).
[0657] Step (b): Preparation of
2-(3-Cyanophenyl)-3,4-dihydro-2H-1,4-benzo- xazin-3-one 28
[0658] To o-aminophenol hydrochloride (3.29 g, 13.1 mmol) in DMSO
(15 mL) was added sodium hydride (2.63 g, 65.8 mmol). After
bubbling and evolution of heat ceased, a solution of (10) (3.29 g,
13.1 mmol) in DMSO (10 mL) was added dropwise over 15 minutes.
After evolution of heat ceased, the mixture was stirred at
70.degree. C. for 4 hours. The reaction mixture was cooled, diluted
with water, and extracted with ethyl acetate (5.times.500 mL). The
combined organic extracts were washed with brine (200 mL), dried
with magnesium sulfate, filtered, and evaporated in vacuo. The
residue was purified on a silica gel column eluted with 25% ethyl
acetate in dichloromethane. The product (11) was isolated 0.55 g
(17%) as an orange solid.
[0659] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.8.47 (1H, s),
7.80-7.72 (2H, m), 7.64 (1H, m), 7.49 (1H, m), 7.15-6.97 (3H, m),
6.82 (1H, m), 5.70 (1H, s).
[0660] Step (c): Preparation of
4-(5-Bromopentyl)-2-(3-cyanophenyl)-3,4-di-
hydro-2H-1,4-benzoxazin-3-one 29
[0661] To the benzoxazinone (11) (0.72 g, 2.87 mmol) in DMF (5 mL)
was added sodium hydride (0.126 g, 3.15 mmol), and the solution was
stirred at 70.degree. C. for 15 minutes until bubbling stopped. To
this solution was added 1,5-dibromopentane (1.57 mL, 11.5 mmol) and
the solution was stirred at 70.degree. C. for additional 3 hours.
The solution was cooled, diluted with water, and extracted with
ethyl acetate (5.times.200 mL). The combined organic extracts were
washed with brine (2.times.100 mL), dried with magnesium sulfate,
filtered, and evaporated in vacuo. The residue was purified on a
silica gel column eluted with 20% to 40% ethyl acetate in hexane.
The product (12) was isolated 0.64 (56%) as a yellow oil.
[0662] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.71 (2H, m), 7.61
(1H, m), 7.46 (1H, m), 7.12-7.03 (3H, m), 6.97 (1H, m), 5.69 (1H,
s), 3.98 (2H, m), 3.41 (2H, m), 1.91 (2H, m), 1.71 (2H, m), 1.55
(2H, m).
[0663] Step (d): Preparation of
4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-pyrid-
inyl]pentyl-2-(3-cyanophenyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one
30
[0664] To (12) (1.08 g, 2.70 mmol) was added
cis-2,6-dimethylpiperidine (8 mL, 60 mmol). The solution was
stirred at 70.degree. C. for 16 hours. The solution was cooled,
diluted with water, and extracted with ethyl acetate (3.times.200
mL). The combined organic extracts were washed with saturated
sodium bicarbonate (2.times.100 mL), washed with brine (2.times.100
mL), dried with magnesium sulfate, filtered, evaporated in vacuo,
coevaporated with toluene, and dried under high vacuum to give 1.09
g (94%) of (13) as a yellow oil.
[0665] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.63 (2H, m), 7.54
(1H, m), 7.40 (1H, m), 7.13 (1H, m), 7.03-6.85 (3H, m), 5.63 (1H,
s), 3.91 (2H, m), 2.91 (2H, m), 2.70 (2H, m), 2.61-2.06 (4H, m)
1.64-1.18 (8H, bm), 1.06 (6H, m).
[0666] HPLC: RT=13.88 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
[0667] Step (e): Preparation of
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-py-
ridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-N-hydroxybenzen-
ecarboximidamide 31
[0668] To (13) (1.09 g, 2.53 mmol) in methanol (30 mL) were added
hydroxylamine hydrochloride (0.438 g, 6.30 mmol) and
diisopropylethylamine (0.44 mL, 2.53 mmol). The solution was
stirred at room temperature for 16 hours. The solvent was
evaporated in vacuo, and the oil was dried under high vacuum to
give (14) in quantitative yield.
[0669] HPLC: RT=8.39 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
[0670] Step (f): Preparation of
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-py-
ridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-N-hydroxytriflu-
oroacetatebenzenecarboximidamide 32
[0671] To (14) (0.53 g, 1.14 mmol) was added trifluoroacetic
anhydride (7 mL), and the solution was stirred at room temperature
for 2 hours. The solvent was removed in vacuo to give (15) as a
yellow oil in quantitative yield.
[0672] HPLC: RT=17.44 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0. 1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
[0673] Step (g): Preparation of
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-py-
ridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboxim-
idamide 33
[0674] To (15) (0.57 g, 1.13 mmol) in trifluoroacetic acid (16 mL)
was added 20% palladium on carbon (0.1 g), and the mixture was
hydrogenated at 23.degree. C. for 48 hours. The mixture was
filtered and the filter pad washed with trifluoroacetic acid. The
combined filtrate and washings were evaporated in vacuo, and the
residue was purified by preparative HPLC (Vydac 218TP1022 C-18,
eluted with a mixture of solvents consisting of (i) 0.1%
trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid
in acetonitrile, gradient profile 95:5 (i):(ii) to 60:40 (i):(ii)
over 90 minutes, flow rate 20 mL/minute, .lambda.=214 nM) and
lyophilized to give 251 mg (50%) of the bis TFA salt of (16). To
(16) in acetonitrile (2 mL) and water (2 mL) was added
Amberlite.RTM. IRA-400(Cl) ion exchange resin (3.36 g). The mixture
was filtered, and the filtrate was lyophilized to give 155 mg (26%)
of the bis hydrochloride salt (16).
[0675] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.9.44 (1H, s), 9.19
(2H, s), 7.80 (2H, m), 7.64 (2H, m), 7.28 (1H, m), 7.11-7.01 (3H,
m), 5.93 (1H, s), 3.97 (2H, m), 3.18 (2H, bs), 3.03 (2H, bs),
1.75-1.36 (12H, bm), 1.23 (6H, m).
[0676] CI MS M+=449.
[0677] HPLC: RT=8.26. (Beckman 235328 C-18 5 .mu.m 4.6 mm.times.25
cm, eluted with a mixture of solvents consisting of (i) 0.1%
trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid
in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90 (i):(ii)
over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214 nM).
Example 3
[0678]
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)-1-benzenecarboximidamide
[0679] Step (a): Preparation of
2-(3-Cyanophenyl)-3,4-dihydro-2H-1,4-benzo- thiazin-3-one 34
[0680] To o-aminothiophenol (2.39 mL, 22.3 mmol) in DMF (60 mL) was
added sodium hydride (3.61 g, 90.3 mmol). After bubbling and
evolution of heat ceased, a solution of (10) (5.67 g, 22.6 mmol) in
DMSO (40 mL) was added dropwise over 15 minutes. After evolution of
heat ceased, the mixture was stirred at 50.degree. C. for 6 hours
and at room temperature for 16 hours. The reaction mixture was
cooled, diluted with water, and extracted with ethyl acetate
(5.times.500 mL). The combined organic extracts were washed with
brine (200 mL), dried with magnesium sulfate, filtered, and
evaporated in vacuo. The residue was absorbed onto silica gel and
purified on a silica gel column eluted with 1% to 4% methanol in
dichloromethane. The residue was crystallized from ethyl acetate
and hexane to give 1.71 g (29%) of product (17) as a tan solid.
[0681] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.10.97 (1H, s),
7.75 (1H, m), 7.57 (2H, m), 7.32 (1H, m), 7.20 (1H, m), 7.00 (3H,
m), 5.10 (1H, s).
[0682] Step (b): Preparation of
4-(5-Bromopentyl)-2-(3-cyanophenyl)-3,4-di-
hydro-2H-1,4-benzothiazin-3-one 35
[0683] To the benzothiazinone (17) (0.75 g, 2.82 mmol) in DMF (5
mL) was added sodium hydride (0.124 g, 3.09 mmol), and the solution
was stirred at 70.degree. C. for 15 minutes until bubbling stopped.
To this solution was added 1,5-dibromopentane (1.54 mL, 11.2 mmol),
and the solution was stirred at 70.degree. C. for additional 16
hours. The solution was cooled, diluted with water, and extracted
with ethyl acetate (3.times.300 mL). The combined organic extracts
were washed with brine (2.times.100 mL), dried with magnesium
sulfate, filtered, and evaporated in vacuo. The residue was
purified on a silica gel column eluted with 20% to 30% ethyl
acetate in hexane. The product (18) was isolated 0.66 (52%) as a
yellow oil.
[0684] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.57 (3H, m), 7.38
(2H, m), 7.25 (1H, m), 7.11-7.01(2H, m), 4.64 (1H, s), 4.09 (2H,
m), 3.40 (2H, m), 1.91 (2H, m), 1.70 (2H, m), 1.53 (2H, m).
[0685] Step (c): Preparation of
4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-pyrid-
inyl]pentyl-2-(3-cyanophenyl)-3,4-dihydro-2H-1,4-benzothiazin-3-one
36
[0686] To (18) (0.66 g, 1.59 mmol) was added
cis-2,6-dimethylpiperidine (6.0 mL, 44 mmol). The solution was
stirred at 70.degree. C. for 48 hours. The solution was cooled,
diluted with water, and extracted with ethyl acetate (3.times.200
mL). The combined organic extracts were washed with saturated
sodium bicarbonate (2.times.100 mL), washed with brine (2.times.100
mL), dried with magnesium sulfate, filtered, evaporated in vacuo,
coevaporated with toluene, and dried under high vacuum to give 0.69
g (97%) of (19) as a yellow oil.
[0687] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.55 (3H, m), 7.37
(2H, m), 7.24 (1H, m), 7.10-7.00 (2H, m), 4.63 (1H, s), 4.07 (2H,
m), 2.74 (2H, m), 2.47 (2H, m), 1.76-1.22 (12H, bm), 1.08 (6H,
m).
[0688] HPLC: RT=14.16 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
[0689] Step (d): Preparation of
3-(4-5-[(2R,6S)-2.6-Dimethylhexahydro-1-py-
ridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-N-hydroxybenz-
enecarboximidamide 37
[0690] To (19) (0.30 g, 0.67 mmol) in methanol (10 mL) were added
hydroxylamine hydrochloride (0.116 g, 1.67 mmol) and
diisopropylethylamine (0.12 mL, 0.67 mmol). The solution was
stirred at room temperature for 24 hours. The solvent was
evaporated in vacuo, and the oil was dried under high vacuum to
give (20) in quantitative yield.
[0691] HPLC: RT=8.83 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
[0692] Step (e): Preparation of
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-py-
ridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-N-hydroxyacet-
atebenzenecarboximidamide 38
[0693] To (20) (0.32 g, 0.66 mmol) was added acetic anhydride (2
mL) and the solution was stirred at room temperature for 2 hours.
The solution was diluted with acetic acid, and the solvent was
evaporated in vacuo to give (21) as a yellow oil in quantitative
yield.
[0694] HPLC: RT=12.08 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate I.5 mL/minute, .lambda.=214
nM).
[0695] Step (f): Preparation of
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-py-
ridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-benzenecarbox-
imidamide 39
[0696] To (21) (0.34 g, 0.65 mmol) in acetic acid (2 mL) was added
20% palladium on carbon (45 mg) and hydrogenated at 23.degree. C.
for 2 hours. The mixture was filtered through Celite and the filter
pad washed with acetic acid. The combined filtrate and washings
were evaporated in vacuo, and purified by preparative HPLC (Vydac
218TP1022 C-18, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 95:5 (i):(ii) to 60:40
(i):(ii) over 90 minutes, flow rate 20 mL/minute, .lambda.=214 nM)
and lyophilized to give 50 mg (16%) of product (22) as a fluffy
off-white solid.
[0697] .sup.1H NMR (DMSO, 400 MHz): .delta.9.33 (1H, s), 9.18 (1H,
s), 7.69 (3H, m), 7.55 (1H, m), 7.41 (2H, m), 7.33 (1H, m), 7.07
(1H, m), 5.11 (1H, s), 4.09 (2H, m), 3.38 (2H, m), 3.24 (2H, m),
3.10 (2H, m), 2.91 (2H, m), 1.84 (2H, m), 1.66-1.33 (6H, bm), 1.24
(6H, m).
[0698] CI MS M+1=465, M-1=464.
[0699] HPLC: RT=8.92 min. (86%) and 8.19 min. (13%). (Beckman
235328 C-18 5 .mu.m 4.6 mm.times.25 cm, eluted with a mixture of
solvents consisting of (i) 0.1% trifluoroacetic acid in water, and
(ii) 0.1% trifluoroacetic acid in acetonitrile, gradient profile
80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5
mL/minute, .lambda.=214 nM).
Example 4
[0700]
3-(4-5-[(2R,6S)-2,6-Dimethylhexahydro-1-pyridinyl]pentyl-3-oxo-3,4--
dihydro-2H-1,4-benzothiazin-2-yl)-1-benzenecarbothioamide 40
[0701] In a three-necked flask, intermediate (13) (0.49 g, 1.14
mmol) was dissolved in pyridine (50 mL). Nitrogen was bubbled
through the solution for 30 minutes. Hydrogen sulfide was bubbled
through the yellow solution for 20 minutes. The solution turned
green and the flask was sealed and stirred for 24 hours at room
temperature. HPLC indicated that the reaction was complete.
Nitrogen was bubbled through the solution for 30 minutes. The
solution was evaporated in vacuo, coevaporated with toluene, and
purified by preparative HPLC (Vydac 218TP1022 C-18, eluted with a
mixture of solvents consisting of (i) 0.1% trifluoroacetic acid in
water, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradient
profile 95:5 (i):(ii) to 60:40 (i):(ii) over 90 minutes, flow rate
20 mL/minute, .lambda.=214 nM) and lyophilized to give 28 mg (6%)
of product (23) as a yellow solid.
[0702] .sup.1H NMR (DMSO, 400 MHz): .delta.9.92 (1H, s), 9.55 (1H,
s), 7.97 (1H, s), 7.75 (1H, m), 7.48 (1H, m), 7.41 (1H, m), 7.25
(1H, m), 7.14-6.99 (3H, m), 5.91 (1H, s), 3.99 (2H, m), 3.37 (2H,
bs), 3.24 (2H, bs), 3.11 (2H, m), 2.92 (2H, bs), 1.84 (2H, m),
1.70-1.38 (6H, m), 1.23 (6H, m).
[0703] CI MS M+1=466.
[0704] HPLC: RT=12.48 min. (Beckman 235328 C-18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nM).
Example 5
[0705]
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-
-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximidamide
[0706] Step (a): Preparation of
2-(benzyloxy)-5-bromobenzenecarbaldehyde 41
[0707] To 5-bromosalicylaldehyde (24) (10.01 g, 49.8 mmol) in DMF
(50 mL) were added benzyl bromide (6.5 mL, 54.6 mmol) and potassium
carbonate (13.76 g, 99.6 mmol). The reaction mixture was stirred at
room temperature for 72 hours. The solution was diluted with water,
and extracted with ethyl acetate (3.times.200 mL). The combined
organic extracts were washed with brine (2.times.100 mL), dried
with magnesium sulfate, filtered, evaporated in vacuo, and dried
under high vacuum. The product (25) was crystallized from ethyl
acetate in hexane to give 10.96 g (76%) as a white solid.
[0708] .sup.1H NMR (CDCl.sub.3, 300M): .delta.10.47(1H, s),
7.95(1H, m), 7.61(1H, m), 7.43-7.39(5H, m), 6.95(1H, m), 5.18(2H,
s).
[0709] Step (b): Preparation of
1-[2-(benzyloxy)-5-bromophenyl]-2,2,2-tric- hloro-1-ethanol 42
[0710] Into a mixture of lead(II) bromide (1.38 g, 3.76 mmol) and
finely cut aluminum foil (1.02 g, 37.8 mmol) in DMF (188 mL) were
added (25) (10.96 g, 37.6 mmol) and carbon tetrachloride (7.6 mL,
78.8 mmol), and the mixture was stirred at ambient temperature 3
hours. The reaction was quenched with aqueous IN hydrochloric acid
(100 mL), and the mixture was extracted with ethyl acetate
(3.times.300 mL). The combined organic extracts were washed with
brine (200 mL), dried with magnesium sulfate, filtered, evaporated
in vacuo, and dried under high vacuum to give the trichloromethyl
carbinol (26) as a brown oil in quantitative yield.
[0711] .sup.1H NMR (CDCl.sub.3, 300MHz): .delta.7.82(1H, m),
7.46-7.37(6H, m), 6.87(1H, m), 5.71(1H, s), 5.11(2H, m), 3.85(1H,
bs).
[0712] Step (c): Preparation of
2-[2-(benzyloxy)-5-bromophenyl]-2H-1,4-ben- zoxazin-3(4H)-one
43
[0713] To o-aminophenol hydrochloride (0.88 g, 6.04 mmol) in DMSO
(15 mL) was added sodium hydride (1.21 g, 30.2 mmol). After
bubbling and evolution of heat ceased, a solution of (26) (2.50 g,
6.09 mmol) in DMSO (10 mL) was added dropwise over 30 minutes at
room temperature. After evolution of heat ceased, the mixture was
stirred at 70.degree. C. for 4 hours. The reaction mixture was
cooled, diluted with water, and extracted with ethyl acetate
(5.times.500 mL). The combined organic extracts were washed with
brine (200 mL), dried with magnesium sulfate, filtered, and
evaporated in vacuo. The residue was purified on a silica gel
column eluted with 20% ethyl acetate in hexane. The product (27)
was isolated 0.67 g (27%) as a solid.
[0714] .sup.1H NMR (CDCl.sub.3, 300MHz): .delta.7.91(1H, bs),
7.51(1H, m), 7.43(1H, m), 7.27(5H, m), 6.97-6.85(4H, m), 6.67(1H,
m), 5.83(1H, s), 5.05(2H, m).
[0715] Step (d): Preparation of
4-(benzyloxy)-3-(3-oxo-3,4-dihydro-2H-1,4--
benzoxazin-2-yl)benzenecarbonitrile 44
[0716] A mixture of the benzoxazinone (27) (0.17 g, 0.477 mmol) and
cuprous cyanide (0.09 g, 1.00 mmol) in DMF (3 mL) was stirred at
160.degree. C. for 16 hours in a sealed tube. The solution was
cooled, diluted with water (50 mL) and ammonium hydroxide (50 mL),
and extracted with ethyl acetate (3.times.100 mL). The combined
organic extracts were washed with brine (2.times.100 mL), dried
with magnesium sulfate, filtered, evaporated in vacuo, and dried
under high vacuum to give 0.16 g (94%) of product (28) as a
solid.
[0717] .sup.1H NMR (CDCl.sub.3, 300MHz): .delta.9.82(1H, bs),
7.73-7.64(2H, m), 7.31(5H, m), 7.06-6.96(4H, m), 6.70(1H, m),
5.86(1H, s), 5.15(2H, m). CI MS M+1=357 M-1=356.
[0718] Step (e): Preparation of
4-(benzyloxy)-3-[4-(5-bromopentyl)-3-oxo-3-
,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarbonitrile 45
[0719] To the benzoxazinone (28) (1.63 g, 4.57 mmol) in DMF (5 mL)
was added sodium hydride (0.20 g, 5.00 mmol) and the solution was
stirred at 0.degree. C. for 10 minutes until bubbling stopped. To
this solution was added 1,5-dibromopentane (2.5 mL, 18.3 mmol) and
the solution was stirred at 0.degree. C. for additional 2 hours.
The solution was diluted with water, and extracted with ethyl
acetate (5.times.200 mL). The combined organic extracts were washed
with brine (2.times.100 mL), dried with magnesium sulfate,
filtered, and evaporated in vacuo. The residue was purified on a
silica gel column eluted with 20% ethyl acetate in hexane. The
product (29) was isolated 1.14 g (61%) as a foam.
[0720] 1H NMR (CDCl.sub.3, 300MHz): .delta.7.63(2H, m), 7.31(5H,
m), 7.07-6.94(5H, m), 5.83(1H, s), 5.14(2H, m), 3.89(2H, m),
3.37(2H, m), 1.86(2H, m), 1.55(4H, m)
[0721] CI MS M+1=507/505 M-1=506/504.
[0722] Step (f): Preparation of
4-(benzyloxy)-3-(4-5-[(2R,6S)-2,6-dimethyl-
tetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl-
)benzenecarbonitrile 46
[0723] To (29) (1.14 g, 2.26 mmol) was added
cis-2,6-dimethylpiperidine (10 mL, 74 mmol). The solution was
stirred at 70.degree. C. for 16 hours. The solution was cooled,
diluted with water, and extracted with ethyl acetate (3.times.200
mL). The combined organic extracts were washed with saturated
sodium bicarbonate (2.times.100 mL), washed with brine (2.times.100
mL), dried with magnesium sulfate, filtered, evaporated in vacuo,
coevaporated with toluene, and dried under high vacuum to give (30)
as a yellow oil in quantitative yield.
[0724] 1H NMR (CDCl.sub.3, 300 MHz): .delta.7.56(2H, m), 7.25(5H,
m), 7.10(1H, m), 7.00-6.89(4H, m), 5.78(1H, s), 5.09(2H, m),
3.80(2H, m), 2.64(2H, bs), 2.37(2H, bs), 1.59-1.15(12H, bm),
1.00(6H, m).
[0725] HPLC: RT=16.26 minutes (Beckman 235328 C18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nm).
[0726] Step (g): Preparation of
4-(benzyloxy)-3-(4-5-[(2R,6S)-216-dimethyl-
tetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl-
)-N-hydroxybenzenecarboximidamide 47
[0727] To (30) (1.21 g, 2.25 mmol) in methanol (25 mL) were added
hydroxylamine hydrochloride (0.39 g, 5.61 mmol) and
diisopropylethylamine (0.39 mL, 2.24 mmol). The solution was
stirred at room temperature for 16 hours. The solvent was
evaporated in vacuo and the oil was dried under high vacuum to give
(31) in quantitative yield.
[0728] HPLC: RT=13.46 minutes (Beckman 235328 C18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nm).
[0729] Step (h): Preparation of
4-(benzyloxy)-3-(4-5-[(2R,6S)-2,6-dimethyl-
tetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl-
)-N-[(2,2.2-trifluoroacetyl)oxy]benzenecarboximidamide 48
[0730] To (31) (1.28 g, 2.24 mmol) was added trifluoroacetic
anhydride (10 mL) and the solution was stirred at room temperature
for 2 hours. The solvent was removed in vacuo to give (32) as a
yellow oil in quantitative yield.
[0731] HPLC: RT=21.62 minutes (Beckman 235328 C18 5 .mu.m 4.6
mm.times.25 cm, eluted with a mixture of solvents consisting of (i)
0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic
acid in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90
(i):(ii) over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214
nm).
[0732] Step (i): Preparation of
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-
H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxyben-
zenecarboximidamide 49
[0733] To (32) (0.1.49 g, 2.24 mmol) in trifluoroacetic acid (32
mL) was added 20% palladium on carbon (0.2 g) and hydrogenated at
23.degree. C. for 48 hours. The mixture was filtered and the filter
pad washed with trifluoroacetic acid. The combined filtrate and
washings were evaporated in vacuo, and the residue was purified by
preparative HPLC (Vydac 218TP54 C 18, eluted with a mixture of
solvents consisting of (i) 0.1% trifluoroacetic acid in water, and
(ii) 0.1% trifluoroacetic acid in acetonitrile, gradient profile
95:5 (i):(ii) to 60:40 (i):(ii) over 90 minutes, flow rate 20
mL/minute, .lambda.=214 nm) and lyophilized to afford a white
powder. To the white powder in acetonitrile (2 mL) and water (200
mL) was added Amberlite.RTM. IRA-400(Cl) ion exchange resin. The
mixture was filtered, and the filtrate was lyophilized to give 553
mg (45%) of (33) as a white solid.
[0734] .sup.1H NMR (DMSO, 300 MHz): .delta.11.22(1H, s), 9.16(1H,
s), 8.86(2H, s), 7.74(2H, m), 7.25(1H, m), 7.11-6.95(4H, m),
5.78(1H, s), 4.06-3.93(2H, m), 3.17(2H, m), 3.05(2H, m),
1.79-1.37(12H, m), 1.23(6H, m).
[0735] CI MS M+1=465
[0736] HPLC: RT=8.22 (Beckman 235328 C18 5 .mu.m 4.6 mm.times.25
cm, eluted with a mixture of solvents consisting of (i) 0.1%
trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid
in acetonitrile, gradient profile 80:20 (i):(ii) to 10:90 (i):(ii)
over 23 minutes, flow rate 1.5 mL/minute, .lambda.=214 nm).
Example 6
[0737]
3-((2S)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl--
3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximidamide
[0738] Step (a): Preparation of
2-(benzyloxy)-5-bromobenzenecarbaldehyde 50
[0739] 5-bromosalicylaldehyde (34) (50.0g, 0.249 moles) was
suspended in 150 ml EtOH with stirring. KOH (13.97 g, 0.249 moles)
was dissolved in 40 ml water and added to the aldehyde suspension.
After 30 minutes benzyl bromide (51.05 g, 35.5 ml, 0.298 moles) was
added slowly. The mixture was refluxed overnight. After cooling to
room temperature water (50 mL) was added and then after 5 minutes
an off white solid was collected by filtration. This was dried
overnight in vacuum to afford 61.71 g of the desired product (35),
84.6% yield. 1H NMR (CDCl.sub.3) .delta.10.46 (1H, s), 7.94 (1H,
d), 7.60 (1H, dd), 7.41 (5H, m), 6.95 (1H, d), 5.18 (2H, s).
[0740] APCI MS: No M+1, M-91 (201). HPLC: 20.91 min. on C-18 column
@ 1.5 ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1% TFA).fwdarw.90%
CH3CN(0.1% TFA) in H2O(0.1% TFA) (0.fwdarw.22 min.)
[0741] Step (b): Preparation of
2-[2-(benzyloxy)-5-bromophenyl]-2-hydroxya- cetonitrile 51
[0742] To a suspension of (35) (50 g, 0.172 moles) in MeOH (400 mL)
was added KCN (50.31 g, 0.773 moles) which generated a yellow
color. Acetic acid (15.72 ml, 0.275 moles) was added dropwise over
10 minutes, and the reaction stirred at room temp. for 2.5 hours.
The mixture was filtered and concentrated by 75%. Ethyl acetate
(250 mL) was added and then after washing with water (2.times.150
ml), sat. NaCl (1.times.150 ml), the organic phase was dried over
MgSO.sub.4, and finally concentrated to a brown oil.
Chromatographed on flash silica using 10%-.fwdarw.20% ethyl acetate
in hexane affords (36) 35.4 g desired product, 64.8% yield. (1H NMR
CDCl.sub.3) .delta.7.58 (1H, d), 7.35-7.50 (6H, m), 6.95 (1H, d),
5.55 (1H, d), 5.18 (2H, s), 3.30 (1H, d). APCI MS No M+1, M-91
(201): HPLC: 18.04 min. on C-18 column @ 1.5 ml/min. 20% CH3CN(0.1%
TFA) in H2O(0.1% TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(.,1% TFA)
(0.fwdarw.22 min.)
[0743] Step (c): Preparation of methyl
2-[2-(benzyloxy)-5-bromophenyl]-2-h- ydroxyacetate 52
[0744] Diethyl ether (45 mL), dioxane (45 mL), MeOH (12 mL) were
mixed at room temp. and then HCL gas was bubbled into the solution
for 3-4 minutes at a good rate (to make a saturated HCl solution).
The HCl solution was added to the (36) (35.2 g, 0.111 moles), which
after 15 minutes caused a thick white ppt to form.
[0745] After an additional 45 minutes of stirring the white solid
was filtered and washed with diethyl ether (3.times.100 ml). This
solid was then stirred into 200 ml of 1:1 dioxane:water, and
allowed to stir until the mixture became homogenous, approx. 1
hour. Water (100 mL) was added and the solution was extracted with
ethyl acetate (2.times.200 ml). The organic layer was dried over
MgSO.sub.4, evaporated to afford a clear oil, which afforded (37)
as a waxy white solid after drying overnight under high (31.3 g,
80.4%). (1H NMR CDCl.sub.3) .delta.7.42 (1H, d), 7.3-7.4 (6H, m)
6.80 (1H, d), 5.32 (1H, bd), 5.10 (2H) dd,), 3.7 (3H, s,), 3.6 (1H,
bd). APCI MS M+23, No M+1. HPLC: 17.43 min. on C-18 column @ 1.5
ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1% TFA).fwdarw.90% CH3CN(0.1%
TFA) in H2O(0.1% TFA) (0.fwdarw.22 min.)
[0746] Step (d): Preparation of methyl
2-[2-(benzyloxy)-5-bromophenyl]-2-o- xoacetate 53
[0747] Methylene chloride (30 mL) was cooled to minus70.degree. C.
under N.sub.2 with stirring via dry ice/acetone bath, and then
oxalyl chloride (3.07 ml, 0.035 moles) was added. DMSO (4.97 ml,
0.70 moles) was then added as a 1:1 mix with CH.sub.2Cl.sub.2
slowly down the side of the flask, not allowing the temperature to
go above -60 .degree. C. This was stirred for 15 minutes, and then
the alcohol (37) (10.26 g, 0.026 moles) was added as a solution in
CH.sub.2Cl.sub.2, dropwise, again not allowing the temp. to climb
above -60.degree. C. This mixture was stirred at -65.degree. C. for
30 minutes, then added Et.sub.3N (20.40 ml, 0.145 moles) dropwise,
not allowing temp. to reach -60 .degree. C. Upon warming to room
temp., water (150 ml) was added and the product was extracted into
ethylacetate. The organic phase was dried over MgSO.sub.4, and then
rotovaped to a pale yellow solid, (38) 10.03 g, 98% yield. (1H NMR
CDCl.sub.3) .delta.7.99 (1H, d), 7.65 (1H, dd), 7.38-7.42 (5H, m),
6.96 (1H, d), 5.05 (2H, s), 3.35 (3H, s). APCI MS No M+1, M-91
(257). HPLC: 20.95 min. on C-18 column @ 1.5 ml/min. 20% CH3CN(0.1%
TFA) in H20(0.1% TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(0.1% TFA)
(0.fwdarw.22 min.)
[0748] Step (e): Preparation of methyl
(2R)-2-[2-(benzyloxy)-5-bromophenyl- ]-2-hydroxyethanoate 54
[0749] The ketoester (38) (12.9 g, 0.037 moles) was slurried in
CH.sub.2Cl.sub.2 (6 mL), then R-Alpine Borane (14.07 ml, 0.052
moles) was added dropwise and the slurry allowed to stir at room
temp. After 5 days an additional amount of R-Alpine Borane (10.0
ml, 0.037 moles) was added and the mixture was stirred for another
24 hours. Acetaldehyde (6.0 ml) was added together with
CH.sub.2Cl.sub.2 (100 ml) and ethanolamine (4.0 ml), and then the
mixture was stirred for 1 hour. The mixture was evaporated by
.about.50% and then columned directly on flash silica using
15.fwdarw.20% ethyl acetate in hexane to afford the desired product
(39), 12.2 g 94% yield. (1H NMR CDCl.sub.3) .delta.7.42 (1H, d),
7.3-7.4 (6H, m) 6.80 (1H, d), 5.32 (1H, bd), 5.10 (2H, dd), 3.7(3H,
s), 3.6 (1H, bd). APCI MS M+23, No M+1. HPLC: 17.43 min. on C-18
column @ 1.5 ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1%
TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(0.1% TFA) (0.fwdarw.22 min.)
Chiral HPLC 8.07 min. (95%ee) @ 2.0 ml/min. 20% EtOH (0.1% TEA) in
Hexane on (Phenomenex) Chirex (R)-NGLY and DNB chiral column.
[0750] Step (f): Preparation of methyl
(2S)-2-[2-(benzyloxy)-5-bromophenyl- ]-2-(2-nitrophenoxy)ethanoate
55
[0751] The chiral alcohol (39) (5.0 g, 0.014 moles) was dissolved
in ethyl acetate (75 mL), then triphenyl phosphine (4.85 g, 0.018
moles) and o-nitro phenol (2.37 g, 0.017 moles) were added with
stirring. The reaction was put under N.sub.2 and cooled to
-40.degree. C. via dry ice/acetone bath, and the DIAD (3.63 ml,
0.018 moles) was added dropwise. The reaction stirred at
-40.degree. C. for 2 hours. The volume was reduced by .about.50%
and the reaction was chromatographed on flash silica using
15%.fwdarw.20% ethyl acetate in hexane to afford desired product
(40) (5.6 g, 83.3%). (1H NMR CDCl.sub.3) .delta.7.85 (1H, dd), 7.71
(1H, d), 7.3-7.45 (6H, m), 7.07 (1H, t), 7.0 (1H, d), 6.85 (1H, d),
6.20 (1H, s), 5.12 (2H, dd), 3.72 (3H, s). HPLC: 22.07 min. on C-18
column @ 1.5 ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1%
TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(0.1% TFA) (0.fwdarw.22 min.)
No separation of enantiomers on chrial HPLC.
[0752] Step (g): Preparation of
(2S)-2-[2-(benzyloxy)-5-bromophenyl]-2H-1,- 4-benzoxazin-3(4H)-one
56
[0753] The chiral ether (40) (9.3 g, 0.020 moles) was dissolved in
400 ml MeOH and then 10 g of neutral RaNi was added (washed with
water 10.times., then MeOH 3.times.). The mixture was placed under
H.sub.2 at 53.8 psi. A pressure drop to 48.0 psi after 15 hrs was
noted. The reaction was filtered and evaporated which after
chromatography, on flash silica using 20% ethyl acetate in hexane,
afforded the desired product (41) (5.17 g, 64%, and 92.8% ee via
chiral HPLC). Variable results were obtained on attempts to improve
the enantiomeric excess by recrystallisation from EtOAc. The
filtrate typically contained material of enriched enantiomeric
excess. Thus material was ultimately obtained of 95.5%ee. (1H NMR
CDCl.sub.3) .delta.8.2 (1H, bs), 7.52 (1H, d), 7.42 (1H, dd),
7.33-7.42 (5H, m), 6.82-6.98 (4H, m), 6.68 (1H, d), 5.82 (1H, s)
5.02 (1H, dd) APCI MS M+1(411). HPLC: 17.48 min. on C-18 column @
1.5 ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1% TFA).fwdarw.90%
CH3CN(0.1% TFA) in H2O(0.1% TFA) (0.fwdarw.22 min.). Chiral HPLC
6.12 min. (95.5%ee) @ 2.0 ml/min. 20% EtOH (.1% TEA) in Hexane on
(Phenomenex) Chirex (R)-NGLY and DNB chiral column.
[0754] Step (h): Preparation of
4-(benzyloxy)-3-[(2S)-3-oxo-3,4-dihydro-2H-
-1,4-benzoxazin-2-yl]benzenecarbonitrile 57
[0755] To (41) (4.15 g, 0.010 moles) in DMF (6 mL) was added CuCN
(1.57 g, 0.18 moles) and the mixture heated to 160.degree. C. with
stirring under N.sub.2 overnight. The reaction mixture was cooled
to R.T. and then ethyl acetate (100 mL) was added. Washing with
sat. brine/NH.sub.4OH (9:1) (2.times.130 ml), drying over
MgSO.sub.4, and then evaporation afforded a brown solid. A portion
was crystallised from ethylacetate to afford (0.76 g) and the
remainder was purified by chromatography 25%.fwdarw.50% ethyl
acetate in hexane to afford another 1.53 g, (2.29 g, 63.6%). (1H
NMR CDCl.sub.3) .delta.8.26 (1H, bs), 7.72 (1H, d), 7.65 (1H dd),
7.30 (5H, s), 7.03 (1H, d), 6.91-6.98 (3H, m), 6.72 (1H, dd), 5.86
(1H, s), 5.14 (2H, dd). APCI MS M+1 (357). HPLC: 17.80 min. on C-18
column @ 1.5 ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1%
TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(0.1% TFA) (0.fwdarw.22 min.)
Chiral HPLC 6.51 min. @ 2.0 ml/min. 20% EtOH (0.1% TEA) in Hexane
on (Phenomenex) Chirex (R)-NGLY and DNB chiral column.
[0756] Step (i): Preparation of
4-(benzyloxy)-3-[(2S)-4-(5-bromopentyl)-3--
oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarbonitrile 58
[0757] To (42) (2.2 g, 0.0062 moles) in dry DMF (15 mL) under
N.sub.2 with stirring was added dibromopentane (3.76 ml, 0.025
moles) and then the mixture was cooled too 0.degree. C. KN(TMS)2
(11.11 ml 0.5M sol., 0.0055 moles) was added dropwise over
.about.15 minutes and the mixture was stirred for 1 h at 0.degree.
C., then at room temp for 2 hrs. Ethyl acetate (75 mL) was added
and the mixture extracted with water (2.times.50 ml), dried the
organic layer over MgSO.sub.4 and rotovaped off solvent.
Chromatography on flash silica to get afforded the required product
(43) (1.51 g, 48%). (1H NMR CDCl.sub.3) .delta.7.65 (2H, d), 7.31
(5H, s), 6.94-7.07 (5H, m), 5.82 (1H, s), 5.14 (2H, dd), 3.89 (2H,
dd), 3.37 (2H, t), 1.87 (2H, m), 1.58 (2H, m), 1.50 (2H, m,). APCI
MS M+1 (505). HPLC: 23.01 min. on C-18 column @ 1.5 ml/min. 20%
CH.sub.3CN(0.1% TFA) in H2O(0.1% TFA).fwdarw.90% CH.sub.3CN(0.1%
TFA) in H.sub.2O(0.1% TFA) (0.fwdarw.22 min.)
[0758] Step (j): Preparation of
4-(benzyloxy)-3-[(2S)-4-(5-iodopentyl)-3-o-
xo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarbonitrile 59
[0759] To (43) (1.49 g, 0.0029 moles) in acetone (20 ml) and added
the NaI (2.21 g, 0.015 moles) and then the mixture was refluxed for
1 hour, filtered, rotovaped off acetone, slurried up in 30 ml ethyl
acetate and washed with 30 ml H.sub.2O, then 30 ml sat NaCl, dried
the organic layer over MgSO.sub.4 and rotovaped to a yellow oil
(44), 1.48 g crude. (1H NMR CDCl.sub.3) .delta.7.63 (2H, d), 7.31
(5H, s), 6.93-7.10 (5H, m,) 5.81 (1H, s), 5.15 (2H, dd,), 3.88 (2H,
t), 3.15 (2H, t), 1.82 (2H, m), 1.60 (2H, m), 1.45 (2H, m). APCI MS
M+1 (553). HPLC: 23.54 min. on C-18 column @ 1.5 ml/min. 20%
CH3CN(0.1% TFA) in H2O(0.1% TFA).fwdarw.90% CH3CN(0.1% TFA) in
H2O(0.1% TFA) (0.fwdarw.22 min.)
[0760] Step (k): Preparation of
4-(benzyloxy)-3-((2S)-4-5-[(2R,6S)-2,6-dim-
ethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-
-2-yl)benzenecarbonitrile 60
[0761] To (44) in dry DMF (2 mL) was added cis-2,6
dimethylpiperidine (2 mL) and the mixture stirred at room temp.
overnight. Added 30 ml ethyl acetate and washed with
H.sub.2O(2.times.30 ml), dried the organic layer over MgSO.sub.4
and rotovaped to a pale yellow oil, 1.27 g, 80.4% yield over 2
steps. Used without purification in next reaction. (1H NMR)
.delta.7.61-7.64 (2H, m), 7.31 (5H, s), 6.95-7.06 (5H, m), 5.84
(1H, s), 5.14 (2H, m), 3.88 (2H, m), 2.68-2.73 (2H, m), 2.43 (2H,
m), 1.21-1.76 (12H, m), 1.04-1.10 (6H, m) APCI MS M+1 (538). HPLC:
14.95 min. on C-18 column @ 1.5 ml/min. 20% CH3CN(0.1% TFA) in
H2O(0.1% TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(0.1% TFA)
(0.fwdarw.22 min.)
[0762] Step (1): Preparation of
4-(benzyloxy)-3-((2S)-4-5-[(2R,6S)-2,6-dim-
ethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-
-2-yl)-N-hydroxybenzenecarboximidamide 61
[0763] To (45) (0.54 g, 0.001 moles) in 5 ml MeOH was added
hydroxylamine HCl (0.208 g, 0.003 moles), then
diisopropylethylamine (0.348 ml, 0.002 moles) was added dropwise
and the reaction stired overnight at room temp. Rotovaped off MeOH,
added 50 ml CH.sub.2Cl.sub.2 and washed with sat. NaHCO.sub.3,
dried the organic layer over MgSO.sub.4 and rotovaped to a white
waxy solid (46), 0.560 mg crude. Used without purification in next
reaction. (1H NMR) .delta.7.46-7.53 (2H, m), 7.20-7.27 (5H, m),
6.85-6.94 (5H, m), 5.85 (1H, s), 5.03 (2H, s), 3.87-3.95 (1H, m),
3.71-3.78 (1H, m), 2.71-2.74 (2H, m), 2.47 (2H, bm), 1.19-1,64
(12H, m), 0.98-1.09 (6H, m). APCI MS M+1 (571). HPLC: 11.14 min. on
C-18 column @ 1.5 ml/min. 20% CH3CN(0.1% TFA) in H2O(0.1%
TFA).fwdarw.90% CH3CN(0.1% TFA) in H2O(0.1% TFA) (0.fwdarw.22
min.)
[0764] Step (m): Preparation of
3-((2S)-4-5-[(2R,6S)-2,6-dimethyltetrahydr-
o-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydro-
xybenzenecarboximidamide 62
[0765] To (46) (0.50 g, 0.00087 moles) in TFA (2 mL) was added 4m1
TFAA (4 mL) and the mixture stirred at room temperature, under
N.sub.2, overnight. Rotovaped off the solvent to get a gray oil.
Added TFA (5 mL), then added 0.060 g 20% Pd/C, evacuated the flask,
filled with H.sub.2 (via balloon), repeated, and let stir under an
atmosphere of H.sub.2 overnight. Filtered the reaction through
celite, washed with CH.sub.2Cl.sub.2 then rotovaped off the
solvent. Chromatographed on prep HPLC. Converted the clean
fractions to the HCl salt by running through IRA 400(Cl) resin as
an aqueous solution. Lyophilized to get 0.060 g desired product
(47). (1H NMR_D.sub.2O) .delta.7.60-7.65 (2H, m,), 7.18 (1H, d),
6.97-7.07 (3H, m), 6.90 (1H, d) 5.70 (1H, s), 4.07-4.12 (1H, m),
3.80-3.85 (1H, m), 1.24-1.77 (12H, m), 1.07-1.14 (6H, m). APCI MS
M+1 (465). HPLC: 8.31 min. on C-18 column @ 1.5 ml/min. 20%
CH3CN(0.1% TFA) in H2O(0.1% TFA).fwdarw.90% CH3CN(0.1% TFA) in
H2O(0.1% TFA) (0.fwdarw.22 min.) Chiral HPLC 11.10 min. (90% ee) @
1.0 ml/min. 20% EtOH, 20% MeOH(0.1 mM NH4Ac), 60% hexane on
(Phenomenex) Chirex (R)-NGLY and DNB chiral column.
Intermediates
[0766] 2-(3-Cyanophenyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one
[0767] Step (a): Preparation of
2-[(3-cyanophenyl)methylene]malononitrile 63
[0768] Into a mixture of 3-cyanobenaldehyde (I1) (24.8 g, 0.189
mol) and malononitrile (11.9 mL, 0.189 mol) in dioxane (120 mL) was
added piperidine (1.5 mL) slowly. The solution was stirred at room
temperature for 1 hour. The precipitate was filtered, washed with
water, and dried in the high vacuum oven to give 7.11 g (21%) of
product (I2) as yellow solid. To the filtrate was added ethanol and
water and 10.29 g (30%) of additional product crystallized as
yellow solid.
[0769] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.8.17 (1H, m), 8.51
(1H, m), 7.87 (2H, m), 7.68 (1H, m).
[0770] Step (b): Preparation of
3-(3-Cyanophenyl)-2,2-oxiranedicarbonitril- e 64
[0771] In a three-necked flask, intermediate (I2) (17.38 g, 97.0
mmol) was dissolved in acetonitrile (90 mL) and THF (113 mL) at
room temperature with vigorous stirring. Sodium hypochlorite (183
mL) was added dropwise, while the pH of the solution was maintained
between 4.5 and 6 throughout the addition by adding 2N sulfuric
acid (20 mL). Once the addition was complete, stirring was
continued for 20 minutes. Ethyl acetate was added, and the layers
were separated. The aqueous layer was extracted with ethyl acetate
(3.times.300 mL). The combined organic extracts were washed with
brine (2.times.100 mL), dried with magnesium sulfate, filtered, and
evaporated in vacuo. The residue was flushed through a pad of
silica gel eluting with 50% ethyl acetate in hexane. The product
(I3) was isolated 11.18 g (58%) as a tan solid.
[0772] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.83 (1H, m), 7.76
(1H, m), 7.67 (2H, m), 4.78 (1H, s).
[0773] Step (c): Preparation of 2-Bromo-2-(3-cyanophenyl)acetic
acid 65
[0774] To the epoxide (I3) (5.12 g, 26.2 mmol) in THF (30 mL) was
added 48% HBr (4.4 mL), and the solution was refluxed for 3 hours.
The THF was removed in vacuo, and the residue was dissolved in
ether (200 mL). The acid is extracted from ether with 1N NaOH (100
mL). The aqueous solution was then acidified with HCl, and the acid
is extracted with ether (2.times.200 mL). The combined organic
phases were dried over magnesium sulfate, filtered, evaporated in
vacuo, and dried under high vacuum to give 4.32 g (69%) of (I4) as
a brown oil.
[0775] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.83 (1H, m), 7.73
(1H, m), 7.55 (1H, m), 7.41 (1H, m), 5.26 (1H, s).
[0776] Step (d): Preparation of 2-Bromo-2-(3-cyanophenyl)acetyl
chloride 66
[0777] To the acid (I4) (1.01 g, 4.21 mmol) in dichloromethane (12
mL) were added oxalyl chloride (1 equiv.) and a catalytic amount of
DMF (0.1 mL). Bubbling occurred and the resulting solution was
stirred for 1 hour. The solvent was removed in vacuo to give (I5)
in quantitative yield as a brown oil.
[0778] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.80-7.72 (3H, m),
7.592 (1H, m), 5.64 (1H, s).
[0779] Step (e): Preparation of
N1-(2-Hydroxyphenyl)-2-bromo-2-(3-cyanophe- nyl)acetamide 67
[0780] To (I5) (1.08 g, 4.17 mmol) in dichloromethane (10 mL) were
added o-aminophenol hydrochloride (0.62 g, 4.26 mmol) and
diisopropylethylamine (0.72 mL, 4.11 mmol). The solution was
stirred at room temperature for 4 hours. The solution was diluted
with water and extracted with ethyl acetate (5.times.100 mL). The
combined organic extracts were washed with brine (200 mL), dried
with magnesium sulfate, filtered, and evaporated in vacuo to give
(I6) in quantitative yield as a brown oil.
[0781] Step (f): Preparation of
2-(3-Cyanophenyl)-3,4-dihydro-2H-1,4-benzo- xazin-3-one 68
[0782] To the benzoxazinone (I6) (1.38 g, 4.17 mmol) in DMF (5 mL)
was added potassium carbonate (1.40 g, 10.1 mmol), and the solution
was stirred at room temperature for 1 hour. The solution was
diluted with water and extracted with ethyl acetate (3.times.150
mL). The combined organic extracts were washed with brine
(2.times.100 mL), dried with magnesium sulfate, filtered, and
evaporated in vacuo. The residue was purified on a silica gel
column eluted with 25% ethyl acetate in dichloromethane. The
product (I1) was isolated 0.48 g (46%) as a light orange solid.
[0783] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.99 (1H, s), 7.75
(2H, m), 7.64 (1H, m), 7.49 (1H, m), 7.11-6.97 (3H, m), 6.80 (1H,
m), 5.69 (1H, s).
[0784] Alternative Procedure for Preparation of
2-(3-Cyanophenyl)-3,4-dihy- dro-2H-1,4-benzoxazin-3-one
[0785] In a similar manner to steps (a) through (f) described
above, but starting from 3-bromobenzaldehyde,
2-(3-bromophenyl)-3,4-dihydro-2H-1,4-b- enzoxazin-3-one may be
prepared. 69
[0786] To a solution of
2-(3-bromophenyl)-3,4-dihydro-2H-1,4-benzoxazin-3-- one (I7) (3.00
g, 9.87 mmol) in DMF (20 mL) was added Zinc cyanide (0.68 g, 5.79
mmol) and then tetrakistriphenylphosphine palladium (0) (0.96 g, 8
mol %). The degassed solution was heated at 100.degree. C. for 5
hours, cooled to room temperature, and then treated with water (50
mL). The product was extracted into ethyl acetate (2.times.100 mL),
washed with brine (50 mL), dried over MgSO.sub.4, and then purified
by silica gel chromatography, eluant 50% ethyl acetate in hexane.
This process affords the title compound (1.866 g, 76%) that was
recrystallized from ethanol/water.
[0787] (APCI MS) 251.
[0788] Analysis C.sub.15H.sub.10N.sub.2O.sub.2:
[0789] Required: C, 71.99; H. 4.03; N, 11.19.
[0790] Found: C, 71.59; H. 4.22; N, 10.96.
[0791] Procedure for Preparing methyl
2-bromo-2-(3-bromophenyl)acetate: 70
[0792] To 3-bromophenylacetic acid (10 g, 47 mmol) under argon was
added PBr.sub.3 (11.2 mL, 118 mmol) and the suspension stirred at
room temperature for 45 minutes. Bromine (11.1 mL, 216 mmol) was
added dropwise over 5 minutes. The mixture was stirred at
100.degree. C. for 3 hours and then cooled. Anhydrous methanol (35
mL) was added dropwise over 30 minutes, and then the reaction
mixture was diluted with ether (400 mL), washed with 5% NaHCO.sub.3
(800 mL), brine (200 mL), and then dried over MgSO.sub.4. The
mixture was filtered and concentrated in vacuo to afford material
of sufficient purity to use directly.
[0793] Alternative Procedure for Preparing
2-(5-bromo-2-methoxyphenyl)-2H-- 1,4-benzoxazin-3(4H)-one: 71
[0794] To 2-bromo-2H-1,4-benzoxazin-3(4H)-one (I10) (1.40 g, 6.14
mmoles) in methylene chloride (20 mL) was added 4-bromoanisole and
then tin (IV) chloride. Addition of tin (IV) chloride caused a
brown solution to form. The solution was refluxed for 5 hours,
diluted with methylene chloride (100 mL) and washed with water
(2.times.50 mL). After drying over Magnesium sulphate the mixture
was concentrated until the product (I11) precipitated (0.58 g).
Concentration of the mother liquors and chromatography on silica
gel afforded an additional amount of product (I11) (0.55 g).
[0795] (APCI MS) 334
[0796] Preparation of
4-methoxy-3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-y-
l)benzenecarbonitrile 72
[0797] To a solution of
2-(5-bromo-2-methoxyphenyl)-2H-1,4-benzoxazin-3(4H- )-one (I11)
(0.90 g, 2.70 mmoles) in DMF (10 mL) was added copper (I) cyanide
(1.3 g, 5 equiv.) and the mixture heated at 160.degree. C. for 12
hours. The mixture was cooled and methylene chloride (100 mL) and
aqueous ammonium hydroxide (10 mL) were added. The methylene
chloride layer was separated and dried over MgSO.sub.4 which
afforded the required product (I12) (0.67 g, 89%) upon evaporation
in vacuo.
[0798] (APCI MS) 281
[0799] The invention compounds have demonstrated factor Xa,
thrombin, and factor VIIa inhibitory activity in the standard
assays commonly employed by those skilled in the art.
[0800] Determination of Factor Xa IC.sub.50 and K.sub.i
Constants
[0801] The ability of compounds to act as inhibitors of human
factor Xa catalytic activity is assessed by determination of that
concentration of test substance that inhibits by 50% (IC.sub.50)
the ability of human factor Xa to cleave the chromogenic substrate
S2765 (N-CBz-D-Arg-L-Gly-L-Arg-p-nitroanilide. 2HCl, DiaPharma).
Typically, 145 .mu.L human factor Xa (1 nM final, Enzyme Research
Laboratories) in 10 mM HEPES, 150 mM NaCl, 0.1% BSA, pH 7.4 (HBSA
buffer), and 5 .mu.L of test substance in DMSO (2% final) are
incubated for 60 minutes at room temperature. Following preheating
to 37.degree. C. for 5 minutes, to this mixture is added 100 .mu.L
of S2765 (400 .mu.M final) in HBSA buffer. The velocity of S2765
hydrolysis is determined at 37.degree. C. by measuring the initial
rate of change of the optical density at OD.sub.405 nM every 10
seconds for 5 minutes using a ThermoMax.RTM. Kinetic Microplate
Reader.
[0802] For K.sub.i determinations, the assay conditions were
essentially the same as above except for the following. The
concentration of factor Xa was 50 pM, and that of the substrate, in
this case a fluorogenic S2765 (i.e., S2765 with AMC tag instead of
pNA, California Peptide Research), was over the range of 10 to 500
.mu.M. The test compound and substrate in HBSA buffer were
incubated as above, and the reaction was initiated with
enzyme-buffer. The data (steady-state velocity at various
concentrations of the substrate and the inhibitors) of the
competitive inhibition was analyzed using the methods described by
Segel (Enzyme Kinetics, Wiley Interscience Publications, 1993). A
non-linear regression program, Kaleidograph and/or Microsoft Excel,
was used to estimate the kinetic parameters (K.sub.m, V.sub.max,
and K.sub.i) by use of Michaelis-Menten and reciprocal Dixon plot
fits.
[0803] Determination of Thrombin IC.sub.50 and K.sub.i
Constants
[0804] The ability of compounds to act as inhibitors of human
thrombin catalytic activity is assessed by determination of that
concentration of test substance that inhibits by 50% (IC.sub.50)
the ability of human thrombin to cleave the chromogenic substrate
Chromozym TH (Tosyl-Gly-Pro-Arg-pNA*Ac, Boehringer Mannheim).
Typically, 145 .mu.L human thrombin (0.75 nM, Enzyme Research
Laboratories) in a HPB buffer (10 mM HEPES, 100 mM NaCl, 0.05% BSA,
0.1% PEG-8000, pH 7.4) and 5 .mu.L of test substance in DMSO (2%
final) are incubated for 60 minutes at room temperature. Following
preheating to 37.degree. C. for 5 minutes, to this mixture is added
100 .mu.L of Chromozym TH (24 .mu.M final) in HPB buffer. The
velocity of Chromozym TH hydrolysis is determined at 37.degree. C.
by measuring the initial rate of change of the optical density at
OD 405 nM every 10 seconds for 5 minutes using a ThermoMax.RTM.
Kinetic Microplate Reader.
[0805] For K.sub.i determinations, the assay conditions were
essentially the same as the aforementioned except for the
following. The concentration of thrombin used was 50 pM, and that
of a fluorogenic Chromozym TH (i.e., Chromozym TH with AMC instead
of pNA tag, Novabiochem) was over the range of 1 to 40 .mu.M. The
test compound and substrate in HPB buffer were incubated as above,
and the reaction was initiated with enzyme-buffer and run at
24.degree. C. Kinetic analysis was performed as for factor Xa
K.sub.i determinations.
[0806] Determination of Trypsin IC.sub.50 and K.sub.i
Constants.
[0807] The ability of compounds to act as inhibitors of human
trypsin catalytic activity is assessed by determination of that
concentration of test substance that inhibits by 50% (IC.sub.50)
the ability of human trypsin to cleave the chromogenic substrate
S2222 (N-Bz-L-Ile-L-Glu-L-Gly- -L-Arg-p-nitroanilide. HCl,
DiaPharma). Typically, 145 .mu.L human trypsin (0.5 nM final) in 10
mM HEPES, 150 mM NaCl, 0.1% BSA, and 5 .mu.L of the test substance
in DMSO (2% final) are incubated for 60 minutes at room
temperature. Following preheating to 37.degree. C. for 5 minutes,
to this mixture is added 100 .mu.L of S2222 in HBSA buffer (100
.mu.M final), and the velocity of S2222 hydrolysis is determined at
37.degree. C. by measuring the optical density at OD 405 nM every
10 seconds over 5 minutes using a ThermoMax.RTM. Kinetic Microplate
Reader.
[0808] For K.sub.i determinations, the assay conditions were
essentially the same as the aforementioned except that the reaction
was initiated with enzyme-buffer and run at 24.degree. C. using a
substrate range of 10 to 500 .mu.M. Kinetic analysis was performed
as for factor Xa K.sub.i determinations.
[0809] Determination of Tissue Factor/Factor VIa IC.sub.50
[0810] The ability of compounds to act as inhibitors of the
catalytic activity of human tissue factor/factor VIa complex is
assessed by determination of that concentration of test substance
that inhibits by 50% (IC.sub.50 the ability of a complex of human
recombinant tissue factor/factor VIIa to cleave the chromogenic
substrate Spectrozyme VIIa (CH.sub.3SO.sub.2-D-CHA-Arg-pNA*AcOH,
American Diagnostica). Typically, 50 .mu.L human factor VIIa
(Enzyme Research Laboratories) is incubated for 10 minutes as a 1:1
mixture (5 nM final each) with 95 .mu.L recombinant human tissue
factor (American Diagnostica) in a modified HBSA buffer (10 mM
Hepes, 5 mM CaCl.sub.2, 0.1% BSA, pH 8.0). Then 5 .mu.L of the test
substance in DMSO (2% final) is added and incubated for 60 minutes
at room temperature. Following preheating to 37.degree. C. for 5
minutes, to this mixture is added 100 .mu.L of Spectrozyme VIIa
(500 .mu.M final) in modified HBSA, and the velocity of Spectrozyme
VIIa hydrolysis is determined at 37.degree. C. by measuring the
optical density at an OD.sub.405 nM every 10 seconds over 5 minutes
using a ThermoMax.RTM. Kinetic Microplate Reader.
[0811] In Vitro Assay for Human Prothrombinase
[0812] This assay demonstrates the ability of test compounds of the
invention to inhibit the human prothrombinase (PTase) complex
(typically comprising of human factor Va, human factor Xa,
Ca.sup.2+, and phospholipid moiety) and thereby the subsequent
cleavage of prothrombin to yield thrombin. For determination of
IC.sub.50 (PTase) of the compounds of the invention, PTase activity
was expressed by thrombin activity.
[0813] PTase reaction was performed in 100 .mu.L of mixture
containing PTase (20 .mu.M) PCPS (Avanti Polar Lipids following a
procedure modified from Barenholz et al., Biochemistry,
1977;16:2806-2810) in a 30:70 ratio, 2.5 nM human factor Va (Enzyme
Research Laboratories) and 2.5 pM human factor Xa (Enzyme Research
Laboratories) in modified HEPES buffer (10 mM Hepes, 150 mM NaCl,
0.1% PEG-8000, 0.05% BSA, 2.5 mM CaCl.sub.2, pH 7.4), 3 .mu.M human
prothrombin (Enzyme Research Laboratories) and varied
concentrations of the test compounds (1 nM to 100 .mu.M in DMSO, 2%
final). Reaction was started by co-incubating PTase with test
compound for 60 minutes at room temperature, followed by addition
of prothrombin for 6 minutes at room temperature. Next, the
reaction was quenched by the addition of 100 .mu.L of 20 mM EDTA.
Activity of the thrombin (product) is then measured in the presence
of 50 .mu.L S2238 (250 .mu.M final, H-D-Phe-Pip-Arg-pNA*Ac,
DiaPharma) as substrate by measuring the change at 37.degree. C. in
OD.sub.405 nM for 5 minutes at 10 second intervals using a
ThermoMax.RTM. Kinetic Microplate Reader.
[0814] Example 5 in this assay has an IC50 of 0.00017 uM
[0815] Determination of Prothrombin Time (PT)
[0816] Rat, rabbit, dog, and human blood (typically 1.8 mL) was
collected and added to a sodium citrate solution (3.8%) to afford a
1:10 dilution. After centrifugation (2000 g for 10 minutes), the
blood plasma was stored at -70.degree. C. to 0.degree. C.
Conventional prothrombin time (PT) tests were carried out in the
presence of various concentrations of test compound and the
concentration of test compound required to double the clotting time
determined. Typically, the test compound (50 .mu.L volume of
varying concentrations 0.1 .mu.M to 1000 .mu.M) and blood plasma
(100 .mu.L volume) were incubated at 37.degree. C. for 10 minutes,
and then tissue thromboplastin, typically Neoplastine from American
Bioproducts, with calcium was added. Fibrin formation and the time
required for a clot to form were determined using an automated ST4
Clot Detection System in duplicate.
[0817] In an ex-vivo modification of this assay, drug was
administered intravenously or orally to a group of rats or rabbits.
At various times blood samples were collected, and the PT
coagulation assay as described above were performed.
[0818] Arterio-Venous Shunt Stasis Antithrombotic Model
[0819] In vivo measurements of antithrombotic activity were
performed according to the procedure of Vogel et al., Thromb. Res.,
1989;54:399-410. Briefly, the vena cava was exposed, collateral
veins were ligated, and sutures were loosely located around the
inferior vena cava. These sutures were tightened after drug
administration to induce stasis within the ligated portion of the
vena cava. After an appropriate time, the thrombus was isolated and
weighed. The effect of varying drug concentrations administered
intravenously or orally on thrombus mass reflected antithrombotic
activity.
[0820] Alternatively, and according to the procedure of Smith et
al., Br. J. Pharmacol., 1982;77:29-38, the left jugular and right
carotid artery were exposed and cannulated. A shunt, which contains
silk threads or preweighed cotton, is then inserted which connects
the two cannulated vessels. Once drug has been administered, the
shunt is closed, and the thrombus that forms on the foreign surface
in the shunt is removed after a period of time. Clot weight then
reflects antithrombotic activity.
[0821] Arterial Thrombosis Model
[0822] FeCl.sub.3 Induced Carotid Arterial Injury Model
[0823] The FeCl.sub.3 induced injury to the carotid artery in rats
was induced according to the method described by Kurz K. D., Main
R. W., Sandusky G. E., Thrombosis Research, 1990;60:269-280 and
Schumacher W. A. et al., J. Pharmacology and Experimental
Therapeutics, 1993;267:1237-1242.
[0824] Male, Sprague-Dawley rats (375-410 g) were anesthetized with
urethane (1500 mg.backslash.kg ip). Animals were laid on a
37.degree. C. heating pad. The carotid artery was exposed through a
midline cervical incision. Careful blunt dissection was used to
isolate the vessel from the carotid sheath. Using forceps, the
artery was lifted to provide sufficient clearance to insert two
small pieces of polyethylene tubing (PE-205) underneath it. A
temperature probe (Physitemp MT23/3) was placed between one of the
pieces of tubing and the artery. Injury was induced by topical
application on the carotid artery above the temperature probe of a
small disc (3 mm dia.) of Whatman No. 1 filter paper previously
dipped in a 35% solution of FeCl.sub.3. The incision area was
covered with aluminum foil in order to protect the FeCl.sub.3 from
degradation by light. The vessel temperature was monitored for 60
minutes after application of FeCl.sub.3 as an indication of blood
flow. Vessel temperature changes were recorded on a thermistor
(Cole-Palmer Model 08533-41).
[0825] The time between the FeCl.sub.3 application and the time at
which the vessel temperature decreased abruptly (>2.4.degree.
C.) was recorded as the time to occlusion of the vessel. The fold
shift in mean occlusion time (MOT), therefore, refers to the time
to occlusion in drug treated animal divided by control time to
occlusion. Inhibitor compounds were given as an IV bolus (0.75
mg/kg) followed immediately by an IV infusion (50 .mu.g/kg/min via
femoral vein).
2 Thrombin Trypsin Xa VIIa % IC.sub.50 IC.sub.50 IC.sub.50 inhib. @
Structure Name .mu.M .mu.M .mu.M 100 .mu.M 73 3-(4-5-[(2R,6S)-2,6-
Dimethyltetrahydro- 1(2H)-pyridinyl]- pentyl-3-oxo-3,4-
dihydro-2H-1,4- benzothiazin-2-yl)- benzenecarboximidamide (Example
3) 1.78 0.782 0.108 31 74 3(4-5-[(2R,6S)-2,6- Dimethyltetrahydro-
1(2H)- pyridinyl]pentyl-3- oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-
yl)- benzenecarboximidamide (Example 2) 2.020 0.474 0.007 30 75
3-(4-5-[(2R,6S)-2,6- dimethyltetrahydro- 1(2H)- pyridinyl]pentyl-3-
oxo-3,4-dihydro-2H- 1,4-benzoxazin-2- yl)-4- hydroxybenzenecarb
oximidamide (Example 5) 1.03 0.38 <0.001 29 76 3-((2S)-4-5-
[(2R,6S)-2,6- dimethyltetrahydro- 1(2H)- pyridinyl]pentyl-3-
oxo-3,4-dihydro-2H- 1,4-benzoxazin-2- yl)-4- hydroxybenzenecarb
oximidamide (Example 6) 1.39 0.75 0.003 (Ki 0.076 nM) 37
[0826] Biological Data of Examples 2 and 5
[0827] In Vitro Diluted Prothrombin Time (dPT) Assay
[0828] The effects of Examples 2 and 5 on dPT were evaluated using
pooled plasma from rabbits, dogs, and human volunteers. Both
compounds concentration-dependently prolonged dPT and displayed a
similar potency in rabbit and dog plasma. In human plasma, however,
Example 5 was more potent than Example 2 by approximately one order
of magnitude. The concentrations which caused 5-fold prolongation
of dPT for Examples 2 and 5 were 1.1 and 0.97 .mu.M in rabbit
plasma, 1.8 and 1.2 .mu.M in dog plasma, and 0.53 and 0.063 .mu.M
in human plasma, respectively.
3 In Vitro Diluted Prothrombin Time (dPT) Assay 2X 5X 10X Rabbit
DX-9065a (.mu.M) 1.4 21.8 96.8 Example 2 (.mu.M) 0.33 1.1 2.4
Example 5 (.mu.M) 0.44 0.97 1.86 Dog DX-9065a (.mu.M) 2.5 51.1
118.6 Example 2 (.mu.M) 0.57 1.8 4.9 Example 5 (.mu.M) 0.84 1.2
1.81 Human DX-9065a (.mu.M) 0.06 0.53 1.3 Example 2 (.mu.M) 0.17
0.53 1.2 Example 5 (.mu.M) 0.0069 0.063 0.157 The data is the
concentrations that cause 2-, 5-, and 10-fold prolongation of
baseline values of dPT. DX-9065a is a reference factor Xa
inhibitor
[0829] The effects of Example 2 on thrombosis and hemostasis has
been studied in a rabbit veno-venous shunt model of thrombosis. In
that model, a plastic shunt which contains cotton thread was
inserted into abdominal vena cava and thrombus developed inside the
shunt under control conditions. The end points of the experiment
are the time to occlusion (TTO) and thrombus weight. Example 2 was
given to the rabbit via jugular vein as a single bolus followed by
constant infusion for 140 minutes. Three doses have been tested in
a total of 15 rabbits (5 rabbits in each group): 30 .mu.g/kg+1
.mu.g/kg/min, 60 .mu.g/kg+2 .mu.g/kg/min, and 90 .mu.g/kg+3
.mu.g/kg/min. Example 2 dose-dependently prolonged the time to
occlusion and reduced the net thrombus weight. In the highest dose
group, TTO was increased from 16.8.+-.5.4 minutes under control
condition to 98.2.+-.21.8 minutes with no occlusive thrombus
formation during the 120-minute test period in 4 out of 5 animals.
The net thrombus weight was reduced from 56.4.+-.4.3 to 21.3.+-.7.8
mg in that group. Example 2, at the highest dose, prolonged aPTT,
TT, PT, and bleeding time by 5.4-, 1.5-, 1.8-, and 2.5-fold,
respectively. In contrast, there were only slight increases for ACT
in all 3 groups.
[0830] The foregoing biological tests have been used to establish
the compounds of this invention are useful for preventing and
treating thrombotic disorders, for example venous thrombosis, deep
vein thrombosis, thrombophlebitis, arterial embolism, coronary and
cerebral arterial thrombosis, cerebral embolism, kidney embolism,
pulmonary embolism, first or recurrent myocardial infarction,
unstable angina, and cerebral infarction, stroke,
atherosclerosis.
[0831] The compounds of the present invention can be administered
alone or in combination with one or more therapeutic agents. These
include, for example, other anticoagulant, antiplatelet, or
platelet inhibitory agents which include non-steroidal
anti-inflammatory agents such as aspirin, ibuprofen, naproxen
sodium, indomethacin, piroxicam and ticlopidine, thrombin
inhibitors such as argatroban, efegatran, inogatran, factor VIIa
inhibitors, thrombolytic or fibrinolytic agents such as tissue
plasminogen activator, urokinase or streptokinase, and GP IIIb-IIa
antagonists.
[0832] The compounds are thus well suited to formulation for
convenient administration to mammals for the prevention and
treatment of such disorders. The following examples further
illustrate typical formulations provided by the invention.
4 Formulation 1 Ingredient Amount compound of Formulas 1-8 200 mg
sodium benzoate 5 mg isotonic saline 1000 mL
[0833] The above ingredients are mixed and dissolved in the saline
for IV administration to a human suffering from, for example,
arterial thrombosis.
5 Formulation 2 Ingredient Amount compound of Formulas 1-8 100 mg
cellulose, microcrystalline 400 mg stearic acid 5 mg silicon
dioxide 10 mg sugar, confectionery 50 mg
[0834] The ingredients are blended to uniformity and pressed into a
tablet that is well suited for oral administration to a human for
preventing, for example, cerebral infarction.
6 Formulation 3 Ingredient Amount compound of Formulas 1-8 200 mg
starch, dried 250 mg magnesium stearate 10 mg
[0835] The ingredients are combined and milled to afford material
suitable for filling hard gelatin capsules administered to humans
suffering from, for example, venous thrombosis.
7 Formulation 4 Ingredient Amount % wt./wt. compound of Formulas
1-8 1 Polyethylene glycol 1000 74.5 Polyethylene glycol 4000
24.5
[0836] The ingredients are combined via melting and then poured
into molds containing 2.5 g total weight.
8 Formulation 5 Ingredient Amount % wt./wt. compound of Formulas
1-8 0.1% Propellant 11/12 98.9% Oleic acid 1%
[0837] The ingredients are dispersed in oleic acid with the
propellant. The mixture is added to an aerosol container fitted
with a metering device.
* * * * *