6-membered aromatics as factor Xa inhibitors

67 Pages·2013·4.71 MB·English

US006060491A
United States Patent [19] [11] Patent Number: 6,060,491
Pruitt et al. [45] Date of Patent: May 9, 2000
[54] 6-MEMBERED AROMATICS AS FACTOR XA Edmunds et al., “Cardiovascular and Pulmonary Diseases”,
INHIBITORS AnnualReports in Medicinal Chemistry, (1996) vol. 31, pp.
51—60.
[75] Inventors: James Russell Pruitt, Landenberg, Pa.;
Donald Joseph Phillip Pinto; Mimi
TidWell et al., “Strategies for Anticoagulation With Synthetic
Lifen Quan, both of Newark, Del.;
Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibi
Ruth Richmond WeXler, Wilmington,
Del. tors”, Thrombosis Research, (1980) vol. 19, pp. 339—349.
[73] Assignee: Dupont Pharmaceuticals, Wilmington, SturZebecher et al., “Synthetic Inhibitors of Serine Protein
Del. ases XXIII. Inhibition of Factor Xa by Diamidines”, Th rom
bosis Research, (1980) vol. 17, pp. 545—548.
[21] Appl. No.2 09/099,663
[22] Filed: Jun. 18, 1998 Primary Examiner—Zinna Northington Davis
Related US. Application Data [57] ABSTRACT
[60] Provisional application No. 60/050,214, Jun. 19, 1997.
The present application describes 6-membered aromatics of
[51] Int. Cl.7 ........................ .. A61K 31/44; C07D 211/82
formula I:
[52] US. Cl. ........................ .. 514/355; 546/314; 546/315;
564/86; 514/354; 514/631
[58] Field of Search ................................... .. 546/314, 316;
514/354, 355, 631; 564/86
[56] References Cited
FOREIGN PATENT DOCUMENTS
9616940 6/1996 WIPO .
or pharmaceutically acceptable salt forms thereof, Wherein
OTHER PUBLICATIONS
D may be CHZNH2 or C(=NH)NH2, Which are useful as
Kunitada et al., “Factor Xa Inhibitors”, Current Pharma inhibitors of factor Xa.
ceutical Design, 1996, vol. 2, pp. 531—542.
Shi—Shan Mao, “Factor Xa Inhibitors”, Perspectives in Drug
Discovery and Design, vol. 1 (1993), pp. 423—430. 15 Claims, No Drawings
6,060,491
1 2
6-MEMBERED AROMATICS AS FACTOR XA treatment of thromboembolic disorders. It is thus desirable
INHIBITORS to discover neW factor Xa inhibitors.
SUMMARY OF THE INVENTION
This application claims the bene?t of US. Provisional
Application No. 60/050,214, ?led Jun. 19, 1997. Accordingly, one object of the present invention is to
provide novel 6-membered aromatics Which are useful as
FIELD OF THE INVENTION
factor Xa inhibitors or pharmaceutically acceptable salts or
This invention relates generally to novel 6-membered prodrugs thereof.
aromatics Which are inhibitors of trypsin-like serine protease It is another object of the present invention to provide
enzymes, especially factor Xa, pharmaceutical compositions 10 pharmaceutical compositions comprising a pharmaceuti
containing the same, and methods of using the same as cally acceptable carrier and a therapeutically effective
anticoagulant agents for treatment and prevention of throm
amount of at least one of the compounds of the present
boembolic disorders. invention or a pharmaceutically acceptable salt or prodrug
form thereof.
BACKGROUND OF THE INVENTION
15
It is another object of the present invention to provide a
WO 96/28427 describes benZamidine anticoagulants of
method for treating thromboembolic disorders comprising
the formula:
administering to a host in need of such treatment a thera
peutically effective amount of at least one of the compounds
of the present invention or a pharmaceutically acceptable
20
salt or prodrug form thereof.
These and other objects, Which Will become apparent
during the folloWing detailed description, have been
achieved by the inventors’ discovery that compounds of
formula (I):
25
30
Wherein Z1 and Z2 are O, N(R), S or OCH2 and the central
ring may be phenyl or a variety of heterocycles. The
presently claimed compounds do not contain the Z1 linker or or pharmaceutically acceptable salt or prodrug forms
the substitution pattern of the above compounds. 35 thereof, Wherein A, B, D, E, M, R“, Rlb, and Z are de?ned
WO 95/18111 addresses ?brinogen receptor antagonists,
beloW, are effective factor Xa inhibitors.
containing basic and acidic termini, of the formula:
DETAILED DESCRIPTION OF PREFERRED
EMBODIMENTS
40
[1] Thus, in a ?rst embodiment, the present invention
provides novel compounds of formula I:
Wherein R1 represents the basic termini, U is an alkylene or 45
heteroatom linker, V may be a heterocycle, and the right
hand portion of the molecule represents the acidic termini.
The presently claimed compounds do not contain the acidic \E /\
termini of WO 95/18111.
Activated factor Xa, Whose major practical role is the
generation of thrombin by the limited proteolysis of pro or a stereoisomer or pharmaceutically acceptable salt form
thrombina holds a central position that links the intrinsic and thereof, Wherein;
eXtrinsic activation mechanisms in the ?nal common path ring M contains from 0—4 N atoms;
Way of blood coagulation. The generation of thrombin, the
?nal serine protease in the pathWay to generate a ?brin clot, 55
from its precursor is ampli?ed by formation of prothrom
binase compleX (factor Xa, factor V, Ca2+ and
E is selected from phenyl, 2-pyridyl, 4-pyridyl, pyrimidyl,
phospholipid). Since it is calculated that one molecule of
and piperidinyl substituted With 1 R;
factor Xa can generate 138 molecules of thrombin (Elodi, S.,
Varadis K.: Optimization of conditions for the catalytic e?rect 60 R is selected from H, F, Cl, Br, I, 0R3, SR3, CO2R3, N02,
of the factor IXa-factor VIII Complex." Probable role of the and CH2OR3, and (CR8R9)tNR8R9;
complex in the ampli?cation of blood coagulation. Th romb. alternatively, E and R combine to form methylenedioXy or
ethylenedioXy;
Res. 1979, 15, 617—629), inhibition of factor Xa may be
more ef?cient than inactivation of throibin in interrupting th Z is selected from a bond, C1_4 alkylene, (CH2),O(CH2),,
e blood coagulation system. (CHZLNRXCHZL, (CHZWOXCHZL, (CHZ).C(O)O
Therefore, ef?cacious and speci?c inhibitors of factor Xa (CHZL, (CHZ).OC(O> (0112)., (CHZ>.C(O>NR3(CHZ).,
are needed as potentially valuable therapeutic agents for the (CHZ>.NR3C(O>(CHZ),, (CHZ).OC(O)O(CHZ)., (CH2)
6,060,491
3 4
r Oc(O)NR3(cH2>r, (cH2),NR3c(O)O(cH2)r, (CH2), R317, at each occurrence, is selected from H, CL4 alkyl,
NR3c(O)NR3(cH2)r, (cH2>rs(O>p(cH2>,, (CH2), and phenyl;
SO2NR3(CH2),, (CH2),NR3SO2(CH2),, and (CH2), R36, at each occurrence, is selected from C1_4 alkyl, and
phenyl;
NR3SO2NR3(CH2)r, provided that Z does not form a
N—N, N—O, N—S, NCHZN, NCHZO, or NCHZS A is selected from:
bond With ring M or group A; C3_1O carbocyclic residue substituted With 0—2 R4, and
R“ and Rlb are independently absent or selected from 5—10 rnernbered heterocyclic system containing from
—(CH2),—R1', —CH=CH—R1', NCH2R1", 1—4 heteroatorns selected from the group consisting
OCH2R1", SCH2R1", NH(CH2)2(CH2),R1', O(CH2)2 of N, O, and S substituted With 0—2 R4;
(CH2)R1V> and S(CH2)2(CH2)R1V; 1O B is selected from: H, Y, and X—Y;
alternatively, R1“ and Rlb, When attached to adjacent X is selected from C1_4 alkylene, —CR2 (CRZRZb) (CH2),
carbon atoms, together With the atoms to Which they are
attached form a 5—8 rnernbered saturated, partially
saturated or unsaturated ring substituted With 0—2 R4
and Which contains from 0—2 heteroatorns selected 15
from the group consisting of N, O, and S;
alternatively, When Z is C(O)NH and R1“ is attached to a
ring carbon adjacent to Z, then R“ is a C(O) Which
replaces the amide hydrogen of Z to form a cyclic
irnide;
R1’ is selected from H, C1_3 alkyl, F, Cl, Br, I, —CN,
—CHO, (CF2),CF3, (CH2),OR2, NR2R2“, C(O)R2C,
OC(O)R2, (CF2),CO2R2C, S(O)pR2b, NR2(CH2),OR2, Y is selected from:
CH(=NR2C)NR2R2“, NR2C(O)R2b, NR2C(O)NHR2b, (CH2),NR2R2“, provided that X—Y do not form a
NR2C(O)2R2“, OC(O)NR2“R2b, C(O)NRZRZ“, C(O) 25 N—N, O—N, or S—N bond,
C3_1O carbocyclic residue substituted With 0—2 R4“, and
NR2(CH2)rOR2, SOZNRZRZ“, NRZSOZRZb, C3_6 car
5—10 rnernbered heterocyclic system containing from
bocyclic residue substituted With 0—2 R4, and 5—10
1—4 heteroatorns selected from the group consisting
rnernbered heterocyclic system containing from 1—4
of N, O, and S substituted With 0—2 R4“;
heteroatorns selected from the group consisting of N,
O, and S substituted With 0—2 R4;
R1" is selected from H, CH(CH2OR2 2, C(O)R2C, C(O)
NR2R2”, S(O)R2b, S(O)2R2b, and SOZNRZRZH;
R2, at each occurrence, is selected from H, CF3, CL6
alkyl, benZyl, C3_6 carbocyclic residue substituted With 35
0—2 R417, and 5—6 rnernbered heterocyclic system con
taining from 1—4 heteroatorns selected from the group
consisting of N, O, and S substituted With 0—2 R4b;
R2“, at each occurrence, is selected from H, CF3, CL6 alternatively, one R4 is a 5—6 rnernbered arornatic hetero
alkyl, benZyl, phenethyl, C3_6 carbocyclic residue sub
cycle containing from 1—4 heteroatorns selected from
stituted With 0—2 R417, and 5—6 rnernbered heterocyclic the group consisting of N, O, and S;
system containing from 1—4 heteroatorns selected from
thebgroup consisting of N, O, and S substituted With 0—2
R4 ;
R217, at each occurrence, is selected from CF3, CL4 alkoXy, 45
CL6 alkyl, benZyl, C3_6 carbocyclic residue substituted
With 0—2 R417, and 5—6 rnernbered heterocyclic system
containing from 1—4 heteroatorns selected from the
grclup consisting of N, O, and S substituted With 0—2
R4 ;
alternatively, one R4“ is a 5—6 rnernbered arornatic het
R26, at each occurrence, is selected from CF3, OH, CL4 erocycle containing from 1—4 heteroatorns selected
alkoXy, C1_6 alkyl, benZyl, C3_6 carbocyclic residue from the group consisting of N, O, and S and substi
substituted With 0—2 R417, and 5—6 rnernbered hetero tuted With 0—1 R5;
cyclic systern containing from 1—4 heteroatorns
55
selected from the group consisting of N, O, and S
substituted With 0—2 R4b;
alternatively, R2 and R2“, together With the atom to Which
they are attached, combine to form a 5 or 6 rnernbered
saturated, partially saturated or unsaturated ring sub
stituted With 0—2 R417 and containing from 0—1 addi
tional heteroatorns selected from the group consisting
of N, O, and S; R5, at each occurrence, is selected from CF3, CL6 alkyl,
R3, at each occurrence, is selected from H, CL4 alkyl, and phenyl substituted With 0—2 R6, and benZyl substituted
phenyl; With 0—2 R6;
65
R3“, at each occurrence, is selected from H, CL4 alkyl, R6, at each occurrence, is selected from H, OH, (CH2),
and phenyl; OR2, F, Cl, Br, I, C1_4 alkyl, CN, NO2, (CH2),NR2R2“,
6,060,491
R7, at each occurrence, is selected from H, OH, C1_6 alkyl, 5
CL6 alkylcarbonyl, CL6 alkoXy, CL4 alkoxycarbonyl,
(CH2)n-phenyl, C6_1O aryloXy, C6_1O aryloXycarbonyl,
C6_1O arylrnethylcarbonyl, CL4 alkylcarbonyloxy C1_4
alkoXycarbonyl, C6_1O arylcarbonyloXy C1_4
alkoxycarbonyl, C1_6 alkylarninocarbonyl, 1O
phenylarninocarbonyl, and phenyl-C1_4 alkoXycarbo
nyl;
R8, at each occurrence, is selected from H, CL6 alkyl and
(CH2)n-phenyl; 15
alternatively, R7 and R8 combine to form a 5 or 6
rnernbered saturated, ring Which contains from 0—1
lb
additional heteroatorns selected from the group con- R \ —N\
sisting of N, O, and S; 20 \ /N
R9, at each occurrence, is selected from H, CL6 alkyl and
(CH2)n-Ph@ny1;
n is selected from 0, 1, 2, and 3;
In is selected from 0, 1, and 2; 25 /—N/Rlb
p is selected from 0, 1, and 2; N\ /
r is selected from 0, 1, 2, and 3;
s is selected from 0, 1, and 2; and, 30
t is selected from 0 and 1.
[2] In a preferred embodi.m ent, the present i. nventi. on N=\/\ R1b
provides novel compounds of formulae Ia—Io: \ /N
35
21
R13
f/“AR
40 _ _ 1b
N N
\ /
b 45
R13
/__ _—\ /R 1b N=N Rlb
50
55 /
65
6,060,491
-continued
Rlb
_N
11%
1O
and
Rlb
N/ N 15
as
wherein:
Z is selected from a bond, CHZO, OCH2, CHZNH,
NHCH2, CH2C(O), C(O)CH2, C(O)NH, C(O)NH,
CH2S(O)2, S(O)2(CH2), SOZNH, and SOZNH;
25
B is selected from: Y, X—Y, and NRZRZH;
Y is selected from one of the following carbocyclic and
heterocyclic systems which are substituted with 0—2
R4a;
phenyl, piperidinyl, piperaZinyl, pyridyl, pyrimidyl,
furanyl, morpholinyl, thiophenyl, pyrrolyl,
pyrrolidinyl, oXaZolyl, isoXaZolyl, thiaZolyl,
isothiaZolyl, pyraZolyl, imidaZolyl, oXadiaZole,
thiadiaZole, triaZole, 1,2,3-oXadiaZole, 1,2,4
oXadiaZole, 1,2,5-oXadiaZole, 1,3,4-oXadiaZole, 1,2, 35
3-thiadiaZole, 1,2,4-thiadiaZole, 1,2,5-thiadiaZole,
1,3,4-thiadiaZole, 1,2,3-triaZole, 1,2,4-triaZole, 1,2,
5-triaZole, 1,3,4-triaZole, benZofuran,
benZothiofuran, indole, benZimidaZole, benZoXaZole,
benZthiaZole, indaZole, benZisoXaZole,
benZisothiaZole, and isoindaZole;
Y may also be selected from the following bicyclic
heteroaryl ring systems:
45
55
N
wherein
18y XAN N\ \ K
D is selected from C(=NR7)NR8R9 and; (CR8R9)t
N’ || u >
NR8R9;
\/K1\/N and N / /\R4;
R is selected from H, F, Cl, 0R3, CH2OR3, CHZNHZ;
A is selected from:
piperidinyl,
K is selected from O, S, NH, and N. 65
piperaZinyl,
[3] In a more preferred embodiment, the present invention
provides novel compounds of formulae: C5_6 carbocyclic residue substituted with 0—2 R4, and
6,060,491
9
5—6 membered heteroaryl containing from 1—4 heteroa
toms selected from the group consisting of N, O, and
S substituted With 0—2 R4;
Y is selected from one of the following carbocyclic and
heterocyclic systems Which are substituted With 0—2
R4a;
phenyl, piperidinyl, piperaZinyl, pyridyl, pyrimidyl,
furanyl, morpholinyl, thiophenyl, pyrrolyl,
pyrrolidinyl, oXaZolyl, isoXaZolyl, thiaZolyl,
isothiaZolyl, pyraZolyl, imidaZolyl, benZimidaZolyl,
10
oXadiaZole, thiadiaZole, triaZole, 1,2,3-oXadiaZole,
1,2,4-oXadiaZole, 1,2,5-oXadiaZole, 1,3,4
oXadiaZole, 1,2,3-thiadiaZole, 1,2,4-thiadiaZole, 1,2,
5-thiadiaZole, 1,3,4-thiadiaZole, 1,2,3-triaZole, 1,2,4
triaZole, 1,2,5-triaZole, and 1,3,4-triaZole.
[4] In an even more preferred embodiment, the present
[5] In a further preferred embodiment, the present inven
invention provides novel compounds Wherein:
tion provides novel compounds selected from:
E is phenyl;
N-(2‘-Aminosulfonyl-[ 1, 1‘]biphen-4-yl)-2-(3‘
D is selected from C(=NH)NH2 and CHZNHZ; amidinophenyl)nicotinamide;
R is selected from H, F, Cl, and Br; 20
N-[S-(2-aminosulfonyl)phenylpyrid-2-yl]-2-(3‘
A is selected from: amidinophenyl)nicotinamide;
C5_6 carbocyclic residue substituted With 0—2 R4, and
N-[S-(2-t-butylaminosulfonyl)phenylpyrid-2-yl]-2-(3‘
5—6 membered heteroaryl containing from 1—3 heteroa
amidinophenyl)nicotinamide; and,
toms selected from the group consisting of N, O, and
S substituted With 0—2 R4; 25 N-[S-(2-aminosulfonyl)phenylpyrid-2-yl]-2-(3‘
carboXamidophenyl)nicotinamide;
Y is selected from one of the folloWing carbocyclic and
heterocyclic systems Which are substituted With 0—2 or a pharmaceutically acceptable salt thereof.
R4a; In a second embodiment, the present invention provides
phenyl, piperidinyl, piperaZinyl, pyridyl, pyrimidyl, novel pharmaceutical compositions, comprising: a pharma
furanyl, morpholinyl, thiophenyl, pyrrolyl, ceutically acceptable carrier and a therapeutically effective
pyrrolidinyl, oXaZolyl, isoXaZolyl, thiaZolyl, amount of a compound of formula (I) or a pharmaceutically
isothiaZolyl, pyraZolyl, imidaZolyl, benZimidaZolyl, acceptable salt form thereof.
oXadiaZole, thiadiaZole, triaZole, 1,2,3-oXadiaZole, In a third embodiment, the present invention provides a
1,2,4-oXadiaZole, 1,2,5-oXadiaZole, 1,3,4 novel method for treating or preventing a thromboembolic
oXadiaZole, 1,2,3-thiadiaZole, 1,2,4-thiadiaZole, 1,2, 35 disorder, comprising: administering to a patient in need
5-thiadiaZole, 1,3,4-thiadiaZole, 1,2,3-triaZole, 1,2,4 thereof a therapeutically effective amount of a compound of
triaZole, 1,2,5-triaZole, and 1,3,4-triaZole; formula (I) or a pharmaceutically acceptable salt form
thereof.
R2, at each occurrence, is selected from H, CF3, CL6
alkyl, benZyl, C5_6 carbocyclic residue substituted With
DEFINITIONS
0—2 R417, and 5—6 membered heterocyclic system con
taining from 1—4 heteroatoms selected from the group The compounds herein described may have asymmetric
consisting of N, O, and S substituted With 0—2 R4b; centers. Compounds of the present invention containing an
R2“, at each occurrence, is selected from H, CF3, CL6 asymmetrically substituted atom may be isolated in optically
alkyl, benZyl, phenethyl, C5_6 carbocyclic residue sub active or racemic forms. It is Well knoWn in the art hoW to
45
stituted With 0—2 R417, and 5—6 membered heterocyclic prepare optically active forms, such as by resolution of
system containing from 1—4 heteroatoms selected from racemic forms or by synthesis from optically active starting
thebgroup consisting of N, O, and S substituted With 0—2 materials. Many geometric isomers of ole?ns, C=N double
bonds, and the like can also be present in the compounds
R217, at each occurrence, is selected from CF3, CL4 alkoXy, described herein, and all such stable isomers are contem
C1_6 alkyl, benZyl, C5_6 carbocyclic residue substituted plated in the present invention. Cis and trans geometric
With 0—2 R417, and 5—6 membered heterocyclic system isomers of the compounds of the present invention are
containing from 1—4 heteroatoms selected from the described and may be isolated as a mixture of isomers or as
grclup consisting of N, O, and S substituted With 0—2 separated isomeric forms. All chiral, diastereomeric, race
R4 ; mic forms and all geometric isomeric forms of a structure
55
R26, at each occurrence, is selected from CF3, OH, C1_4 are intended, unless the speci?c stereochemistry or isomeric
alkoXy, C1_6 alkyl, benZyl, C5_6 carbocyclic residue form is speci?cally indicated.
substituted With 0—2 R417, and 5—6 membered hetero The term “substituted,” as used herein, means that any
cyclic system containing from 1—4 heteroatoms one or more hydrogens on the designated atom is replaced
selected from the group consisting of N, O, and S With a selection from the indicated group, provided that the
substituted With 0—2 R4b; designated atom’s normal valency is not exceeded, and that
alternatively, R2 and R2“, together With the atom to Which the substitution results in a stable compound. When a
they are attached, combine to form a ring selected from substitent is keto (i.e., :0), then 2 hydrogens on the atom
imidaZolyl, morpholino, piperaZinyl, pyridyl, and are replaced. Keto substituents are not present on aromatic
pyrrolidinyl, substituted With 0—2 R4b; moieties.
65
R4, at each occurrence, is selected from H, :0, OR2, The present invention is intended to include all isotopes of
CHZORZ, F, Cl, C1_4 alkyl, NR2R2“, CH2NR2R2”, C(O) atoms occurring in the present compounds. Isotopes include
6,060,491
11 12
those atoms having the same atomic number but different monocyclic or bicyclic or 7- to 10-membered bicyclic
mass numbers. By Way of general example and Without heterocyclic ring Which is saturated partially unsaturated or
limitation, isotopes of hydrogen include tritium and deute unsaturated (aromatic), and Which consists of carbon atoms
rium. Isotopes of carbon include C-13 and C-14. and from 1 to 4 heteroatoms independently selected from the
group consisting of N, O and S and including any bicyclic
When any variable (e.g., R6) occurs more than one time
group in Which any of the above-de?ned heterocyclic rings
in any constituent or formula for a compound, its de?nition
is fused to a benZene ring. The nitrogen and sulfur heteroa
at each occurrence is independent of its de?nition at every
toms may optionally be oxidiZed. The heterocyclic ring may
other occurrence. Thus, for example, if a group is shoWn to
be attached to its pendant group at any heteroatom or carbon
be substituted With 0—2 R6, then said group may optionally
atom Which results in a stable structure. The heterocyclic
be substituted With up to tWo R6 groups and R6 at each
rings described herein may be substituted on carbon or on a
occurrence is selected independently from the de?nition of nitrogen atom if the resulting compound is stable. If spe
R6. Also, combinations of substituents and/or variables are ci?cally noted, a nitrogen in the heterocycle may optionally
permissible only if such combinations result in stable com be quaterniZed. It is preferred that When the total number of
pounds. S and O atoms in the heterocycle exceeds 1, then these
When a bond to a substituent is shoWn to cross a bond 15 heteroatoms are not adjacent to one another. It is preferred
connecting tWo atoms in a ring, then such substituent may be that the total number of S and O atoms in the heterocycle is
bonded to any atom on the ring. When a substituent is listed not more than 1. As used herein, the term “aromatic hetero
Without indicating the atom via Which such substituent is cyclic system” is intended to mean a stable 5- to
7-membered monocyclic or bicyclic or 7- to 10-membered
bonded to the rest of the compound of a given formula, then
bicyclic heterocyclic aromatic ring Which consists of carbon
such substituent may be bonded via any atom in such
atoms and from 1 to 4 heterotams independently selected
substituent. Combinations of substituents and/or variables
from the group consisting of N, O and S. It is preferred that
are permissible only if such combinations result in stable
the total number of S and O atoms in the aromatic hetero
compounds.
cycle is not more than 1.
As used herein, “alkyl” is intended to include both Examples of heterocycles include, but are not limited to,
branched and straight-chain saturated aliphatic hydrocarbon 25 acridinyl, aZocinyl, benZimidaZolyl, benZofuranyl,
groups having the speci?ed number of carbon atoms. benZothiofuranyl, benZothiophenyl, benZoxaZolyl,
Examples of alkyl include, but are not limited to, methyl, benZthiaZolyl, benZtriaZolyl, benZtetraZolyl, benZisoxaZolyl,
ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, benZisothiaZolyl, benZimidaZolinyl, carbaZolyl, 4aH
and s-pentyl. “Haloalkyl” is intended to include both carbaZolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
branched and straight-chain saturated aliphatic hydrocarbon decahydroquinolinyl, 2H,6H-1,5,2-dithiaZinyl, dihydrofuro
groups having the speci?ed number of carbon atoms, sub [2,3-b]tetrahydrofuran, furanyl, furaZanyl, imidaZolidinyl,
imidaZolinyl, imidaZolyl, 1H-indaZolyl, indolenyl,
stituted With 1 or more halogen (for example —CVFW Where
indolinyl, indoliZinyl, indolyl, 3H-indolyl, isobenZofuranyl,
v=1 to 3 and W=1 to (2v+1)). Examples of haloalkyl include,
isochromanyl, isoindaZolyl, isoindolinyl, isoindolyl,
but are not limited to, tri?uoromethyl, trichloromethyl,
penta?uoroethyl, and pentachloroethyl. “Alkoxy” represents 35 isoquinolinyl, isothiaZolyl, isoxaZolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiaZolyl, 1,2,3
an alkyl group as de?ned above With the indicated number
oxadiaZolyl, 1,2,4-oxadiaZolyl, 1,2,5-oxadiaZolyl, 1,3,4
of carbon atoms attached through an oxygen bridge.
oxadiaZolyl, oxaZolidinyl, oxaZolyl, oxaZolidinyl,
Examples of alkoxy include, but are not limited to, methoxy,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenaZinyl,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
phenothiaZinyl, phenoxathiinyl, phenoxaZinyl, phthalaZinyl,
n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to piperaZinyl, piperidinyl, pteridinyl, purinyl, pyranyl,
include saturated ring groups, such as cyclopropyl, pyraZinyl, pyraZolidinyl, pyraZolinyl, pyraZolyl,
cyclobutyl, or cyclopentyl. Alkenyl” is intended to include pyridaZinyl, pyridooxaZole, pyridoimidaZole,
hydrocarbon chains of either a straight or branched con?gu pyridothiaZole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
ration and one or more unsaturated carbon-carbon bonds pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinaZolinyl, quinolinyl,
45
Which may occur in any stable point along the chain, such 4H-quinoliZinyl, quinoxalinyl, quinuclidinyl,
as ethenyl, propenyl and the like. “Alkynyl” is intended to tetrahydrofuranyl, tetrahydroisoquinolinyl,
include hydrocarbon chains of either a straight or branched tetrahydroquinolinyl, 6H-1,2,5-thiadiaZinyl, 1,2,3
con?guration and one or more triple carbon-carbon bonds thiadiaZolyl, 1,2,4-thiadiaZolyl, 1,2,5-thiadiaZolyl, 1,3,4
Which may occur in any stable point along the chain, such thiadiaZolyl, thianthrenyl, thiaZolyl, thienyl, thienothiaZolyl,
as ethynyl, propynyl and the like. thienooxaZolyl, thienoimidaZolyl, thiophenyl, triaZinyl, 1,2,
“Halo” or “halogen” as used herein refers to ?uoro, 3-triaZolyl, 1,2,4-triaZolyl, 1,2,5-triaZolyl, 1,3,4-triaZolyl,
chloro, bromo, and iodo; and “counterion” is used to rep and xanthenyl. Preferred heterocycles include, but are not
resent a small, negatively charged species such as chloride, limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyraZolyl,
bromide, hydroxide, acetate, sulfate, and the like. pyrrolidinyl, imidaZolyl, indolyl, benZimidaZolyl,
55
As used herein, “carbocycle” or “carbocyclic residue” is lH-indazolyl, oxaZolidinyl, benZotriaZolyl, benZisoxaZolyl,
intended to mean any stable 3- to 7-membered monocyclic oxindolyl, benZoxaZolinyl, or isatinoyl. Also included are
or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of fused ring and Spiro compounds containing, for example,
Which may be saturated, partially unsaturated, or aromatic. the above heterocycles.
Examples of such carbocycles include, but are not limited to, The phrase “pharmaceutically acceptable” is employed
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
herein to refer to those compounds, materials, compositions,
cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,
and/or dosage forms Which are, Within the scope of sound
[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]
medical judgment, suitable for use in contact With the tissues
bicyclooctane, ?uorenyl, phenyl, naphthyl, indanyl, of human beings and animals Without excessive toxicity,
adamantyl, or tetrahydronaphthyl. 65 irritation, allergic response, or other problem or
As used herein, the term “heterocycle” or “heterocyclic complication, commensurate With a reasonable bene?t/risk
system” is intended to mean a stable 5- to 7-membered ratio.
6,060,491
13 14
As used herein, “pharmaceutically acceptable salts” refer “Therapeutically effective amount” is intended to include
to derivatives of the disclosed compounds Wherein the an amount of a compound of the present invention or an
parent compound is modi?ed by making acid or base salts amount of the combination of compounds claimed effective
thereof. Examples of pharmaceutically acceptable salts
to inhibit HIV infection or treat the symptoms of HIV
include, but are not limited to, mineral or organic acid salts infection in a host. The combination of compounds is
of basic residues such as amines; alkali or organic salts of preferably a synergistic combination. Synergy, as described
acidic residues such as carboxylic acids; and the like. The for example by Chou and Talalay, Adv. EnZyme Regul.
pharmaceutically acceptable salts include the conventional
22:27—55 (1984), occurs When the effect (in this case,
non-toxic salts or the quaternary ammonium salts of the
inhibition of HIV replication) of the compounds When
parent compound formed, for example, from non-toxic
administered in combination is greater than the additive
inorganic or organic acids. For example, such conventional
effect of the compounds When administered alone as a single
non-toxic salts include those derived from inorganic acids
agent. In general, a synergistic effect is most clearly dem
such as hydrochloric, hydrobromic, sulfuric, sulfamic,
onstrated at suboptimal concentrations of the compounds.
phosphoric, nitric and the like; and the salts prepared from
organic acids such as acetic, propionic, succinic, glycolic, Synergy can be in terms of loWer cytotoxicity, increased
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, 15 antiviral effect, or some other bene?cial effect of the com
maleic, hydroxymaleic, phenylacetic, glutamic, benZoic, bination compared With the individual components.
salicylic, sulfanilic, 2-acetoxybenZoic, fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, SYNTHESIS
isethionic, and the like.
The compounds of the present invention can be prepared
The pharmaceutically acceptable salts of the present
invention can be synthesiZed from the parent compound in a number of Ways knoWn to one skilled in the art of
organic synthesis. The compounds of the present invention
Which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by can be synthesiZed using the methods described beloW,
reacting the free acid or base forms of these compounds With together With synthetic methods knoWn in the art of syn
a stoichiometric amount of the appropriate base or acid in 25 thetic organic chemistry, or variations thereon as appreciated
Water or in an organic solvent, or in a mixture of the tWo; by those skilled in the art. Preferred methods include, but are
generally, nonaqueous media like ether, ethyl acetate, not limited to, those described beloW. The reactions are
ethanol, isopropanol, or acetonitrile are preferred. Lists of performed in a solvent appropriate to the reagents and
suitable salts are found in Remington’s Pharmaceutical materials employed and suitable for the transformations
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., being effected. It Will sometimes require a judgment to
1985, p. 1418, the disclosure of Which is hereby incorpo modify the order of synthetic steps or to select one particular
rated by reference. process scheme over another in order to obtain a desired
“Prodrugs” are intended to include any covalently bonded compound of the invention. It Will also be recogniZed that
carriers Which release the active parent drug according to another major consideration in the planning of any synthetic
formula (I) in vivo When such prodrug is administered to a route in this ?eld is the judicious choice of the protecting
35
mammalian subject. Prodrugs of a compound of formula (I) group used for the protection of the reactive functional
are prepared by modifying functional groups present in the groups present in the compounds described in this invention.
compound in such a Way that the modi?cations are cleaved, An authoritative account describing the many alternatives to
either in routine manipulation or in vivo, to the parent the trained practitioner is Greene and Wuts (Protective
compound. Prodrugs include compounds of formula (I) Groups in Organic Chemistry, Wiley and Sons, 1991). All
Wherein a hydroxy, amino, or sulfhydryl group is bonded to references cited herein are hereby incorporated in their
any group that, When the prodrug or compound of formula entirety herein by reference. Compounds of this invention
(I) is administered to a mammalian subject, cleaves to form Where B is either a carbocyclic or heterocyclic residue as
a free hydroxyl, free amino, or free sulfhydryl group, de?ned in Formula 1 are coupled to A as shoWn generically
respectively. Examples of prodrugs include, but are not and by speci?c example in Schemes 1 and 2, respectively.
45
limited to, acetate, formate and benZoate derivatives of Either or both of A and B may be substituted With 0—2 R4.
alcohol and amine functional groups in the compounds of W is de?ned as a suitable protected nitrogen, such as NO2
formula (I), and the like. Preferred prodrugs are amidine or NHBOC; a protected sulfur, such as S-tBu or SMOM; or
prodrugs Wherein D is C(=NR7)NH2, and R7 is selected a methyl ester. Halogen-metal exchange of the bromine in
from OH, C1_4 alkoxy, C6_1O aryloxy, C1_4 alkoxycarbonyl, bromo-B With n-butyl lithium, quenching With triisopropyl
C6_1O aryloxycarbonyl, C6_1O arylmethylcarbonyl, C1_4 alky borate and acidic hydrolysis gives the required boronic acid,
lcarbonyloxy C1_4 alkoxycarbonyl, and C6_1O arylcarbony B—B(OH)2. The W—A—Br subunit may be already linked
loxy C1_4 alkoxycarbonyl. More preferred prodrugs are to ring M before the SuZuki coupling reaction. Deprotection
Where R7 is OH, methoxy, ethoxy, benZyloxycarbonyl, provides the complete subunit.
methoxycarbonyl, and methylcarbonyloxymethoxycar
55
bonyl.
Scheme 1
“Stable compound” and “stable structure” are meant to B—Br
indicate a compound that is suf?ciently robust to survive 1) n-BuLi
isolation to a useful degree of purity from a reaction mixture, 2) (iPrO)3B
and formulation into an ef?cacious therapeutic agent. 3) HCI
“Substituted” is intended to indicate that one or more
hydrogens on the atom indicated in the expression using
“substituted” is replaced With a selection from the indicated I
group(s), provided that the indicated atom’s normal valency
A Pdm) W—A—B
is not exceeded, and that the substitution results in a stable 65 l
compound. When a substituent is keto (i.e., :0) group, then Br
2 hydrogens on the atom are replaced.
6,060,491
15 16
-continued
Scheme 1 TABLE A-continued
Preparation of Amide Ester, Urea, Sulfonamide and
Sulfamide Linkages Between A and B.
then the reactive to give the following
If A contains: substituent of Y is: product A—X—Y:
a secondary NH ClC(O)—Y A—C(O)—Y
as part of a
Scheme 2 describes a typical example of how the A-B ring or chain
A—OH as a ClC(O)—Y A—O—C(O)—Y
subunit is prepared for attachment to ring M.
substituent
4-Bromoaniline is protected as Boc-derivative and the A—NHR2 as a C1C(O)—CR2R2“— A—NR2—C(O)—CR2R2“—Y
coupled to 2-(t-butylamino)sulfonylphenylboronic acid substituent —Y
under Suzuki conditions. 2-(t-Butylamino) 15 a secondary NH ClC(O)—CR2R2“— A—C(O)—CR2R2“—Y
as part of a —Y
sulfonylphenylboronic acid is prepared by the method ring or chain
described by Rivero (Bioorg. Med. Chem. Lett. 1994, 189). A—OH as a ClC(O)—CR2R2“— A—O—C(O)—CR2R2“—Y
Deprotection with TFA can provide the aminobiphenyl com substituent —Y
A—NHR2 as a ClC(O)—CNR2—Y A—NR2—C(O)—CNR2—Y
pound. The aminobiphenyl is then coupled to the core ring
substituent
structures as described below. a secondary NH C1C(O)—CNR2—Y A—C(O)—CNR2—Y
as part of a
ring or chain
Scheme 2
A—OH as a C1C(O)—CNR2—Y A—O—C(O)—CNR2—Y
B(OH)2 substituent
25 A—NHR2 as a ClSO2—Y A—NR2—SO2—Y
NH; NHBOC SOZNH-t-Bu
substituent
a secondary NH ClSO2—Y A—SO2—Y
NaH as part of a
(BOC)2O ring or chain
—> Pd(0) A—NHR2 as a ClSO2—CR2R2“— A—NR2—SO2—CR2R2“—Y
substituent —Y
a secondary NH C1SO2—CR2R2“— A—SO2—CR2R2“—Y
Br Br as part of a —Y
NHBOC NHZ ring or chain
A—NHR2 as a ClSO2—NR2—Y A—NR2—SO2—NR2—Y
substituent
a secondary NH ClSO2—NR2—Y A—SO2—NR2—Y
as part of a
ring or chain
TFA
—> A—C(O)Cl HO—Y as a A—C(O)—O—Y
substituent
SOZNH-t-Bu SOZNH-t-Bu
A—C(O)Cl NHR2—Y as a A—C(O)—NR2—Y
substituent
A—C(O)Cl a secondary NH as A—C(O)—Y
part of a ring or
chain
A—CR2R2“C(O)C1 HO—Y as a A—CR2R2“C(O)—O—Y
When B is de?ned as X—Y, the following description substituent
applies. Groups A and B are available either through com A—CR2R2“C(O)Cl NHR2—Y as a A—CR2R2“C(O)—NR2—Y
substituent
mercial sources, known in the literature or readily synthe
A—CR2R2“C(O)Cl a secondary NH as A—CR2R2“C(O)—Y
siZed by the adaptation of standard procedures known to
part of a ring or
practitioners skilled in the art of organic synthesis. the chain
required reactive functional groups appended to analogs of A—SO2C1 NHR2—Y as a A—SO2—NR2—Y
A and B are also available either through commercial substituent
sources, known in the literature or readily synthesiZed by the A—SOZCl a secondary NH as A—SO2—Y
part of a ring or
adaptation of standard procedures known to practitioners
chain
skilled in the art of synthesis. In the tables that follow the
55 A—CR2R2“SO2C1 NHR2—Y as a A—CR2R2“SO2—NR2—Y
chemistry required to effect the coupling of A to B is substituent
outlined. A—CRZRZQSOZCl a secondary NH as A—CR2R2“SO2—Y
part of a ring or
TABLE A chain
Preparation of Amide Ester, Urea, Sulfonamide and
Sulfamide Linkages Between A and B.
then the reactive to give the following
If A contains: substituent of Y is: product A—X—Y: The chemistry of Table A can be carried out in aprotic
A—NHR2 as a C1C(O)—Y A—NR2—C(O)—Y 65 solvents such as a chlorocarbon, pyridine, benZene or
substituent toluene, at temperatures ranging from —20° C. to the re?ux
point of the solvent and with or without a trialkylamine base.
6,060,491
17 18
Lett. 1992, 235). The sulfone can be prepared according to
TABLE B the method of Satoh (Chem. Lett. 1992, 381) using
m-chloroperbenzoic acid.
Preparation of Ketone Linkages between A and B. Scheme 3 describes the synthesis of compounds Wherein
M is a benzene ring and Q is a protected precursor of group
then the reactive to give the following
D of Formula I and V is a nitro, protected sulfonamide or
ester group and precursor of group Z of Formula I. The V
group is placed on an appropriately substituted phenol either
via nitration as shoWn by Poirier et al. (Tetrahedron 1989,
45(5), 1415), sulfonylation as shoWn by Kuznetsov (Akad.
10
Nauk SSSR Ser. Khim 1990, 8, 1888) or carboxylation by
Sartori et al. (Synthesis 1988, 10, 763). Bromination With
The coupling chemistry of table B can be carried out by triphenylphosphine and bromine (J. Am. Chem. Soc. 1964,
a variety of methods. The Grignard reagent required for Y is 86, 964) gives the desired bromide. Suzuki coupling With the
prepared from a halogen analog of Y in dry ether, appropriate boronic acid provides the desired substituted
dimethoxyethane or tetrahydrofuran at 0° C. to the re?ux 15 pyridine.
point of the solvent. This Grignard reagent can reacted
directly under very controlled conditions, that is loW tem
Scheme 3
perature (—20° C. or loWer) and With a large excess of acid
chloride or With catalytic or stoichiometric copper
bromide'dimethyl sul?de complex in dimethyl sul?de as a 20
solvent or With a variant thereof. Other methods available
include transforming the Grignard reagent to the cadmium
reagent and coupling according to the procedure of Carson
and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling
mediated by Fe(acac)3 according to Fiandanese et al. (Tern 25
Lett. 1984, 4805), or a coupling mediated by manganese (II)
catalysis (Cahiez and Laboue, Terr. Lett. 1992, 33(31),
4437).
TABLE C 30
Schemes 4, 5, 6, and 7 describe the synthesis of com
pounds Wherein M is pyridine and Q is a protected precursor
Preparation of Ether and Thioether linkages betWeen
A and B. of group D of Formula I. Each scheme represents a different
substitution pattern for the pyridine ring. In Scheme 4, a
then the reactive to give the folloWing suitably protected aldehyde is subjected to base-catalyzed
35 condensation With an activated ester to give after deprotec
tion the desired aldehyde. Re?uxing With ammonium chlo
ride as shoWn by DornoW and Ische (Chem. Ber. 1956, 89,
876) provides the pyridinol Which is brominated With POBr3
(Tjeenk et al. Rec. Trav. Chim. 1948, 67, 380) to give the
40 desired 2-bromopyridine. Suzuki coupling With the appro
priate boronic acid provides the desired substituted pyridine.
The ether and thioether linkages of Table C can be
Scheme 4
prepared by reacting the tWo components in a polar aprotic
coR1b
solvent such as acetone, dimethylformamide or dimethyl 45
sulfoxide in the presence of a base such as potassium
o
carbonate, sodium hydride or potassium t-butoxide at a </ CH0 1) NaOEt
temperature ranging from ambient to the re?ux point of the
solvent used. O EtOZC v
—>
or 2) H30+
TABLE D
Preparation of —SO— and —SO2— linkages from O
thioether of Table C.
then it is oxidized then it is oxidized 55
With Wet With m
If the starting Alumina/Oxone to chloroperbenzoic acid
material is: give: to give:
A—S—Y A—S(O)—Y A—SO2—Y
60
The thioethers of Table C serve as a convenient starting
material for the preparation of the sulfoxide and sulfone
analogs of Table D. A combination of Wet alumina and 65
Oxone can provide a reliable reagents for the oxidation of Treatment of an appropriately substituted
the thioether to the sulfoxide as shoWn by Greenhalgh (Syn. 5 -ethoxyoxazole With an alkene as shoWn by Kondrat’eva et