Potassium channel inhibitors and method

159 Pages·2013·3.93 MB·English

US006150356A
United States Patent [19] [11] Patent Number: 6,150,356
Lloyd et al. [45] Date of Patent: Nov. 21, 2000
[54] POTASSIUM CHANNEL INHIBITORS AND WO97/26300 7/1997 WIPO.
METHOD WO98/04521 2/1998 WIPO.
WO99/37607 7/1999 WIPO.
[75] Inventors: John Lloyd, Yardley, Pa.; Heather J. OTHER PUBLICATIONS
Finlay, LaWrenceville, N.J.; Wayne
Vaccaro, Yardley; Karnail S. AtWal, Lohrman et al., “A New Class Of Inhibitors . . . ”, P?ugers
NeWtoWn, both of Pa.; Michael F. Arch—Eur. J. Physiol. (1995) 429:517—530.
Gross, Durham; Kerry L. Spear, AtWal et al., “Cardioselective Anti—Ischemic ATP—Sensitive
Raleigh, both of NC. Potassium Channel Openers”, J. Med. Chem. (1993) vol. 36,
3971—3974.
[73] Assignee: Bristol-Myers Squibb Company, Evans et al., “Short Ef?cient Synthesis Of
PriIlCeIOIl, N-J- 2,2—Dimethyl—2H—Pyranopyridines”, Synthetic Communi
cations, 18(10), 1111—1118 (1988).
[21] App], N()_j 09/375,955 Ding, “A Convenient Synthesis Of 6—Substituted—2,
_ 2—Dimethyl—2H—1—BenZopyrans”, Synthetic Communica
[22] Flledl Aug- 17, 1999 tions, 26 (22),4267—4273 (1996).
AtWal et al., “A Facile Synthesis Of Cyanoguanidens From
Related US. Application Data
Thioureas”, Tetrahedron Letters, vol. 30, 7313—7316 (1989).
[60] Provisional application No. 60/098,709, Sep. 1, 1998. Bargar et al., “3,4—Dihydro—2—phenyl—2H—pyrano[2,3—b]
[51] Int. Cl.7 .................... .. C07D 215/42; C07D 311/68; pyridines With Potent Antirhinovirus Activity”, J. Med.
A61K 31/352 Chem. (1986), 29, 1590—1595.
[52] US. Cl. ............... .. 514/218; 514/233.5; 514/252.14; Primary Examiner—Mukund J. Shah
514/252.2; 514/253.01; 514/253.09; 514/254.01;
Assistant Examiner—Deepak R. Rao
514/254.11; 514/226; 514/320; 514/337;
Attorney, Agent, or Firm—Burton Rodney
514/364; 514/397; 514/422; 514/456; 540/575;
544/151; 544/277; 544/295; 544/376; 546/196; [57] ABSTRACT
546/283.1; 548/131; 548/311.4; 548/525; _
549/399; 549/404 Indanes, benZopyrans and analogues thereof are potassium
[58] Field Of Search ............................... .. 514/218 233.5 Channel inhibitors and blockers of 1K1“ and have the Struc
514/255, 266, 320, 337, 364, 397, 422, me
456, 252.14, 252.2, 253.01, 253.09, 254.01,
254.11; 540/575; 544/151, 277, 295, 376; ,R1
546/196, 283.1; 548/131, 311.4, 525, 549/399, R\N/SO2
404
‘/A
[56] References Cited QAIQ X2_R2
U.S. PATENT DOCUMENTS B\D X1
5,082,858 1/1992 Garcia et al. . 514/456
égliilaittagl' " Where A, B, D, Q, X1, R, R1, X2 and R2 are as de?ned herein.
’ ’ ' ~~~~~~~~~~~~~~~~~~~~~~~~ " These compounds are useful as antiarrhythmic agents. In
FOREIGN PATENT DOCUMENTS addition, a method is provided for preventing cardiac
389861131 8/1995 European Pat‘ Off‘ ' arrhythmia employing the above compounds.
807629A1 11/1997 European Pat. Off. .
WO97/25983 7/1997 WIPO . 14 Claims, No Drawings
6,150,356
1 2
POTASSIUM CHANNEL INHIBITORS AND
METHOD
This application claims priority from US. application
Ser. No. 60/098,709 ?led Sep. 1, 1998.
(Where R6 and R7 are independently selected from H, aryl,
FIELD OF THE INVENTION
alkyl, arylalkyl or cycloalkyl, or R6 and R7 can be taken
The present invention relates to indanes and benZopyrans together With the nitrogen atom to Which they are attached
and analogues thereof Which are potassium channel inhibi
10 to form a 5 to 8 rnernbered ring); or R and R1 can be taken
tors and thus are useful as antiarrhythrnic agents.
together With the —N—S— atoms to form a 5- to
8-rnernbered ring;
BRIEF DESCRIPTION OF THE INVENTION
X2 is a single bond,
In accordance With the present invention, novel indanes
and benZopyrans and analogues thereof are provided Which 15
are potassium channel inhibitors and have the structure
or —O— (Where R8 is H, alkyl, alkenyl, aryl, arylalkyl,
20
cycloalkyl or cycloalkylalkyl);
R2 is H, alkyl, arylalkyl,
O
ll
25
including pharrnaceutically acceptable salts thereof, prodrug
esters thereof, and all stereoisorners thereof, Wherein
A, B and D are independently selected from CH or N; X1
is 30 R11
R3
(where R10 and R11 are independently selected from H,
(CL. alkyl, arylalkyl or cycloalkyl, or R10 and R11 can be taken
together With the nitrogen to Which they are attached to form
a 5-to 8-rnernbered ring); and Q is
(Where n is 1, 2 or 3), O, NR5, S, SO, S02,
40
R12—heterocycle
(Where R12 is alkyl, arylalkyl, aryl,
R16
Wherein the hetero atom in each of the above groups is
linked to the aromatic ring; (Where R3 and R4 are indepen
heterocycle, heterocycloalkyl,
dently H, alkyl, arylalkyl or cycloalkyl, or R3 and R4 can be
taken together With the carbon to Which they are attached to
—N—heterocycle,
form a 5 to 8 carbon containing ring; and R5 is H, alkyl,
alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl); 55
R14
R is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,
heterocycloalkyl, or cycloalkylalkyl;
R1 is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, (Where R14 can be any of the R8 groups), CF3 alkoXy,
heterocycloalkyl, O aryloXy, arylalkoXy, cycloalkyl or cycloalkylalkyl, and
Where R15 and R16 are independently selected from H, alkyl,
—N—heterocycle arylalkyl, heterocyclo, cycloalkyl, arnino arninoalkyl, or
heterocycloalkyl or R15 and R16 can be taken together With
the nitrogen to Which they are attached to form a 5- to
8-rnernbered ring Which may optionally contain an addi
(Where R5“ can be any of the R5 groups), cycloalkyl, tional nitrogen in the ring and/or an amino group or an
cycloalkylalkyl or arninoalkyl group attached to the ring; and
6,150,356
and R12 is
R16 R16
(wherein this moiety is as de?ned With respect to R12); then at least one of R15 and R16 contains an additional amino
group or R15 and R16 taken together With the nitrogen atom
With the proviso that Where X1 is
to Which they are attached form a ring Which contains an
10 additional nitrogen atom in the ring and/or an amino group
or an aminoalkyl group attached to the ring; and/or
(5) Where Q is
15
and A, B and D are all carbon, then
(1) Where Q is
and R13 is
(11:0
0:
R16
25
and R12 or R13 is then at least one of R15 and R16 contains an additional amino
group or R15 and R16 taken together With the nitrogen atom
to Which they are attached form a ring Which contains an
additional nitrogen atom in the ring and/or an amino group
R16 or an aminoalkyl group attached to the ring.
Preferred compounds of formula I of the invention can
have the folloWing structural formulae:
at least one of R15 or R16 is, aryl, arylalkyl, heterocyclo or
heterocycloalkyl, or alkyl of 4 to 12 carbons; and/or
35
(2) Q is other than
(Where R12 is methyl, ethyl, CF3 or alkoXy); and/or
(3) Where Q is
45
and R12 is
—N—heterocycle,
R14
55
then heterocycle is a monocyclic or bicyclic heterocycle ring
containing from 5 to 10 ring members, containing one to ?ve
nitrogen atoms, and/or one or tWo oXygen atoms, and/or one
sulfur atom; and/or
(4) Where Q is
65
6,150,356
6
-continued X1 is
Ie
Tm Tm T3
R SO’ R1
\ N/ 2
—O—C—, —§— — or C—,
| | I,
O N
/ CH3 CH3
X2_R2
A and B are each CH;
If 10 D is N or CH; and
Q is
O
ll
15
R16 R16
In addition, in accordance With the present invention, a
method for preventing, inhibiting or treating cardiac
Preferred are compounds of formula I Wherein Q is
arrhythmia, including atrial arrhythmia, is provided, Wherein
a compound of formula I is administered in a therapeutically
R15 0 effective amount Which inhibits the IKur potassium channel.
\ The formula I compound employed in the above method
/N—C or heterocycle—N—C—
has the structure
R16 R14 25
Wherein heterocycle is a monocyclic ring (cycloheteroalkyl
ring or heteroaryl ring) containing 5 or 6 ring members
Which include one or tWo nitrogen atoms in the ring and/or
one oxygen atom in the ring.
Also preferred are compounds of formula I Where
R is H;
R1 is aryl or alkyl; 35 including pharmaceutically acceptable salts thereof, prodrug
esters thereof, and all stereoisomers thereof, Wherein
X2 is O or a single bond;
A, B and D are independently selected from CH or N;
X1 is
R3
((3%.
45
(Where n is 1, 2 or 3), O, NR5, S, SO, S02,
Where R3 and R4 are each H and/or alkyl; up
A and B are each CH;
D is N or CH; and
Q is
O
ll 55
Wherein the heteroatom in each of the above groups is linked
to the aromatic ring; (Where R3 and R4 are independently H,
Where R15 and R16 are H, aryl, aralkyl or aminoalkyl. Still alkyl, arylalkyl or cycloalkyl, or R3 and R4 can be taken
more preferred are compounds of formula I Where together With the carbon to Which they are attached to form
a 5 to 8 carbon containing ring; and R5 is H, alkyl, alkenyl,
R is H; aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R1 is aryl; R is H, alkyl, alkenyl, aryl, arylalkyrl, heterocycloalkyl,
65 cycloalkyl, or cycloalkylalkyl;
X2 is O or a single bond; R1 is alkyl, arylalkyl, aryl, alkenyl, heterocyclo,
R2 is H; heterocycloalkyl,
6,150,356
7 8
can be taken together With the nitrogen to Which they are
—N—heterocycle attached to form a 5- to 8-rnernbered ring (Which may
optionally contain an additional nitrogen in the ring and/or
an amino group or an arninoalkyl group attached to the ring);
and
R13 is
(Where R5“ can be any of the R5 groups), cycloalkyl,
cycloalkylalkyl or
R6
R16
10
(Wherein this moiety is as de?ned With respect to R12).
(Where R6 and R7 are independently selected from H, aryl, DETAILED DESCRIPTION OF THE
alkyl, arylalkyl or cycloalkyl, or R6 and R7 can be taken INVENTION
together With the nitrogen atom to Which they are attached
The folloWing de?nitions apply to the terms as used
to form a 5 to 8 rnernbered ring); or R and R1 can be taken
throughout this speci?cation, unless otherWise limited in
together With the —N—S— atoms to form a 5- to
speci?c instances.
8-rnernbered ring;
Unless otherWise indicated, the term “loWer alkyl”,
X2 is a bond,
“alkyl” or “alk” as employed herein alone or as part of
another group includes both straight and branched chain
hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20
carbons, more preferably 1 to 12 carbons, in the normal
chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
25 isobutyl, pentyl, heXyl, isoheXyl, heptyl, 4,4-dirnethylpentyl,
or —O— (Where R8 is H, alkyl, alkenyl, aryl, arylalkyl, octyl, 2,2,4-trirnethylpentyl, nonyl, decyl, undecyl, dodecyl,
cycloalkyl or cycloalkylalkyl);
the various additional branched chain isorners thereof, and
R2 is H, alkyl, arylalkyl,
the like as Well as such groups including 1 to 4 substituents
Which may be halogen, haloalkyl, alkyl, alkoXy, alkenyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, arnino,
hydroXy, heteroaryl, cycloheteroalkyl, alkanoylarnino,
alkylarnido, arylcarbonylarnino, acyl, nitro, cyano,thiol,
alkylthio or any of the alkyl or aryl substituents set out
herein.
35 Unless otherWise indicated, the term “cycloalkyl” as
R11
employed herein alone or as part of another group includes
saturated or partially unsaturated (containing 1 or 2 double
(where R10 and R11 are independently selected from H, alkyl bonds) cyclic hydrocarbon groups containing 1 to 3 rings,
arylalkyl or cycloalkyl, or R10 and R11 can be taken together including rnonocyclicalkyl, bicyclicalkyl and tricyclicalkyl,
With the nitrogen to Which they are attached to form a 5- to containing a total of 3 to 20 carbons forming the rings,
8-rnernbered ring); and preferably 4 to 12 carbons, forming the ring and Which may
Qis be fused to one aromatic ring as described for aryl, Which
include cyclopropyl, cyclobutyl, cyclopentyl, cycloheXyl,
cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl,
cycloheXenyl,
R12—heterocycle
(Where R12 is alkyl, arylalkyl, aryl,
R16 55
heterocycle, heterocycloalkyl,
any of Which groups may be optionally substituted With 1 to
4 substituents Which may be any of the alkyl or aryl
—N—heterocycle substituents set out herein.
The term “cycloalkenyl” as employed herein alone or as
R14
part of another group refers to cyclic hydrocarbons contain
ing 5 to 20 carbons, preferably 6 to 12 carbons and 1 or 2
Where R14 can be any of the R8 groups), alkoXy, aryloXy, double bonds. EXernplary cycloalkenyl groups include
arylalkoXy, cycloalkyl or cycloalkylalkyl, and Where R15 65 cyclopentenyl, cycloheXenyl, cycloheptenyl, cyclooctenyl,
and R16 are independently selected from H, alkyl, arylalkyl, cycloheXadienyl, and cycloheptadienyl, Which may be
heterocyclo, cycloalkyl or heterocycloalkyl, or R15 and R16 optionally substituted as de?ned for cycloalkyl.
6,150,356
9
The term “aryl” as employed herein alone or as part of
another group refers to monocyclic and bicyclic aromatic
groups containing 6 to 10 carbons in the ring portion (such
as phenyl or naphthyl including 1-naphthyl and 2-naphthyl)
and may optionally include one to three additional rings
fused to a carbocyclic ring or a heterocyclic ring (such as
group; examples of acyl groups include any of the R1 groups
aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and
attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl,
may be optionally substituted through available carbon aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl
atoms With 1, 2, or 3 groups selected from hydrogen, halo, and the like.
haloalkyl, alkyl, haloalkyl, alkoXy, haloalkoXy, alkenyl,
The term “alkanoyl” as used herein alone or as part of
tri?uoromethyl, tri?uoromethoXy, alkynyl, cycloalkylalkyl, another group refers to alkyl linked to a carbonyl group.
cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, Unless otherWise indicated, the term “loWer alkenyl” or
arylalkyl, aryloXy, aryloXyalkyl, arylalkoXy, arylthio, “alkenyl” as used herein by itself or as part of another group
arylaZo, heteroarylalkyl, heteroarylalkenyl, 15 refers to straight or branched chain radicals of 2 to 20
heteroarylheteroaryl, heteroaryloXy, hydroXy, nitro, cyano, carbons, preferably 3 to 12 carbons, and more preferably 1
to 8 carbons in the normal chain, Which include one to siX
amino, substituted amino Wherein the amino includes 1 or 2
double bonds in the normal chain, such as vinyl, 2-propenyl,
substituents (Which are alkyl, aryl or any of the other aryl 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-heXenyl,
compounds mentioned in the de?nitions), thiol, alkylthio, 3-heXenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,
arylthio, heteroarylthio, arylthioalkyl, alkoXyarylthio,
3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12
alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,
tetradecatrienyl, and the like, and Which may be optionally
arylaminocarbonyl, alkoXycarbonyl, aminocarbonyl,
substituted With 1 to 4 substituents, namely, halogen,
alkylcarbonyloXy, arylcarbonyloXy, alkylcarbonylamino, haloalkyl, alkyl, alkoXy, alkenyl, alkynyl, aryl, arylalkyl,
arylcarbonylamino, arylsul?nyl, arylsul?nylalkyl, arylsulfo 25 cycloalkyl, cycloalkenyl, amino, hydroXy, heteroaryl,
cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonyl
nylamino or arylsulfonaminocarbonyl.
amino, acyl, nitro, cyano, thiol, alkylthio or any of the alkyl
The term “aralkyl”, “aryl-alkyl” or “arylloWer alkyl” as
or aryl substituents set out herein.
used herein alone or as part of another group refers to alkyl
Unless otherWise indicated, the term “LoWer alkynyl” or
groups as discussed above having an aryl substituent, such
“alkynyl” as used herein by itself or as part of another group
as benZyl or phenethyl, or naphthylpropyl, or an aryl as refers to straight or branched chain radicals of 2 to 20
de?ned above. carbons, preferably 2 to 12 carbons and more preferably 2 to
The term “lower alkoXy”, “alkoXy”, “aryloXy” or 8 carbons in the normal chain, Which include one triple bond
“aralkoXy” as employed herein alone or as part of another in the normal chain, such as 2-propynyl, 3-butynyl,
2-butynyl, 4-pentynyl, 3-pentynyl, 2-heXynyl, 3-heXynyl,
group includes any of the above alkyl, aralkyl or aryl groups
2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,
linked to an oXygen atom.
4-decynyl,3-undecynyl, 4-dodecynyl and the like, and Which
The term “amino” as employed herein alone or as part of may be optionally substituted With 1 to 4 substituents,
another group may optionally be independently substituted namely, halogen, haloalkyl, alkyl, alkoXy, alkenyl, alkynyl,
With one or tWo substituents, Which may be the same or aryl, arylalkyl, cycloalkyl, amino, heteroaryl,
different, such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, cycloheteroalkyl, hydroXy, alkanoylamino, alkylamido,
heteroaryl, heteroarylalkyl, cycloheteroalkyl, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or
cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, any of the alkyl or aryl substituents set out herein.
haloalkyl, hydroXyalkyl, alkoXyalkyl or thioalkyl. These Where alkyl groups as de?ned above have single bonds
substituents may be further substituted With a carboXylic for attachment to other groups at tWo different carbon atoms,
acid or any of the alkyl or aryl substituents set out above. In they are termed “alkylene” groups and may optionally be
addition, the amino substituents may be taken together With substituted as de?ned above for “alkyl”.
the nitrogen atom to Which they are attached to form Where alkenyl groups as de?ned above and alkynyl
1-pyrrolidinyl, 1-piperidinyl, 1-aZepinyl, 4-morpholinyl, groups as de?ned above, respectively, have single bonds for
4-thiamorpholinyl, 1-piperaZinyl, 4-alkyl-1-piperaZinyl, attachment at tWo different carbon atoms, they are termed
4-arylalkyl-1-piperaZinyl, 4-diarylalkyl-1-piperaZinyl, “alkenylene groups” and “alkynylene groups”, respectively,
1-pyrrolidinyl, 1-piperidinyl, or 1-aZepinyl, optionally sub and may optionally be substituted as de?ned above for
“alkenyl” and “alkynyl”.
stituted With alkyl, alkoXy, alkylthio, halo, tri?uoromethyl or
hydroXy. Suitable alkylene, alkenylene or alkynylene groups
55
(CH2)p (Where p is 1 to 8, preferably 1 to 5) (Which may
The term “loWer alkylthio”, “alkylthio”, “arylthio” or
include alkylene, alkenylene or alkynylene groups) as
“aralkylthio” as employed herein alone or as part of another
de?ned herein, may optionally include 1, 2, or 3 substituents
group includes any of the above alkyl, aralkyl or aryl groups
Which include any of the alkyl or aryl substituents set out
linked to a sulfur atom. herein.
The term “loWer alkylamino”, “alkylamino”, Examples of alkylene, alkenylene and alkynylene include
“arylamino”, or “arylalkylamino” as employed herein alone
or as part of another group includes any of the above alkyl,
aryl or arylalkyl groups linked to a nitrogen atom.
The term “acyl” as employed herein by itself or part of 65
another group, as de?ned herein, refers to an organic radical O
linked to a carbonyl
6,150,356
11 12
optionally via the linker (CH2)p (Which is de?ned above),
such as
OeQnO/(J
CH3 CH3 CH3
—CHCH3CH3—, —CHCHCH3—,
:
CH3
CH3
20
and the like. The above groups may include 1 to 4 substitu
CH3 ents such as alkyl, halo, oxo and/or any of the alkyl or aryl
F C1 substituents set out herein. In addition, any of the above
rings can be fused to a cycloalkyl, aryl, heteroaryl or
cycloheteroalkyl ring.
25
The term “heteroaryl” as used herein alone or as part of
another group refers to a 5- or 6- membered aromatic ring
Which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,
CH3
oxygen or sulfur,and such rings fused to an aryl, cycloalkyl,
heteroaryl or cycloheteroalkyl ring (e.g. benZothiophenyl,
indolyl), and includes possible N-oxides. The heteroaryl
group may optionally include 1 to 4 substituents such as any
35 of the alkyl or aryl substituents set out above. Examples of
heteroaryl groups include the folloWing:
CH3
CH3
1:} <21}
The term “halogen” or “halo” as used herein alone or as 171% N
part of another group refers to chlorine, bromine, ?uorine,
and iodine as Well as CF3, With chlorine or ?uorine being
preferred.
The term “metal ion” refers to alkali metal ions such as
sodium, potassium or lithium and alkaline earth metal ions
such as magnesium and calcium, as Well as Zinc and
aluminum. 55
The term “heterocycle” or “heterocyclo” as used herein
alone or as part of another group refers to a “cyclohet 51
eroalkyl” group or a “heteroaryl” group as de?ned herein
after.
The term “heterocycloalkyl” as used herein alone or as
part of another group refers to a heterocycle linked through
a carbon to an alkyl group.
The term “cycloheteroalkyl” as used herein alone or as N—\\ \vN=N I \ N
part of another group refers to a 5-, 6- or 7-membered
saturated or partially unsaturated ring Which includes 1 to 2 65
hetero atoms such as nitrogen, oxygen and/or sulfur, linked
through a carbon atom or a heteroatom, Where possible,
6,150,356
13 14
-continued or aryl-sulfonic acids Which are unsubstituted or substituted,
for example by halogen, for example methane- or p-toluene
sulfonic acid. Corresponding acid addition salts can also be
formed having, if desired, an additionally present basic
center. The compounds of formula I having at least one acid
{61J>5 , ‘i
group (for example COOH) can also form salts With bases.
Suitable salts With bases are, for example, metal salts, such
as alkali metal or alkaline earth metal salts, for example
sodium, potassium or magnesium salts, or salts With ammo
10
nia or an organic amine, such as morpholine,
thiomorpholine, piperidine, pyrrolidine, a mono-, di- or
tri-loWer alkylamine, for example ethyl-, tert-butyl-,
diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl
15 propylamine, or a mono-, di- or trihydroxy loWer
alkylamine, for example mono-, di- or triethanolamine.
Corresponding internal salts may furthermore be formed.
Salts Which are unsuitable for pharmaceutical uses but
Which can be employed, for example, for the isolation or
20
puri?cation of free compounds I or their pharmaceutically
acceptable salts, are also included.
A preferred salt of the compounds of formula I is the
monohydrochloride salt.
25
and the like.
All stereoisomers of the compounds of the instant inven
The term “cycloheteroalkylalkyl” as used herein alone or tion are contemplated, either in admixture or in pure or
as part of another group refers to cycloheteroalkyl groups as substantially pure form. The compounds of the present
de?ned above linked through a C atom or heteroatom to a 30 invention can have asymmetric centers at any of the carbon
(CH2)p chain.
atoms including any one of the R substituents.
Consequently, compounds of formula I can exist in enan
The term “heteroarylalkyl” or “heteroarylalkenyl” as used
tiomeric or diastereomeric forms or in mixtures thereof. The
herein alone or as part of another group refers to a heteroaryl
processes for preparation can utiliZe racemates, enantiomers
group as de?ned above linked through a C atom or heteroa 35 or diastereomers as starting materials. When diastereomeric
tom to a —(CH2)p— chain, alkylene or alkenylene as or enantiomeric products are prepared, they can be separated
de?ned above. by conventional methods for example, chromatographic or
fractional crystalliZation.
The term “polyhaloalkyl” as used herein refers to an
“alkyl” group as de?ned above Which includes from 2 to 9, 40 It should be understood that the present invention includes
preferably from 2 to 5, halo substituents, such as F or Cl, prodrug forms of the compounds of formula I such as
preferably F, such as CF3CH2, CF3 or CF3CF2CH2. alkylesters of acids or any of the prodrugs disclosed in
“Prodrugs”, D. G. Waller, C. F. George, Br. J. Clin. Pharmac.
The term “polyhaloalkyloxy” as used herein refers to an (1989), 28, 497—507; “Prodrugs for the improvement of drug
45
“alkoxy” or “alkyloxy” group as de?ned above Which absorption via different routes of administration”, L. P.
includes from 2 to 9, preferably from 2 to 5, halo Balant, E. Doelker, P. Burt, Eur. J. Drug Metab. Pharma
substituents, such as F or Cl, preferably F, such as cokinet. (1990), 15, 143—153; “Prodrugs as a means to
CF3CH2O, CF30 or CF3CF2CH2O. improve the delivery of peptide drugs”, H. Bundgaard,
Advanced Drug Delivery RevieWs (1992), 8, 1—38; “Novel
The compounds of formula I can be present as salts, in chemical approaches in prodrug design” (1991), Drugs of
particular pharmaceutically acceptable salts. If the com the Future, 16, 443—458; and in US. application Ser. No.
pounds of formula I have, for example, at least one basic 08/641,718, ?led May 2, 1996, and in US. Pat. No. 5,561,
center, they can form acid addition salts. These are formed, 146 Which are incorporated herein by reference.
for example, With strong inorganic acids, such as mineral 55
The compounds of the instant invention may, for example,
acids, for example sulfuric acid, phosphoric acid or a
hydrohalic acid, With strong organic carboxylic acids, such be in the free or hydrate form, and may be obtained by
methods exempli?ed by the folloWing descriptions.
as alkanecarboxylic acids of 1 to 4 carbon atoms Which are
unsubstituted or substituted, for example, by halogen, for
The compounds of formula I may be prepared by the
60
example acetic acid, such as saturated or unsaturated dicar exemplary processes described in the folloWing reaction
boxylic acids, for example oxalic, malonic, succinic, maleic, schemes. Exemplary reagents and procedures for these reac
fumaric, phthalic or terephthalic acid, such as hydroxycar tions appear hereinafter and in the Working Examples.
boxylic acids, for example ascorbic, glycolic, lactic, malic,
tartaric or citric acid, such as amino acids, (for example 65 Compounds of formula I of the invention can be prepared
aspartic or glutamic acid or lysine or arginine), or benZoic by using the sequence of steps outlined in General Schemes
acid, or With organic sulfonic acids, such as (C1—C4)-alkyl 1 to 8 set out beloW.
6,150,356
General Scheme 1
H R ]_ S _ Cl
RN
NC A 0 NC
III
I \ XZ-RZ 5 u 1fo ny 1 at1' on
B / 1
\D X
II
1
R R15—NH
O — 1
R15 A \\ O R 16
\N \ 0 VI HO
I I X2—R2 w
16
R B\D/ X1
IA
Referring to General Scheme 1, amide compounds of the
invention of formula IA may be prepared starting With nitrile
II Which is made to undergo a sulfonylation by reacting II 30
With a sulfonylating agent III (employing a molar ratio of
III:II Within the range from about 1:1 to about 10:1) in the
presence of a base such as triethylamine or diisopropylethy
lamine in an inert organic solvent such as acetonitrile and/or 35
dichloromethane, to form sulfonylated compound IV.
Compound IV is then subjected to nitrile hydrolysis by
F = o, s, so, 502, NR20
treating an aqueous solution of IV With sodium peroxide and
E and G = N, CH,
then With strong acid such as hydrochloric acid, to form the
R21 : alkyl or aryl
acid V.
IB
Acid V is treated With amine VI (employing a molar of 45
VI:V Within the range from about 1:1 to about 10:1) and a
dehydrating agent such as l-(3-dimethylaminopropyl)-3
ethylcarbodiimide With 4-dimethylaminopyridine in the Referring to General Scheme 2, compounds of the inven
presence of an inert solvent such as acetonitrile and/or tion of formula IB may be prepared from acid V employing
dimethylformamide, to form amide compounds of the inven
methods knoWn in the literature and described in “Compre
tion IA.
hensive Heterocyclic Chemistry”, A. Katritsky et al,
Pergamon, Elsevier Science, Inc., (1996).
The starting nitrile II in General Scheme 1 may be
prepared as described in K. AtWal et al, J. Med. Chem. 55
(1993) 36, 3971—3974 and references cited therein. Where F is oxygen and E and G are nitrogen, compound
IB may be prepared by reaction of the acid V With a
General Scheme 2 hydroXyamidine in the presence of a dehydrating agent such
R1 as (benZotriaZol-1-yloXy)tripyrrolidinophosphonium
0 RN S/
T0 hexa?uorophosphate (PyBOP) and a tertiary amine such as
A triethylamine in an inert organic solvent such as dichlo
\ O
HO Heterocycle formation romethane. The resulting acylhydroXyamidine can be treated
B \D/ X1 With a base such as potassium, sodium or cesium carbonate
65
in an inert organic solvent such as tetrahydrofuran to provide
V
compound IB.
6,150,356
General Scheme 3
R1
H /
RN RN—S§O
OZN A OZN A \\O
\ Sulfonylation \
I X2_R2 (R1 so c1 b ) I X2—R2
B / _ 2 : 336 B /
\D X1 III \D X1
X XI
Reduction
(KBH4,CuC1)
R1 R1
R15 RN 5 RN 5/
| H — \§\ O — \%\ O
N N A 0 .d. HZN A 0
R16/ cyanoguani ine \
I I X2_R2 formgition I X2_R2
NC/ N B \D/ X1 )L B \D/ X1
IC R15\N N/CN XII
R15 Na
XIII
When R15 or R16 is aryl
and a carbodiimide
Referring to General Scheme 3, compounds of the inven about 1:1 to about 5:1) in the presence of a carbodiimide
tion of formula IC Where either R15 or R16 is aryl may be such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
prepared starting With compound X Which is made to 30
and an inert organic solvent such as anhydrous dimethyl
undergo sulfonylation by reacting nitro compound X With
formamide, dichloromethane or acetonitrile to form cyan
sulfonylating agent III (employing a molar ratio of III:X
oguanidine of the invention IC.
Within the range from about 1:1 to about 10:1) in the
presence of a base such as triethylamine and an inert organic
The starting nitro compound X may be prepared folloW
solvent such as dichloromethane to form sulfonylated com 35
pound XI. ing procedures as described in WO9804521.
Compound XI is reduced, for example, by reacting XI
The sodium salt of a cyanothiourea XIII may be prepared
With KBH4 in the presence of CuCl to form aniline XII.
Aniline XII is then subjected to cyanoguanidine formation from the corresponding isothiocyanate and cyanamide as
by reacting XII With an N-cyanothiourea sodium salt XIII described in AtWal, K. S.; Ahmed, S. Z., O’Reilly, B. O.
(employing a molar ratio of XIII:XII Within the range from Tetrahedron Letters (1989) 30, 7313.
General Scheme 4
NC \ R 1
/ IN RN S/
v0 )\ H To
A \
PhO N A
\ PhO OPh \ O
2_R2 XIV , I I X2_R2
X
D/ X1 NC/ N B \D/ X 1
XII XV
15
cyanoguanidine R \ T / H
formation R16
XVI
(Where R15 or R16
are alkyl)