U.S. patent application number 10/894719 was filed with the patent office on 2004-12-30 for acylated piperidine derivatives as melanocortin-4 receptor agonists.
Invention is credited to Chu, Lin, Goulet, Mark T., Louridas, Bonnie, Ujjainwalla, Feroze, Warner, Daniel, Wyvratt, Matthew J..
Application Number | 20040266821 10/894719 |
Document ID | / |
Family ID | 32770902 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040266821 |
Kind Code |
A1 |
Ujjainwalla, Feroze ; et
al. |
December 30, 2004 |
Acylated piperidine derivatives as melanocortin-4 receptor
agonists
Abstract
Certain novel 4-substituted N-acylated piperidine derivatives
are agonists of the human melanocortin receptor(s) and, in
particular, are selective agonists of the human melanocortin-4
receptor (MC-4R). They are therefore useful for the treatment,
control, or prevention of diseases and disorders responsive to the
activation of MC-4R, such as obesity, diabetes, sexual dysfunction,
including erectile dysfunction and female sexual dysfunction.
Inventors: |
Ujjainwalla, Feroze; (Scotch
Plains, NJ) ; Chu, Lin; (Scotch Plains, NJ) ;
Goulet, Mark T.; (Westfield, NJ) ; Louridas,
Bonnie; (Monmouth Junction, NJ) ; Wyvratt, Matthew
J.; (Mountainside, NJ) ; Warner, Daniel;
(Stoneham, MA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
32770902 |
Appl. No.: |
10/894719 |
Filed: |
July 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10894719 |
Jul 20, 2004 |
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10356897 |
Feb 3, 2003 |
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10356897 |
Feb 3, 2003 |
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PCT/US02/05724 |
Feb 25, 2002 |
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60272258 |
Feb 28, 2001 |
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60300118 |
Jun 22, 2001 |
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Current U.S.
Class: |
514/316 ;
514/318; 514/326; 546/187; 546/193; 546/207 |
Current CPC
Class: |
C07D 211/64 20130101;
C07D 401/06 20130101; G01M 17/007 20130101; C07D 413/06 20130101;
C07D 491/08 20130101; C07D 401/14 20130101; A61K 31/445 20130101;
C07D 211/62 20130101; C07D 413/14 20130101; G01M 15/12
20130101 |
Class at
Publication: |
514/316 ;
514/318; 514/326; 546/187; 546/193; 546/207 |
International
Class: |
A61K 031/4545; A61K
031/454; C07D 41/14; C07D 43/14 |
Claims
1. A compound of structural formula I: 214or a pharmaceutically
acceptable salt thereof, wherein r is 1 or 2; s is 0, 1, or 2; n is
0, 1 or 2; p is 0, 1, or 2; R.sup.1 is selected from the group
consisting of hydrogen, amidino, C.sub.1-4 alkyliminoyl, C.sub.1-10
alkyl, (CH.sub.2).sub.n--C.sub.3-7 cycloalkyl,
(CH.sub.2).sub.n-phenyl, (CH.sub.2).sub.n-naphthyl, and
(CH.sub.2).sub.n-heteroaryl wherein heteroaryl is selected from the
group consisting of (1) pyridinyl, (2) furyl, (3) thienyl, (4)
pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8)
pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl,
(12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl,
(16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19)
indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which
phenyl, naphthyl, and heteroaryl are unsubstituted or substituted
with one to three groups independently selected from R.sup.3; and
alkyl and cycloalkyl are unsubstituted or substituted with one to
three groups independently selected from R.sup.3 and oxo; R.sup.2
is selected from the group consisting of phenyl, naphthyl, and
heteroaryl wherein heteroaryl is selected from the group consisting
of (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5)
oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9)
isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl,
(13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16)
benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl,
(20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl,
naphthyl, and heteroaryl are unsubstituted or substituted with one
to three groups independently selected from R.sup.3; each R.sup.3
is independently selected from the group consisting of C.sub.1-6
alkyl, (CH.sub.2).sub.n-phenyl, (CH.sub.2).sub.n-naphthyl,
(CH.sub.2).sub.n-heteroaryl, (CH.sub.2).sub.n-heterocyclyl,
(CH.sub.2).sub.nC.sub.3-7 cycloalkyl, halogen, OR.sup.4,
(CH.sub.2).sub.nN(R.sup.4).sub.2, (CH.sub.2).sub.nC.ident.N,
(CH.sub.2).sub.nCO.sub.2R.sup.4, NO.sub.2,
(CH.sub.2).sub.nNR.sup.4SO.sub- .2R.sup.4
(CH.sub.2).sub.nSO.sub.2N(R.sup.4).sub.2,
(CH.sub.2).sub.nS(O).sub.pR.sup.4,
(CH.sub.2).sub.nNR.sup.4C(O)N(R.sup.4)- .sub.2,
(CH.sub.2).sub.nC(O)N(R.sup.4).sub.2, (CH.sub.2).sub.nNR.sup.4C(O)-
R.sup.4, (CH.sub.2).sub.nNR.sup.4CO.sub.2R.sup.4,
(CH.sub.2).sub.nNR.sup.4- C(O)-heteroaryl,
(CH.sub.2).sub.nC(O)NR.sup.4N(R.sup.4).sub.2,
(CH.sub.2).sub.nC(O)NR.sup.4NR.sup.4C(O)R.sup.4,
O(CH.sub.2).sub.nC(O)N(R- .sup.4).sub.2, CF.sub.3,
CH.sub.2CF.sub.3, OCF.sub.3, and OCH.sub.2CF.sub.3; in which
heteroaryl is as defined above; phenyl, naphthyl, heteroaryl,
cycloalkyl, and heterocyclyl are unsubstituted or substituted with
one to three substituents independently selected from halogen,
hydroxy, oxo, C.sub.1-4 alkyl, trifluoromethyl, and C.sub.1-4
alkoxy; and wherein any methylene (CH.sub.2) carbon atom in R.sup.3
is unsubstituted or substituted with one to two groups
independently selected from halogen, hydroxy, and C.sub.1-4 alkyl;
or two substituents when on the same methylene (CH.sub.2) group are
taken together with the carbon atom to which they are attached to
form a cyclopropyl group; each R.sup.4 is independently selected
from the group consisting of hydrogen, C.sub.1-6 alkyl,
(CH.sub.2).sub.n-phenyl, (CH.sub.2).sub.n-heteroaryl,
(CH.sub.2).sub.n-naphthyl, (CH.sub.2).sub.n-heterocyclyl,
(CH.sub.2).sub.nC.sub.3-7 cycloalkyl, and (CH.sub.2).sub.nC.sub.3-7
bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocyclyl, and
cycloalkyl are unsubstituted or substituted with one to three
groups independently selected from halogen, C.sub.1-4 alkyl,
hydroxy, and C.sub.1-4 alkoxy; or two R.sup.4 groups together with
the atom to which they are attached form a 4- to 8-membered mono-
or bicyclic ring system optionally containing an additional
heteroatom selected from O, S, and NC.sub.1-4 alkyl; each R.sup.5
is independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-naphthyl, (CH.sub.2).sub.n-heteroaryl, and
(CH.sub.2).sub.nC.sub.3-7 cycloalkyl; wherein heteroaryl is as
defined above; phenyl, naphthyl, and heteroaryl are unsubstituted
or substituted with one to three groups independently selected from
R.sup.3; alkyl and cycloalkyl are unsubstituted or substituted with
one to three groups independently selected from R.sup.3 and oxo;
and wherein any methylene (CH.sub.2) in R.sup.5 is unsubstituted or
substituted with one to two groups independently selected from
halogen, hydroxy, and C.sub.1-4 alkyl; or two R.sup.5 groups
together with the atom to which they are attached form a 5- to
8-membered mono- or bicyclic ring system optionally containing an
additional heteroatom selected from O, S, and NC.sub.1-4 alkyl; and
X is selected from the group consisting of C.sub.1-8 alkyl,
(CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-naphthyl, (CH.sub.2).sub.n-heteroaryl,
(CH.sub.2).sub.nheterocyclyl, (CH.sub.2).sub.nC.ident.N,
(CH.sub.2).sub.nCON(R.sup.5R.sup.5),
(CH.sub.2).sub.nCO.sub.2R.sup.5, (CH.sub.2).sub.nCOR.sup.5,
(CH.sub.2).sub.nNR.sup.5C(O)R.sup.5,
(CH.sub.2).sub.nNR.sup.5CO.sub.2R.sup.5,
(CH.sub.2).sub.nNR.sup.5C(O)N(R.- sup.5).sub.2,
(CH.sub.2).sub.nNR.sup.5SO.sub.2R.sup.5,
(CH.sub.2).sub.nS(O).sub.pR.sup.5,
(CH.sub.2).sub.nSO.sub.2N(R.sup.5)(R.s- up.5),
(CH.sub.2).sub.nOR.sup.5, (CH.sub.2).sub.nOC(O)R.sup.5,
(CH.sub.2).sub.nOC(O)OR.sup.5,
(CH.sub.2).sub.nOC(O)N(R.sup.5).sub.2,
(CH.sub.2).sub.nN(R.sup.5)(R.sup.5), and (CH.sub.2).sub.nNR.sup.5
SO.sub.2N(R.sup.5)(R.sup.5); wherein heteroaryl is as defined
above; phenyl, naphthyl, and heteroaryl are unsubstituted or
substituted with one to three groups independently selected from
R.sup.3; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or
substituted with one to three groups independently selected from
R.sup.3 and oxo; and wherein any methylene (CH.sub.2) in X is
unsubstituted or substituted with one to two groups independently
selected from halogen, hydroxy, and C.sub.1-4 alkyl;
2. The compound of claim 1 wherein R.sup.1 is selected from the
group consisting of hydrogen, C.sub.1-6 alkyl,
(CH.sub.2).sub.0-1C.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.0-1-phenyl; wherein phenyl is unsubstituted or
substituted with one to three groups independently selected from
R.sup.3; and alkyl and cycloalkyl are optionally substituted with
one to three groups independently selected from R.sup.3 and
oxo.
3. The compound of claim 1 wherein R.sup.2 is phenyl or thienyl
optionally substituted with one to three groups independently
selected from R.sup.3.
4. The compound of claim 3 wherein R.sup.2 is phenyl optionally
substituted with one to three groups independently selected from
R.sup.3.
5. The compound of claim 1 wherein X is selected from the group
consisting of (CH.sub.2).sub.n-phenyl, (CH.sub.2).sub.n-naphthyl,
(CH.sub.2).sub.n-heteroaryl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl,
and (CH.sub.2).sub.n-heterocyclyl; wherein phenyl, naphthyl, and
heteroaryl are optionally substituted with one to three groups
independently selected from R.sup.3; cycloalkyl and heterocyclyl
are optionally substituted with one to three groups independently
selected from R.sup.3 and oxo; and wherein any methylene (CH.sub.2)
group in X is unsubstituted or substituted with one to two groups
independently selected from halogen, hydroxy, and C.sub.1-4
alkyl.
6. The compound of claim 5 wherein X is selected from the group
consisting of (CH.sub.2).sub.0-1-phenyl,
(CH.sub.2).sub.0-1-heteroaryl, and (CH.sub.2).sub.0-1-heterocyclyl;
wherein phenyl and heteroaryl are optionally substituted with one
to three groups independently selected from R.sup.3; heterocyclyl
are optionally substituted with one to three groups independently
selected from R.sup.3 and oxo; and CH.sub.2 is unsubstituted or
substituted with one to two groups independently selected from
halogen, hydroxy, and C.sub.1-4 alkyl.
7. The compound of claim 6 wherein X is phenyl optionally
substituted with one to three groups independently selected from
R.sup.3.
8. The compound of claim 1 wherein r is 1 or 2 and s is 1.
9. The compound of claim 1 of structural formula IIa or IIb of the
indicated trans relative stereochemical configuration: 215or a
pharmaceutically acceptable salt thereof; wherein r is 1 or 2; n is
0, 1, or 2; p is 0, 1, or 2; R.sup.1 is hydrogen, amidino,
C.sub.1-4 alkyliminoyl, C.sub.1-6 alkyl, C.sub.5-6 cycloalkyl,
(CH.sub.2).sub.0-1 phenyl, or (CH.sub.2).sub.0-1 heteroaryl;
wherein phenyl and heteroaryl are unsubstituted or substituted with
one to three groups independently selected from R.sup.3; and alkyl
and cycloalkyl are unsubstituted or substituted with one to three
groups independently selected from R.sup.3 and oxo; R.sup.2 is
phenyl or thienyl optionally substituted with one to three groups
independently selected from R.sup.3; each R.sup.3 is independently
selected from the group consisting of C.sub.1-6 alkyl,
(CH.sub.2).sub.n-heteroaryl, (CH.sub.2).sub.n-heterocyclyl,
halogen, OR.sup.4, (CH.sub.2).sub.nN(R.sup.4).sub.2,
(CH.sub.2).sub.nC.ident.N (CH.sub.2).sub.nCO.sub.2R.sup.4,
(CH.sub.2).sub.nNR.sup.4SO.sub.2R.sup.4
(CH.sub.2).sub.nSO.sub.2N(R.sup.4).sub.2,
(CH.sub.2).sub.nS(O).sub.pR.sup- .4,
(CH.sub.2).sub.nNR.sup.4C(O)N(R.sup.4).sub.2,
(CH.sub.2).sub.nC(O)N(R.- sup.4).sub.2,
(CH.sub.2).sub.nNR.sup.4C(O)R.sup.4, (CH.sub.2).sub.nNR.sup.-
4CO.sub.2R.sup.4, (CH.sub.2).sub.nNR.sup.4C(O)-heteroaryl,
(CH.sub.2).sub.nC(O)NR.sup.4N(R.sup.4).sub.2,
(CH.sub.2).sub.nC(O)NR.sup.- 4NR.sup.4C(O)R.sup.4,
O(CH.sub.2).sub.nC(O)N(R.sup.4).sub.2, CF.sub.3, CH.sub.2CF.sub.3,
OCF.sub.3, and OCH.sub.2CF.sub.3; in which phenyl, naphthyl,
heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or
substituted with one to three substituents independently selected
from halogen, hydroxy, oxo, C.sub.1-4 alkyl, trifluoromethyl, and
C.sub.1-4 alkoxy; and wherein any methylene (CH.sub.2) carbon atom
in R.sup.3 is unsubstituted or substituted with one to two groups
independently selected from halogen, hydroxy, and C.sub.1-4 alkyl;
or two substituents when on the same methylene (CH.sub.2) group are
taken together with the carbon atom to which they are attached to
form a cyclopropyl group; each R.sup.4 is independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, phenyl,
heteroaryl, (CH.sub.2).sub.0-1 heterocyclyl, and C.sub.3-6
cycloalkyl; wherein alkyl, phenyl, hetroaryl, heterocyclyl, and
cycloalkyl are unsubstituted or substituted with one to three
groups independently selected from halogen, C.sub.1-4 alkyl,
hydroxy, and C.sub.1-4 alkoxy; or two R.sup.4 groups together with
the atom to which they are attached form a 4- to 8-membered mono-
or bicyclic ring system optionally containing an additional
heteroatom selected from O, S, and NC.sub.1-4alkyl; and X is phenyl
or heteroaryl each of which is optionally substituted with one to
three groups independently selected from R.sup.3.
10. The compound of claim 1 of structural formula IIIa or IIIb of
the indicated trans relative stereochemical configuration: 216or a
pharmaceutically acceptable salt thereof; wherein r is 1 or 2;
R.sup.1 is hydrogen, C.sub.1-4 alkyl, or (CH.sub.2).sub.0-1 phenyl;
each R.sup.3 is independently selected from the group consisting of
C.sub.1-6 alkyl, (CH.sub.2).sub.0-1-heteroaryl,
(CH.sub.2).sub.0-1-heterocyclyl, halogen, OR.sup.4,
(CH.sub.2).sub.0-1N(R.sup.4).sub.2, (CH.sub.2).sub.0-1C.ident.N- ,
(CH.sub.2).sub.0-1CO.sub.2R.sup.4,
(CH.sub.2).sub.0-1NR.sup.4SO.sub.2R.s- up.4
(CH.sub.2).sub.0-1SO.sub.2N(R.sup.4).sub.2,
(CH.sub.2).sub.0-1S(O).su- b.pR.sup.4,
(CH.sub.2).sub.0-1NR.sup.4C(O)N(R.sup.4).sub.2,
(CH.sub.2).sub.0-1C(O)N(R.sup.4).sub.2,
(CH.sub.2).sub.0-1NR.sup.4C(O)R.s- up.4,
(CH.sub.2).sub.0-1NR.sup.4CO.sub.2R.sup.4,
(CH.sub.2).sub.0-1NR.sup.- 4C(O)-heteroaryl,
(CH.sub.2).sub.0-1C(O)NR.sup.4N(R.sup.4).sub.2,
(CH.sub.2).sub.0-1C(O)NR.sup.4NR.sup.4C(O)R.sup.4,
O(CH.sub.2).sub.0-1C(O)N(R.sup.4).sub.2, CF.sub.3,
CH.sub.2CF.sub.3, OCF.sub.3, and OCH.sub.2CF.sub.3; in which
phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are
unsubstituted or substituted with one to three substituents
independently selected from halogen, hydroxy, oxo, C.sub.1-4 alkyl,
trifluoromethyl, and C.sub.1-4 alkoxy; and wherein any methylene
(CH.sub.2) carbon atom in R.sup.3 is unsubstituted or substituted
with one to two groups independently selected from halogen,
hydroxy, and C.sub.1-4 alkyl; or two substituents when on the same
methylene (CH.sub.2) group are taken together with the carbon atom
to which they are attached to form a cyclopropyl group; and each
R.sup.4 is independently selected from the group consisting of
hydrogen, C.sub.1-8 alkyl, phenyl, heteroaryl, (CH.sub.2).sub.0-1
heterocyclyl, and C.sub.3-6 cycloalkyl; wherein alkyl, phenyl,
heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or
substituted with one to three groups independently selected from
halogen, C.sub.1-4 alkyl, hydroxy, and C.sub.1-4 alkoxy; or two
R.sup.4 groups together with the atom to which they are attached
form a 4- to 8-membered mono- or bicyclic ring system optionally
containing an additional heteroatom selected from O, S, and
NC.sub.1-4 alkyl.
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. A method for the treatment or prevention of disorders, diseases
or conditions responsive to the activation of the melanocortin-4
receptor in a mammal in need thereof which comprises administering
to the mammal a therapeutically or prophylactically effective
amount of a compound according to claim 1.
17. A method for the treatment of obesity in a mammal in need
thereof which comprises administering to the mammal a
therapeutically or prophylactically effective amount of a compound
according to claim 1.
18. A method for the treatment or prevention of diabetes mellitus
in a mammal in need thereof comprising administering to the mammal
a therapeutically or prophylactically effective amount of a
compound according to claim 1.
19. A method for the treatment or prevention of male or female
sexual dysfunction in a mammal in need thereof comprising
administering to the mammal a therapeutically or prophylactically
effective amount of a compound according to claim 1.
20. A method for the treatment or prevention of erectile
dysfunction in a mammal in need thereof comprising administering to
the mammal a therapeutically or prophylactically effective amount
of a compound according to claim 1.
21. A pharmaceutical composition which comprises a compound of
claim 1 and a pharmaceutically acceptable carrier.
22. The pharmaceutical composition of claim 21 further comprising a
second active ingredient selected from the group consisting of an
insulin sensitizer, an insulin mimetic, a sulfonylurea, an
.alpha.-glucosidase inhibitor, an HMG-CoA reductase inhibitor, an
anti-obesity serotonergic agent, a .beta.3 adrenoreceptor agonist,
a neuropeptide Y1 or Y5 antagonist, a pancreatic lipase inhibitor,
a melanin-concentrating hormone receptor antagonist, and a
cannabinoid CB.sub.1 receptor antagonist or inverse agonist.
23. The pharmaceutical composition of claim 21 further comprising a
second active ingredient selected from the group consisting of a
type V cyclic-GMP-selective phosphodiesterase inhibitor, an
.alpha..sub.2-adrenergic receptor antagonist, and a dopaminergic
agent.
24. A method of treating erectile dysfunction in a mammal in need
thereof comprising administering to the mammal a therapeutically
effective amount of the composition of claim 23.
25. A method of treating erectile dysfunction in a mammal in need
thereof comprising administering to the mammal a therapeutically
effective amount of a compound of claim 1 in combination with a
type V cyclic-GMP-selective phosphodiesterase inhibitor, an
.alpha..sub.2-adrenergic receptor antagonist, or a dopaminergic
agent.
26. A method of treating diabetes or obesity in a mammal in need
thereof comprising administering to the mammal a therapeutically
effective amount of a compound of claim 1 in combination with an
insulin sensitizer, an insulin mimetic, a sulfonylurea, an
.alpha.-glucosidase inhibitor, an HMG-CoA reductase inhibitor, an
anti-obesity serotonergic agent, a .beta.3 adrenoreceptor agonist,
a neuropeptide Y1 or Y5 antagonist, a pancreatic lipase inhibitor,
a melanin-concentrating hormone receptor antagonist, or a
cannabinoid CB.sub.1 receptor antagonist or inverse agonist.
27. A method of treating obesity in a mammal in need thereof
comprising administering to the mammal a therapeutically effective
amount of the composition of claim 22.
28. The compound of claim 1 wherein the pharmaceutically acceptable
salt thereof is the hydrochloride salt.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of PCT/US02/05724, filed
Feb. 25, 2002, and also claims priority to U.S. provisional
applications Ser. Nos. 60/272,258, filed Feb. 28, 2001, and
60/300,118, filed Jun. 22, 2001, both now abandoned, the contents
of all of the foregoing of which are hereby incorporated by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to acylated piperidine
derivatives, their synthesis, and their use as melanocortin
receptor (MC-R) agonists. More particularly, the compounds of the
present invention are selective agonists of the melanocortin-4
receptor (MC-4R) and are thereby useful for the treatment of
disorders responsive to the activation of MC-4R, such as obesity,
diabetes, male sexual dysfunction, and female sexual
dysfunction.
BACKGROUND OF THE INVENTION
[0003] Pro-opiomelanocortin (POMC) derived peptides are known to
affect food intake. Several lines of evidence support the notion
that the G-protein coupled receptors (GPCRs) of the melanocortin
receptor (MC-R) family, several of which are expressed in the
brain, are the targets of POMC derived peptides involved in the
control of food intake and metabolism. A specific single MC-R that
may be targeted for the control of obesity has not yet been
identified, although evidence has been presented that MC-4R
signalling is important in mediating feed behavior (S. Q. Giraudo
et al., "Feeding effects of hypothalamic injection of
melanocortin-4 receptor ligands," Brain Research, 80: 302-306
(1998)).
[0004] Evidence for the involvement of MC-R's in obesity includes:
i) the agouti (A.sup.vy) mouse which ectopically expresses an
antagonist of the MC-IR, MC-3R and -4R is obese, indicating that
blocking the action of these three MC-R's can lead to hyperphagia
and metabolic disorders; ii) MC-4R knockout mice (D. Huszar et al.,
Cell, 88: 131-141 (1997)) recapitulate the phenotype of the agouti
mouse and these mice are obese; iii) the cyclic heptapeptide MT-II
(a non-selective MC-1R, -3R, -4R, and -5R agonist) injected
intracerebroventricularly (ICV) in rodents, reduces food intake in
several animal feeding models (NPY, ob/ob, agouti, fasted) while
ICV injected SHU-9119 (MC-3R and 4R antagonist; MC-1R and -5R
agonist) reverses this effect and can induce hyperphagia; iv)
chronic intraperitoneal treatment of Zucker fatty rats with an
.alpha.-NDP-MSH derivative (HP228) has been reported to activate
MC-1R, -3R, -4R, and -5R and to attenuate food intake and body
weight gain over a 12-week period (I. Corcos et al., "HP228 is a
potent agonist of melanocortin receptor-4 and significantly
attenuates obesity and diabetes in Zucker fatty rats," Society for
Neuroscience Abstracts, 23: 673 (1997)).
[0005] Five distinct MC-R's have thus far been identified, and
these are expressed in different tissues. MC-1R was initially
characterized by dominant gain of function mutations at the
Extension locus, affecting coat color by controlling phaeomelanin
to eumelanin conversion through control of tyrosinase. MC-1R is
mainly expressed in melanocytes. MC-2R is expressed in the adrenal
gland and represents the ACTH receptor. MC-3R is expressed in the
brain, gut, and placenta and may be involved in the control of food
intake and thermogenesis. MC-4R is uniquely expressed in the brain,
and its inactivation was shown to cause obesity (A. Kask, et al.,
"Selective antagonist for the melanocortin-4 receptor (HS014)
increases food intake in free-feeding rats," Biochem. Biophys. Res.
Commun., 245: 90-93 (1998)). MC-5R is expressed in many tissues,
including white fat, placenta and exocrine glands. A low level of
expression is also observed in the brain. MC-5R knockout mice
reveal reduced sebaceous gland lipid production (Chen et al., Cell,
91: 789-798 (1997)).
[0006] Erectile dysfunction denotes the medical condition of
inability to achieve penile erection sufficient for successful
sexual intercourse. The term "impotence" is oftentimes employed to
describe this prevalent condition. Approximately 140 million men
worldwide, and, according to a National Institutes of Health study,
about 30 million American men suffer from impotency or erectile
dysfunction. It has been estimated that the latter number could
rise to 47 million men by the year 2000. Erectile dysfunction can
arise from either organic or psychogenic causes, with about 20% of
such cases being purely psychogenic in origin. Erectile dysfunction
increases from 40% at age 40, to 67% at age 75, with over 75%
occurring in men over the age of 50. In spite of the frequent
occurrence of this condition, only a small number of patients have
received treatment because existing treatment alternatives, such as
injection therapies, penile prosthesis implantation, and vacuum
pumps, have been uniformly disagreeable [for a discussion, see "ABC
of sexual health--erectile dysfunction," Brit. Med. J. 318: 387-390
(1999)]. Only more recently have more viable treatment modalities
become available, in particular orally active agents, such as
sildenafil citrate, marketed by Pfizer under the brand name of
Viagra.RTM.. (See "Emerging pharmacological therapies for erectile
dysfunction," Exp. Opin. Ther. Patents 9: 1689-1696 (1999)).
Sildenafil is a selective inhibitor of type V phosphodiesterase
(PDE-V), a cyclic-GMP-specific phosphodiesterase isozyme [see R. B.
Moreland et al., "Sildenafil: A Novel Inhibitor of
Phosphodiesterase Type 5 in Human Corpus Cavernosum Smooth Muscle
Cells," Life Sci., 62: 309-318 (1998)]. Prior to the introduction
of Viagra on the market, less than 10% of patients suffering from
erectile dysfunction received treatment. Sildenafil is also being
evaluated in the clinic for the treatment of female sexual
dysfunction.
[0007] The regulatory approval of Viagra.RTM. for the oral
treatment of erectile dysfunction has invigorated efforts to
discover even more effective methods to treat erectile dysfunction.
Several additional selective PDE-V inhibitors are in clinical
trials. UK-114542 is a sildenafil backup from Pfizer with
supposedly improved properties. Tadalafil or IC-351 (ICOS Corp.) is
claimed to have greater selectivity for PDE-V over PDE-VI than
sildenafil. Other PDE-V inhibitors include vardenafil from Bayer,
M-54033 and M-54018 from Mochida Pharmaceutical Co., and E-4010
from Eisai Co., Ltd.
[0008] Other pharmacological approaches to the treatment of
erectile dysfunction have been described [see, e.g., "Latest
Findings on the Diagnosis and Treatment of Erectile Dysfunction,"
Drug News & Perspectives, 9: 572-575 (1996); "Oral
Pharmacotherapy in Erectile Dysfunction," Current Opinion in
Urology, 7:349-353 (1997)]. A product under clinical development by
Zonagen is an oral formulation of the alpha-adrenoceptor antagonist
phentolamine mesylate under the brand name of Vasomax.RTM..
Vasomax.RTM. is also being evaluated for the treatment of female
sexual dysfunction.
[0009] Drugs to treat erectile dysfunction act either peripherally
or centrally. They are also classified according to whether they
"initiate" a sexual response or "facilitate" a sexual response to
prior stimulation [for a discussion, see "A Therapeutic Taxonomy of
Treatments for Erectile Dysfunction: An Evolutionary Imperative,"
Int. J. Impotence Res., 9: 115-121 (1997)]. While sildenafil and
phentolamine act peripherally and are considered to be "enhancers"
or "facilitators" of the sexual response to erotic stimulation,
sildenafil appears to be efficacious in both mild organic and
psychogenic erectile dysfunction. Sildenafil has an onset of action
of 30-60 minutes after an oral dose with the effect lasting about 4
hours, whereas phentolamine requires 5-30 minutes for onset with a
duration of 2 hours. Although sildenafil is effective in a majority
of patients, it takes a relatively long time for the compound to
show the desired effects. The faster-acting phentolamine appears to
be less effective and to have a shorter duration of action than
sildenafil. Oral sildenafil is effective in about 70% of men who
take it, whereas an adequate response with phentolamine is observed
in only 35-40% of patients. Both compounds require erotic
stimulation for efficacy. Since sildenafil indirectly increases
blood flow in the systemic circulation by enhancing the smooth
muscle relaxation effects of nitric oxide, it is contraindicated
for patients with unstable heart conditions or cardiovascular
disease, in particular patients taking nitrates, such as
nitroglycerin, to treat angina. Other adverse effects associated
with the clinical use of sildenafil include headache, flushing,
dyspepsia, and "abnormal vision," the latter the result of
inhibition of the type VI phosphodiesterase isozyme (PDE-VI), a
cyclic-GMP-specific phosphodiesterase that is concentrated in the
retina. "Abnormal vision" is defined as a mild and transient
"bluish" tinge to vision, but also an increased sensitivity to
light or blurred vision.
[0010] Synthetic melanocortin receptor agonists (melanotropic
peptides) have been found to initiate erections in men with
psychogenic erectile dysfunction [See H. Wessells et al.,
"Synthetic Melanotropic Peptide Initiates Erections in Men With
Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled
Crossover Study," J. Urol., 160: 389-393 (1998); Fifteenth American
Peptide Symposium, Jun. 14-19, 1997 (Nashville Tenn.)]. Activation
of melanocortin receptors of the brain appears to cause normal
stimulation of sexual arousal. In the above study, the centrally
acting .alpha.-melanocyte-stimulating hormone analog, melanotan-II
(MT-II), exhibited a 75% response rate, similar to results obtained
with apomorphine, when injected intramuscularly or subcutaneously
to males with psychogenic erectile dysfunction. MT-II is a
synthetic cyclic heptapeptide,
Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH.sub.- 2, which contains the
4-10 melanocortin receptor binding region common to .alpha.-MSH and
adrenocorticotropin, but with a lactam bridge. It is a
non-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., Life
Sciences, Vol. 58, 1777-1784, 1996). MT-II (also referred to as
PT-14) (Erectide.RTM.) is presently in clinical development by
Palatin Technologies, Inc. and TheraTech, Inc. as a non-penile
subcutaneous injection formulation. It is considered to be an
"initiator" of the sexual response. The time to onset of erection
with this drug is relatively short (10-20 minutes) with a duration
of action approximately 2.5 hours. Adverse reactions observed with
MT-II include nausea, flushing, loss of appetite, stretching, and
yawning and may be the result of activation of MC-1R, MC-2R, MC-3R,
and/or MC-5R. MT-II must be administered parenterally, such as by
subcutaneous, intravenous, or intramuscular route, since it is not
absorbed into the systemic circulation when given by the oral
route.
[0011] MT-II's erectogenic properties apparently are not limited to
cases of psychogenic erectile dysfunction in that men with a
variety of organic risk factors developed penile erections upon
subcutaneous injection of the compound; moreover, the level of
sexual desire was significantly higher after MT-II administration
than after placebo [see H. Wessells, "Effect of an Alpha-Melanocyte
Stimulating Hormone Analog on Penile Erection and Sexual Desire in
Men with Organic Erectile Dysfunction," Urology, 56: 641-646
(2000)].
[0012] Compositions of melanotropic peptides and methods for the
treatment of psychogenic erectile dysfunction are disclosed in U.S.
Pat. No. 5,576,290, assigned to Competitive Technologies. Methods
of stimulating sexual response in females using melanotropic
peptides have been disclosed in U.S. Pat. No. 6,051,555.
[0013] Spiropiperidine and piperidine derivatives have been
disclosed in WO 99/64002 (16 Dec. 1999); WO 00/74679 (14 Dec.
2000); WO 01/70708 (27 Sep. 2001); WO 01/70337 (27 Sep. 2001); and
WO 01/91752 (6 Dec. 2001) as agonists of the melanocortin
receptor(s) and particularly as selective agonists of the MC-4R
receptor and thereby useful for the treatment of diseases and
disorders, such as obesity, diabetes, and sexual dysfunction,
including erectile dysfunction and female sexual dysfunction.
[0014] Because of the unresolved deficiencies of the various
pharmacological agents discussed above, there is a continuing need
in the medical arts for improved methods and compositions to treat
individuals suffering from psychogenic and/or organic sexual
dysfunction. Such methods should have wider applicability, enhanced
convenience and ease of compliance, short onset of action,
reasonably long duration of action, and minimal side effects with
few contraindications, as compared to agents now available.
[0015] It is therefore an object of the present invention to
provide acylated piperidine derivatives which are melanocortin
receptor agonists and thereby useful to treat obesity, diabetes,
male sexual dysfunction, and female sexual dysfunction.
[0016] It is another object of the present invention to provide
acylated piperidine derivatives which are selective agonists of the
melanocortin-4 (MC-4R) receptor.
[0017] It is another object of the present invention to provide
pharmaceutical compositions comprising the melanocortin receptor
agonists of the present invention with a pharmaceutically
acceptable carrier.
[0018] It is another object of the present invention to provide
methods for the treatment or prevention of disorders, diseases, or
conditions responsive to the activation of the melanocortin-4
receptor in a mammal in need thereof by administering the compounds
and pharmaceutical compositions of the present invention.
[0019] It is another object of the present invention to provide
methods for the treatment or prevention of obesity, diabetes
mellitus, male sexual dysfunction, and female sexual dysfunction by
administering the compounds and pharmaceutical compositions of the
present invention to a mammal in need thereof.
[0020] It is another object of the present invention to provide
methods for the treatment of erectile dysfunction by administering
the compounds and pharmaceutical compositions of the present
invention to a mammal in need thereof.
[0021] These and other objects will become readily apparent from
the detailed description that follows.
SUMMARY OF THE INVENTION
[0022] The present invention relates to novel 4-substituted
N-acylated piperidines of structural formula I: 1
[0023] These acylated piperidine derivatives are effective as
melanocortin receptor agonists and are particularly effective as
selective melanocortin-4 receptor (MC-4R) agonists. They are
therefore useful for the treatment and/or prevention of disorders
responsive to the activation of MC-4R, such as obesity, diabetes as
well as male and female sexual dysfunction, in particular, male
erectile dysfunction.
[0024] The present invention also relates to pharmaceutical
compositions comprising the compounds of the present invention and
a pharmaceutically acceptable carrier.
[0025] The present invention also relates to methods for the
treatment or prevention of disorders, diseases, or conditions
responsive to the activation of the melanocortin-4 receptor in a
mammal in need thereof by administering the compounds and
pharmaceutical compositions of the present invention.
[0026] The present invention also relates to methods for the
treatment or prevention of obesity, diabetes mellitus, male sexual
dysfunction, and female sexual dysfunction by administering the
compounds and pharmaceutical compositions of the present
invention.
[0027] The present invention also relates to methods for treating
erectile dysfunction by administering the compounds and
pharmaceutical compositions of the present invention.
[0028] The present invention also relates to methods for treating
erectile dysfunction by administering the compounds of the present
invention in combination with a therapeutically effective amount of
another agent known to be useful to treat the condition.
[0029] The present invention also relates to methods for treating
or preventing obesity by administering the compounds of the present
invention in combination with a therapeutically effective amount of
another agent known to be useful to prevent or treat the
condition.
[0030] The present invention also relates to methods for treating
or preventing diabetes by administering the compounds of the
present invention in combination with a therapeutically effective
amount of another agent known to be useful to prevent or treat the
condition.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present invention relates to 4-substituted N-acylated
piperidine derivatives useful as melanocortin receptor agonists, in
particular, as selective MC-4R agonists. Compounds of the present
invention are described by structural formula I: 2
[0032] or a pharmaceutically acceptable salt thereof;
[0033] wherein
[0034] r is 1 or 2;
[0035] s is 0, 1, or 2;
[0036] n is 0, 1 or 2;
[0037] p is 0, 1, or 2;
[0038] R.sup.1 is selected from the group consisting of
[0039] hydrogen,
[0040] amidino,
[0041] C.sub.1-4 alkyliminoyl,
[0042] C.sub.1-10 alkyl,
[0043] (CH.sub.2).sub.n--C.sub.3-7 cycloalkyl,
[0044] (CH.sub.2).sub.n-phenyl,
[0045] (CH.sub.2).sub.n-naphthyl, and
[0046] (CH.sub.2).sub.n-heteroaryl wherein heteroaryl is selected
from the group consisting of
[0047] (1) pyridinyl,
[0048] (2) furyl,
[0049] (3) thienyl,
[0050] (4) pyrrolyl,
[0051] (5) oxazolyl,
[0052] (6) thiazolyl,
[0053] (7) imidazolyl,
[0054] (8) pyrazolyl,
[0055] (9) isoxazolyl,
[0056] (10) isothiazolyl,
[0057] (11) pyrimidinyl,
[0058] (12) pyrazinyl,
[0059] (13) pyridazinyl,
[0060] (14) quinolyl,
[0061] (15) isoquinolyl,
[0062] (16) benzimidazolyl,
[0063] (17) benzofuryl,
[0064] (18) benzothienyl,
[0065] (19) indolyl,
[0066] (20) benzthiazolyl, and
[0067] (21) benzoxazolyl;
[0068] in which phenyl, naphthyl, and heteroaryl are unsubstituted
or substituted with one to three groups independently selected from
R.sup.3; and alkyl and cycloalkyl are unsubstituted or substituted
with one to three groups independently selected from R.sup.3 and
oxo;
[0069] R.sup.2 is selected from the group consisting of
[0070] phenyl,
[0071] naphthyl, and
[0072] heteroaryl wherein heteroaryl is selected from the group
consisting of
[0073] (1) pyridinyl,
[0074] (2) furyl,
[0075] (3) thienyl,
[0076] (4) pyrrolyl,
[0077] (5) oxazolyl,
[0078] (6) thiazolyl,
[0079] (7) imidazolyl,
[0080] (8) pyrazolyl,
[0081] (9) isoxazolyl,
[0082] (10) isothiazolyl,
[0083] (11) pyrimidinyl,
[0084] (12) pyrazinyl,
[0085] (13) pyridazinyl,
[0086] (14) quinolyl,
[0087] (15) isoquinolyl,
[0088] (16) benzimidazolyl,
[0089] (17) benzofuryl,
[0090] (18) benzothienyl,
[0091] (19) indolyl,
[0092] (20) benzthiazolyl, and
[0093] (21) benzoxazolyl;
[0094] in which phenyl, naphthyl, and heteroaryl are unsubstituted
or substituted with one to three groups independently selected from
R.sup.3;
[0095] each R.sup.3 is independently selected from the group
consisting of
[0096] C.sub.1-6 alkyl,
[0097] (CH.sub.2).sub.n-phenyl,
[0098] (CH.sub.2).sub.n-naphthyl,
[0099] (CH.sub.2).sub.n-heteroaryl,
[0100] (CH.sub.2).sub.n-heterocyclyl,
[0101] (CH.sub.2).sub.nC.sub.3-7 cycloalkyl,
[0102] halogen,
[0103] OR.sup.4,
[0104] (CH.sub.2).sub.nN(R.sup.4).sub.2,
[0105] (CH.sub.2).sub.nC.ident.N,
[0106] (CH.sub.2).sub.nCO.sub.2R.sup.4,
[0107] NO.sub.2,
[0108] (CH.sub.2).sub.nNR.sup.4SO.sub.2R.sup.4
[0109] (CH.sub.2).sub.nSO.sub.2N(R.sup.4).sub.2,
[0110] (CH.sub.2).sub.nS(O).sub.pR.sup.4,
[0111] (CH.sub.2).sub.nNR.sup.4C(O)N(R.sup.4).sub.2,
[0112] (CH.sub.2).sub.nC(O)N(R.sup.4).sub.2,
[0113] (CH.sub.2).sub.nNR.sup.4C(O)R.sup.4,
[0114] (CH.sub.2).sub.nNR.sup.4CO.sub.2R.sup.4,
[0115] (CH.sub.2).sub.nNR.sup.4C(O)-heteroaryl,
[0116] (CH.sub.2).sub.nC(O)NR.sup.4N(R.sup.4).sub.2,
[0117] (CH.sub.2).sub.nC(O)NR.sup.4NR.sup.4C(O)R.sup.4,
[0118] O(CH.sub.2).sub.nC(O)N(R.sup.4).sub.2,
[0119] CF.sub.3,
[0120] CH.sub.2CF.sub.3,
[0121] OCF.sub.3, and
[0122] OCH.sub.2CF.sub.3;
[0123] in which heteroaryl is as defined above; phenyl, naphthyl,
heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or
substituted with one to three substituents independently selected
from halogen, hydroxy, oxo, C.sub.1-4 alkyl, trifluoromethyl, and
C.sub.1-4 alkoxy; and wherein any methylene (CH.sub.2) carbon atom
in R.sup.3 is unsubstituted or substituted with one to two groups
independently selected from halogen, hydroxy, and C.sub.1-4 alkyl;
or two substituents when on the same methylene (CH.sub.2) group are
taken together with the carbon atom to which they are attached to
form a cyclopropyl group;
[0124] each R.sup.4 is independently selected from the group
consisting of
[0125] hydrogen,
[0126] C.sub.1-6 alkyl,
[0127] (CH.sub.2).sub.n-phenyl,
[0128] (CH.sub.2).sub.n-heteroaryl,
[0129] (CH.sub.2).sub.n-naphthyl,
[0130] (CH.sub.2).sub.n-heterocyclyl,
[0131] (CH.sub.2).sub.nC.sub.3-7 cycloalkyl, and
[0132] (CH.sub.2).sub.nC.sub.3-7 bicycloalkyl;
[0133] wherein alkyl, phenyl, heteroaryl, heterocyclyl, and
cycloalkyl are unsubstituted or substituted with one to three
groups independently selected from halogen, C.sub.1-4 alkyl,
hydroxy, and C.sub.1-4 alkoxy; or two R.sup.4 groups together with
the atom to which they are attached form a 4- to 8-membered mono-
or bicyclic ring system optionally containing an additional
heteroatom selected from O, S, and NC.sub.1-4 alkyl;
[0134] each R.sup.5 is independently selected from the group
consisting of
[0135] hydrogen,
[0136] C.sub.1-8 alkyl,
[0137] (CH.sub.2).sub.n-phenyl,
[0138] (CH.sub.2).sub.n-naphthyl,
[0139] (CH.sub.2).sub.n-heteroaryl, and
[0140] (CH.sub.2).sub.nC.sub.3-7 cycloalkyl;
[0141] wherein heteroaryl is as defined above; phenyl, naphthyl,
and heteroaryl are unsubstituted or substituted with one to three
groups independently selected from R.sup.3; alkyl and cycloalkyl
are unsubstituted or substituted with one to three groups
independently selected from R.sup.3 and oxo; and wherein any
methylene (CH.sub.2) in R.sup.5 is unsubstituted or substituted
with one to two groups independently selected from halogen,
hydroxy, and C.sub.1-4 alkyl; or two R.sup.5 groups together with
the atom to which they are attached form a 5- to 8-membered mono-
or bicyclic ring system optionally containing an additional
heteroatom selected from O, S, and NC.sub.1-4 alkyl;
[0142] X is selected from the group consisting of
[0143] C.sub.1-8 alkyl,
[0144] (CH.sub.2).sub.nC.sub.3-8 cycloalkyl,
[0145] (CH.sub.2).sub.n-phenyl,
[0146] (CH.sub.2).sub.n-naphthyl,
[0147] (CH.sub.2).sub.n-heteroaryl,
[0148] (CH.sub.2).sub.nheterocyclyl,
[0149] (CH.sub.2).sub.nC.ident.N,
[0150] (CH.sub.2).sub.nCON(R.sup.5R.sup.5),
[0151] (CH.sub.2).sub.nCO.sub.2R.sup.5,
[0152] (CH.sub.2).sub.nCOR.sup.5,
[0153] (CH.sub.2).sub.nNR.sup.5C(O)R.sup.5,
[0154] (CH.sub.2).sub.nNR.sup.5CO.sub.2R.sup.5,
[0155] (CH.sub.2).sub.nNR.sup.5C(O)N(R.sup.5).sub.2,
[0156] (CH.sub.2).sub.nNR.sup.5SO.sub.2R.sup.5,
[0157] (CH.sub.2).sub.nS(O).sub.pR.sup.5,
[0158] (CH.sub.2).sub.nSO.sub.2N(R.sup.5)(R.sup.5),
[0159] (CH.sub.2).sub.nOR.sup.5,
[0160] (CH.sub.2).sub.nOC(O)R.sup.5,
[0161] (CH.sub.2).sub.nOC(O)OR.sup.5,
[0162] (CH.sub.2).sub.nOC(O)N(R.sup.5).sub.2,
[0163] (CH.sub.2).sub.nN(R.sup.5)(R.sup.5), and
[0164] (CH.sub.2).sub.nNR.sup.5SO.sub.2N(R.sup.5)(R.sup.5);
[0165] wherein heteroaryl is as defined above; phenyl, naphthyl,
and heteroaryl are unsubstituted or substituted with one to three
groups independently selected from R.sup.3; alkyl, cycloalkyl, and
heterocyclyl are unsubstituted or substituted with one to three
groups independently selected from R.sup.3 and oxo; and wherein any
methylene (CH.sub.2) in X is unsubstituted or substituted with one
to two groups independently selected from halogen, hydroxy, and
C.sub.1-4 alkyl; and
[0166] Y is selected from the group consisting of
[0167] hydrogen,
[0168] C.sub.1-8 alkyl,
[0169] C.sub.2-6 alkenyl,
[0170] (CH.sub.2).sub.nC.sub.3-8 cycloalkyl,
[0171] (CH.sub.2).sub.n-phenyl,
[0172] (CH.sub.2).sub.n-naphthyl,
[0173] (CH.sub.2).sub.n-heteroaryl, and
[0174] (CH.sub.2).sub.n-heterocyclyl;
[0175] wherein heteroaryl is as defined above, and phenyl,
naphthyl, and heteroaryl are unsubstituted or substituted with one
to three groups independently selected from R.sup.3; alkyl,
cycloalkyl, and heterocyclyl are optionally substituted with one to
three groups independently selected from R.sup.3 and oxo; and
wherein any methylene (CH.sub.2) in Y is unsubstituted or
substituted with one to two groups independently selected from
halogen, hydroxy, and C.sub.1-4 alkyl.
[0176] In one embodiment of the compounds of structural formula I,
R.sup.1 is selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, (CH.sub.2).sub.0-1C.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.0-1-phenyl; wherein phenyl is unsubstituted or
substituted with one to three groups independently selected from
R.sup.3; and alkyl and cycloalkyl are optionally substituted with
one to three groups independently selected from R.sup.3 and
oxo.
[0177] In a second embodiment of the compounds of structural
formula I, R.sup.2 is phenyl or thienyl optionally substituted with
one to three groups independently selected from R.sup.3. In a class
of this embodiment, R.sup.2 is phenyl optionally substituted with
one to three groups independently selected from R.sup.3.
[0178] In a third embodiment of the compounds of structural formula
I, X is selected from the group consisting of
[0179] (CH.sub.2).sub.n-phenyl,
[0180] (CH.sub.2).sub.n-naphthyl,
[0181] (CH.sub.2).sub.n-heteroaryl,
[0182] (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, and
[0183] (CH.sub.2).sub.n-heterocyclyl;
[0184] wherein heteroaryl is as defined above, and phenyl,
naphthyl, and heteroaryl are optionally substituted with one to
three groups independently selected from R.sup.3; cycloalkyl and
heterocyclyl are optionally substituted with one to three groups
independently selected from R.sup.3 and oxo; and wherein any
methylene (CH.sub.2) group in X is unsubstituted or substituted
with one to two groups independently selected from halogen,
hydroxy, and C.sub.1-4 alkyl. In a class of this embodiment, X is
selected from the group consisting of (CH.sub.2).sub.0-1-phenyl,
(CH.sub.2).sub.0-1-heteroaryl, (CH.sub.2).sub.0-1-heterocyclyl;
wherein phenyl and heteroaryl are optionally substituted with one
to three groups independently selected from R.sup.3; heterocyclyl
is optionally substituted with one to three groups independently
selected from R.sup.3 and oxo; and CH.sub.2 is unsubstituted or
substituted with one to two groups independently selected from
halogen, hydroxy, and C.sub.1-4 alkyl. In a subclass of this class,
X is phenyl optionally substituted with one to three groups
independently selected from R.sup.3.
[0185] In a fourth embodiment of compounds of formula I, Y is
hydrogen.
[0186] In yet a further embodiment of compounds of structural
formula I, r is 1 or 2and s is 1.
[0187] In yet a further embodiment of the compounds of the present
invention, there are provided compounds of structural formula IIa
or IIb of the indicated relative stereochemical configurations
having the trans orientation of the R.sup.2 and piperidinecarbonyl
substituents: 3
[0188] or a pharmaceutically acceptable salt thereof;
[0189] wherein
[0190] r is 1 or 2;
[0191] n is 0, 1, or 2;
[0192] p is 0, 1, or 2;
[0193] R.sup.1 is hydrogen, amidino, C.sub.1-4 alkyliminoyl,
C.sub.1-6 alkyl, C.sub.5-6 cycloalkyl, (CH.sub.2).sub.0-1 phenyl,
(CH.sub.2).sub.0-1 heteroaryl; wherein phenyl and heteroaryl are
unsubstituted or substituted with one to three groups independently
selected from R.sup.3, and alkyl and cycloalkyl are unsubstituted
or substituted with one to three groups independently selected from
R.sup.3 and oxo;
[0194] R.sup.2 is phenyl or thienyl optionally substituted with one
to three groups independently selected from R.sup.3;
[0195] each R.sup.3 is independently selected from the group
consisting of
[0196] C.sub.1-6 alkyl,
[0197] (CH.sub.2).sub.n-heteroaryl,
[0198] (CH.sub.2).sub.n-heterocyclyl,
[0199] halogen,
[0200] OR.sup.4,
[0201] (CH.sub.2).sub.nN(R.sup.4).sub.2,
[0202] (CH.sub.2).sub.nC.ident.N,
[0203] (CH.sub.2).sub.nCO.sub.2R.sup.4,
[0204] (CH.sub.2).sub.nNR.sup.4SO.sub.2R.sup.4
[0205] (CH.sub.2).sub.nSO.sub.2N(R.sup.4).sub.2,
[0206] (CH.sub.2).sub.nS(O).sub.pR.sup.4,
[0207] (CH.sub.2).sub.nNR.sup.4C(O)N(R.sup.4).sub.2,
[0208] (CH.sub.2).sub.nC(O)N(R.sup.4).sub.2,
[0209] (CH.sub.2).sub.nNR.sup.4C(O)R.sup.4,
[0210] (CH.sub.2).sub.nNR.sup.4CO.sub.2R.sup.4,
[0211] (CH.sub.2).sub.nNR.sup.4C(O)-heteroaryl,
[0212] (CH.sub.2).sub.nC(O)NR.sup.4N(R.sup.4).sub.2,
[0213] (CH.sub.2).sub.nC(O)NR.sup.4NR.sup.4C(O)R.sup.4,
[0214] O(CH.sub.2).sub.nC(O)N(R.sup.4).sub.2,
[0215] CF.sub.3,
[0216] CH.sub.2CF.sub.3,
[0217] OCF.sub.3, and
[0218] OCH.sub.2CF.sub.3;
[0219] in which heteroaryl is as defined above; phenyl, naphthyl,
heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or
substituted with one to three substituents independently selected
from halogen, hydroxy, oxo, C.sub.1-4 alkyl, trifluoromethyl, and
C.sub.1-4 alkoxy; and wherein any methylene (CH.sub.2) group in
R.sup.3 is unsubstituted or substituted with one to two groups
independently selected from halogen, hydroxy, and C.sub.1-4 alkyl;
or two substituents when on the same methylene (CH.sub.2) group are
taken together with the carbon atom to which they are attached to
form a cyclopropyl group;
[0220] each R.sup.4 is independently selected from the group
consisting of
[0221] hydrogen,
[0222] C.sub.1-8 alkyl,
[0223] phenyl,
[0224] heteroaryl,
[0225] (CH.sub.2).sub.0-1 heterocyclyl, and
[0226] C.sub.3-6 cycloalkyl;
[0227] wherein alkyl, phenyl, heteroaryl, heterocyclyl, and
cycloalkyl are unsubstituted or substituted with one to three
groups independently selected from halogen, C.sub.1-4 alkyl,
hydroxy, and C.sub.1-4 alkoxy; or two R.sup.4 groups together with
the atom to which they are attached form a 4- to 8-membered mono-
or bicyclic ring system optionally containing an additional
heteroatom selected from O, S, and NC.sub.1-4 alkyl; and
[0228] X is phenyl or heteroaryl each of which is optionally
substituted with one to three groups independently selected from
R.sup.3.
[0229] In yet a further embodiment of the compounds of the present
invention, there are provided compounds of structural formula IIIa
or IIIb of the indicated relative stereochemical configurations
having the trans orientation of the phenyl and piperidinecarbonyl
substituents: 4
[0230] or a pharmaceutically acceptable salt thereof;
[0231] wherein
[0232] r is 1 or 2;
[0233] R.sup.1 is hydrogen, C.sub.1-4 alkyl, or (CH.sub.2).sub.0-1
phenyl;
[0234] each R.sup.3 is independently selected from the group
consisting of
[0235] C.sub.1-6 alkyl,
[0236] (CH.sub.2).sub.0-1-heteroaryl,
[0237] (CH.sub.2).sub.0-1-heterocyclyl,
[0238] halogen,
[0239] OR.sup.4,
[0240] (CH.sub.2).sub.0-1N(R.sup.4).sub.2,
[0241] (CH.sub.2).sub.0-1C.ident.N,
[0242] (CH.sub.2).sub.0-1CO.sub.2R.sup.4,
[0243] (CH.sub.2).sub.0-1NR.sup.4SO.sub.2R.sup.4
[0244] (CH.sub.2).sub.0-1SO.sub.2N(R.sup.4).sub.2,
[0245] (CH.sub.2).sub.0-1S(O)R.sup.4,
[0246] (CH.sub.2).sub.0-1NR.sup.4C(O)N(R.sup.4).sub.2,
[0247] (CH.sub.2).sub.0-1C(O)N(R.sup.4).sub.2,
[0248] (CH.sub.2).sub.0-1NR.sup.4C(O)R.sup.4,
[0249] (CH.sub.2).sub.0-1NR.sup.4CO.sub.2R.sup.4,
[0250] (CH.sub.2).sub.0-1NR.sup.4C(O)-heteroaryl,
[0251] (CH.sub.2).sub.0-1C(O)NR.sup.4N(.sup.4).sub.2,
[0252] (CH.sub.2).sub.0-1C(O)NR.sup.4NR.sup.4C(R)R.sup.4,
[0253] O(CH.sub.2).sub.0-1C(O)N(R.sup.4).sub.2,
[0254] CF.sub.3,
[0255] CH.sub.2CF.sub.3,
[0256] OCF.sub.3, and
[0257] OCH.sub.2CF.sub.3;
[0258] in which phenyl, naphthyl, heteroaryl, cycloalkyl, and
heterocyclyl are unsubstituted or substituted with one to two
substituents independently selected from halogen, hydroxy, oxo,
C.sub.1-4 alkyl, trifluoromethyl, and C.sub.1-4 alkoxy; and wherein
any methylene (CH.sub.2) group in R.sup.3 is unsubstituted or
substituted with one to two groups independently selected from
halogen, hydroxy, and C.sub.1-4 alkyl; or two substituents when on
the same methylene (CH.sub.2) group are taken together with the
carbon atom to which they are attached to form a cyclopropyl group;
and
[0259] each R.sup.4 is independently selected from the group
consisting of
[0260] hydrogen,
[0261] C.sub.1-8 alkyl,
[0262] phenyl,
[0263] heteroaryl,
[0264] (CH.sub.2).sub.0-1 heterocyclyl, and
[0265] C.sub.3-6 cycloalkyl;
[0266] wherein alkyl, phenyl, heteroaryl, heterocyclyl, and
cycloalkyl are unsubstituted or substituted with one to three
groups independently selected from halogen, C.sub.1-4 alkyl,
hydroxy, and C.sub.1-4 alkoxy; or two R.sup.4 groups together with
the atom to which they are attached form a 4- to 8-membered mono-
or bicyclic ring system optionally containing an additional
heteroatom selected from O, S, and NC.sub.1-4 alkyl.
[0267] Illustrative but nonlimiting examples of compounds of the
present invention that are useful as melanocortin-4 receptor
agonists are the following: 5678910
[0268] or a pharmaceutically acceptable salt thereof.
[0269] Further illustrative of the present invention are the
compounds selected from the group consisting of: 1112
[0270] or a pharmaceutically acceptable salt thereof.
[0271] The compounds of structural formula I are effective as
melanocortin receptor agonists and are particularly effective as
selective agonists of MC-4R. They are therefore useful for the
treatment and/or prevention of disorders responsive to the
activation of MC-4R, such as obesity, diabetes as well as male
and/or female sexual dysfunction, in particular, erectile
dysfunction, and further in particular, male erectile
dysfunction.
[0272] Another aspect of the present invention provides a method
for the treatment or prevention of obesity or diabetes in a mammal
in need thereof which comprises administering to said mammal a
therapeutically or prophylactically effective amount of a compound
of structural formula I.
[0273] Another aspect of the present invention provides a method
for the treatment or prevention of male or female sexual
dysfunction including erectile dysfunction which comprises
administering to a mammal in need of such treatment or prevention a
therapeutically or prophylactically effective amount of a compound
of structural formula I.
[0274] Another aspect of the present invention provides a
pharmaceutical composition comprising a compound of structural
formula I and a pharmaceutically acceptable carrier.
[0275] Yet another aspect of the present invention provides a
method for the treatment or prevention of male or female sexual
dysfunction including erectile dysfunction which comprises
administering to a mammal in need of such treatment or prevention a
therapeutically or prophylactically effective amount of a compound
of structural formula I in combination with a therapeutically
effective amount of another agent known to be useful for the
treatment of these conditions.
[0276] Yet another aspect of the present invention provides a
method for the treatment or prevention of obesity which comprises
administering to a mammal in need of such treatment or prevention a
therapeutically or prophylactically effective amount of a compound
of structural formula I in combination with a therapeutically
effective amount of another agent known to be useful for the
treatment of this condition.
[0277] Throughout the instant application, the following terms have
the indicated meanings:
[0278] The alkyl groups specified above are intended to include
those alkyl groups of the designated length in either a straight or
branched configuration. Exemplary of such alkyl groups are methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl,
isopentyl, hexyl, isohexyl, and the like.
[0279] The term "halogen" is intended to include the halogen atoms
fluorine, chlorine, bromine and iodine.
[0280] The term "C.sub.1-4 alkyliminoyl" means
C.sub.1-3C(.dbd.NH)--.
[0281] The term "aryl" includes phenyl and naphthyl.
[0282] The term "heteroaryl" includes mono- and bicyclic aromatic
rings containing from 1 to 4 heteroatoms selected from nitrogen,
oxygen and sulfur. "5- or 6-Membered heteroaryl" represents a
monocyclic heteroaromatic ring; examples thereof include thiazole,
oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole,
triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine,
pyrimidine, pyrazine, and the like. Bicyclic heteroaromatic rings
include, but are not limited to, benzothiadiazole, indole,
benzothiophene, benzofuran, benzimidazole, benzisoxazole,
benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline,
purine, furopyridine and thienopyridine.
[0283] The term "5- or 6-membered carbocyclyl" is intended to
include non-aromatic rings containing only carbon atoms such as
cyclopentyl and cyclohexyl.
[0284] The term "5 and 6-membered heterocyclyl" is intended to
include non-aromatic heterocycles containing one to four
heteroatoms selected from nitrogen, oxygen and sulfur. Examples of
a 5 or 6-membered heterocyclyl include piperidine, morpholine,
thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran,
piperazine, and the like.
[0285] Certain of the above defined terms may occur more than once
in the above formula and upon such occurrence each term shall be
defined independently of the other; thus for example,
NR.sup.4R.sup.4 may represent NH.sub.2, NHCH.sub.3,
N(CH.sub.3)CH.sub.2CH.sub.3, and the like.
[0286] An embodiment of the term "mammal in need thereof" is a
"human in need thereof," said human being either male or
female.
[0287] The term "composition", as in pharmaceutical composition, is
intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0288] "Erectile dysfunction" is a disorder involving the failure
of a male mammal to achieve erection, ejaculation, or both.
Symptoms of erectile dysfunction include an inability to achieve or
maintain an erection, ejaculatory failure, premature ejaculation,
or inability to achieve an orgasm. An increase in erectile
dysfunction is often associated with age and is generally caused by
a physical disease or as a side-effect of drug treatment.
[0289] By a melanocortin receptor "agonist" is meant an endogenous
or drug substance or compound that can interact with a melanocortin
receptor and initiate a pharmacological response characteristic of
the melanocortin receptor. By a melanocortin receptor "antagonist"
is meant a drug or a compound that opposes the melanocortin
receptor-associated responses normally induced by another bioactive
agent. The "agonistic" properties of the compounds of the present
invention were measured in the functional assay described below.
The functional assay discriminates a melanocortin receptor agonist
from a melanocortin receptor antagonist.
[0290] By "binding affinity" is meant the ability of a
compound/drug to bind to its biological target, in the the present
instance, the ability of a compound of structural formula I to bind
to a melanocortin receptor. Binding affinities for the compounds of
the present invention were measured in the binding assay described
below and are expressed as IC.sub.50's.
[0291] "Efficacy" describes the relative intensity with which
agonists vary in the response they produce even when they occupy
the same number of receptors and with the same affinity. Efficacy
is the property that enables drugs to produce responses. Properties
of compounds/drugs can be categorized into two groups, those which
cause them to associate with the receptors (binding affinity) and
those that produce a stimulus (efficacy). The term "efficacy" is
used to characterize the level of maximal responses induced by
agonists. Not all agonists of a receptor are capable of inducing
identical levels of maximal responses. Maximal response depends on
the efficiency of receptor coupling, that is, from the cascade of
events, which, from the binding of the drug to the receptor, leads
to the desired biological effect.
[0292] The functional activities expressed as EC.sub.50's and the
"agonist efficacy" for the compounds of the present invention at a
particular concentration were measured in the functional assay
described below.
[0293] Optical Isomers--Diastereomers--Geometric
Isomers--Tautomers
[0294] Compounds of structural formula I contain one or more
asymmetric centers and can thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. The present invention is meant to
comprehend all such isomeric forms of the compounds of structural
formula I.
[0295] Some of the compounds described herein contain olefinic
double bonds, and unless specified otherwise, are meant to include
both E and Z geometric isomers.
[0296] Some of the compounds described herein may exist as
tautomers such as keto-enol tautomers. The individual tautomers as
well as mixtures thereof are encompassed within the compounds of
structural formula I.
[0297] Compounds of structural formula I may be separated into
their individual diastereoisomers by, for example, fractional
crystallization from a suitable solvent, for example methanol or
ethyl acetate or a mixture thereof, or via chiral chromatography
using an optically active stationary phase. Absolute
stereochemistry may be determined by X-ray crystallography of
crystalline products or crystalline intermediates which are
denivatized, if necessary, with a reagent containing an asymmetric
center of known absolute configuration.
[0298] Alternatively, any stereoisomer of a compound of the general
formula I, IIa, IIb, IIIa, and IIIb may be obtained by
stereospecific synthesis using optically pure starting materials or
reagents of known absolute configuration.
[0299] Salts
[0300] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids. Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic salts, manganous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, lithium,
magnesium, potassium, and sodium salts. Salts derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines,
and basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine, and the like.
[0301] When the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,
isethionic, lactic, maleic, malic, mandelic, methanesulfonic,
malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic,
succinic, sulfuric, tartaric, p-toluenesulfonic acid,
trifluoroacetic acid, and the like. Particularly preferred are
citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric,
sulfuric, and tartaric acids.
[0302] It will be understood that, as used herein, references to
the compounds of Formula I are meant to also include the
pharmaceutically acceptable salts, such as the hydrochloride
salts.
[0303] Utility
[0304] Compounds of formula I are melanocortin receptor agonists
and as such are useful in the treatment, control or prevention of
diseases, disorders or conditions responsive to the activation of
one or more of the melanocortin receptors including, but are not
limited to, MC-1, MC-2, MC-3, MC-4, or MC-5. Such diseases,
disorders or conditions include, but are not limited to, obesity
(by reducing appetite, increasing metabolic rate, reducing fat
intake or reducing carbohydrate craving), diabetes mellitus (by
enhancing glucose tolerance, decreasing insulin resistance),
hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder
disease, sleep apnea, depression, anxiety, compulsion, neuroses,
insomnia/sleep disorder, substance abuse, pain, male and female
sexual dysfunction (including impotence, loss of libido and
erectile dysfunction), fever, inflammation, immunemodulation,
rheumatoid arthritis, skin tanning, acne and other skin disorders,
neuroprotective and cognitive and memory enhancement including the
treatment of Alzheimer's disease. Some compounds encompassed by
formula I show highly selective affinity for the melanocortin-4
receptor (MC-4R) relative to MC-1R, MC-2R, MC-3R, and MC-5R, which
makes them especially useful in the prevention and treatment of
obesity, as well as male and/or female sexual dysfunction,
including erectile dysfunction.
[0305] "Male sexual dysfunction" includes impotence, loss of
libido, and erectile dysfunction.
[0306] "Erectile dysfunction" is a disorder involving the failure
of a male mammal to achieve erection, ejaculation, or both.
Symptoms of erectile dysfunction include an inability to achieve or
maintain an erection, ejaculatory failure, premature ejaculation,
or inability to achieve an orgasm. An increase in erectile
dysfunction and sexual dysfunction can have numerous underlying
causes, including but not limited to (1) aging, (b) an underlying
physical dysfunction, such as trauma, surgery, and peripheral
vascular disease, and (3) side-effects resulting from drug
treatment, depression, and other CNS disorders.
[0307] "Female sexual dysfunction" can be seen as resulting from
multiple components including dysfunction in desire, sexual
arousal, sexual receptivity, and orgasm related to disturbances in
the clitoris, vagina, periurethral glans, and other trigger points
of sexual function. In particular, anatomic and functional
modification of such trigger points may diminish the orgasmic
potential in breast cancer and gynecologic cancer patients.
Treatment of female sexual dysfunction with an MC-4 receptor
agonist can result in improved blood flow, improved lubrication,
improved sensation, facilitation of reaching orgasm, reduction in
the refractory period between orgasms, and improvements in arousal
and desire. In a broader sense, "female sexual dysfunction" also
incorporates sexual pain, premature labor, and dysmenorrhea.
[0308] Administration and Dose Ranges
[0309] Any suitable route of administration may be employed for
providing a mammal, especially a human with an effective dosage of
a compound of the present invention. For example, oral, rectal,
topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, creams, ointments, aerosols, and
the like. Preferably compounds of Formula I are administered orally
or topically.
[0310] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated. Such dosage may be ascertained readily by
a person skilled in the art.
[0311] When treating obesity, in conjunction with diabetes and/or
hyperglycemia, or alone, generally satisfactory results are
obtained when the compounds of the present invention are
administered at a daily dosage of from about 0.001 milligram to
about 100 milligrams per kilogram of animal body weight, preferably
given in a single dose or in divided doses two to six times a day,
or in sustained release form. In the case of a 70 kg adult human,
the total daily dose will generally be from about 0.07 milligrams
to about 3500 milligrams. This dosage regimen may be adjusted to
provide the optimal therapeutic response.
[0312] When treating diabetes mellitus and/or hyperglycemia, as
well as other diseases or disorders for which compounds of formula
I are useful, generally satisfactory results are obtained when the
compounds of the present invention are administered at a daily
dosage of from about 0.001 milligram to about 100 milligram per
kilogram of animal body weight, preferably given in a single dose
or in divided doses two to six times a day, or in sustained release
form. In the case of a 70 kg adult human, the total daily dose will
generally be from about 0.07 milligrams to about 350 milligrams.
This dosage regimen may be adjusted to provide the optimal
therapeutic response.
[0313] For the treatment of sexual dysfunction compounds of the
present invention are given in a dose range of 0.001 milligram to
about 100 milligram per kilogram of body weight, preferably as a
single dose orally or as a nasal spray.
[0314] Combination Therapy
[0315] Compounds of Formula I may be used in combination with other
drugs that are used in the treatment/prevention/suppression or
amelioration of the diseases or conditions for which compounds of
Formula I are useful. Such other drugs may be administered, by a
route and in an amount commonly used therefor, contemporaneously or
sequentially with a compound of Formula I. When a compound of
Formula I is used contemporaneously with one or more other drugs, a
pharmaceutical composition containing such other drugs in addition
to the compound of Formula I is preferred. Accordingly, the
pharmaceutical compositions of the present invention include those
that also contain one or more other active ingredients, in addition
to a compound of Formula I.
[0316] Examples of other active ingredients that may be combined
with a compound of Formula I for the treatment or prevention of
obesity and/or diabetes, either administered separately or in the
same pharmaceutical compositions, include, but are not limited
to:
[0317] (a) insulin sensitizers including (i) PPAR.gamma. agonists
such as the glitazones (e.g. troglitazone, pioglitazone,
englitazone, MCC-555, BRL49653 and the like), and compounds
disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847; (ii)
biguanides such as metformin and phenformin;
[0318] (b) insulin or insulin mimetics;
[0319] (c) sulfonylureas, such as tolbutamide and glipizide;
[0320] (d) .alpha.-glucosidase inhibitors (such as acarbose),
[0321] (e) cholesterol lowering agents such as (i) HMG-CoA
reductase inhibitors (lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, and other statins), (ii) sequestrants
(cholestyramine, colestipol and a dialkylaminoalkyl derivatives of
a cross-linked dextran), (ii) nicotinyl alcohol nicotinic acid or a
salt thereof, (iii) proliferator-activater receptor .alpha.
agonists such as fenofibric acid derivatives (gemfibrozil,
clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of
cholesterol absorption for example beta-sitosterol and (acyl
CoA:cholesterol acyltransferase) inhibitors for example melinamide,
(v) probucol, (vi) vitamin E, and (vii) thyromimetics;
[0322] (f) PPAR.delta. agonists, such as those disclosed in
WO97/28149;
[0323] (g) anti-obesity serotonergic agents, such as fenfluramine,
dexfenfluramine, phentermine, and sibutramine;
[0324] (h) .beta.3-adrenoreceptor agonists;
[0325] (i) pancreatic lipase inhibitors, such as orlistat;
[0326] (j) feeding behavior modifying agents, such as neuropeptide
Y1 and Y5 antagonists, such as those disclosed in WO 97/19682, WO
97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 01/14376, and
U.S. Pat. No. 6,191,160; melanin-concentrating hormone (MCH)
receptor antagonists, such as those disclosed in WO 01/21577 and WO
01/21169; and orexin-1 receptor antagonists;
[0327] (k) PPAR.alpha. agonists such as described in WO 97/36579 by
Glaxo;
[0328] (l) PPAR.gamma. antagonists as described in WO97/10813;
[0329] (m) serotonin reuptake inhibitors such as fluoxetine,
paroxetine, and sertraline;
[0330] (n) growth hormone secretagogues, such as MK-0677;
[0331] (o) cannabinoid receptor ligands, such as cannabinoid
CB.sub.1 receptor antagonists or inverse agonists; and
[0332] (p) protein tyrosine phosphatase-1B (PTP-1B) inhibitors.
[0333] Examples of anti-obesity agents that can be employed in
combination with a compound of Formula I are disclosed in "Patent
focus on new anti-obesity agents," Exp. Opin. Ther. Patents, 10:
819-831 (2000); "Novel anti-obesity drugs," Exp. Opin. Invest.
Drugs, 9: 1317-1326 (2000); and "Recent advances in feeding
suppressing agents: potential therapeutic strategy for the
treatment of obesity, Exp. Opin. Ther. Patents, 11: 1677-1692
(2001). The role of neuropeptide Y in obesity is discussed in Exp.
Opin. Invest. Drugs, 9: 1327-1346 (2000). Cannabinoid receptor
ligands are discussed in Exp. Opin. Invest. Drugs, 9: 1553-1571
(2000).
[0334] Examples of other active ingredients that may be combined
with a compound of Formula I for the treatment or prevention of
male or female sexual dysfunction, in particular, male erectile
dysfunction, either administered separately or in the same
pharmaceutical compositions, include, but are not limited to (a)
type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitors,
including sildenafil and (6R,
12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyra-
zino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351); (b)
alpha-adrenergic receptor antagonists, including phentolamine and
yohimbine or pharmaceutically acceptable salts thereof; (c)
dopamine receptor agonists, such as apomorphine or pharmaceutically
acceptable salts thereof; and (d) nitric oxide (NO) donors.
[0335] Pharmaceutical Compositions
[0336] Another aspect of the present invention provides
pharmaceutical compositions which comprises a compound of Formula I
and a pharmaceutically acceptable carrier. The pharmaceutical
compositions of the present invention comprise a compound of
Formula I as an active ingredient or a pharmaceutically acceptable
salt thereof, and may also contain a pharmaceutically acceptable
carrier and optionally other therapeutic ingredients. The term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including
inorganic bases or acids and organic bases or acids.
[0337] The compositions include compositions suitable for oral,
rectal, topical, parenteral (including subcutaneous, intramuscular,
and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal
inhalation), or nasal administration, although the most suitable
route in any given case will depend on the nature and severity of
the conditions being treated and on the nature of the active
ingredient. They may be conveniently presented in unit dosage form
and prepared by any of the methods well-known in the art of
pharmacy.
[0338] In practical use, the compounds of Formula I can be combined
as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
In preparing the compositions for oral dosage form, any of the
usual pharmaceutical media may be employed, such as, for example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like in the case of oral liquid
preparations, such as, for example, suspensions, elixirs and
solutions; or carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like in the case of oral solid
preparations such as, for example, powders, hard and soft capsules
and tablets, with the solid oral preparations being preferred over
the liquid preparations.
[0339] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form in
which case solid pharmaceutical carriers are obviously employed. If
desired, tablets may be coated by standard aqueous or nonaqueous
techniques. Such compositions and preparations should contain at
least 0.1 percent of active compound. The percentage of active
compound in these compositions may, of course, be varied and may
conveniently be between about 2 percent to about 60 percent of the
weight of the unit. The amount of active compound in such
therapeutically useful compositions is such that an effective
dosage will be obtained. The active compounds can also be
administered intranasally as, for example, liquid drops or
spray.
[0340] The tablets, pills, capsules, and the like may also contain
a binder such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0341] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor.
[0342] Compounds of formula I may also be administered
parenterally. Solutions or suspensions of these active compounds
can be prepared in water suitably mixed with a surfactant such as
hydroxy-propylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils.
Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of microorganisms.
[0343] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0344] Preparation of Compounds of the Invention
[0345] The compounds of structural formula I of the present
invention can be prepared according to the procedures of the
following Schemes and Examples, using appropriate materials and are
further exemplified by the following specific examples. Moreover,
by utilizing the procedures described in detail in PCT
International Application Publications WO 99/64002 (16 Dec. 1999)
and WO 00/74679 (14 Dec. 2000), which are incorporated by reference
herein in their entirety, in conjunction with the disclosure
contained herein, one of ordinary skill in the art can readily
prepare additional compounds of the present invention claimed
herein. The compounds illustrated in the examples are not, however,
to be construed as forming the only genus that is considered as the
invention. The Examples further illustrate details for the
preparation of the compounds of the present invention. Those
skilled in the art will readily understand that known variations of
the conditions and processes of the following preparative
procedures can be used to prepare these compounds. The instant
compounds are generally isolated in the form of their
pharmaceutically acceptable salts, such as those described
previously hereinabove. The free amine bases corresponding to the
isolated salts can be generated by neutralization with a suitable
base, such as aqueous sodium hydrogencarbonate, sodium carbonate,
sodium hydroxide, and potassium hydroxide, and extraction of the
liberated amine free base into an organic solvent followed by
evaporation. The amine free base isolated in this manner can be
further converted into another pharmaceutically acceptable salt by
dissolution in an organic solvent followed by addition of the
appropriate acid and subsequent evaporation, precipitation, or
crystallization. All temperatures are degrees Celsius unless
otherwise noted. Mass spectra (MS) were measured by electron-spray
ion-mass spectroscopy.
[0346] The phrase "standard peptide coupling reaction conditions"
means coupling a carboxylic acid with an amine using an acid
activating agent such as EDC, DCC, and BOP in an inert solvent such
as dichloromethane in the presence of a catalyst such as HOBT. The
use of protecting groups for the amine and carboxylic acid
functionalities to facilitate the desired reaction and minimize
undesired reactions is well documented. Conditions required to
remove protecting groups are found in standard textbooks such as
Greene, T, and Wuts, P. G. M., Protective Groups in Organic
Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. CBZ
and BOC are commonly used protecting groups in organic synthesis,
and their removal conditions are known to those skilled in the art.
For example, CBZ may be removed by catalytic hydrogenation in the
presence of a noble metal or its oxide such as palladium on
activated carbon in a protic solvent such as methanol or ethanol.
In cases where catalytic hydrogenation is contraindicated due to
the presence of other potentially reactive functionalities, removal
of CBZ groups can also be achieved by treatment with a solution of
hydrogen bromide in acetic acid or by treatment with a mixture of
TFA and dimethylsulfide. Removal of BOC protecting groups is
carried out with a strong acid, such as trifluoroacetic acid,
hydrochloric acid, or hydrogen chloride gas, in a solvent such as
methylene chloride, methanol, or ethyl acetate.
[0347] Abbreviations Used in the Description of the Preparation of
the Compounds of the Present Invention:
[0348] BOC (boc) t-butyloxycarbonyl
[0349] BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate
[0350] Bu butyl
[0351] calc. calculated
[0352] CBZ (Cbz) benzyloxycarbonyl
[0353] c-hex cyclohexyl
[0354] c-pen cyclopentyl
[0355] c-pro cyclopropyl
[0356] DEAD diethyl azodicarboxylate
[0357] DIEA diisopropylethylamine
[0358] DMAP 4-dimethylaminopyridine
[0359] DMP N,N-dimethylformamide
[0360] EDC 1-(3-dimethylaminopropyl)3-ethylcarbodiimide HCl
[0361] eq. equivalent(s)
[0362] ES-MS electron spray ion-mass spectroscopy
[0363] Et ethyl
[0364] EtOAc ethyl acetate
[0365] HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
[0366] HOAt 1-hydroxy-7-azabenzotriazole
[0367] HOBt 1-hydroxybenzotriazole hydrate
[0368] HPLC high performance liquid chromatography
[0369] LDA lithium diisopropylamide
[0370] MC-xR melanocortin receptor (x being a number)
[0371] Me methyl
[0372] MF molecular formula
[0373] MS mass spectrum
[0374] Ms methanesulfonyl
[0375] OTf trifluoromethanesulfonyl
[0376] Ph phenyl
[0377] Phe phenylalanine
[0378] Pr propyl
[0379] prep. prepared
[0380] PyBrop bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate
[0381] r.t. room temperature
[0382] TFA trifluoroacetic acid
[0383] THF tetrahydrofuran
[0384] TLC thin-layer chromatography.
[0385] Reaction Schemes A-L illustrate the methods employed in the
synthesis of the compounds of the present invention of structural
formula I. All substituents are as defined above unless indicated
otherwise.
[0386] Reaction Scheme A illustrates a key step in the synthesis of
the novel compounds of structural formula I of the present
invention. As shown in reaction Scheme A, the reaction of a
4-substituted piperidine or 4-substituted tetrahydropyridine of
type 1 with a carboxylic acid derivative of formula 2 affords a
title compound of structural formula I. The amide bond coupling
reaction illustrated in reaction Scheme A is conducted in an
appropriate inert solvent such as dimethylformamide (DMF),
methylene chloride or the like and may be performed with a variety
of reagents suitable for amide coupling reactions such as
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
or benzotriazol-1-yloxytripyrrolidinephosphonium
hexafluorophosphate (PyBOP). Preferred conditions for the amide
bond coupling reaction shown in reaction Scheme A are known to
those skilled in organic synthesis. Such modifications may include,
but are not limited to, the use of basic reagents such as
triethylamine (TEA) or N-methylmorpholine (NMM), or the addition of
an additive such as 1-hydroxy-7-azabenzotriazole (HOAt) or
1-hydroxybenzotriazole (HOBt). Alternatively, 4-substituted
piperidines or 4-substituted tetrahydropyridines of formula 1 may
be treated with an active ester or acid chloride derived from
carboxylic acid 2 which also affords compounds of structural
formula I. The amide bond coupling shown in reaction Scheme A is
usually conducted at temperatures between 0.degree. C. and room
temperature, occasionally at elevated temperatures, and the
coupling reaction is typically conducted for periods of 1 to 24
hours.
[0387] When 1 is a 4-substituted tetrahydropyridine, the amide
coupling product can be reduced to form the corresponding
piperidine derivative (I) by hydrogenation in a solvent such as
ethanol, ethyl acetate, acetic acid or mixtures thereof using a
noble metal catalyst on carbon such as platinum (IV) oxide,
palladium-on-carbon, or palladium hydroxide.
[0388] If it is desired to produce a compound of structural formula
I wherein R.sup.1 is a hydrogen, the N-BOC protected analogs of
structural formula I may be used in the synthesis and deprotected
under acidic conditions, for instance using trifluoroacetic acid in
a solvent like methylene chloride or hydrogen chloride in a solvent
such as ethyl acetate at room temperature.
[0389] When it is desired to prepare compounds of structural
formula I wherein R.sup.1 is not a hydrogen, the compounds of
general formula I (R.sup.1.dbd.H) may be further modified using the
methodology described below in reaction Scheme M. 13
[0390] Reaction Schemes B-I illustrate methods for the synthesis of
the carboxylic acids of general formula 2 that are utilized in the
amide bond coupling reaction shown in reaction Scheme A. Reaction
Schemes J-L illustrate additional methods for the synthesis of
4-substituted piperidines of general formula 1 that are used in
that same step.
[0391] Reaction Scheme B illustrates a preferred method for the
synthesis of compounds of general formula 2 wherein r is 2 and s is
1 such that the resulting heterocycle is a 3-aryl-4-piperidine
carboxylic acid derivative 10. The synthesis of 10 begins with a
commercially available .beta.-keto ester such as 3. Generally a
protecting group interchange of an N-BOC group for the N-benzyl
group is performed initially. Thus a .beta.-keto ester of formula 3
is subjected to debenzylation by hydrogenolysis using a
palladium-on-carbon catalyst in a solvent system such as 1:1
ethanol-water under a hydrogen atmosphere. The resulting piperidone
4 is then protected as its tert-butyl carbamate using BOC anhydride
in the presence of a base and a suitable solvent. For example, this
can be accomplished in a two phase mixture of chloroform and
aqueous sodium bicarbonate as shown. Incorporation of the 3-aryl
substituent is then performed in two steps. First, the .beta.-keto
ester group is converted to the corresponding vinyl triflate 6
using trifluoromethanesulfonic anhydride and an organic base like
N,N-diisopropylethylamine in an aprotic solvent such as methylene
chloride. The resulting vinyl triflate 6 is then subjected to a
palladium-catalyzed cross-coupling reaction with an aryl boronic
acid (7) using a palladium (II) catalyst such as
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II).
Preferred conditions for this reaction are the use of a
toluene-ethanol-aqueous sodium carbonate solvent system at an
elevated temperature, for instance 50-100.degree. C., for a period
of 2-24 hours. The resulting aryl-substituted tetrahydropyridine
derivative 8 can be reduced to a piperidine such as 9 using a
variety of known techniques and the method chosen will determine
the stereochemical outcome of the product. For instance,
hydrogenation of 8 with a palladium on carbon catalyst in a solvent
such as ethanol affords cis-3,4-disubstituted piperidines of
general formula 9. Alternatively, a dissolving metal reduction
using a metal, such as magnesium in methanol, reduces the double
bond of 8 and produces a mixture of both cis and trans
3,4-disubstituted piperidines of formula 9. The resulting mixture
of cis and trans diastereoisomers may be separated
chromatographically or it may be subsequently epimerized to afford
the pure trans isomer of 9 by treating the mixture with a base like
sodium methoxide in methanol. Finally, hydrolysis of either the cis
or trans 3-aryl-4-piperidine carboxylic ester 9 affords either a
cis or trans 3-aryl-4-piperidine carboxylic acid of general formula
10, corresponding to an acid of general formula 2 wherein r is 2
and s is 1. The cis or trans carboxylic acids of general formula 10
are produced as racemates and either may be resolved to afford
enantiomerically pure compounds by methods known in organic
synthesis. Preferred methods include resolution by crystallization
of diastereoisomeric salts derived from acids 10 and a chiral amine
base or the use of chiral stationary phase liquid chromatography
columns. 14
[0392] Reaction Scheme C illustrates a preferred method for the
synthesis of compounds of general formula 2 wherein r is 1 and s is
2, such that the resulting heterocycle is a
4-aryl-3-piperidine-carboxylic acid derivative 17. The synthesis of
17 is similar to the one shown in reaction Scheme B, and may begin
with either of the commercially available .beta.-keto esters 11 or
12. Conversion of one of these starting materials to the
N-BOC-protected piperidine 13 is performed as shown and the
resulting .beta.-keto ester is subjected to the two-step arylation
protocol previously described to yield 15. Reduction of the double
bond of 15 using conditions appropriate for obtaining either cis or
trans 17 is followed by ester hydrolysis which affords either a cis
or trans 4-aryl-3-piperidine-carboxylic acid of general formula 17
which corresponds to an acid of general formula 2 wherein r is 1
and s is 2. The cis or trans carboxylic acids of general formula 17
are produced as racemates and either may be resolved to afford
enantiomerically pure compounds by methods known in organic
synthesis. Preferred methods include resolution by crystallization
of diastereoisomeric salts derived from the acids 17 and a chiral
amine base or by the use of chiral stationary phase liquid
chromatography columns. 15
[0393] The synthesis of the N-BOC protected carboxylic acids of
general formula 10 and 17 illustrated in reaction Schemes B and C
are useful for the preparation of title compounds of structural
formula I bearing a variety of R.sup.1 substituents as noted above.
For the synthesis of certain title compounds of structural formula
I, for instance when it is desired that R.sup.1 be a tert-butyl
group, it is preferable to incorporate that R.sup.1 substituent at
an earlier stage of the synthesis. The synthesis of a
1-substituted-3-ketopiperidine-4-carboxylic ester (21) is shown in
reaction Scheme D. A primary amine 18 bearing a desired R.sup.1
substituent like a tert-butyl group is reacted with ethyl
4-bromobutyrate at elevated temperature in the absence of a solvent
to afford the N-substituted ethyl 4-aminobutyrate 19. The amino
ester 19 is then alkylated a second time with ethyl bromoacetate in
a high boiling inert solvent such as toluene and in the presence of
a base such as powdered potassium carbonate. The resulting
aminodiesters of general formula 20 are then cyclized using an
intramolecular Dieckmann reaction to afford piperidines such as 21.
The Dieckmann reaction is performed using a strong base such as
potassium tert-butoxide or the like, in an aprotic solvent such as
THF at temperatures between room temperature and the boiling point
of the solvent. The resulting 1-substituted-3-ketopiper-
idine-4-carboxylic ester 21 corresponds to a compound of general
formula 5 shown in reaction Scheme B, where the BOC group is
replaced with the desired R.sup.1 substituent. The compounds of
general formula 21 may then be converted to compounds of general
formula 2 where the R.sup.1 substituent replaces the BOC group
using the reaction sequence illustrated in reaction Scheme B.
16
[0394] When it is desirable to synthesize a compound of general
formula 17 wherein the BOC group is replaced with a substituent
group R.sup.1, a reaction sequence similar to the one illustrated
in reaction Scheme C may be employed as shown in reaction Scheme E.
An amine 18 bearing the desired R.sup.1 substituent is first
subjected to a Michael addition with excess ethyl acrylate in the
presence of a solvent such as THF or ethanol. The resulting diester
22 is then converted to a
1-substituted-4-ketopiperidine-3-carboxylic ester 23 using an
intramolecular Dieckmann reaction under conditions similar to those
illustrated in reaction Scheme C. The substituted piperidine 23
corresponds to a compound of general formula 13 shown in reaction
Scheme C, wherein the BOC group is replaced with the desired
R.sup.1 substituent. The compounds of general formula 23 may then
be converted to compounds of general formula 2 where the R.sup.1
substituent replaces the BOC group using the methodology
illustrated in reaction Scheme C. 17
[0395] Reaction Scheme F illustrates a strategy for the synthesis
of compounds of general formula 2 when the values of r and s are
selected such that the resulting heterocycle is a
3-aryl-4-pyrrolidine carboxylic acid derivative (29). The preferred
method for the synthesis of compounds of general formula 29
involves the azomethine ylid 3+2 cycloaddition reaction of an
azomethine ylid precursor of general formula 25 and a substituted
cinnamic ester 24. The azomethine cycloaddition reaction of 24 and
25 affords the 3,4-disubstituted pyrrolidine 26, and the
stereochemical relationship of the substituents on the newly formed
pyrrolidine ring is determined by the stereochemistry of the double
bond in the cinnamate ester 24. Thus the trans ester 24 affords a
trans 3,4-disubstituted pyrrolidine of formula 26 as shown. The
corresponding cis cinnamate ester affords a cis 3,4-disubstituted
pyrrolidine of general formula 26. Cis or trans
3-arylpyrrolidine-4-carboxylic esters of general formula 26 may be
resolved to afford enantiomerically pure compounds using a method
such as resolution by crystallization of the diastereoisomeric
salts derived from 26 and a chiral carboxylic acid, or directly by
the use of chiral stationary phase liquid chromatography columns.
Reaction Scheme F illustrates the case where a trans cinnamic ester
24 is converted to a trans 3,4-disubstituted pyrrolidine 26 and its
subsequent resolution affords the enantiomerically pure trans
pyrrolidine esters 27 and 28. Finally, the esters of general
formula 26 (or their pure enantiomers 27 and 28) are hydrolyzed to
the corresponding amino acid hydrochlorides of general formula 29
as shown at the bottom of reaction Scheme F.
[0396] Amino acids of general formula 29 are zwitterionic.
Therefore it is in some cases difficult to achieve efficient
separation and purification of these compounds from aqueous
reactions or workups. In these cases it is preferred to effect the
hydrolysis using a reagent such potassium trimethylsilanolate in
diethyl ether. Under these conditions the potassium salt of the
carboxylic acid is produced which affords an easily isolated
precipitate in ether. The resulting salt is then converted to the
corresponding amino acid hydrochloride by treatment with excess
hydrogen chloride in a suitable solvent such as ethyl acetate.
Alternatively, esters such as 26 may be converted directly to the
amino acid hydrochlorides 29 under acidic hydrolysis conditions.
The hydrolysis of the ester 26 is achieved by prolonged reaction
with concentrated hydrochloric acid at an elevated temperature. For
example, this reaction may be conducted in 8 M hydrochloric acid at
reflux overnight. The reaction mixture is then cooled and
evaporated in vacuo to afford the amino acid hydrochloride 29. The
amino acid hydrochlorides of general formula 29 correspond to an
amino acid hydrochloride of general formula 2 wherein both r and s
are 1 and may be employed directly in the amide bond coupling step
illustrated in reaction Scheme A to produce the compounds of the
present invention of structural formula I. 18
[0397] Another preferred method for the synthesis of
enantiomerically pure 3-arylpyrrolidine-4-carboxylic acid
derivatives is illustrated in reaction Scheme G. In this synthetic
method, a substituted cinnamic acid of general formula 29 is first
derivatized with a chiral auxilliary such as
(S)-(-)-4-benzyl-2-oxazolidinone (30). The acylation of chiral
auxiliary 30 with cinnamic acids of formula 29 is performed by
initial activation of the acid to afford a mixed anhydride.
Typically acids of general formula 29 are reacted with an acid
chloride such as pivaloyl chloride in the presence of a base such
as triethylamine and in a suitable aprotic solvent such as THF. The
intermediate cinnamyl-pivaloyl anhydride is converted to the
product 31 by reaction with the oxazolidinone 30 in the presence of
lithium chloride, an amine base such as triethylamine and in a
solvent such as THF, and the reaction is conducted at temperatures
between -20.degree. C. and room temperature for periods of 1-24
hours. Alternatively, the oxazolidinone 30 may be deprotonated with
a strong base such as n-butyllithium in THF at low temperatures
such as -78.degree. C. and then reacted with a mixed anhydride
obtained from acid 29 and an acid chloride like pivaloyl chloride
as noted above. The cinnamyl oxazolidinone of general formula 31,
which is produced by either of these methods, is then reacted with
the azomethine ylid precursor 25 in a manner similar to that
described in reaction Scheme F, and the products of the reaction
are the substituted pyrrolidines of general formulas 33 and 34 as
shown. The products 33 and 34 are diastereoisomers of each other
and may therefore be separated by standard methods such as
recrystallization or by liquid chromatography on a solid support
such as silica gel. As discussed above, if the trans isomer of the
cinnamic acid of general formula 29 is employed in the first step
of reaction Scheme G, then a trans isomer of the substituted
cinnamyl oxazolidinone 31 is produced. If such a trans cinnamyl
oxazolidinone is then subjected to the azomethine ylid
cycloaddition with an azomethine ylid precursor of formula 25, the
products are the diastereoisomeric trans-disubstituted pyrrolidines
related to 33 and 34. 19
[0398] The azomethine ylid cycloaddition reactions shown in
reaction Schemes F and G are generally conducted with the
commercially available azomethine ylid precursor
N-(methoxymethyl)-N-(trimethylsilylmethyl)-benz- ylamine (5,
R.sup.1.dbd.--CH.sub.2Ph). When the R.sup.1 substituent in the
title compounds of structural formula I is chosen to be a group
other than benzyl, it is generally preferable to remove the benzyl
group from the substituted pyrrolidine compound at this point, and
replace it with a more readily removed protecting group such as an
N-BOC group. Reaction Scheme H illustrates this process with a
generalized 3,4-disubstituted pyrrolidine of formula 32. The
preferred method for removal of the N-benzyl group from compounds
of general formula 32 will depend upon the identity of the R.sup.3
substituents. If these substituents are unaffected by hydrogenation
conditions, then the N-benzyl group may be removed by
hydrogenolysis using a palladium on carbon catalyst in a solvent
such as ethanol and in the presence of hydrogen gas or a hydrogen
donor such as formic acid. Occasionally it may be preferred that
one of the substituents R.sup.3 be a halogen or another substituent
defined above which would be reactive under hydrogenation
conditions. In these cases, the compound of general formula 32 is
reacted with 1-chloroethyl chloroformate in an inert solvent such
as toluene at temperatures between room temperature and 110.degree.
C. (Olafson, R. A. et al. J. Org. Chem. 1984, 49, 2081). The
toluene is then removed, and the residue is heated in methanol for
a period of 15-60 minutes, and the product is the debenzylated
pyrrolidine of general formula 35. The resulting pyrrolidine 35 is
then protected as its tert-butyl carbamate (36) using BOC anhydride
in the presence of a base and a suitable solvent. For example, this
can be accomplished in a two phase mixture of chloroform and
aqueous sodium bicarbonate as shown in reaction Scheme H.
[0399] The oxazolidinone chiral auxilliary is next hydrolyzed from
the pyrrolidines of general formula 36 as shown at the bottom of
reaction Scheme H. The hydrolysis reaction is accomplished using
lithium hydroperoxide generated in situ from lithium hydroxide and
30% aqueous hydrogen peroxide. The reaction is typically conducted
in a solvent system such as aqueous THF, and the reaction is
performed at temperatures between 0.degree. C. and room temperature
for a period of 1-6 hours. The resulting carboxylic acids of
general formula 37 correspond to carboxylic acids of general
formula 2 where both r and s are 1. Using the methodology presented
in reaction Scheme A, the compounds of general formula 37 may then
be converted to the compounds of the present invention of
structural formula I. 20
[0400] As noted previously in the discussion of reaction Scheme D,
it may occasionally be preferable to incorporate the R.sup.1
substituent into the substituted pyrrolidine of general formula 37
at an earlier stage of the synthesis, for instance when it is
desired that R.sup.1 be a tert-butyl group. In such cases, it is
possible to utilize 20 an azomethine ylid precursor (25) bearing
the desired R.sup.1 substituent in the cycloaddition reactions
illustrated in reaction Schemes F and G. Reaction Scheme I
illustrates the preparation of azomethine precursors of formula 25
starting with amines of general formula 18. Reaction of the amine
of formula 18 with chloromethyltrimethylsilane at high temperature
and in the absence of solvent affords the
N-trimethylsilylmethyl-substitu- ted amine of general formula 38.
Subsequent reaction of 38 with aqueous formaldehyde in the presence
of methanol and a base such as potassium carbonate then affords the
generalized ylid precursor 25 which can be utilized in the
cycloaddition reactions discussed above. 21
[0401] Reaction Schemes J-L illustrate additional methods for the
synthesis of the 4-substituted piperidines of general formula 1
which are required in the amide bond coupling step illustrated in
reaction Scheme A. As shown in Reaction Scheme J, treatment of
enoltriflate 39 (prepared as described in: Rohr, M.; Chayer, S.;
Garrido, F.; Mann, A.; Taddei, M.; Wermuth, C-G. Heterocycles 1996,
43, 2131-2138.) with bis(pinacolato)diboron reagent in the presence
of a suitable palladium (II) catalyst such as
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropall- adium (II)
(Pd(dppf)Cl.sub.2) and potassium acetate in a polar, inert organic
solvent such as methyl sulfoxide at about 80.degree. C. under an
inert atmosphere for a period of 6-24 hours provided the vinyl
dioxaborolane 40. Borolane 40 can be further reacted with an aryl
halide such as 41 in the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium (0) (Pd(Ph.sub.3).sub.4) and
potassium phosphate in an inert solvent such as
N,N-dimethylformamide to give the coupled 4-aryl tetrahydropyridine
product 42. The tert-butyloxycarbonyl protecting group can be
removed by any of the known methods such as treatment with a protic
acid such as hydrogen chloride in an inert organic solvent such as
ethyl acetate or trifluoroacetic acid in methylene chloride to give
amine 43. Alternatively, it is sometimes desirable to reduce the
double bond in synthetic intermediate 42. This can be effected by
treatment with hydrogen at atmospheric or elevated pressure and a
noble metal catalyst on carbon such as palladium (0) or
platinum(IV) oxide in an inert organic solvent such as ethanol,
ethyl acetate, acetic acid or mixtures thereof to give the
4-arylpiperidine 44. Removal of the tert-butyloxycarbonyl
protecting group as described above provides amine 45. Both amine
intermediates, 43 and 45, may be used as coupling partners in
Reaction Scheme A. 22
[0402] As shown in Reaction Scheme K, aryl groups containing
substituents with acidic hydrogens (e.g. 46 and 48) can modified by
alkylation under known protocols. For instance, treatment of esters
46 or 48 with a strong base such a lithium diisopropylamide at low
temperature in an inert organic solvent such as tetrahydrofuran can
form an intermediate enolate which can be reacted in a second step
with any alkylating agent (B-LG) such as iodomethane, iodoethane,
1,2-dibromoethane or the like to form the corresponding alkylated
product. In addition to ester groups, related amides and
functionalities that promote the formation of a stable anion can be
alkylated under similar protocols. 23
[0403] Ester intermediates such as 47 and 49 may be further
modified by conversion to the corresponding carboxylic acids and
coupled with amines to form amides as described in Reaction Scheme
L. Conversion of the methyl esters 47 and 49 to the carboxylic acid
can be effected by dealkylation using potassium trimethylsilanolate
at room temperature in an inert organic solvent such as
tetrahydrofuran for a period of about one to about 24 hours to
provide, after acidification, the corresponding carboxylic acids.
In certain cases, a base-catalyzed hydrolysis known to those
skilled in the art may be used to effect this same transformation.
These acids may be reacted further to form amides by treatment with
a primary or secondary amine under a variety of amide coupling
protocols such as described in Scheme A to provide intermediates 50
and 51. 24
[0404] Reaction Scheme M illustrates general methods for the
elaboration of an R.sup.1 substituent following assembly of a
compound of structural formula I (wherein R.sup.1.dbd.BOC) as
described in reaction Scheme A. The N-BOC protected compound of
structural formula I is first deprotected under acidic conditions
for instance by treatment with hydrogen chloride in ethyl acetate
or using trifluoroacetic acid in dichloromethane. The resulting
heterocyclic compound of structural formula I (R.sup.1.dbd.H) may
then be subjected to one of several alkylation strategies known in
organic chemistry. For instance, compounds (I) (R.sup.1.dbd.H) may
be utilized in a reductive amination reaction with a suitable
carbonyl containing partner (2). The reductive amination is
achieved by initial formation of an imine between the amine of
formula I (R.sup.1.dbd.H) and either an aldehyde or ketone of
formula 52. The intermediate imine is then treated with a reducing
agent capable of reducing carbon-nitrogen double bonds such as
sodium cyanoborohydride or sodium triacetoxyborohydride and an
alkylated product of structural formula I is produced.
Alternatively, a heterocyclic compound of structural formula (I)
(R.sup.1.dbd.H) may be directly alkylated using an alkylating agent
such as 53 in a polar aprotic solvent such as DMF. In this
reaction, the substituent Z of compound 53 is a good leaving group
such as a halide, mesylate or triflate and the product is the
compound of structural formula I bearing the R.sup.1 substituent.
25
[0405] The following Examples are provided to illustrate the
invention and are not to be construed as limiting the scope of the
invention in any manner. Intermediate 1-7 was prepared as described
in Scheme N following the general procedure described in Scheme F.
26
[0406] Step A: Preparation of
N-tert-butyl-N-(trimethylsilylmethyl)amine (N-1)
[0407] A mixture of tert-butylamine (18.0 mL, 171 mmol) and
(chloromethyl)trimethylsilane (7.00 g, 57.1 mmol) was heated in a
thick-walled glass tube at 200.degree. C. overnight. After cooling
to ambient temperature, the reaction mixture was poured into 1 N
NaOH and extracted three times with diethyl ether. The combined
organic extracts were washed with brine, dried (MgSO.sub.4), and
the volatiles evaporated in vacuo. Distillation (atmospheric
pressure; .about.135.degree. C.) of the residual liquid gave the
title compound as a colorless liquid (7.67 g).
[0408] Step B: Preparation of
N-tert-butyl-N-(methoxymethyl)-N-(trimethyls- ilylmethyl)amine
(N-2)
[0409] N-tert-Butyl-N-(trimethylsilylmethyl)amine (N-1) (8.47 g,
53.1 mmol) was added dropwise, over approximately 30 min, via a
pressure equalizing addition funnel to a stirred solution of
aqueous formaldehyde (5.98 mL of a 37 wt. % solution in water, 79.7
mmol) at 0.degree. C. (ice cooling). After 45 min, methanol (6.45
mL, 159.3 mmol) was added and the resulting solution was saturated
with potassium carbonate. After stirring vigorously for
approximately 5 h, the aqueous phase was removed. The organic phase
was saturated with potassium carbonate and stirred overnight. The
reaction mixture was poured into water and extracted three times
with diethyl ether. The combined organic extracts were washed with
brine, dried (MgSO.sub.4) and the volatiles evaporated in vacuo.
Distillation (high vacuum; .about.70.degree. C.) of the residual
liquid afforded the title compound as a colorless liquid (3.50
g).
[0410] Step C: Preparation of methyl
(3R,4S)-1-tert-butyl-4-(2,4-difluorop-
henyl)pyrrolidine-3-carboxylate and methyl
(3S,4R)-1-tert-butyl-4-(2,4-dif-
luorophenyl)pyrrolidine-3-carboxylate (N-3)
[0411] Trifluoroacetic acid (116 .mu.L, 1.51 mmol) was added to a
solution of the product of step B (3.07 g, 15.1 mmol) and methyl
(2E)-3-(2,4-difluorophenyl)prop-2-enoate (2.99 g, 15.1 mmol) in
methylene chloride (60 mL) at ambient temperature. After 18 h, the
reaction mixture was poured into saturated aqueous sodium
bicarbonate and extracted three times with methlene chloride. The
combined organic extracs were washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. Purification of the
residue by normal phase medium pressure liquid chromatography on
silica gel (gradient elution;0-9% methanol (containing 10% v/v
ammonium hydroxide)/methylene chloride as eluent) gave the title
compound as a colorless liquid (3.50 g, 78%). The racemic titled
compound was resolved into its enantiomeric components using
preparative chiral high pressure liquid chromatography on CHIRALPAK
AD Phase (5% isopropanol/heptanes as eluent) to give in order of
elution: methyl
(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate
enantiomer (1.37 g) as a colorless oil followed by the methyl
(3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate
enantiomer (1.18 g) as a colorless oil.
[0412] Step D: Preparation of
(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)p-
yrrolidine-3-carboxylic acid hydrochloride salt (1-7)
[0413] A mixture of the methyl
(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)-
pyrrolidine-3-carboxylate enantiomer of Step C (1.37 g, 4.61 mmol)
and potassium trimethylsilanolate (0.68 g, 5.30 mmol) in diethyl
ether (23 mL) was stirred at room temperature overnight. A
saturated solution of hydrogen chloride in ethyl acetate was then
added, the volatiles were evaporated and the residual solid used
without further purification in the preparation of Examples
detailed below. 27
EXAMPLE 1
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbo-
nyl}piperidin-4-yl)-5-chlorophenyl]-N-methylacetamide (1-11)
Step A: Preparation of methyl(2-bromo-5-chlorophenyl)acetate
(1-2)
[0414] A solution of (2-bromo-5-chlorophenyl)acetic acid (1-1)
(15.0 g, 60.1 mmol) and concentrated sulfuric acid (0.150 mL of a
36N solution) in methanol (120 mL) was heated at reflux for
approximately 15 h. After cooling to room temperature, the reaction
mixture was concentrated in vacuo and the residue partitioned
between methylene chloride and saturated aqueous sodium
bicarbonate. The organic layer was separated and the aqueous phase
re-extracted twice with methylene chloride. The combined organic
extracts were washed with water, brine, dried (MgSO.sub.4) and the
volatiles evaporated. The residual colorless liquid (15.9 g) was
used without further purification in the Step C below.
Step B: Preparation of tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-4)
[0415] A vigorously stirred suspension of the tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate
(1-3) (1.00 g, 3.02 mmol; prepared as described in Rohr, M.;
Chayer, S.; Garrido, F.; Mann, A.; Taddei, M.; Wermuth, C-G.
Heterocycles 1996, 43, 2131-2138), bis(pinacolato)diboron (0.844 g
3.32 mmol), potassium acetate (0.889 g, 9.06 mmol) and
[1,1'-bis(diphenylphosphino)-ferrocene]dichlorop- alladium(II)
(0.123 g of a 1:1 complex with methylene chloride, 0.151 mmol) in
methyl sulfoxide (20 mL) was degassed via three vacuum/nitrogen
ingress cycles and then heated at 80.degree. C. for approximately
15 h. After cooling to ambient temperature, the reaction mixture
was filtered through celite.RTM. eluting copiously with ethyl
acetate. The filtrate was poured into water/brine (1:1) and the
organic phase separated. The aqueous phase was re-extracted three
times with ethyl acetate and the combined organic extracts were
washed with brine, dried (MgSO.sub.4) and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
gel (gradient elution; 0%-25% ethyl acetate/hexanes as eluent)
furnished 1-4 as a white solid (0.660 g).
Step C: Preparation of tert-butyl
4-[4-chloro-2-(2-methoxy-2-oxoethyl)phen-
yl]-3,6-dihydropyridine-1(2H)-carboxylate (1-5)
[0416] A vigorously stirred mixture of the tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-
-carboxylate (1-4) (1.40 g, 4.53 mmol),
methyl(2-bromo-5-chlorophenyl)acet- ate (1-2) (1.31 g, 4.98 mmol),
potassium phosphate tribasic (2.85 g, 13.6 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.262 g, 0.227 mmol) in
N,N-dimethylformamide (22 mL) was degassed via three
vacuum/nitrogen ingress cycles and then heated at 100.degree. C.
for approximately 18 h. After cooling to room temperature, the
reaction mixture was poured into water and extracted three times
with ethyl acetate. The combined organic extracts were washed with
brine, dried (MgSO.sub.4) and concentrated in vacuo. Purification
of the crude residue by flash chromatography on silica gel
(gradient elution; 0%-25% ethyl acetate/hexanes as eluent) afforded
1-5 (0.967 g) as a colorless oil.
Step D: Preparation of methyl
[5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)- phenyl]acetate
hydrochloride (1-6)
[0417] A saturated solution of hydrogen chloride in ethyl acetate
(6 mL) was added to a solution of tert-butyl
4-[4-chloro-2-(2-methoxy-2-oxoethyl-
)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (1-5) (0.950 g, 2.60
mmol) in methylene chloride (6 mL) at 0.degree. C. After 1 h, the
volatiles were evaporated in vacuo, and the crude residue
triturated twice with dry diethyl ether to give 1-6 (0.690 g) as a
flocculent pale yellow solid (m/z (ES) 266 (MH.sup.+).
Step E: Preparation of methyl
[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoro-
phenyl)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlorop-
henyl]acetate (1-8)
[0418] N,N-diisopropylethylamine (1.36 mL, 7.80 mmol) was added to
a stirred suspension of
(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolid-
ine-3-carboxylic acid (1-7) (0.831 g, 2.60 mmol), methyl
[5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]acetate
hydrochloride (1-6) (0.690 g, 2.60 mmol),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethy- luronium
hexafluorophosphate (1.19 g, 3.12 mmol) and
1-hydroxy-7-azabenzotriazole (0.425 g, 3.12 mmol) in
N,N-dimethylformamide (5.2 mL) at ambient temperature. After
approximately 18 h, the reaction mixture was poured into saturated
aqueous sodium bicarbonate and extracted three times with ethyl
acetate. The combined organic extracts were washed with water,
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
gel (gradient elution; 0%-15% methanol (containing 10% v/v ammonium
hydroxide)/methylene chloride as eluent) provided 1-8 as a pale
yellow oil (nz/z (ES) 531 (MH.sup.+).
Step F: Preparation of methyl
[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoro-
phenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]acetate
(1-9)
[0419] A mixture of methyl
[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophe-
nyl)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlorophen-
yl]acetate (1-8) (2.60 mmol) and platinum (IV) oxide (0.300 g) in
ethanol/glacial acetic acid (1:1, 20 mL) was hydrogenated at
atmospheric pressure for approximately 15 h. The resulting mixture
was filtered through a short column of celite.RTM., eluting
copiously with ethanol. The filtrate was evaporated and the residue
was partitioned between methylene chloride and saturated aqueous
sodium bicarbonate. The organic layer was separated and the aqueous
phase was re-extracted twice with methylene chloride. The combined
organic extracts were washed with water, brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. Purification of the
crude residue by flash chromatography on silica gel (gradient
elution; 0%-15% methanol (containing 10% v/v ammonium
hydroxide)/methylene chloride as eluent) furnished 1-9 (1.25 g) as
a colorless foam (m/z (ES) 533 (MH.sup.+).
Step G: Preparation of
[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)-
pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]acetic acid
(1-10)
[0420] Potassium trimethylsilanolate (0.900 g, 7.05 mmol) was added
to a stirred solution of methyl
[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoroph-
enyl)pyrrolidin-3-yl]carbonyl}-piperidin-4-yl)-5-chlorophenyl]acetate
(1-9) (1.25 g, 2.35 mmol) in tetrahydrofuran (24 mL) at room
temperature. After approximately 15 h, the volatiles were
evaporated in vacuo and the crude residue was treated with a
saturated solution of hydrogen chloride in ethyl acetate. After
approximately 5 min, the reaction mixture was concentrated under
reduced pressure and the crude residue triturated twice with dry
diethyl ether to give 1-10 as an amorphous white solid (m/z (ES)
519 (MH.sup.+).
Step H: Preparation of
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoropheny-
l)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]-N-methylacetami-
de (1-11)
[0421] N,N-diisopropylethylamine (0.166 mL, 0.953 mmol) was added
to a stirred suspension of
[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)-
pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]acetic acid
(1-10) (40.0 mg), methylamine.HCl (42.9 mg, 0.635 mmol),
O-(7-azabenzotriazol-1-- yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (48.3 mg, 0.127 mmol) and
1-hydroxy-7-azabenotriazole (17.3 mg, 0.127 mmol) in
N,N-dimethylformamide (0.65 mL) at ambient temperature. After
approximately 18 h, the reaction mixture was poured into saturated
aqueous sodium bicarbonate and extracted three times with ethyl
acetate. The combined organic extracts were washed with water,
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
Purification of the residue by preparative reversed phase high
pressure liquid chromatography on YMC Pack Pro C18 phase (gradient
elution; 0%-100% acetonitrile/water as eluent, 0.1% TFA modifier)
gave 1-11 as a buff white solid (m/z (ES) 532 (MH.sup.+).
[0422] Following procedures similar to that described above for
Example 1, the following compounds were prepared:
1 28 Parent Ion m/z Ex. # R.sup.3a R.sup.3b (M + H) 2 H 29 498 3 H
30 526 4 H 31 524 5 H 32 526 6 H 33 538 7 H 34 484 8 H 35 498 9 H
36 512 10 H 37 510 11 H 38 470 12 4-F CN 470 13 4-Cl 39 504 14 4-Cl
40 518 15 H 41 499 16 H 42 498 17 H 43 512 18 H 44 512 19 H 45 526
20 H 46 538 21 H 47 524 22 H 48 540 23 H 49 526 24 H 50 540 25 H 51
540 26 H 52 538 27 4-Cl 53 546 28 4-Cl 54 560 29 4-Cl 55 560 30
4-Cl 56 574 31 4-Cl 57 558 32 4-Cl 58 572 33 4-Cl 59 546 34 4-Cl 60
574 35 4-Cl 61 560 36 4-Cl 62 574 37 4-Cl 63 558 38 4-Cl 64 572 39
4-Cl 65 586 40 4-Cl 66 588 41 4-Cl 67 519 42 4-Cl 68 533 43 H 69
534 44 5-F 70 503 45 3-CH.sub.3 71 499 46 3-CH.sub.3 72 498 47
3-CH.sub.3 73 512 48 4-CH.sub.3 74 513 49 4-CH.sub.3 75 498 50 4-Cl
76 561 51 5-Me 77 498 52 4-F 78 503 53 4-Cl 79 532 54 4-Cl 80 532
55 4-Cl 81 560 56 4-Cl 82 546 57 4-Cl 83 544 58 4-Cl 84 544 59
4,5-di-F 85 520 60 4-F 86 568 61 4-CF.sub.3 87 552
[0423] 8889
EXAMPLE 62
4-[2-(2-azetidin-1-yl-1-methyl-2-oxoethyl)-4-chlorophenyl]-1-{[(3S,4R)-1-t-
ert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl)piperidine
(2-7)
Step A: Preparation of methyl 2-(2-bromo-5-chlorophenyl)propanoate
(2-1)
[0424] A solution of n-butyllithium (1.67 mL of a 2.5 M solution in
hexanes, 4.17 mmol) was added dropwise via syringe to a stirred
solution of diisopropylamine (0.61 mL, 4.36 mmol) in
tetrahydrofuran (10 mL) at -78.degree. C. After approximately 10
min, the reaction mixture was warmed to 0.degree. C. and aged for
another 10 min. After re-cooling to -78.degree. C., a solution of
methyl (2-bromo-5-chlorophenyl)acetate (1-2) (1.00 g, 3.79 mmol) in
tetrahydrofuran (10 mL) was added dropwise via syringe and the
resulting yellow mixture was stirred at -78.degree. C. for
approximately 30 min. Iodomethane (0.35 mL, 5.69 mmol) was added
and after 1 h, the reaction mixture was warmed to ambient
temperature and quenched with saturated aqueous ammonium chloride.
The resulting mixture was poured into water and extracted three
times with ethyl acetate. The combined organic extracts were washed
with brine, dried (MgSO.sub.4) and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent)
furnished 2-1 as a colorless oil (1.00 g).
Step B: Preparation of tert-butyl
4-[4-chloro-2-(2-methoxy-1-methyl-2-oxoe-
thyl)phenyl]-3,6-dihydropyridine-1 (2H)-carboxylate (2-2)
[0425] A vigorously stirred mixture of tert-butyl
4-(4,4,5,5-tetramethyl-1-
,2,3-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate
(1.01 g, 3.27 mmol), methyl 2-(2-bromo-5-chlorophenyl)propanoate
(2-1) (1.00 g, 3.60 mmol), potassium phosphate tribasic (2.08 g,
9.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.189 g,
0.164 mmol) in N,N-dimethylformamide (13 mL) was degassed via three
vacuum/nitrogen ingress cycles and then heated at 100.degree. C.
for approximately 18 h. After cooling to room temperature, the
reaction mixture was poured into water and extracted three times
with ethyl acetate. The combined organic extracts were washed with
brine, dried (MgSO.sub.4) and concentrated in vacuo. Purification
of the crude residue by flash chromatography on silica gel
(gradient elution; 0-25% ethyl acetate/hexanes as eluent) afforded
2-2 (0.73 g) as a colorless oil.
Step C: Preparation of methyl
2-[5-chloro-2-(1,2,3,6-tetrahydropyridin-4-y- l)phenyl]propanoate
(2-3)
[0426] A saturated solution of hydrogen chloride in ethyl acetate
(6 mL) was added to a solution of tert-butyl
4-[4-chloro-2-(2-methoxy-1-methyl-2-
-oxoethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (0.730 g,
1.92 mmol) in methylene chloride (6 mL) at 0.degree. C. After 1 h,
the volatiles were evaporated in vacuo, and the crude residue
triturated twice with dry diethyl ether to give 2-3 (0.605 g) (m/z
(ES) 280 (MH.sup.+).
Step D: Preparation of methyl
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluo-
rophenyl)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlor-
ophenyl]propanoate (2-4)
[0427] N,N-diisopropylethylamine (1.00 mL, 5.76 mmol) was added to
a stirred suspension of
(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolid-
ine-3-carboxylic acid (1-7) (0.614 g, 1.92 mmol), methyl
2-[5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]propanoate
(2-3) (0.605 g, 1.92 mmol),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroni- um
hexafluorophosphate (0.876 g, 2.30 mmol) and
1-hydroxy-7-azabenzotriazo- le (0.314 g, 2.30 mmol) in
N,N-dimethylformamide (3.8 mL) at ambient temperature. After
approximately 18 h, the reaction mixture was poured into saturated
aqueous sodium bicarbonate and extracted three times with ethyl
acetate. The combined organic extracts were washed with water,
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
gel (gradient elution; 0-15% methanol (containing 10% v/v ammonium
hydroxide)/methylene chloride as eluent) provided 2-4 as a pale
yellow oil; (m/z (ES) 545 (MH.sup.+).
Step E: Preparation of methyl
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluo-
rophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]propanoat-
e (2-5)
[0428] A mixture of methyl
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorop-
henyl)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chloroph-
enyl]propanoate (2-4) (1.92 mmol) and platinum (IV) oxide (0.350 g)
in ethanol/glacial acetic acid (1:1, 20 mL) was hydrogenated at
atmospheric pressure for approximately 15 h. The resulting mixture
was filtered through a short column of celite.RTM., eluted
copiously with ethanol. The filtrate was evaporated and the residue
was partitioned between methylene chloride and saturated aqueous
sodium bicarbonate. The organic layer was separated and the aqueous
phase was re-extracted twice with methylene chloride. The combined
organic extracts were washed with water, brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. Purification of the
crude residue by flash chromatography on silica gel (gradient
elution; 0-15% methanol (containing 10% v/v ammonium
hydroxide)/methylene chloride as eluent) furnished 2-5 (0.95 g) as
a colorless foam (m/z (ES) 547 (MH.sup.+).
Step F: Preparation of
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoropheny-
l)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlorophenyl-
]propanoic acid (2-6)
[0429] Potassium trimethylsilanolate (0.645 g, 5.03 mmol) was added
to a stirred solution of methyl
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoro-
phenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]propanoate
(2-5) (1.10 g, 2.01 mmol) in tetrahydrofuran (10 mL) at room
temperature. After approximately 15 h, the volatiles were
evaporated in vacuo and the crude residue was treated with a
saturated solution of hydrogen chloride in ethyl acetate. After
approximately 5 min, the reaction mixture was concentrated under
reduced pressure and the crude residue triturated twice with dry
diethyl ether to give 2-6 as an amorphous white solidm/z 533
(MH.sup.+).
Step G:
4-[2-(2-azetidin-1-yl-1-methyl-2-oxoethyl)-4-chlorophenyl]-1-{[(3S-
,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}piperidin-
e (2-7)
[0430] N,N-diisopropylethylamine (0.162 mL, 0.931 mmol) was added
to a stirred suspension of
2-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluoropheny-
l)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlorophenyl-
]propanoic acid (2-6) (50.0 mg), azetidine.HCl (72.6 mg, 0.776
mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (59.0 mg, 0.155 mmol) and
1-hydroxy-7-azabenzotriazole (21.1 mg, 0.155 mmol) in
N,N-dimethylformamide (0.8 mL) at ambient temperature. After
approximately 18 h, the reaction mixture was poured into saturated
aqueous sodium bicarbonate and extracted three times with ethyl
acetate. The combined organic extract was washed with water, brine,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification of
the crude residue by preparative reversed phase high pressure
liquid chromatography on YMC Pack Pro C18 phase (gradient elution;
0-100% acetonitrile/water as eluent, 0.1% TFA modifier) gave 2-7 as
the trifluoroacetate salt (m/z (ES) 572 (MH.sup.+).
[0431] Following a procedure similar to that described above for
Example 62, the following compounds were prepared:
2 90 Parent Ion m/z Ex. # R.sup.3a R.sup.3b (M + H) 63 Cl 91 546 64
F 92 65 Cl 93 560 66 Cl 94 574 67 Cl 95 574 68 Cl 96 588 69 Cl 97
572 70 Cl 98 586 71 Cl 99 600 72 Cl 100 614 73 Cl 101 560 74 Cl 102
588 75 Cl 103 574 76 Cl 104 588 77 Cl 105 602 78 Cl 106 572 79 Cl
107 586 80 Cl 108 600 81 Cl 109 572 82 Cl 110 572 83 Cl 111 84 Cl
112 561 85 H 113 527 86 Cl 114 87 H 115 526 88 Cl 116 586 89 F 117
570 90 H 118 552 91 Cl 119 584 92 F 120 93 Cl 121 558 94 Cl 122 95
F 123 556 96 Cl 124 519 97 Cl 125 530 98 5-F 126 544 99 F 127 588
100 F 128 600 101 Cl 129 561 102 Cl 130 603 103 Cl 131 603
[0432] 132133
EXAMPLE 104
N-{(1S)-1-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3--
yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]ethyl}acetamide
(3-10)
Step A: Preparation of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide
(3-2)
[0433] N,N-diisopropylethylamine (1.10 mL, 6.36 mmol) was added to
a stirred solution of 2-bromo-5-chlorobenzoic acid (3-1) (0.500 g,
2.12 mmol), N,O-dimethylhydroxylamine.HCl (0.310 g, 3.18 mmol), and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (1.21 g, 3.18 mmol) in N,N-dimethylformamide
(8.5 mL) at ambient temperature. After 3 h, the reaction mixture
was poured into water and extracted three times with ethyl acetate.
The combined organic extracts were washed with saturated aqueous
sodium bicarbonate, brine, dried (MgSO.sub.4) and concentrated in
vacuo. Purification of the crude residue by flash chromatography on
silica gel (gradient elution; 0-25% ethyl acetate/hexanes as
eluent) gave 3-2 (0.56 g) as a colorless solid.
Step B: Preparation of 1-(2-bromo-5-chlorophenyl)ethanone (3-3)
[0434] Methylmagnesium bromide (4.26 mL of a 1.4M solution in
tetrahydrofuran/toluene, 5.97 mmol) was added dropwise to a stirred
solution of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide (3-1)
(0.554 g, 1.99 mmol) in tetrahydrofuran (20 mL) at approximately
0.degree. C. After 1 h, 1N hydrochloric acid (5 mL) was added and
the resulting biphasic mixture was stirred vigorously for about 10
min. The reaction mixture was poured into water and extracted three
times with ethyl acetate. The combined organic extracts were washed
with brine, dried (MgSO.sub.4) and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
gel (gradient elution; 0-10% ethyl acetate/hexanes as eluent)
provided 3-3 (0.44 g) as a colorless oil.
Step C: Preparation of (1R)-1-(2-bromo-5-chlorophenyl)ethanol
(3-4)
[0435] Trimethylborate (1.74 mL, 15.4 mmol) was added to a stirred
solution of (S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol
(3.24 g, 12.8 mol) in tetrahydrofuran (350 mL) at room temperature.
After 1.25 h, borane-methyl sulfide complex (70.4 mL of a 2M
solution in tetrahydrofuran, 0.141 mol) was added slowly and a
gentle effervesence was observed. The resulting solution was cooled
to approximately 0.degree. C. and a solution of
1-(2-bromo-5-chlorophenyl)ethanone (3-3) (30.0 g, 0.128 mmol) in
tetrahydrofuran (150 mL) was then added uniformly over 1 h. After
the addition, the resulting mixture was allowed to warm to ambient
temperature and aged overnight. The reaction mixture was
concentrated under reduced pressure to approximately one quarter of
its original volume, poured into 1N hydrochloric acid and extracted
three times with ethyl acetate. The combined organic extracts were
washed with brine, dried (MgSO.sub.4) and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
gel (9% ethyl acetate/hexanes as eluent) afforded 3-4 as a
colorless solid (25.8 g; 98:2 S/R enantiomeric ratio).
Step D: Preparation of tert-butyl
4-{4-chloro-2-[(1R)-1-hydroxyethyl]pheny- l}-3,6-dihydropyridine-1
(2H)-carboxylate (3-5)
[0436] A vigorously stirred mixture of tert-butyl
4-(4,4,5,5-tetramethyl-1-
,2,3-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate
(1-4) (34.0 g, 0.110 mol), (1R)-1-(2-bromo-5-chlorophenyl)ethanol
(3-4) (25.8 g, 0.110 mmol), potassium phosphate tribasic (70.0 g,
0.330 mol) and tetrakis(triphenylphosphine)palladium(0) (2.54 g,
2.20 mmol) in N,N-dimethylformamide (440 mL) was degassed via three
vacuum/nitrogen ingress cycles and then heated at 100.degree. C.
for approximately 18 h. After cooling to room temperature, the
reaction mixture was poured into ice/water (.about.1:1) and
extracted three times with ethyl acetate. The combined organic
extracts were washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. Purification of the crude residue by flash
chromatography on silica gel (25% ethyl acetate/hexanes as eluent)
afforded 3-5 (27.7 g) as a pale yellow foam.
Step E: Preparation of tert-butyl
4-{4-chloro-2-[(1S)-1-(azido)ethyl]pheny- l
1-3,6-dihydropyridine-1-carboxylate (3-6)
[0437] A solution of diethyl azodicarboxylate (49.6 mL, 0.315 mol)
was added dropwise to a stirred mixture of tert-butyl
4-{4-chloro-2-[(1R)-1-h-
ydroxyethyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (3-5)
(26.7 g, 78.9 mmol), Zn(N.sub.3).sub.2.2 Py (prepared according to
the method described by Viaud, M-C; Rollin, P. in Synthesis 1990:
130-131) (48.5 g, 0.158 mol), triphenylphosphine (82.7 g, 0.315
mol) and imidazole (21.5 g, 0.315 mol) in dichloromethane at
approximately 0.degree. C. After the addition, the resulting
mixture was allowed to warm to ambient temperature and stirred
vigorously for 3 d. The reaction mixture was filtered through a
short column of silica gel eluted with the appropriate volume of
dichloromethane to remove excess salts and polar byproducts. The
filtrate was concentrated in vacuo and the crude residue was
purified by flash chromatography on silica gel (12.5% ethyl
acetate/hexanes as eluent) to furnish 3-6 (23.9 g) as a viscous
pale yellow oil.
Step F: Preparation of tert-butyl
4-{2-[(1S)-1-aminoethyl]-4-chlorophenyl}- piperidine-1-carboxylate
(3-7)
[0438] A mixture of tert-butyl
4-{4-chloro-2-[(1S)-1-(azido)ethyl]phenyl}--
3,6-dihydropyridine-1-carboxylate (3-6) (22.9 g, 63.1 mmol) and
platinum (IV) oxide (1.08 g, 4.73 mmol) in ethanol/glacial acetic
acid (1:1, 200 mL) was hydrogenated at atmospheric pressure for
approximately 15 h. The resulting mixture was degassed via three
vacuum/hydrogen ingress cycles to remove the liberated nitrogen and
the hydrogenation was then continued for a further 24 h. The
reaction mixture was filtered through a short column of
celite.RTM., eluted copiously with ethanol. The filtrate was
evaporated and the residue was partitioned between methylene
chloride and 1N sodium hydroxide. The organic layer was separated
and the aqueous phase was re-extracted twice with methylene
chloride. The combined organic extracts were washed with water,
brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo to give
crude (.about.70% pure) 3-7 as a colorless foam.
Step G: Preparation of tert-butyl
4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlor-
ophenyl}piperidine-1-carboxylate (3-8)
[0439] Acetyl chloride (1.71 mL, 24.0 mmol) was added to a solution
of crude tert-butyl
4-{2-[(1S)-1-aminoethyl]-4-chlorophenyl}piperidine-1-car- boxylate
(3-7) (5.42 g of .about.70% pure material, 11.2 mmol) and
triethylamine (6.69 mL, 48.0 mmol) in dichloromethane at
approximately 0.degree. C. After 2 h, the reaction mixture was
poured into water and extracted three times with ethyl acetate. The
combined organic extracts were washed with brine, dried
(MgSO.sub.4) and concentrated in vacuo. Purification of the crude
residue by flash chromatography on silica gel (gradient elution; 35
to 50% ethyl acetate/hexanes as eluent) provided tert-butyl
4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlorophenyl}piperidine-1-c-
arboxylate (3-8) as a pale yellow foam (4.1 g). If desired, traces
of the minor R-enantiomer could be removed using preparative chiral
high pressure liquid chromatography on CHIRALPAK AD Phase, (7.5%
ethano/heptanes as eluent) to give in order of elution:
R-enantiomer as a colorless solid followed by the S-enantiomer as a
colorless solid.
Step H: Preparation of
N-[(1S)-1-(5-chloro-2-piperidin-4-ylphenyl)ethyl]ac- etamide
hydrochloride (3-9)
[0440] A saturated solution of hydrogen chloride in ethyl acetate
(15 mL) was added to a stirred solution of tert-butyl
4-{2-[(1S)-1-(acetylamino)e-
thyl]-4-chlorophenyl}piperidine-1-carboxylate (3-8) (3.66 g, 9.61
mmol) in methylene chloride (15 mL) at 0.degree. C. After 3 h, the
volatiles were evaporated in vacuo, and the crude residue
triturated twice with dry diethyl ether to give 3-9 (3.05 g) as a
colorless solid.
Step I: Preparation of
N-{(1S)-1-[2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-diflu-
orophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]ethyl}ac-
etamide (3-10)
[0441] N,N-diisopropylethylamine (5.86 mL, 33.6 mmol) was added to
a stirred suspension of
(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolid-
ine-3-carboxylic acid hydrochloride (3-9) (3.07 g, 9.61 mmol),
N-[(1S)-1-(5-chloro-2-piperidin-4-ylphenyl)ethyl]acetamide
hydrochloride (3.05 g, 9.61 mmol), and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylur- onium
hexafluoro-phosphate (4.38 g, 11.5 mmol) in N,N-dimethylformamide
(20 mL) at ambient temperature. After approximately 18 h, the
reaction mixture was poured water and extracted three times with
ethyl acetate. The combined organic extracts were washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
Purification of the residue by flash chromatography on silica gel
(gradient elution; 0-9% methanol (containing 10% v/v ammonium
hydroxide)/methylene chloride as eluent) provided 3-10 (5.2 g) as a
foam m/z (ES) 546 (MH.sup.+).
[0442] High resolution mass spectrum: calcd. for
C.sub.30H.sub.39ClF.sub.2- N.sub.3O.sub.2: (MH+): m/z 546.26.2699;
Found: m/z 546.2693.
[0443] The hydrochloride salt of 3-10 was prepared as follows: A
saturated solution of hyrogen chloride in ethyl acetate (20 mL) was
added to a stirred solution of 3-10 (5.20 g 9.52 mmol) in methylene
chloride (20 mL) at 0.degree. C. After 10 min, the volatiles were
evaporated in vacuo, and the crude residue was triturated twice
with dry diethyl ether give 3-10 HCl (5.55 g) as a colorless
solid.
[0444] Following procedures similar to that described above and for
Example 1, the following compounds were prepared:
3 134 Parent Ion m/z Ex. # R.sup.3a R.sup.3b (M + H) 105 H NH.sub.2
442 106 H 135 484 107 H 136 498 108 H 137 512 109 H 138 526 110 H
139 552 111 H 140 540 112 H 141 538 113 H 142 566 114 H 143 564 115
H 144 546 116 H 145 520 117 H 146 456 118 H 147 541 119 H 148 541
120 H 149 513 121 H 150 513 122 H 151 555 123 H 152 498 124 H 153
512 125 H 154 526 126 H 155 540 127 H 156 555 128 H 157 526 129 H
158 541 130 H 159 131 H 160 601 132 H 161 538 133 H 162 537 134 H
163 554 135 H 164 537 136 H 165 552 137 H 166 537 138 H 167 551 139
H 168 468 140 Cl 169 504 141 Cl 170 546 142 F 171 530 143 Cl 172
546 144 Cl 173 546 145 Cl 174 586 146 F 175 147 Cl 176 560 148 F
177 149 Cl 178 574 150 Cl 179 588 151 Cl 180 561 152 F 181 153 Cl
182 603 154 Cl 183 155 F 184 544 156 H 185 157 H 186 512 158 Cl 187
544 159 Cl 188 544 160 F 189 544 161 CF.sub.3 190 580 162 Cl 191
560 163 Et 192 540 164 Cl 193 504 165 Cl 194 614 166 Cl 195 615 167
Cl 196 612 168 Cl 197 610 169 Cl 198 574 170 Cl 199 610 171 Cl 200
544 172 Cl 201 544 173 Cl 202 546 174 Cl 203 558 175 Cl 204 544 176
Cl 205 544 177 Cl 206 546 178 Cl 207 546 179 F 208 530 180 F 209
530
EXAMPLES 181-184
[0445] Following a procedure similar to that described above for
Example 1 but using corresponding
1-(t-butyl)-3-(2,4-difluorophenyl)-piperidine-4-c- arboxylic acid
intermediate for the peptide coupling reaction with an
appropriately substituted 4-phenyl-piperidine intermediate, the
following compounds were prepared:
4 210 Parent Ion m/z Ex. # R.sup.3a R.sup.3b (M + H) 181 H COOMe
499 182 H 211 498 183 H CH.sub.2CH.sub.2CN 184 Cl COOMe 533
EXAMPLE 185
[0446] 212
[0447] This example was prepared following a procedure similar to
that described above for Example 1 but using
(3R,4S)-1-tert-butyl-4-(2,4-diflu-
orophenyl)pyrrolidine-3-carboxylic acid for the peptide coupling
reaction; mass spectrum: m/z 518 (M+H).
EXAMPLE 186
[0448] Following procedures similar to that described above for
Example 1, the following compound was also prepared: 213
Biological Assays
[0449] A. Binding Assay. The Membrane Binding Assay was Used to
Identify Competitive Inhibitors of .sup.125I-NDP-Alpha-MSH Binding
to Cloned Human MCRs Expressed in Mouse L- or Chinese Hamster Ovary
(CHO)-Cells.
[0450] Cell lines expressing melanocortin receptors were grown in
T-180 flasks containing selective medium of the composition: I L
Dulbecco's modified Eagles Medium (DMEM) with 4.5 g L-glucose, 25
mM Hepes, without sodium pyruvate, (Gibco/BR1); 100 ml 10%
heat-inactivated fetal bovine serum (Sigma); 10 mL 10,000 unit/mL
penicillin & 10,000 .mu.g/mL streptomycin (Gibco/BR1); 10 ml
200 mM L-glutamine (Gibco/BR1); 1 mg/mL geneticin (G418)
(Gibco/BR1). The cells were grown at 37.degree. C. with CO.sub.2
and humidity control until the desired cell density and cell number
was obtained.
[0451] The medium was poured off and 10 mls/monolayer of
enzyme-free dissociation media (Specialty Media Inc.) was added.
The cells were incubated at 37.degree. C. for 10 min or until cells
sloughed off when flask was banged against hand.
[0452] The cells were harvested into 200 mL centrifuge tubes and
spun at 1000 rpm, 4.degree. C., for 10 min. The supernatant was
discarded and the cells were resuspended in 5 mls/monolayer
membrane preparation buffer having the composition: 10 mM Tris pH
7.2-7.4; 4 .mu.g/mL Leupeptin (Sigma); 10 .mu.M Phosphoramidon
(Boehringer Mannheim); 40 .mu.g/mL Bacitracin (Sigma); 5 .mu.g/mL
Aprotinin (Sigma); 10 mM Pefabloc (Boehringer Mannheim). The cells
were homogenized with motor-driven dounce (Talboy setting 40),
using 10 strokes and the homogenate centrifuged at 6,000 rpm,
4.degree. C., for 15 min.
[0453] The pellets were resuspended in 0.2 mls/monolayer membrane
prep buffer and aliquots were placed in tubes (500-1000 .mu.L/tube)
and quick frozen in liquid nitrogen and then stored at -80.degree.
C.
[0454] Test compounds or unlabelled NDP-.alpha.-MSH was added to
100 .mu.L of membrane binding buffer to a final concentration of 1
.mu.M. The membrane binding buffer had the composition: 50 mM Tris
pH 7.2; 2 mM CaCl.sub.2; 1 mM MgCl.sub.2; 5 mM KCl; 0.2% BSA; 4
.mu.g/mL Leupeptin (SIGMA); 10 .mu.M Phosphoramidon (Boehringer
Mannheim); 40 .mu.g/mL Bacitracin (SIGMA); 5 .mu.g/mL Aprotinin
(SIGMA); and 10 mM Pefabloc (Boehringer Mannheim). One hundred
.mu.L of membrane binding buffer containing 10-40 .mu.g membrane
protein was added, followed by 100 .mu.M .sup.125I-NDP-.alpha.-MSH
to final concentration of 100 .mu.M. The resulting mixture was
vortexed briefly and incubated for 90-120 min at room temp while
shaking.
[0455] The mixture was filtered with Packard Microplate 196 filter
apparatus using Packard Unifilter 96-well GF/C filter with 0.1%
polyethyleneimine (Sigma). The filter was washed (5 times with a
total of 10 .mu.L per well) with room temperature of filter wash
having the composition: 50 mM Tris-HCl pH 7.2 and 20 mM NaCl. The
filter was dried, and the bottom sealed and 50 .mu.L of Packard
Microscint-20 was added to each well. The top was sealed and the
radioactivity quantitated in a Packard Topcount Microplate
Scintillation counter.
[0456] B. Functional Assay. Functional Cell Based Assays Were
Developed to Discriminate Melanocortin Receptor Agonists from
Antagonists.
[0457] Cells (for example, CHO-- or L-cells or other eukaryotic
cells) expressing a human melanocortin receptor (see e.g. Yang-Y K;
Ollmann-M M; Wilson-B D; Dickinson-C; Yamada-T; Barsh-G S; Gantz-I;
Mol-Endocrinol. March 1997; 11(3): 274-80) were dissociated from
tissue culture flasks by rinsing with Ca and Mg free phosphate
buffered saline (14190-136, Life Technologies, Gaithersburg, Md.)
and detached following 5 min incubation at 37.degree. C. with
enzyme free dissociation buffer (S-014-B, Specialty Media,
Lavellette, N.J.). Cells were collected by centrifugation and
resuspended in Earle's Balanced Salt Solution (14015-069, Life
Technologies, Gaithersburg, Md.) with additions of 10 mM HEPES pH
7.5, 5 mM MgCl.sub.2, 1 mM glutamine and 1 mg/ml bovine serum
albumin. Cells were counted and diluted to 1 to
5.times.10.sup.6/mL. The phosphodiesterase inhibitor
3-isobutyl-1-methylxanthine was added to cells to 0.6 mM.
[0458] Test compounds were diluted in dimethylsulfoxide (DMSO)
(10.sup.-5 to 10.sup.-10 M) and 0.1 volume of compound solution was
added to 0.9 volumes of cell suspension; the final DMSO
concentration was 1%. After room temperature incubation for 45 min,
cells were lysed by incubation at 100.degree. C. for 5 min to
release accumulated cAMP.
[0459] cAMP was measured in an aliquot of the cell lysate with the
Amersham (Arlington Heights, Ill.) cAMP detection assay (RPA556).
The amount of cAMP production which resulted from an unknown
compound was compared to that amount of cAMP produced in response
to alpha-MSH which was defined as a 100% agonist. The EC.sub.50 is
defined as the compound concentration which results in half maximal
stimulation, when compared to its own maximal level of
stimulation.
[0460] Antagonist assay: Antagonist activity was defined as the
ability of a compound to block cAMP production in response to
alpha-MSH. Solution of test compounds and suspension of receptor
containing cells were prepared and mixed as described above; the
mixture was incubated for 15 min, and an EC.sub.50 dose
(approximately 10 nM alpha-MSH) was added to the cells. The assay
was terminated at 45 min and cAMP quantitated as above. Percent
inhibition was determined by comparing the amount of cAMP produced
in the presence to that produced in the absence of test
compound;
[0461] C. In Vivo Food Intake Models.
[0462] 1) Overnight food intake. Sprague Dawley rats are injected
intracerebroventricularly with a test compound in 400 nL of 50%
propylene glycol/artificial cerebrospinal fluid one hour prior to
onset of dark cycle (12 hours). Food intake is determined using a
computerized system in which each rat's food is placed on a
computer monitored balance. Cumulative food intake for 16 h post
compound administration is measured.
[0463] 2) Food intake in diet induced obese mice. Male C57/B316J
mice maintained on a high fat diet (60% fat calories) for 6.5
months from 4 weeks of age are are dosed intraperitoneally with
test compound. Food intake and body weight are measured over an
eight day period. Biochemical parameters relating to obesity,
including leptin, insulin, triglyceride, free fatty acid,
cholesterol and serum glucose levels are determined.
[0464] D. Rat Ex Copula Assay
[0465] Sexually mature male Caesarian Derived Sprague Dawley (CD)
rats (over 60 days old) are used with the suspensory ligament
surgically removed to prevent retraction of the penis back into the
penile sheath during the ex copula evaluations. Animals receive
food and water ad lib and are kept on a normal light/dark cycle.
Studies are conducted during the light cycle.
[0466] 1) Conditioning to Supine Restraint for Ex Copula Reflex
Tests. This conditioning takes .about.4 days. Day 1, the animals
are placed in a darkened restrainer and left for 15-30 minutes. Day
2, the animals are restrained in a supine position in the
restrainer for 15-30 minutes. Day 3, the animals are restrained in
the supine position with the penile sheath retracted for 15-30
minutes. Day 4, the animals are restrained in the supine position
with the penile sheath retracted until penile responses are
observed. Some animals require additional days of conditioning
before they are completely acclimated to the procedures;
non-responders are removed from further evaluation. After any
handling or evaluation animals are given a treat to ensure positive
reinforcement.
[0467] 2) Ex Copula Reflex Tests. Rats are gently restrained in a
supine position with their anterior torso placed inside a cylinder
of adequate size to allow for normal head and paw grooming. For a
400-500 gram rat, the diameter of the cylinder is approximately 8
cm. The lower torso and hind limbs are restrained with a
non-adhesive material (vetrap). An additional piece of vetrap with
a hole in it, through which the glans penis will be passed, is
fastened over the animal to maintain the preputial sheath in a
retracted position. Penile responses will be observed, typically
termed ex copula genital reflex tests. Typically, a series of
penile erections will occur spontaneously within a few minutes
after sheath retraction. The types of normal reflexogenic erectile
responses include elongation, engorgement, cup and flip. An
elongation is classified as an extension of the penile body.
Engorgement is a dilation of the glans penis. A cup is defined as
an intense erection where the distal margin of the glans penis
momentarily flares open to form a cup. A flip is a dorsiflexion of
the penile body.
[0468] Baseline and or vehicle evaluations are conducted to
determine how and if an animal will respond. Some animals have a
long duration until the first response while others are
non-responders altogether. During this baseline evaluation latency
to first response, number and type of responses are recorded. The
testing time frame is 15 minutes after the first response.
[0469] After a minimum of 1 day between evaluations, these same
animals are administered the test compound at 20 mg/kg and
evaluated for penile reflexes. All evaluations are videotaped and
scored later. Data are collected and analyzed using paired 2 tailed
t-tests to compared baseline and/or vehicle evaluations to drug
treated evaluations for individual animals. Groups of a minimum of
4 animals are utilized to reduce variability.
[0470] Positive reference controls are included in each study to
assure the validity of the study. Animals can be dosed by a number
of routes of administration depending on the nature of the study to
be performed. The routes of administration includes intravenous
(IV), intraperitoneal (IP), subcutaneous (SC) and intracerebral
ventricular (ICV).
[0471] E. Models of Female Sexual Dysfunction
[0472] Rodent assays relevant to female sexual receptivity include
the behavioral model of lordosis and direct observations of
copulatory activity. There is also a urethrogenital reflex model in
anesthetized spinally transected rats for measuring orgasm in both
male and female rats. These and other established animal models of
female sexual dysfunction are described in McKenna K E et al, A
Model For The Study of Sexual Function In Anesthetized Male And
Female Rats., Am. J. Physiol. (Regulatory Integrative Comp. Physiol
30): R1276-R1285, 1991; McKenna K E et al, Modulation By Peripheral
Serotonin of The Threshold For Sexual Reflexes In Female Rats,
Pharm. Bioch. Behav., 40:151-156, 1991;. and Takahashi L K et al,
Dual Estradiol Action In The Diencephalon And The Regulation Of
Sociosexual Behavior In Female Golden Hamsters, Brain Res.,
359:194-207, 1985.
[0473] Representative compounds of the present invention were
tested and found to bind to the melanocortin-4 receptor. These
compounds were generally found to have IC.sub.50 values less than 2
.mu.M. Representative compounds of the present invention were also
tested in the functional assay and found generally to activate the
melanocortin-4 receptor with EC.sub.50 values less than 1
.mu.M.
Examples of a Pharmaceutical Compositions
[0474] As a specific embodiment of an oral composition of a
composition of the present invention, 5 mg of Example 168 is
formulated with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size O hard gelatin
capsule.
[0475] As another specific embodiment of an oral composition of a
compound of the present invention, 2.5 mg of Example 104 is
formulated with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size O hard gelatin
capsule.
[0476] As another specific embodiment of an oral composition of a
compound of the present invention, 10 mg of Example 88 is
formulated with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size O hard gelatin
capsule.
[0477] While the invention has been described and illustrated in
reference to certain preferred embodiments thereof, those skilled
in the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the preferred doses as set forth hereinabove may be applicable
as a consequence of variations in the responsiveness of the mammal
being treated for severity of bone disorders caused by resorption,
or for other indications for the compounds of the invention
indicated above. Likewise, the specific pharmacological responses
observed may vary according to and depending upon the particular
active compound selected or whether there are present
pharmaceutical carriers, as well as the type of formulation and
mode of administration employed, and such expected variations or
differences in the results are contemplated in accordance with the
objects and practices of the present invention. It is intended,
therefore, that the invention be limited only by the scope of the
claims which follow and that such claims be interpreted as broadly
as is reasonable.
* * * * *