6.5-PYRROLOPIPERIDINE TACHYKININ RECEPTOR ANTAGONISTS

ANTAGONISTES 6,5-PYRROLOPIPERIDINE DES RECEPTEURS DE TACHYKININE

English Abstract

The present invention is directed to certain hydroxymethyl ether
hydroisoindoline compounds which are useful as
neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in
particular substance P. The invention is also concerned
with pharmaceutical formulations comprising these compounds as active
ingredients and the use of the compounds and their
formulations in the treatment of certain disorders, including emesis, urinary
incontinence, LUTS, depression, and anxiety.

French Abstract

L'invention concerne certains composés hydroisoindolines d'hydroxyméthyl éther qui sont utiles en tant qu'antagonistes du récepteur de neurokinine-1 (NK-1), et des inhibiteurs de tachykinine et en particulier de la substance P. L'invention concerne également des formulations pharmaceutiques comprenant ces composés comme principes actifs et l'utilisation des composés et de leurs formulations dans le traitement de certains troubles, y compris l'émèse, l'incontinence urinaire, les SBAU, la dépression et l'anxiété.

Claims

WHAT IS CLAIMED IS:


1. A compound of the formula I:
Image
and pharmaceutically acceptable salts thereof and individual enantiomers and
diastereomers
thereof, wherein:
X is N or CH,
R1 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl, -
COOH,
or phenyl,
(3) cyclopentenone,
(4) -(CO)-C1-6alkyl, which is optionally substituted with hydroxyl,
(5) -(CO)-NH2,
(6) -(CO)-NHC1-6alkyl,
(7) -(CO)-N(C1-6alkyl)(C1-6alkyl),
(8) -C1-4alkyl-(CO)-NH2,
(9) -C1-4alkyl-(CO)-NHC1-6alkyl,
(10)-C1-4alkyl-(CO)-N(C1-6alkyl)(C1-6alkyl),
(11) -(CO)-O-C1-6alkyl,
(12) -(CO)-C3-6cycloalkyl,

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Image
(14) -(CO)-HET, wherein HET is selected from the group consisting of

Image
Wherein Ra is selected from H, and C1-3alkyl and Rb is selected from H, C1-
4alkyl, -(CO)-CH3
and -(CO)-NH2,
R2, R3, R4 and R5 are each independently selected from the group consisting
of:
(1) hydrogen, and
(2) methyl;
R6 is independently selected from the group consisting of:
(1) hydrogen, and
(2) fluorine.

2. The compound of Claim l of the formula Ia:
Image
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wherein R1, R2, R3, R4, R5, R6, and X are defined herein,
or a pharmaceutically acceptable salt thereof and individual enantiomers and
diastereomers
thereof.

3. A compound according to Claim 1 wherein R1 is selected from the group
consisting of
R1 is selected from the group consisting of:
(1) hydrogen,
(2) C1-3alkyl, which is unsubstituted or substituted with hydroxyl or phenyl,
(3) cyclopent-2-en-1-one, which is unsubstituted or substituted with hydroxyl,

(4) -(CO)-C1-3alkyl,
(5) -(CO)-NH2,
(6) -(CO)-NHC1-3alkyl,
(7) -(CO)-N(C1-3alkyl)(C1-3alkyl), and
Image

wherein the alkyl portion of choices (4),(6) and (7) of R1 are optionally
substituted with halo,
hydroxyl or phenyl.

4. The compound of Claim 1 wherein R1 is selected from the group
consisting of:
(1) hydrogen,
(2) cyclopent-2-en-1-one,
(3) 1,2-oxazol-4(5H)-one,
(4) 2,2-dimethylpropanoyl,
(5) methylpropanoyl,
(6) CH3NH-(CO)-,
(7) (CH3)2-N-(CO)-, and
Image

5. The compound of Claim 1 wherein R6 is hydrogen.
6. The compound of Claim 1 wherein R6 is fluorine.
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7. The compound of Claim 1 wherein R5 is hydrogen.
8. The compound of Claim 1 wherein R5 is methyl.

9. The compound of Claim 1 wherein X is N.
10. The compound of Claim 1 of the formula Ia:
Image

or a pharmaceutically acceptable salt thereof and individual enantiomers and
diastereomers
thereof wherein
X is N or CH,
R1 is selected from the group consisting of:
(1) hydrogen,
(2) cyclopent-2-en-1-one,
(3) 1,2-oxazol-4(5H)-one,
(4) 2,2-dimethylpropanoyl,
(5) methylpropanoyl,
(6) CH3NH-(CO)-,
(7) (CH3)2-N-(CO)-, and
Image

R6 is independently selected from the group consisting of:
(1) hydrogen, and
(2) fluorine;
R5 is independently selected from the group consisting of:
(1) hydrogen, and

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(2) methyl.

11. A cornpotund according to claim 10 wherein X is N.

12. A compound which is selected from the group consisting of:
Image
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Image
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Image
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Image
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Image
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Image
or a pharmaceutically acceptable salt thereof

13. A pharmaceutical composition which comprises an inert carrier and a
compound of Claim 1.

14. A method for the treatment of pain or inflammation, migraine, emesis,
postherpetic neuralgia, depression, anxiety or urinary incontenence, and LUTS
which method
comprises administration to a patient in need thereof a therapeutically
effective amount of the
compound of Claim 1.

15. A method according to Claim 14 for the treatment of urinary incontinence
or LUTS.

16. A method of antagonizing the effect of substance P at its receptor site or

for the blockade of neurokinin-1 receptors in a patient in need thereof
comprising administration
to said patient a therapeutically effective amount of the compound of Claim 1.

17. A method of treating a physiological disorder associated with an excess of

tachykinins in a patient in need thereof comprising administration to said
patient a therapeutically
effective amount of a compound of Claim 1.

18. Use of a compound according to Claim 1 for the manufacture of a
medicament for antagonizing the effect of substance P at its receptor site or
for the blockade of
neurokinin-1 receptors in a mammal comprising combining a compound of the
present invention
or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier or
diluent.

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Description

CA 02690737 2009-12-11
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TITLE OF THE INVENTION
6.5 -PYRROLOPIPERIDINE TACHYKININ RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
Substance P is a naturally occurring undecapeptide belonging to the tachykinin
family of peptides, the latter being so-named because of their prompt
contractile action on
extravascular smooth muscle tissue. The tachykinins are distinguished by a
conserved carboxyl-
terminal sequence. In addition to substance P, the known mammalian tachykinins
include
neurokinin A and neurokinin B. The current nomenclature designates the
receptors for substance
P, neurokinin A, and neurokinin B as neurokinin- I(NK-1), neurokinin-2 (NK-2),
and
neurokinin-3 (NK-3), respectively.
Tachykinin, and in particular substance P, antagonists are useful in the
treatment
of clinical conditions which are characterized by the presence of an excess of
tachykinin, in
particular substance P, activity, including disorders of the central nervous
system, nociception
and pain, gastrointestinal disorders, disorders of bladder fiinction and
respiratory diseases.
SUMMARY OF THE INVENTION
The present invention is directed to certain hydroxymethyl ether
hydroisoindoline
compounds of Formula (I) which are useful as neurokinin-l. (NK-1) receptor
antagonists, and
inhibitors of tachykinin and in particular substance P. The invention is also
concerned with
pharmaceutical formulations comprising these compounds as active ingredients
and the use of
the compounds and their forinulations in the treatment of certain disorders,
including emesis,
urinary incontinence, LUTS, depression, and anxiety.

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DETAILED DESCRIPTION OF TI-IE INVENTION
In one embodiment the present invention is directed to coznpou.nds of the
formula
F3C ~ CF3

/
R~ R3
x R4

N Q

R'5
N
I
R'
and pharmaceutically acceptable salts thereof aald individual enantiomers and
diastereomers
thereof, wherein:
X is N or CH;
RI is selected from the group consisting of
(1) hydrogen,
(2) C X-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl, -
COOH,
or phenyl,
(3) cyclopentenone,
(4) -(CO)-C I _6alkyl, which is optionally substituted with hydroxyl,
(5) -(CO)-NH2,
(6) -(CO)-NHC I _6alkyl,
(7) --(C O)-N(C 1..6alkyl)(C I _6alkyl),
(8) -CI..4alkyl-(CO)-NH2,
(9) -C I..4alkyl-(CO)-NHC I ..6alkyl,
(10) -C 1 _q.alkyl-(C O)-N(C i _&alkyl)(C 1 -6alkyl),
( I 1) -(C O)-O-C I_6alkyl,
(12) -(CO)-C3_6cycloalkyl,

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N_.~~ -\
0~ ~O or Ci
or oro
0
N~~A
~~ or
(13) O
(14) -(CO)-HET, wherein HET is selected from the group consisting of
Ra

0 NH 0--Rb
o X
N
OD and
HD
Wherein Ra is selected from H, and C I_3alkyl and Rb is selected fromH, C
1_4alkyl, -(CO)-CH3
and -(CO)-NH2,
R2, R3, R4 and R5 are each independently selected from the group consisting
of:
(1) hydrogen, and
(2) methyl;
R6 is independently selected from the group consisting of:
(1) hydrogen, and
(2) fluorine.
Within this embodiment there is a genus of compound of formula Ia:
F3C CF3

R? Rs
X R4
N ~0-
R 6
R5
N
I
R' Za

wherein RI, R2, R3, R4, R5, R6, and X are defined herein,
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or a pharmaceutically acceptable salt thereof and individual enantiomers and
diastereomers
thereof.

Within this embodiment there is a genus of compounds of Formula I wherein
R1 is selected from the group consisting ofl
(1) hydrogen,
(2) C 1 -3 alkyl, which is unsubstituted or substituted with hydroxyl or
phenyl,
(3) cyclopent-2-en-J.-one, which is unsubstituted or substituted with
hydroxyl,
(4) -(CO)-C1-3alkyl,
(5) --(CO)-NH2,
(6) =-(CO)TNHC 1-3 alkyl,
(7) =-(CO)-N(C 1-3alkyl)(C 1-3 alkyl), and
N

O_-~O
(8)

wherein the alkyl portion of choices (4), (6) and (7) of R1 are optionally
substituted with halo,
hydroxyl or phenyl.

Within this embodiment there is a genus of compounds of Formula I wherein R1
is selected from the group consisting of:
(1) hydrogen,
(2) cyclopent-2-en-l-one,
(3) 1,2-oxazol-4(51-1')-one,
(4) 2,2-dimethylpropanoyl,
(5) nzethylpropanoyl,
(6) CH3NH-(CO)-,
(7) (CH3)2-N-(CO)-, and
O N
~O
~g)

Within this embodiment there is a genus of compounds of Formula I wherein R6
is hydrogen.

Withzn this embodiment there is a genus of compounds of Formula I wherein R6
is fluorine.

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Within this embodiment there is a genus of compounds of Foz-znula I wherein R5
is hydrogen.

Within this embodiment there is a genus of compounds of Formula I wherein R5
is methyl.

Within this embodiment there is a genus of compounds of formula Ia :
F3C CF3

1
R2 R3
X R4

N X' O
R6
R5
N
I
R' Ia

or a pharinaceutically acceptable salt thereof and individual enantiomers and
diastereomers
thereof wherein
R1 is selected from the group consisting of:
(1) hydrogen,
(2) cyclopent-2-en- I -one,
(3) 1,2-oxazoZ-4(5H)-one,
(4) 2,2-dimethylpropazaoyl,
(5) methylpropanoyl,
(6) CH3NH-(CO)-,
(7) (CH3)2-N-(CO)-, and
O~[O
(8) 9
R6 is independently selected from the group consisting of
( I ) hydrogen, and
(2) fluorine;
R5 is independently selected from the group consisting of:
(1) hydrogen,and

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(2) methyl.

Within this embodiment, it is preferred that X is N.
Specific embodiments of the present invention include a compound which is
selected from the group consisting of the subject compounds of the Examples
herein and
pharmaceutically acceptable salts thereof and individual enantiomers and
diastereomers thereof.

Specific embodiments of the present invention include a compound which is
selected from the group consisting of the subject compounds of the Examples
herein and
phan-naceutically acceptable salts thereof and individual enantiomers and
diastereomers thereof.
The compounds of the present invention may contain one or more asymmetric
centers and can thus occur as racemates and racemic inixtu.res, single
enantiomers,
diastereomeric mixtures and individual diastereomers. Additional asymmetric
centers may be
present depending upon the nature of the various substituents on the molecule.
Each such
asyznmetric center will independently produce two optical isomers and it is
intended that all of
the possible optical isomers and diastereomers in mixtures and as pure or
partially purified
compounds are included within the ambit of this invention. The present
invention is meant to
comprehend all such isomeric forms of these compoun.ds. Formula I shows the
stracture of the
class of compounds without preferred stereochemistry. The independent
syntheses of these
diastereomers or their chromatographic separations may be achieved as known in
the art by
appropriate modification of the methodology disclosed herein. Their absolute
stereochemistry
may be determined by the x-ray crystallography of crystalline products or
crystalline
intermediates which are derivatized, if necessary, with a reagent containing
an asymmetric center
of known absolute configuration. If desired, racemic mixtures of the
coinpounds may be
separated so that the individual enantiomers are isolated. The separation can
be carried out by
methods well known in the art, such as the coupling of a racemic mixture of
compounds to an
enantiomerically pure compound to form a diastereomeric mixture, followed by
separation of the
individual diastereomers by standard methods, such as fractional
crystallization or
chromatography. The coupling reaction is often the formation of salts using an
enantiornerically
pure acid or base. The diasteromeric derivatives may then be converted to the
pure enantiomers
by cleavage of the added chiral residue. The racemic mixture of the compounds
can also be
separated directly by chromatographic methods utilizing chiral stationary
phases, which methods
are well known in the art. Alternatively, any enantiomer of a compound may be
obtained by
stereoselective synthesis using optically pure starting materials or reagents
of known
confzguration by methods well known in the art.
There are several acceptable methods of naming the compounds discussed herein:
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,OH
N CH3
~ ~ CH~
0 ~ CH3

For example, the above compound can be named either as "(3aR,4R,5S,7aR) tert-
butyl-5-hydroxy-4-(2-zn.ethylphenyl)octahydro-2H-isoindole-2-carboxylate" or
"tert-butyl
(3aR,4R,5S,7aR)-5-hydroxy-4-phenyloctahydro-2H-isoandole-2-carboxylate". The
core structure
may be generally referred to as octahydroisoindole, hexahydroisoindoline,
perhydroisoindoline,
hydroisoindoline, or hydroisoindole compounds.
As appreciated by those of skill in the art, halo or halogen as used herein
are
intended to include fluoro, chloro, bromo and iodo. Similarly, C i_g, as in C
1_6alkyl is defined to
identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or
branched arrangement, such
that Cl_8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-
butyl, iso-butyl, tert-
butyl, pentyl, and hexyl. A group which is designated as being independently
substituted with
substituents may be independently substituted with multiple numbers of such
substituents.
The ternm "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, amm.onium,
calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts,
manganous, potassium,
sodium, zinc, and the like. Particularly preferred are the ammonium, calcium,
magnesium,
potassium, and sodium salts. Salts in the solid form may exist in more than
one crystal structure,
and may also be in the form of hydrates. 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'-dibenzylethylene-diamine,
diethylamine, 2-
diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediatnine,
N-ethyl-
morpholine, N-ethylpiperidine, glucarnine, glucosamine, histidine,
hydrabamine, isopropylamine,
lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines,
theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and
the like. When
the compound of the present invention is basic, salts may be prepared from
phannaceutically
acceptable non-toxic acids, including inorganic and organic acids. Such acids
include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, funa.aric,
gluconic, glutarnic,
hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic,
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nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-
toluenesulfonic acid, and
the like. Particularly preferred are citric, hydrobromic, hydrochloric,
maleic, phosphoric,
sulfuric, fu.nlaric, and tartaric acids. It will be understood that, as used
herein, references to the
compounds of the present invention are meant to also include the
pharmaceutically acceptable
salts.
Exemplifying the invention is the use of the compounds disclosed in the
Examples and herein. Specific compounds within the present invention include a
compound
which selected from the group consisting of the compounds disclosed in the
following Examples
and pharmaceutically acceptable salts thereof and individual diastereomers
thereof.
The compounds of the present invention are useful in the prevention and
treatment of a wide variety of clinical conditions which are characterized by
the presence of an
excess of tachykinin, in particular substance P, activity. Thus, for example,
an excess of
tachykinin, and in particular substance P, activity is implicated in a variety
of disorders of the
central nervous system. Such disorders include mood disorders, such as
depression or more
particularly depressive disorders, for example, single episodic or recurrent
major depressive
disorders and dysthymic disorders, or bipolar disorders, for example, bipolar
I disorder, bipolar Il
disorder and cyclothymic disorder; anxiety disorders, such as panic disorder
with or without
agoraphobia, agoraphobia without history of panic disorder, specific phobias,
for example,
specific anirn.al phobias, social phobias, obsessive-coin.pul,sive disorder,
stress disorders
including post-traumatic stress disorder and acute stress disorder, and
generalised anxiety
disorders; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders,
schizoaffective disorders, delusional disorders, brief psychotic disorders,
shared psychotic
disorders and psychotic disorders with delusions or hallucinations; delerium,
dementia, and
amnestic and other cognitive or neurodegenerative disorders, such as
Alzheimer's disease, senile
dementia, dementia of the Alzheimer's type, vascular dementia, and other
dementias, for
example, due to HIV disease, head trauma, Parkinson's disease, Huntington's
disease, Pick's
disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies;
Parkinson's disease and other
extra-pyramidal movement disorders such as medication-induced movement
disorders, for
example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome,
neuroleptic-
induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-
induced tardive
dyskinesia and medication-induced postural tremour; substance-related
disorders arising from the
use of alcohol, arnphetamines (or amphetamine-like substances) caffeine,
cannabis, cocaine,
hallucinogens, inhalants and aerosol propellants, nicotine, opioids,
phenylglycidine derivatives,
sedatives, hypnotics, and anxiolytics, which substance-related disorders
include dependence and
abuse, intoxication, withdrawal, intoxication deleriwn, withdrawal delerium,
persisting dementia,
psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and
sleep disorders;
epilepsy; Down's syndrome; demyelinating diseases such as MS and ALS and other

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neuropathological disorders such as peripheral neuropathy, for example
diabetic and
chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal
neuralgia, segmental
or intercostal neuralgia and other neuralgias; and cerebral vascular disorders
due to acute or
chron.ic cerebrovascular damage such as cerebral infarction, subarachnoid haen-
iorrhage or
cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in
nociception
and pain. The compounds of the present invention will therefore be of use in
the prevention or
treatment of diseases and conditions in which pain predominates, including
soft tissue and
peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis,
zxa.usculo-skeletal
pain, particularly after trauma, spinal pain, myofascial pain syndromes,
headache, episiotomy
pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye
pain, orofacial pain,
for example, odontalgia, abdominal pain, gynaecological pain, for example,
dysmenorrhoea, and
labour pain; pain associated with nerve and root damage, such as pain
associated with peripheral
nerve disorders, for example, nerve entrapment and brachial plexus avulsions,
amputation,
peripheral neuropathies, tic douloureux, atypical facial pain, nerve root
daixaage, and
arachnoiditis; pain associated with carcinoma, often referred to as cancer
pain; central nervous
system pain, such as pain due to spinal cord or brain stem damage; low back
pain; sciatica;
ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in
the
treatment of respiratory diseases, particularly those associated with excess
mucus secretion, such
as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis,
cystic fibrosis and
asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory
diseases such as
inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid
arthritis, pruritis and
sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders
such as poison ivy;
ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the
like; ophthalmic
conditions associated with cell proliferation such as proliferative
vitreoretinopathy; cutaneous
diseases such as contact dermatitis, atopic dermatitis, urticaria, and other
ezematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in
the
treatment of neoplasms, including breast tumours, neuroganglioblastomas and
small cell
carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in
the
treatment of gastrointestinal (GT) disorders, including inflammatory disorders
and diseases of the
GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric
lymphomas, disorders
associated with the neuronal control of viscera, ulcerative colitis, Crohn's
disease, irritable bowel
syndrome and emesis, including acute, delayed or anticipatory emesis such as
emesis induced by
chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy,
vestibular disorders, for
example, motion sickness, vertigo, dizziness and Meniere's disease, surgery,
migraine, variations
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in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion,
over indulgence in
food or drink, acid stomach, waterbrash or regurgitation, heartburn, for
example, episodic,
nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in
the
treatment of a variety of other conditions including stress related somatic
disorders; reflex
sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological
reactions such
as rejection of transplanted tissues and disorders related to immune
enhancement or suppression
such as systemic lupus erythematosus; plasma extravasation resulting from
cytokine
chemotherapy, disorders of bladder finiction such as cystitis, bladder
detrusor hyper-reflexia,
frequent urination, urinary incontinence and LUTS, including the prevention or
treatment of
overactive bladder with symptoms of urge urinary incontinence, urgency, and
frequency;
fibrosing and collagen diseases such as scleroderma and eosinophilic
fascioliasis; disorders of
blood flow caused by vasodilation and vasospastic diseases such as angina,
vascular headache,
migraine and Reynaud`s disease; and pain or nociception attributable to or
associated with any of
the foregoing conditions, especially the transmission of pain in migraine.
As used herein, the term "urinary incontinence" is intended to include a range
of
conditions including urge incontinence, stress incontinence, overflow
incontinence, functional
incontinence, neurogenic incontinence, post-prostatectomy incontinence,
urinary frequency,
urinary urgency, nocturia, enuresis, and related conditions in mammalian
subjects. In more
detailed embodiments, the lower urinary tract disorder, or targeted symptoms
for treatment
arising therefrom, may include overactive bladder, including neurogenic and
non-neurogenic
overactive bladder, interstitial cystitis, prostatitis, prostadynia, and
benign prostatic hyperplasia.
In further embodiments, the methods and compositions of the invention are
effective for
preventing or treating excessive micturition in subjects suffering from lower
urinary tract
disorders.
The coinpounds of the present invention are also of value in the treatment of
a
combination of the above conditions, in particular in the treatment of
combined post-operative
pain and post-operative nausea and vomiting.
The compounds of the present invention are particularly useful in the
prevention
or treatment of emesis, including acute, delayed or anticipatory emesis, such
as emesis induced
by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion,
surgery, migraine,
and variations in intercranial pressure. For example, the compounds of the
present invention are
of use optionally in combination with other antiemetic agents for the
prevention of acute and
delayed nausea and vomiting associated with initial and repeat courses of
moderate or highly
emetogenic cancer chemotherapy, including high-dose cisplatin. Most
especially, the compounds
of the present invention are of use in the treatment of einesis induced by
antineoplastic
(cytotoxic) agents, including those routinely used in cancer chemotherapy, and
emesis induced by

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other pharmacological agents, for example, rolipram. Examples of such
chemotherapeutic agents
include alkylating agents, for example, ethyleneimine compounds, alkyl
sulphonates and other
compounds with an alkylating action such as nitrosoureas, cisplatin and
dacarbazine;
antimetabolites, for example, folic acid, purine or pyrimidine antagonists;
mitotic inhibitors, for
example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic
antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by
D. J. Stewart in
Nausea and Vomiting: Recent Research and Clinical,4dvances, Eds. J. Kucharczyk
et al, CRC
Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page
188. Commonly
used chemotherapeutic agents include cisplatin, dacarbazine (DTIC),
dactinomycin,
mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), loinustine
(CCNU),
doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,
etoposide,
methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and
chlorainbucil [R. T. Gralla et
al in Cancer Treatment Reports (1984) f 8(1), 163-1721.
A fu.rther aspect of the present invention comprises the use of a compound of
the
present invention for achieving a clr.ronobiologic (circadian rhythm phase-
shifting) effect and
alleviating circadian rhytlun disorders in a mammal. The present invention is
further directed to
the use of a compound of the present invention for blocking the phase-shifting
effects of light in
a m.arnrnal.
A ftuther aspect of the present invention comprises the use of a compound of
the
present invention in the treatment of Lower urinary tract symptoms (LUTS).
LUTS in men
include, but are not, restricted to a complex of obstructive (voiding) and
irritative (storage or
filling) symptoms, which include increased frequency, nocturia, poor urinary
stream and
hesitancy or delay in starting urinary flow. LUTS are recognized as arising
from changes in
urethral resistance induced by the enlarging prostate as well as contraction
of the prostatic
smooth muscle. The resulting increase in urethral resistance restricts the
outflow of urine and
causes secondary changes are induced in the bladder. A characteristic pattern
of unstable bladder
contractions, also known as irritable bladder, is often observed in men with
morphological BPH.
The present invention is fizrther directed to the use of a compound of the
present
invention or a phamxaceutically acceptable salt thereof, for enhancing or
improving sleep quality
as well as preventing and treating sleep disorders and sleep disturbances in a
mammal. hi
particular, the present invention provides a method for enhancing or improving
sleep quality by
increasing sleep efficiency and augmenting sleep maintenance. In addition, the
present invention
provides a method for preventing and treating sleep disorders and sleep
disturbances in a
mammal which comprising the administration of a compound of the present
invention or a
pharmaceutically acceptable salt thereof The present invention is useful for
the treatment of
sleep disorders, including Disorders of Initiating aiid Maintaining Sleep
(insomnias) ("DTMS")
which can arise from psychophysiological causes, as a consequence of
psychiatric disorders

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(particularly related to anxiety), from drugs and alcohol use and abuse
(particularly during
withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless
legs and non
specific REM disturbances as seen in ageing.
The particularly preferred embodiments of the instant invention are the
treatment
of emesis, urinary incontinence, depression or anxiety by administration of
the compounds of the
present invention to a subject (human or animal) in need of such treatment.
The present invention is directed to a method for the manufacture of a
medicament for antagonizing the effect of substance P at its receptor site or
for the blockade of
neurolc.inin:-1 receptors in a mammal comprising combining a compound of the
present invention
with a phara.naceutical carrier or diluent. The present invention is further
directed to a method for
the manufacture of amedicajuent for the treatment of a physiological disorder
associated with an
excess of tachykinins in a mammal comprising combining a compound of the
present invention
with a pharmaceutical carrier or d.iluent.
The present invention also provides a method for the treatrnent or prevention
of
physiological disorders associated with an excess of tachykinins, especially
substance P, which
method coinprises administration to a patient in need thereof of a tachykinin
reducing amount of
a compound of the present invention or a composition comprising a compound of
the present
invention.
As used herein, the term "treatrnent" or "to treat" refers to the
administration of
the compounds of the present invention to reduce, ameliorate, or eliminate
either the symptoms
or underlying cause of the noted disease conditions, in a subject (human or
animal) that suffers
from that condition or displays clinical indicators thereof.
The terrn "prevention" or "to prevent" refers to the administration of the
compounds of the present invention to reduce, ameliorate, or eliminate the
risk or likelihood of
occurrence of the noted disease conditions, in a subject (human or animal)
susceptible or
predisposed to that condition.
The compounds of this invention are useful for antagonizing tachykinins, in
particular substance P in the treatment of gastrointestinal disorders, central
nervous system
disorders, inflammatory diseases, pain or migraine and asthma in a mammal in
need of such
treatment. This activity can be demonstrated by the following assays.
Rece tor Ex ression in COS: To express the cloned human neurokinin-l receptor
(NK1R) transiently in COS, the eDNA for the human NK1R was cloned into the
expression
vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the
ampicillin
resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II
site.
Transfection of 20 ug of the plasmid DNA into 10 million COS cells was
achieved by
electroporation in 800 ul of transfection buffer (135 mM NaC1, 1.2 mM CaC12,
1.2 mM MgC12,
2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and
950
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uF using the IBI GENEZAPPER (IBI, New Haven, CT). The cells were incubated in
10% fetal
calf serum, 2 mM glutarnine, 100U/ml penlcillin-streptomycin, and 90 / DMEM
media (GBCO,
Grand Island, NY) in 5% C02 at 37 C for three days before the binding assay.
Stable Expression in CHO: To establish a stable cell line expressin.g the
cloned
human NK1 R, the eDNA was subeloned into the vector pRcCMV (INVTTROGEN).
Transfection of 20 ug of the plasmid DNA into CHO cells was achieved by
electroporation in
800 ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA
at 300 V and
950 uF using the IBI GENEZAPPER (IBI). The transfected cells were incubated in
CHO media
[10 % fetal calf serum, 100 U/ml pennicilin-streptomycin, 2 mM glutamine,
1/500 hypoxanthine-
thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418
(GIBCO)] in 5%.C02 at 37 C until colonies were visible. Each colony was
separated and
propagated. The cell clone with the highest number of human NKIR was selected
for
subsequent applications such as drug screening.
Assay Protocol using COS or CHO: The binding assay of human NKXR
expressed in either COS or CHO cells is based on the use of 1251-substance
F(1251-SP, from
DU PONT, Boston, MA) as a radioactively labeled ligand which competes with
unlabeled
substance P or any other ligand for binding to the human NKI R. Monolayer cell
cultures of COS
or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA,
Lavallette, NJ)
and resuspended in appropriate volume of the binding buffer (50 mM Tris pH
7.5, 5 mM MnC12,
150 mM NaCI, 0.04 mg/ml bacitracin, 0.004 rng/ml leupeptin, 0.2 rng/rnl BSA,
0.01 mM
phosphoramidon) such that 200 ul of the cell suspension would give rise to
about 10,000 cpm of
specific 1251-SP binding (approximately 50,000 to 200,000 cells). In the
binding assay, 200 ul
of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 1251_SP and
20 ul of unlabeled
substance P or any other test compound. The tubes were incubated at 4 C or at
room
temperature for 1 hour with gentle shaking. The bound radioactivity was
separated from
unbou.nd radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) which was
pre-wetted
with 0.1 % polyethylenimine. The filter was washed with 3 ml of wash buffer
(50 mM Tris pH
7.5, 5 rnM MnCl2, 150 mM NaCI) tl-uee times and its radioactivity was
determined by gamma
counter. The activation of phospholipase C by NKIR may also be measured in CHO
cells
expressing the human NK1 R by determining the accumulation of inositol
monophosphate which
is a degradation product of IP3. CHO cells are seeded in 12-well plate at
250,000 cells per well.
After incubating in Ck10 media for 4 days, cells are loaded with 0.025 uCi/ml
of 3H-myoinositol
by overnight incubation. The extracellular radioactivity is removed by washing
with phosphate
buffered saline. LiCl is added to the well at final concentration of 0.1 mM
with or without the
test compound, and incubation is continued at 37 C for 15 min. Substance P is
added to the well
at final concentration of 0.3 nM to activate the human NK1R. After 30 min of
incubation at
37 C, the media is removed and 0.1 N HCl is added. Each well is sonicated at 4
C and extracted

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with CHC13/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1X$
ion
exchange column. The colunin is washed with 0.1 N formic acid followed by
0.025 M
ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with
0.2 M
ammonium formate-0.1 N formic acid and quantitated by beta counter.
In particular, the intrinsic tachykinin receptor antagonist activities of the
compounds of the present invention may be demonstrated by this assay. The
compounds of the
invention have activity in the aforementioned assay in the range of 0.05 nM to
10 M. The
Examples hereinunder were found to have the following activity:

Example TC50 nM Exam Ie IC50 (nM) Example 1C50 (nM)
1 1.7 13 0.083 25 0.052
2 0.25 14 00.044 26 0.031
3 12. 15 0.071 27 ----
4 0.17 16 0.152 28 0.077
5 15 17 0.081 29 0.115
6 0.16 18 0.068 30 0.072
7 0.53 19 0.090 31 0.057
8 1.19 20 0.185 32 ----
9 0.041 21 0.085 33 0.066
0.066 22 0.089 34 0.048
11 0.060 23 0.094 35 0.111
12 0.043 24 --~W 36 0.108
The activity of the present compounds may also be demonstrated by the assay
disclosed by Lei, et al., British J. Phannacol., 105, 261-262 (1992).
According to a ftarther or alternative aspect, the present invention provides
a
compound of the present invention for use as a composition that may be
administered to a subject
in need of a reduction of the ainount of tachykinin or substance P in their
body.
The term "composition" as used herein is intended to encompass a product
comprising specified ingredients in predetermined ainounts or proportions, as
well as any product
which results, directly or indirectly, from combination of the specified
ingredients in the
specified amounts. This term in relation to pharmaceutical compositions is
intended to
encompass a product comprising one or more active ingredients, and an optional
carrier
comprising inert ingredients, as well as any product which results, directly
or i-odirectly, 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. In general, pharmaceutical compositions are
prepared by

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unifortnly and intimately bringing the active ingredient into association with
a liquid carrier or a
finely divided solid carrier or both, and then, if necessary, shaping the
product into the desired
formulation. In the phartnaceutical composition the active object compound is
included in an
amount sufficient to produce the desired effect upon the process or condition
of diseases.
Accordingly, the pharmaceu.tical compositions of the present invention
encompass any
composition made by admixing a compound of the present invention and a
pharmaceutically
acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier,
diluent or excipient
must be compatible with the other ingredients of the formulation and not
deleterious to the
recipient thereof
Pharmaceutical compositions intended for oral use may be prepared according to
any method known to the art for the manufacture of pharmaceutical compositions
and such
compositions may contain one or more agents selected from the group consisting
of sweetening
agents, flavoring agents, coloring agents and preserving agents in order to
provide
pharmaceutically elegant and palatable preparations. Tablets contain the
active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients which are
suitable for the
ma.nufactYre of tablets. These excipients may be for example, inert diluents,
such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and
disintegrating agents, for example, corn starch, or alginic acid; binding
agents, for example
starch, gelatin or acacia, and lubricating agents, for example magnesium
stearate, stearic acid or
talc. The tablets may be uncoated or they may be coated by known techniques to
delay
disintegration and absorption in the gastrointestinal tract and thereby
provide a sustained action
over a longer period. Compositions for oral use may also be presented as hard
gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent, for
example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein
the active ingredient
is mixed with water or an oil medium, for example peanut oil, liquid paraffin,
or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients
suitable for the manufacture of aqueous suspensions. Oily suspensions may be
formulated by
suspending the active ingredient in a suitable oil. Oil-in-water emulsions may
also be employed.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the
addition of water provide the active ingredient in admixture with a dispersing
or wetting agent,
suspending agent and one or more preservatives.
Pharmaceutical compositions of the present compounds may be in the form of a
sterile injectable aqueous or oleagenous suspension. The compounds of the
present invention
may also be administered in the fonn of suppositories for rectal
administration. For topical use,
creams, ointments, jellies, solutions or suspensions, etc., containing the
compounds of the
present invention may be employed. The compounds of the present invention may
also be
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formulated for administered by inhalation. The compounds of the present
invention may also be
administered by a transdermal patch by methods known in the art.
The compositions containing compounds of the present invention may be
presented in unit dosage form and may be prepared by any of the inethods well
known in the art
of pharmacy. The terzn "unit dosage form" is taken to mean a single dose
wherein all active and
inactive ingredients are combined in a suitable system, such that the patient
or person
adminstering the drug to the patient can open a single container or package
with the entire dose
contained therein, and does not have to mix any components together from two
or more
containers or packages. Typical examples of unit dosage forms are tablets or
capsules for oral
administration, single dose vials for injection, or suppositories for rectal
administration. This list
of unit dosage forms is not intended to be limiting in airy way, but merely to
represent typical
examples in the pharmacy arts of unit dosage forms.
The compositions containing compounds of the present invention may also be
presented as a kit, whereby two or more components, which may be active or
inactive
ingredients, carriers, diluents, and the like, are provided with instructions
for preparation of the
actual dosage foran by the patient or person administering the drug to the
patient. Such kits may
be provided with all necessary materials and ingredients contained therein, or
they may contain
instructions for using or making materials or components that must be obtained
independently by
the patient or person administering the drug to the patient.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient
must
be compatible with the other ingredients of the forrnulation and not
deleterious to the recipient
thereof.
The terms "administration of" or "administering a" compound should be
understood to mean providing a compound of the invention to the individual in
need of treatment
in a form that can be introduced into that individuals body in a
therapeutically useful form and
therapeutically effective ainount, including, but not limited to: oral dosage
forms, such as tablets,
capsules, syrups, suspensions, and the like; injectable dosage forms, such as
IV, IM, or IP, and
the like; transdermal dosage forms, including creams, jellies, powders, or
patches; buccal dosage
forms; inhalation powders, sprays, suspensions, and the like; and rectal
suppositories.
The term "therapeutically effective amount" refers to a sufficient quantity of
the
compounds of the present invention, in a suitable composition, and in a
suitable dosage fon-n. to
treat or prevent the noted disease conditions.
The cor.n.pou.nds of the present invention may be administered in combination
with
another substance that has a complimentary effect to the tachykinin and
substance P inhibitors of
the present invention.
Accordingly, in the prevention or treatinent of emesis, a compound of the
present
invention may be used in conjunction with other anti-emetic agents, especially
5HT3 receptor
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antagonists, such as ondansetron, granisetron, tropisetron, palenosetron and
zatisetron, a
corticosteroid, such as dexamethasone, or GABAB receptor agonists, such as
baclofen.
Likewise, for the prevention or treatment of migraine a compound of the
present invention may
be used in conjunction with other anti-migraine agents, such as ergotamines or
5HT1 agonists,
especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
It will be appreciated that for the treatment of depression or anxiety, a
compound
of the present invention may be used in conjunction with other anti-depressant
or anti-anxiety
agents, such as norepinephrine reuptake inhibitors, selective serotonin
reuptake inhibitars
(SSRIs), monoamine oxidase inhibitors (MAGIs), reversible inhibitors of
m.onoan-iine oxidase
(RIMAs), scrotonin and noradrenaline reuptake inhibitors (SNRIs), a-
adrenoreceptor
antagonists, atypical anti-depressants, benzodiazepines, 5-HTzA agonists or
antagonists,
especially 5-HTIA partial agonists, corticotropin releasing factor (CRF)
antagonists, and
pharmaceutically acceptable salts thereof. For the treatment or prevention of
eating disorders,
including obesity, bulimia nervosa and compulsive eating disorders, a compound
of the present
invention may be used in conjunction with other anorectic agents. It will be
appreciated that for
the treatment or prevention of pain or nociception or inflammatory diseases, a
compound of the
present invention may be used in conjunction with an antiinflam.matory or
analgesic agent such
as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-
lipoxygenase, a
cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin
iiihibitor, such as
an intexleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide
or an inhibitor of the
synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a
cytokine-suppressing
antiinflana.a.natory agent.

For the treatment of urinary incontinence and LUTS, a compound of the
invention
may be used in combination with a 03 adrenergic receptor ([33AR) agonist ((33
agonist), and/or
an anti-muscatinic and optionally an alpha-1 adrenergic antagonist, or a
steroid type 115-alpha-
reductase inhibitor.

For purposes of this specification the 03 agonist is intended to include N-[4-
[2-
[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl)phenyl]-4-[4-(3-
cyclopentylpropyl)-5-tetrazolon-
1-yl] benzenesulfonamide.
2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl] amino]ethyllphenyl]-4-[4-[4-
(trifluoromethyl)phenyl]thiazol-2-=yl]benzenesulfonarnide. Appropriate daily
amounts of the 03
agonist include 10mg, 25,mg, 50mg, 100mg, 125mg, 200mg, 250mg and 375mg. These
beta 3
agonists are discussed and may be prepared as disclosed in US 5,561,142 and US
6,011,048,
which are hereby incorporated by reference.

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For purposes of this specification, anti-musearinc agents included, but are
not
limited to tolterodine, oxybutynin, trospium, vaanicamide, solifenacin,
propiverine, S-
oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by
GlaxoSmithKline, TD6301, RBX9841, DDP200, axad PLD179. See, for example, US
5,382,600;
US 3,176,019; US 3,480,626; US 4,564,621; US 5,096,890; US 6,017,927; US
6,174,896; US
5,036,098; US 5,932,607; US 6,713,464; US 6,858,650; and DD 106643. See also,
US
6,103,747; US 6,630,162; US 6,770,295; US 6,911,217; US 5,164,190; US
5,601,839; US
5,834,010; US 6,743,441; W02002000652; W0200400414853. These also include
trospium
chloride, darifenacin and imidafenacin (KRP-197). As will be appreciate by
those of skill in the
art, these drugs may be administered orally or topically in standard or
extended release forms,
such as extended release tolterodine, extended relesase oxybutynin and
transdermal oxybutynin.
Within. the aspect of the invention discussed above, there is a genus wherein
the
anti-muscarinic agent is selected from tolterodine, oxybutynin, trospium,
vamicamide,
solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla,
fesoterodine, SVT40776,
202405 by GlaxoSnzathKlin.e, TD6301, RBX9841, DDP200, and PLD179.

Within the aspect of the invention discussed above, there is a genus wherein
the
anti-muscarinic agent is selected from the group consisting of trospium
chloride, darifenacin and
imidafenacin.

Within the aspect of the invention discussed above, there is a genus wherein
the
anti-muscarinic agent is selected from the group consisting of extended
release tolterodine,
extended relsease oxybutynin and transdermal oxybutynin.
For purposes of this specification the 5-alpha reductase inhibitor includes,
but is
not limited to finasteride, dutasteride, turosteride and epristeride.

By the term "fnasteride" as used here is meant the compound as designated by 4-

azaandrost-l-ene-17-carboxamide, N-(1,1-dirnethylethyl)-3-oxo-,(5 a,17B). FDA
approved
doses for finasteride are 1 mg and 5mg, once a day.

By the term "dutasteride" as used herein is meant the compound as designated
by
(5 a, 17i3)-N-{2, 5 bis(trifluoromethyl)phen.yl}-3-oxo-4-azaandrost-l-ene-17-
carboxamide. FDA
approved doses for f nasteride are 1 mg and 5mg, once a day. The FDA approved
dose for
dutasteride is 0.5mg, once a day. The FDA approved dose for dutasteride is
0.5mg, once a day.
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For purposes of this specification the alpha- adrenergic receptor antagonist
is
selected from amsulosin, terazosin, doxazosin, alfuzosin, indoramin and
prazosin.

By the teri-n "amsulosin" (e.g. Flomax or tamsulosin hydrochloride) as used
herein
is meant the compound designated as (-)-(R)-5-[2-[[2-(O-
ethoxyphenoxy)ethyl]amino]propyl]-2-
methoxyben.zenesulf onamide and salts, hydrates and solvates thereof.
Amsulosin is disclosed in
U.S. Pat. No. 4,703,063 and claimed in U.S. Pat. No. 4,987,152 as being useful
in treating lower
urinary tract dysfunction. FDA approved doses include 0.4mg once a day for
tamsulosin
hydrochloride.
By the term "terazosin" as used herein is meant the compound 1-(4--amino-6,7-
dimethoxy-2quinazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]p iperazine and
salts, hydrates and
solvates thereof. Terazosin is disclosed in U.S. Pat. No. 4,251,532. FDA
approved doses
include 1, 2, 5 and 10mg once a day for terazosin hydrochloride.
By the term doxazosin as used herein is meant the compound 1-(4-amino-6,7-
dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-l,4-benzodioxin-2 -yl)carbonyl]-
piperazine and salts,
hydrates and solvates thereof. Doxazosin is disclosed in U.S. Pat. No.
4,188,390. FDA
approved doses include 1, 2, 4 and 8 mg once a day for doxazosin mesylate.
By the term "alfuzosin" (e.g. Uroxatral) as used herein is meant the compound
N-
[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylaznino]propyl]tetrahydro- 2-
furancarboxamide and salts, hydrates and solvates thereof. Alfuzosin is
disclosed in U.S. Pat.
No. 4,315,007. FDA approved doses include 10 mg once a day for alfuzosin
hydrochloride.
By the term "indoramin" as used herein is meant the compound N-[[1-[2-(1H-
indol-3-yl)ethyl]-4-piperidinyl]benzamine. Indoramin is disclosed in U.S. Pat.
No. 3,527,761.
By the term "prazosin" as used herein is meant a compound of the formula 1-(4-
amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine. and
solvates thereof.
Prazosin is disclosed in U.S. Pat. No. 3,511,836. FDA approved doses include
1, 2 and 5 mg
once a day for prazosin hydrochloride.

It will be appreciated that wheii using any combination described herein, both
the
compound of the present invention and the other active agent(s) will be
administered to a patient,
within a reasonable period of time. The compowads may be in the same
pharmaceutically
acceptable carrier and therefore administered simultaneonsly. They may be in
separate
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pharnnaceutical carriers such as conventional oral dosage fonns which are
taken simultaneously.
The term "combination" also refers to the case where the compounds are
provided in separate
dosage fornas and are administered sequentially. Therefore, by way of example,
one active
component may be administered as a tablet and then, within a reasonable period
of time, the
second active component may be administered either as an oral dosage forzn
such as a tablet or a
fast-dissolving oral dosage form. By a "fast dissolving oral fonnulation" is
meant, an oral
delivery fornn which when placed on the tongue of a patient, dissolves within
about 10 seconds.
By "reasonable period of time" is meant a time period that is not in excess of
about 1 hour. That is, for example, if the first active component is provided
as a tablet, then
within one hour, the second active component should be administered, either in
the same type of
dosage fornn, or another dosage form which provides effective delivery of the
medicaznent.
The compounds of this invention may be administered to patients (animals and
humans) in need of such treatment in dosages that will provide optimal
pharmaceutical efficacy.
It will be appreciated that the dose required for use in any particular
application will vary from
patient to patient, not only with the particular compound or composition
selected, but also with
the route of administration, the nature of the condition being treated, the
age and condition of the
patient, concurrent medication or special diets then being followed by the
patient, and other
factors which those skilled in the art will recognize, with the appropriate
dosage ultimately being
at the discretion of the attendant physician.
In the treatrnent of the conditions associated with an excess of tachykinins,
a
suitable dosage level of the compounds of the present invention, or
pharmaceutically acceptable
salts thereof, is about 0.001 to 50 mg/kg per day, in particular about 0.01 to
about 25 mg/kg, such
as from about 0.05 to about 10 mg/kg per day. The dosage range will generally
be about 0.5 to
1000 mg per patient per day, which may be adininistered in single or multiple
doses. Preferably,
the dosage range will be about 0.5 mg to 500 mg per patient per day; more
preferably about 0.5
mg to 200 mg per patient per day; and eveia more preferably about 5 mg to 50
mg per patient per
day. Specific dosages of the compounds of the present invention, or
pharmaceutically acceptable
salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg,
and 500 mg.
Pharmaceutical compositions of the present invention may be provided in a
formulation comprising about 0.5 mg to 1000 mg active ingredient; more
preferably comprising
about 0.5 mg to 500 mg active ingredient; or 0.5 mg to 250 mg active
ingredient; or 1 mg to 100
mg active ingredient. Specific pharmaceutical compositions for treatment or
prevention of excess
tachykinins comprise about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg of
active ingredient.
Several methods for preparing the compounds of this invention are illustrated
in
the following Examples. Starting materials and the requisite intermediates are
in some cases
commercially available, or can be prepared according to literature procedures
or as illustrated
-20-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
herein. All ~H NMR spectra were obtained on instrumentation at field strength
of 400 or 500
MHz.
EXAMPLE 1
CF3

CF3
N O

F
O
3- 3aSR 4RS 7aSR -5- 3 5-bis trifluorometh 1 hen 1 ace 1-4- 4-fluoro hen 1
octah dro-2H
rrolo 3 4-c idin-2- 1 e clo ent-2-en-l-one

Step A: N-[(1E)-(4-fluorophenyl)methyl ne]-1-[(trimethylsilyl)oxylethylenaminc
F
N
is E~0--~

To a stirred solution of 41 mL(41 msnol, in hexanes) LHMDS in 60 rnL dry ether
under nitrogen atmosphere at 0 C was added 4.4 mL (41 mmol) of 4-
fluorobenzaldehyde. After
1 hr, to this mixture was added a triethylamine (6.4 mL, 45.5 mmol) and acetyl
chloride (2.92
mL, 41 mmol). After 5 min, cold bath was removed and the mixture was allowed
to stirred at rt
for 2.5 hr. Then, TMSCI (5.19 mL, 41 mrnol) was added to quench the reaction.
After 10 min,
the mixture was filtered of1'the white solid through a cake of celite. The
solution was removed all
volatiles to give a yellow oil as the title compound.
'H NMR (CDC13, ppm): $ 7.82 - 7.88 (m, 2H), 7.14 (t, 21-1), 4.69 (s, 1 H),
4.34 (s, 1 H).

-21-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
Step dinxethyl (2RS,3RS, 4SR)-2-(4-fluorophenyl)-6-oxopiperid'rne-3,4-
dicarboxylate
F

NH "O'CO2CH3
0 CO2CH3
A solution of N-[(1E)-(4-fluorophenyl)methylene]-1-
[(trixnethylsilyl)oxy]ethylenarn.ine (1.65 g, 6.95 mmol, step A) and dimethyl
fizmarate (1.0 g,
6.95 mmol) in 20 mL of toluene was heated under N2 in a 80 C oil bath for 16
hr. Toluene was
removed by vacuum and the residue was added 3 5 mL of methanol. After stirring
at rt for 10
min, the white suspension was filtered to give the title compound as a white
solid.lV1S: 310
(M+1).

Step C: tert-butyl(2RS,3RS,4SR)-2-(4-fluorophenyl)-
3,4Tbis(hydroxymethyl)piperidine-l-
carboxylate
F
( \
O ~
-O~N `~"~"OH
OH
A solution of dimethyl (2RS,3RS,4SR)-2-(4-fluorophenyl)-6-oxopiperidine-3,4-
dicarboxylate (0.51 g, 1.65 mmol, step B) in 50 mL of THF at 0 C was added
LiBH4 (6.6 mL,
13.2 mmol, 2N solution in THF). Then the cold bath was removed and the mixture
was allowed
to stir at rt for 16 hr. The reaction was added with 10 mL 2N HCl and stirred
at rt for 21ir. Then
v latiles were removed under vacuum. The residue was dried with toluene (3x)
and was added
50 mL of THF and BH3-SMe2 (8.25 mL, 16.5 mmol, as a 2N solution in THF). The
mixture was
heated to reflux under N2 for 2 hr and was cooled to rt. Upon removal of
volatiles, the residue
was dissolved in 20 mL of ethanol and was heated in 96 C oil bath for 2 hr.
Upon removal of
volatiles, the residue was dissolved in mixture of dioxzne and water (15 mL,
2:1 by volume) and
was added triethylamine (0.70 mL, 4.95 mmol) and (Boc)20 (0.72 g, 3.29 mmol)
at rt. After 20
rnin, it was removed of volatiles and was worked up with EtOAc/NaHCOa/NaCI.
The organic
phase was dried with NaZSO4 and was filtered. Upon removal of solvent, it was
purified by
Horizon MPLC using a gradient eluting system of 0-5% methanol in CH2CI.2 to
afford the title
compound. MS: 362 (M+Na).

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CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
Stet~ D: tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4Wfluorophenyl)octahydro-5H-
pyrrolo [3,4-c]pyri dine-5-carboxylate
F

0 / \
~-O--N
N
A solution of tert-butyl(2RS,3RS,4SR)-2-(4-fluorophenyl)-3,4--
bis(hydroxymethyl)piperidine-1-carboxylate (0.38 g, 1.12 rrunol), DMAP (3.4
mg, 0.28 mmol),
triethylamine (0.070 mL, 5.04 zmxa.oi) in 12 mL of CH202 was added MsC1(0.26
mL, 3.36
mmol) at 0 C. After 25 nn.in, the reaction was quenched with NaHCO3. The
mixture was worked
up with EtOAc/NaHCO3/NaC1. The organic phase was dried with Na2SO4 and was
filtered. Upon
removal of solvent, it was dissolved in 30 mL of n-butyl alcohol and was added
benzylamine
(0.73 ml, 6.7 inmo1). The mixture was heated in a 102 C oil bath for 7 hrs.
It was worked up
with EtOAc/NaOH/NaC1 and was dried with NaZSO4 and was filtered. Upon removal
of solvent,
it was purified by Horizon MPLC using a gradient eluting system of 0 to 50%
(EtOAc/Hex/ 2N
NH3 in rnethanol- 10 : 10 : 1) in hexanes to afford the title compound. MS:
411 (M+1).
Step E: (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-IH-pyrrolo[3,4-
c)pyridine
F

N
A solution of tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-
5FT pyrrolo[3,4-c]pyridine-5-carboxylate (0.20 g, 0.48 rnzn.ol) in 12 mL of 4
M HC1 in dioxane
was stirred at rt for 2 hr and was removed volatiles to give the title
compound as HCl salt. MS:
311 (M+1).

- 23 -


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
St~: (3aSR,4RS,7aSR)-2-benzyl-4-(4-flnorophenyl)octahydro-lH-pyrrolo[3,4-
c]pyridine
F
F
F F

F O
F ~
N
F

To a solution of (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-
pyrrolo[3,4-c]pyridine (62.8 mg, 0.056 mmol, intermediate step E) and DMAP (2
mg) and N-(3-
dinmethylam.inopropyl)-N'-ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol)
and 3,5-
bis(trifluorozxa.ethyl)-bez-zzeneacetic acid (30 mg, 0.11 mmol) in 3 mL of
CH2CI7 was added N, N-
diisopropylethylanaine (0.33 mmol, 0.058 mL) and the mixture was stiired at rt
for 1 hr. Upon
removal of volatiles, it was purified by reverse phase HPLC to give the title
compouxzd. MS: 565
(M+1).

Step G: (3aS'R,4RS,7aSR)-5-~[3,5-bis(trifluoromethyl)phenyl)acetyl}-4-(4-
fluorophenyl)octahydro-1 H-pyrrolo [3,4-c]pyridine
F
F
F F

O
F N
F NH
F

a solution oi'(3aSR,4RS,7aS'R)-2-benzyl-4-(4-fluoz-ophenyl)octahydro-lH-
pyrarolo[3,4-c]pyridin.e
(115 mg, 0.17 mmol, intermediate step F) in 10 mL of MeOH was added Pd(OH)2
(80 mg, 20%
Pd on carbon) and the mixture was shaken under 50 psi of hydrogen for 1 hr. It
was filtered 0.2
micron PTFE filter. The title compound was obtained after reinoval of
methanol. MS: 475
(M+1),

-24-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
St ep H: 3--[(3aSR,4RS,7a,SR)-5-~[3,5-bis(trifluoromethyl)phenyl]acetyl}-4-(4T
fluorophenyl)octahydro-2H pyrrolo[3,4-c]pyridan-2-yl]cyclopez,it-2-en-1-one

CF3
/ (

\ CF3
N O

F
O

A solution of (3aS'R,4RS,7aSR)-5-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-4T(4-

fluorophenyl)octahydro-lH-pyrrolo[3,4-c]pyridine (0.032 g, 0.054 man.ol), TsOH
monohydrate
(2.7 mg) and 1,3-cyclopentanedione (8 mg, 0.082 mzxa.ol) in 3 mL of toluene
was heated in 100
C oil bath for 3 hrs. Afi:er removal of volatiles, the residue was purified by
reverse phase HPLC
to afford the title compound. MS: 555 (M+1).
EXAMPLE 2, EXAMPLE 3, and EXAMPLE 4
3-l(3aSR,4RS,7aSR)-5-12-[3,5-bis trifluoromethyl phenXljpropanoyI}-4(4-
fluoro heig 1 octah dro-2H- rrolo 3 4-c idin-2- 1 c clo ent-2-en-l-one
CF3

CF3
N 0

F
Q

-25-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
CF3
/ I

~ CF3
N O
CI:''~~ F

3 W 3aSR 4RS 7aSR -5- 2- 3 5-bis trifluorometh 1 hen 1-2-meth 1 ro ano 1-4- 4-
fluorohcLi 1 octah dro-2H rrolo 3 4-c ridin-2- 1 c c1o ent-2-en-l-one

A solution of 3-[(3aSR,4RS,7aSR)-5-{[3,5-bis(trifluoronlethyl)phenyl]acetyll-4-

(4-fluorophenyl)octahydro-2Hpyrrolo[3,4-c]pyridin-2-yl]cyclopent-2-en-l-one
(27 rng, 0.049
mmol) in 2 mL of THF was added LHMDS (0.1.36 mmol, 0.136 mL in THF) at -78 C
and was
stirred at -78 C for 10 inin. Then iodomethane (0.0095 mL, 0. 15 mmol) was
added. After 30
rnin, the reaction was quei-iched with HOAc. Upon removal of volatiles, the
title compounds
were isolated by reverse phase HPLC. The first and third fractions as the
monoalkylation
products, MS: 568 (M+l). The second fraction as the dimethylation product, MS:
583 (M+1).
EXA.MPLE 5

CF3

CF3
N O

F
O~

CL
0
3-12-[(3aSR,4RS,7aSR)-5-1[3,5-bis(trifluoromethyl)phen lly 1ace . ityJ-4-(4-
fluorophenyl)octahydro-2H pyrroloF3,4-c]pyridzn-2-yl1-2-oxoeth_yl}-1,3-
oxazolidin-2-one
The title compound was prepared from 3 aSR,4RS, 7aSR)-5 - ~ [3,5 -
bis(trifluorornethyl)phenyllacetyl}-4-(4-fluorophenyl)octahydro-1H pyrrolo[3,4-
c]pyridine and
(2-oxo-l,3-oxazolidin-3-yl)acetic acid by the procedure in Example 1, step F.
MS: 602 (M+1).
-26-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
EXAMPLE 6

CF3 CF3
N

N~O
N-=I /
F
O
(3aSR, 4RS, 7aSR)-1V-11-[3,5Tbis(trifluoromethyl phen 1~]ethyll-4-~4-
fluorophenyl)-N-meth,r
(3-oxocyclopent-l-en-1-yl octah_ydro-5H-py~TOlo[3,4-c]pyridine-5-carboxan~ide
St~pe ,,,V,,, A: ~ 1-[3,5-bis(triflnorornethyl)phenyl]ethyl}methylcarbamac
chloride
CF3 CF3

N
CI'1~1, O

A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethan.amine (0.54 g,
1.99 mmol) in chloroform (18 mL) was added a solution of Cs2CO3 (3.90 g, 11.9
mmol) in 8 mL
of water. To this suspension at OoC was added a solution of phosgene (4.2 znL,
7.97 mmol, 20 %
in toluene). The mixture was stirred at rt for 1 hr. The mixture was diluted
with water and
extracted with methylene chloride (2x50 mL). The organic phase was dried with
Na2SO4, filtered
and concentrated to afford the title compound.
1 HNMR (CDC13, ppM): & 7.89 (s, 1H), 7.77 (s, 2H), 5.77-5.78 (m, 1H), 2.91 and
2.81 (s, 311).
1.72 and 1.70 (s, 314).

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CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
Step B: (3aSR,4RS,7aSR)-2-benzyl-.N-~ 1-[3,5-
bis(trifluorarnethyl)phenyl]ethyl}-4-(4-
fluorophenyl)-N-methylactahydro-5H-pyrrolo [3 ,4-c] pyridine- 5 -carboxan-iide
CF3 CF3

N
No
N--'~ F
6
A solution of 11J3,5-bis(trifluoromethyl)phenyl]ethyl}methylcarbanlic chloride
(0.18 g, 0.53 nunal), DMAP (2 mg), N, N-diisopropylethylainine (0.23 mL, 1.34
mmol) and
3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydra-1H pyrrolo[3,4-c]pyridii-
ie (0.083 g, 0.27
mmol) in methylene chloride (10 rnL) was stirred at rt for 72 hrs. Upon
removal of solvent, it
was purified by reverse phase HPLC to afford the title compound. MS: 608
(M+l).
St .e~C (3aSR, 4RS,7aSR)-N-{1-[3,5-bis(triflnorornethyl)phenyl]ethyl1 -4-(4-
fluoraphenyl)-N-niethyloctahydro-5H-pyrrola[3,4-c]pyridine-5-carboxamide
cF3 CF3

N
N"~o
NH-~ F

The title compound was prepared from 3aSR,4RS,7aSR)-2-benzyl-N{1-[3,5-
bis(trifluorornethyl)phenyl]ethyl}-4-(4-fluorophenyl)-N rnethyloctahydraT5H
pyrrolo[3,4-
c]pyridine-5-carboxamide by the procedure in Example 1, step G. MS: 518 (M+1).

-28-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270

Step D: (3aSR,4RS,7aSR)-N {1-[3,5-bis(trifluoromethyl)phenyllethyl~-4-(4-
fluorophenyl)-
N methyl-2-(3-oxocyclopent-l-en-l-yl)octahydro-5H pyrrolo[3,4-c]pyridine-5-
carboxamide
CF3 CF3
N
NQ

F
O
The title compound was prepared from (3aSR,4RS,7aSR)-N-j1-[3,5-
bis(trifluoromcthyl)phcnyl]ethyl}-4-(4-fluorophenyl)-11r methyloctahydro-5H
pyrrolo[3,4-
c]pyridine-5-carboxarnide by the procedure in Example 1, step H. MS: 598
(M+1).

EXAMPLE 7
(3aSR,4RS,7aSR)-N- 1-f.3,5-bis(trifluorometllyl)phenylIet11y1~4-(4-
fluorophenyl)-1~ meth r1-2-
tetrah clro-2H- an-4- lcarbon 1 octah dro-5,11- nolo 3 4-c rid'zne-5-
carboxamide
CF3 CF3

'N
NO

F
o
The title compound was prepared from (3aSR,4RS,7aSR)-N-{1-[3,5-
bis(trifluorometb.yl)phenyl]e-thyl}-4-(4-flnorophenyl)-N methyloctahydro-5H-
pyrrolo[3,4-
c]pYridine-5-carboxamide and tetrahydro-2H-pyran-4-carboxylic acid by the
procedure in
Example 1, step F. MS: 630 (M+I).

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CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
EXAMPLE 8 (L-001946286)

O
c~ N ~N ~~ -
CF3

3aS 4R 7-2-be . 1-N- 1R -1- 3 5-bis trifluorozneth 1 hen 1 eth 1-N-z-neth 1-4
2-
methylplaoyl)octahydro-5H pyrroloL3,4-clp,~ridiiae-5-carboxarmide

Step A: NN [(lE)-(2-methylphenyl)methylene]-1-
[(trimethylsilyl)oxy]ethylenamine
The title compound was prepared according to Example 1, step A.
'H NMR (CDC13, ppm): Fi 4.71 (s, IH), 4.35 (s, IH), 2.57 (s, 3H), 0.34 (s,
9H).

St~pe _Bw dimethyl (2RS,3RS,4SR)-2-(2-methylphenyl)-6-oxopiperidine-3,4-
dicarboxylate
~ \
~
~~ .,CO2CH3
O CO2CH3

The title compound was prepared from N[(1L)-(2-methylphenyl)methylene]-1.-
[(trimethyisilyl)oxy]ethylenamine azid dimethyl fumarate according to Example
1, step B. MS:
306 (M+ l).

-30-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270

Step C: tert-bntyl (2RS,3RS,4SR)-3,4-bis(hydroxymethyl)-2-(2-
methylphenyl)piperidine-1-
carboxylate

O
~O~N OH
OH

The title compound was prepared from dimethyl (2RS,3RS,4SR)-2-(2-
rza.ethylphenyl)-6-oxopiperidin.e-3,4-dicaxboxylate according to Exwnple 1,
step C.
MS: 358 (M+Na).

Step D: tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro-5H=
pyrrolo[3,4-clpyridine-5-carboxylate )0X N\ -

N
The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4-
bis(hyd.roxymethyl)-2-(2-methylphenyl)piperidine-l-carboxylate according to
Example 1, step D.
MS: 407 (M+1).

Step E: (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro-lI-1-pyrrolo[3,4-
c]pyridine

NH ~
N
The title compound was prepared from tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2-
methylphenyl)octahydro-SH-pyr.rolo[3,4-c]pyridine-5-carboxylate according to
Example 1, step
E. MS: 307 (M+I).

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CA 02690737 2009-12-11
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Step F: {(1R)-1-[3,5-bis(trifluorornethyl)phenyl]ethylI nlethylcarbainic
chloride

CF3 CF3
'N'

CIO
The title compound was prepared from (1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-

methylethanan-iine according to Example 6, step A.

Step G: (3aS,4R,7aS)-2-benzyl-N- {(1R)-1-[3,5-
bis(trifluoroam.ethyl)phenyl]ethyl~-.N-
rnethyl-4-(2-methylphenyl)octahydro-5H-pyrrolo [3 ,4-e] pyridine- 5-
carboxana.ide
o
CF
N N ~N -
CF3
A solution of {(1R)-I-[3,5-bis(trifluoromethyl)phenyl]ethyl) methylcarbamic
chloride (3.3 g, 9.9 mmol), DMAP (20 mg), N, N-diisopropylethylamine (2.1 inL,
12 mmol) and
3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H pyrrolo[3,4-c]pyridine
(1.5 g, 4.9
mmol) in methylene Chloride (50 inL) was stirred at rt for 72 hrs. Upon
removal of volatiles, the
residue was purified by Horizon MPLC using a gradient eluting system of 30 -
100% EtOAc in
hexanes to afford the title cornpowid as the fast fraction. MS: 604 (M+1).
EXAMPLE 9

I
o

C3 N N
I \Nf!
CF3
3aS 4R 7-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-N-meth 1-4- 2-
meth 1 hen 1 octah dro-5H- rrolo 3 4-c idine-5-carboxamide

The title compound was prepared from 3aS,4R,7aS)-2-benzyl-N {(1R)-1-[3,5-
bis(trifluoromethyl)phenyl]ethyl]-N methyl-4-(2-methylphenyl)octahydroW5H-
pyrrolo[3,4-
-32-


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
c]pyridine-5-carboxamide (Example 8, Step G) with the same method as in
Example 1, step E.
MS: 514 (M+1).

EXAMPLE 10

CF3 \ CF3
N/
NO

(3 a~S,4R,7a,D-N-{(1 R)-l-j3,5-bis(trifluoramethyl)aheUI1 ethyl } -N-metlZyl-4-
(2-meth.ylpheziyl)-2-
(3-oxacyclopen.t-l-en-1-~)actahydra-SH-pMala[3,4-elpyrid'zne-5-caxboxan aide

The title compaund was prepared from(3aS,4R,7aS')-N-{(1R)- 1- [3,5-
bis(trifluoromethyl)phenyl]ethyl}-N-methyl-4-(2-zn.ethylpheny1)octahydra-SH
pyrrolo[3,4-
e]pyyridine-5-carbaxamide (Example 9) with the same method as in Example 1,
step E. MS: 594
(M+1)=

EXAMPLE 11 and EXAMPLE 12
CF3 CF'3
'N.

N -~--O
N-~
N}~2-~
0
3aS 4R 7-N'- 1R -1- 3 5-bis trifluororneth 1 hen 1 eth 1-N5-n-ieth 1-4- 2-
meth 1 hen 1 tetrah dro-1H- rrolo 3 4-c idine-2 5 3H4 -dicarboxamide
_33_


CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
CF3 CF3
(
N
N~O

N-=I /
O-~
N
O
3aS 4R 7-N- 1R -1- 3 5-bis trifluororneth 1 hen i eth 1-N-meth 1-4- 2-zneth 1
hen 1-2-
4-oxo-4 5-dih dro-1 3-oxazol-2- 1 octah dro-5H- rrolo 3 4-c idine-5-
carboxamide

A solution of (3aS,4R,7aS)-N=1 (1R)-1-(3,5-bis(trifluorpmethyl)phenyl]ethyl}-N-

methyl-4-(2-methylphenyl)octahydro-5H pyrrolo[3,4-c]pyridine-5-carboxarnide
(27 mg, 0.051
mmol) in methylene chloride (5 mL) was added chloroacetyl isocyanate (0.009
znL, 0,11 mmol)
at rt. After 30 nain, volatile was removed and the residue was added 10 mL of
water. The mixture
was heated in a 100 C oil bath for 1 h. Upon removal of volatiles. The
residue was purified by
reverse phase HPLC to give the title compounds. The first fraction is the
dicarboxamide, MS:
557 (M+1). The second fraction is the oxazolone, MS: 597 (M+1.).

EXAMPLE 13

CF3 CF3
N.
N'~a
N --~I /
O
fl
3aS4R 7-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-Nmeth 1-4- 2-meth 1 hen 1-
2-
5-axo-2 5-dih drofuran-3- 1 octah dro-5H- rrola 3 4-c ridine-5-carboxamide

A solution of (3a.S`,4R,7aS)-N {(1R)-1-[3,5-bis(trifluoromethyl)phenyl]cthyl) -
N-
methyl-4-(2-znethylphenyl)octahydro-5FI pyrrolo[3,4-c]pyridine-5-carboxamide
(24 mg, 0.047
zntxiol) and tetronic acid (15 mg, 0.15 mmol) in 2-propanol (3 mL) was heated
at reflux for 3 hrs.

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CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
Upon removal of volatiles. The residue was purified by reverse phase HPLC to
give the title
compound. MS: 596 (M+1).

EXAMPLE 14
CF3 CF3
'N.

N --'--
3aS4R 7--N 1R -1- 3 5-bis trifluororneth 1 hen 1 eth 1-2-iso ro1-N-meth 1-4- 2
meth 1 hen 1 octah dro-5H rrolo 3 4-c rzdine-5-carboxamide

A solution of (3aS,4R,7a.S)-N f(IR)-1-[3,5-bis(trifluaromethyl)phenyl]ethyl}-N
inethyl-4-(2-methylphenyl)actahydro-5H pyr.rolo[3,4-c]pyridine-5-carboxamide
(20 mg, 0.039
nunol), acetone (0.011 mL, 0.15 m-inol) and NaB(OAc)3H in methylene chloride
(5 mL) was
stirred at rt for 16 hrs. Upon removal of volatiles. The residue was purified
by reverse phase
HPLC to give the title compound. MS: 556 (M+1).

EXAMPLE 15 and EXAMPLE 16
CF3 CF3
1

~, N

N ~O
N-=

~Q
NH2

(3aS,4R,7at~)-2-(2-ainino-2-oxoethyl)-N-I(1R)-1-[3,5-
bis(nifluoraznethyl)ullenylIeth, 1N
methyl-4=(2-meth
~lpheLiyl)oCtahydro-5H-pyrralo[3 ,4-c] pyridine-5Tcarboxamide
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CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
CF3 CF3

'N.
N --~-O
N----~

CO2H
3aS 4R 7 -5- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1 meth 1 amino carbon 1-
4- 2-
meth 1 hen 1 octah dr -2H ol0 3 4-c din-2- 1 acetic acid
A solution of (3 aS,4R,7aS)-N {(1R)-1-[3,5-bis(triflnoromethyl)phenyl] ethyl}-
N-
fnethyl-4-(2-rnethyllahenyl)octahydro-5H Pyrrolo[3,4-c]pyridine-5-carboxamide
(25mg, 0.039
m.znol), chloroacetamide (9 mg, 0.097 mmol) and Cs2CO3 (33mg, 0.097 mmol) in 2
mL of
dioxane was heated in a 100 C oil bath for 16 hrs. Upon removal of volatiles.
The residue was
purified by reverse phase HPLC to give the title compounds. The first faction
is the amide, MS:
(571). The second fraction is the acid, MS: 572 (M+1).

EXAMPLE 17

CF3
CF3 z

~
N --~-O
0
OH
3aS4R 7-N- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-2- 2-2-h drox ro an a 1-
N-
meth i-4- 2-meth 1 hen 1 octah dro-5H rrolo 3 4-c ridine-5Wcaz'boxamide

The title compound was prepared from(3aS,4R,7aS)-N-{(1R)-1-[3,5-
bis(trifluoromethyl)phenyl] ethyl}-N methyl-4-(2-methylphenyl)octahydro-5H-
pyrrolo[3,4-
c]pyridineW5-carboxamide (Example 9) and (2S)-2-(acetyloxy)pxapanoic acid with
the same
method as in Example 1, step F.

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CA 02690737 2009-12-11
WO 2009/002770 PCT/US2008/067270
MS: 586 (M+l).

EXAMI'LE 18
CF3 CF3
N

N~o
O

(3aS,4R,7an-2-ace ,tYl-N {(1R)-l- 3,5-bis trifluoromethyl)uhenyl]ethyl} -N-
methyl-4-(2-
rnethylphenyl)octahydro-5H-uyrrolo f 3,4-c]pyridine-5-carboxamzde

The title compound was prepared from(3aS,4R,7aS)-N-{(1R)-1-[3,5-
bis(trifluorornethyl)phenyl]ethyl]-N-methyl-4-(2-methylphenyl)octahydro-5H-
pyrrolo[3,4-
c]pyridine-5-carboxatnide (Example 9) with the same method as in Example l,
step F. MS; 556
(M+1).

EXA.MPLE 19
GF3 CF3
NNa
N-7
0

N
0
3aS 4R 7-N 1R -l- 3 5--bis trifluorometh 1 hen 1 eth 1-.11T aneth 1-2- 1-meth
1-6-
oxa i erzdin-3- 1 carborz 1-4- 2-meth 1 hen 1 octah dro-5H- rrolo 3 4-c ridine-
5-
carboxarnide
The title compound was prepared from(3aS,4R,7aS)-N ~(1R)-1-[3,5-
bis(trifluoromethyl)phenyl] ethyl ) -N-methyl-4-(2-methylphenyl)octahydro-5H-
pyrrolo [3,4-
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clpyridine-5-carboxanaide (Example 9) and 1-methyl-6-oxopiperidine-3-
carboxylic acid with the
same method as in Example 1, step F. MS: 653 (M+1).

EXAMPLE 20
CF3 CF3
N
NO
O

N
~ -NH2
O

3aS 4R 7 -2- 1-faminocarboLiyl)piperidin-4-yllcarboUl.1-N-.tf 1R -1- 3 5-
bis trifluorameth 1 hen 1 eth 1-N metb 1-4- 2-meth 1 hen 1 octah dro-5H- rrolo
3 4-
cl pyridin.e-5-carboxamide
The title compound was prepared from(3aS,4R,7aS')-N f (1R)-1-[3,5-
bis(triflnororn.ethyl)phenyl]ethylI -N-methyl-4-(2-rnethylphenyl)octahydro-5H
pyrrolo[3,4-
c]pyridine-5-carboxamide (Example 9) and 1-(aminocarbonyl)piperidineW4-
carboxylic acid with
the same method as in Example 1, step F. MS: 668 (M+1).
EXAMPLE 21
CF3 CF3
N

Na
a

3aS4R 7-N- i.R -1- 3 5-bis trifluorometh 1 b.en 1 eth 1-N-meth 1-4- 2-m.eth 1
hen 1-2-
tetrah dro-2H- ran-4- i octah dro-5H rrolo 34-c idine-5-carboxamide

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The title compound was prepared 1'rona.(3aS,4R,7aS)-N-{(1R)-1-[3,5-
bis(trifluoromethyl)phenyllethyl } -N-methyl-4-(2-methylphenyl )octahydra-5H-
pyrrolo [3,4-
c]pyridine-5-carboxamide (Example 9) with the same method as in Example 14.
MS: 598 (M+1).

EXAMPLE 22
CF3 CF3
N-'~'d

N
O~

3aS4R 7 -2- 1-ace 1 i eridin-4- I-N- lR -1- 3 5Tbis trifluorometh 1hen 1 eth 1-
.N
meth 1-4- 2-meth I hen 1 octah dro-5H o10 3 4-c ridine-5-ca.rboxamide
The title compowld was prepared from(3aS,4R,7aS)-1V {(1R)- 1- [3,5-
bis(trifluoromethyl)phenyl]ethylI -N methyl-4-(2-methylphenyl)octahydro-5H
pyrrolo[3,4-
c]pyridine-5-carboxamide (Example 9) with the same method as in Example 14.
MS: 639 (M+1).

EXAMPLE 23
CF3 \ CF3
N~ /

O
OH

3aS4R 7-N 1 R -1- 3 5-bis trifluorometh 1 hen 1 eth -2- 1- 3-h drox -2 2-
dimeth 1 ro 1 i eridin-4- 1-N-rneLb 1-4- 2-meth 1 hen 1 octah dro-5H oIo 3 4
clpvridine-5-caxbox.amide

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St~A: tert-butyl (3aSR,4RS,7aSR)-2-(3-hydroxy-2,2-dimethylpropyl)-4-(2-
rnethylphenyl)octahydro-5H-pyrrolo [3,4-c]pyrxdine-5-carboxylate

o
oH
,)-0

The title compound was prepared from tert-butyl (2RS',3RS,4SR)-3,4-
bis(hydroxymethyl)-2-(2-rnethylphenyl)piperidine-l-carboxylate according to
Example 1, step D.
MS: 403 (M+l).

St~B tert-butyl (3aSR,4RS,7aSR)-2-[3-(acetyloxy)-2,2-dimethylpropyl]-4-(2-
methylphenyl)octahydro-5H pyrrolo[3,4-c]pyridine-5-carboxylate

~-~
0 ~ Q
)-0
~ o
~1

A solution of tert-butyl(3aSR,4RS,7aSR)-2-(3-hydroxy-2,2-dimethylpropyl)-4-(2-
methylphenyl)octahydro-5H pyrrolo[3,4-c]pyridine-5-caz'boxylate (84 mg, 0.21
mmol), Ae20
(0.104 rnL, 1.05 mmol) and DAMP (2 mg) in 5 mL of pyridine was stirred at rt
for 1 hr. Upon
removal of volatiles, the crude was purified by preparative TLC (MeOH/CH?,CI2
= 5:95) to afford
the title compound. MS: 445 (M+l).

Step C: 3-[(3aS,4R,7aS)-5-{[{(1R)-1-[3,5-
bis(trifluoromethyl)phenyl]ethyl ~ (methyl)amino] carbonyl} -4-(2-
methylphenyl)octahydro-2H pyrrolo[3,4-c]pyridin-2-yl]-2,2-dirnethylpropyl
acetate
o4
F F o 0
F I N ~ N
F ~
F
The title compound was prepared from tert-butyl (3aSR, 4RS,7aSR)-2-[3-
(acetyloxy)-2,2-dimethylpropyl]-4--(2-methylphenyl)octahydro-5H pyrrolo[3,4-
c]pyridine-5-
carboxylate according to and Eample 1, step E and Example 8, step G. MS: 642
(M+1).

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CA 02690737 2009-12-11
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Step D: tert-butyl (3aS,4R,7aS)-2-(3-hydroxy-2,2-dzmethylpropyl)-4-(2-
methylphenyl)octahydro-5H-pyrro lo[3,4-c]pyridine-5-carboxylate

A solution of 3-[(3aS,4R,7a.S`)-5-1[{(1R)-1-[3,5-bis(trifluoromethyl)
phenyl]ethyl)(methyl)amino]carbonyl}-4-(2-methylphenyl)octahydro-2H
pyrrolo[3,4-c]pyridin-
2-yl]-2,2-dimethylpropyl acetate (32 mg, 0.05 mmol) in 3 mL of methanol was
added 3 drops of
2N NaOH solution. The mixture was stirred at rt for 3 hrs. Upon removal of
volatiles, the crude
was purified by reverse phase HPLC to afford the title compound. MS: 600
(M+l).

EXAMPLE 24
CF3 CF3
N

N0
O
NH2
3aS 4R 7-2- 1- 3-amino-2 2-dimeth 1-3-oxo ro l i eridin-4- 1-N 1R -1- 3 5-
bis trifluorometh 1 hen 1 eth 1-N-meth 1-4- 2-meth 1 hen 1 octah dro-5H zTolo
3 4-
capyridine-5--carboxamide
The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4-
bis(hydroxymethyl)-2-(2-methylphenyl)piperidine-l-carboxylate and 3-amino-2,2-
dimethylpropanaznide according to steps in Example 8. MS: 613 (M+I).

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EXAMPLE 25

(3aS,4R,7a.S;)-2-benzyl-N ((1R)-1-G3,5-bis(trifluoronaethjl)pheUl, ethI}-4T(4-
fluoro-2-
methylphenyl -N-methyloctahydro-5H-prolo[3,4-elpyridine-5-carboxamide
F
o
CF
N~N ~N -
CF3
The title compound was prepared according to steps in Example 8. MS: 622
(M+l ).

EXAMPLE 26

3aS 4R 7 -N 1R -1- 3 5-bis trifluorormeth 1 hen 1 eth 1-4- 4-fluoro-2-rneth 1
hen 1-N-
meth loctah dro-5H- rolo 3 4-c idine-5-carboxamide
F
o
C3 NN ~
NFi
CF3
The title compound was prepared from (3aS,4R,7aS)-2-benzyl-N {(lR)-1-[3,5-
bi s(trifluoromethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-
methyloctahydro- 5H-
pyrrolo[3,4-c]pyridine-5-=carboxamide with the same method as in Example 1,
step E. MS: 532
(M+1).

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CA 02690737 2009-12-11
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EXAMPLE 27

CF3 CF3
Nl-~, O

N--'~ F
O

3aS 4R 7-N- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-4- 4-fluora-2-meth 1
hen I TN
rneth 1-2- 3-oxoc cla ent-l-en-1- 1 actah dro-SH- rrolo 3 4-c ridine-5-
carboxamide
The title compound was prepared from (3aS,4R,7aS)-1V {(1R)-1-[3,5-
bis(trifluoromethyl)phenyl] ethyl I -4 W (4-fluoro-2-methylphenyl)-N-
rnethyloctahydro- 5H-
pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1,
step H. MS: 612
(M+ 1).

EXAMPLE 28
CF3 CF3
N

NO
N---' F
N

O
(3aS,4R,7a@-N {..(1R)-l-[3,5-bis(trifluoraxn.ethyl)nen~lethyX-4-(4-fluc~ra-2-
meth ly phenyX)-N
meth,yl-2-(4-oxo-4,5-dihydro-143-oxazal-2-yl octahydra-5H-pyrrolo[3,4-
c].pyridine-5-
carboxamide
The title compound was prepared with the same procedure as Example 12. MS:
615 (M+1).

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EXAMPLE 29

GF3 CF3
N

NO
N-~ F
D 1
O
3aS 4R 7-N- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-4- 4-fluoro-2-meth 1
hen 1-N-
meth 1-2- 5-oxo-2 5-dih drof-uran-3- 1 octah dro-5H rrolo 3 4-~c idine-5-
carboxamide

The title compound was prepared from (3aS,4R,7aS)-N-I(1R)-l-[3,5-
bis(trifluoromethyl)phenyl] ethyl) -4-(4-fluoro-2-rnethylphenyl)-N
rnethyloctahydro-5H-
pyrrolo[3,4-c]pyridzne-5-carboxatnide with the same method as in Example 13.
MS: 614 (M+1).
EXAMPLE 30

CF3 CF3
1

~, N
NO
N-7 F
H

3aS4R 7-N- 1R -1- 3 5-bis triflnorometh 1 hen 1 eth 1-4- 4-fluoro-2-meth 1 hen
1-2-
2-2-h drox ra ano l-N meth loctah dro-5H- ola 3 4-c idine-5-carboxamide
The title compound was prepared from (3aS,4R,7axS')-N-{(1R)-1-[3,5-
bis(triflnoromethyl)phenyl] ethyl) -4-(4-fluoro-2-methylphenyl)-N methyl
octahydro-5H-
pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1,
step F. MS: 604
(M+l).

_44..


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EXAMPLE 31
CF3 CF3
N

NO
N--
0~', OH

(3 aS,4R, 7aS)-N- {(1R)-1- f3,5 -bis(trifluoromethyl)phen~llethyll-4-(4
Wfluoro-2-met.liyll2herayl)-2-
2R -2-h drox ro ano l-N-meth loctah dro-5H rrolo 3 4Wc xxdine-5-carboxamide
The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5-
bis(trifluoromethyl)phenyt]ethyl}-4-(4-fluoro-2-methylphenyl)-N
methyloctahydro-51-1-
pyrrolo[3,4-c]pyridine-5-carboxamxde with the same method as in Example 1,
step F. MS: 604
(M+1).

EXAMPLE 32
F F
F F
F F
~N

N-~-O

F
o=~

(3a.S',4R,7aq-2-acetyZ-N-f (1R)-1- 3,5-bis~trifluoromethyl)pheUljqhy1l-4-(4-
fl.uoro-2-
nra ethylpheUl)-N-meLhyloctahydro-SH-tayr.rolo[3 24-cjayridxne-5-carboxamxde

The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5-
bis(trzfluorometiryl)phenyl]etb.yi}-4-(4-fluoro-2-methylphenyl)-N-
methyloctahydro-5H-
pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1,
step F. MS:574
(M+1).

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EXAMPLE 33
F F
F
F
F
F
'N

No

F
0

3aS 4R 7-N 1R -1- 3 S-bis trifluorometh 1 hen 1 eth I-2- 2 2-dianeth 1 ro ano
1-4- 4-
fluoro-2-meth 1 hen 1-N-meth loctah dro-5H- ol0 3 4-c idine-5-carboxam.ide

The title compound was prepared from (3aS,4R,7aS)-N f(1R)-1-[3,S-
bis(trifluorornethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-
methyloctahydro-5H-
pyrrolo[3,4-c]pyridine-5-carboxana.ide with the same method as in Example 1,
step F. MS 616
(M+1).

EXAMPLE 34
F F
F F
F F
N

N-~-O

F
0

O
3aS4R 7-N- 1R -1- 3 STbis trifluorometh 1 hen 1 eth i-4- 4-fluoro-2-meth 1 hen
1-N
meth 1-2- tetrah dro-2H ran-4- lcarbon 1 octah dro-SH- ol0 3 4-c ridine-S-
carboxamide
The title compound was prepared from (3aS,4R,7aS)-N {(1R)-1-[3,5-
bi,s(trifluoromethyl)phenyl]ethylI -4-(4-fluoro-2-methylphenyl)-N-
methyloctahydro-5H
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pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1,
step F. MS: 644
(M+1)=

EXAMPLE 35
F F
F
F

N
N -~-O

F

3aS 4R 7-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-4- 4-fluoro-2-meth 1 hen
1-N-
meth I-2- tetrah dro-2H ran-4- I octah dro-5I-f- 010 3 4-c 'rdine-5-
carboxamide
The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-l-[3,5-
bis(trifluoromethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-
methyloctahydro-5H-
pyrrolo[3,4-clpyridine-5-carboxamide with the same method as in Example 14.
MS: 616 (M+1).
EXAMPLE 36
F F
F
F

1~ N
Na
N-~ F
N
O:-,

(3aS,4R,7aS)-2-(1-acetylpiperidin.-4-yl)-N f(1R)-I-j3 5-bis
trifluoromethyl)phenyl ethyl}-4-(4-
fluoro-2Tmethylphenyl)-N-metl loctahydro-5.H-pyrrolo[3,4-c]pyridine-5-
carboxamide
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The title compound was prepared from (3aS,4R,7aS)-1V {(1R)-1-[3,5-
bis(trifluoromethyi)phenyl] ethyl } -4-(4--fluaro-2-methylphenyl)-N-
methyloctahydro-5H
pyrroio[3,4-c]pyridine-5-carboxamide with the same method as in Example 14.
MS: 658 (M+1).

While the inventzon has been described and illustrated with reference to
certain
particular embodiments thereof, those skilled in the art will appreciate that
various adaptations,
changes, modifications, substitutions, deletions, or additions of procedures
and protocols may be
made without departing from the spirit and scope of the invention. For
example, effective
dosages other than the particular dosages as set forth herein above may be
applicable as a
consequence of variations in responsiveness of the mammal being treated for
any of the
indications with the compounds of the invention indicated above.

-48-