U.S. patent application number 12/470317 was filed with the patent office on 2009-09-10 for cyclobutyl amine derivatives.
This patent application is currently assigned to Abbott Laboratories. Invention is credited to Marlon D. Cowart, Arthur A. Hancock, Kathryn J. Hancock, Huaqing Liu.
Application Number | 20090227593 12/470317 |
Document ID | / |
Family ID | 37450864 |
Filed Date | 2009-09-10 |
United States Patent
Application |
20090227593 |
Kind Code |
A1 |
Liu; Huaqing ; et
al. |
September 10, 2009 |
CYCLOBUTYL AMINE DERIVATIVES
Abstract
Compounds of formula (I) ##STR00001## are useful in treating
conditions or disorders prevented by or ameliorated by histamine-3
receptor ligands. Also disclosed are pharmaceutical compositions
comprising the histamine-3 receptor ligands, methods for using such
compounds and compositions, and a process for preparing compounds
within the scope of formula (I).
Inventors: |
Liu; Huaqing; (Buffalo
Grove, IL) ; Hancock; Arthur A.; (Libertyville,
IL) ; Hancock; Kathryn J.; (Libertyville, IL)
; Cowart; Marlon D.; (Round Lake Beach, IL) |
Correspondence
Address: |
PAUL D. YASGER;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD, DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Assignee: |
Abbott Laboratories
Abbott Park
IL
|
Family ID: |
37450864 |
Appl. No.: |
12/470317 |
Filed: |
May 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11444825 |
Jun 1, 2006 |
7553964 |
|
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12470317 |
|
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60687357 |
Jun 3, 2005 |
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Current U.S.
Class: |
514/252.05 ;
514/343; 514/408; 544/238; 546/276.4; 548/566 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
25/16 20180101; A61P 25/08 20180101; C07D 417/10 20130101; A61P
35/00 20180101; A61P 1/08 20180101; C07D 401/10 20130101; A61P 3/00
20180101; A61P 25/02 20180101; A61P 37/08 20180101; A61P 3/10
20180101; A61P 11/06 20180101; A61P 25/04 20180101; A61P 27/16
20180101; A61P 25/00 20180101; A61P 25/28 20180101; A61P 25/30
20180101; C07D 403/10 20130101; A61P 15/00 20180101; C07D 207/06
20130101; A61P 25/14 20180101; A61P 25/20 20180101; A61P 25/24
20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/252.05 ;
548/566; 514/408; 514/343; 546/276.4; 544/238 |
International
Class: |
A61K 31/501 20060101
A61K031/501; C07D 207/08 20060101 C07D207/08; A61K 31/40 20060101
A61K031/40; A61K 31/4439 20060101 A61K031/4439; C07D 401/02
20060101 C07D401/02; C07D 403/02 20060101 C07D403/02; A61P 25/28
20060101 A61P025/28 |
Claims
1. A compound of formula: ##STR00018## or a pharmaceutically
acceptable salt, ester, amide, or prodrug thereof, wherein: one of
R.sub.1 and R.sub.2 is a group of the formula
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b; the other of R.sub.1 and
R.sub.2 is selected from the group consisting of hydrogen, alkyl,
alkoxy, halogen, cyano, and thioalkoxy; R.sub.3, R.sub.3a, and
R.sub.3b are each independently selected from the group consisting
of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy; R.sub.4
and R.sub.5 are each independently selected from the group
consisting of alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and
cycloalkyl, or R.sub.4 and R.sub.5 taken together with the nitrogen
atom to which each is attached form a non-aromatic ring of the
formula: ##STR00019## R.sub.7, R.sub.8, R.sub.9, and R.sub.10 at
each occurrence are each independently selected from the group
consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and
alkyl; R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each
independently selected from the group consisting of hydrogen,
hydroxyalkyl, alkyl, and fluoroalkyl; R.sub.6a is selected from the
group consisting of a 5- to 6-membered heteroaryl ring,
cyanophenyl, an 8- to 10-membered bicyclic heteroaryl ring, and a
4- to 8-membered heterocyclic ring; R.sub.6b is selected from the
group consisting of hydrogen, a 5- to 6-membered heteroaryl ring,
phenyl, an 8- to 10-membered bicyclic heteroaryl ring, and a 4- to
8-membered heterocyclic ring; Q is O or S; L is
--[C(R.sub.16)(R.sub.17)].sub.k; L.sub.2 is selected from the group
consisting of a bond, --O--, --C(.dbd.O)--, --S--, --NH--,
--N(R.sub.16)C(.dbd.O)--, --C(.dbd.O)N(R.sub.16), and --N(alkyl)-;
L.sub.3 is selected from the group consisting of a bond, --O--,
--C(.dbd.O)--, --S--, --N(R.sub.16)C(.dbd.O)--,
--C(.dbd.O)N(R.sub.16), and --N(R.sub.15)--; R.sub.15 is selected
from the group consisting of hydrogen, alkyl, acyl, alkoxycarbonyl,
amido, and formyl; R.sub.16 and R.sub.17 at each occurrence are
independently selected from the group consisting of hydrogen and
alkyl; R.sub.x and R.sub.y at each occurrence are independently
selected from the group consisting of hydrogen, hydroxy, alkyl,
alkoxy, alkylamino, fluoro, and dialkylamino; k is 0, 1, or 2; m is
an integer from 1 to 5; and n is 0 or 1.
2. The compound of claim 1, wherein R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond,
R.sub.6b is hydrogen, L.sub.3 is a bond, and R.sub.6a is selected
from a 5- or 6-membered heteroaryl ring.
3. The compound of claim 2, wherein R.sub.6a is an unsubstituted or
substituted ring selected from the group consisting of furyl,
imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolonyl,
[1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,3]oxadiazolyl,
[1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl,
thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl,
[1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl,
pyridazinonyl, pyridonyl, and pyrimidinonyl.
4. The compound of claim 2, wherein R.sub.6a is an unsubstituted or
substituted ring selected from the group consisting of pyrimidinyl,
pyridazinonyl, pyridinyl, and pyrazolyl.
5. The compound of claim 1, wherein R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond,
R.sub.6b is hydrogen, L.sub.3 is a bond, and R.sub.6a is selected
from a 8- to 10-membered bicyclic heteroaryl ring.
6. The compound of claim 5, wherein R.sub.6a is an unsubstituted or
substituted ring selected from the group consisting of indolyl,
benzothienyl, benzofuranyl, indazolyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl,
quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl,
thieno[2,3-d]imidazole, and pyrrolopyrimidinyl.
7. The compound of claim 6, wherein R.sub.6a is unsubstituted or
substituted benzothiazolyl.
8. The compound of claim 1, wherein one of R.sub.3, R.sub.3a, and
R.sub.3b is halogen and the others are hydrogen.
9. The compound of claim 1, wherein R.sub.4 and R.sub.5 taken
together with the nitrogen atom to which each is attached form a 4-
to 8-membered non-aromatic ring represented by formula (a).
10. The compound of claim 9, wherein at least one substituent
represented by R.sub.7, R.sub.8, R.sub.9, and R.sub.10 is selected
from the group consisting of alkyl, fluoroalkyl, and hydroxyalkyl
or at least one substituent represented by R.sub.x or R.sub.y is
alkyl, fluoro, or hydroxy.
11. The compound of claim 1, wherein R.sub.4 and R.sub.5 are taken
together with the nitrogen atom to which each is attached to form a
(2R)-methylpyrrolidine ring or (2S)-methylpyrrolidine ring.
12. The compound of claim 1, wherein the compound has the formula
##STR00020## wherein L, n, R.sub.1, R.sub.2, R.sub.3, R.sub.3a,
R.sub.3b, R.sub.4, and R.sub.5 are each as defined in claim 1.
13. The compound of claim 12, wherein R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond,
R.sub.6b is hydrogen, L.sub.3 is a bond, R.sub.6a is selected from
a 5- or 6-membered heteroaryl ring, and R.sub.4 and R.sub.5 taken
together with the nitrogen atom to which each is attached form a 4-
to 8-membered non-aromatic ring represented by formula (a).
14. The compound of claim 1, wherein the compound has the formula
##STR00021## wherein L, n, R.sub.1, R.sub.2, R.sub.3, R.sub.3a,
R.sub.3b, R.sub.4, and R.sub.5 are each as defined in claim 1.
15. The compound of claim 14, wherein R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond,
R.sub.6b is hydrogen, L.sub.3 is a bond, R.sub.6a is selected from
a 5- or 6-membered heteroaryl ring, and R.sub.4 and R.sub.5 taken
together with the nitrogen atom to which each is attached form a 4-
to 8-membered non-aromatic ring represented by formula (a).
16. The compound of claim 1, selected from the group consisting of
4'-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbon-
itrile;
4'-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-c-
arbonitrile;
4'-[3-(2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-biphenyl-4-carbonitrile;
4'-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-biphenyl-4-carbonitril-
e;
5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyrimid-
ine;
2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]--
phenyl}-pyridine;
2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyridine;
2,6-dimethyl-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyridine;
2,6-dichloro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyridine;
4'-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonit-
rile;
5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-py-
rimidine;
2-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-2H-pyridazin-3-one;
4'-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbon-
itrile;
5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}--
pyrimidine;
2,4-dimethoxy-5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-p-
henyl}-pyrimidine;
2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-pheny-
l}-pyrimidine;
2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-p-
henyl}-pyrimidine;
5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotin-
onitrile;
2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobuty-
l]-phenyl}-benzothiazole;
2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-pyridine;
1,3,5-trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phen-
yl}-1H-pyrazole;
5-{2-fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-pyrimidine;
4'-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-ca-
rbonitrile;
4'-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-trans-cyclobutyl}-biphenyl-4--
carbonitrile;
4'-{3-[(2S)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-ca-
rbonitrile;
2,6-difluoro-3-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phe-
nyl}-pyridine;
5-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidi-
ne;
4'-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-biphenyl-4-carb-
onitrile;
1,3,5-trimethyl-4-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-ci-
s-cyclobutyl]-phenyl}-1H-pyrazole;
2-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H--
pyridazin-3-one;
2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-p-
henyl}-pyrimidine;
2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobuty-
l]-phenyl}-pyrimidine; and
4'-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutylmethyl}-biphenyl-4-ca-
rbonitrile.
17. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 in combination with a
pharmaceutically acceptable carrier.
18. A method of selectively modulating the effects of histamine-3
receptors in a mammal comprising administering an effective amount
of a compound of claim 1.
19. A method of treating a condition or disorder modulated by the
histamine-3 receptors in a mammal comprising administering an
effective amount of a compound of claim 1.
20. The method according to claim 19, wherein the condition or
disorder is selected from the group consisting of attention-deficit
hyperactivity disorder (ADHD), deficits in attention, dementia, and
diseases with deficits of memory, learning, schizophrenia,
cognitive deficits of schizophrenia, cognitive deficits and
dysfunction in psychiatric disorders, Alzheimer's disease, mild
cognitive impairment, epilepsy, seizures, allergic rhinitis, and
asthma, motion sickness, dizziness, Meniere's disease, vestibular
disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome
X, insulin resistance syndrome, metabolic syndrome, pain, including
neuropathic pain, neuropathy, sleep disorders, narcolepsy,
pathological sleepiness, jet lag, drug abuse, mood alteration,
bipolar disorder, depression, obsessive compulsive disorder,
Tourette's syndrome, Parkinson's disease, and medullary thyroid
carcinoma, melanoma, and polycystic ovary syndrome.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S. patent
application Ser. No. 11/444,825, filed Jun. 1, 2006, which claims
priority to U.S. Provisional Patent Application Ser. No.
60/687,357, filed Jun. 3, 2005, all of which are hereby
incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] The invention relates to cyclobutyl amine compounds,
compositions comprising such compounds, methods for making the
compounds, and methods of treating conditions and disorders using
such compounds and compositions.
DESCRIPTION OF RELATED TECHNOLOGY
[0003] Histamine is a well-known modulator of neuronal activity. At
least four types of histamine receptors have been reported in the
literature, typically referred to as histamine-1, histamine-2,
histamine-3, and histamine-4. The class of histamine receptor known
as histamine-3 receptors is believed to play a role in
neurotransmission in the central nervous system.
[0004] The histamine-3 (H.sub.3) receptor was first characterized
pharmacologically on histaminergic nerve terminals (Nature,
302:832-837 (1983)), where it regulates the release of
neurotransmitters in both the central nervous system and peripheral
organs, particularly the lungs, cardiovascular system and
gastrointestinal tract. H.sub.3 receptors are thought to be
disposed presynaptically on histaminergic nerve endings, and also
on neurons possessing other activity, such as adrenergic,
cholinergic, serotoninergic, and dopaminergic activity. The
existence of H.sub.3 receptors has been confirmed by the
development of selective H.sub.3 receptor agonists and antagonists
((Nature, 327:117-123 (1987); Leurs and Timmerman, ed. "The History
of H.sub.3 Receptor: a Target for New Drugs," Elsevier (1998)).
[0005] The activity at the H.sub.3 receptors can be modified or
regulated by the administration of H.sub.3 receptor ligands. The
ligands can demonstrate antagonist, inverse agonist, agonist, or
partial agonist activity. For example, H.sub.3 receptors have been
linked to conditions and disorders related to memory and cognition
processes, neurological processes, cardiovascular function, and
regulation of blood sugar, among other systemic activities.
Although various classes of compounds demonstrating H.sub.3
receptor-modulating activity exist, it would be beneficial to
provide additional compounds demonstrating activity at the H.sub.3
receptors that can be incorporated into pharmaceutical compositions
useful for therapeutic methods.
SUMMARY OF THE INVENTION
[0006] The invention is directed to cyclobutyl amines and, more
particularly, bicyclic- and tricyclic-substituted cyclobutyl amine
derivatives. Accordingly, one aspect of the invention relates to
compounds of formula (I):
##STR00002##
or a pharmaceutically acceptable salt, ester, amide, or prodrug
thereof, wherein:
[0007] one of R.sub.1 and R.sub.2 is a group of the formula
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b;
[0008] the other of R.sub.1 and R.sub.2 is selected from hydrogen,
alkyl, alkoxy, halogen, cyano, and thioalkoxy;
[0009] R.sub.3, R.sub.3a, and R.sub.3b are each independently
selected from hydrogen, alkyl, alkoxy, halogen, cyano, and
thioalkoxy;
[0010] R.sub.4 and R.sub.5 are each independently selected from
alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl, or
R.sub.4 and R.sub.5 taken together with the nitrogen atom to which
each is attached form a non-aromatic ring of the formula:
##STR00003##
[0011] R.sub.7, R.sub.8, R.sub.9, and R.sub.10 at each occurrence
are each independently selected from hydrogen, hydroxyalkyl,
fluoroalkyl, cycloalkyl, and alkyl;
[0012] R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each
independently selected from hydrogen, hydroxyalkyl, alkyl, and
fluoroalkyl;
[0013] R.sub.6a is selected from a 5- to 6-membered heteroaryl
ring, cyanophenyl, an 8- to 10-membered bicyclic heteroaryl ring,
and a 4- to 8-membered heterocyclic ring;
[0014] R.sub.6b is selected from hydrogen, a 5- to 6-membered
heteroaryl ring, phenyl, an 8- to 10-membered bicyclic heteroaryl
ring, and a 4- to 8-membered heterocyclic ring;
[0015] Q is selected from O and S;
[0016] L is --[C(R.sub.16)(R.sub.17)].sub.k;
[0017] L.sub.2 is selected from a bond, --O--, --C(.dbd.O)--,
--S--, --NH--, --N(R.sub.16)C(.dbd.O)--, --C(.dbd.O)N(R.sub.16),
and --N(alkyl)-;
[0018] L.sub.3 is selected from a bond, --O--, --C(.dbd.O)--,
--S--, --N(R.sub.16)C(.dbd.O)--, --C(.dbd.O)N(R.sub.16), and
--N(R.sub.15)--;
[0019] R.sub.15 is selected from hydrogen, alkyl, acyl,
alkoxycarbonyl, amido, and formyl;
[0020] R.sub.16 and R.sub.17 at each occurrence are independently
selected from hydrogen and alkyl;
[0021] R.sub.x and R.sub.y at each occurrence are independently
selected from hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro,
and dialkylamino;
[0022] k is 0, 1, or 2;
[0023] m is an integer from 1 to 5; and
[0024] n is 0 or 1.
[0025] Another aspect of the invention relates to pharmaceutical
compositions comprising compounds of the invention. Such
compositions can be administered in accordance with a method of the
invention, typically as part of a therapeutic regimen for treatment
or prevention of conditions and disorders related to H.sub.3
receptor activity.
[0026] Yet another aspect of the invention relates to a method of
selectively modulating H.sub.3 receptor activity. The method is
useful for treating, or preventing conditions and disorders related
to H.sub.3 receptor modulation in mammals. More particularly, the
method is useful for treating or preventing conditions and
disorders related to memory and cognition processes, neurological
processes, cardiovascular function, and body weight. Accordingly,
the compounds and compositions of the invention are useful as a
medicament for treating or preventing H.sub.3 receptor modulated
disease.
[0027] Processes for making compounds of the invention also are
contemplated.
[0028] The compounds, compositions comprising the compounds,
methods for making the compounds, and methods for treating or
preventing conditions and disorders by administering the compounds
are further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0029] Certain terms as used in the specification are intended to
refer to the following definitions, as detailed below.
[0030] The term "acyl" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through a
carbonyl group, as defined herein. Representative examples of acyl
include, but are not limited to, acetyl, 1-oxopropyl,
2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
[0031] The term "acyloxy" as used herein means an acyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of acyloxy include, but are
not limited to, acetyloxy, propionyloxy, and isobutyryloxy.
[0032] The term "alkenyl" as used herein means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons, and
preferably 2, 3, 4, 5, or 6 carbons, and containing at least one
carbon-carbon double bond formed by the removal of two hydrogens.
Representative examples of alkenyl include, but are not limited to,
ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,
5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
[0033] The term "alkoxy" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0034] The term "alkoxyalkoxy" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through another alkoxy group, as defined herein. Representative
examples of alkoxyalkoxy include, but are not limited to,
tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and
methoxymethoxy.
[0035] The term "alkoxyalkyl" as used herein means an alkoxy group,
as defined herein, appended to the parent molecular moiety through
an alkyl group, as defined herein. Representative examples of
alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
[0036] The term "alkoxycarbonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0037] The term "alkoxyimino" as used herein means an alkoxy group,
as defined herein, appended to the parent molecular moiety through
an imino group, as defined herein. Representative examples of
alkoxyimino include, but are not limited to, ethoxy(imino)methyl
and methoxy(imino)methyl.
[0038] The term "alkoxysulfonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl, and propoxysulfonyl.
[0039] The term "alkyl" as used herein means a straight or branched
chain hydrocarbon containing from 1 to 10 carbon atoms, and
preferably 1, 2, 3, 4, 5, or 6 carbons. Representative examples of
alkyl include, but are not limited to, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,
2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
[0040] The term "alkylamino" as used herein means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a NH group. Representative examples of alkylamino include, but are
not limited to, methylamino, ethylamino, isopropylamino, and
butylamino.
[0041] The term "alkylcarbonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to,
methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl,
and the like.
[0042] The term "alkylsulfonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl.
[0043] The term "alkynyl" as used herein means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms, and preferably 2, 3, 4, or 5 carbons, and containing at
least one carbon-carbon triple bond. Representative examples of
alkynyl include, but are not limited to, acetylenyl, 1-propynyl,
2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
[0044] The term "amido" as used herein means an amino, alkylamino,
or dialkylamino group appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of amido include, but are not limited to, aminocarbonyl,
methylaminocarbonyl, dimethylaminocarbonyl, and
ethylmethylaminocarbonyl.
[0045] The term "amino" as used herein means a --NH.sub.2
group.
[0046] The term "aryl" as used herein means a monocyclic
hydrocarbon aromatic ring system. Representative examples of aryl
include, but are not limited to, phenyl.
[0047] The aryl groups of this invention are substituted with 0, 1,
2, 3, 4, or 5 substituents independently selected from acyl,
acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkylcarbonyl,
formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
mercapto, nitro, thioalkoxy, NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)sulfonyl.
[0048] The term "arylalkyl" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl, 2-phenylethyl
and 3-phenylpropyl.
[0049] The term "carbonyl" as used herein means a --C(.dbd.O)--
group.
[0050] The term "carboxy" as used herein means a --CO.sub.2H group,
which may be protected as an ester group --CO.sub.2-alkyl.
[0051] The term "cyano" as used herein means a --CN group.
[0052] The term "cyanophenyl" as used herein means a --CN group
appended to the parent molecular moiety through a phenyl group,
including, but not limited to, 4-cyanophenyl, 3-cyanophenyl, and
2-cyanophenyl.
[0053] The term "cycloalkyl" as used herein means a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons. Examples
of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
[0054] The cycloalkyl groups of the invention are substituted with
0, 1, 2, 3, or 4 substituents selected from acyl, acyloxy, alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,
alkyl, alkynyl, amido, carboxy, cyano, ethylenedioxy, formyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
methylenedioxy, oxo, thioalkoxy, and --NR.sub.AR.sub.B.
[0055] The term "cycloalkylcarbonyl" as used herein means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of cycloalkylcarbonyl include, but are not
limited to, cyclopropylcarbonyl, cyclopentylcarbonyl,
cyclohexylcarbonyl, and cycloheptylcarbonyl.
[0056] The term "dialkylamino" as used herein means two independent
alkyl groups, as defined herein, appended to the parent molecular
moiety through a nitrogen atom. Representative examples of
dialkylamino include, but are not limited to, dimethylamino,
diethylamino, ethylmethylamino, and butylmethylamino.
[0057] The term "fluoro" as used herein means --F.
[0058] The term "fluoroalkyl" as used herein means at least one
fluoro group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of fluoroalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,
and 2,2,2-trifluoroethyl.
[0059] The term "formyl" as used herein means a --C(O)H group.
[0060] The term "halo" or "halogen" as used herein means Cl, Br, I,
or F.
[0061] The term "haloalkoxy" as used herein means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, 2-fluoroethoxy,
trifluoromethoxy, and pentafluoroethoxy.
[0062] The term "haloalkyl" as used herein means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0063] The term "heteroaryl", as used herein, refers to an aromatic
ring containing 1, 2, 3, or 4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, or a tautomer thereof. Such rings
can be monocyclic or bicyclic as further described herein.
Heteroaryl rings are connected to the parent molecular moiety, or
to L.sub.2 or L.sub.3, wherein L.sub.2 and L.sub.3 are defined in
formula (I), through a carbon or nitrogen atom.
[0064] The terms "monocyclic heteroaryl" or "5- or 6-membered
heteroaryl ring", as used herein, refer to 5- or 6-membered
aromatic rings containing 1, 2, 3, or 4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a tautomer thereof.
Examples of such rings include, but are not limited to, a ring
wherein one carbon is replaced with an O or S atom; one, two, or
three N atoms are arranged in a suitable manner to provide an
aromatic ring; or a ring wherein two carbon atoms in the ring are
replaced with one O or S atom and one N atom. Such rings can
include, but are not limited to, a six-membered aromatic ring
wherein one to four of the ring carbon atoms are replaced by
nitrogen atoms, five-membered rings containing a sulfur, oxygen, or
nitrogen in the ring; five membered rings containing one to four
nitrogen atoms; and five membered rings containing an oxygen or
sulfur and one to three nitrogen atoms. Representative examples of
5- to 6-membered heteroaryl rings include, but are not limited to,
furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolonyl,
[1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,3]oxadiazolyl,
[1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl,
thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl,
[1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl,
pyridazinonyl, pyridonyl, and pyrimidinonyl.
[0065] The term "bicyclic heteroaryl" or "8- to 10-membered
bicyclic heteroaryl ring", as used herein, refers to an 8-, 9-, or
10-membered bicyclic aromatic ring containing at least 3 double
bonds, and wherein the atoms of the ring include 1, 2, 3, 4, or 5
heteroatoms independently selected from oxygen, sulfur, and
nitrogen. Representative examples of 8- to 10-membered bicyclic
heteroaryl rings include indolyl, benzothienyl, benzofuranyl,
indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,
benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl,
quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl,
naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, and
pyrrolopyrimidinyl.
[0066] Heteroaryl groups of the invention, whether monocyclic or
bicyclic, can be substituted with 0, 1, 2, 3, or 4 substituents
independently selected from acyl, acyloxy, alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,
alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl,
amido, carboxy, cyano, cycloalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, thioalkoxy,
--NR.sub.AR.sub.B, (NR.sub.AR.sub.B)carbonyl, and
(NR.sub.AR.sub.B)sulfonyl. Heteroaryl groups of the present
invention that are substituted may be present as tautomers.
[0067] The terms "heterocyclic ring" and "heterocycle", as used
herein, refer to a four-, five-, six-, seven-, or eight-membered
ring containing at least one saturated carbon atom, and also
containing one, two, or three heteroatoms independently selected
from the group consisting of nitrogen, oxygen, and sulfur. Four-
and five-membered rings may have zero or one double bond.
Six-membered rings may have zero, one, or two double bonds. Seven-
and eight-membered rings may have zero, one, two, or three double
bonds. The heterocycle groups of the invention can be attached
through a carbon atom or a nitrogen atom. Representative examples
of nitrogen-containing heterocycles include, but are not limited
to, azepanyl, azetidinyl, aziridinyl, azocanyl, morpholinyl,
piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl,
dihydrothiazolyl, dihydropyridinyl, and thiomorpholinyl.
Representative examples of non-nitrogen containing heterocycles
include, but are not limited to, dioxanyl, dithianyl,
tetrahydrofuryl, dihydropyranyl, and tetrahydropyranyl.
[0068] The heterocycles of the invention are substituted with 0, 1,
2, 3, or 4 substituents independently selected from acyl, acyloxy,
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amido,
arylalkyl, arylalkoxycarbonyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
thioalkoxy, --NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)sulfonyl.
[0069] The term "hydroxy" as used herein means an --OH group.
[0070] The term "hydroxyalkyl" as used herein means at least one
hydroxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl,
3-hydroxypropyl, 2,3-dihydroxypentyl, and
2-ethyl-4-hydroxyheptyl.
[0071] The term "hydroxy-protecting group" means a substituent
which protects hydroxyl groups against undesirable reactions during
synthetic procedures. Examples of hydroxy-protecting groups
include, but are not limited to, methoxymethyl, benzyloxymethyl,
2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl,
triphenylmethyl, 2,2,2-trichloroethyl, t-butyl, trimethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, methylene acetal,
acetonide benzylidene acetal, cyclic ortho esters,
methoxymethylene, cyclic carbonates, and cyclic boronates.
Hydroxy-protecting groups are appended onto hydroxy groups by
reaction of the compound that contains the hydroxy group with a
base, such as triethylamine, and a reagent selected from an alkyl
halide, alkyl trifilate, trialkylsilyl halide, trialkylsilyl
triflate, aryldialkylsilyltriflate, or an alkylchloroformate,
CH.sub.2I.sub.2, or a dihaloboronate ester, for example with
methyliodide, benzyl iodide, triethylsilyltriflate, acetyl
chloride, benzylchloride, or dimethylcarbonate. A protecting group
also may be appended onto a hydroxy group by reaction of the
compound that contains the hydroxy group with acid and an alkyl
acetal.
[0072] The term "imino" as defined herein means a --C(.dbd.NH)--
group.
[0073] The term "mercapto" as used herein means a --SH group.
[0074] The term "--NR.sub.AR.sub.B" as used herein means two
groups, R.sub.A and R.sub.B, which are appended to the parent
molecular moiety through a nitrogen atom. R.sub.A and R.sub.B are
independently selected from hydrogen, alkyl, acyl, and formyl.
Representative examples of --NR.sub.AR.sub.B include, but are not
limited to, amino, dimethylamino, methylamino, acetylamino, and
acetylmethylamino.
[0075] The term "(NR.sub.AR.sub.B)alkyl" as used herein means an
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)alkyl include, but are
not limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl,
2-(amino)ethyl, 2-(ethylmethylamino)ethyl, and the like.
[0076] The term "(NR.sub.AR.sub.B)carbonyl" as used herein means an
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, (ethylmethylamino)carbonyl, and the
like.
[0077] The term "(NR.sub.AR.sub.B)sulfonyl" as used herein means a
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)sulfonyl include, but
are not limited to, aminosulfonyl, (methylamino)sulfonyl,
(dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
[0078] The term "nitro" as used herein means a --NO.sub.2
group.
[0079] The term "nitrogen protecting group" as used herein means
those groups intended to protect a nitrogen atom against
undesirable reactions during synthetic procedures. Nitrogen
protecting groups comprise carbamates, amides, N-benzyl
derivatives, and imine derivatives. Preferred nitrogen protecting
groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),
formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),
tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).
Nitrogen-protecting groups are appended onto primary or secondary
amino groups by reacting the compound that contains the amine group
with base, such as triethylamine, and a reagent selected from an
alkyl halide, an alkyl trifilate, a dialkyl anhydride, for example
as represented by (alkyl-O).sub.2C.dbd.O, a diaryl anhydride, for
example as represented by (aryl-O).sub.2C.dbd.O, an acyl halide, an
alkylchloroformate, or an alkylsulfonylhalide, an
arylsulfonylhalide, or halo-CON(alkyl).sub.2, for example
acetylchloride, benzoylchloride, benzylbromide,
benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,
pivaloylchloride, (tert-butyl-O--C.dbd.O).sub.2O, trifluoroacetic
anhydride, and triphenylmethylchloride.
[0080] The term "oxo" as used herein means (.dbd.O).
[0081] The term "sulfonyl" as used herein means a --S(O).sub.2--
group.
[0082] The term "thioalkoxy" as used herein means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of thioalkoxy include, but
are no limited to, methylthio, ethylthio, and propylthio.
[0083] As used herein, the term "antagonist" encompasses and
describes compounds that prevent receptor activation by an H.sub.3
receptor agonist alone, such as histamine, and also encompasses
compounds known as "inverse agonists". Inverse agonists are
compounds that not only prevent receptor activation by an H.sub.3
receptor agonist, such as histamine, but also inhibit intrinsic
H.sub.3 receptor activity.
Compounds of the Invention
[0084] Compounds of the invention can have the formula (I) as
described above.
[0085] In compounds of formula (I), one of R.sub.1 and R.sub.2 is a
group of the formula -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b. The other
group of R.sub.1 and R.sub.2 is selected from hydrogen, alkyl,
alkoxy, halogen, cyano, and thioalkoxy. Preferably, R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b and R.sub.2 is selected from
hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy. When one
of R.sub.1 or R.sub.2 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, then
the other is preferably hydrogen.
[0086] L.sub.2 is selected from a bond, --O--, --C(.dbd.O)--,
--S--, --NH--, --N(R.sub.16)C(.dbd.O)--, --C(.dbd.O)N(R.sub.16),
and --N(alkyl)-. It is preferred that L.sub.2 is a bond.
[0087] L.sub.3 is selected from a bond, --O--, --C(.dbd.O)--,
--S--, --N(R.sub.16)C(.dbd.O)--, --C(.dbd.O)N(R.sub.16), and
--N(R.sub.15)--, wherein R.sub.15 is selected from the group
consisting of hydrogen, alkyl, acyl, alkoxycarbonyl, amido, and
formyl. It is preferred that L.sub.3 is a bond.
[0088] R.sub.6a is selected from a 5- to 6-membered heteroaryl
ring, cyanophenyl, an 8- to 10-membered bicyclic heteroaryl ring,
and a 4- to 8-membered heterocyclic ring. The 5- to 6-membered
heteroaryl ring, 8- to 10-membered bicyclic heteroaryl ring, and 4-
to 8-membered heterocyclic ring for R.sub.6a can be substituted or
unsubstituted.
[0089] R.sub.6b is selected from hydrogen, a 5- to 6-membered
heteroaryl ring, phenyl, an 8- to 10-membered bicyclic heteroaryl
ring, and a 4- to 8-membered heterocyclic ring. The 5- to
6-membered heteroaryl ring, phenyl, 8- to 10-membered bicyclic
heteroaryl ring, and 4- to 8-membered heterocyclic ring for
R.sub.6b can be substituted or unsubstituted.
[0090] Specific examples of 5- to 6-membered heteroaryl rings
suitable for R.sub.6a and R.sub.6b include, but are not limited to,
furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolonyl,
[1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,3]oxadiazolyl,
[1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl,
thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl,
[1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl,
pyridazinonyl, pyridonyl, and pyrimidinonyl. Preferred 5- to
6-membered heteroaryl rings are, for example, pyrimidinyl,
pyridazinonyl, pyridinyl, and pyrazolyl. Each of the 5 to
6-membered heteroaryl rings is independently unsubstituted or
substituted with substituents as described herein, for example as
in the Examples or the Definitions.
[0091] Examples of 8- to 10-membered bicyclic heteroaryl rings
suitable for R.sub.6a and R.sub.6b include, but are not limited to,
indolyl, benzothienyl, benzofuranyl, indazolyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl,
quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl,
thieno[2,3-d]imidazole, and pyrrolopyrimidinyl. Preferred 8- to
10-membered bicyclic heteroaryl rings are, for example,
benzothiazolyl. Each of the 8- to 10-membered bicyclic heteroaryl
rings is independently unsubstituted or substituted with
substituents as described herein, for example as in the Examples or
the Definitions.
[0092] Examples of 4- to 8-membered heterocyclic ring suitable for
R.sub.6a and R.sub.6b include, but are not limited to, azepanyl,
azetidinyl, aziridinyl, azocanyl, morpholinyl, piperazinyl,
piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl,
dihydropyridinyl, thiomorpholinyl, dioxanyl, dithianyl,
tetrahydrofuryl, dihydropyranyl, and tetrahydropyranyl. Each of the
heterocyclic ring is independently unsubstituted or substituted
with substituents as described herein, for example as in the
Examples or the Definitions.
[0093] In one preferred embodiment, the group R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond;
R.sub.6b is hydrogen; L.sub.3 is a bond; R.sub.6a is selected from
a 5- or 6-membered heteroaryl ring; and R.sub.2, R.sub.3, R.sub.3a,
R.sub.3b, R.sub.4, R.sub.5, L, and n are as otherwise described
[0094] In another preferred embodiment, the group R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond;
R.sub.6b is hydrogen; L.sub.3 is a bond; R.sub.6a is selected from
a 8- to 10-membered bicyclic heteroaryl ring; and R.sub.2, R.sub.3,
R.sub.3a, R.sub.3b, R.sub.4, R.sub.5, L, and n are as otherwise
described herein.
[0095] In another preferred embodiment, the group R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond;
R.sub.6b is hydrogen; L.sub.3 is a bond; R.sub.6a is selected from
a 4- to 8-membered heterocyclic ring; and R.sub.2, R.sub.3,
R.sub.3a, R.sub.3b, R.sub.4, R.sub.5, L, and n are as otherwise
described herein.
[0096] Each of R.sub.3, R.sub.3a, and R.sub.3b are independently
selected from hydrogen, alkyl, alkoxy, halogen, cyano, and
thioalkoxy. Preferably, R.sub.3, R.sub.3a, and R.sub.3b are
hydrogen, or, one of R.sub.3, R.sub.3a, and R.sub.3b is halogen and
the others are hydrogen. The preferred halogen is fluorine.
[0097] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl,
and cycloalkyl. Alternatively, R.sub.4 and R.sub.5 taken together
with the nitrogen atom to which each is attached form a
non-aromatic ring of the formula:
##STR00004##
[0098] R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each
independently selected from hydrogen, hydroxyalkyl, fluoroalkyl,
cycloalkyl, and alkyl.
[0099] R.sub.x and R.sub.y at each occurrence are independently
selected from the group consisting of hydrogen, hydroxy, alkyl,
alkoxy, alkylamino, fluoro, and dialkylamino.
[0100] Preferably, at least one carbon in a group of formula (a) is
substituted, such that either one of R.sub.7, R.sub.8, R.sub.9, or
R.sub.10, or one of R.sub.x and R.sub.y, is other than hydrogen.
The preferred substituents for R.sub.7, R.sub.8, R.sub.9, or
R.sub.10, when substituted, are hydroxyalkyl, fluoroalkyl, or
alkyl. The preferred alkyl group is more particularly, methyl. The
preferred substituents for R.sub.x or R.sub.y, when substituted,
are alkyl, fluoro, or hydroxy.
[0101] Groups of formula (a) are preferred for R.sub.4 and R.sub.5
when taken together to form a non-aromatic ring. The preferred
group for R.sub.4 and R.sub.5 when taken together with the nitrogen
atom to which each is attached to form a group of formula (a) is
(2R)-methylpyrrolidine or (2S)-methylpyrrolidine.
[0102] R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each
independently selected from hydrogen, hydroxyalkyl, alkyl, and
fluoroalkyl. Preferably, at least three substituents selected from
R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are hydrogen.
[0103] Q is selected from O and S. The preferred atom for Q is
oxygen.
[0104] The preferred group for R.sub.4 and R.sub.5 when taken
together with the nitrogen atom to which each is attached to form a
group of formula (b) is morpholinyl.
[0105] The variable m is an integer from 1 to 5.
[0106] L is --[C(R.sub.16)(R.sub.17)].sub.k, wherein R.sub.16 and
R.sub.17 at each occurrence are independently selected from
hydrogen and alkyl, and k is 0, 1, or 2. Preferably, k is 0 or
1.
[0107] The variable n is 0 or 1. Preferably, n is 0.
[0108] One embodiment of compounds of the invention are those of
formula (II):
##STR00005##
wherein L, n, R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.3b,
R.sub.4, and R.sub.5 are as previously described.
[0109] In one preferred embodiment of compounds of the invention of
formula (II), the group R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond;
R.sub.6b is hydrogen; L.sub.3 is a bond; R.sub.6a is selected from
a 5- or 6-membered heteroaryl ring; R.sub.4 and R.sub.5, when taken
together with the nitrogen atom to which each is attached, form a
4- to 8-membered non-aromatic ring represented by formula (a), and
R.sub.2, R.sub.3, R.sub.3a, R.sub.3b, L, and n are as previously
described.
[0110] Another embodiment of compounds of the invention are those
of formula (III):
##STR00006##
wherein L, n, R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.3b,
R.sub.4, and R.sub.5 are as previously described.
[0111] In one preferred embodiment of compounds of the invention of
formula (III), the group R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2 is a bond;
R.sub.6b is hydrogen; L.sub.3 is a bond; R.sub.6a is selected from
a 5- or 6-membered heteroaryl ring; R.sub.4 and R.sub.5 when taken
together with the nitrogen atom to which each is attached to form a
4- to 8-membered non-aromatic ring represented by formula (a), and
R.sub.2, R.sub.3, R.sub.3a, R.sub.3b, L, and n are as previously
described.
[0112] Specific examples of compounds contemplated as within the
scope of the invention include, but are not limited to, the
following: [0113]
4'-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbon-
itrile; [0114]
4'-{3[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitr-
ile; [0115]
4'-[3-(2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-biphenyl-4-carbonitrile;
[0116]
4'-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-biphenyl-4-carb-
onitrile; [0117]
5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyrimidin-
e; [0118]
2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobu-
tyl]-phenyl}-pyridine; [0119]
2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyridine; [0120]
2,6-dimethyl-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyridine; [0121]
2,6-dichloro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyridine; [0122]
4'-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonit-
rile; [0123]
5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimid-
ine; [0124]
2-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-2H-pyri-
dazin-3-one; [0125]
4'-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbon-
itrile; [0126]
5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimid-
ine; [0127]
2,4-dimethoxy-5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-p-
henyl}-pyrimidine; [0128]
2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-pheny-
l}-pyrimidine; [0129]
2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-p-
henyl}-pyrimidine; [0130]
5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotin-
onitrile; [0131]
2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-benzothiazole; [0132]
2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-pyridine; [0133]
1,3,5-trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phen-
yl}-1H-pyrazole; [0134]
5-{2-fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-pyrimidine; [0135]
4'-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-ca-
rbonitrile; [0136]
4'-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-trans-cyclobutyl}-biphenyl-4--
carbonitrile; [0137]
4'-{3-[(2S)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-ca-
rbonitrile; [0138]
2,6-difluoro-3-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phe-
nyl}-pyridine; [0139]
5-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidi-
ne; [0140]
4'-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-biphenyl-
-4-carbonitrile; [0141]
1,3,5-trimethyl-4-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobu-
tyl]-phenyl}-1H-pyrazole; [0142]
2-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H--
pyridazin-3-one; [0143]
2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-p-
henyl}-pyrimidine; [0144]
2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobuty-
l]-phenyl}-pyrimidine; and [0145]
4'-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutylmethyl}-biphenyl-4-ca-
rbonitrile.
[0146] A preferred compound is
2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-pheny-
l}-pyrimidine.
[0147] Compounds of the invention may exist as stereoisomers
wherein, asymmetric or chiral centers are present. These
stereoisomers are "R" or "S" depending on the configuration of
substituents around the chiral carbon atom. The terms "R" and "S"
used herein are configurations as defined in IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, in Pure
Appl. Chem., 1976, 45: 13-30. The invention contemplates various
stereoisomers and mixtures thereof and these are specifically
included within the scope of this invention. Stereoisomers include
enantiomers and diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the
invention may be prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and optional
liberation of the optically pure product from the auxiliary as
described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's
Textbook of Practical Organic Chemistry", 5th edition (1989),
Longman Scientific & Technical, Essex CM20 2JE, England, or (2)
direct separation of the mixture of optical enantiomers on chiral
chromatographic columns or (3) fractional recrystallization
methods.
Methods for Preparing Compounds of the Invention
[0148] The compounds of the invention can be better understood in
connection with the following synthetic schemes and methods which
illustrate a means by which the compounds can be prepared.
[0149] Abbreviations which have been used in the descriptions of
the schemes and the examples that follow are: Ac for acetyl; atm
for atmosphere(s); BINAP for
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc for
butyloxycarbonyl; Bu for butyl; DCM for dichloromethane; DMAP for
4-(N,N-dimethylamino)pyridine; DMF for N,N-dimethylformamide; DMSO
for dimethylsulfoxide; dppf for
1,1'-bis(diphenylphosphino)ferrocene; EDTA for
ethylenediaminetetraacetic acid; Et for ethyl; EtOH for ethanol;
EtOAc for ethyl acetate; HPLC for high pressure liquid
chromatography; IPA for isopropyl alcohol; IPAC or IPAc for
isopropyl acetate; LDA for lithium diisopropylamide; NBS for
N-bromosuccinimide; NIS for N-iodosuccinimide; Me for methyl; MeOH
for methanol; Ms for methanesulfonyl; MTBE for tert-butyl methyl
ether; Pd for palladium; tBu for tert-butyl; TEA for triethylamine;
TFA for trifluoroacetic acid; THF for tetrahydrofuran; and Ts for
para-toluenesulfonyl; rt for "room temperature" or ambient
temperature suitably ranging 15-40.degree. C.
[0150] The compounds of this invention can be prepared by a variety
of synthetic procedures. Representative procedures are shown in,
but are not limited to, Schemes 1-10.
##STR00007##
[0151] Compounds of formulas (9), (10), and (11), wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in
formula (I), R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, and
R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
be prepared as described in Scheme 1. Alkenes of formula (1)
wherein X is Cl, Br, I, or triflate, purchased or prepared using
methodologies known to those of ordinary skill in the art, can be
reacted with a ketene such as, but not limited to, dichloroketene
generated in situ from trichloroacetyl chloride and activated Zn,
to provide cyclobutanones of formula (2). References that describe
this cycloaddition reaction and the subsequent reduction to form
the cyclobutanones of formula (3), may be found in the following:
L. R. Krepski et al., J. Org. Chem., 43:2879-1882 (1978); W. T.
Brandy et al., J. Org. Chem., 32:3703-3705 (1967); R. R. Srivastava
et al., J. Org. Chem., 64:8495-8500 (1999); T. D. Penning et al.,
J. Med. Chem., 43:721-735 (2000). Cyclobutanones of formula (2) can
be reduced with a reducing agent, such as, but not limited to, Zn
to provide cyclobutanones of formula (3). Cyclobutanones of formula
(3) can be treated with a reducing agent such as, but not limited
to, borane-pyridine complex, in the presence of an amine of formula
(4), via a reaction known as reductive amination, to provide amines
of formula (5). References that describe this methodology may be
found in the following: M. D. Bomann et al., J. Org. Chem.,
60:5995-5960 (1995); A. E. Moormann et al., Synth. Commun.,
23:789-795 (1993); A. Pelter et al., J. Chem. Soc., PT I, 4:717-720
(1984). Separation of products by, for example, using column
chromatography provides trans-substituted cyclobutanes of formula
(6) and cis-substituted cyclobutanes of formula (7).
[0152] Suzuki reaction can be used to convert compounds of formula
(5) to compounds of formula (9) wherein n, R.sub.3, R.sub.3a,
R.sub.3b, R.sub.4, and R.sub.5 are as defined in formula (I),
R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy,
and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, wherein L.sub.2
is a bond and R.sub.6a, and L.sub.3 and R.sub.6b are as defined in
formula (I). In such a Suzuki reaction, amines of formula (5),
wherein X is triflate, I, Br, or Cl can be reacted with boronic
acids or boronic esters of formula (8) wherein R.sub.101 is
hydrogen or alkyl, a metal catalyst such as, but not limited to,
palladium diacetate or Pd(PPh.sub.3).sub.4, optionally with a Pd
ligand added such as 2-(dicyclohexylphosphino)biphenyl or
tris(2-furyl)phosphine, and a base such as, but not limited to,
aqueous 0.2 M K.sub.3PO.sub.4 or sodium carbonate.
[0153] Alternatively, pinacol borane reagents such as, but not
limited to, those represented by formula (8a) can be used in place
of boronic acids or esters of formula (8) in the Suzuki reaction.
References that describe the Suzuki reaction methodogy may be found
in the following: N. Miyaura et al., Chem. Rev. 95:2457 (1995) and
references cited in the article.
[0154] Likewise, amines of formulas (6) or (7) can be subjected to
the Suzuki reaction conditions as outlined above to provide the
corresponding amines of formula (10) or (11) wherein n, R.sub.3,
R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in formula
(I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano or
thioalkoxy, and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond and R.sub.6a, and L.sub.3 and R.sub.6b
are as defined in formula (I).
[0155] There are many aryl, heteroaryl, and heterocyclic boronic
acids and boronic acid esters that are available commercially or
that can be prepared as described in the scientific literature of
synthetic organic chemistry. Examples of boronic acid and boronic
acid ester reagents for the synthesis of compounds of formula (I)
are provided, but not limited to, reagents shown in Table 1, below,
and the following description.
TABLE-US-00001 TABLE 1 Examples of Boronic Acid and Boronic Acid
Ester Reagents Boronic Acid or Boronic Commercial Source, Chemical
Abstracts Acid Ester Number (CAS #), or Literature Reference
2-pyrimidinone-5- CAS #373384-19-1 boronic acid
2-methoxypyrimidine-5- Frontier Scientific, Inc., Logan, UT, USA
boronic acid 1H-pyrimidine-2,4- Specs, Fleminglaan, the Netherlands
dione-5-boranic acid CAS #70523-22-7; Schinazi, Raymond F.;
Prusoff, William H., Synthesis of 5-
(dihydroxyboryl)-2'-deoxyuridine and related boron-containing
pyrimidines, Journal of Organic Chemistry (1985), 50(6), 841-7.
pyridine-3-boronic CAS #1692-25-7, Frontier Scientific, Inc., acid
Logan, UT, USA 2,4-dimethoxy- CAS #89641-18-9, Frontier Scientific,
Inc., pyrimidine-5- Logan, UT, USA boronic acid
2-methoxy-5-pyridine Digital Specialty Chemicals, Dublin, NH;
boronic acid CAS #163105-89-3; New shelf-stable halo- and
alkoxy-substituted pyridylboronic acids and their Suzuki
cross-coupling reactions to yield heteroarylpyridines, Parry, Paul
R.; Bryce, Martin R.; Tarbit, Brian, Department of Chemistry,
Synthesis (2003), (7), 1035- 1038; Functionalized Pyridylboronic
Acids and Their Suzuki Cross-Coupling Reactions To Yield Novel
Heteroarylpyridines, Parry, Paul R.; Wang, Changsheng; Batsanov,
Andrei S.; Bryce, Martin R.; Tarbit, Brian, Journal of Organic
Chemistry (2002), 67(21), 7541-7543. pyrimidine-5-boronic CAS
#109299-78-7, S. Gronowitz, et al., acid "On the synthesis of
various thienyl- and selenienylpyrimidines", Chem. Scr. 26(2):
305-309 (1986). pyrimidine-5-boronic Umemoto, et al., Angew. Chem.
Int. Ed. acid, pinacol ester 40(14): 2620-2622 (2001).
2-methylpyridine-5- SYNCHEM OHG boronic acidhydrate
Heinrich-Plett-Strassse 40; Kassel, D- 34132; Germany; CAS
#659742-21-9 2H-Pyran, 3,6-dihydro- CAS #287944-16-5; Murata, Miki;
Oyama, 4-(4,4,5,5-tetramethyl- Takashi; Watanabe, Shinji; Masuda,
1,3,2-dioxaborolan-2-yl) Yuzuru, Synthesis of alkenylboronates via
palladium-catalyzed borylation of alkenyl triflates (or iodides)
with pinacolborane. Synthesis(2000), (6), 778-780.
1(2H)-Pyridinecarboxylic CAS #286961-14-6; A versatile synthesis
acid, 3,6-dihydro-4-(4,4, of 4-aryltetrahydropyridines via
palladium 5,5-tetramethyl-1,3,2- mediated Suzuki cross-coupling
with cyclic dioxaborolan-2-yl)-, 1,1- vinyl boronates, Eastwood,
Paul R., dimethylethyl ester Discovery Chemistry, Aventis Pharma,
Essex, UK., Tetrahedron Letters (2000), 41(19), 3705-3708.
(5-cyano-3-pyridinyl)- CAS #497147-93-0; boronic acid Chemstep
Institut du PIN - University Bordeaux 1 351 cours de la liberation
Talence Cedex, 33450 France
[0156] Boronic acids or boronic acid esters of formula (8), (8a),
(18) and (18a) can be prepared from corresponding halides or
triflates via either (1) metal exchange with an organo lithium
agent followed with addition of alkyl borate or pinacolborate or
(2) cross coupling with a reagent such as, but not limited to,
bis(pinacolato)diboron (CAS #73183-34-3). References that describe
the first methodology may be found in the following: B. T. O'Neill,
et al., Organic Letters, 2:4201 (2000); M. D. Sindkhedkar, et al.,
Tetrahedron, 57:2991 (2001); W. C. Black, et al., J. Med. Chem.,
42:1274 (1999); R. L. Letsinger et al., J. Amer. Chem. Soc.,
81:498-501 (1959); and F. I. Carroll et al., J. Med. Chem.,
2229-2237 (2001). References that describe the second methodology
may be found in the following: T. Ishiyama et al., Tetrahedron,
57:9813-9816 (2001); T. Ishiyama et al., J. Org. Chem.,
60:7508-7510 (1995); and Takagi et al., Tetrahedron Letters,
43:5649-5651 (2002).
[0157] Another method for preparation of boronic acids and boronic
acid esters is the reaction described in O. Baudoin, et al., J.
Org. Chem., 65:9268-9271 (2000), in which aryl and heteroaryl
halides or triflates are reacted with a dialkyloxyborane such as
pinacolborane, in the presence of triethylamine and palladium (II)
acetate in dioxane.
[0158] Alternatively, utilizing other coupling methods such as
Stille coupling, compounds of formulas (9), (10), and (11) wherein
n, R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined
in formula (I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano
or thioalkoxy, and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond and R.sub.6a, L.sub.3, and R.sub.6b are
as defined in formula (I), can be prepared from amines of formulas
(5), (6), and (7) respectively, by treatment with organostannanes
of formula (R.sub.102).sub.3SnR.sub.1 wherein R.sub.102 is alkyl or
aryl, in the presence of a palladium source such as
tris(dibenzylidineacetone)dipalladium (CAS # 52409-22-0) or
palladium diacetate, and a ligand such as tri(2-furyl)phosphine
(CAS # 5518-52-5) or triphenylarsine. The reaction is generally
performed in a solvent such as DMF at a temperature from about
25.degree. C. to about 150.degree. C. Such methods are described,
for instance, in J. K. Stille Angew. Chem. Int. Ed. 25:508 (1986)
and T. N. Mitchell, Synthesis, 803 (1992).
[0159] While many stannanes are commercially available or described
in the literature that support the Stille coupling reaction where
compounds of formulas (5), (6), and (7) can be transformed to
compounds of formulas (9), (10), and (11), respectively, it is also
possible to prepare new stannanes from arylhalides, aryltriflates,
heteroarylhalides, and heteroaryltriflates by reaction with
hexa-alkyl distannanes of formula ((R.sub.102).sub.3Sn).sub.2
wherein R.sub.102 is alkyl or aryl, in the presence of a palladium
source like Pd(Ph.sub.3P).sub.4. Example of hexa-alkyl distannanes
include, but not limited to, hexamethyldistannane (CAS # 661-69-8).
Such methods are described, for instance in Krische, et. al.,
Helvetica Chimica Acta 81 (11):1909-1920 (1998), and in Benaglia,
et al., Tetrahedron Letters 38:4737-4740 (1997). These reagents can
be reacted with (5), (6), and (7) to afford compounds of formulas
(9), (10), and (11) respectively as described under Stille
conditions, or for example under the conditions reported by A. F.
Littke et al., J. of Amer. Chem. Soc. 124:6343-6348 (2002).
[0160] Compounds of formulas (9), (10), and (11) wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in
formula (I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano or
thioalkoxy, and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.3 and R.sub.6b are as defined in formula (I), L.sub.2
is a bond, and R.sub.6a is a nitrogen-containing heteroaryl or
heterocyclic ring linked to the parent moiety through the nitrogen,
can be prepared by heating compounds of formulas (5), (6), and (7)
respectively, with heteroaryl or heterocyclic rings of formula
H--R.sub.6aL.sub.3R.sub.6b wherein H is a hydrogen on the nitrogen
atom, in the presence of a base such as, but not limited to, sodium
t-butoxide or cesium carbonate, a metal catalyst such as, but not
limited to copper metal or CuI, palladium diacetate, and optionally
with a ligand such as, but not limited to, BINAP or
tri-tertbutylphosphine. The reaction can be conducted in a solvent
such as, but not limited to, dioxane, toluene or pyridine.
References that describe these methods may be found in the
following: J. Hartwig et al., Angew. Chem. Int. Ed. 37:2046-2067
(1998); J. P. Wolfe et al., Acc. Chem. Res., 13:805-818 (1998); M.
Sugahara et al., Chem. Pharm. Bull., 45:719-721 (1997); J. P. Wolfe
et al., J. Org. Chem., 65:1158-1174 (2000); F. Y. Kwong et al.,
Org. Lett., 4:581-584 (2002); A. Klapars et al., J. Amer. Chem.
Soc., 123:7727-7729 (2001); B. H. Yang et al., J. Organomet. Chem.,
576:125-146 (1999); and A. Kiyomori et al., Tet. Lett.,
40:2657-2640 (1999).
[0161] Compounds of formulas (9), (10), and (11) wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in
formula (I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy, and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is --NH-- or --N(alkyl)-, and R.sub.6a, R.sub.6b,
and L.sub.3 are as defined for a compound of formula (I) can be
prepared by heating compounds of formula (5), (6), and (7)
respectively, with a compound of formula
H.sub.2N--R.sub.6a-L.sub.3-R.sub.6b or
HN(alkyl)-R.sub.6a-L.sub.3-R.sub.6b with a base such as, but not
limited to, sodium t-butoxide or cesium carbonate in the presence
of a metal catalyst such as, but not limited to, copper metal or
CuI, palladium diacetate, and also optionally with a ligand such
as, but not limited to, BINAP, or tri-tert-butylphosphine. The
reaction can be performed in a solvent such as dioxane, toluene, or
pyridine. References that describe these methodologies may be found
in the following: J. Hartwig, et al., Angew. Chem. Int. Ed.,
37:2046-2067 (1998); J. P. Wolfe et al., Acc. Chem. Res.,
13:805-818 (1998); J. P. Wolfe et al., J. Org. Chem., 65:1158-1174
(2000); F. Y. Kwong et al., Org. Lett., 4:581-584 (2002); and B. H.
Yang et al., J. Organomet. Chem., 576:125-146 (1999).
[0162] Compounds of formulas (9), (10), and (11) wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4 and R.sub.5 are as defined in
formula (I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy, and R.sub.1 is L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is oxygen and R.sub.6a, and L.sub.3 and R.sub.6b
are as defined in formula (I) can be prepared by heating compounds
of formula (5), (6), and (7) respectively with a compound of
formula HOR.sub.6a-L.sub.3-R.sub.6b using a base such as, but not
limited to, sodium hydride in a solvent such as toluene or
N,N-dimethylformamide, in the presence of a metal containing
catalyst such as CuI or palladium diacetate. References that
describe these methodologies may be found in the following: J.
Hartwig et al., Angew. Chem. Int. Ed., 37:2046-2067 (1998); K. E.
Torraca et al., J. Amer. Chem. Soc., 123:10770-10771 (2001); S.
Kuwabe et al., J. Amer. Chem. Soc., 123:12202-12206 (2001); K. E.
Toracca et al., J. Am. Chem. Soc., 122:12907-12908 (2000); R.
Olivera et al., Tet. Lett., 41:4353-4356 (2000); J.-F. Marcoux et
al., J. Am. Chem. Soc., 119:10539-10540 (1997); A. Aranyos et al.,
J. Amer. Chem. Soc., 121:4369-4378 (1999); T. Satoh et al., Bull.
Chem. Soc. Jpn., 71:2239-2246 (1998); J. F. Hartwig, Tetrahedron
Lett., 38:2239-2246 (1997); M. Palucki et al., J. Amer. Chem. Soc.,
119:3395-3396 (1997); N. Haga et al, J. Org. Chem., 61:735-745
(1996); R. Bates et al., J. Org. Chem., 47:4374-4376 (1982); T.
Yamamoto et al., Can. J. Chem., 61:86-91 (1983); A. Aranyos et al.,
J. Amer. Chem. Soc., 121:4369-4378 (1999); and E. Baston et al.,
Synth. Commun., 28:2725-2730 (1998).
[0163] Compounds of formulas (9), (10), and (11) wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4 and R.sub.5 are as defined in
formula (I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy, and R.sub.1 is L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is sulfur and R.sub.6a, and L.sub.3 and R.sub.6b
are as defined for a compound of formula (I) can be prepared by
heating compounds of formula (5), (6), and (7) respectively with a
compound of formula HSR.sub.6a-L.sub.3-R.sub.6b in the presence of
a base, and with or without a metal catalyst such as CuI or
palladium diacetate, in a solvent such as dimethylformamide or
toluene. References that describe these methodologies may be found
in the following: G. Y. Li et al., J. Org. Chem., 66:8677-8681
(2001); Y. Wang et al., Bioorg. Med. Chem. Lett., 11:891-894
(2001); G. Liu et al., J. Med. Chem., 44:1202-1210 (2001); G. Y. Li
et al., Angew. Chem. Int. Ed., 40:1513-1516 (2001); U. Schopfer et
al., Tetrahedron, 57:3069-3074 (2001); and C. Palomo et al., Tet.
Lett., 41:1283-1286 (2000); A. Pelter et al., Tet. Lett.,
42:8391-8394 (2001); W. Lee et al., J. Org. Chem., 66:474-480
(2001); and A. Toshimitsu et al., Het. Chem., 12:392-397
(2001).
##STR00008##
[0164] Similarly, compounds of formulas (9), (10), and (11) wherein
n, R.sub.3, R.sub.3a, R.sub.3b, R.sub.4 and R.sub.5 are as defined
in formula (I), R.sub.1 is hydrogen, alkyl, alkoxy, halogen, cyano,
or thioalkoxy, and R.sub.2 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
be prepared as described in Scheme 2, from compounds of formula
(12) wherein X is Cl, Br, I, or triflate, using the reaction
conditions that are outlined in Scheme 1, except for substituting
boronic acid or esters of formula (18) for (8) and pinacol borane
reagents of formula (18a) for (8a) for the Suzuki reactions, and
except for substituting organostannes of formula
(R.sub.102).sub.3SnR.sub.2 for (R.sub.102).sub.3SnR.sub.1 for
Stille coupling. References that describe the Suzuki reaction
methodogy may be found in the following: N. Miyaura et al., Chem.
Rev. 95:2457 (1995) and references cited in the article.
##STR00009##
[0165] Alternatively, trans-substituted cyclobutyl amines of
formula (10), wherein n, R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and
R.sub.5 are as defined in formula (I); R.sub.1 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, and R.sub.2 is hydrogen, alkyl,
alkoxy, halogen, cyano, or thioalkoxy, wherein L.sub.2 is a bond,
--N(H), --N(alkyl), --O--, or --S--, and R.sub.6a, L.sub.3, and
R.sub.6b are as defined in formula (I), can be prepared as
described in Scheme 3. Cyclobutanones of formula (3) can be treated
with a reducing agent such as, but not limited to, sodium
borohydride, lithium selectride, or lithium aluminium hydride to
provide cis substituted cyclobutyl alcohols of formula (19).
Reference for this method may be found in: E. Dehmlow et al.,
Chemische Berichte, 126:2759-2763 (1993). Alcohols of formula (19)
can be treated with an agent such as, but not limited to, triflate
anhydride, tosyl chloride, or mesyl chloride in the presence of a
base such as, but not limited to, potassium carbonate, to provide
compounds of formula (20) wherein R.sub.103 is triflate, tosylate,
or mesylate respectively. Compounds of formula (20) can be treated
with an amine of formula (4), optionally in the presence of a base
such as, but not limited to, potassium carbonate or sodium
carbonate, to provide trans substituted cyclobutyl amines of
formula (6). Compounds of formula (6) can be converted to amines of
formula (10) using the reaction conditions described in Scheme
1.
##STR00010##
[0166] Similarly, trans-substituted cyclobutyl amines of formula
(10), wherein n, R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5
are as defined in formula (I); R.sub.2 is
-L.sub.2-R.sub.6a-L.sub.3-R.sub.6b, and R.sub.1 is hydrogen, alkyl,
alkoxy, halogen, cyano, or thioalkoxy, wherein L.sub.2 is a bond,
--N(H), --N(alkyl), --O--, or --S--, and R.sub.6a, L.sub.3, and
R.sub.6b are as defined in formula (I), can be prepared as
described in Scheme 4. Cyclobutanones of formula (14) wherein X is
Br, Cl, or I, can be converted to amines of formula (10) using the
reaction conditions as described in Scheme 3, except for
substituting boronic acid or esters of formula (18) for (8) and
pinacol borane reagents of formula (18a) for (8a) for the Suzuki
reactions, and except for substituting organostannes of formula
(R.sub.102).sub.3SnR.sub.2 for (R.sub.102).sub.3SnR.sub.1 for
Stille coupling.
##STR00011## ##STR00012##
[0167] Compounds of formulas (27), (28), and (29), wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in
formula (I); R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy; and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
be prepared as described in Scheme 5. Cyclobutanones of formula
(3), wherein X is Br, Cl, or I, can be treated with the anion of
diethyl isocyanomethylphosphonate generated with an organo lithium
reagent such as, but not limited to, n-butyllithium,
sec-butyllithium, or tert-butyllithium to provide aldehydes of
formula (23). Aldehydes of formula (23) can be treated with a
reducing agent such as, but not limited to, borane-pyridine complex
or sodium triacetoxyborohydride, in the presence of an amine of
formula (4) via a reaction known as reductive amination to provide
amines of formula (24). The trans and cis amines of formulas (25)
and (26) may be separated or purified by, for instance, using
column chromatography. The amines of formulas (24), (25), and (26)
can be processed as described in Scheme 1 to provide compounds of
formulas (27), (28), and (29) respectively.
[0168] Alternatively, compounds of formula (28) and (29), wherein
n, R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined
in formula (I), R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano,
or thioalkoxy, and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
also be prepared from the aldehyde of formula (23) wherein the
aldehyde is first purified to obtain separately, the cis isomer of
formula (43) and the trans isomer of formula (42) by use of column
chromatography. The trans aldehyde (42) can be converted to the
trans amine of (25) by the process of reductive amination as
described above, followed by conversion to compounds of formula
(28) by use of the reaction conditions previously described in
Scheme 1 for the conversion of (6) to (10) and (7) to (11).
Similarly, the cis aldehyde (43) can be converted to the cis amines
of formula (29).
##STR00013##
[0169] Compounds of structures (27), (28), and (29) wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in
formula (I); R.sub.1 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy; and R.sub.2 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
be prepared from ketones of formula (14) wherein X is Br, Cl, or I
as shown in Scheme 6, using the reaction conditions as described in
Scheme 5, except for substituting boronic acid or esters of formula
(18) for (8) and pinacol borane reagents of formula (18a) for (8a)
for the Suzuki reactions, and except for substituting organostannes
of formula (R.sub.102).sub.3SnR.sub.2 for
(R.sub.102).sub.3SnR.sub.1 for Stille coupling.
##STR00014##
[0170] Compounds of formulas (35), (36), and (37), wherein n,
R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined in
formula (I); R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy; and R.sub.1 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
be prepared as described in Scheme 7. Cyclobutanones of formula
(3), wherein X is Br, Cl, or 1, can be treated with the anion of
triethyl phosphonoacetate generated with a base such as, but not
limited to, sodium hydride to provide an intermediate which is then
hydrogenated in the presence of a catalyst such as, but not limited
to, palladium or platinum, to provide esters of formula (30).
Esters of formula (30) can be treated with a reducing agent such
as, but not limited to, lithium aluminum hydride or sodium
borohydride to provide alcohols of formula (31). Alcohols of
formula (31) can be converted to compounds of formula (32) using
the transformation as outlined in Scheme 3, employing the reaction
conditions used in the conversion of compounds of formula (19) to
compounds of formula (10). Compounds of formula (32) can be
converted to compounds of formula (35) using the reaction
conditions outlined in Scheme 1 for the transformation of compounds
of formula (5) to compounds of formula (9). Separation of products
of formula (30) using for instance, column chromatography, provides
the pure trans-cyclobutane esters of formula (33) and the pure
cis-cyclobutane esters of formula (34). The esters of formulas (33)
and (34) can then separately, be converted to the amines of formula
(36) and (37) using the conditions for the conversion of compounds
of formula (30) to compounds of formula (35).
##STR00015##
[0171] Likewise compounds of formulas (35), (36), and (37), wherein
n, R.sub.3, R.sub.3a, R.sub.3b, R.sub.4, and R.sub.5 are as defined
in formula (I); R.sub.1 is hydrogen, alkyl, alkoxy, halogen, cyano,
or thioalkoxy; and R.sub.2 is -L.sub.2-R.sub.6a-L.sub.3-R.sub.6b,
wherein L.sub.2 is a bond, --N(H), --N(alkyl), --O--, or --S--, and
R.sub.6a, L.sub.3, and R.sub.6b are as defined in formula (I), can
be prepared as described in Scheme 8. Cyclobutanones of formula
(14) wherein X is Br, Cl or I, can be converted to amines of
formulas (35), (36), and (37) using the reaction conditions as
described in Scheme 7, except for substituting boronic acid or
esters of formula (18) for (8) and pinacol borane reagents of
formula (18a) for (8a) for the Suzuki reactions, and except for
substituting organostannes of formula (R.sub.102).sub.3SnR.sub.2
for (R.sub.102).sub.3SnR.sub.1 for Stille coupling.
##STR00016##
[0172] Alternatively, alkenes of formula (1), wherein n, R.sub.3,
R.sub.3a, and R.sub.3b, are as defined in formula (I); R.sub.2 is
hydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy; and X is
Cl, Br, or I can be treated with 1-acetyl pyrrolidine and triflate
anhydride in the presence of a base such as, but not limited to,
lutidine, followed by in situ hydrolysis, to provide cyclobutanones
of formula (3). References that describe this methodology may be
found in the following: L. Ghosez et al., Tetrahedron Lett.,
27:5211-5214 (1986); I. Marko et al., J. Amer. Chem. Soc., 107:2192
(1981); C. Houge et al., J. Amer. Chem. Soc., 104:2920 (1982); J.
B. Falmagre et al., Angew. Chem. Int. Ed., 20:879 (1981).
[0173] Likewise, cyclobutanones of formula (14), wherein n,
R.sub.3, R.sub.3a, and R.sub.3b, are as defined in formula (I);
R.sub.1 is hydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy;
and X is Cl, Br, or I, can be prepared from alkenes of formula (12)
using the reaction conditions as outlined above.
##STR00017##
[0174] Alkenes of formula (1) wherein X is I, Br or Cl or hydroxy;
n, R.sub.3, R.sub.3a, and R.sub.3b are as defined in formula (I);
and R.sub.2 is hydrogen, alkyl, alkoxy, halogen, cyano, or
thioalkoxy; can be purchased or prepared as described in Scheme 10.
Halides of formula (38), wherein Y is I, Br, or triflate (prepared
by the treatment of phenols with triflate anhydride), can be
treated with tin reagent of formula (39) in the presence of a
palladium source such as
dichlorobis(triphenylphosphine)palladium(II) (CAS# 13965-03-2) or
tris(dibenzylidineacetone)dipalladium (CAS # 52409-22-0) or
palladium diacetate, and a ligand such as tri(2-furyl)phosphine
(CAS # 5518-52-5) or triphenyl phosphine, in a solvent such as DMF
at 25-150.degree. C. to provide the alkenes of formula (1).
[0175] Alternatively, alkenes of formula (1) wherein n is 0 can be
prepared through substituted benzaldehydes via Wittig reaction,
which is well-known to those skilled in the art of organic
synthesis. References that describe these methods may be found in
the following: S. Li et al., Chemische Berichte, 123:1441-1442
(1990); T. Kauffmann et al., Tetrahedron Lett., 22:5031-5034
(1981).
[0176] Likewise, alkenes of formula (12) wherein X is I, Br or Cl
or hydroxy; n, R.sub.3, R.sub.3a, and R.sub.3b are as defined in
formula (I); and R.sub.1 is hydrogen, alkyl, alkoxy, halogen,
cyano, or thioalkoxy; can be purchased or prepared using the
reaction conditions outlined above.
[0177] The compounds and intermediates of the invention may be
isolated and purified by methods well-known to those skilled in the
art of organic synthesis. Examples of conventional methods for
isolating and purifying compounds can include, but are not limited
to, chromatography on solid supports such as silica gel, alumina,
or silica derivatized with alkylsilane groups, by recrystallization
at high or low temperature with an optional pretreatment with
activated carbon, thin-layer chromatography, distillation at
various pressures, sublimation under vacuum, and trituration, as
described for instance in "Vogel's Textbook of Practical Organic
Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and
Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE,
England.
[0178] The compounds of the invention have at least one basic
nitrogen whereby the compound can be treated with an acid to form a
desired salt. For example, a compound may be reacted with an acid
at or above room temperature to provide the desired salt, which is
deposited, and collected by filtration after cooling. Examples of
acids suitable for the reaction include, but are not limited to
tartaric acid, lactic acid, succinic acid, as well as mandelic,
atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic,
naphthalenesulfonic, benzensulfonic, carbonic, fumaric, maleic,
gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic,
phosphoric, sulfuric, citric, or hydroxybutyric acid,
camphorsulfonic, malic, phenylacetic, aspartic, glutamic, and the
like.
Compositions of the Invention
[0179] The invention also provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
formula (I) in combination with a pharmaceutically acceptable
carrier. The compositions comprise compounds of the invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions can be
formulated for oral administration in solid or liquid form, for
parenteral injection or for rectal administration.
[0180] The term "pharmaceutically acceptable carrier", as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other non-toxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
[0181] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally", as used herein,
refers to modes of administration which include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous,
intraarticular injection and infusion.
[0182] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof. Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0183] These compositions may also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of microorganisms may
be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form may be brought about by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0184] In some cases, in order to prolong the effect of a drug, it
is often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0185] Suspensions, in addition to the active compounds, may
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0186] If desired, and for more effective distribution, the
compounds of the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
[0187] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0188] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0189] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0190] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0191] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
[0192] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples
of materials which can be useful for delaying release of the active
agent can include polymeric substances and waxes.
[0193] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0194] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0195] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0196] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, ear drops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
[0197] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0198] Powders and sprays can contain, in addition to the compounds
of this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
[0199] Compounds of the invention may also be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0200] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y., (1976), p 33 et seq.
[0201] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants, which can be required. Opthalmic
formulations, eye ointments, powders and solutions are contemplated
as being within the scope of this invention. Aqueous liquid
compositions comprising compounds of the invention also are
contemplated.
[0202] The compounds of the invention can be used in the form of
pharmaceutically acceptable salts, esters, or amides derived from
inorganic or organic acids. The term "pharmaceutically acceptable
salts, esters and amides", as used herein, refer to carboxylate
salts, amino acid addition salts, zwitterions, esters and amides of
compounds of formula (I) which are, within the scope of sound
medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation,
allergic response, and the like, are commensurate with a reasonable
benefit/risk ratio, and are effective for their intended use.
[0203] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well-known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
[0204] Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate. Preferred salts of the compounds of the invention are
the tartrate and hydrochloride salts.
[0205] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0206] Examples of acids which can be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid, and citric acid.
[0207] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium, and aluminum salts, and the like,
and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the such as. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
[0208] The term "pharmaceutically acceptable ester", as used
herein, refers to esters of compounds of the invention which
hydrolyze in vivo and include those that break down readily in the
human body to leave the parent compound or a salt thereof. Examples
of pharmaceutically acceptable, non-toxic esters of the invention
include C.sub.1-to-C.sub.6 alkyl esters and C.sub.5-to-C.sub.7
cycloalkyl esters, although C.sub.1-to-C.sub.4 alkyl esters are
preferred. Esters of the compounds of formula (I) may be prepared
according to conventional methods. For example, such esters may be
appended onto hydroxy groups by reaction of the compound that
contains the hydroxy group with acid and an alkylcarboxylic acid
such as acetic acid, or with acid and an arylcarboxylic acid such
as benzoic acid. In the case of compounds containing carboxylic
acid groups, the pharmaceutically acceptable esters are prepared
from compounds containing the carboxylic acid groups by reaction of
the compound with base such as triethylamine and an alkyl halide,
alkyl trifilate, for example with methyliodide, benzyl iodide,
cyclopentyl iodide. They also may be prepared by reaction of the
compound with an acid such as hydrochloric acid and an
alkylcarboxylic acid such as acetic acid, or with acid and an
arylcarboxylic acid such as benzoic acid.
[0209] The term "pharmaceutically acceptable amide", as used
herein, refers to non-toxic amides of the invention derived from
ammonia, primary C.sub.1-to-C.sub.6 alkyl amines and secondary
C.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,
the amine may also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2
dialkyl secondary amides are preferred. Amides of the compounds of
formula (I) may be prepared according to conventional methods.
Pharmaceutically acceptable amides are prepared from compounds
containing primary or secondary amine groups by reaction of the
compound that contains the amino group with an alkyl anhydride,
aryl anhydride, acyl halide, or aryl halide. In the case of
compounds containing carboxylic acid groups, the pharmaceutically
acceptable esters are prepared from compounds containing the
carboxylic acid groups by reaction of the compound with base such
as triethylamine, a dehydrating agent such as dicyclohexyl
carbodiimide or carbonyl diimidazole, and an alkyl amine,
dialkylamine, for example with methylamine, diethylamine,
piperidine. They also may be prepared by reaction of the compound
with an acid such as sulfuric acid and an alkylcarboxylic acid such
as acetic acid, or with acid and an arylcarboxylic acid such as
benzoic acid under dehydrating conditions as with molecular sieves
added. The composition can contain a compound of the invention in
the form of a pharmaceutically acceptable prodrug.
[0210] The term "pharmaceutically acceptable prodrug" or "prodrug",
as used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use. Prodrugs of the invention may be
rapidly transformed in vivo to a parent compound of formula (I),
for example, by hydrolysis in blood. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.
Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987), hereby
incorporated by reference.
[0211] The invention contemplates pharmaceutically active compounds
either chemically synthesized or formed by in vivo
biotransformation to compounds of formula (I).
Methods of the Invention
[0212] The compounds and compositions of the invention are useful
for treating and preventing certain diseases and disorders in
humans and animals. As an important consequence of the ability of
the compounds of the invention to modulate the effects of
histamine-3 receptors in cells, the compounds described in the
invention can affect physiological processes in humans and animals.
In this way, the compounds and compositions described in the
invention are useful for treating and preventing diseases and
disorders modulated by histamine-3 receptors. Typically, treatment
or prevention of such diseases and disorders can be effected by
selectively modulating the histamine-3 receptors in a mammal, by
administering a compound or composition of the invention, either
alone or in combination with another active agent as part of a
therapeutic regimen.
[0213] The compounds of the invention, including but not limited to
those specified in the examples, possess an affinity for the
histamine-3 receptors and therefore, the compounds of the invention
may be useful for the treatment and prevention of diseases or
conditions such as attention-deficit hyperactivity disorder (ADHD),
deficits in attention, dementia, and diseases with deficits of
memory, learning, schizophrenia, cognitive deficits of
schizophrenia, cognitive deficits and dysfunction in psychiatric
disorders, Alzheimer's disease, mild cognitive impairment,
epilepsy, seizures, allergic rhinitis, and asthma, motion sickness,
dizziness, Meniere's disease, vestibular disorders, vertigo,
obesity, diabetes, type II diabetes, Syndrome X, insulin resistance
syndrome, metabolic syndrome, pain, including neuropathic pain,
neuropathy, sleep disorders, narcolepsy, pathological sleepiness,
jet lag, drug abuse, mood alteration, bipolar disorder, depression,
obsessive compulsive disorder, Tourette's syndrome, Parkinson's
disease, and medullary thyroid carcinoma, melanoma, and polycystic
ovary syndrome. The ability of histamine-3 receptor modulators, and
consequently the compounds of the invention, to prevent or treat
such disorders is demonstrated by examples found in the following
references.
[0214] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
attention-deficit hyperactivity disorder (ADHD), and deficits in
attention, may be demonstrated by Cowart, et al. J. Med. Chem.
2005, 48, 38-55; Fox, G. B., et al. "Pharmacological Properties of
ABT-239: II. Neurophysiological Characterization and Broad
Preclinical Efficacy in Cognition and Schizophrenia of a Potent and
Selective Histamine H.sub.3 Receptor Antagonist", Journal of
Pharmacology and Experimental Therapeutics (2005) 313, 176-190;
"Effects of histamine H.sub.3 receptor ligands GT-2331 and
ciproxifan in a repeated acquisition avoidance response in the
spontaneously hypertensive rat pup." Fox, G. B., et al. Behavioural
Brain Research (2002), 131 (1,2), 151-161; Yates, et al. JPET
(1999) 289, 1151-1159 "Identification and Pharmacological
Characterization of a Series of New 1H-4-Substituted-Imidazoyl
Histamine H.sub.3 Receptor Ligands"; Ligneau, et al. Journal of
Pharmacology and Experimental Therapeutics (1998), 287, 658-666;
Tozer, M. Expert Opinion Therapeutic Patents (2000) 10, page 1045;
M. T. Halpern, "GT-2331" Current Opinion in Central and Peripheral
Nervous System Investigational Drugs (1999) 1, pages 524-527;
Shaywitz et al., Psychopharmacology, 82:73-77 (1984); Dumery and
Blozovski, Exp. Brain Res., 67:61-69 (1987); Tedford et al., J.
Pharmacol. Exp. Ther., 275:598-604 (1995); Tedford et al., Soc.
Neurosci. Abstr., 22:22 (1996); and Fox, et al., Behav. Brain Res.,
131:151-161 (2002); Glase, S. A., et al. "Attention deficit
hyperactivity disorder: pathophysiology and design of new
treatments." Annual Reports in Medicinal Chemistry (2002), 37
11-20; Schweitzer, J. B., and Holcomb, H. H. "Drugs under
investigation for attention-deficit hyperactivity disorder" Current
Opinion in Investigative Drugs (2002) 3, p. 1207.
[0215] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
dementia, and diseases with deficits of memory and learning, may be
demonstrated by "Two novel and selective nonimidazole H.sub.3
receptor antagonists A-304121 and A-317920: II. In vivo behavioral
and neurophysiological characterization." Fox, G. B., et al.
Journal of pharmacology and experimental therapeutics (2003 June),
305 (3), 897-908; "Identification of novel H.sub.3 receptor
(H.sub.3R) antagonist with cognition enhancing properties in rats."
Fox, G. B.; Inflammation Research (2003), 52 (Suppl. 1), S31-S32;
Bernaerts, P., et al. "Histamine H.sub.3 antagonist thioperamide
dose-dependently enhances memory consolidation and reverses amnesia
induced by dizocilpine or scopolamine in a one-trial inhibitory
avoidance task in mice" Behavioural Brain Research 154 (2004)
211-219; Onodera, et al. Nauyn-Schmiedebergs' Arch. Pharmacol.
(1998), 357, 508-513; Prast, et al. Brain Research (1996) 734,
316-318; Chen, et al. Brain Research (1999) 839, 186-189 "Effects
of histamine on MK-801-induced memory deficits in radial maze
performance in rats"; Passani, et al. "Central histaminergic system
and cognition" Neuroscience and Biobehavioral Reviews (2000) 24, p
107-113.
[0216] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
schizophrenia, cognitive deficits of schizophrenia, and cognitive
deficits, may be demonstrated by Fox, G. B., et al.
"Pharmacological Properties of ABT-239: II. Neurophysiological
Characterization and Broad Preclinical Efficacy in Cognition and
Schizophrenia of a Potent and Selective Histamine H.sub.3 Receptor
Antagonist", Journal of Pharmacology and Experimental Therapeutics
(2005) 313, 176-190 and by "Enhancement of prepulse inhibition of
startle in mice by the H.sub.3 receptor antagonists thioperamide
and ciproxifan." Browman, Kaitlin E., et al. Behavioural Brain
Research (2004), 153 (1), 69-76; "H.sub.3 receptor blockade by
thioperamide enhances cognition in rats without inducing locomotor
sensitization."; Komater, V. A., et al. Psychopharmacology (Berlin,
Germany) (2003), 167 (4), 363-372; AA Rodrigues, F P Jansen, R
Leurs, H Timmerman and G D Prell "Interaction of clozapine with the
histamine H.sub.3 receptor in rat brain" British Journal of
Pharmacology (1995), 114 (8), pp. 1523-1524; Passani, et al.
"Central histaminergic system and cognition" Neuroscience and
Biobehavioral Reviews (2000) 24, p 107-113; Morriset, S., et al.
"Atypical Neuroleptics Enhance Histamine Turnover in Brain Via
5-Hydroxytryptamine.sub.2A Receptor Blockade" Journal of
Pharmacology and Experimental Therapeutics (1999) 288, pages
590-596.
[0217] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
dysfunction in psychiatric disorders, Alzheimer's disease, and mild
cognitive impairment may be demonstrated by Meguro, et al.
Pharmacology, Biochemistry and Behavior (1995) 50 (3), 321-325;
Esbenshade, T., et al. "Pharmacological and behavioral properties
of A-349821, a selective and potent human histamine H3 receptor
antagonist" Biochemical Pharmacology 68 (2004) 933-945; Huang,
Y.-W., et al. "Effect of the histamine H3-antagonist clobenpropit
on spatial memory deficits induced by MK-801 as evaluated by radial
maze in Sprague-Dawley rats" Behavioural Brain Research 151 (2004)
287-293; Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol.
Pharmacol. (1989) 67, p. 75-78; P. Panula, et al., Neuroscience
(1997) 82, 993-997; Haas, et al., Behav. Brain Res. (1995) 66, p.
41-44; De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986),
283, p. 193-198; Kamei et al., Psychopharmacology, (1990) 102, p.
312-318; Kamei and Sakata, Jpn. J. Pharmacol. (1991), 57, p.
437-482; Schwartz et al., Psychopharmacology, The Fourth Generation
of Progress. Bloom and Kupfer (eds). Raven Press, New York, (1995)
397; and Wada, et al., Trends in Neurosci. (1991) 14, p. 415.
[0218] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
epilepsy, and seizures, may be demonstrated by Harada, C., et al.
"Inhibitory effect of iodophenpropit, a selective histamine H3
antagonist, on amygdaloid kindled seizures" Brain Research Bulletin
(2004) 63 p, 143-146; as well as by Yokoyama, et al., Eur. J.
Pharmacol. (1993) 234, p. 129-133; Yokoyama, et al. European
Journal of Pharmacology (1994) 260, p. 23; Yokoyama and Iinuma, CNS
Drugs (1996) 5, p. 321; Vohora, Life Sciences (2000) 66, p.
297-301; Onodera et al., Prog. Neurobiol. (1994) 42, p. 685; Chen,
Z., et al. "Pharmacological effects of carcinine on histaminergic
neurons in the brain" British Journal of Pharmacology (2004) 143,
573-580; R. Leurs, R. C. Vollinga and H. Timmerman, "The medicinal
chemistry and therapeutic potential of ligands of the histamine
H.sub.3 receptor", Progress in Drug Research (1995) 45, p. 170-165;
Leurs and Timmerman, Prog. Drug Res. (1992) 39, p. 127; H. Yokoyama
and K. Iinuma, "Histamine and Seizures: Implications for the
treatment of epilepsy", CNS Drugs, 5 (5): 321-330 (1995); and K.
Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and T. Watanabe,
"AQ-0145, A newly developed histamine H.sub.3 antagonist, decreased
seizure susceptibility of electrically induced convulsions in
mice", Meth. Find. Exp. Clin. Pharmacol., 17 (C):70-73 (1995);
Yawata, et al. "Role of histaminergic neurons in development of
epileptic seizures in EL mice" Molecular Brain Research 132 (2004)
13-17.
[0219] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
allergic rhinitis, and asthma, may be demonstrated by McLeod, R.
L., Mingo, G. G., Herczku, C., DeGennaro-Culver, F., Kreutner, W.,
Egan, R. W., Hey, J. A., "Combined histamine H1 and H3 receptor
blockade produces nasal decongestion in an experimental model of
nasal congestion" Am. J. Rhinol. (1999a) 13, p. 391-399; McLeod,
Robbie L.; Egan, Robert W.; Cuss, Francis M.; Bolser, Donald C.;
Hey, John A. (Allergy, Schering-Plough Research Institute,
Kenilworth, N.J., USA.) Progress in Respiratory Research (2001), 31
(in New Drugs for Asthma, Allergy and COPD), pp. 133-136; A.
Delaunois A., et al., "Modulation of acetylcholine, capsaicin and
substance P effects by histamine H.sub.3 receptors in isolated
perfused rabbit lungs," European Journal of Pharmacology (1995)
277, p. 243-250; Dimitriadou, et al., "Functional relationship
between mast cells and C-sensitive nerve fibres evidenced by
histamine H.sub.3-receptor modulation in rat lung and spleen,"
Clinical Science (1994), 87, p. 151-163.
[0220] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
motion sickness, dizziness, Meniere's disease, vestibular
disorders, and vertigo, may be demonstrated by Pan, et al. Methods
and Findings in Clinical Pharmacology (1998), 20 (9), 771-777;
O'Neill, et al. Methods and Findings in Clinical Pharmacology
(1999) 21 (4), 285-289; and by R. Leurs, R. C. Vollinga and H.
Timmerman, "The medicinal chemistry and therapeutic potential of
ligands of the histamine H.sub.3 receptor," Progress in Drug
Research (1995), 45, p. 170-165, Lozada, et al. "Plasticity of
histamine H.sub.3 receptor expression and binding in the vestibular
nuclei after labyrinthectomy in rat" BioMedCentral Neuroscience
2004, 5:32.
[0221] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
obesity, diabetes, type II diabetes, Syndrome X, insulin resistance
syndrome, and metabolic syndrome, may be demonstrated by Hancock,
A. A. "Antiobesity effects of A-331440, a novel non-imidazole
histamine H3 receptor antagonist" European Journal of Pharmacology
(2004) 487, 183-197; Hancock, A. A., et al. "Histamine H.sub.3
antagonists in models of obesity" Inflamm. res. (2004) 53,
Supplement 1 S47-S48; as well as by E. Itoh, M. Fujimiay, and A.
Inui, "Thioperamide, A histamine H.sub.3 receptor antagonist,
powerfully suppresses peptide YY-induced food intake in rats,"
Biol. Psych. (1999) 45 (4), p. 475-481; S. I. Yates, et al.,
"Effects of a novel histamine H.sub.3 receptor antagonist, GT-2394,
on food intake and weight gain in Sprague-Dawley rats," Abstracts,
Society for Neuroscience, 102.10:219 (November, 2000); and C.
Bjenning, et al., "Peripherally administered ciproxifan elevates
hypothalamic histamine levels and potently reduces food intake in
the Sprague Dawley rat," Abstracts, International Sendai Histamine
Symposium, Sendai, Japan, #P39 (November, 2000); Sakata T; et al.
"Hypothalamic neuronal histamine modulates ad libitum feeding by
rats." Brain research (1990 Dec. 24), 537 (1-2), 303-6.
[0222] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat pain,
including neuropathic pain and neuropathy, may be demonstrated by
Malmberg-Aiello, Petra; Lamberti, Claudia; Ghelardini, Carla;
Giotti, Alberto; Bartolini, Alessandro. British Journal of
Pharmacology (1994), 111 (4), 1269-1279; Hriscu, Anisoara; Gherase,
Florenta; Pavelescu, M.; Hriscu, E. "Experimental evaluation of the
analgesic efficacy of some antihistamines as proof of the
histaminergic receptor involvement in pain." Farmacia, (2001), 49
(2), 23-30, 76.
[0223] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat sleep
disorders, including narcolepsy and pathological sleepiness, and
jet lag, may be demonstrated by Barbier, A. J., et al. "Acute
wake-promoting actions of JNJ-5207852, a novel, diamine-based
H.sub.3 antagonist" British Journal of Pharmacology (2004) 1-13;
Monti et al., Neuropsychopharmacology (1996) 15, 31-35; Lin et al.,
Brain Res. (1990) 523, p. 325-330; Monti, et al.,
Neuropsychopharmacology (1996) 15, p. 31-35; Ligneau, et al.
Journal of Pharmacology and Experimental Therapeutics (1998), 287,
658-666; Sakai, et al., Life Sci. (1991) 48, p. 2397-2404;
Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol.,
(1989) 67, p. 75-78; P. Panula, et al., Neuroscience (1998) 44,
465-481; Wada, et al., Trends in Neuroscience (1991) 14, p. 415;
and Monti, et al., Eur. J. Pharmacol. (1991), 205, p. 283; Dvorak,
C., et al. "4-Phenoxypiperidines: Potent, Conformationally
Restricted, Non-Imidazole Histamine H.sub.3 Antagonists" Journal of
Medicinal Chemistry (2005) 48, 2229-2238.
[0224] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat drug
abuse. Amphetamine is an abused stimulant in humans. It, and
similar abused drugs stimulate locomotor activity in animals, and
it has been found that the H.sub.3 antagonist thioperamide
suppresses the locomotor stimulation induced by amphetamine;
therefore H.sub.3 antagonists are likely to be useful for treating
drug abuse as may be demonstrated by Clapham J.; Kilpatrick G. J.
"Thioperamide, the selective histamine H.sub.3 receptor antagonist,
attenuates stimulant-induced locomotor activity in the mouse",
European journal of pharmacology (1994), 259 (2), 107-14.
[0225] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat mood
alteration, bipolar disorder, depression, obsessive compulsive
disorder, and Tourette's syndrome, may be demonstrated by Lamberti,
et al. British Journal of Pharmacology (1998) 123, 1331-1336;
Perez-Garcia C, et. al., Psychopharmacology (Berlin) (1999) 142
(2): 215-20.
[0226] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
Parkinson's disease (a disease wherein patients have deficits in
ability to initiate movements, and patients' brain have low
dopamine levels) may be demonstrated by Sanchez-Lemus, E., et al.
"Histamine H.sub.3 receptor activation inhibits dopamine D.sub.1
receptor-induced cAMP accumulation in rat striatal slices"
Neuroscience Letters (2004) 364, p. 179-184; Sakai, et al., Life
Sci. (1991) 48, 2397-2404; Fox, G. B., et al. "Pharmacological
Properties of ABT-239: II. Neurophysiological Characterization and
Broad Preclinical Efficacy in Cognition and Schizophrenia of a
Potent and Selective Histamine H.sub.3 Receptor Antagonist" Journal
of Pharmacology and Experimental Therapeutics, 313:176-190, 2005;
Chen, Z., et al. "Pharmacological effects of carcinine on
histaminergic neurons in the brain" British Journal of Pharmacology
(2004) 143, 573-580.
[0227] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
medullary thyroid carcinoma, melanoma, polycystic ovary syndrome,
may be demonstrated by Polish Med. Sci. Mon. (1998) 4 (5): 747;
Adam Szelag, "Role of histamine H.sub.3-receptors in the
proliferation of neoplastic cells in vitro," Med. Sci. Monitor
(1998) 4 (5):747-755; and C. H. Fitzsimons, et al., "Histamine
receptors signalling in epidermal tumor cell lines with H-ras gene
alterations," Inflammation Res. (1998) 47 (Suppl 1):S50-S51.
[0228] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting memory or
cognition, for example Alzheimer's disease, attention-deficit
hyperactivity disorder, schizophrenia, or the cognitive deficits of
schizophrenia.
[0229] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0230] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
invention can be employed in pure form or, where such forms exist,
in pharmaceutically acceptable salt, ester, amide or prodrug form.
Alternatively, the compound can be administered as a pharmaceutical
composition containing the compound of interest in combination with
one or more pharmaceutically acceptable carriers. The phrase
"therapeutically effective amount" of the compound of the invention
means a sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the
compounds and compositions of the invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well known in the
medical arts. For example, it is well within the skill of the art
to start doses of the compound at levels lower than required to
achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved.
[0231] The total daily dose of the compounds of this invention
administered to a human or lower animal may range from about 0.003
to about 30 mg/kg/day. For purposes of oral administration, more
preferable doses can be in the range of from about 0.01 to about
0.1 mg/kg/day. If desired, the effective daily dose can be divided
into multiple doses for purposes of administration; consequently,
single dose compositions may contain such amounts or submultiples
thereof to make up the daily dose.
[0232] The compounds and processes of the invention will be better
understood by reference to the following examples, which are
intended as an illustration of and not a limitation upon the scope
of the invention.
EXAMPLES
Example 1
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carboni-
trile
Example 1A
3-(4-Bromo-phenyl)-cis-cyclobutanol
[0233] To a solution of 3-(4-bromo-phenyl)-cyclobutanone (3 g, 13.3
mmol) (J. Med. Chem., 43:721-735 (2000)), in anhydrous ether (100
mL) cooled to -20.degree. C. was dropwise added lithium aluminum
hydride (1M in THF, 15 mL). The mixture was then allowed to warm to
room temperature and stirred for 4 hours. The reaction was slowly
quenched with NaOH (1M, 0.8 mL), H.sub.2O (0.8 mL) and NaOH (1M,
0.8 mL) sequentially. After stirring for about 30 minutes, the
mixture was filtered through a layer of diatomaceous earth and
washed with extra ether (100 mL). The filtrate was evaporated under
reduced pressure to provide a colorless oil as the title compound
(3.01 g, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.0 (m,
2H), 2.76 (m, 2H), 2.92 (m, 1H), 4.28 (m, 1H), 7.09 (d, J=9 Hz,
2H), 7.41 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 244
(M+NH.sub.4).sup.+.
Example 1B
1-[3-(4-Bromo-phenyl)-trans-cyclobutyl]-(2R)-2-methyl-pyrrolidine
[0234] The product from Example 1A (3 g, 13.2 mmol) was dissolved
in anhydrous dichloromethane (120 mL) and cooled to 0.degree. C.
The solution was treated with K.sub.2CO.sub.3 (5.46 g, 39.6 mmol),
followed by trifluoroacetic acid anhydride (3.35 mL, 19.8 mmol),
and stirred at room temperature for three hours. The reaction
mixture was treated with a solution of (R)-2-methylpyrrolidine
(prepared according to the procedure that described in: R.
Altenbach et al., WO 2004043458, and Y. Pu et al., Organic Process
Research & Development, 9 (1), 45-50, 2005) (2 g, 23.7 mmol) in
toluene, stirred overnight and partitioned between dichloromethane
and H.sub.2O. The organic extraction was dried (MgSO.sub.4),
filtered, concentrated and chromatographed on silica gel eluting
with a gradient of 1% to 2% (9:1 MeOH:concentrated NH.sub.4OH) in
dichloromethane, providing the title compound as a brownish oil
(1.3 g, 34%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.11 (d,
J=9 Hz, 3H), 1.46 (m, 1H), 1.78 (m, 2H), 1.98 (m, 1H), 2.20 (m,
1H), 2.35 (m, 2H), 2.58 (m, 3H), 3.03 (m, 1H), 3.34 (m, 1H), 3.47
(m, 1H), 7.23 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H); (DCI/NH.sub.3)
m/z 294 (M+H).sup.+.
Example 1C
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carboni-
trile
[0235] To a solution of the product from Example 1B (50 mg, 0.17
mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen
was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol),
dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 .mu.mol),
and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated
at 90.degree. C. for 5 hrs, cooled to ambient temperature and
partitioned between ethyl acetate (25 mL) and H.sub.2O (10 mL). The
organic extraction was washed with brine, dried (MgSO.sub.4),
filtered, concentrated, and chromatographed on silica gel eluting
with 3% (9:1 MeOH:concentrated NH.sub.4OH) in dichloromethane to
provide 41 mg of the title compound. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 1.15 (d, J=6 Hz, 3H), 1.49 (m, 1H), 1.79 (m,
2H), 2.01 (m, 1H), 2.29 (m, 1H), 2.43 (m, 2H), 2.63 (m, 3H), 3.07
(m, 1H), 3.43 (m, 1H), 3.54 (m, 1H), 7.41 (d, J=9 Hz, 2H), 7.62 (d,
J=9 Hz, 2H), 7.75 (AB q, 4H); (DCI/NH.sub.3) m/z 317
(M+H).sup.+.
Example 2
4'-{3[(2R)-2-Methyl-Pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitri-
le
Example 2A
1-[3-(4-Bromo-phenyl)-cis-cyclobutyl]-(2R)-2-methyl-pyrrolidine
[0236] To a solution of 3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.44
mmol) in ethanol (20 mL) was added a solution of
(R)-2-methylpyrrolidine (prepared according to the procedure that
described in: R. Altenbach et al., WO 2004043458, and Y. Pu et al.,
Organic Process Research & Development, 9 (1), 45-50, 2005)
(0.75 g, 8.9 mmol) in toluene. Borane-pyridine complex (0.67 mL,
6.6 mmol) was added subsequently and stirred at ambient temperature
for 16 hours. The mixture was concentrated under reduced pressure
to dryness and partitioned between ethyl acetate and H.sub.2O. The
organic layers were washed with brine, dried (MgSO.sub.4) and
concentrated under reduced pressure. Chromatography of the residue
eluting with a gradient of 1-2% (9:1 MeOH:concentrated NH.sub.4OH)
in dichloromethane provided the title compound (680 mg, 52%) as the
faster eluting component and the product from Example 1B (76 mg,
6%) as the slower eluting component. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.15 (d, J=6 Hz, 3H), 1.46 (m, 1H), 1.77 (m,
2H), 1.99 (m, 1H), 2.07 (m, 2H), 2.34 (m, 1H), 2.58 (m, 3H), 3.04
(m, 2H), 3.17 (m, 1H), 7.17 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H);
(DCI/NH.sub.3) m/z 294 (M+H).sup.+.
Example 2B
4'-{3[(2R)-2-Methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitri-
le
[0237] A solution of the product from Example 2A (100 mg, 0.34
mmol), 4-cyanophenyl boronic acid (65 mg, 0.44 mmol),
dichlorobis(triphenylphosphine)palladium(II) (12 mg, 17 .mu.mol)
and potassium carbonate (120 mg, 0.85 mmol) under an atmosphere of
nitrogen in isopropyl alcohol (8 mL) was heated at reflux for 5
hrs. Then, the reaction mixture was cooled to ambient temperature.
The mixture was partitioned between ethyl acetate (25 mL) and
H.sub.2O (10 mL). The organic layer was washed with brine, dried
with magnesium sulfate, filtered, concentrated, and chromatographed
on silica gel, eluting with 3% (9:1 MeOH:conc NH.sub.4OH) in
dichloromethane to provide 36 mg of the title compound. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.21 (d, J=6 Hz, 3H), 1.54 (m, 1H),
1.84 (m, 2H), 2.07 (m, 1H), 2.18 (m, 2H), 2.57 (m, 2H), 2.71 (m,
2H), 3.11 (m, 1H), 3.27 (m, 2H), 7.39 (d, J=9 Hz, 2H), 7.64 (d, J=9
Hz, 2H), 7.79 (s, 4H); (DCI/NH.sub.3) m/z 317 (M+H).sup.+.
Example 3
4'-[3-(2-Methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-biphenyl-4-carbonitrile
Example 3A
1-[3-(4-Bromo-phenyl)-cis-cyclobutyl]-2-methyl-pyrrolidine
[0238] The title compound was prepared using the procedure
described in Example 2A except substituting racemic
2-methylpyrrolidine for (R)-2-methylpyrrolidine. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta.1.16 (d, J=6 Hz, 3H), 1.46 (m, 1H), 1.78
(m, 2H), 2.08 (m, 3H), 2.39 (m, 1H), 2.49 (m, 1H), 2.61 (m, 2H),
3.07 (m, 3H), 7.17 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H);
(DCI/NH.sub.3) m/z 294 (M+H).sup.+.
Example 3B
4'-[3-(2-Methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-biphenyl-4-carbonitrile
[0239] The title compound was prepared using the procedure
described in Example 2B except substituting the product from
Example 3A for the product from Example 2A. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.22 (d, J=6 Hz, 3H), 1.54 (m, 1H), 1.84 (m,
2H), 2.05 (m, 1H), 2.19 (m, 2H), 2.57 (m, 2H), 2.71 (m, 2H), 3.27
(m, 3H), 7.39 (d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, 2H), 7.79 (s, 4H);
(DCI/NH.sub.3) m/z 317 (M+H).sup.+.
Example 4
(.+-.)4'-[3-(2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-biphenyl-4-carbon-
itrile
Example 4A
(.+-.)1-[3-(4-Bromo-phenyl)-trans-cyclobutyl]-2-methyl-pyrrolidine
[0240] The title compound was prepared using the procedure
described in Example 1B except substituting racemic
2-methylpyrrolidine for (R)-2-methylpyrrolidine. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 1.24 (d, J=6 Hz, 3H), 1.60 (m, 1H), 1.90
(m, 2H), 2.12 (m, 1H), 2.36 (m, 1H), 2.45 (m, 1H), 2.67 (m, 3H),
2.96 (m, 1H), 3.24 (m, 1H), 3.60 (m, 2H), 7.25 (d, J=9 Hz, 2H),
7.46 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 294 (M+H).sup.+.
Example 4B
(.+-.)4'-[3-(2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-biphenyl-4-carbon-
itrile
[0241] The title compound was prepared using the procedure
described in Example 2B except substituting the product from the
Example 4A for the product from Example 2A. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.24 (d, J=6 Hz, 3H), 1.60 (m, 1H), 1.90 (m,
2H), 2.12 (m, 1H), 2.41 (m, 1H), 2.53 (m, 1H), 2.70 (m, 3H), 2.92
(m, 1H), 3.24 (m, 1H), 3.62 (m, 2H), 7.46 (d, J=9 Hz, 2H), 7.67 (d,
J=9 Hz, 2H), 7.80 (s, 4H); (DCI/NH.sub.3) m/z 317 (M+H).sup.+.
Example 5
5-{4-[3-({2R}-2-Methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyrimidine
[0242] The title compound was prepared using the procedure
described in Example 2B except substituting 5-pyrimidineboronic
acid (CAS # 109299-78-7) for 4-cyanophenylboronic acid. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.22 (d, J=6 Hz, 3H), 1.54 (m, 1H),
1.85 (m, 2H), 2.07 (m, 1H), 2.19 (m, 2H), 2.57 (m, 2H), 2.72 (m,
2H), 3.15 (m, 1H), 3.26 (m, 2H), 7.45 (d, J=9 Hz, 2H), 7.68 (d, J=9
Hz, 2H), 9.05 (s, 2H), 9.11 (s, 1H); (DCI/NH.sub.3) m/z 294
(M+H).sup.+.
Example 6
2,6-Difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-pheny-
l}-pyridine
[0243] The title compound was prepared using the procedure
described in Example 2B except substituting
2,6-difluoropyridine-3-boronic acid (CAS # 136466-94-9) for
4-cyanophenylboronic acid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.24 (d, J=6 Hz, 3H), 1.55 (m, 1H), 1.87 (m, 2H), 2.08 (m,
1H), 2.21 (m, 2H), 2.60 (m, 2H), 2.74 (m, 1H), 2.84 (m, 1H), 3.18
(m, 1H), 3.29 (m, 2H), 7.06 (dd, J=9 Hz, J=3 Hz, 1H), 7.38 (d, J=9
Hz, 2H), 7.51 (dd, J=9 Hz, J=3 Hz, 2H), 8.14 (dd, J=18 Hz, J=9 Hz,
1H); (DCI/NH.sub.3) m/z 329 (M+H).sup.+.
Example 7
2,6-Difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phe-
nyl}-pyridine
[0244] The title compound was prepared using the procedure
described in Example 1C except substituting
2,6-difluoropyridine-3-boronic acid (CAS # 136466-94-9) for
4-cyanophenylboronic acid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.28 (d, J=6 Hz, 3H), 1.61 (m, 1H), 1.93 (m, 2H), 2.14 (m,
1H), 2.45 (m, 1H), 2.55 (m, 1H), 2.73 (m, 3H), 3.04 (m, 1H), 3.32
(m, 1H), 3.64 (m, 2H), 7.07 (dd, J=9 Hz, J=3 Hz, 1H), 7.46 (d, J=9
Hz, 2H), 7.55 (dd, J=9 Hz, J=3 Hz, 2H), 8.16 (dd, J=18 Hz, J=9 Hz,
1H); (DCI/NH.sub.3) m/z 329 (M+H).sup.+.
Example 8
2,6-Dimethyl-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phe-
nyl}-pyridine
[0245] The title compound was prepared using the procedure
described in Example 1C except substituting
2,6-dimethylpyridine-3-boronic acid for 4-cyanophenylboronic acid.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.23 (d, J=6 Hz, 3H),
1.56 (m, 1H), 1.88 (m, 2H), 2.09 (m, 1H), 2.39 (m, 1H), 2.50 (m,
1H), 2.43 (s, 3H), 2.45 (s, 3H), 2.69 (m, 3H), 2.86 (m, 1H), 3.22
(m, 1H), 3.64 (m, 2H), 7.17 (d, J=6 Hz, 1H), 7.30 (d, J=9 Hz, 2H),
7.42 (d, J=9 Hz, 2H), 7.52 (d, J=6 Hz, 1H); (DCI/NH.sub.3) m/z 321
(M+H).sup.+.
Example 9
2,6-Dichloro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phe-
nyl}-pyridine
[0246] The title compound was prepared using the procedure
described in Example 1C except substituting
2,6-dichloropyridine-3-boronic acid (CAS # 148493-34-9) for
4-cyanophenylboronic acid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.22 (d, J=6 Hz, 3H), 1.60 (m, 1H), 1.88 (m, 2H), 2.08 (m,
1H), 2.38 (m, 1H), 2.51 (m, 1H), 2.69 (m, 3H), 2.85 (m, 1H), 3.18
(m, 1H), 3.61 (m, 2H), 7.44 (s, 4H), 7.49 (d, J=9 Hz, 1H), 7.81 (d,
J=9 Hz, 1H); (DCI/NH.sub.3) m/z 362 (M+H).sup.+.
Example 10
4'-{3-[(2S)-2-Methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitr-
ile
[0247] The title compound was prepared using the procedure
described in Example 2, except substituting (S)-2-methylpyrrolidine
(prepared according to the procedure that described in: R.
Altenbach et al., WO 2004043458, and Y. Pu et al., Organic Process
Research & Development, 9 (1), 45-50, 2005) for
(R)-2-methylpyrrolidine in Example 2A. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.31 (d, J=6 Hz, 3H), 1.65 (m, 1H), 1.95 (m,
2H), 2.26 (m, 3H), 2.68 (m, 1H), 2.78 (m, 2H), 3.26 (m, 4H), 7.40
(d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 2H), 7.79 (s, 4H); (DCI/NH.sub.3)
m/z 317 (M+H).sup.+.
Example 11
5-{4-[3-({2R}-2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidi-
ne
[0248] The title compound was prepared using the procedure
described in Example 1C except substituting 5-pyrimidineboronic
acid (CAS # 109299-78-7) for 4-cyanophenylboronic acid. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.17 (d, J=6 Hz, 3H), 1.54 (m, 1H),
1.83 (m, 2H), 2.05 (m, 1H), 2.32 (m, 1H), 2.50 (m, 2H), 2.66 (m,
3H), 3.10 (m, 1H), 3.48 (m, 1H), 3.58 (m, 1H), 7.51 (d, J=9 Hz,
2H), 7.69 (d, J=9 Hz, 2H), 9.05 (s, 2H), 9.11 (s, 1H);
(DCI/NH.sub.3) m/z 294 (M+H).sup.+.
Example 12
2-{4-[3-({2R}-2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-2H-pyrid-
azin-3-one
[0249] A solution of the product from Example 1B (40 mg, 0.14
mmol), 3(2H)-pyridazinone (CAS # 504-30-3, 20 mg, 0.2 mmol), copper
(13 mg, 0.2 mmol), and potassium carbonate (38 mg, 0.27 mmol) in
anhydrous DMF was heated to 140.degree. C. under an atmosphere of
nitrogen for 16 hours. Then, the reaction mixture was cooled to
ambient temperature, treated with H.sub.2O and extracted with ethyl
acetate (2.times.25 mL). The organic layers were combined, washed
with brine and dried with magnesium sulfate. After filtration, the
organic layer was concentrated and the resulting oil was purified
on preparative HPLC on a Waters.TM. Symmetry C8 column (25
mm.times.100 mm, 7 .mu.m particle size) using a gradient of 10% to
100% acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at
a flow rate of 40 mL/min to provide 5 mg of the title compound as a
trifluoroacetic acid salt. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.46 (d, J=6 Hz, 3H), 1.78 (m, 1H), 2.10 (m, 2H), 2.33 (m,
1H), 2.68 (m, 2H), 2.81 (m, 2H), 3.18 (m, 1H), 3.59 (m, 2H), 3.74
(m, 1H), 4.10 (m, 1H), 7.09 (dd, J=9 Hz, J=3 Hz, 1H), 7.48 (d, J=9
Hz, 2H), 7.50 (m, 1H), 7.56 (d, J=9 Hz, 2H), 8.04 (m, 1H);
(DCI/NH.sub.3) m/z 310 (M+H).sup.+.
Example 13
4'-{3-[(2S)-2-Methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carboni-
trile
Example 13A
1-[3-(4-Bromo-phenyl)-trans-cyclobutyl]-(2S)-2-methyl-pyrrolidine
[0250] The title compound was prepared using the procedure
described in Example 1B except substituting (S)-2-methylpyrrolidine
(prepared according to the procedure that described in: R.
Altenbach et al., WO 2004043458, and Y. Pu et al., Organic Process
Research & Development, 9 (1), 45-50, 2005) for
(R)-2-methylpyrrolidine in Example 1B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.13 (d, J=6 Hz, 3H), 1.49 (m, 1H), 1.79 (m,
2H), 1.99 (m, 1H), 2.23 (m, 1H), 2.36 (m, 2H), 2.59 (m, 3H), 3.04
(m, 1H), 3.36 (m, 1H), 3.46 (m, 1H), 7.24 (d, J=9 Hz, 2H), 7.44 (d,
J=9 Hz, 2H); (DCI/NH.sub.3) m/z 294 (M+H).sup.+.
Example 13B
4'-{3-[(2S)-2-Methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbon-
itrile
[0251] The title compound was prepared using the procedure
described in Example 1C except substituting the product from
Example 13A for the product from Example 1B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.36 (d, J=6 Hz, 3H), 1.72 (m, 1H), 2.01 (m,
2H), 2.24 (m, 1H), 2.55 (m, 1H), 2.63 (m, 1H), 2.78 (m, 2H), 3.02
(m, 1H), 3.25 (m, 1H), 3.42 (m, 1H), 3.69 (m, 1H), 3.90 (m, 1H),
7.47 (d, J=9 Hz, 2H), 7.68 (d, J=9 Hz, 2H), 7.80 (AB q, 4H);
(DCI/NH.sub.3) m/z 317 (M+H).sup.+.
Example 14
5-{4-[3-({2S}-2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidi-
ne
[0252] The title compound was prepared using the procedure
described in Example 1C, except substituting 5-pyrimidineboronic
acid (CAS # 109299-78-7) for 4-cyanophenylboronic acid and
substituting the product from Example 13A for the product from
Example 1B. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.1.17 (d, J=6
Hz, 3H), 1.51 (m, 1H), 1.83 (m, 2H), 2.03 (m, 1H), 2.33 (m, 1H),
2.46 (m, 2H), 2.65 (m, 3H), 3.09 (m, 1H), 3.46 (m, 1H), 3.59 (m,
1H), 7.50 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 2H), 9.06 (s, 2H), 9.11
(s, 1H); (DCI/NH.sub.3) m/z 294 (M+H).sup.+.
Example 15
2,4-Dimethoxy-5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyrimidine
[0253] The title compound was prepared using the procedure
described in Example 1C, except substituting the product from
Example 13A for the product from Example 1B and substituting
2,4-dimethoxypyrimidine-5-boronic acid (CAS # 89641-18-9) for
4-cyanophenylboronic acid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.30 (d, J=6 Hz, 3H), 1.66 (m, 1H), 1.87 (m, 2H), 2.19 (m,
1H), 2.47 (m, 1H), 2.55 (m, 1H), 2.73 (m, 3H), 3.37 (m, 2H), 3.63
(m, 1H), 3.79 (m, 1H), 4.04 (s, 6H), 7.39 (d, J=9 Hz, 2H), 7.50 (d,
J=9 Hz, 2H), 8.24 (s, 1H); (DCI/NH.sub.3) m/z 354 (M+H).sup.+.
Example 16
2-Methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-pyrimidine
Example 16A
3-(4-Bromo-phenyl)-cis-cyclobutanol
[0254] To a solution of 3-(4-bromo-phenyl)-cyclobutanone (3 g, 13.3
mmol) (J. Med. Chem., 43:721-735 (2000)), in anhydrous ether (100
mL) cooled to -20.degree. C. was dropwise added lithium aluminum
hydride (1M in THF, 15 mL). The mixture was then allowed to warm to
room temperature and stirred for 4 hours. The reaction was slowly
quenched with NaOH (1M, 0.8 mL), H.sub.2O (0.8 mL) and NaOH (1M,
0.8 mL) sequentially. After stirring for about 30 minutes, the
mixture was filtered through a layer of diatomaceous earth and
washed with extra ether (100 mL). The filtrate was evaporated under
reduced pressure to provide a colorless oil as the title compound
(3.01 g, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.0 (m,
2H), 2.76 (m, 2H), 2.92 (m, 1H), 4.28 (m, 1H), 7.09 (d, J=9 Hz,
2H), 7.41 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 244
(M+NH.sub.4).sup.+.
Example 16B
1-[3-(4-Bromo-phenyl)-trans-cyclobutyl]-(2R)-2-methyl-pyrrolidine
[0255] The product from Example 16A (3 g, 13.2 mmol) was dissolved
in anhydrous dichloromethane (120 mL) and cooled to 0.degree. C.
The solution was treated with K.sub.2CO.sub.3 (5.46 g, 39.6 mmol),
followed by trifluoroacetic acid anhydride (3.35 mL, 19.8 mmol),
and stirred at room temperature for three hours. The reaction
mixture was treated with a solution of (R)-2-methylpyrrolidine
(prepared according to the procedure that described in WO
2004043458, and Y. Pu et al., Organic Process Research &
Development, 9 (1), 45-50, 2005) (2 g, 23.7 mmol) in toluene,
stirred for 16 hours and partitioned between dichloromethane and
H.sub.2O. The organic extraction was dried (MgSO.sub.4), filtered,
concentrated and chromatographed on silica gel eluting with a
gradient of 1% to 2% (9:1 MeOH:concentrated NH.sub.4OH) in
dichloromethane, providing the title compound as a brownish oil
(1.3 g, 34%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.11 (d,
J=9 Hz, 3H), 1.46 (m, 1H), 1.78 (m, 2H), 1.98 (m, 1H), 2.20 (m,
1H), 2.35 (m, 2H), 2.58 (m, 3H), 3.03 (m, 1H), 3.34 (m, 1H), 3.47
(m, 1H), 7.23 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H); (DCI/NH.sub.3)
m/z 294 (M+H).sup.+.
Example 16C
2-Methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl-
}-pyrimidine
[0256] To a solution of the product from Example 16B (50 mg, 0.17
mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen
was added 2-methoxypyrimidine-5-boronic acid (Frontier Scientific,
Inc., Logan, Utah, USA) (30 mg, 0.2 mmol),
dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 .mu.mol),
and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated
at 90.degree. C. for 5 hrs, cooled to ambient temperature and
partitioned between ethyl acetate (25 mL) and H.sub.2O (10 mL). The
organic extraction was washed with brine, dried (MgSO.sub.4),
filtered, concentrated, and chromatographed on silica gel eluting
with 3% (9:1 MeOH:concentrated NH.sub.4OH) in dichloromethane to
provide 41 mg of the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.13 (d, J=6 Hz, 3H), 1.47 (m, 1H), 1.77 (m,
2H), 1.99 (m, 1H), 2.27 (m, 1H), 2.41 (m, 2H), 2.62 (m, 3H), 3.05
(m, 1H), 3.38 (m, 1H), 3.55 (m, 1H), 4.05 (s, 3H), 7.46 (d, J=9 Hz,
2H), 7.59 (d, J=9 Hz, 2H), 8.81 (s, 2H); (DCI/NH.sub.3) m/z 324
(M+H).sup.+.
Example 17
2,4-Dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-ph-
enyl}-pyrimidine
[0257] The title compound was prepared using the procedure
described in Example 1C except substituting
2,4-dimethoxypyrimidine-5-boronic acid (CAS # 89641-18-9) for
4-cyanophenylboronic acid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.20 (d, J=6 Hz, 3H), 1.55 (m, 1H), 1.85 (m, 2H), 2.06 (m,
1H), 2.34 (m, 1H), 2.48 (m, 1H), 2.66 (m, 4H), 3.15 (m, 1H), 3.36
(m, 1H), 3.56 (m, 1H), 4.04 (s, 6H), 7.38 (d, J=9 Hz, 2H), 7.47 (d,
J=9 Hz, 2H), 8.25 (s, 1H); (DCI/NH.sub.3) m/z 354 (M+H).sup.+.
Example 18
5-{4-[3-({2R}-2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotino-
nitrile
Example 18A
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile
[0258] A mixture of 5-bromo-3-cyano pyridine (5 g),
pinacolatodiborane (9.02 g, 1.3 eq), PdCl.sub.2
(dppf):CH.sub.2Cl.sub.2 (0.67 g, 0.03 eq), dppf (0.41 g, 0.03 eq)
and potassium acetate (8.04 g, 3 eq) in dioxane (100 ml) was heated
to 85.degree. C. under nitrogen for 3 hours. The mixture was cooled
to room temperature, diluted with 100 ml ethyl acetate and the
solid was filtered off. The filtrate was concentrated to black oil
(14.5 g). Chromatography (silica gel, 5:95 methanol:chloroform)
gave yellow crystals (6.67 g). This was slurried with 60 ml hexane
and the precipitate was filtered and vacuum dried at 45.degree. C.
to give the title compound (4.5 g).
Example 18B
5-{4-[3-({2R}-2-Methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotino-
nitrile
[0259] The title compound was prepared using the procedure
described in Example 1C except substituting the product of Example
18A for 4-cyanophenylboronic acid. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.14 (d, J=6 Hz, 3H), 1.50 (m, 1H), 1.80 (m,
2H), 2.01 (m, 1H), 2.30 (m, 1H), 2.43 (m, 2H), 2.64 (m, 3H), 3.07
(m, 1H), 3.41 (m, 1H), 3.57 (m, 1H), 7.49 (d, J=9 Hz, 2H), 7.70 (d,
J=9 Hz, 2H), 8.45 (m, 1H), 8.85 (d, J=3 Hz, 1H), 9.08 (d, J=3 Hz,
1H); (DCI/NH.sub.3) m/z 318 (M+H).sup.+.
Example 19
2-Methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-
-benzothiazole
Example 19A
2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole
[0260] A solution of 5-bromo-2-methyl-benzothiazole (2 g, 8.8
mmol), bis(pinacolato)diboron (2.7 g, 10.6 mmol), potassium acetate
(3.1 g, 31.7 mmol) and Pd(dppf).sub.2Cl.sub.2 dichloromethane
complex (1:1) (360 mg, 0.51 mmol) in anhydrous tetrahydrofuran (70
mL) under a nitrogen atmosphere was heated to reflux overnight.
After cooling to ambient temperature, the reaction mixture was
filtered through diatomaceous earth and washed with ethyl acetate.
The filtrate was washed with water and brine, dried (MgSO.sub.4)
and concentrated. The residue was chromatographed on silica gel
eluting with 10% ethyl acetate in hexanes to provide the title
compound as white crystals (1.96 g, 81%). .sup.1H NMR (300 MHz,
CD.sub.3Cl.sub.3) .delta. 1.37 (s, 12H), 2.84 (s, 3H), 7.75 (d, J=9
Hz, 1H), 7.82 (d, J=9 Hz, 1H), 8.38 (s, 1H); (DCI/NH.sub.3) m/z 276
(M+H).sup.+.
Example 19B
2-Methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-
-benzothiazole
[0261] The title compound was prepared using the procedure
described in Example 1C except substituting the product from
Example 19A for 4-cyanophenylboronic acid. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.14 (d, J=6 Hz, 3H), 1.50 (m, 1H), 1.80 (m,
2H), 2.01 (m, 1H), 2.28 (m, 1H), 2.41 (m, 2H), 2.62 (m, 3H), 2.85
(s, 3H), 3.04 (m, 1H), 3.40 (m, 1H), 3.55 (m, 1H), 7.43 (d, J=9 Hz,
2H), 7.67 (m, 3H), 7.96 (d, J=9 Hz, 1H), 8.09 (d, J=3 Hz, 1H);
(DCI/NH.sub.3) m/z 363 (M+H).sup.+.
Example 20
2-Methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-
-pyridine
[0262] The title compound was prepared using the procedure
described in Example 1C except substituting
2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
(prepared according to the procedure described in J. Org. Chem.
67:7541-7543 (2002)) for 4-cyanophenylboronic acid. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.14 (d, J=6 Hz, 3H), 1.49 (m, 1H),
1.79 (m, 2H), 2.01 (m, 1H), 2.28 (m, 1H), 2.42 (m, 2H), 2.62 (m,
3H), 3.05 (m, 1H), 3.39 (m, 1H), 3.53 (m, 1H), 3.94 (s, 3H), 6.88
(d, J=9 Hz, 1H), 7.41 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.93
(dd, J=9 Hz, J=3 Hz, 1H), 8.35 (d, J=3 Hz, 1H); (DCI/NH.sub.3) m/z
307 (M+H).sup.+.
Example 21
1,3,5-Trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-pheny-
l}-1H-pyrazole
Example 21A
1,3,5-Trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazo-
le
[0263] A solution of 4-bromo-1,3,5-trimethyl-1H-pyrazole (1 g, 5.3
mmol) in anhydrous THF (20 mL) cooled to -78.degree. C. under a
nitrogen atmosphere was treated dropwise with n-butyl lithium (4.2
mL, 1.6 M in hexane) and stirred at room temperature for 20
minutes. Then,
2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.7 mL, 8.3
mmol) was added dropwise at -78.degree. C. and allowed to warm to
ambient temperature overnight. Ethyl acetate was added and the
mixture was filtered through diatomaceous earth. The filtrate was
concentrated and chromatographed on silica gel eluting with 40%
ethyl acetate in hexanes to provide the title compound as white
crystals (996 mg, 77%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.29 (s, 12H), 2.33 (s, 3H), 2.37 (s, 3H), 3.69 (s, 3H);
(DCI/NH.sub.3) m/z 237 (M+H).sup.+.
Example 21B
1,3,5-Trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-pheny-
l}-1H-pyrazole
[0264] The title compound was prepared using the procedure
described in Example 1C except substituting the product from
Example 21A for 4-cyanophenylboronic acid. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.17 (d, J=6 Hz, 3H), 1.48 (m, 1H), 1.80 (m,
2H), 2.00 (m, 1H), 2.17 (s, 3H), 2.23 (s, 3H), 2.28 (m, 1H), 2.41
(m, 2H), 2.62 (m, 3H), 3.06 (m, 1H), 3.41 (m, 1H), 3.52 (m, 1H),
3.75 (s, 3H), 7.20 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H);
(DCI/NH.sub.3) m/z 324 (M+H).sup.+.
Example 22
5-{2-Fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-
-pyrimidine
Example 22A
1-Bromo-2-fluoro-4-vinyl-benzene
[0265] A solution of 1-bromo-2-fluoro-4-iodo-benzene (1 g, 3.32
mmol), tributyl(vinyl)tin (0.97 mL, 3.32 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (116 mg, 0.17 mmol) in
anhydrous DMF (3 mL) was heated in a microwave reactor to
160.degree. C. for 5 minutes. Ether (20 mL) and H.sub.2O (5 mL)
were added and partitioned. The organic layer was washed with
water, brine, dried (MgSO.sub.4), filtered, and concentrated. The
residue was chromatographed on silica gel eluting with hexanes to
provide the title compound as a colorless oil (360 mg, 54%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.33 (d, J=9 Hz, 1H),
5.76 (d, J=18 Hz, 1H), 6.63 (dd, J=18 Hz, J=9 Hz, 1H), 7.05 (dd,
J=9 Hz, J=1 Hz, 1H), 7.16 (dd, J=9 Hz, J=1 Hz, 1H), 7.49 (t, J=9
Hz, 1H); (DCI/NH.sub.3) m/z 201 (M+H).sup.+.
Example 22B
3-(4-Bromo-3-fluoro-phenyl)-cyclobutanone
[0266] To a solution of the product from Example 22A (320 mg, 1.59
mmol) and a well stirred suspension of activated Zn--Cu, prepared
according to the procedure described in J. Org. Chem., 43:2879-2882
(1978), in anhydrous ether (20 mL) under nitrogen was added a
solution of phosphorus oxychloride (0.22 mL, 2.38 mmol) and
trichloroacetyl chloride (0.25 mL, 2.22 mmol) in anhydrous ether
(20 mL) dropwise, and then stirred for two days. The reaction
mixture was filtered through diatomaceous earth and washed with
ether. The ethereal solution was concentrated in vacuo to ca. 1/4
of its original volume. Pentane (100 mL) was added and the solution
stirred for a few minutes to precipitate the zinc salts. The
solution was decanted from the residue, washed successively with
H.sub.2O, a cold saturated NaHCO.sub.3 solution and brine, dried
(MgSO.sub.4), filtered and concentrated to provide 275 mg of a
residue. The residue was taken up in acetic acid (3 mL) and Zn
powder (115 mg, 1.8 mmol) was added. The mixture was stirred at
room temperature for 30 minutes and then heated to 120.degree. C.
for 2 hrs. After cooling to room temperature, the reaction mixture
was filtered through diatomaceous earth, and washed with ethyl
acetate. The filtrate was washed with H.sub.2O and brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel eluting with 10% ethyl acetate in
hexanes to provide the title compound as a colorless oil (59 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.16-3.27 (m, 2H),
3.47-3.57 (m, 2H), 3.66 (p, J=6 Hz, 1H), 6.98 (dd, J=9 Hz, J=3 Hz,
1H), 7.07 (dd, J=9 Hz, J=3 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H);
(DCI/NH.sub.3) m/z 243 (M+H).sup.+.
Example 22C
3-(4-Bromo-3-fluoro-phenyl)-cis-cyclobutanol
[0267] The title compound was prepared using the procedure
described in Example 1A, substituting the product from Example 22B
for 3-(4-bromo-phenyl)-cyclobutanone. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 2.0 (m, 2H), 2.78 (m, 2H), 2.92 (p, J=6 Hz,
1H), 4.28 (p, J=6 Hz, 1H), 6.88 (dd, J=7.5 Hz, J=3 Hz, 1H), 6.98
(dd, J=7.5 Hz, J=3 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H); (DCI/NH.sub.3)
m/z 262 (M+NH.sub.4).sup.+.
Example 22D
1-[3-(4-Bromo-3-fluoro-phenyl)-trans-cyclobutyl]-(2R)-2-methyl-pyrrolidine
[0268] The title compound was prepared using the procedure
described in Example 1B except substituting the product from
Example 22C for the product from Example 1A. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.12 (d, J=6 Hz, 3H), 1.48 (m, 1H), 1.78 (m,
2H), 2.00 (m, 1H), 2.23 (m, 1H), 2.36 (m, 2H), 2.59 (m, 3H), 3.03
(m, 1H), 3.34 (m, 1H), 3.48 (m, 1H), 7.06 (dd, J=9 Hz, J=3 Hz, 1H),
7.17 (dd, J=9 Hz, J=3 Hz, 1H), 7.53 (t, J=9 Hz, 1H); (DCI/NH.sub.3)
m/z 312 (M+H).sup.+.
Example 22E
5-{2-Fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-
-pyrimidine
[0269] The title compound was prepared using the procedure
described in Example 1C except substituting the product from
Example 22D for the product from Example 1B and substituting
pyrimidine-5-boronic acid for 4-cyanophenylboronic acid. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. 1.16 (d, J=6 Hz, 3H), 1.50 (m,
1H), 1.82 (m, 2H), 2.05 (m, 1H), 2.32 (m, 1H), 2.45 (m, 2H), 2.68
(m, 3H), 3.09 (m, 1H), 3.44 (m, 1H), 3.60 (m, 1H), 7.31 (t, J=9 Hz,
2H), 7.58 (t, J=9 Hz, 1H), 9.0 (s, 2H), 9.14 (s, 1H);
(DCI/NH.sub.3) m/z 312 (M+H).sup.+.
Example 23
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-car-
bonitrile
Example 23A
3-(4-Bromo-phenyl)-trans-cyclobutanecarbaldehyde (A1) and
3-(4-bromo-phenyl)-cis-cyclobutanecarbaldehyde (A2)
[0270] To a solution of diethyl isocyanomethylphosphonate (0.86 mL,
5.3 mmol) in anhydrous ether (45 mL) at -78.degree. C. under
nitrogen was added n-butyl lithium (2.13 mL, 2.5 M in hexane) and
the resulting mixture was stirred at -78.degree. C. for 1 hr. Then,
3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.4 mmol) in anhydrous ether
(15 mL) was added dropwise over 30 minutes. The reaction mixture
was allowed to warm to ambient temperature and stirred 16 hours.
Concentrated hydrochloric acid (9.5 mL) was added dropwise and the
reaction mixture was stirred at room temperature for 5 hrs. The
mixture was partitioned between ethyl acetate and water. The layers
were separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel eluting with 2-3% ethyl acetate in
hexanes to provide 3-(4-bromo-phenyl)-trans-cyclobutanecarbaldehyde
(281 mg, 27%) as the faster eluting isomer (A1) and
3-(4-bromo-phenyl)-cis-cyclobutanecarbaldehyde (508 mg, 48%) as the
slower eluting isomer (A2). A1: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 2.37 (m, 2H), 2.72 (m, 2H), 3.16 (m, 1H), 3.53 (p, J=6 Hz,
1H), 7.09 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 9.95 (s, 1H);
(DCI/NH.sub.3) m/z 239 (M+H).sup.+; A2: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 2.35 (m, 2H), 2.55 (m, 2H), 3.21 (m, 1H), 3.52
(p, J=6 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 9.73
(s, 1H); (DCI/NH.sub.3) m/z 239 (M+H).sup.+.
Example 23B
1-[3-(4-Bromo-phenyl)-cis-cyclobutylmethyl]-(2R)-2-methyl-pyrrolidine
[0271] A solution of the slower eluting isomer (A2) from Example
23A (508 mg, 2.1 mmol) in ethanol (15 mL) under nitrogen was
treated with NaBH.sub.4 (121 mg, 3.2 mmol) at 0.degree. C., warmed
to ambient temperature for 2 hrs and concentrated under reduced
pressure. The residue was dissolved in ethyl acetate, washed with
water, then washed with brine, and dried (MgSO.sub.4), filtered,
and concentrated. The residue was dissolved in dichloromethane (15
mL) and methanesulfonyl chloride (0.19 mL, 2.55 mmol) was added at
0.degree. C., followed with triethylamine (0.43 mL, 3.2 mmol). The
reaction was stirred at ambient temperature for 16 hours. The
mixture was diluted with dichloromethane, washed with H.sub.2O,
dried (MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel eluting with ethyl
acetate:dichloromethane:hexane (2:30:60) to provide the
corresponding mesylate (326 mg). The obtained mesylate was
dissolved in acetonitrile (15 mL). To this solution was added a
solution of (R)-2-methylpyrrolidine (prepared according to the
procedure that described in: R. Altenbach et al., WO 2004043458,
and Y. Pu et al., Organic Process Research & Development, 9
(1), 45-50, 2005) (230 mg, 2.07 mmol) in toluene, followed with
K.sub.2CO.sub.3 (850 mg, 6.16 mmol). The reaction was heated to
65.degree. C. and stirred 16 hours. Ethyl acetate (80 mL) was added
and the mixture was washed with water, then washed with brine, and
dried (MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel eluting with 2% (9:1
MeOH:concentrated NH.sub.4OH) in dichloromethane to provide the
title compound as a colorless oil (250 mg). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.12 (d, J=6 Hz, 3H), 1.40 (m, 1H), 1.76 (m,
4H), 1.94 (m, 1H), 2.16 (m, 2H), 2.32 (m, 1H), 2.52 (m, 3H), 2.93
(m, 1H), 3.12 (m, 1H), 3.36 (m, 1H), 7.12 (d, J=9 Hz, 2H), 7.40 (d,
J=9 Hz, 2H); (DCI/NH.sub.3) m/z 308 (M+H).sup.+.
Example 23C
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-car-
bonitrile
[0272] A solution of the product from Example 23B (30 mg, 0.1
mmol), 4-cyanophenylboronic acid (22 mg, 0.15 mmol), potassium
carbonate (41 mg, 0.3 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (6 mg, 5 .mu.mol) in
isopropyl alcohol (2 mL) under an atmosphere of nitrogen was heated
at 90.degree. C. for 5 hrs. The reaction mixture was cooled to
ambient temperature. Water (2 mL) was added and the mixture was
extracted with ethyl acetate (5 mL). The organic layer was washed
with brine, dried (MgSO.sub.4), filtered and concentrated. The
resulting oil was purified on preparative HPLC on a Waters.TM.
Symmetry.RTM. C8 column (25 mm.times.100 mm, 7 .mu.m particle size)
using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over
8 min (10 min run time) at a flow rate of 40 mL/min to provide 20
mg of the title compound as a trifluoroacetic acid salt. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. 1.46 (d, J=6 Hz, 3H), 1.74 (m,
1H), 2.08 (m, 4H), 2.35 (m, 1H), 2.68 (m, 3H), 3.09 (m, 1H), 3.18
(m, 1H), 3.47 (m, 3H), 3.68 (m, 1H), 7.39 (d, J=9 Hz, 2H), 7.62 (d,
J=9 Hz, 2H), 7.78 (s, 4H); (DCI/NH.sub.3) m/z 331 (M+H).sup.+.
Example 24
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-ylmethyl]-trans-cyclobutyl}-biphenyl-4-c-
arbonitrile
Example 24A
1-[3-(4-Bromo-phenyl)-trans-cyclobutylmethyl]-(2R)-2-methyl-pyrrolidine
[0273] The title compound was prepared using the procedure
described in Example 23B substituting the faster eluting isomer
(A1) from Example 23A for the slower eluting isomer (A2) from
Example 23A. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.18 (d, J=6
Hz, 3H), 1.44 (m, 1H), 1.79 (m, 2H), 2.02 (m, 1H), 2.27 (m, 7H),
2.60 (m, 1H), 3.13 (m, 2H), 3.54 (m, 1H), 7.20 (d, J=9 Hz, 2H),
7.43 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 308 (M+H).sup.+.
Example 24B
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-ylmethyl]-trans-cyclobutyl}-biphenyl-4-c-
arbonitrile
[0274] The trifluoroacetic acid salt of the title compound was
prepared using the procedure described in Example 23C except
substituting the product from Example 24A for the product from
Example 23B. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.48 (d, J=6
Hz, 3H), 1.75 (m, 1H), 2.10 (m, 2H), 2.39 (m, 3H), 2.48 (m, 2H),
2.83 (m, 1H), 3.22 (m, 2H), 3.51 (m, 1H), 3.67 (m, 3H), 7.43 (d,
J=9 Hz, 2H), 7.66 (d, J=9 Hz, 2H), 7.80 (s, 4H); (DCI/NH.sub.3) m/z
331 (M+H).sup.+.
Example 25
4'-{3-[(2S)-2-Methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-car-
bonitrile
Example 25A
1-[3-(4-bromo-phenyl)-cis-cyclobutylmethyl]-2-methyl-pyrrolidine
[0275] The title compound was prepared using the procedure
described in Example 23B except substituting
(S)-2-methylpyrrolidine for (R)-2-methyl pyrrolidine. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.12 (d, J=6 Hz, 3H), 1.40 (m, 1H),
1.76 (m, 4H), 1.94 (m, 1H), 2.16 (m, 2H), 2.32 (m, 1H), 2.52 (m,
3H), 2.93 (m, 1H), 3.12 (m, 1H), 3.36 (m, 1H), 7.12 (d, J=9 Hz,
2H), 7.40 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 308 (M+H).sup.+.
Example 25B
4'-{3-[(2S)-2-Methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-ca-
rbonitrile
[0276] The title compound was prepared using the procedure
described in Example 23C except substituting the product from
Example 25A for the product from Example 23B. The obtained
trifluoroacetic acid salt was dissolved in water, treated with NaOH
(10%), extracted with dichloromethane and separated. The organic
was dried (MgSO.sub.4), filtered, and concentrated to provide the
title compound as a colorless oil. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.25 (d, J=6 Hz, 3H), 1.54 (m, 1H), 1.89 (m,
5H), 2.12 (m, 1H), 2.61 (m, 5H), 3.15 (m, 2H), 3.50 (m, 1H), 7.35
(d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, 2H), 7.79 (s, 4H); (DCI/NH.sub.3)
m/z 331 (M+H).sup.+.
Example 26
2,6-Difluoro-3-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phen-
yl}-pyridine
[0277] The trifluoroacetic acid salt of the title compound was
prepared using the procedure described in Example 23C except
substituting 2,6-difluoropyridine-3-boronic acid (CAS #
136466-94-9) for 4-cyanophenylboronic acid. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.46 (d, J=6 Hz, 3H), 1.73 (m, 1H), 2.07 (m,
4H), 2.33 (m, 1H), 2.68 (m, 3H), 3.09 (m, 1H), 3.18 (m, 1H), 3.45
(m, 2H), 3.57 (m, 1H), 3.67 (m, 1H), 7.07 (dd, J=9 Hz, J=3 Hz, 1H),
7.37 (d, J=9 Hz, 2H), 7.51 (dd, J=9 Hz, J=3 Hz, 2H), 8.14 (dd, J=12
Hz, J=6 Hz, 1H); (DCI/NH.sub.3) m/z 343 (M+H).sup.+.
Example 27
5-{4-[3-(2-Methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidin-
e
[0278] The trifluoroacetic acid salt of the title compound was
prepared using the procedure described in Example 23C except
substituting 5-pyrimidineboronic acid (CAS # 109299-78-7) for
4-cyanophenylboronic acid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.46 (d, J=6 Hz, 3H), 1.74 (m, 1H), 2.07 (m, 4H), 2.33 (m,
1H), 2.69 (m, 3H), 3.08 (m, 1H), 3.19 (m, 1H), 3.45 (m, 2H), 3.58
(m, 1H), 3.68 (m, 1H), 7.43 (d, J=9 Hz, 2H), 7.68 (d, J=9 Hz, 2H),
9.05 (s, 2H), 9.12 (s, 1H); (DCI/NH.sub.3) m/z 308 (M+H).sup.+.
Example 28
4'-[3-(2-Methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-biphenyl-4-carbonit-
rile
Example 28A
1-[3-(4-bromo-phenyl)-cis-cyclobutylmethyl]-2-methyl-pyrrolidine
[0279] The title compound was prepared using the procedure
described in Example 23B except substituting 2-methylpyrrolidine
for (R)-2-methylpyrrolidine.
Example 28B
4'-[3-(2-Methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-biphenyl-4-carbonit-
rile
[0280] The title compound was prepared using the procedure
described in Example 23C, except substituting the product from
Example 28A for the product from Example 23B. The obtained
trifluoroacetic acid salt was dissolved in water, treated with NaOH
(10%), extracted with dichloromethane, and separated. The organic
layer was dried (MgSO.sub.4), filtered, and concentrated to provide
the title compound as a colorless oil. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.32 (d, J=6 Hz, 3H), 1.62 (m, 1H), 1.96 (m,
4H), 2.18 (m, 1H), 2.59 (m, 3H), 2.79 (m, 1H), 3.05 (m, 1H), 3.24
(m, 2H), 3.45 (m, 1H), 3.52 (m, 1H), 7.36 (d, J=9 Hz, 2H), 7.63 (d,
J=9 Hz, 2H), 7.78 (s, 4H); (DCI/NH.sub.3) m/z 331 (M+H).sup.+.
Example 29
1,3,5-Trimethyl-4-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobut-
yl]-phenyl}-1H-pyrazole
[0281] The title compound was prepared using the procedure
described in Example 23C substituting the product from Example 21A
for 4-cyanophenylboronic acid. The obtained trifluoroacetic acid
salt was dissolved in water, treated with NaOH (10%), extracted
with dichloromethane and separated. The organic was dried (MgSO4),
filtered and concentrated to provide the title compound as a
colorless oil. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.14 (d,
J=6 Hz, 3H), 1.44 (m, 1H), 1.80 (m, 4H), 1.96 (m, 1H), 2.15 (s,
3H), 2.18 (m, 2H), 2.22 (s, 3 H), 2.36 (m, 1H), 2.55 (m, 3H), 2.95
(m, 1H), 3.16 (m, 1H), 3.43 (m, 1H), 3.74 (s, 3H), 7.16 (d, J=9 Hz,
2H), 7.26 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 338 (M+H).sup.+.
Example 30
2-{4-[3-({2R}-2-Methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H-p-
yridazin-3-one
[0282] A solution of the product from Example 23B (49 mg, 0.16
mmol), 2H-pyridazin-3-one (30 mg, 0.3 mmol),
trans-(1R,2R)--N,N'-bismethyl-1,2-cyclohexane diamine (45 mg, 0.32
mmol), CuI (30 mg, 0.16 mmol), and K.sub.2CO.sub.3 (65 mg, 0.48
mmol) in dioxane (3 mL) was heated in a microwave reactor to
190.degree. C. for 5 hrs. The reaction mixture was cooled to
ambient temperature and diluted with ethyl acetate (25 mL). The
mixture was washed with H.sub.2O, brine, dried with magnesium
sulfate, filtered, and concentrated. The residue was
chromatographed on silica gel eluting with a gradient of 2-5% (9:1
MeOH:concentrated NH.sub.4OH) in dichloromethane/ethyl
acetate/hexanes (1:1:1) to provide 20 mg of the title compound.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.45 (d, J=6 Hz, 3H),
1.73 (m, 1H), 2.07 (m, 4H), 2.33 (m, 1H), 2.68 (m, 3H), 3.09 (m,
1H), 3.19 (m, 1H), 3.45 (m, 2H), 3.64 (m, 2H), 7.08 (dd, J=9 Hz,
J=3 Hz, 1H), 7.38 (d, J=9 Hz, 2H), 7.49 (m, 3H), 7.08 (dd, J=3 Hz,
J=1 Hz, 1H); (DCI/NH.sub.3) m/z 324 (M+H).sup.+.
Example 31
2-Methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-ph-
enyl}-pyrimidine
[0283] The title compound was prepared using the procedure
described in Example 23C except substituting
2-methoxy-5-pyrimidineboronic acid (Frontier Scientific, Inc.,
Logan, Utah, USA) for 4-cyanophenylboronic acid. The obtained
trifluoroacetic acid salt was dissolved in water, treated with NaOH
(10%), extracted with dichloromethane and separated. The organic
was dried (MgSO.sub.4), filtered and concentrated to provide the
title compound as a colorless oil. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.32 (d, J=6 Hz, 3H), 1.61 (m, 1H), 1.95 (m,
4H), 2.17 (m, 1H), 2.64 (m, 5H), 3.04 (m, 1H), 3.23 (m, 1H), 3.44
(m, 1H), 3.53 (m, 1H), 4.95 (s, 3H), 7.36 (d, J=9 Hz, 2H), 7.57 (d,
J=9 Hz, 2H), 8.80 (s, 2H); (DCI/NH.sub.3) m/z 338 (M+H).sup.+.
Example 32
2,4-Dimethoxy-5-{4-[3-({2
R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine
[0284] The title compound was prepared using the procedure
described in Example 23C except substituting
2,4-dimethoxy-5-pyrimidineboronic acid (CAS # 89641-18-9) for
4-cyanophenylboronic acid. The obtained trifluoroacetic acid salt
was dissolved in water, treated with NaOH (10%), extracted with
dichloromethane and separated. The organic was dried (MgSO.sub.4),
filtered and concentrated to provide the title compound as a
colorless oil. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.14 (d,
J=6 Hz, 3H), 1.42 (m, 1H), 1.77 (m, 4H), 1.96 (m, 1H), 2.19 (m,
2H), 2.34 (m, 1H), 2.55 (m, 3H), 2.94 (m, 1H), 3.15 (m, 1H), 3.43
(m, 1H), 4.03 (s, 6H), 7.26 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H),
8.23 (s, 1H); (DCI/NH.sub.3) m/z 368 (M+H).sup.+.
Example 33
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-cis-cyclobutylmethyl}-biphenyl-4-car-
bonitrile
Example 33A
3-(4-Bromo-benzyl)-2,2-dichloro-cyclobutanone
[0285] To a solution of 1-allyl-4-bromo-benzene (400 mg, 2 mmol)
and activated Zn--Cu (200 mg, 3 mmol) in anhydrous ether (30 mL)
was added dropwise a mixture of phosphorus oxychloride (0.3 mL, 3.2
mmol) and trichloroacetyl chloride (0.34 mL, 3 mol) in anhydrous
ether (10 mL). After the addition, the reaction was stirred at room
temperature overnight. The reaction mixture was filtered through
diatomaceous earth and washed with ether. The ethereal solution was
concentrated in vacuo to ca. 1/4 of its original volume. Pentane
(100 mL) was added and the solution stirred for a few minutes to
precipitate the zinc salts. The solution was decanted from the
residue, washed successively with H.sub.2O, a cold saturated
NaHCO.sub.3 solution and brine, dried (MgSO.sub.4), filtered and
concentrated to provide 275 mg of a residue. Chromatography of the
residue on silica gel eluting with 6% ethyl acetate in hexanes
afforded the title compound as the white solid (115 mg, 18%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.8 (dd, J=15 Hz, J=6 Hz,
1H), 3.05 (dd, J=15 Hz, J=6 Hz, 1H), 3.18 (m, 1H), 3.30 (m, 2H),
7.12 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 308
(M+H).sup.+.
Example 33B
3-(4-Bromo-benzyl)-cyclobutanone
[0286] A solution of the product from Example 33A (115 mg, 0.37
mmol) in acetic acid (4 mL) was treated with Zn powder (60 mg, 0.93
mm) at room temperature and stirred for 1 hr and then heated to
120.degree. C. for 2 hrs. The reaction mixture was cooled to room
temperature, filtered through a layer of diatomaceous earth and
washed with ethyl acetate. The filtrate was washed with H.sub.2O,
brine, dried (MgSO.sub.4), filtered and concentrated. The residue
was chromatographed on silica gel eluting with 10% ethyl acetate in
hexanes to provide the title compound as a white solid (82 mg,
95%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.66-2.81 (m, 3H),
2.86 (d, J=6 Hz, 2H), 3.08-3.19 (m, 2H), 7.06 (d, J=9 Hz, 2H), 7.43
(d, J=9 Hz, 2H); (DCI/NH.sub.3) m/z 239 (M+H).sup.+.
Example 33C
1-[3-(4-Bromo-benzyl)-cis-cyclobutyl]-(2R)-2-methyl-pyrrolidine
[0287] To a solution of the product from Example 33B (80 mg, 0.34
mmol) in ethanol (8 mL) was added (R)-2-methylpyrrolidine (prepared
according to the procedure that described in: R. Altenbach et al.,
WO 2004043458, and Y. Pu et al., Organic Process Research &
Development, 9 (1), 45-50, 2005) (57 mg, 0.67 mmol) in toluene (3
mL) followed with dropwise addition of borane-pyridine complex (52
.mu.l, 0.51 mmol) in ethanol (2 mL). The reaction was stirred at
room temperature for 3 hrs and concentrated under reduced pressure.
The resulting residue was chromatographed on silica gel eluting
with a gradient of 1% to 2% (9:1 MeOH:concentrated NH.sub.4OH) in
dichloromethane to provide the title compound (45 mg) and the
corresponding trans isomer (19 mg). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.17 (d, J=6 Hz, 3H), 1.50 (m, 1H), 1.70 (m,
4H), 2.04 (m, 1H), 2.27 (m, 3H), 2.46 (m, 1H), 2.68 (d, J=6 Hz,
2H), 2.70 (m, 1H), 3.07 (m, 2H), 7.07 (d, J=9 Hz, 2H), 7.39 (d, J=9
Hz, 2H); (DCI/NH.sub.3) m/z 308, 310.
Example 33D
4'-{3-[(2R)-2-Methyl-pyrrolidin-1-yl]-cis-cyclobutylmethyl}-biphenyl-4-car-
bonitrile
[0288] The title compound was prepared using the procedure
described in Example 1C except substituting the product from
Example 33C for the product from Example 1B. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.1.24 (d, J=6 Hz, 3H), 1.60 (m, 1H), 1.86 (m,
4H), 2.14 (m, 1H), 2.35 (m, 3H), 2.66 (m, 1H), 2.79 (d, J=6 Hz,
2H), 2.81 (m, 1H), 3.21 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.60 (d, J=9
Hz, 2H), 7.78 (s, 4H); (DCI/NH.sub.3) m/z 331 (M+H).sup.+.
Example 34
Determination of Biological Activity
[0289] To determine the effectiveness of representative compounds
of this invention as histamine-3 receptor ligands (H.sub.3 receptor
ligands), the following tests were conducted according to methods
previously described (European Journal of Pharmacology, 188:219-227
(1990); Journal of Pharmacology and Experimental Therapeutics,
275:598-604 (1995); Journal of Pharmacology and Experimental
Therapeutics, 276:1009-1015 (1996); and Biochemical Pharmacology,
22:3099-3108 (1973)).
[0290] Briefly, male Sprague-Dawley rat brain cortices were
homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA
containing protease inhibitor cocktail (Calbiochem) using a
polytron set at 20,500 rpm. Homogenates were centrifuged for 20
minutes at 40,000.times.g. The supernatant was decanted, and
pellets were weighed. The pellet was resuspended by polytron
homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease
inhibitors and centrifuged for 20 minutes at 40,000.times.g. The
membrane pellet was resuspended in 6.25 volumes (per gram wet
weight of pellet) of 50 mM Tris-HCl/5 mM EDTA with protease
inhibitors and aliquots flash frozen in liquid N.sub.2 and stored
at -70.degree. C. until used in assays. Rat cortical membranes (12
mg wet weight/tube) were incubated with
(3H)--N-.alpha.-methylhistamine (.about.0.6 nM) with or without
H.sub.3 receptor antagonists in a total incubation volume of 0.5 mL
of 50 mM Tris-HCl/5 mM EDTA (pH 7.7). Test compounds were dissolved
in DMSO to provide a 20 mM solution, serially diluted and then
added to the incubation mixtures prior to initiating the incubation
assay by addition of the membranes. Thioperamide (3 .mu.M) was used
to determine nonspecific binding. Binding incubations were
conducted for 30 minutes at 25.degree. C. and terminated by
addition of 2 mL of ice cold 50 mM Tris-HCl (pH 7.7) and filtration
through 0.3% polyethylenimine-soaked Unifilter plates (Packard).
These filters were washed 4 additional times with 2 mL of ice-cold
50 mM Tris-HCl and dried for 1 hour. Radioactivity was determined
using liquid scintillation counting techniques. Results were
analyzed by Hill transformation and K.sub.i values were determined
using the Cheng-Prusoff equation.
[0291] Generally, representative compounds of the invention
demonstrated binding affinities in the above assay from about 0.05
nM to about 150 nM. Preferred compounds of the invention bound to
histamine-3 receptors with binding affinities from about 0.05 nM to
about 10 nM. More preferred compounds of the invention bound to
histamine-3 receptors with binding affinities from about 0.05 nM to
about 0.2 nM.
[0292] Compounds of the invention are histamine-3 receptor ligands
that modulate function of the histamine-3 receptor by altering the
activity of the receptor. These compounds may be inverse agonists
that inhibit the basal activity of the receptor or they may be
antagonists that completely block the action of receptor-activating
agonists. These compounds may also be partial agonists that
partially block or partially activate the histamine-3 receptor or
they may be agonists that activate the receptor.
[0293] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations, or methods, or any combination of such
changes and modifications of use of the invention, may be made
without departing from the spirit and scope thereof.
* * * * *