U.S. patent application number 10/294814 was filed with the patent office on 2003-10-16 for azetidinyl diamines useful as ligands of the nociceptin receptor orl-1.
This patent application is currently assigned to Schering Corporation. Invention is credited to Burnett, Duane A., Caplen, Mary Ann, Czarniecki, Michael F., Domalksi, Martin S., Ho, Ginny D., Tulshian, Deen, Wu, Wen-Lian.
Application Number | 20030195185 10/294814 |
Document ID | / |
Family ID | 23297560 |
Filed Date | 2003-10-16 |
United States Patent
Application |
20030195185 |
Kind Code |
A1 |
Burnett, Duane A. ; et
al. |
October 16, 2003 |
Azetidinyl diamines useful as ligands of the nociceptin receptor
ORL-1
Abstract
Disclosed are nociceptin ORL-1 receptor agonists of the formula
1 wherein: (a) R.sub.1 is optionally substituted alkyl, fluorenyl,
pyrimidinyl or optionally substituted piperidinyl; R.sub.2 is H;
and R.sub.3 is --C(H)(R)--NR.sub.7R.sub.8; R is H, optionally
substituted aryl or arylalkyl, or heteroaryl; R.sub.7 is
--(CH.sub.2).sub.xR.sub.9, optionally substituted
tetrahydronaphthyl, or cycloalkyl; and R.sup.8 is H; or R.sub.7 and
R.sub.8 together form a substituted piperidinyl or piperazinyl
ring; x is 0-10; and R.sub.9 is H, alkoxy, optionally substituted
phenyl, naphthyl, heteroaryl, pyrrolidinyl, pyrrolidonyl,
optionally substituted piperidinyl or diphenylmethyl; or (b)
R.sub.2is --NHR.sub.7or 2 and R.sub.3 is H; pharmaceutical
compositions; and methods of using the compounds to treat cough and
pain.
Inventors: |
Burnett, Duane A.;
(Bernardsville, NJ) ; Caplen, Mary Ann;
(Sayreville, NJ) ; Czarniecki, Michael F.;
(Watchung, NJ) ; Domalksi, Martin S.; (Verona,
NJ) ; Ho, Ginny D.; (Murray Hill, NJ) ;
Tulshian, Deen; (Lebanon, NJ) ; Wu, Wen-Lian;
(Edison, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
23297560 |
Appl. No.: |
10/294814 |
Filed: |
November 14, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60332284 |
Nov 16, 2001 |
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Current U.S.
Class: |
514/210.01 ;
514/210.2; 544/333; 546/207; 548/950 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 25/24 20180101; C07D 401/04 20130101; C07D 205/04 20130101;
A61P 25/22 20180101; A61P 11/08 20180101; A61P 25/00 20180101; C07D
401/06 20130101; C07D 405/06 20130101; A61P 11/06 20180101; A61P
25/32 20180101; C07D 233/56 20130101; A61P 11/14 20180101; A61P
11/10 20180101; C07D 417/06 20130101; C07D 249/08 20130101; C07D
401/12 20130101; C07D 231/12 20130101; C07D 405/14 20130101; C07D
401/14 20130101; A61P 11/12 20180101; C07D 405/12 20130101; C07D
403/12 20130101; A61P 11/00 20180101; C07D 403/04 20130101 |
Class at
Publication: |
514/210.01 ;
514/210.2; 548/950; 546/207; 544/333 |
International
Class: |
A61K 031/506; A61K
031/454; A61K 031/397; C07D 43/02; C07D 205/00 |
Claims
What is claimed is:
1. A compound represented by the formula 171or a pharmaceutically
acceptable salt or solvate thereof, or a diastereomer or enantiomer
thereof, wherein: (a) R.sub.1 is
--(CH.sub.2).sub.nCHR.sub.4R.sub.5, fluorenyl, pyrimidinyl or 172n
is 0, 1, 2 or 3; R.sub.2 is H; and R.sub.3 is
--C(H)(R)--NR.sub.7R.sub.8; R is H, aryl, R.sub.6-aryl,
aryl(CH.sub.2).sub.1-2, R.sub.6-aryl(CH.sub.2).sub.1-2 or
heteroaryl; R.sub.4 is H, aryl, R.sub.6-aryl, heteroaryl,
C.sub.1-6alkyl, C.sub.3-6 cycloalkyl or C.sub.2-6 alkenyl; R.sub.5
is aryl, R.sub.6-aryl, heteroaryl, C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, C.sub.2-6 alkenyl or fluorenyl, provided that when
R.sub.4 and R.sub.5 are each phenyl, R is not phenyl or
R.sub.6-phenyl; or R.sub.4 is H and R.sub.5 is tetrahydronaphthyl
or tetrahydronaphthyl substituted with 1 or 2 substituents selected
from the group consisting of halogen, C.sub.1-6 alkoxy, hydroxy,
C.sub.1-6 alkyl and trihalo(C.sub.1-6)alkyl; R.sub.6 is 1 or 2
substituents independently selected from the group consisting of
halogen, C.sub.1-6 alkoxy, hydroxy, phenyl, phenoxy, C.sub.1-6
alkyl, trihalo(C.sub.1-6)alkyl, amino, amido, --NO.sub.2, naphthyl,
benzoyl and benzyloxy, or 2 adjacent ring carbon atoms can be
substituted by methylenedioxy; R.sub.7 is
--(CH.sub.2).sub.xR.sub.9, tetrahydronaphthyl, tetrahydronaphthyl
substituted with 1 or 2 R.sub.10 groups, or C.sub.5-C.sub.7
cycloalkyl; and R.sup.8 is H; or R.sub.7 and R.sub.8 together form
a ring of the formula 173x is 0to 10; R.sub.9 is H, C.sub.1-C.sub.6
alkoxy, phenyl, phenyl substituted with 1 or 2 R.sub.10 groups,
naphthyl, pyridyl, imidazolyl, furanyl, pyrrolidinyl, pyrrolidonyl,
piperidinyl, N--(C.sub.1-C.sub.6 alkyl)-piperidinyl,
N-aryl(C.sub.1-C.sub.6 alkyl)piperidinyl or diphenylmethyl;
R.sub.10 is independently selected from the group consisting of
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, --OCF.sub.3
and methylenedioxy; R.sub.11 is aryl(C.sub.1-C.sub.6)alkyl,
di-aryl(C.sub.1-C.sub.6)alkyl or piperidinyl; and R.sub.17 is H,
C.sub.1-C.sub.6 alkyl or benzyl; or (b) R.sub.2is --NHR.sub.7 or
174and R.sub.3 is H; and R.sub.1 and R.sub.7 are as defined in
(a).
2. The compound of claim 1 wherein R.sub.1 is
--(CH.sub.2).sub.nCHR.sub.4R- .sub.5 and n is 0 or 1.
3. The compound of claim 2 wherein R.sub.4 is aryl, R.sub.6-aryl or
heteroaryl and R.sub.5 is aryl or C.sub.1-C.sub.6 alkyl.
4. The compound of claim 3 wherein n is 0, R.sub.4 is phenyl,
R.sub.6-phenyl or pyridyl and R.sub.5 is phenyl, R.sub.6-phenyl or
C.sub.2-C.sub.5 alkyl.
5. The compound of claim 4 wherein R.sub.6 is halogen.
6. The compound of claim 1 wherein R.sub.2 is H and R.sub.3 is
--C(H)(R)--NR.sub.7R.sub.8.
7. The compound of claim 6 wherein R is R.sub.6-phenyl, benzyl or
R.sub.6-benzyl.
8. The compound of claim 7 wherein R.sub.6 is 1 or 2 substituents
independently selected from the group consisting of --CF.sub.3,
halogen, benzyloxy and --CH.sub.3.
9. The compound of claim 7 wherein R.sub.7 and R.sub.8 are each
H.
10. The compound of claim 1 selected from the group consisting of
175176177178179
11. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 1 in combination
with a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising: a therapeutically
effective amount of at least one compound of claim 1; a
therapeutically effective amount of one or more additional agents
selected from the group consisting of: antihistamines,
5-lipoxy-genase inhibitors, leukotriene inhibitors, H.sub.3
inhibitors, .beta.-adrenergic receptor agonists, xanthine
derivatives, .alpha.-adrenergic receptor agonists, mast cell
stabilizers, anti-tussives, expectorants, NK.sub.1, NK.sub.2 and
NK.sub.3 tachykinin receptor antagonists, and GABA.sub.B agonists;
and a pharmaceutically acceptable carrier.
13. A method of treating cough, pain, anxiety, asthma, depression
or alcohol abuse comprising administering an effective amount of at
least one compound of claim 1 to a mammal in need of such
treatment.
14. The method of claim 13, wherein in addition to at least one
compound of claim I, an effective amount of one or more additional
agents for treating cough, allergy or asthma symptoms selected from
the group consisting of: antihistamines, 5-lipoxy-genase
inhibitors, leukotriene inhibitors, H.sub.3 inhibitors,
.beta.-adrenergic receptor agonists, xanthine derivatives,
.alpha.-adrenergic receptor agonists, mast cell stabilizers,
anti-tussives, expectorants, NK.sub.1, NK.sub.2 and NK.sub.3
tachykinin receptor antagonists, and GABA.sub.B agonists is
administered.
Description
BACKGROUND OF THE INVENTION
[0001] The G protein coupled nociceptin receptor known as ORL1 has
been shown to be involved in the modulation of pain in animal
models. It bears high homology to the classic opioid receptors
(.mu., k, .delta.), but has little cross reactivity with their
native ligands. Current opioid analgesics target these classic
opioid receptors, but have limiting side effect profiles (e.g.
tolerance, physical dependence, respiratory depression and decrease
of gastrointestinal function). ORL1 receptors are colocalized in
regions of the CNS similar to the opiod receptors, as well as in
the periphery.
[0002] Nociceptin, the endogenous ligand to ORL1, was discovered in
1995 and shown to be a peptide ligand that activates the ORL1
receptor, but not the classic opioid receptors. Initial reports
have suggested that nociceptin and the ORL1 receptor are involved
in a newly discovered pathway involved in the perception of pain.
Further reports have shown nociceptin to be analgesic when
administered intrathecally to rodents. The in vivo efficacy of
nociceptin in animal models of pain is similar to that of the
endogenous opioids. Nociceptin is also reported to act as an
anxiolytic agent when administered into the brains of rodents. The
in vivo efficacy in rodent anxiety models is similar to classic
benzodiazepine anxiolytics. In addition, nociceptin has been
recently reported to inhibit capsaicin induced bronchoconstriction
in isolated guinea pig lung tissue, suggesting a role for ORL1
agonists in the treatment of cough. Together, these data suggest
that nociceptin receptor agonists may have significant analgesic,
anxiolytic, or antitussive properties.
SUMMARY OF THE INVENTION
[0003] Compounds of the invention are represented by formula I:
3
[0004] or a pharmaceutically acceptable salt or solvate thereof, or
a diastereomer or enantiomer thereof, wherein:
[0005] (a) R.sub.1 is --(CH.sub.2).sub.nCHR.sub.4R.sub.5,
fluorenyl, pyrimidinyl or 4
[0006] n is 0, 1, 2 or 3;
[0007] R.sub.2 is H; and R.sub.3 is --C(H)(R)--NR.sub.7R.sub.8;
[0008] R is H, aryl, R.sub.6-aryl, aryl(CH.sub.2).sub.1-2,
R.sub.6-aryl(CH.sub.2).sub.1-2 or heteroaryl;
[0009] R.sub.4 is H, aryl, R.sub.6-aryl, heteroaryl, C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl or C.sub.2-6 alkenyl;
[0010] R.sub.5 is aryl, R.sub.6-aryl, heteroaryl, C.sub.1-6 alkyl,
C.sub.3-6 cycloalkyl, C.sub.2-6 alkenyl or fluorenyl, provided that
when R.sub.4 and R.sub.5 are each phenyl, R is not phenyl or
R.sub.6-phenyl;
[0011] or R.sub.4 is H and R.sub.5 is tetrahydronaphthyl or
tetrahydronaphthyl substituted with 1 or 2 substituents selected
from the group consisting of halogen, C.sub.1-6 alkoxy, hydroxy,
C.sub.1-6alkyl and trihalo(C.sub.1-6)alkyl;
[0012] R.sub.6 is 1 or 2 substituents independently selected from
the group consisting of halogen, C.sub.1-6alkoxy, hydroxy, phenyl,
phenoxy, C.sub.1-6alkyl, trihalo(C.sub.1-6)alkyl, amino, amido,
--NO.sub.2, naphthyl, benzoyl and benzyloxy, or 2 adjacent ring
carbon atoms can be substituted by methylenedioxy;
[0013] R.sub.7 is --(CH.sub.2).sub.xR.sub.9, tetrahydronaphthyl,
tetrahydronaphthyl substituted with 1 or 2 R.sub.10 groups, or
C.sub.5-C.sub.7 cycloalkyl; and R.sup.8 is H;
[0014] or R.sub.7 and R.sub.8 together form a ring of the formula
5
[0015] x is 0 to 10;
[0016] R.sub.9 is H, C.sub.1-C.sub.6 alkoxy, phenyl, phenyl
substituted with 1 or 2 R.sub.10 groups, naphthyl, pyridyl,
imidazolyl, furanyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,
N--(C.sub.1-C.sub.6 alkyl)-piperidinyl, N-aryl(C.sub.1-C.sub.6
alkyl)piperidinyl or diphenylmethyl;
[0017] R.sub.10 is independently selected from the group consisting
of halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl,
--OCF.sub.3 and methylenedioxy;
[0018] R.sub.11 is aryl(C.sub.1-C.sub.6)alkyl,
di-aryl(C.sub.1-C.sub.6)alk- yl or piperidinyl; and
[0019] R.sub.17 is H, C.sub.1-C.sub.6 alkyl or benzyl;
[0020] or
[0021] (b) R.sub.2 is --NHR.sub.7 or 6
[0022] and R.sub.3 is H; and
[0023] R.sub.1 and R.sub.7 are as defined in (a).
[0024] In another aspect, the invention relates to a pharmaceutical
composition comprising at least one compound of formula I and a
pharmaceutically acceptable carrier.
[0025] The compounds of the present invention are agonists of the
ORL-1 receptor, and therefore, in another aspect, the invention
relates to a method of treating cough, pain, anxiety, asthma,
alcohol abuse or depression, comprising administering to a mammal
in need of such treatment an effective amount of at least one
compound of formula I.
[0026] In another aspect, the invention relates to a method of
treating cough, comprising administering to a mammal in need of
such treatment: (a) an effective amount of at least one compound of
formula I; and (b) an effective amount of one or more additional
agents for treating cough, allergy or asthma symptoms selected from
the group consisting of: antihistamines, 5-lipoxygenase inhibitors,
leukotriene inhibitors, H.sub.3 inhibitors, .beta.-adrenergic
receptor agonists, xanthine derivatives, .alpha.-adrenergic
receptor agonists, mast cell stabilizers, anti-tussives,
expectorants, NK.sub.1, NK.sub.2 and NK.sub.3 tachykinin receptor
antagonists, and GABA.sub.B agonists.
[0027] In still another aspect, the invention relates to a
pharmaceutical composition comprising at least one compound of
formula I and one or more additional agents selected from the group
consisting of: antihistamines, 5-lipoxygenase inhibitors,
leukotriene inhibitors, H.sub.3 inhibitors, .beta.-adrenergic
receptor agonists, xanthine derivatives, .alpha.-adrenergic
receptor agonists, mast cell stabilizers, anti-tussives,
expectorants, NK.sub.1, NK.sub.2.sub..sub.2 and NK.sub.3.sub..sub.3
tachykinin receptor antagonists, and GABA.sub.B agonists.
DETAILED DESCRIPTION
[0028] Referring to formula I above, preferred are compounds of (a)
or (b) wherein R.sub.1 is --(CH.sub.2).sub.nCHR.sub.4R.sub.5 and n
is 0 or 1, more preferably 0. R.sub.4 is preferably aryl,
R.sub.6-aryl or heteroaryl, more preferably phenyl, R.sub.6-phenyl
or pyridyl. R.sub.5 is preferably aryl or C.sub.1-C.sub.6 alkyl,
more preferably phenyl, R.sub.6-phenyl or C.sub.2-C.sub.5 alkyl,
provided both R.sub.4 and R.sub.5 are not phenyl when R is
optionally substituted phenyl. When R.sub.6 is a substituent on
R.sub.4 or R.sub.5, it is preferably halogen, especially
fluoro.
[0029] Preferred are compounds of formula I (a), i.e., those
wherein R.sub.2 is H and R.sub.3 is --C(H)(R)--NR.sub.7R.sub.8. R
is preferably R.sub.6-phenyl, benzyl or R.sub.6-benzyl. When
R.sub.6 is a substituent on R, it is preferably 1 or 2 substituents
independently selected from the group consisting of --CF.sub.3,
halogen, benzyloxy and --CH.sub.3, wherein halogen is preferably
chloro or fluoro. R.sub.7 and R.sub.8 are preferably each H.
[0030] As used herein, the following terms are used as defined
below unless otherwise indicated:
[0031] alkyl represents straight and branched carbon chains
containing from 1 to 6 carbon atoms, for example methyl, ethyl,
propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl
and the like;
[0032] alkenyl represents an alkyl chain of 2 to 6 carbon atoms
comprising one or two double bonds in the chain, e.g., vinyl,
propenyl or butenyl;
[0033] alkoxy represents an alkyl moiety covalently bonded to an
adjacent structural element through an oxygen atom, for example,
methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like;
[0034] aryl represents a monoaromatic ring or a bicyclic fused
carbocyclic ring system of 6- to 10 carbon atoms, for example
phenyl and naphthyl;
[0035] cycloalkyl represents saturated carbocyclic rings of from 3
to 7 carbon atoms, as specified in the definitions;
[0036] halo represents fluoro, chloro, bromo and iodo;
[0037] heteroaryl means a single ring heteroaromatic group of 5 to
6 atoms comprised of 2 to 5 carbon atoms and 1 to 3 heteroatoms
independently selected from the group consisting of N, O and S,
provided that the rings do not include adjacent oxygen and/or
sulfur atoms. Examples of single-ring heteroaryl groups are
pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl,
thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.
N-Oxides are also contemplated, e.g. pyridyl N-oxide.
[0038] Certain compounds of the invention may exist in different
stereoisomeric forms (e.g., enantiomers, diastereoisomers and
atropisomers). The invention contemplates all such stereoisomers
both in pure form and in mixture, including racemic mixtures.
[0039] Certain compounds will be acidic in nature, e.g. those
compounds which possess a phenolic hydroxyl group. These compounds
may form pharmaceutically acceptable salts. Examples of such salts
may include sodium, potassium, calcium, aluminum, gold and silver
salts. Also contemplated are salts formed with pharmaceutically
acceptable amines such as ammonia, alkyl amines,
hydroxyalkylamines, N-methylglucamine and the like.
[0040] Certain basic compounds also form pharmaceutically
acceptable salts, e.g., acid addition salts. For example,
pyrido-nitrogen atoms may form salts with strong acid, while
compounds having basic substituents such as amino groups also form
salts with weaker acids. Examples of suitable acids for salt
formation are hydrochloric, sulfuric, phosphoric, acetic, citric,
oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,
maleic, methanesulfonic and other mineral and carboxylic acids well
known to those skilled in the art. The salts are prepared by
contacting the free base form with a sufficient amount of the
desired acid to produce a salt in the conventional manner. The free
base forms may be regenerated by treating the salt with a suitable
dilute aqueous base solution such as dilute aqueous NaOH, potassium
carbonate, ammonia and sodium bicarbonate. The free base forms
differ from their respective salt forms somewhat in certain
physical properties, such as solubility in polar solvents, but the
acid and base salts are otherwise equivalent to their respective
free base forms for purposes of the invention.
[0041] All such acid and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0042] Compounds of formula I can be prepared using procedures
known in the art. For example, compounds of formula I wherein
R.sub.3 is --C(H)(R)--NR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8
are each H and R is R.sub.6-phenyl can be prepared according to the
following overall synthetic scheme: 7
[0043] When R.sub.6 is an amino or hydroxy group, it must be
protected by a suitable protecting group by a method well known in
the art.
[0044] Following are details of the steps (A-K) in the above
procedure. The procedures are exemplified for specific compounds,
but those skilled in the art will recognize that other compounds of
formula I can be made by similar procedures.
[0045] The following abbreviations are used in this application: RT
(room temperature); Et.sub.2O (ether), EtOAc (ethyl acetate); Ph
(phenyl); Et (ethyl); and TFA (trifluoroacetic acid).
[0046] Step A: 8
[0047] To a solution of ethyl 2,4-dibromobutyrate (36.31 g, 0.132
mol) in CH.sub.3CN (140 ml) was added aminodiphenylmethane (73.59
g, 0.402 mol). The solution was stirred at RTfor 1 h, then heated
to 55.degree. C. for 20 h. The suspension was cooled to RT and the
precipitated salt was collected by filtration and washed with
Et.sub.2O. The combined filtrate and Et.sub.2O washings were
concentrated in vacuo and the residue dissolved in Et.sub.2O (400
ml). The solution was washed with saturated NaHCO.sub.3 (100 ml)
and the wash was extracted with Et.sub.2O (2.times.100 ml). The
combined ethereal solutions were washed with saturated NaCl (100
ml), dried over MgSO.sub.4, and concentrated in vacuo to give 49.99
g of an oil which slowly solidified. This material was purified by
SiO.sub.2 chromatography eluting with 2% EtOAc in hexanes
progressing to 10% EtOAc in hexanes. Concentration of the
appropriate fractions gave 25.67 g (66%) of the desired product as
a white solid. MS: calcd for C.sub.19H.sub.21NO.sub.2oH.sup.+
m/z=296.16, observed m/z=296.1 (M+1).sup.+.
[0048] The following compounds were prepared by an analogous
procedure:
1 9 Prep. R.sub.1 Analytical Data 1b PhCH.sub.2 MS calcd for
C.sub.13H.sub.17NO.sub.2oH.sup.+ m/z = 220.1 observed m/z = 220 (M
+ 1).sup.+ 1c CH.sub.2.dbd.CHCH.sub.2 MS calcd for
C.sub.9H.sub.15NO.sub.2oH.sup.+ m/z = 170.1 observed m/z = 170 (M +
1).sup.+ Step B: 10 11
[0049] To a stirred solution of 1a (7.00 g, 23.7 mmol) in dry THF
(50 ml) at -75.degree. C. under Ar was added a cooled (-78.degree.
C.) 1 M solution of DiBAL-H in toluene (28.4 ml, 28.4 mmol)
dropwise via a cannula over .about.1 h. The reaction was stirred
for 1 h at -70.degree. C. It was quenched by the careful addition
of several small portions of Na.sub.2SO.sub.4o(H.sub.2O).sub.10.
The reaction was stirred at RT, then diluted with EtOAc (200 ml).
It was filtered through Celite and concentrated in vacuo to give
5.98 g of a white solid. This material was triturated with 10%
EtOAc in hexanes to give the desired aldehyde 2a as a white solid
(3.09 g, 52%). MS: calc'd for C.sub.17H.sub.17NOoH.sup.+
m/z=252.14, observed m/z=252.20 (M+1).sup.+.
[0050] The following compounds were prepared by an analogous
procedure:
2 12 Prep. R.sub.1 Analytical Data 2b PhCH.sub.2 .sup.1H NMR
(400MHz, CDCl.sub.3) .delta. 9.47 (d, J= 3.9Hz, 1H, CHO), 7.25-7.40
(m, 5H, Ph), 3.60-3.90 (m, 3H), 2.95-3.30 (m, 2H), 2.00-2.40 (m,
2H) 2c CH.sub.2.dbd.CHCH.sub.2 .sup.1H NMR (400MHz, CDCl.sub.3)
.delta. 9.73 (d, J=2.6Hz, 1H, CHO), 5.75-5.90 (m, 1H), 5.10-5.30
(m, 2H), 2.90-3.80 (m, 5H), 2.00-2.40 (m, 2H) Step C: 13 14 15
[0051] A solution of 2a (15.00 g, 59.7 mmol) in dry THF(75 ml) was
cooled to -40.degree. C. underN.sub.2. To this solution was added a
0.5M solution of 3-chlorophenylmagnesium-bromide (155.2 ml, 77.6
mmol) in THF dropwise over 1.25 h. The reaction was stirred with
gradual warming to 0.degree. C. over 2.5 h. The reaction was
quenched by the dropwise addition of water (20 ml) while
maintaining the 0.degree. C. temperature. The reaction was warmed
to RT and additional water (150 ml) was added. The solution was
extracted with EtOAc (2.times.700 ml). The combined EtOAc layers
were washed with brine (200 ml) and dried over Na.sub.2SO.sub.4.
The solvent was removed in vacuo to give 20.78 g of a semisolid
residue. This residue was recrystallized from EtOH to give 8.76 g
of the erythro isomer 3a as a white solid. The mother liquor was
concentrated to give an orange oil. The resulting oil was purified
by flash chromatography over 500 g of SiO.sub.2, eluting with a
gradient of 3% EtOAc in hexanes, progressing slowly to 18% EtOAc in
hexanes. The less polar erythro isomer 3a eluted first to give
another 3.61 g, followed by 4.20 g of the more polar threo isomer
4a.
[0052] Analytical data for 3a: MS calcd for
C.sub.23H.sub.22ClNOoH.sup.+ m/z=364.15, observed m/z=364.1
(M+1).sup.+. Analytical data for 4a: MS calcd for
C.sub.23H.sub.22ClNOoH.sup.+ m/z=364.15, observed m/z=364.35
(M+1).sup.+
[0053] The following compounds were prepared by an analogous
procedure: 16
[0054] wherein
[0055] R.sub.1 and R.sub.6 are as defined in the table:
3 Prep. R.sub.1 R.sub.6 Analytical Data 3b PhCH.sub.2 3-CF.sub.3 MS
calcd for C.sub.18H.sub.18F.sub.3NOoH.sup.+ m/z=322.14 observed
m/z=322 (M+1).sup.+ 3c CH.sub.2.dbd. 3-CF.sub.3 MS calcd for
C.sub.14H.sub.16F.sub.3NOoH.sup.+ m/z=272.13 CHCH.sub.2 observed
m/z=272 (M+1).sup.+ 3d CH.sub.2.dbd. 3-Cl MS calcd for
C.sub.13H.sub.16ClNOoH.sup.+ m/z=238.10 CHCH.sub.2 observed m/z=238
(M+1).sup.+ 3e Ph.sub.2CH 3-CF.sub.3 MS calcd for
C.sub.24H.sub.22F.sub.3NOoH.sup.+ m/z=398.17 observed m/z=398.2
(M+1).sup.+ 3f Ph.sub.2CH 3-OCH.sub.3 MS calcd for
C.sub.24H.sub.25NO.sub.2oH.sup.+ m/z=360.20 observed m/z=360.3
(M+1).sup.+ 3g Ph.sub.2CH 3-CH.sub.3 MS calcd for
C.sub.24H.sub.25NOoH.sup.+ m/z=344.20 observed m/z=344 (M+1).sup.+
3h Ph.sub.2CH 4-OCH.sub.3 MS calcd for
C.sub.24H.sub.25NO.sub.2oH.sup.+ m/z=360.20 observed m/z=360
(M+1).sup.+ 3i Ph.sub.2CH 3-NH.sub.2 MS calcd for
C.sub.23H.sub.24N.sub.2OoH.sup.+ m/z=345.20 observed m/z=345
(M+1).sup.+ 3j Ph.sub.2CH 3-F MS calcd for C.sub.23H.sub.22FNOoH.s-
up.+ m/z=348.18 observed m/z=348 (M+1).sup.+ 3k Ph.sub.2CH 3-F-4-
MS calcd for C.sub.24H.sub.24FNOoH.sup.+ m/z=362.19 CH.sub.3
observed m/z=362.1 (M+1).sup.+ 3l Ph.sub.2CH 3,5-F.sub.2 MS calcd
for C.sub.23H.sub.21F.sub.2NOoH.sup.+ m/z=366.17 observed m/z=366
(M+1).sup.+ 3m Ph.sub.2CH 4-CH.sub.3 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51 (d, 2H, J=10), 7.47 (d, 2H, J=9),
7.34-7.42 (m, 4H), 7.25-7.41 (m, 2H), 7.08 (d, 2H, J=9), 7.00 (d,
2H, J=9), 4.60 (s, 1H, CHPh.sub.2), 3.87 (s, 1H), 3.51 (m, 1H),
3.37-3.44 (m, 2H), 2.77- 2.84 (m, 1H), 2.32 (s, 3H, Me), 2.20-2.31
(m, 1H), 1.04-1.12 (m, 1H) 3n Ph.sub.2CH 4-Cl .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51 (d, 2H, J=8), 7.47 (d, 2H, J=8), 7.34-7.40
(m, 4H), 7.28-7.31 (m, 2H), 7.25 (d, 2H, J=8), 7.07 (d, 2H, J=8),
4.61 (s, 1H, CHPh.sub.2), 3.96 (br s, 1H), 3.58 (dt, 1H, J=3, 8),
3.40-3.43 (m, 2H), 2.82 (q, 1H, J=9), 2.09-2.21 (m, 1H), 1.52 (dq,
1H, J=3, 8) 3o PhCH.sub.2 4-PhO .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.52 (d, 2H, J=8), 7.50 (d, 2H, J=8), 7.28-7.42 (m, 9H),
7.09-7.16 (m, 2H), 7.01 (d, 2H, J=8), 6.94 (d, 2H, J=8), 4.65 (s,
1H, CHPh.sub.2), 3.92 (s, 1H), 3.62 (dt, 1H, J=4, 8), 3.43-3.47 (m,
2H), 2.85 (q, 1H, J=4), 2.28-2.34 (m, 1H) 3p Ph.sub.2CH 2-CH.sub.3
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50-7.53 (m, 4H),
7.30-7.42 (m, 4H), 7.10-7.20 (m, 4H), 7.02 (d, 2H, J=8), 4.61 (s,
1H, CHPh.sub.2), 4.00 (s, 1H), 3.76 (d, 1H, J= 3), 3.63 (m, 1H),
3.45 (m, 1H), 2.81 (m, 1H), 2.36 (m, 1H), 1.85 (s, 3H), 1.52-1.57
(m, 1H) 4b PhCH.sub.2 3-CF.sub.3 MS calcd for
C.sub.18H.sub.18F.sub.3NOoH.sup.+ m/z=322.14 observed m/z=322
(M+1).sup.+ 4c CH.sub.2.dbd. 3-CF.sub.3 MS calcd for
C.sub.14H.sub.16F.sub.3NOoH.sup.+ m/z=272.13 CHCH.sub.2 observed
m/z=272 (M+1).sup.+ 4d CH.sub.2.dbd. 3-Cl MS calcd for
C.sub.13H.sub.16ClNOoH.sup.+ m/z=238.10 CHCH.sub.2 observed m/z=238
(M+1).sup.+ 4e Ph.sub.2CH 3-CF.sub.3 MS calcd for
C.sub.24H.sub.22F.sub.3NOoH.sup.+ m/z=398.17 observed m/z=398.2
(M+1).sup.+ 4f Ph.sub.2CH 3-OCH.sub.3 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.45 (d, 2H, J=9 Hz, ArH) 7.20-7.38 (m, 9H,
ArH) 6.86 (d, 1H, J=9 Hz, ArH) 6.78-6.82 (m, 2H, ArH) 4.56 (br s,
1H) 4.51 (d, 1H, J=4 Hz) 3.82 (s, 3H, OCH.sub.3) 3.65 (q, 1H, J=7
Hz) 3.30-3.38 (m, 1H) 2.84 (q, 1H, J=7 Hz) 2.34 (Br s, 1H) 2.00
(qu, 1H, J=7 Hz) 1.78- 1.88 (m, 1H) 4g Ph.sub.2CH 3-CH.sub.3
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45 (d, 2H, J=9 Hz, ArH)
7.18-7.38 (m, 9H, ArH) 7.15 (d, 1H, J=9 Hz, ArH) 6.98-7.03 (m, 2H,
ArH) 4.98 (br s, 1H) 4.45 (d, 1H, J=5 Hz) 3.56 (q, 1H, 5 Hz) 3.28
(m, 1H) 2.78 (q, 1H, 6 Hz) 2.30 (s, 3H, CH.sub.3) 1.86-1.97 (m, 1H)
1.68-1.78 (m, 1H) 4h Ph.sub.2CH 4-OCH.sub.3 -- 4j Ph.sub.2CH 3-F
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (d, 2H, J=9 Hz, ArH)
7.15-7.32 (m, 9H, ArH) 6.95 (d, 1H, J=9 Hz, ArH) 6.82-6.89 (m, 2H,
ArH) 4.48 (br s, 1H) 4.42-4.46 (m, 1H) 3.58 (q, 1H, J=5 Hz)
3.30-3.35 (m, 1H) 2.80 (q, 1H, J=7 Hz) 2.58 (br s, 1H) 1.92-2.05
(m, 1H 1.78-1.86 (m,1H) 4k Ph.sub.2CH 3-F-4- -- CH.sub.3 4l
Ph.sub.2CH 3,5-F.sub.2 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.12-7.35 (m, 10H, ArH) 6.53-6.66 (m, 3H, ArH) 4.48 (br s, 1H) 4.35
(br s, 1H) 3.60-3.67 (m, 1H) 3.30-3.40 (m, 1H) 2.80-2.89 (m, 1H)
2.65 (br s, 1H) 1.90-2.08 (m, 2H) 4m Ph.sub.2CH 4-CH.sub.3 .sup.1H
NMR (400MHz, CDCl.sub.3) .delta. 7.50 (d, 2H, J=10, ArH), 7.23-7.38
(m, 8H), 7.14 (d, 2H, J=9, ArH), 7.10 (d, 2H, J=9, ArH), 4.47-4.62
(br m, 2H), 3.52-3.63 (br m, 1H), 3.23-3.37 (br m, 1H), 2.73-2.86
(br m, 1H), 2.33 (s, 3H, Me), 1.89-2.00 (m, 2H), 1.71-1.82 (m, 1H)
4o PhCH.sub.2 4-PhO .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.54
(d, 2H, J=8), 7.28-7.36 (m, 9H), 7.18 (d, 2H, J=8), 7.04-7.10 (m,
2H), 6.96 (d, 2H, J=8), 6.88 (d, 2H, J=8), 4.52 (s, 1H,
CHPh.sub.2), 4.45 (d, 1H, J=8), 3.55 (q, 1H, J=4), 3.24-3.34 (m,
1H), 2.78 (q, 1h, J=4), 1.85-1.97 (m, 1H, 1.71-1.79 (m, 1H)
[0056] The following compounds were also prepared by an analogous
procedure: 17
[0057] wherein
[0058] R.sub.1 and R are as defined in the table (wherein Ph is
phenyl):
4 Prep. R.sub.1 R Analytical Data 3q Ph.sub.2CH PhCH.sub.2 MS calcd
for C.sub.24H.sub.25NOoH.sup.+ m/z=344.2 observed m/z=344
(M+1).sup.+ 3r Ph.sub.2CH 4-BnO- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.14-7.48 (m, PhCH.sub.2 17H), 6.86 (d, 2H, J=8), 4.99 (t,
2H, J=4), 4.52 (s, 1H, CHPh.sub.2), 3.92 (s, 1H), 3.66 (s, 1H),
3.52 (dt, 1H, J=4, 8), 3.33 (dt, 1H, J=4, 8), 2.71 (q, 1HO J=4),
2.21 (m, 1H), 1.72 (s, 2H), 1.39 (q, 1H, J=4) 4s Ph.sub.2CH 2- MS
calcd for C.sub.20H.sub.20N.sub.2OSoH.sup.+ m/z=337.14 thi-
observed m/z=337 (M+1).sup.+ azolyl 3ac+ Ph.sub.2CH 3,5-Cl.sub.2-
-- 4ac C.sub.6H.sub.3- (mix) CH.sub.2
[0059] Step D: 18
[0060] To an argon degassed solution of erythro alcohol 3a (2.00 g,
5.50 mmol) and triphenylphosphine (2.89 g, 11.0 mmol) in toluene
(27 ml) was added Zn(N.sub.3).sub.2o2Pyr complex (1.27 g, 4.13
mmol). To the resulting suspension at RT was added
diiso-propylazodicarboxylate (2.20 ml, 11.0 mmol) dropwise over 25
min. A slight exotherm was noted. The reaction was stirred at RT
for 1.5 h, filtered through Celite, and concentrated in vacuo to
give 8.23 g of a foamy residue. The residue was purified by
chromatography over 450 g SiO.sub.2. The erythro and threo azides
were eluted with a gradient starting with 0.5% EtOAc in hexanes and
progressing to 6% EtOAc in hexanes to give two main fractions.
Fraction 1 contained 0.96 g of a mixture of the erythro and threo
azides, 6a and 5a respectively. Fraction 2 contained 0.51 g of the
more polar threo azide, 5a.
[0061] Analytical data for 5a: MS calcd for
C.sub.23H.sub.21ClN.sub.4oH.su- p.+ m/z=389.15, observed m/z=389.15
(M+1).sup.+
[0062] The following compounds were prepared by an analogous
procedure:
5 19 20 Prep. R.sub.1 R.sub.6 Analytical Data 5b PhCH.sub.2
3-CF.sub.3 MS calcd for C.sub.18H.sub.17F.sub.3N.sub.4oH.sup.+ m/z
= 347.15 observed m/z = 347 (M + 1).sup.+ 5c
CH.sub.2.dbd.CHCH.sub.2 3-CF.sub.3 MS calcd for
C.sub.14H.sub.15F.sub.3N.sub.4oH.sup.+ m/z = 297.13 observed m/z =
297 (M + 1).sup.+ 5d CH.sub.2.dbd.CHCH.sub.2 3-Cl MS calcd for
C.sub.13H.sub.15ClN.sub.4oH.sup- .+ m/z = 263.11 observed m/z = 263
(M + 1).sup.+ 5e Ph.sub.2CH 3-CF.sub.3 .sup.1H NMR (400MHz,
CDCl.sub.3) .delta. 7.20-7.63 (m, 14H), 4.62 (s, 1H), 3.73 (m, 2H),
3.09 (m, 1H), 2.70 (q, 1H), 1.82 (m, 1H), 1.53 (m, 1H) 5f
Ph.sub.2CH 3-OCH.sub.3 MS calcd for
C.sub.24H.sub.24N.sub.4OoH.sup.+ m/z = 385.20 observed m/z = 385.1
(M + 1).sup.+ 5g Ph.sub.2CH 3-CH.sub.3 .sup.1H NMR (400MHZ,
CDCl.sub.3) .delta. 7.08-7.46 (m, 14H), 4.88 (s, 1H), 3.87 (m, 1H),
3.54 (d, 1H), 3.17 (m, 1H), 2.59 (q, 1H), 2.38 (s, 3H) 2.33 (m,
1H), 1.81 (m, 1H) 5h Ph.sub.2CH 4-OCH.sub.3 .sup.1H NMR (400MHz,
CDCl.sub.3) .delta. 7.14-7.50 (m, 12H), 6.88 (d, 2H), 4.18 (s, 1H),
3.89 (d, 1H), 3.83 (s, 3H), 3.58 (m, 1H), 3.13 (m, 1H), 2.68 (m,
1H), 1.66 (m, 2H) 5j Ph.sub.2CH 3-F .sup.1H NMR (400MHz,
CDCl.sub.3) .delta. 7.19-7.48 (m, 11H), 7.12 (m, 3H), 4.63 (s, 1H),
3.78 (d, 1H), 3.64 (m, 1H), 3.13 (m, 1H), 2.69 (q, 1H), 1.77 (m,
1H), 1.60 (m, 1H) 5k Ph.sub.2CH 3-F-4-CH.sub.3 .sup.1H NMR (400MHz,
CDCl.sub.3) .delta. 7.12-7.53 (m, 11H), 6.95 (d, 2H), 4.64 (s, 1H),
3.78 (d, 1H), 3.60 (m, 1H), 3.14 (m, 1H), 2.69 (q, 1H), 2.28 (s,
3H), 1.75 (m, 1H), 1.63 (m, 1H) 51 Ph.sub.2CH 3,5-F.sub.2 .sup.1H
NMR (400MHz, CDCl.sub.3) .delta. 7.20-7.48 (m, 10H), 6.88 (d, 2H),
6.76 (t, 1H), 4.60 (s, 1H), 3.65 (m, 2H), 3.15 (m, 1H), 2.70 (q,
1H), 1.83 (m, 1H), 1.57 (m, 1H) 5m Ph.sub.2CH 4-CH.sub.3 MS calcd
for C.sub.24H.sub.24N.sub.4oH.sup.+ m/z = 369.21 observed m/z =
369.2 (M + 1).sup.+ 5n Ph.sub.2CH 4-Cl MS calcd for
C.sub.23H.sub.21ClN.sub.4oH.sup.+ m/z = 389.15 observed m/z = 389
(M + 1 ).sup.+ 5o Ph.sub.2CH 4-PhO .sup.1H NMR (400MHz, CDCl.sub.3)
.delta. 7.20-7.44 (m, 4H), 7.19-7.35 (m, 9H), 7.11 (t, 2H, J=8),
7.01 (d, 2H, J=8), 6.98 (d, 2H, J=8), 4.65 (s, 1H, CHPh.sub.2),
3.87 (d, 1H, J=8), 3.62 (q, 1H, J=4), 3.12-3.20 (m, 1H), 3.07 (q,
1H, J=4), 1.62-1.80 (m, 2H) 5p Ph.sub.2CH 2-CH.sub.3 .sup.1H NMR
(400MHz, CDCl.sub.3) .delta. 7.53 (d, 2H, J=7), 7.36-7.40 (m, 6H),
7.25-7.31 (m, 2H), 7.18-7.23 (m, 4H), 4.84 (s, 1H, CHPh.sub.2),
4.66 (d, 1H, J=7), 3.70 (q, 1H, J=8), 3.26 (m, 1H), 2.78 (q, 1H,
J=7), 2.46 (s, 3H), 1.72 (m, 2H) 6b PhCH.sub.2 3-CF.sub.3 MS calcd
for C.sub.18H.sub.17F.sub.3N.sub.4oH.sup.+ m/z = 347.15 observed
m/z = 347 (M + 1).sup.+ 6c CH.sub.2.dbd.CHCH.sub.2 3-CF.sub.3 MS
calcd for C.sub.14H.sub.15F.sub.3N.- sub.4oH.sup.+ m/z = 297.13
observed m/z = 297 (M + 1).sup.+ 61 Ph.sub.2CH 3-NH.sub.2 .sup.1H
NMR (400MHz, CDCl.sub.3) .delta. 7.11-7.46 (m, 11H), 6.86 (d, 1H),
6.76 (s, 1H), 6.65 (d, 1H), 4.96 (s, 1H), 3.86 (m, 1H), 3.72 (br s,
2H), 3.48 (d, 1H), 3.17 (m, 1H), 2.51 (m, 1H), 2.34 (m, 1H), 1.79
(m, 1H) 6k Ph.sub.2CH 3-F-4-CH.sub.3 MS calcd for
C.sub.24H.sub.23FN.sub.4oH.sup.+ m/z = 387.20 observed m/z = 387 (M
+ 1).sup.+ 6m Ph.sub.2CH 4-CH.sub.3 MS calcd for
C.sub.24H.sub.24N.sub.4oH.sup.+ m/z = 369.21 observed m/z = 369.2
(M + 1).sup.+
[0063] The following compounds were also prepared by an analogous
procedure:
6 21 22 Ex. R.sub.1 R Analytical Data 5q Ph.sub.2CH PhCH.sub.2
.sup.1H NMR (400MHz, CDCl.sub.3) .delta. 7.04-7.52 (m, 15H), 4.78
(s, 1H), 4.60 (d, 1H, J=10), 3.64 (q, 1H, J=9), 3.21 (m, 1H), 2.73
(q, 1H, J=8), 2.20 (s, 2H), 1.66 (m, 2H) 5r Ph.sub.2CH
4-BnOPhCH.sub.2 MS calcd for C.sub.31H.sub.30N.sub.4OoH.sup.+ m/z =
475.25 observed m/z = 475 (M + 1).sup.+ 5s Ph.sub.2CH 2-thiazolyl
.sup.1H NMR (400MHz, CDCl.sub.3) .delta. 7.15-7.70 (m, 12H), 4.54
(s, 1H), 4.10 (m, 1H), 3.75 (d, 1H, J=3), 3.48 (m, 1H), 2.78 (q,
1H, J=8), 2.28 (m, 1H), 1.78 (m, 1H)
[0064] Step E: 23
[0065] To a solution of the threo azide 5a (0.50 g, 1.29 mmol) in
CH.sub.3OH (10 ml) at 0.degree. C. was added NiCl.sub.2o6H.sub.2O
(1.47 g, 6.19 mmol). To this solution was added NaBH.sub.4 (0.39 g,
10.3 mmol) in portions. The reaction was stirred at 0.degree. C.
for 1.5 h, then quenched with the dropwise addition of .about.3.4
ml water. It was partitioned between water (40 ml) and EtOAc (100
ml). The aqueous layer was extracted with EtOAc (2.times.100 ml).
The combined EtOAc layers were washed with brine (50 ml), dried
over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give
0.473 g of an oil. The oil was purified by column chromatography
over 100 g SiO.sub.2, eluting with a solvent gradient starting with
0.5% CH.sub.3OH in CH.sub.2Cl.sub.2 and progressing to 3%
CH.sub.3OH in CH.sub.2Cl.sub.2. Concentration of the appropriate
fractions gave 0.31 g of the desired racemic threo amine 7a as an
oil. The enantiomers were separated by preparative HPLC on a
Chiracel OJ column eluting with 5% EtOH in hexanes containing 0.2%
Et.sub.2NH.
[0066] Analytical data for racemic 7a :
[0067] MS calcd for C.sub.23H.sub.23ClN.sub.2oH.sup.+ m/z=363.16,
observed m/z=363.10 (M+1).sup.+
[0068] Analytical data for the first eluted enantiomer 7a-E1:
[0069] MS calcd for C.sub.23H.sub.23ClN.sub.2oH.sup.+ m/z =363.16,
observed m/z=363.30 (M+1).sup.+
[0070] Analytical data for the second eluted enantiomer 7a-E2:
[0071] MS calcd for C.sub.23H.sub.23ClN.sub.2oH.sup.+ m/z =363.16,
observed m/z=363.30 (M+1).sup.+
[0072] The following compounds were prepared by an analogous
procedure: 24
[0073] wherein
[0074] R.sub.1 and R.sub.6 are defined in the table:
7 Prep. R.sub.1 R.sub.6 Analytical Data 7b PhCH.sub.2 3-CF.sub.3 MS
calcd for C.sub.18H.sub.19F.sub.3N.sub.2oH.sup.+ m/z=321.16
observed m/z=321 (M+1).sup.+ 7c CH.sub.2.dbd. 3-CF.sub.3 MS calcd
for C.sub.14H.sub.17F.sub.3N.sub.2oH.sup.+ m/z=271.14 CHCH.sub.2
observed m/z=271 (M+1).sup.+ 7d CH.sub.2.dbd. 3-Cl MS calcd for
C.sub.13H.sub.17ClN.sub.2oH.sup.+ m/z=237.12 CHCH.sub.2 observed
m/z=237.1 (M+1).sup.+ 7e Ph.sub.2CH 3-CF.sub.3 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+ m/z=397.19 observed
m/z=397.4 (M+1).sup.+ 7e-E1 Ph.sub.2CH 3-CF.sub.3 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+ m/z=397.19 observed
m/z=397.4 (M+1).sup.+ 7e-E2 Ph.sub.2CH 3-CF.sub.3 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+ m/z=397.19 observed
m/z=397.4 (M+1).sup.+ 7f Ph.sub.2CH 3-OCH.sub.3 MS calcd for
C.sub.24H.sub.26N.sub.2OoH.sup.+ m/z=359.21 observed m/z=359.1
(M+1).sup.+ 7g Ph.sub.2CH 3-CH.sub.3 MS calcd for
C.sub.24H.sub.26N.sub.2oH.sup.+ m/z=343.22 observed m/z=343
(M+1).sup.+ 7h Ph.sub.2CH 4-OCH.sub.3 MS calcd for
C.sub.24H.sub.26N.sub.2OoH.sup.+ m/z=359.21 observed m/z=359.1
(M+1).sup.+ 7j Ph.sub.2CH 3-F MS calcd for C.sub.23H.sub.23FN.sub.-
2oH.sup.+ m/z=347.19 observed m/z=347 (M+1).sup.+ 7k Ph.sub.2CH
3-F-4-CH.sub.3 MS calcd for C.sub.24H.sub.25FN.sub.2oH.sup.+
m/z=361.21 observed m/z=361.1 (M+1).sup.+ 7l Ph.sub.2CH 3,5-F.sub.2
MS calcd for C.sub.23H.sub.22F.sub.2N.sub.2oH.sup.+ m/z=365.19
observed m/z 365.1 (M+1).sup.+ 7m Ph.sub.2CH 4-CH.sub.3 MS calcd
for C.sub.24H.sub.26N.sub.2oH.sup.+ m/z=343.22 observed m/z=343.4
(M+1).sup.+ 7n Ph.sub.2CH 4-Cl MS calcd for
C.sub.23H.sub.23ClN.sub.2oH.sup.+ m/z=363.16 observed m/z=363
(M+1).sup.+ 7n-E1 Ph.sub.2CH 4-Cl MS calcd for
C.sub.23H.sub.23ClN.sub.2oH.sup.+ m/z=363.16 observed m/z=363
(M+1).sup.+ 7n-E2 Ph.sub.2CH 4-Cl MS calcd for
C.sub.23H.sub.23ClN.sub.2oH.sup.+ m/z=363.16 observed m/z=363
(M+1).sup.+ 7o Ph.sub.2CH 4-PhO MS calcd for
C.sub.29H.sub.28N.sub.2OoH.sup.+ m/z=421.23 observed m/z=421
(M+1).sup.+ 7p Ph.sub.2CH 2-CH.sub.3 MS calcd for
C.sub.24H.sub.26N.sub.2oH.sup.+ m/z=343.22 observed m/z=343
(M+1).sup.+ 8b PhCH.sub.2 3-CF.sub.3 MS calcd for
C.sub.18H.sub.19F.sub.3N.sub.2oH.sup.+ m/z=321.16 observed m/z=321
(M+1).sup.+ 8c CH.sub.2.dbd. 3-CF.sub.3 MS calcd for
C.sub.14H.sub.17F.sub.3N.sub.2oH.sup.+ m/z=271.14 CHCH.sub.2
observed m/z 271 (M+1).sup.+ 8i Ph.sub.2CH 3-NH.sub.2 MS calcd for
C.sub.23H.sub.25N.sub.3oH.sup.+ m/z=344.21 observed m/z=344.1
(M+1).sup.+ 8k Ph.sub.2CH 3-F-4-CH.sub.3 MS calcd for
C.sub.24H.sub.25FN.sub.2oH.sup.+ m/z=361.21 observed m/z=361.1
(M+1).sup.+
[0075] The following compounds were also prepared by an analogous
procedure:
8 25 Ex. R.sub.1 R Analytical Data 7q Ph.sub.2CH PhCH.sub.2 MS
calcd for C.sub.24H.sub.26N.sub.2oH.sup.+ m/z = 343.22 observed m/z
= 343 (M + 1).sup.+ 7q-E1 Ph.sub.2CH PhCH.sub.2 MS calcd for
C.sub.24H.sub.26N.sub.2oH.sup.+ m/z = 343.22 observed m/z = 343.4
(M + 1).sup.+ 7q-E2 Ph.sub.2CH PhCH.sub.2 MS calcd for
C.sub.24H.sub.26N.sub.2oH.sup.+ m/z = 343.22 observed m/z = 343.4
(M + 1).sup.+ 7r Ph.sub.2CH 4-BnOPhCH.sub.2 MS calcd for
C.sub.31H.sub.32N.sub.2OoH.sup.+ m/z = 449.26 observed m/z = 449.3
(M + 1).sup.+ 7s Ph.sub.2CH 2-thiazolyl MS calcd for
C.sub.20H.sub.21N.sub.3SoH.sup.+ m/z = 336.15 observed m/z = 336.1
(M + 1).sup.+
[0076] Step F: 26
[0077] To a stirred solution of compound 7d (3.41 g, 14.4 mmol) and
Et.sub.3N (1.6 g, 16 mmol) in THF (40 ml) was added a solution of
di-tert-butyl dicarbonate (3.52 g, 16 mmol) in THF (20 ml) over 1
h. The mixture was stirred at RT for another 2 h and then
concentrated. The residue was chromatographed over silica gel,
eluting with a solvent gradient starting with 5% EtOAc in hexanes
progressing to 20% EtOAc in hexanes to give 3.69 g (76%) of product
9a as a colorless oil. MS calcd for
C.sub.18H.sub.25ClN.sub.2O.sub.2oH.sup.+ m/z=337.17, observed
m/z=337 (M+1).sup.+.
[0078] The following compound was prepared by an analogous
procedure: 27
[0079] MS calcd for C.sub.19H.sub.25F.sub.3N.sub.2O.sub.2oH.sup.+
m/z=371.19, observed m/z=371 (M+1).sup.+
[0080] Step G: 28
[0081] A suspension of Pd.sub.2(dba).sub.3 (275 mg, 0.3 mmol) and
DPPB (256 mg, 0.6 mmol) in THF (3 ml) under N.sub.2 was stirred at
RT for 30 min. The above catalyst was added slowly to a stirred
solution of compound 9a and thiosalicylic acid in THF (35 ml). The
mixture was stirred at RT for another 2 h and then concentrated in
vacuo. The residue was chromatographed over silica gel, eluting
with a solvent gradient starting with 20% EtOAc in hexanes
progressing to 66% EtOAc in hexanes containing 1% CH.sub.3OH to
give 1.15 g (73%) of product 10a as a pale yellow solid and 0.15 g
of starting material 9a (8%). MS calcd for
C.sub.15H.sub.21ClN.sub.2O.sub.2oH.sup.+ m/z=297.14, observed
m/z=297 (M+1).sup.+.
[0082] The following compound was prepared by an analogous
procedure: 29
[0083] MS calcd for C.sub.16H.sub.21F.sub.3N.sub.2O.sub.2oH.sup.+
m/z=331.16, observed m/z=331 (M+1).sup.+
[0084] Step H:
[0085] See Example 1.
[0086] Step I:
[0087] See Example 2.
[0088] Step J:
[0089] See Example 3.
[0090] Step K: 30
[0091] To 1-diphenylmethyl-3-hydroxyazetidine (2.00 g, 7.26 mmol),
16, in CH.sub.2Cl.sub.2 (35 ml) was added diisopropylethylamine
(7.6 ml, 44 mmol). The solution was cooled to 0.degree. C. and
sulfurtrioxide-pyridine (3.47 g, 21.8 mmol) in DMSO (6 ml) was
slowly added. The solution was stirred overnight while the cold
bath expired. The solution was partitioned between Et.sub.2O (100
ml) and brine (50 ml). The aqueous layer was extracted with
Et.sub.2O (2.times.50 ml). The combined Et.sub.2O layers were
washed with half-saturated brine (100 ml), dried
overNa.sub.2SO.sub.4, and concentrated in vacuo. The residue was
chromatographed over 60 g SiO.sub.2, eluting with a solvent
gradient starting with 2% EtOAc in hexanes, progressing to 10%
EtOAc in hexanes. Concentration of the appropriate fractions
yielded 1.24 g (72%) of the desired ketone, 17, as a white
solid:
EXAMPLE 1
[0092] 31
[0093] A suspension of compound 10a (20 mg, 0.067 mmol),
4,4'-difluorobenzhydryl chloride (50 mg, 0.21 mmol), Nal (10 mg,
0.067 mmol) and Et.sub.3N (20 mg, 0.2 mmol) in CH.sub.3CN (2 ml)
was stirred at 50.degree. C. for 14 h. The solvent was removed in
vacuo, the residue was suspended in TFA (2 ml) and CH.sub.2Cl.sub.2
(2 ml). The mixture was stirred at RT for 2 h and concentrated. The
residue was purified by preparative TLC, eluting with 33% EtOAc in
hexanes containing 1% CH.sub.3OH to give 12.4 mg (46% in two steps)
of product 1a, which was treated with HCl in ether to generate the
dihydrochloric acid salt. MS calcd for
C.sub.23H.sub.21ClF.sub.2N.sub.2oH.sup.+ m/z=399.14, observed
m/z=399 (M+1).sup.+.
[0094] Enantiomers were resolved using chiral chromatography over
either Chiralcel OD or OJ columns on either the free amine or their
N-Boc derivatives and appear in the tables with the notations, E1
or E2.
[0095] The following compounds were prepared by an analogous
procedure:
9 32 Ex. R.sub.1 R.sub.6 Analytical Data 1b 33 3-Cl MS calcd for
C.sub.23H.sub.21Cl.sub.3N.sub.2oH.sup.+ m/z = 431.08 observed m/z =
431 (M + 1).sup.+ 1c 34 3-Cl MS calcd for
C.sub.23H.sub.21Br.sub.2ClN.sub.2oH.sup.+ m/z = 518.98 observed m/z
= 519.0, 520.9, 521.9 (M + 1).sup.+ 1d 35 3-Cl MS calcd for
C.sub.25H.sub.27ClN.sub.2oH.sup.+ m/z = 391.19 observed m/z = 391
(M + 1).sup.+ 1e 36 3-Cl MS calcd for C.sub.23H.sub.21ClF.sub.-
2N.sub.2oH.sup.+ m/z = 399.14 observed m/z = 399 (M + 1).sup.+ 1f
37 3-Cl MS calcd for C.sub.23H.sub.21Cl.sub.3N.sub.2oH.sup.+ m/z =
431.08 observed m/z = 431 (M + 1).sup.+ 1g 38 3-Cl MS calcd for
C.sub.25H.sub.21ClF.sub.6N.sub.2oH.sup.+ m/z = 499.14 observed m/z
= 499 (M + 1).sup.+ 1h 39 3-Cl MS calcd for
C.sub.22H.sub.22ClN.sub.3oH.sup.+ m/z = 364.16 observed m/z = 364
(M + 1).sup.+ 1h diast 1-E1 40 3-Cl MS calcd for
C.sub.22H.sub.22ClN.sub.3oH.sup.+ m/z = 364.16 observed m/z = 364
(M + 1).sup.+ 1h diast. 1-E2 41 3-Cl MS calcd for
C.sub.22H.sub.22ClN.sub.3oH.sup.+ m/z = 364.16 observed m/z = 364
(M + 1).sup.+ 1i diast. 2 42 3-Cl MS calcd for
C.sub.22H.sub.22ClN.sub.3oH.sup.+ m/z = 364.16 observed m/z = 364
(M + 1).sup.+ 1i diast. 2-E1 43 3-Cl MS calcd for
C.sub.22H.sub.22ClN.sub.3oH.sup.+ m/z = 364.16 observed m/z = 364
(M + 1).sup.+ 1i diast. 2-E2 44 3-Cl MS calcd for
C.sub.22H.sub.22ClN.sub.3oH.sup.+ m/z = 364.16 observed m/z = 364
(M + 1).sup.+ 1j 45 3-Cl MS calcd for C.sub.23H.sub.21ClN.sub.-
2oH.sup.+ m/z = 361.15 observed m/z = 361 (M + 1).sup.+ 1k 46 3-Cl
MS calcd for C.sub.26H.sub.27ClF.sub.2N.sub.2oH.sup.+ m/z = 441.19
observed m/z = 441 (M + 1).sup.+ 1L 47 3-Cl MS calcd for
C.sub.18H.sub.21ClN.sub.2oH.sup.+ m/z = 301.15 observed m/z = 301
(M + 1).sup.+ 1m diast. 1 48 3-Cl MS calcd for
C.sub.19H.sub.23ClN.sub.2oH.sup.+ m/z = 315.16 observed m/z = 315
(M + 1).sup.+ 1n diast. 2 49 3-Cl MS calcd for
C.sub.19H.sub.23ClN.sub.2oH.sup.+ m/z = 315.16 observed m/z = 315
(M + 1).sup.+ 11o diast. 1 50 3-Cl MS calcd for
C.sub.20H.sub.25ClN.sub.2oH.sup.+ m/z = 329.18 observed m/z = 329
(M + 1).sup.+ 1p diast. 2 51 3-Cl MS calcd for
C.sub.20H.sub.25ClN.sub.2oH.sup.+ m/z = 329.18 observed m/z = 329
(M + 1).sup.+ 1q diast. 1 52 3-Cl MS calcd for
C.sub.21H.sub.27ClN.sub.2oH.sup.+ m/z = 343.19 observed m/z = 343
(M + 1).sup.+ 1r diast. 2 53 3-Cl MS calcd for
C.sub.21H.sub.27ClN.sub.2oH.sup.+ m/z = 343.19 observed m/z = 343
(M + 1).sup.+ 1s diast. 1 54 3-Cl MS calcd for
C.sub.22H.sub.29ClN.sub.2oH.sup.+ m/z = 357.20 observed m/z = 357
(M + 1).sup.+ 1t diast. 2 55 3-Cl MS calcd for
C.sub.22H.sub.29ClN.sub.2oH.sup.+ m/z = 357.20 observed m/z = 357
(M + 1).sup.+ 1u diast. 1 56 3-Cl MS calcd for
C.sub.23H.sub.31ClN.sub.2oH.sup.+ m/z = 371.23 observed m/z = 371
(M + 1).sup.+ 1v diast. 2 57 3-Cl MS calcd for
C.sub.23H.sub.31ClN.sub.2oH.sup.+ m/z = 371.23 observed m/z = 371
(M + 1).sup.+ 1w diast. 1 58 3-Cl MS calcd for
C.sub.21H.sub.26ClFN.sub.2oH.sup.+ m/z = 361.18 observed m/z = 361
(M + 1).sup.+ 1x diast. 2 59 3-Cl MS calcd for
C.sub.21H.sub.26ClFN.sub.2oH.sup.+ m/z = 361.18 observed m/z = 361
(M + 1).sup.+ 1y diast. 1 60 3-Cl MS calcd for
C.sub.21H.sub.25ClF.sub.2N.sub.2oH.sup.+ m/z = 379.17 observed m/z
= 379 (M + 1).sup.+ 1z diast. 2 61 3-Cl MS calcd for
C.sub.21H.sub.25ClF.sub.2N.sub.2oH.sup.+ m/z = 379.17 observed m/z
= 379 (M + 1).sup.+ 1aa diast. 1 62 3-Cl MS calcd for
C.sub.20H.sub.26ClN.sub.3oH.sup.+ m/z = 344.19 observed m/z = 344
(M + 1).sup.+ 1ab diast. 2 63 3-Cl MS calcd for
C.sub.20H.sub.26ClN.sub.3oH.sup.+ m/z = 344.19 observed m/z = 344
(M + 1).sup.+ 1ac 64 3-Cl MS calcd for C.sub.19H.sub.31ClN.sub-
.2oH.sup.+ m/z = 323.23 observed m/z = 323 (M + 1).sup.+ 1ad 65
3-Cl MS calcd for C.sub.14H.sub.15ClN.sub.4oH.sup.+ m/z = 275.11
observed m/z = 275 (M + 1).sup.+ 1ae 66 3-Cl MS calcd for
C.sub.16H.sub.16ClN.sub.3O.sub.2oH.sup.+ m/z = 318.10 observed m/z
= 318 (M + 1).sup.+ 1af 67 3-CF.sub.3 MS calcd for
C.sub.20H.sub.17F.sub.9N.sub.2oH.sup.+ m/z = 457.13 observed m/z =
457 (M + 1).sup.+ 1ag 68 3-CF.sub.3 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+ m/z = 397.19 observed m/z =
397 (M + 1).sup.+ 1ah 69 3-CF.sub.3 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+ m/z = 397.19 observed m/z =
397 (M + 1).sup.+ 1ai 70 3-CF.sub.3 MS calcd for
C.sub.25H.sub.21Cl.sub.2F.sub.3N.sub.2OoH.sup.+ m/z = 493.11
observed m/z = 493 (M + 1).sup.+ 1aj 71 3-CF.sub.3 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2OoH.sup.+ m/z = 413.18 observed m/z =
413 (M + 1).sup.+ 1ak 72 3-CF.sub.3 MS calcd for
C.sub.19H.sub.19F.sub.3N.sub.2O.sub.2oH.sup.+ m/z = 365.15 observed
m/z = 365 (M + 1).sup.+ 1al 73 3-CF.sub.3 MS calcd for
C.sub.24H.sub.21F.sub.3N.sub.2oH.sup.+ m/z = 395.17 observed m/z =
395 (M + 1).sup.+ 1am 74 3-CF.sub.3 MS calcd for
C.sub.23H.sub.22F.sub.3N.sub.3oH.sup.+ m/z = 398.18 observed m/z =
398 (M + 1).sup.+ 1an 75 3-CF.sub.3 MS calcd for
C.sub.26H.sub.27F.sub.3N.sub.2oH.sup.+ m/z = 425.22 observed m/z =
425 (M + 1).sup.+ 1ao 76 3-CF.sub.3 MS calcd for
C.sub.23H.sub.22F.sub.3N.sub.3oH.sup.+ m/z = 398.18 observed m/z =
398.1 (M + 1).sup.+ Example 2 77
[0096] To a stirred solution of compound 10b (20 mg, 0.061 mmol),
1-naphthaldehyde (11 mg, 0.070 mmol) and acetic acid (0.06 mmol) in
CH.sub.2Cl.sub.2 (1.5 ml) was added sodium triacetoxyborohydride
(21 mg, 0.10 mmol). The suspension was stirred at RT for 15 h. TFA
(1.5 ml) was added to the solution, and the mixture was stirred at
RT for 1 h. It was concentrated and the residue was purified by
preparative TLC eluting with 33% EtOAc in hexanes containing 1 %
CH.sub.3OH to give 9.8 mg of product (Ex. 2a). The free amine was
treated with HCl in Et.sub.2O to give the dihydrochloric acid salt.
MS calcd for C.sub.22H.sub.21F.sub.3N.sub.2oH.s- up.+ m/z=371.17,
observed m/z=371 (M+1).sup.+.
[0097] The following compounds were prepared by an analogous
procedure:
10 78 Ex. R.sub.1 R.sub.6 Analytical Data 2b 79 3-CF.sub.3 MS calcd
for C.sub.22H.sub.21F.sub.3N.sub.2oH.sup.+ m/z = 371.17 observed
m/z = 371 (M + 1).sup.+ 2c 80 3-CF.sub.3 MS calcd for
C.sub.25H.sub.23F.sub.3N.sub.2oH.sup.+ m/z = 409.19 observed m/z =
409 (M + 1).sup.+ 2e 81 3-CF.sub.3 MS calcd for
C.sub.23H.sub.28F.sub.3N.sub.3oH.sup.+ m/z = 404.23 observed m/z =
404 (M + 1).sup.+ Example 3 82
[0098] To a vial containing 2a (50 mg, 0.20 mmol) in THF (1 ml) was
added 3-chloro-benzylamine (0.22 ml, 0.2 mmol) as a 1M solution in
1,2-dichloroethane. The solution was stirred for 30 min, then
sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added. After
.about.2 h, the reaction was quenched with saturated NaHCO.sub.3
and extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, concentrated and the residue dissolved in
Et.sub.2O. To the ethereal solution was added .about.1 ml of 1M HCl
in Et.sub.2O to give the dihydrochloride salt 3a as a precipitated
solid. MS calcd for C.sub.24H.sub.25ClN.sub.2oH.sup.- + m/z=377.18,
observed m/z=377 (M+1).sup.+.
[0099] The following compounds were prepared by this reductive
amination route:
11 83 Ex. R.sub.7 Analytical Data 3b 84 MS calcd for
C.sub.25H.sub.25F.sub.3N.sub.2o- H.sup.+m/z = 411 observed m/z =
411 (M + 1).sup.+ 3c 85 MS calcd for
C.sub.27H.sub.30N.sub.2oH.sup.+m/z = 383 observed m/z = 383 (M +
1).sup.+ 3d 86 MS calcd for C.sub.25H.sub.27ClN.sub.2oH- .sup.+m/z
= 391 observed m/z = 391 (M + 1 ).sup.+ 3e 87 MS calcd for
C.sub.31H.sub.32N.sub.2oH.sup.+m/z = 433 observed m/z = 433 (M +
1).sup.+ 3f 88 MS calcd for C.sub.32H.sub.34N.sub.2oH.s- up.+m/z =
447 observed m/z = 447 (M + 1).sup.+ 3g 89 MS calcd for
C.sub.25H.sub.27ClN.sub.2oH.sup.+m/z = 391 observed m/z = 391 (M +
1).sup.+ 3h 90 MS calcd for C.sub.24H.sub.24ClFN.sub- .2oH.sup.+m/z
= 395 observed m/z = 395 (M + 1).sup.+ 3i 91 MS calcd for
C.sub.25H.sub.28N.sub.2oH.sup.+m/z = 357 observed m/z = 357 (M +
1).sup.+ 3j 92 MS calcd for C.sub.26H.sub.30N.sub.2O- oH.sup.+m/z =
387 observed m/z = 387 (M + 1).sup.+ 3k 93 MS calcd for
C.sub.24H.sub.25ClN.sub.2oH.sup.+m/z = 377 observed m/z = 377 (M +
1).sup.+ 3l 94 MS calcd for
C.sub.25H.sub.25F.sub.3N.sub.2oH.sup.+m/z = 411 observed m/z = 411
(M + 1).sup.+ 3m 95 MS calcd for C.sub.26H.sub.30N.sub.2OoH.su-
p.+m/z = 387 observed m/z = 387 (M + 1).sup.+ 3n 96 MS calcd for
C.sub.26H.sub.30N.sub.2OoH.sup.+m/z = 387 observed m/z = 387 (M +
1).sup.+ 3o 97 MS calcd for C.sub.24H.sub.32N.sub.2oH.s- up.+m/z =
349 observed m/z = 349 (M + 1).sup.+ 3p 98 MS calcd for
C.sub.25H.sub.28N.sub.2OoH.sup.+m/z = 373 observed m/z = 373 (M +
1).sup.+ 3q 99 MS calcd for C.sub.25H.sub.27ClN.sub.2oH- .sup.+m/z
= 391 observed m/z = 391 (M + 1).sup.+ 3r 100 MS calcd for
C.sub.24H.sub.25ClN.sub.2oH.sup.+m/z = 377 observed m/z = 377 (M +
1).sup.+ 3s C.sub.10H.sub.21-n MS calcd for
C.sub.27H.sub.40N.sub.2oH.sup.+ m/z = 393 observed m/z = 393 (M +
1).sup.+ 3t 101 MS calcd for C.sub.24H.sub.27N.sub.3oH.sup.+m/z =
357 observed m/z = 357 (M + 1).sup.+ 3u 102 MS calcd for
C.sub.24H.sub.24Cl.sub.2N.sub.2oH.sup- .+m/z = 411 observed m/z =
411, 413 (M + 1).sup.+ 3v 103 MS calcd for
C.sub.23H.sub.28N.sub.4oH.sup.+m/z = 361 observed m/z = 361 (M +
1).sup.+ 3w Ph MS calcd for C.sub.23H.sub.24N.sub.2o- H.sup.+ m/z =
329 observed m/z = 329 (M + 1).sup.+ 3x 104 MS calcd for
C.sub.25H.sub.27ClN.sub.2oH.sup.+m/z = 391 observed m/z = 391 (M +
1).sup.+ 3y 105 MS calcd for C.sub.22H.sub.24N.sub.2OoH.sup.+m/z =
333 observed m/z = 333 (M + 1).sup.+ 3z Ph(CH.sub.2).sub.4 MS calcd
for C.sub.27H.sub.32N.sub.2oH.sup.+ m/z = 385 observed m/z = 385 (M
+ 1).sup.+ 3aa 106 MS calcd for C.sub.24H.sub.33N.sub.3oH.sup.+m/z
= 364 observed m/z = 364 (M + 1).sup.+ 3ab 107 MS calcd for
C.sub.21H.sub.28N.sub.2OoH.sup.+m/z = 325 observed m/z = 325 (M +
1).sup.+ 3ac 108 MS calcd for C.sub.23H.sub.25N.sub.3oH.sup.+m/z =
344 observed m/z = 344 (M + 1).sup.+ 3ad 109 MS calcd for
C.sub.23H.sub.25N.sub.3oH.s- up.+m/z = 344 observed m/z = 344 (M +
1).sup.+ 3ae 110 MS calcd for C.sub.30H.sub.30N.sub.2oH.sup.+m/z =
419 observed m/z = 419 (M + 1).sup.+ 3af 111 MS calcd for
C.sub.24H.sub.31N.sub.3Oo- H.sup.+m/z = 378 observed m/z = 378 (M +
1).sup.+ 3ag 112 MS calcd for C.sub.29H.sub.35N.sub.3oH.sup.+m/z =
426 observed m/z = 426 (M + 1).sup.+ 3ah 113 MS calcd for
C.sub.25H.sub.26N.sub.2O.sub.2oH.sup.+m/z = 387 observed m/z = 387
(M + 1).sup.+ 3ai 114 MS calcd for C.sub.25H.sub.25F.sub.3N.su-
b.2oH.sup.+m/z = 411 observed m/z = 411 (M + 1).sup.+ 3aj 115 MS
calcd for C.sub.25H.sub.28N.sub.2OoH.sup.+m/z = 373 observed m/z =
373 (M + 1).sup.+ 3ak 116 MS calcd for
C.sub.23H.sub.25N.sub.3oH.sup.+m/z = 344 observed m/z = 344 (M +
1).sup.+
[0100] The following secondary amines were prepared by this
reductive amination route:
12 117 Ex. --NR.sub.7R.sub.8 Analytical Data 3al 118 MS calcd for
C.sub.29H.sub.34N.sub.2oH.sup.+m/z = 411 observed m/z = 411 (M +
1).sup.+ 3am 119 MS calcd for C.sub.34H.sub.35F.sub.2N.sub.3oH.sup-
.+m/z = 524 observed m/z 524 (M + 1).sup.+ 3an 120 MS calcd for
C.sub.27H.sub.37N.sub.3oH.sup.+m/z = 404 observed m/z = 404 (M +
1).sup.+ 3ao 121 MS calcd for C.sub.28H.sub.33N.sub.3oH- .sup.+m/z
= 412 observed m/z = 412 (M + 1).sup.+
EXAMPLE 4
[0101] The following azetidines were prepared by the reductive
amination route of Example 3, starting with
1-benzhydryl-3-azetidinone:
13 122 Ex. R.sub.7 Analytical Data 4a 123 MS calcd for
C.sub.26H.sub.28N.sub.2oH.su- p.+m/z = 369 observed m/z = 369 (M +
1).sup.+ 4b 124 MS calcd for C.sub.24H.sub.25ClN.sub.2oH.sup.+m/z =
377 observed m/z = 377 (M + 1).sup.+ 4c 125 MS calcd for
C.sub.23H.sub.23ClN.sub- .2oH.sup.+m/z = 363 observed m/z = 363 (M
+ 1).sup.+ 4d 126 MS calcd for C.sub.23H.sub.24N.sub.2oH.sup.+m/z =
329 observed m/z = 329 (M + 1).sup.+ 4e 127 MS calcd for
C.sub.23H.sub.23ClN.sub.2oH.sup.+m/z = 363 observed m/z = 363 (M +
1).sup.+ 4f 128 MS calcd for C.sub.25H.sub.28N.sub.2OoH.s- up.+m/z
= 373 observed m/z = 373 (M + 1).sup.+ 4g 129 MS calcd for
C.sub.24H.sub.26N.sub.2oH.sup.+m/z = 343 observed m/z = 343 (M +
1).sup.+ 4h 130 MS calcd for C.sub.25H.sub.28N.sub.2OoH- .sup.+m/z
= 373 observed m/z = 373 (M + 1).sup.+ 4i 131 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+m/z = 397 observed m/z = 397
(M + 1).sup.+ 4j 132 MS calcd for
C.sub.23H.sub.23ClN.sub.2oH.sup.+m/z = 363 observed m/z = 363 (M +
1).sup.+ 4k 133 MS calcd for C.sub.24H.sub.25ClN.sub.2oH.- sup.+m/z
= 377 observed m/z = 377 (M + 1).sup.+ 4l Ph(CH.sub.2).sub.4 MS
calcd for C.sub.26H.sub.30N.sub.2oH.sup.+ m/z = 371 observed m/z =
371 (M + 1).sup.+ 4m 134 MS calcd for
C.sub.23H.sub.22ClFN.sub.2oH.sup.+m/z = 381 observed m/z = 381 (M +
1).sup.+ 4n 135 MS calcd for C.sub.24H.sub.25ClN.sub.2oH.sup.+m/z =
377 observed m/z = 377 (M + 1).sup.+ 4o 136 MS calcd for
C.sub.31H.sub.32N.sub.2oH.su- p.+m/z = 433 observed m/z = 433 (M +
1).sup.+ 4p 137 MS calcd for
C.sub.23H.sub.22Cl.sub.2N.sub.2oH.sup.+m/z = 397 observed m/z = 397
(M + 1).sup.+ 4q 138 MS calcd for
C.sub.23H.sub.30N.sub.2oH.sup.+m/z = 335 observed m/z = 335 (M +
1).sup.+ 4r C.sub.10H.sub.21-n MS calcd for
C.sub.26H.sub.38N.sub.2oH.sup.+ m/z = 379 observed m/z = 379 (M +
1).sup.+ 4s 139 MS calcd for
C.sub.24H.sub.24N.sub.2O.sub.2oH.sup.+m/z = 373 observed m/z = 373
(M + 1).sup.+ 4t 140 MS calcd for C.sub.21H.sub.22N.sub.2OoH.s-
up.+m/z = 319 observed m/z = 319 (M + 1).sup.+ 4u 141 MS calcd for
C.sub.24H.sub.23F.sub.3N.sub.2oH.sup.+m/z = 397 observed m/z = 397
(M + 1).sup.+ 4v 142 MS calcd for
C.sub.24H.sub.25ClN.sub.2oH.sup.+m/z = 377 observed m/z = 377 (M +
1).sup.+ 4w 143 MS calcd for C.sub.24H.sub.26N.sub.2OoH.s- up.+m/z
= 359 observed m/z = 359 (M + 1).sup.+ 4x 144 MS calcd for
C.sub.27H.sub.26N.sub.2oH.sup.+m/z = 379 observed m/z = 379 (M +
1).sup.+ 4y 145 MS calcd for C.sub.24H.sub.26N.sub.2OoH- .sup.+m/z
= 359 observed m/z = 359 (M + 1).sup.+ 4z 146 MS calcd for
C.sub.30H.sub.30N.sub.2oH.sup.+m/z = 419 observed m/z = 419 (M +
1).sup.+ 4aa 147 MS calcd for C.sub.24H.sub.23F.sub.3N.-
sub.2oH.sup.+m/z = 397 observed m/z = 397 (M + 1).sup.+ 4ab 148 MS
calcd for C.sub.29H.sub.28N.sub.2oH.sup.+m/z = 405 observed m/z =
405 (M + 1).sup.+ 4ac 149 MS calcd for
C.sub.22H.sub.23N.sub.3oH.sup.+m/z = 330 observed m/z = 330 (M +
1).sup.+ 4ad 150 MS calcd for C.sub.20H.sub.26N.sub.2OoH.sup.+m/z =
311 observed m/z = 311 (M + 1).sup.+ 4ae 151 MS calcd for
C.sub.25H.sub.28N.sub.2OoH.sup.+m/z = 373 observed m/z = 373 (M +
1).sup.+
[0102] In a similar manner, the following secondary amines were
prepared:
14 152 Ex. --NR.sub.7R.sub.8 Analytical Data 4af 153 MS calcd for
C.sub.26H.sub.35N.sub.3oH.sup.+ m/z = 390 observed m/z = 390 (M +
1).sup.+ 4ag 154 MS calcd for C.sub.28H.sub.32N.sub.2oH.s- up.+ m/z
= 397 observed m/z = 397 (M + 1).sup.+ 4ah 155 MS calcd for
C.sub.27H.sub.31N.sub.3oH.sup.+ m/z = 398 observed m/z = 398 (M +
1).sup.+ 4ai 156 MS calcd for C.sub.33H.sub.33F.sub.2N.-
sub.3oH.sup.+ m/z = 510 observed m/z = 510 (M + 1).sup.+
EXAMPLE 5
[0103] The following diazetidines were prepared by the reductive
amination route of Example 3:
15 157 Ex. R.sub.7 Analytical Data 5a 158 MS calcd for
C.sub.42H.sub.43N.sub.3oH.su- p.+ m/z = 590 observed m/z = 590 (M +
1).sup.+ 5b 159 MS calcd for C.sub.38H.sub.41N.sub.5oH.sup.+ m/z =
568 observed m/z = 568 (M + 1).sup.+ 5c 160 MS calcd for
C.sub.43H.sub.41N.sub.3oH.- sup.+ m/z = 600 observed m/z = 600 (M +
1).sup.+ 5d 161 MS calcd for C.sub.40H.sub.38F.sub.3N.sub.3oH.sup.+
m/z = 618 observed m/z = 618 (M + 1).sup.+ 5e 162 MS calcd for
C.sub.38H.sub.38N.sub.4oH.sup.+ m/z = 551 observed m/z = 551 (M +
1).sup.+ 5f 163 MS calcd for C.sub.38H.sub.38N.sub.4oH.su- p.+ m/z
= 551 observed m/z = 551 (M + 1).sup.+ 5g 164 MS calcd for
C.sub.39H.sub.44N.sub.4OoH.sup.+ m/z = 585 observed m/z = 585 (M +
1).sup.+ 5h 165 MS calcd for C.sub.40H.sub.39N.sub.3-
O.sub.2oH.sup.+ m/z =594 observed m/z = 594 (M + 1).sup.+ 5i 166 MS
calcd for C.sub.36H.sub.41N.sub.3OoH.sup.+ m/z = 532 observed m/z =
532 (M + 1).sup.+ 5j 167 MS calcd for
C.sub.40H.sub.41N.sub.3oH.sup.+ m/z = 564 observed m/z = 564 (M +
1).sup.+ 5k 168 MS calcd for C.sub.46H.sub.45N.sub.3oH.su- p.+ m/z
= 640 observed m/z = 640 (M + 1).sup.+ 5l C.sub.10H.sub.21-n MS
calcd for C.sub.42H.sub.53N.sub.3oH.sup.+ m/z = 600 observed m/z =
600 (M + 1).sup.+ 5m 169 MS calcd for
C.sub.40H.sub.40ClN.sub.3oH.sup.+ m/z =598 observed m/z = 598 (M +
1).sup.+ 5n 170 MS calcd for C.sub.40H.sub.41N.sub.3OoH.s- up.+ m/z
= 580 observed m/z = 580 (M + 1).sup.+
[0104] Biological Activity of the Compounds
[0105] Nociceptin Binding Assay:
[0106] CHO cell membrane preparation expressing the ORL-1 receptor
(2 mg) was incubated with varying concentrations of
[I.sup.125][Tyr.sup.14]nocic- eptin (3-500 pM) in a buffer
containing 50 mM HEPES (pH7.4), 10 mM NaCl, 1 mM MgCl.sub.2, 1
mg/ml bovine serum albumin and 0.025% bacitacin. In a number of
studies, assays were carried out in buffer 50 mM tris-HCl (pH7.4),
1 mg/ml bovine serum albumin and 0.025% bacitracin. Samples were
incubated for 1 h at room temperature (22.degree. C.).
Radiolabelled ligand bound to the membrane was harvested over GF/B
filters presoaked with 0.1% polyethyleneimine using a Brandell cell
harvester and washed five times with 5 ml cold distilled water.
Nonspecific binding was determined in parallel by similar assays
performed in the presence of 1 .mu.M nociceptin. All assay points
were performed in duplicates of total and nonspecific binding.
Calculations of K.sub.i were made using methods well known in the
art.
[0107] For compounds of this invention, K.sub.i values were
determined to be in the range of about 0.009 to about 50 .mu.M,
with compounds having a K.sub.i value in the range of about 0.009
to about 0.500 .mu.M being preferred.
[0108] Agonist Activity
[0109] Using the procedures described the European Journal of
Pharmacology, 336 (1997), p. 233-242, the agonist activity of
compounds of the invention are determined.
[0110] Cough Studies
[0111] The effect of compounds of formula I are evaluated in
capsaicin-induced cough in the guinea pig according to the methods
of Bolser et al. British Journal of Pharmacology (1995) 114,
735-738. This model is a widely used method to evaluate the
activity of potential antitussive drugs. Overnight fasted male
Hartley guinea pigs (350-450 g, Charles River, Bloomington, Mass.,
USA) are placed in a 12".times.14" transparent chamber. The animals
are exposed to aerosolized capsaicin (300 .mu.M, for 4 min)
produced by a jet nebulizer (Puritan Bennett, Lenexa, Kans., USA)
to elicit the cough reflex. Each guinea pig is exposed only once to
capsaicin. The number of coughs are detected by a microphone placed
in the chamber and verified by a trained observer. The signal from
the microphone is relayed to a polygraph which provides a record of
the number of coughs. Either vehicle (methylcellulose 1 ml/kg,
p.o.) or test compound is given 2 hours before aerosolized
capsaicin. The antitussive activity of baclofen (3 mg/kg, p.o.) is
also tested as a positive control.
[0112] Respiratory Measurements
[0113] Studies are performed on male Hartley guinea pigs ranging in
weight from 450 to 550 g. The animals are fasted overnight but
given water and libitum. The guinea pigs are placed in a
whole-body, head-out plethysmograph and a rubber collar is placed
over the animal's head to provide an airtight seal between the
guinea pig and the plethysmograph. Airflow is measured as a
differential pressure across a wire mesh screen which covered a
1-in hole in the wall of the plethysmograph. The airflow signal is
integrated to a signal proportional to volume using a preamplifier
circuit and a pulmonary function computer (Buxco Electronics,
Sharon, Conn., model XA). A head chamber is attached to the
plethysmograph and air from a compressed gas source (21% O.sub.2,
balance N.sub.2) is circulated through the head chamber for the
duration of study. All respiratory measurements are made while the
guinea pigs breathe this circulating air.
[0114] The volume signal from each animal is fed into a data
acquisition/analysis system (Buxco Electronics, model XA) that
calculates tidal volume and respiratory rate on a breath-by-breath
basis. These signals are visually displayed on a monitor. Tidal
volume and respiratory rate are recorded as an average value every
minute.
[0115] The guinea pigs are allowed to equilibrate in the
plethysmograph for 30 min. Baseline measurements are obtained at
the end of this 30 min period. The guinea pigs are then removed
from the plethysmograph and orally dosed with test compound (e.g.,
10 mg/kg, p.o.), baclofen (3 mg/kg, p.o.) or a methylcellulose
vehicle placebo (2 ml/kg, p.o.). Immediately after dosing, the
guinea pigs are placed into the plethysmograph, the head chamber
and circulating air are reconnected and respiratory variables are
measured at 30, 60, 90 and 120 min post treatment. This study is
performed under ACUC protocol #960103.
[0116] Data Analysis
[0117] The data for tidal volume (V.sub.T), respiratory rate (f)
and minute volume (MV=V.sub.T X f) are made for the baseline
condition and at each time point after the drug or vehicle. The
results are expressed as the mean .+-.SEM.
[0118] One to three compounds of formula I can be administered in
the method of this invention, preferably one.
[0119] For mammals treated for coughing, the nociceptin receptor
ORL-1 agonists of formula I may be administered along with one or
more additional agents for treating cough, allergy or asthma
symptoms selected from antihistamines, 5-lipoxygenase inhibitors,
leukotriene inhibitors, H.sub.3 inhibitors, R-adrenergic receptor
agonists, xanthine derivatives, .alpha.-adrenergic receptor
agonists, mast cell stabilizers, anti-tussives, expectorants,
NK.sub.1, NK.sub.2 and NK.sub.3 tachykinin receptor antagonists,
and GABA.sub.B agonists. One to three additional agents can be
combined with a compound of formula I, preferably one or two, more
preferably one.
[0120] Non limitative examples of antihistamines include:
astemizole, azatadine, azelastine, acrivastine, brompheniramine,
certirizine, chlorpheniramine, clemastine, cyclizine, carebastine,
cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known
as SCH-34117), doxylamine, dimethindene, ebastine, epinastine,
efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine,
levocabastine, mizolastine, equitazine, mianserin, noberastine,
meclizine, norastemizole, picumast, pyrilamine, promethazine,
terfenadine, tripelennamine, temelastine, trimeprazine and
triprolidine.
[0121] Non-limitative examples of histamine H.sub.3 receptor
antagonists include: thioperamide, impromidine, burimamide,
clobenpropit, impentamine, mifetidine, S-sopromidine,
R-sopromidine, SKF-91486, GR-175737, GT-2016, UCL-1199 and
clozapine. Other compounds can readily be evaluated to determine
activity at H.sub.3 receptors by known methods, including the
guinea pig brain membrane assay and the guinea pig neuronal ileum
contraction assay, both of which are described in U.S. Pat. No.
5,352,707. Another useful assay utilizes rat brain membranes and is
described by West et al., "Identification of Two-H.sub.3-Histamine
Receptor Subtypes," Molecular Pharmacology, Vol. 38, pages 610-613
(1990).
[0122] The term "leukotriene inhibitor" includes any agent or
compound that inhibits, restrains, retards or otherwise interacts
with the action or activity of leukotrienes. Non-limitative
examples of leukotriene inhibitors include montelukast
[R-(E)]-1[[[1-[3-[2-(7-chloro-2-quinolinyl-
)-ethenyl]phenyl]-3[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]-methyl]-
cyclopropaneacetic acid and its sodium salt, described in EP 0 480
717;
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)-phenyl)thio)methylcyclopropaneacetic acid, and its sodium
salt, described in WO 97/28797 and U.S. Pat. No. 5,270,324;
1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phen-
yl)-3-(2-(1
-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropanea-
cetic acid, and its sodium salt, described in WO 97/28797 and U.S.
Pat. No. 5,472,964; praniukast,
N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran--
8-yl]-p-(4-phenylbutoxy)benzamide) described in WO 97/28797 and EP
173,516; zafirlukast,
(cyclopentyl-3-[2-methoxy-4-[(o-tolylsulfonyl)carba-
moyl]benzyl]-1-methylindole-5-carbamate) described in WO 97/28797
and EP 199,543; and
[2-[[2(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]ph-
enyl]acetic acid, described in U.S. Pat. No. 5,296,495 and Japanese
patent JP08325265 A.
[0123] The term "5-lipoxygenase inhibitor" or "5-LO inhibitor"
includes any agent or compound that inhibits, restrains, retards or
otherwise interacts with the enzymatic action of 5-lipoxygenase.
Non-limitative examples of 5-lipoxygenase inhibitors include
zileuton, docebenone, piripost, ICI-D2318, and ABT 761.
[0124] Non-limitative examples of .beta.-adrenergic receptor
agonists include: albuterol, bitolterol, isoetharine,
mataproterenol, perbuterol, salmeterol, terbutaline, isoproterenol,
ephedrine and epinephrine.
[0125] A non-limitative example of a xanthine derivative is
theophylline.
[0126] Non-limitative examples of .alpha.-adrenergic receptor
agonists include arylalkylamines, (e.g., phenylpropanolamine and
pseudephedrine), imidazoles (e.g., naphazoline, oxymetazoline,
tetrahydrozoline, and xylometazoline), and cycloalkylamines (e.g.,
propylhexedrine).
[0127] A non-limitative example of a mast cell stabilizer is
nedocromil sodium.
[0128] Non-limitative examples of anti-tussive agents include
codeine, dextromethorphan, benzonatate, chlophedianol, and
noscapine.
[0129] A non-limitative example of an expectorant is
guaifenesin.
[0130] Non-limitative examples of NK.sub.1, NK.sub.2 and NK.sub.3
tachykinin receptor antagonists include CP-99,994 and SR 48968.
[0131] Non-limitatve examples of GABA.sub.B agonists include
baclofen and 3-aminopropyl-phosphinic acid.
[0132] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 70 percent active ingredient. Suitable solid
carriers are known in the art, e.g. magnesium carbonate, magnesium
stearate, talc, sugar, lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration.
[0133] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides or cocoa butter is first melted,
and the active ingredient is dispersed homogeneously therein as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool and thereby solidify.
[0134] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection.
[0135] Liquid form preparations may also include solutions for
intranasal administration.
[0136] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas.
[0137] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0138] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0139] Preferably the compound is administered orally.
[0140] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0141] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.1 mg to 1000 mg,
more preferably from about 1 mg. to 300 mg, according to the
particular application.
[0142] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
increments until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
[0143] The amount and frequency of administration of the compounds
of the invention and the pharmaceutically acceptable salts thereof
will be regulated according to the judgment of the attending
clinician considering such factors as age, condition and size of
the patient as well as severity of the symptoms being treated. A
typical recommended dosage regimen is oral administration of from
10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four
divided doses to provide relief from pain, anxiety, depression,
asthma or alcohol abuse. The compounds are non-toxic when
administered within this dosage range.
[0144] For treating cough, the amount of nociceptin receptor ORL-1
agonist in a unit dose is preferably from about 0.1 mg to 1000 mg,
more preferably, from about 1 mg to 300 mg. A typical recommended
dosage regimen is oral administration of from 1 mg to 2000 mg/day,
preferably 1 to 1000 mg/day, in two to four divided doses. When
treating coughing, the nociceptin receptor ORL-1 agonist may be
administered with one or more additional agents for treating cough,
allergy or asthma symptoms selected from the group consisting of:
antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors,
H.sub.3 inhibitors, .beta.-adrenergic receptor agonists, xanthine
derivatives, .alpha.-adrenergic receptor agonists, mast cell
stabilizers, anti-tussives, expectorants, NK.sub.1, NK.sub.2 and
NK.sub.3 tachykinin receptor antagonists, and GABA.sub.B agonists.
The nociceptin receptor ORL-1 agonist and the additional agents are
preferably administered in a combined dosage form (e.g., a single
tablet), although they can be administered separately. The
additional agents are administered in amounts effective to provide
relief from cough, allergy or asthma symptoms, preferably from
about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg
per unit dose. A typical recommended dosage regimen of the
additional agent is from 1 mg to 2000 mg/day, preferably 1 to 1000
mg/day, in two to four divided doses.
[0145] The following are examples of pharmaceutical dosage forms
which contain a compound of the invention. The scope of the
invention in its pharmaceutical composition aspect is not to be
limited by the examples provided.
Pharmaceutical Dosage Form Examples
EXAMPLE A
Tablets
[0146]
16 No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500
2. Lactose USP 122 113 3. Corn Starch, Food Grade, as a 30 40 10%
paste in Purified Water 4. Corn Starch, Food Grade 45 40 5.
Magnesium Stearate 3 7 Total 300 700
[0147] Method of Manufacture
[0148] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.
Granulate the mixture with Item No. 3. Mill the damp granules
through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the
damp granules. Screen the dried granules if necessary and mix with
Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for
1-3 minutes. Compress the mixture to appropriate size and weigh on
a suitable tablet machine.
EXAMPLE B
Capsules
[0149]
17 No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500
2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4.
Magnesium Stearate NF 7 7 Total 253 700
[0150] Method of Manufacture
[0151] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15
minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture
into suitable two-piece hard gelatin capsules on a suitable
encapsulating machine.
[0152] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and variations thereof will be apparent
to those of ordinary skill in the art. All such alternatives,
modifications and variations are intended to fall within the spirit
and scope of the present invention.
* * * * *