U.S. patent application number 10/483291 was filed with the patent office on 2004-11-25 for carbocyclic hydrazino inhibitors of copper-containing amine oxidases.
Invention is credited to Alaranta, Sakari, Fulop, Ferenc, Lazar, Laszlo, Pihlavisto, Marjo, Smith, David John, Szakonyi, Zsolt, Vainio, Petri.
Application Number | 20040236108 10/483291 |
Document ID | / |
Family ID | 25416395 |
Filed Date | 2004-11-25 |
United States Patent
Application |
20040236108 |
Kind Code |
A1 |
Smith, David John ; et
al. |
November 25, 2004 |
Carbocyclic hydrazino inhibitors of copper-containing amine
oxidases
Abstract
The present invention is directed to carbocyclic hydrazino
compounds that function as inhibitors of copper-containing amine
oxidases commonly known as semicarbazide-sensitive amine oxidases
(SSAO), including the human SSAO known as Vascular Adhesion
Protein-1 (VAP-1). These SSAO inhibitors have therapeutic utility
as drugs to treat conditions and diseases including, but not
limited to, a number of inflammatory conditions and diseases (in
particular chronic inflammatory conditions such as chronic
arthritis, inflammatory bowel diseases, and chronic skin
dermatoses), diseases related to carbohydrate metabolism and to
aberrations in adipocyte differentiation or function and smooth
muscle cell function, and vascular diseases. The novel compounds
have the general formula: 1 or a pharmaceutically acceptable
solvate, hydrate, or salt thereof, wherein R.sup.1 to R.sup.11 are
as defined herein.
Inventors: |
Smith, David John;
(Naantali, FI) ; Fulop, Ferenc; (Szeged, HU)
; Pihlavisto, Marjo; (Kaarina, FI) ; Lazar,
Laszlo; (Szeged, HU) ; Alaranta, Sakari;
(Raisio, FI) ; Vainio, Petri; (Turku, FI) ;
Szakonyi, Zsolt; (Szeged, HU) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W.
WASHINGTON
DC
20005
US
|
Family ID: |
25416395 |
Appl. No.: |
10/483291 |
Filed: |
June 30, 2004 |
PCT Filed: |
July 11, 2002 |
PCT NO: |
PCT/FI02/00630 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10483291 |
Jun 30, 2004 |
|
|
|
09902789 |
Jul 12, 2001 |
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Current U.S.
Class: |
544/406 ;
546/307; 564/150 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 19/04 20180101; C07C 2602/08 20170501; A61P 25/28 20180101;
A61P 17/06 20180101; A61P 9/00 20180101; A61P 29/00 20180101; A61P
37/00 20180101; C07C 243/20 20130101; A61P 3/06 20180101; A61K
31/15 20130101; A61P 19/02 20180101; A61P 3/10 20180101; A61P 17/02
20180101; A61P 11/00 20180101; A61P 25/02 20180101; C07D 273/00
20130101; A61P 11/06 20180101; A61P 9/10 20180101; A61P 3/08
20180101; A61P 1/04 20180101; A61P 17/00 20180101 |
Class at
Publication: |
544/406 ;
546/307; 564/150 |
International
Class: |
C07D 213/72; C07D
241/02 |
Claims
What is claimed is:
1. A compound having the Formula I: 25or an isomer or a
pharmaceutically acceptable solvate, hydrate, or salt thereof:
wherein: R.sup.1 is hydrogen or (C.sub.1-C.sub.4)alkyl, aralkyl,
(C.sub.2-C.sub.5)alkanoyl, aroyl or heteroaroyl; R.sup.2 is
hydrogen, optionally substituted (C.sub.1-C.sub.4)alkyl, or
optionally substituted aralkyl; R.sup.3-R.sup.5 and R.sup.10, which
can be the same or different, are hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, optionally substituted aralkyl, optionally
substituted phenyl or optionally substituted heteroaryl; R.sup.3
and R.sup.10 are cis or trans arranged; R.sup.11 is hydrogen,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)alkanoyl or aralkyl;
R.sup.6-R.sup.9, which can be the same or different, are hydrogen,
optionally substituted (C.sub.1-C.sub.4)alkyl, halogen, hydroxy,
optionally substituted (C.sub.1-C.sub.4)alkoxy, optionally
substituted aralkyloxy, or (C.sub.1-C.sub.4)alkylamino; n is 1, 2
or 3, provided that R.sup.1 is not methyl when R.sup.2 is methyl, n
is 1 and R.sup.3 to R.sup.11 are hydrogen.
2. The compound according to claim 1, wherein, in the compound of
the Formula I, n has the meaning of 1.
3. The compound according to claim 1, wherein, in the compound of
the Formula I, R.sup.1 has the meaning of hydrogen.
4. The compound according to claim 1, wherein, in the compound of
the Formula I, R.sup.2 has the meaning of unsubstituted alkyl,
preferably methyl.
5. The compound according to claim 1, wherein, in the compound of
the Formula I, R.sup.11 is hydrogen.
6. The compound according to claim 1, wherein, in the compound of
the Formula I, R.sup.3 is hydrogen.
7. The compound according to claim 1, wherein, in the compound of
the Formula I, R.sup.4, R.sup.5 and R.sup.10 are hydrogen.
8. The compound according to claim 1, wherein, in the compound of
the Formula I, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
hydrogen.
9. A method of inhibiting a copper-containing amine oxidase
comprising contacting said amine oxidase with an inhibitory
effective amount of a compound of the Formula I' 26or an isomer or
a pharmaceutically acceptable solvate, hydrate, or salt thereof;
wherein: R.sup.1 is hydrogen or (C.sub.1-C.sub.4)alkyl, aralkyl,
(C.sub.2-C.sub.5)alkanoyl, aroyl or heteroaroyl; R.sup.2 is
hydrogen, optionally substituted (C.sub.1-C.sub.4)alkyl, or
optionally substituted aralkyl; R.sup.3-R.sup.5 and R.sup.10, which
can be the same or different, are hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, optionally substituted aralkyl, optionally
substituted phenyl or optionally substituted heteroaryl; R.sup.3
and R.sup.10 are cis or trans arranged; R.sup.11 is hydrogen,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)alkanoyl or aralkyl;
R.sup.6-R.sup.9, which can be the same or different, are hydrogen,
optionally substituted (C.sub.1-C.sub.4)alkyl, halogen, hydroxy,
optionally substituted (C.sub.1-C.sub.4)alkoxy, optionally
substituted aralkyloxy, or (C.sub.1-C.sub.4)alkylamino; n is 1, 2
or 3.
10. The method according to claim 9, wherein said contacting occurs
in vitro.
11. The method according to claim 9, wherein said contacting occurs
in vivo.
12. A method of treating an inflammatory disease or condition, a
disease related to carbohydrate metabolism, a disease related to
aberrations in adipocyte differentiation or function or smooth
muscle cell function, or a vascular disease, comprising
administering to an animal in need or such treatment or prevention
an effective amount of a compound of Formula I': 27or an isomer or
a pharmaceutically acceptable solvate, hydrate, or salt thereof;
wherein: R.sup.1 is hydrogen or (C.sub.1-C.sub.4)alkyl, aralkyl
(C.sub.2-C.sub.5)alkanoyl, aroyl or heteroaroyl; R.sup.2 is
hydrogen, optionally substituted (C.sub.1-C.sub.4)alkyl, or
optionally substituted aralkyl; R.sup.3-R.sup.5 and R.sup.10, which
can be the same or different, are hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, optionally substituted aralkyl, optionally
substituted phenyl or optionally substituted heteroaryl; R.sup.3
and R.sup.10 are cis or trans arranged; R.sup.11 is hydrogen,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)alkanoyl or aralkyl;
R.sup.6-R.sup.9, which can be the same or different, are hydrogen,
optionally substituted (C.sub.1-C.sub.4)alkyl, halogen, hydroxy,
optionally substituted (C.sub.1-C.sub.4)alkoxy, optionally
substituted aralkyloxy, or (C.sub.1-C.sub.4)alkylamino; n is 1, 2
or 3.
13. The method according to claim 12, wherein, in the compound of
the Formula I, n has the meaning of 1.
14. The method according to claim 12, wherein, in the compound of
the Formula I, R.sup.1has the meaning of hydrogen.
15. The method according to claim 12, wherein, in the compound of
the Formula I, R.sup.2 has the meaning of unsubstituted alkyl,
preferably methyl.
16. The method according to claim 12, wherein, in the compound of
the Formula I, R.sup.11 is hydrogen.
17. The method according to claim 12, wherein, in the compound of
the Formula I, R.sup.3 is hydrogen.
18. The method according to claim 12, wherein, in the compound of
the Formula I, R.sup.4, R.sup.5 and R.sup.10 are hydrogen.
19. The method according to claim 12, wherein, in the compound of
the Formula I, R.sup.6, R.sup.7, R.sup.8 and R.sub.9 are
hydrogen.
20. The method of claim 12, wherein said inflammatory disease or
condition is a connective tissue inflammatory disease or
condition.
21. The method of claim 20, wherein said connective tissue
inflammatory disease or condition is selected from the group
consisting of ankylosing spondylitis, Reiter's syndrome, psoriatic
arthritis, osteoarthritis or degenerative joint disease, rheumatoid
arthritis, Sjogren's syndrome, Behret's syndrome, relapsing
polychondritis, systemic lupus erythematosus, discoid lupus
erythematosus, systemic sclerosis, eosinophilic fasciitis,
polymyositis and dermatomyositis, polymyalgia rheumatica,
vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's
granulomatosis, mixed connective tissue disease, and juvenile
rheumatoid arthritis.
22. The method of claim 12, wherein said inflammatory disease or
condition is a gastrointestinal inflammatory disease or
condition.
23. The method of claim 22, wherein said gastrointestinal
inflammatory disease or condition is selected from the group
consisting of Crohn's disease, ulcerative colitis, irritable bowel
syndrome (spastic colon), fibrotic conditions of the liver,
inflammation of the oral mucosa (stomatitis), and recurrent aphtous
stomatitis.
24. The method of claim 12, wherein said inflammatory disease or
condition is a central nervous system inflammatory disease or
condition.
25. The method of claim 24, wherein said central nervous system
inflammatory disease or condition is selected from the group
consisting of multiple sclerosis, Alzheimer's disease, and
ischaemia-reperfusion injury associated with ischemic stroke.
26. The method of claim 12, wherein said inflammatory disease or
condition is a pulmonary inflammatory disease or condition.
27. The method of claim 26, wherein said pulmonary inflammatory
disease or condition is selected from the group consisting of
asthma, chronic obstructive pulmonary disease, and adult
respiratory distress syndrome.
28. The method of claim 12, wherein said inflammatory disease or
condition is a skin inflammatory disease or condition.
29. The method of claim 28, wherein said skin inflammatory disease
or condition is selected from the group consisting of contact
dermatitis, atopic dermatitis, psoriasis, pityriasis rosea, lichen
planus, and pityriasis rubra pilaris.
30. The method of claim 12, wherein said disease related to
carbohydrate metabolism is selected from the group consisting of
diabetes, atherosclerosis, vascular retinopathies, retinopathy,
nephropathy, nephrotic syndrome, polyneuropathy, mononeuropathies,
autonomic neuropathy, foot ulcers, joint problems, and increased
risk of infection.
31. The method of claim 12, wherein said disease related to
aberrations in adipocyte differentiation or function or smooth
muscle cell function is selected from the group consisting of
atherosclerosis and obesity.
32. The method of claim 12, wherein said vascular disease is
selected from the group consisting of atheromatous ateriosclerosis,
nonatheromatous ateriosclerosis, ischemic heart disease, peripheral
aterial occlusion, thromboangiitis obliterans (Buerger's disease),
and Raynaud's disease and phenomenon.
33. The method according to claim 12, wherein the compound is
selected from (1S,2S)-2-(1-Methylhydrazino)-1-indanol
hydrogenmaleate (1R*,2R*)-2-(1-Methylhydrazino)-1-indanol
hydrogenmaleate (1R*,2R*)-2-(1-Ethylhydrazino)-1-indanol
hydrogenmaleate (1R,2R)-2-(1-Methylhydrazino)-1-indanol
hydrogenmaleate (1S,2S)-2-(1-methylhydrazino)-1-indanol
hydrogenmaleate (1S,2S)-2-(1-methylhydrazino)-1-indanol fumarate
(1R,2R)-2-(1-methylhydra- zino)-1-indanol fumarate
(1S,2S)-2-(1-methylhydrazino)-1-indanol succinate
(1R,2R)-2-(1-methylhydrazino)-1-indanol succinate
(1R,2R)-2-(1-methylhydr- azino)-1-indanol (S,S)-tartrate
(1R,2R)-2-(1-methylhydrazino)-1-indanol (R,R)-tartrate
(1S,2S)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate
(1S,2S)-2-(1-methylhydrazino)-1-indanol (R,R)-tartrate or an
isomer, or a pharmaceutically acceptable solvate, hydrate or salt
thereof.
34. A pharmaceutical composition comprising a compound of any one
of the claims 1 to 8 and a pharmaceutically acceptable carrier and
a diluent.
35. A process for preparing a compound of claim 1, comprising:
subjecting an amino alcohol of the Formula II 28to N-nitrosation,
to form a compound of the Formula III 29which compound of the
formula III is thereafter reduced to give the desired compound of
the formula I, in which the substituents R.sup.1 to R.sup.11 have
the meanings given in claim 1, or an isomer, solvate, hydrate or
salt thereof.
36. A process for preparing a compound of the Formula I of claim 1,
comprising reacting an amino alcohol of the Formula II 30wherein
R.sup.11 is hydrogen, with an oxaziridine of the Formula V
31wherein R.sup.12 and R.sup.13 have the meaning of C.sub.1-C.sub.4
alkyl groups, or together represent a 5-7-member saturated
carbocycle, to give an oxadiazine of the formula IV 32which is
hydrolysed to form the desired hydrazine alcohol of the formula I,
wherein R.sup.11 and R.sup.1 are hydrogen, which compound obtained,
if desired, is converted to a compound of the Formula I wherein
R.sup.11 and R.sup.1 have a meaning other than hydrogen as defined
in claim 1, whereby the substituents R.sup.2 to R.sup.10 have the
meanings given in claim 1, or an isomer, solvate, hydrate or salt
thereof.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is in the field of medicinal chemistry
and is directed to carbocyclic hydrazino compounds and their use as
inhibitors of copper-containing amine oxidases (E.C. 1.4.3.6) and
enzymes of significant identity thereto. The compounds of the
present invention have therapeutic utility as drugs to treat
diseases including, but not limited to, inflammatory diseases. In
particular, acute and chronic inflammatory conditions or diseases
such as chronic arthritis, inflammatory bowel diseases and skin
dermatoses as well as diseases related to carbohydrate metabolism
and to aberrations in adipocyte differentiation or function and
smooth muscle cell function may be treated with the compounds.
[0003] 2. Related Art
[0004] VAP-1 is a human endothelial cell adhesion molecule that has
several unique properties that distinguish it from the other
inflammation-related adhesion molecules. It has a unique and
restricted expression pattern and mediates lymphocyte binding to
vascular endothelium (Salmi, M., and Jalkanen, S., Science 257:
1407-1409 (1992)). Inflammation induces the upregulation of VAP-1
to the surface of vascular endothelial cells mediating leukocyte
entry to skin, gut and inflamed synovium (Salmi, M., and Jalkanen,
S., Science 257: 1407-1409 (1992); Salmi, M., et al., J. Exp. Med
178:2255-2260 (1993); Arvillomi, A, et al., Eur. J. Immunol.
26:825-833 (1996); Salmi, M., et al, J. Clin. Invest. 99:2165-2172
(1997); (Salmi, M., and Jalkanen, S., J. Exp. Med. 183:569-579
(1996); J. Exp. Med. 186:589-600 (1997)). One of the most
interesting features of VAP-1 is a catalytic extracellular domain
which contains a monoamine oxidase activity (Smith, D. J., et al.,
J. Exp. Med. 188:17-27 (1998)).
[0005] The cloning and sequencing of the human VAP-1 cDNA revealed
that it encodes a transmembrane protein with homology to a class of
enzymes called the copper-containing amine oxidases (E.C. 1.4.3.6).
Enzyme assays have shown that VAP-1 possesses a monoamine oxidase
(MAO) activity which is present in the extracellular domain of the
protein (Smith, D. J., et al., J. Exp. Med. 188:17-27 (1998)).
Thus, VAP-1 is an ecto-enzyme. Analysis of the VAP-1 MAO activity
showed that VAP-1 belongs to the class of membrane-bound MAO's
termed semicarbazide-sensitive amine oxidases (SSAO). These are
distinguished from the widely distributed mitochondrial MAO-A and B
flavoproteins by amino acid sequence, cofactor, substrate
specificity and sensitivity to certain inhibitors. However, certain
substrates and inhibitors are common to both SSAO and MAO
activities. The mammalian SSAO's can metabolize various monoamines
produced endogenously or absorbed as dietary or xenobiotic
substances. They act principally on primary aliphatic or aromatic
monoamines such as methylamine or benzylamine (Lyles, G. A., Int.
J. Biochem. Cell Biol. 28:259-274 (1996)). Thus, VAP-1 located on
the vascular endothelial cell surface can act on circulating
primary monoamines with the following reaction pathway.
RNH2+O.sub.2+H.sub.2ORCHO+H.sub.2O.sub.2+NH.sub.3
[0006] The physiological substrates of VAP-1 SSAO in man have not
been clearly identified however methylamine is a good substrate for
VAP-1 SSAO. Methylamine is a product of various human biochemical
pathways for the degradation of creatinine, sarcosine and
adrenaline, and is found in various mammalian tissues and in blood.
It can also be derived from the diet by gut bacterial degradation
of dietary precursors. The concentration of methylamine in the
blood can be increased in certain physiological and pathological
situations such as diabetes. Another potential physiological
substrate is aminoacetone.
[0007] VAP-1 SSAO activity has been proposed to be directly
involved in the pathway of leukocyte adhesion to endothelial cells
by a novel mechanism involving direct interaction with an amine
substrate presented on a VAP-1 ligand expressed on the surface of a
leukocyte (Salmi et al. Immunity, (2001)). This publication
describes the direct involvement of VAP-1 SSAO activity in the
process of adhesion of leukocytes to endothelium. Thus inhibitors
of VAP-1 SSAO activity could be expected to reduce leukocyte
adhesion in areas of inflammation and thereby reduce leukocyte
trafficking into the inflamed region and therefore the inflammatory
process itself.
[0008] In human clinical tissue samples expression of VAP-1 is
induced at sites of inflammation. This increased level of VAP-1 can
lead to increased production of H.sub.2O.sub.2 generated from the
action of the VAP-1 SSAO extracellular domain on monoamines present
in the blood. This generation of H.sub.2O.sub.2 in the localized
environment of the endothelial cell could initiate other cellular
events. H.sub.2O.sub.2 is a known signaling molecule that can
upregulate other adhesion molecules and this increased adhesion
molecule expression may lead to enhanced leukocyte trafficking into
areas in which VAP-1 is expressed. It also may be that other
products of the VAP-1 SSAO reaction could have biological effects
also contributing to the inflammatory process. Thus the products of
the VAP-1 SSAO activity may be involved in an escalation of the
inflammatory process which could be blocked by specific SSAO
inhibitors.
[0009] VAP-1 SSAO may be involved in a number of other pathological
conditions associated with an increased level of circulating amine
substrates of VAP-1 SSAO. The oxidative deamination of these
substrates would lead to an increase in the level of toxic
aldehydes and and oxygen radicals in the local environment of the
endothelial cell which could damage the cells leading to vascular
damage. Increased levels of methylamine and aminoacetone have been
reported in patients with Type I and Type II diabetes and it has
been proposed that the vasculopathies such as retinopathy,
neuropathy and nephropathy seen in late stage diabetes could be
treated with specific inhibitors of SSAO activity.
[0010] The development of specific VAP-1 SSAO inhibitors that
modulate VAP-1 activity would be useful for the treatment of acute
and chronic inflammatory conditions or diseases such as chronic
arthritis, inflammatory bowel diseases, and skin dermatoses, as
well as diseases related to carbohydrate metabolism (including
diabetes and complications resulting from diabetes). In addition,
aberrations in adipocyte differentiation or function and smooth
muscle cell function (in particular, atherosclerosis), and various
vascular diseases may be suitable for treatment with VAP-1 SSAO
inhibitors.
SUMMARY OF THE INVENTION
[0011] The present invention is broadly directed to novel
carbocyclic hydrazino compounds of Formula I as well as the use
thereof as inhibitors of the class of copper-containing amine
oxidases known as semicarbazide-sensitive amine oxidases (SSAO),
including the human SSAO known as Vascular Adhesion Protein-1
(VAP-1). As VAP-1 SSAO inhibitors, compounds of the present
invention can function to prevent leukocyte adhesion events
mediated through SSAO activity as well as other functions of VAP-1
SSAO. Compounds of the present invention are therefore useful for
treating a number of inflammatory conditions and diseases of
connective tissue, skin, and the gastrointestinal, central nervous
system, and pulmonary systems, including such conditions as chronic
arthritis, inflammatory bowel diseases, and chronic dermatoses. The
compounds are also useful for treating diseases related to
carbohydrate metabolism (such as diabetes), to aberrations in
adipocyte differentiation or function or smooth muscle cell
function (such as atherosclerosis and obesity), and to various
vascular diseases (such as atheromatous and nonatheromatous
ateriosclerosis, ischemic heart disease, and peripheral aterial
occlusion).
[0012] A further aspect of the present invention is to provide a
pharmaceutical composition useful for treating disorders responsive
to a decrease in SSAO activity, containing an effective amount of a
compound of Formula I in a mixture with one or more
pharmaceutically acceptable carriers or diluents.
[0013] Another embodiment of the present invention is directed to
methods for making compounds of Formula I.
[0014] One aspect of the present invention is directed to novel
compounds of Formula I: 2
[0015] or an isomer or a pharmaceutically acceptable solvate,
hydrate, or salt thereof;
[0016] wherein:
[0017] R.sup.1 is hydrogen or (C.sub.1-C.sub.4)alkyl,
aralkyl,(C.sub.2-C.sub.5)alkanoyl, aroyl or heteroaroyl;
[0018] R.sup.2 is hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, or optionally substituted aralkyl;
[0019] R.sup.3-R.sup.5 and R.sup.10, which can be the same or
different, are hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, optionally substituted aralkyl, optionally
substituted phenyl or optionally substituted heteroaryl;
[0020] R.sup.3 and R.sup.10 are cis or trans arranged;
[0021] R.sup.11 is hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.5)alkanoyl or aralkyl;
[0022] R.sup.6-R.sup.9, which can be the same or different, are
hydrogen, optionally substituted (C.sub.1-C.sub.4)alkyl, halogen,
hydroxy, optionally substituted (C.sub.1-C.sub.4)alkoxy, optionally
substituted aralkyloxy, or (C.sub.1-C.sub.4)alkylamino;
[0023] n is 1, 2 or 3, with the proviso that R.sup.1 is not methyl
when R.sup.2 is methyl, n is 1 and R.sup.3 to R.sup.11 are
hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
[0024] In the description, "(C.sub.1-C.sub.4)alkyl" in the meaning
of an alkyl group, or as part of an alkoxy, alkanoyl or alkyl amino
group can be methyl, ethyl n-propyl, isopropyl, n-butyl, sec-butyl,
tert-butyl and isobutyl.
[0025] The term "(C.sub.2-C.sub.5)-alkanoyl" as employed herein
thus refers to a carbonyl moiety to which is attached an alkyl
group, such as any of the above C.sub.1-C.sub.4 alkyl groups. For
example, this term includes, but is not limited to, ethanoyl
propanoyl, butanoyl, 2-methyl propanoyl.
[0026] The term "halogen" or "halo" as employed herein by itself or
as part of another group refers to chlorine, bromine, fluorine or
iodine, with chlorine being preferred.
[0027] The term "substituted", unless otherwise provided for
herein, refers to one or more groups independently selected from
the group consisting of halo, hydroxy, amino,
di(C.sub.1-C.sub.4)alkylamino, halo(C.sub.1-C.sub.4) alkyl,
ar(C.sub.1-C.sub.4)alkyl, aryl, nitro, (C.sub.1-C.sub.4)alkoxy, and
(C.sub.1-C.sub.4)alkyl as long as the resulting compound is stable.
Preferred optional substituents include: halo,
(C.sub.1-C.sub.4)alkyl, hydroxy and (C.sub.1-C.sub.4)alkoxy and
di(C.sub.1-C.sub.4)alkyl amino.
[0028] Illustrative examples of "substituted (C.sub.1-C.sub.4)alkyl
group" are trifluoromethyl, 2,2,2-trifluoroethyl,
2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-hydroxyethyl,
3-hydroxyethyl, 3-(dimethylamino)propyl and 2-methoxyethyl.
[0029] Aroyl means an aryl group connected to a carbonyl group.
Such an aryl can be an monocyclic or bicyclic aromatic group
containing from 6 to 12 carbons in the ring portion, preferably
6-10 carbons in the ring portion, such as phenyl, naphthyl or
tetrahydronaphthyl. A preferred aryl group is phenyl, which can be
substituted or unsubstituted. Preferable substituents are lower
alkyl (i.e., C.sub.1-C.sub.4 alkyl), especially methyl, or a
halogen or lower alkoxy, such as methoxy, or nitro. As particular
preferred embodiments can be mentioned benzyl,p-methylbenzyl,p-
-chlorobenzyl, 2-phenylethyl and 3-phenylpropyl.
[0030] The term "aralkyl" as employed herein, or as a part of an
aralkyloxy group, should be interpreted as any aryl, such as those
mentioned above, attached to the alkyl, which is a chain of 1 to 6
carbon atoms and which in turn can be straight or branched.
Preferably, the chain contains 1 to 3 carbon atoms. A preferred
aryl group is phenyl, which can be substituted or unsubstituted.
Preferable substituents and embodiments are those mentioned above
for aryl.
[0031] Illustrative examples of "substituted phenyl group" are
o-tolyl, m-tolyl, p-tolyl, p-fluorophenyl, p-chlorophenyl.
[0032] The term "heteroaryl" as employed herein or as a part of
heteroaroyl, refers to groups having 5 to 14 ring atoms and
containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur
heteroatoms (where examples of heteroaryl groups are: thienyl,
benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl,
pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl,
phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,
4.alpha.H-carbazolyl, carbazolyl, .beta.-carbolinyl,
phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,
phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and
phenoxazinyl groups).
[0033] Illustrative and preferred "heteroaryl groups" are
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 1-thienyl,
2-thienyl.
[0034] According to a preferred embodiment, in the compound of the
Formula I, n has the meaning of 1.
[0035] According to a further embodiment, in the compound of
Formula I, R.sup.1 has the meaning of hydrogen.
[0036] According to another preferred embodiment, in the compound
of the Formula I, R.sup.2 has the meaning of unsubstituted alkyl,
such as methyl.
[0037] According to another preferred embodiment, in the compound
of the Formula I, R.sup.11 is hydrogen.
[0038] According to another preferred embodiment, in the compound
of the Formula I, R.sup.3 is hydrogen.
[0039] According to a further preferred embodiment, in the compound
of the Formula I, R.sup.4, R.sup.5 and R.sup.10 are hydrogen.
[0040] According to still a further preferred embodiment, in the
compound of the Formula I, R.sup.6, R.sup.7, R.sup.8 and R.sup.9
are hydrogen.
[0041] According to a second aspect, the invention is directed to a
method for the preparation of the compounds of Formula I.
[0042] Compounds I were synthesized starting from amino alcohols II
either via N-nitroso derivatives III or via oxadiazines IV. Nitroso
compounds III were obtained from amino alcohols II in slightly
acidic aqueous solution by using sodium nitrite (A. A. Potekhin, A.
O. Safronov, Zhur. Org. Khim., 1981, 17,379-386; H. Takahashi, T.
Senda, K. Higashiyama, Chem. Pharm. Bull., 1991, 39, 836-842; J-K.
Shen, H. Katayama, N. Takatsu, I. Shiro, J. Chem. Soc. Perkin
Trans. 1, 1993, 2087-2097) or by using other well known methods of
N-nitrosation (M. A. Zolfigol, M. H. Zebaijadian, G. Chehardoli, H.
Keypour, S. Salehzadeh, M. Shamsipur, J. Org. Chem., 2000, 66,
3619-3620). Reductions of nitroso compounds m were done either in
tetrahydrofurane by using lithium aluminium hydride (H. Takahashi,
T. Senda, K. Higashiyama, Chem. Pharm. Bull., 1991, 39, 836-842) or
in aqueous acetic acid by using zinc dust (D. L. Trepanier, V.
Sprancmanis, K. G. Wiggs, J. Org. Chem., 1964, 29, 668-672). Acidic
hydrolysis of oxadiazines IV (R.sup.12 and R.sup.13 are
(C.sub.1-C.sub.4)alkyl groups or can together represent a
5-7-membered saturated carbocycle), obtained from amino alcohols H
and oxaziridines V (. Schmitz, S. Schramm, Cs. Szntay, Zs. Kardos,
Liebigs Ann. Chem., 1983, 1043-1046), yielded hydrazino alcohols I.
In the compound I obtained, the groups R.sup.11 and R.sup.1 are
hydrogen. These groups can be converted to other groups R.sup.11
and R.sup.1 e.g. using known methods of alkylation and acylation.
3
[0043] Amino alcohols II were used as single diastereomers. The
synthesis of the enantiomers of compounds I started from
enantiomerically pure amino alcohols II. Transformations occurred
without noticeable racemization.
[0044] The compounds I of this invention are useful in the form of
acid addition salts. The expression "pharmaceutically acceptable
acid addition salt" is intended to apply to any non-toxic organic
and inorganic acid addition salts of the base compounds of formula
I. Illustrative inorganic acids, which form suitable salts include
hydrochloric, hydrobromic, sulfuric and phosphoric acids.
Illustrative organic acids, which form suitable salts include
acetic, lactic, malonic, succinic, glutaric, fumaric, malic,
tartaric, citric, ascorbic, maleic, benzoic, phenylacetic,
cinnamic, methanesulfonic and salicylic acids.
[0045] According to a further aspect, the invention concerns a
method of inhibiting a copper-containing amine oxidase, the said
method comprising contacting said amine oxidase with an inhibitory
effective amount of a compound of the Formula I' 4
[0046] or an isomer or a pharmaceutically acceptable solvate,
hydrate, or salt thereof;
[0047] wherein:
[0048] R.sup.1 is hydrogen or (C.sub.1-C.sub.4)alkyl, aralkyl,
(C.sub.2-C.sub.5)alkanoyl, aroyl or heteroaroyl;
[0049] R.sup.2 is hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, or optionally substituted aralkyl;
[0050] R.sup.3-R.sup.5 and R.sup.10, which can be the same or
different, are hydrogen, optionally substituted
(C.sub.1-C.sub.4)alkyl, optionally substituted aralkyl, optionally
substituted phenyl or optionally substituted heteroaryl;
[0051] R.sup.3 and R.sup.10 are cis or trans arranged;
[0052] R.sup.11 is hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.5)alkanoyl or aralkyl;
[0053] R.sup.6-R.sup.9, which can be the same or different, are
hydrogen, optionally substituted (C.sub.1-C.sub.4)alkyl, halogen,
hydroxy, optionally substituted (C.sub.1-C.sub.4)alkoxy, optionally
substituted aralkyloxy, or (C.sub.1-C.sub.4)alkylamino;
[0054] n is 1, 2 or 3.
[0055] In one embodiment, the compounds of Formula I are used to
treat or prevent connective tissue inflammatory conditions and
diseases. In particular, the compounds can be used to treat such
conditions or diseases as rheumatoid arthritis, ankylosing
spondylitis, psoriatic arthritis, and osteoarthritis.
[0056] In another embodiment, the compounds of Formula I are used
to treat or prevent gastrointestinal inflammatory conditions and
diseases, in particular those such as Crohn's disease, ulcerative
colitis, and irritable bowel syndrome.
[0057] In yet another embodiment, the compounds of Formula I are
used to treat central nervous system inflammatory conditions and
diseases, including multiple sclerosis, Alzheimer's disease, and
ischaemia-reperfusion injury associated with ischemic stroke.
[0058] In another embodiment, the compounds of Formula I are used
to treat or prevent pulmonary inflammatory conditions and diseases.
In particular, the compounds can be used to treat or prevent such
conditions or diseases as asthma and adult respiratory distress
syndrome.
[0059] In another embodiment, the compounds of Formula I are used
to treat or prevent chronic inflammatory skin conditions,
especially such inflammatory skin conditions as psoriasis, allergic
lesions, lichen planus, and pityriasis rosea.
[0060] In yet another embodiment, the compounds of Formula I are
used to treat or prevent diseases related to carbohydrate
metabolism and complications thereof such as diabetes and
complications from diabetes, microvascular and macrovascular
diseases such as atherosclerosis, vascular retinopathies,
nephropathies and neuropathies such as polyneuropathy,
mononeuropathies, and autonomic neuropathy.
[0061] In still another embodiment, the compounds of Formula I are
used to treat or prevent diseases related to or caused by
aberrations in adipocyte differentiation or function, such as
atherosclerosis or obesity.
[0062] In another embodiment, the compounds of Formula I are used
to treat or prevent diseases related to or caused by aberrations in
smooth muscle cell function, such as atherosclerosis.
[0063] In another embodiment, the compounds of Formula I are used
to treat or prevent vascular diseases, such as atheromatous and
nonatheromatous arteriosclerosis, ischemic heart disease, and
Raynaud's Disease and Phenomenon.
[0064] The present invention is also directed to pharmaceutical
compositions of these novel compounds of Formula I, as well as to
methods of making such compositions.
[0065] Some of the compounds disclosed herein may contain one or
more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms which are all
included in the invention. The present invention is also meant to
encompass racemic mixtures, resolved forms and mixtures thereof, as
well as the individual enantiomers that may be separated according
to methods that are well know to those of ordinary skill in the
art. When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless specified
otherwise, it is intended to include both E and Z geometric
isomers.
[0066] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms in space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0067] The term "asymmetric center" or "chiral center" refers to a
carbon atom to which four different groups are attached.
[0068] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposeable on its mirror image and hence optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its mirror image rotates the plane of
polarized light in the opposite direction.
[0069] The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
[0070] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule. The phrase "enantiomeric excess" refers to a mixture
wherein one enantiomer is present is a greater concentration than
its mirror image molecule.
[0071] When any variable occurs more than one time in any
constituent or in Formula I, its definition on each occurrence is
independent of its definition at every other occurrence. Also,
combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0072] The present invention provides a method of treating diseases
in which VAP-1 has a role by selectively inhibiting VAP-1 SSAO
activity, which method comprises administering to an animal in need
thereof a therapeutically effective amount of a compound selected
from the class of compounds depicted by Formula I, wherein one or
more compounds of Formula I is administered in association with one
or more non-toxic, pharmaceutically acceptable carriers and/or
diluents and/or adjuvants and if desired other active
ingredients.
[0073] The compounds of the present invention can be used to treat
inflammatory conditions and diseases including but not limited to
connective tissue inflammatory conditions and diseases such as
ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis,
osteoarthritis or degenerative joint disease, rheumatoid arthritis,
Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis,
systemic lupus erythematosus, discoid lupus erythematosus, systemic
sclerosis, eosinophilic fasciitis, polymyositis and
dermatomyositis, polymyalgia rheumatica, vasculitis, temporal
arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed
connective tissue disease, and juvenile rheumatoid arthritis;
gastrointestinal inflammatory conditions and diseases such as
Crohn's disease, ulcerative colitis, irritable bowel syndrome
(spastic colon), fibrotic conditions of the liver, inflammation of
the oral mucosa (stomatitis), and recurrent aphtous stomatitis;
central nervous system inflammatory conditions and diseases such as
multiple sclerosis, Alzheimer's disease, and ischaeniua-reperfusion
injury associated with ischemic stroke; pulmonary inflammatory
conditions and diseases such as asthma, chronic obstructive
pulmonary disease, and adult respiratory distress syndrome; and
skin inflammatory conditions and diseases such as contact
dermatitis, atopic dermatitis, psoriasis, pityriasis rosea, lichen
planus, and pityriasis rubra pilaris.
[0074] Moreover, the compounds of the invention can be used to
treat diseases related to carbohydrate metabolism and complications
thereof, such as diabetes and complications of diabetes including,
but not limited to microvascular and macrovascular disease such as
atherosclerosis, vascular retinopathies, retinopathy, nephropathy
and nephrotic syndrome, neuropathies such as polyneuropathy,
mononeuropathies, and autonomic neuropathy, and foot ulcers and
joint problems, as well as increased risk of infection; diseases
related to or caused by aberrations in adipocyte differentiation or
function such as atherosclerosis and obesity; and vascular diseases
such as -atheromatous and nonatheromatous ateriosclerosis, ischemic
heart disease including myocardial infarction, peripheral aterial
occlusion, thromboangiitis obliterans (Buerger's disease), and
Raynaud's disease and phenomenon.
[0075] In particular, the present compounds can be used to treat
atherosclerosis. It is known that VAP-1 is expressed on adipocytes,
smooth muscle cells, endothelial cells and is related to
inflammation. Atherosclerotic plaque consists of accumulated
intracellular and extracellular lipids, smooth muscle cells,
connective tissue, and glycosaminoglycans. The earliest detectable
lesion of atherosclerosis is the fatty streak (consisting of
lipid-laden foam cells, which are macrophages that have migrated as
monocytes from the circulation into the subendothelial layer of the
intima), which later evolves into the fibrous plaque (consisting of
intimal smooth muscle cells surrounded by connective tissue and
intracellular and extracellular lipids).
[0076] The term "treat inflammation" is intended to include the
administration of compounds of the present invention to a subject
for purposes, which can include prophylaxis, amelioration,
prevention or cure of an inflammatory condition or disease. Such
treatment need not necessarily completely ameliorate the
inflammatory condition or disease. Further, such treatment can be
used in conjunction with other traditional treatments for reducing
the inflammatory condition known to those of skill in the art.
[0077] The compounds of the present invention may be administered
in an effective amount within the dosage range of about 0.1
.mu.g/kg to about 300 mg/kg, preferably between 1.0 .mu.g/kg to 10
mg/kg body weight. Compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times
daily.
[0078] The pharmaceutical compositions of the present invention can
be administered to any animal that can experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are humans, although the invention is not intended to be so
limited.
[0079] The pharmaceutical compositions of the present invention can
be administered by any means that achieve their intended purpose.
For example, administration can be by parenteral, subcutaneous,
intravenous, intraarticular, intrathecal, intramuscular,
intraperitoneal, or intradermal injections, or by transdermal,
buccal, oromucosal, ocular routes or via inhalation. Alternatively,
or concurrently, administration can be by the oral route.
Particularly preferred is oral administration. The dosage
administered will be dependent upon the age, health, and weight of
the recipient, kind of concurrent treatment, if any, frequency of
treatment, and the nature of the effect desired.
[0080] In addition to the pharmacologically active compounds, the
pharmaceutical preparations of the compounds can contain suitable
pharmaceutically acceptable carriers comprising excipients and
auxiliaries that facilitate processing of the active compounds into
preparations that can be used pharmaceutically. The pharmaceutical
preparations of the present invention are manufactured in a manner
that is, itself, known, for example, by means of conventional
mixing, granulating, dragee-making, dissolving, or lyophilizing
processes. Thus, pharmaceutical preparations for oral use can be
obtained by combining the active compounds with solid excipients,
optionally grinding the resulting mixture and processing the
mixture of granules, after adding suitable auxiliaries, if desired
or necessary, to obtain tablets or dragee cores.
[0081] Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders, such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents can be added, such as the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings, that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions can be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol, and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate, are used. Slow-release and
prolonged-release formulations may be used with particular
excipients such as methacrylic acid--ethylacrylate copolymers,
methacrylic acid--ethyl acrylate copolymers, methacrylic
acid--methyl methacrylate copolymers and methacrylic acid--methyl
methylacrylate copolymers. Dye stuffs or pigments can be added to
the tablets or dragee coatings, for example, for identification or
in order to characterize combinations of active compound doses.
[0082] Other pharmaceutical preparations that can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules that may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids such as fatty oils or liquid
paraffin. In addition, stabilizers may be added.
[0083] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example water-soluble salts and alkaline solutions. Especially
preferred salts are maleate, fumarate, succinate, S,S tartrate, R,R
tartrate. In addition, suspensions of the active compounds as
appropriate oily injection suspensions can be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for
example, sesame oil, or synthetic fatty acid esters, for example,
ethyl oleate or triglycerides or polyethylene glycol-400 (the
compounds are soluble in PEG-400). Aqueous injection suspensions
can contain substances that increase the viscosity of the
suspension, for example sodium carboxymethyl cellulose, sorbitol,
and/or dextrarl Optionally, the suspension may also contain
stabilizers.
[0084] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered and obvious to those skilled in
the art are within the spirit and scope of the invention.
EXAMPLE 1
(1S,2S)-2-(1-methylhydrazino)-1-indanol hydrogenmaleate (1)
[0085] A solution of NaNO.sub.2 (11.25 g, 163 mmol) in H.sub.2O (80
ml) was added dropwise to a suspension
of(1S,2S)-2-methylamino-1-indanol (13.30 g, 81.5 mmol) in H.sub.2O
(150 ml) with vigorous stirring on an ice-cold bath, and then AcOH
(7.39 g, 123 mmol) was added dropwise. The mixture was stirred at
room temperature for 12 h, then was extracted with EtOAc
(4.times.150 ml). The combined organic phases were dried (sicc.
Na.sub.2SO.sub.4) and evaporated under reduced pressure to give
14.35 g N-nitroso derivative as a crystalline product which was
used in the next step without further purification.
[0086] A solution of(1S,2S)-2-methylamino-N-nitroso-1-indanol
(10.00 g, 52.0 mmol) in THF (80 ml) was added dropwise to a
strirred and ice-cooled suspension of LiAlH.sub.4 (3.95 g, 104
mmol) in THF (200 ml), and the mixture was stirred at ambient
temperature for 3 h. The excess of LiAlH.sub.4 was decomposed with
a mixture of H.sub.2O (8 ml) and THF (50 ml), the resulting
precipitate was filtered off and washed with EtOAc (4.times.100
ml). The combined filtrate and washings were dried (sicc.
Na.sub.2SO.sub.4) and evaporated under reduced pressure. The
crystalline residue was treated with an equivalent amount of maleic
acid in a mixture of EtOH and Et.sub.2O to give crystalline
hydrogenmaleate salt which was filtered off and recrystallized.
[0087] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 3.08 (4H, om,
CHCH.sub.2, NCH.sub.3), 3.43 (1H, m, CHCH.sub.2), 3.87 (1H, m,
NCH), 5.47 (1H, d, J=6.6 Hz, OCH), 6.29 (2H, s, CHCOOH), 7.34 (1H,
m, C.sub.6H.sub.4), 7.39 (3H, m, C.sub.6H.sub.4).
EXAMPLE 2
(1R*,2R*)-2-(1-Ethylhydrazino)-1-indanol hydrogenmaleate (2)
[0088] A solution of NaNO.sub.2 (1.38 g, 20 mmol) in H.sub.2O (10
ml) was added dropwise to a suspension of
(1R*,2R*)-2-ethylamino-1-indanol (1.77 g, 10 mmol) in H.sub.2O (50
ml) with vigorous stirring on an ice-cold bath, and then AcOH (0.90
g, 15 mmol) was added dropwise. The mixture was stirred at room
temperature for 8 h, then was extracted with EtOAc (4.times.50 ml).
The combined organic phases were dried (sicc. Na.sub.2SO.sub.4) and
evaporated under reduced pressure to give 1.95 g N-nitroso
derivative as crystalline product which was used in the next step
without further purification.
[0089] A solution of (1R*,2R*)-2-ethylamino-N-nitroso-1-indanol
(1.95 g, 9.5 mmol) in THF (20 ml) was added dropwise to a strirred
suspension of LiAlH.sub.4 (0.72 g, 19.0 mmol) in THF (50 ml), and
the mixture was stirred and refluxed for 2 h. The excess of
LiAlH.sub.4 was decomposed with a mixture of H.sub.2O (1.5 ml) and
THF (20 ml), the resulting precipitate was filtered off and washed
with EtOAc (2.times.75 ml). The combined filtrates were dried
(sicc. Na.sub.2SO.sub.4) and evaporated under reduced pressure. The
oily residue was treated with an equivalent amount of maleic acid
in a mixture of EtOH and Et.sub.2O to give crystalline
hydrogenmaleate salt which was filtered off and recrystallized.
[0090] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 1.41 (3H, t,
J=7.2 Hz, CH.sub.3), 3.14 (1H, dd, J=16.2, 8.3 Hz, CHCH.sub.2),
3.47 (3H, om, CHCH.sub.2, NCH.sub.2), 4.04 (1H, m, NCH), 5.46 (1H,
d, J=6.4, OCH), 6.29 (2H, s, CHCOOH) 7.30-7.45 (4H, om,
C.sub.6H.sub.4).
EXAMPLE 3
(1R*,2R*)-2-(1-Ethylhydrazino)-1-indanol hydrogenmaleate (2)
[0091] To a solution of 1-oxa-2-azaspiro[2.5]octane (1.12 g, 9.9
mmol) in ether (20 ml) a solution of
(1R*,2R*)-2-ethylamino-1-indanol (1.75 g, 9.9 mmol) in THF (25 ml)
was added. The reaction mixture was stirred at room temperature for
45 minutes then evaporated to dryness. 5% Hydrochloric acid (50 ml)
was added to the residue and the mixture was stirred at ambient
temperature for 1 h. The mixture was washed with Et.sub.2O
(2.times.30 ml), made alkaline with Na.sub.2CO.sub.3 under
ice-cooling and extracted with EtOAc (3.times.50 ml). The combined
EtOAc extracts were dried (sicc. Na.sub.2SO.sub.4) and evaporated
under reduced pressure. The oily residue was treated with an
equivalent amount of maleic acid in a mixture of EtOH and Et.sub.2O
to give crystalline hydrogenmaleate salt which was filtered off and
recrystallized.
[0092] .sup.1H-NMR (400 MHz, D.sub.2O): see Example 2
EXAMPLE 4
(1R*,2R*)-2-(1-Methylhydrazino)-1-indanol hydrogenmaleate (4)
[0093] To an ice-cooled and stirred suspension of zinc dust (2.62
g, 40 mmol) in H.sub.2O (10 ml) a solution of
(1R*,2R*)-2-methylamino-N-nitroso- -1-indanol(1.92 g,10 mmol,
prepared from (1R*,2R*)-2-methylamino-1-indanol according to
Example 1) in AcOH (18 ml) was added dropwise over a period of 45
min. During the addition, the temperature of the reaction mixture
was maintained at 20-25.degree. C. by external cooling. After the
addition was completed, the mixture was stirred at 50.degree. C.
for 1 h, then filtered by suction, and the zinc residue was washed
with a mixture of H.sub.2O (15 ml) and AcOH (5 ml). The combined
filtrate and washings were concentrated to ca. 10 ml in vacuo. The
iced-cooled solution was made basic with NaOH-solution and
extracted with Et.sub.2O (4.times.50 ml). The combined ethereal
extracts were dried (sicc. Na.sub.2SO.sub.4) and evaporated in
reduced pressure. The crystalline residue was treated with an
equivalent amount of maleic acid in a mixture of EtOH and Et.sub.2O
to give crystalline hydrogenmaleate salt which was filtered off and
recrystallized.
[0094] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 3.05 (1H, m,
CHCH.sub.2), 3.11 (3H, s, NCH.sub.3), 3.43 (1H, m, CHCH.sub.2),
3.86 (1H, m, NCH), 5.47 (1H, d, J=6.6 Hz, OCH), 6.28 (2H, s,
CHCOOH), 7.34 (1H, m, C.sub.6H.sub.4), 7.39 (3H, m,
C.sub.6H.sub.4).
EXAMPLE 5
(1R*,2R*)-2-(1-Ethylhydrazino)-1-indanol hydrogenmaleate (2)
[0095] To a stirred suspension of
(1R*,2R*)-2-ethylamino-N-nitroso-1-indan- ol (1.94 g, 9.4 mmol,
prepared from of(1R*,2R*)-2-ethylamino-1-indanol (1.77 g, 10 mmol)
according to Example 2), zinc dust (2.46 g, 37.6 mmol) and H.sub.2O
(15 ml), glacial acetic acid (3.00 g, 50 mmol) was added dropwise
over a period of 1 h. During the addition, the temperature of the
reaction mixture was maintained at 25-30.degree. C. by external
cooling. Subsequently the reaction mixture was stirred at
60.degree. C. for 1 h, allowed to cool, and the excess zinc dust
filtered by suction and washed with H.sub.2O (15 ml). The combined
filtrate and washings were made basic with aqueous NaOH-solution
and extracted with CHCl.sub.3 (4.times.50 ml). The combined organic
phases were dried (sicc. Na.sub.2SO.sub.4) and evaporated under
reduced pressure. The oily residue was treated with an equivalent
amount of maleic acid in a mixture of EtOH and Et.sub.2O to give
crystalline hydrogenmaleate salt which was filtered off and
recrystallized.
[0096] .sup.1H-NMR (400 MHz, D.sub.2O): see Example 2
EXAMPLE 6
(1R,2R)-2-(1-methylhydrazino)-1-indanol hydrogenmaleate (6)
[0097] (1R,2R)-2-(1-methylhydrazino)-1-indanol (1.45 g, 8.1 mmol,
prepared from (1R,2R)-2-methylamino-1-indanol (1.63 g, 10mmol)
according to Example 1) was treated with an equivalent amount of
maleic acid in a mixture of EtOH and Et.sub.2O to give crystalline
hydrogenmaleate salt which was filtered off and recrystallized.
[0098] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): same as that
of the (1S,2S)-enantiomer in Example 1.
EXAMPLE 7
(1S,2S)-2-(1-methylhydrazino)-1-indanol fumarate (7)
[0099] (1S,2S)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1S,2S)2-methylamino-1-indanol according to Example
1) was treated with fumaric acid (0.47 g, 4 mmol) in a mixture of
EtOH and Et.sub.2O to give crystalline fumarate salt which was
filtered off and recrystallized.
[0100] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 3.05
(2.times.4H, om, CHCH.sub.2, NCH.sub.3), 3.42 (2.times.1H, m,
CHCH.sub.2), 3.83 (2.times.1H, m, NCH), 5.46 (2.times.1H, d, J=6.6
Hz, OCH), 6.50 (2H, s, HOOCCH=CHCOOH), 7.34 (2.times.1H, m,
C.sub.6H.sub.4), 7.40 (2.times.3H, m, C.sub.6H.sub.4).
EXAMPLE 8
(1R,2R)-2-(1-methylhydrazino)-1-indanol fumarate (8)
[0101] (1R,2R)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1R,2R)-2-methylamino-1-indanol according to Example
1) was treated with fumaric acid (0.47 g, 4 mmol) in a mixture of
EtOH and Et.sub.2O to give crystalline fumarate salt which was
filtered off and recrystallized.
[0102] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): same as that
of the (1S,2S)-enantiomer in Example 7.
EXAMPLE 9
(1S,2S)-2-(1-methylhydrazino)-1-indanol succinate (9)
[0103] (1S,2S)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol
prepared from (1S,2S) 2-methylamino-1-indanol according to Example
1) was treated with succinic acid (0.48 g, 4 mmol) in a mixture of
EtOH and Et.sub.2O to give crystalline succinate salt which was
filtered off and recrystallized.
[0104] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 2.45 (4H, s,
HOOCCH.sub.2CH.sub.2COOH), 3.04 (2.times.4H, om, CHCH.sub.2,
NCH.sub.3), 3.39 (2.times.1H, m, CHCH.sub.2), 3.73 (2.times.1H, m,
NCH), 5.43 (2.times.1H, d, J=6.5 Hz, OCH), 7.30-7.45 (2.times.4H,
om, C.sub.6H.sub.4).
EXAMPLE 10
(1R,2R)-2-(1-methylhydrazino)-1-indanol succinate (10)
[0105] (1R,2R)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1R,2R)-2-methylamino-1-indanol according to Example
1) was treated with succinic acid (0.48 g, 4 mmol) in a mixture of
EtOH and Et.sub.2O to give crystalline succinate salt which was
filtered off and recrystallized.
[0106] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): same as that
of the (1S,2S)-enantiomer in Example 9.
EXAMPLE 11
(1S,2S)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate (11)
[0107] (1S,2S)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1S,2S) 2-methylamino-1-indanol according to Example
1) was treated with (S,S)-tartaric acid (0.60 g, 4 mmol) in EtOH to
give crystalline (S,S)-tartrate salt which was filtered off and
recrystallized.
[0108] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 3.06
(2.times.4H, om, CHCH.sub.2, NCH.sub.3), 3.42 (2.times.1H, m,
CHCH.sub.2), 3.84 (2.times.1H, m, NCH), 4.34 (2H, s,
HOOCCHOHCHOHCOOH), 5.47 (2.times.1H, d, J=6.5 Hz, OCH), 7.30-7.45
(2.times.4H, om, C.sub.6H.sub.4).
EXAMPLE 12
(1R,2R)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate (12)
[0109] (1R,2R)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1R,2R)-2-methylamino-1-indanol according to Example
1) was treated with (S,S)-tartaric acid (0.60 g, 4 mmol) in a
mixture of EtOH and EtOAc to give crystalline (S,S)-tartrate salt
which was filtered off and recrystallized.
[0110] .sup.1H-NM (400 MHz, D.sub.2O) .delta. (ppm): 3.06
(2.times.4H, om, CHCH.sub.2, NCH.sub.3),3.43 (2.times.11H, m,
CHCH.sub.2), 3.84 (2.times.1H, m, NCH), 4.34 (2H, s,
HOOCCHOHCHOHCOOH), 5.47 (2.times.1H, d, J=6.5 Hz, OCH), 7.30-7.45
(2.times.4H, om, C.sub.6H.sub.4).
EXAMPLE 13
(1S,2S)-2-(1-methylhydrazino)-1-indanol (R,R)-tartrate (13)
[0111] (1R,2R)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1R,2R)-2-methylamino-1-indanol according to Example
1) was treated with (R,R)-tartaric acid (0.60 g, 4 mmol) in a
mixture of EtOH and EtOAc to give crystalline (R,R)-tartrate salt
which was filtered off and recrystallized.
[0112] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): same as that
of (1R,2R)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate in
Example 12.
EXAMPLE 14
(1R,2R)-2-(1-methylhydrazino)-1-indanol (R,R)-tartrate (14)
[0113] (1S,2S)-2-(1-methylhydrazino)-1-indanol (1.43 g, 8 mmol,
prepared from (1S,2S) 2-methylamino-1-indanol according to Example
1) was treated with (R,R)-tartaric acid (0.60 g, 4 mmol) in EtOH to
give crystalline (R,R)-tartrate salt which was filtered off and
recrystallized.
[0114] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): same as that
of (1S,2S)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate in
Example 11.
EXAMPLE 19
(1S,2S)-2-(1-methylhydrazino)-1-methoxyindane hydrogenmaleate
(19)
[0115] 55% Sodium hydride suspension (2.00 g, 45.9 mmol) was washed
with n-hexane and suspended in THF (50 ml). A solution
of(1S,2S)-2-methylamino- -N-nitroso-1-indanol prepared according to
Example 1 (2.88 g, 15 mmol) in THF (90 ml) was degassed with
N.sub.2 flushing and added dropwise to the NaH suspension with
stirring and continuous N.sub.2 flushing at 0.degree. C. over a
period of 1 h. Stirring was continued at 0.degree. C. for 2 h, then
a solution of MeI (3.40 g, 24.0 mmol) in THF (30 ml) was added
dropwise to the stirred suspension at 0.degree. C. The mixture was
allowed to warm to room temperature and the excess of NaH
decomposed by addition of MeOH. The solution evaporated to dryness,
the residue was dissolved in H.sub.2O (50 ml) and extracted with
Et.sub.2O (3.times.50 ml). The combined ethereal extracts were
washed with H.sub.2O (50 ml) then dried (Na.sub.2SO.sub.4) and
evaporated under reduced pressure to give 2.6 g thick yellow oil
which was used in the next step without further purification.
[0116] A solution of
(1S,2S)-2-methylamino-N-nitroso-1-methoxyindane (2.47 g, 12.0 mmol)
in THF (30 ml) was added dropwise to a strirred and ice-cooled
suspension of LiAlH.sub.4 (1.80 g, 47.4 mmol) in THF (90 ml). The
mixture was stirred at 0.degree. C. for 3 h, then allowed to warm
to room temperature. The excess of LiAlH.sub.4 was decomposed with
a mixture of H.sub.2O (3.6 ml) and THF (25 ml), the resulting
precipitate was filtered off and washed with EtOAc (2.times.75 ml).
The combined filtratee were dried (sicc. Na.sub.2SO.sub.4) and
evaporated under reduced pressure. The residue was treated with an
equivalent amount of maleic acid in a mixture of EtOH and Et.sub.2O
to give crystalline hydrogenmaleate salt, which was filtered off
and recrystallized.
[0117] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 3.01 (3H, s
NCH.sub.3), 3.14 (1H, dd, J=5.8, 17.1 Hz, CHCH.sub.2), 3.48 (1H,
dd, J=8.3, 17.1 Hz, CHCH.sub.2), 3.55 (3H, s OCH.sub.3), 4.11 (1H,
m, NCH), 5.33 (1H, d, J=4.5 Hz, OCH), 6.29 (2H, s, CHCOOH),
7.36-7.52 (4H, m, C.sub.6H.sub.4).
1TABLE 1 Physical data of the synthesized racemic compounds
Elemental analysis M.p. Yield Formula Calcd./Found (%) Synthetic
Number Structure (.degree. C.) (%) (M.w.) C H N method 4 5 102-103
74 62 C.sub.14H.sub.18N.sub.2O.sub.5(294.30) 57.14 56.89 6.16 6.01
9.52 9.43 Example 4 2 6 92-94 68 45 61 C.sub.15H.sub.20N.sub.2O.s-
ub.5(308.33) 58.43 58.22 6.45 6.15 9.09 9.16 Example 2 Example 3
Example 5
[0118]
2TABLE 2 Physical data of the synthesized enantiomeric compounds
Elemental analysis M.p. Yield Formula Calcd./Found (%) Synthetic
Number Structure (.degree. C.) [.alpha.].sub.D.sup.20 (%) (M.w.) C
H N method 1 7 104-106 +23 (MeOH, c = 0.5) 74
C.sub.14H.sub.18N.sub.2O.sub.5(294.30) 57.14 57.37 6.16 6.03 9.52
9.45 Example 1 6 8 104-106 -23 (MeOH, c = 0.5) 72
C.sub.14H.sub.18N.sub.2O.sub.5(294.30) 57.14 56.86 6.16 5.92 9.52
9.49 Example 6 7 9 163-166 +25 (MeOH, c = 0.5) 72
C.sub.24H.sub.32N.sub.4O.sub.6(472.54) 61.00 59.61 6.83 6.70 11.86
11.84 Example 7 8 10 162-164 -25 (MeOH, c = 0.5) 69
C.sub.24H.sub.32N.sub.4O.sub.6(472.54) 61.00 59.99 6.83 6.76 11.86
11.72 Example 8 9 11 132-134 +24 (MeOH, c = 0.5) 62
C.sub.24H.sub.34N.sub.4O.sub.6(474.55) 60.74 60.53 7.22 7.18 11.81
11.87 Example 9 10 12 130-132 -22 (MeOH, c = 0.5) 65
C.sub.24H.sub.34N.sub.4O.sub.6(474.55) 60.74 60.81 7.22 7.05 11.81
11.64 Example 10 11 13 170-173 +13 (MeOH, c = 0.5) 73
C.sub.24H.sub.34N.sub.4O.sub.8(506.55) 56.91 56.68 6.77 6.39 11.06
11.01 Example 11 12 14 155-157 -33 (MeOH, c = 0.5) 66
C.sub.24H.sub.34N.sub.4O.sub.8(506.55) 56.91 57.14 6.77 6.75 11.06
10.92 Example 12 13 15 156-158 +31 (MeOH, c = 0.5) 68
C.sub.24H.sub.34N.sub.4O.sub.8(506.55) 56.91 56.60 6.77 6.43 11.06
10.99 Example 13 14 16 171-173 -13 (MeOH, c = 0.5) 71
C.sub.24H.sub.34N.sub.4O.sub.8(506.55) 56.91 56.86 6.77 6.60 11.06
10.87 Example 14 19 17 113-115 +33 (c = 0.5, MeOH)
C.sub.15H.sub.20N.sub.2O.sub.5(308.34) Example 19
EXAMPLE A
(1S,2S)-2-(1-methylhydrazino)-1-indanol (SZE 5298)
[0119] A solution of (1S,2S)-2-methylamino-N-nitroso-1-indanol
(1.92 g, 10.0 mmol) in THF (20 ml) was added dropwise to a strirred
and ice-cooled suspension of LiAlH.sub.4 (0.76 g, 20 mmol) in THF
(50 ml), and the mixture was stirred at ambient temperature for 3
h. The excess of LiAlH.sub.4 was decomposed with a mixture of
H.sub.2O (1.5 ml) and THF (20 ml), the resulting precipitate was
filtered off and washed with EtOAc (4.times.50 ml). The combined
filtrate and washings were dried (sicc. Na.sub.2SO.sub.4) and
evaporated under reduced pressure. The crystalline residue was
filtered and washed with Et.sub.2O.
[0120] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 2.59 (3H,
s, NCH.sub.3), 2.69 (1H, m, CHCH.sub.2), 2.89 (1H, m, CHCH.sub.2),
2.99 (1H, m, NCH), 3.48 (3H, br s, OH, NH.sub.2), 5.22 (1H, d,
J=7.1 Hz, OCH), 7.12-7.28 (3H, om, C.sub.6H.sub.4), 7.38 (1H, d,
J=6.9 Hz, C.sub.6H.sub.4).
EXAMPLE B/1
(1R,2S)-2-(1-methylhydrazino)-1-indanol (SZE 0000)
[0121] A solution of NaNO.sub.2 (0.17 g, 2.46 mmol) in H.sub.2O (2
ml) was added dropwise to a suspension of
(1R,2S)-2-methylamino-1-indanol (0.2 g, 1.23 mmol) in H.sub.2O (5
ml) with vigorous stirring on an ice-cold bath, and then AcOH (0.11
g, 1.83 mmol) was added dropwise. The mixture was stirred at room
temperature for 12 h, then was extracted with EtOAc (4.times.10
ml). The combined organic phases were dried (sicc.
Na.sub.2SO.sub.4) and evaporated under reduced pressure to give
0.20 g N-nitroso derivative as a crystalline product which was used
in the next step without further purification.
[0122] A solution of (1R,2S)-2-methylamino-N-nitroso-1-indanol
(0.20 g, 1.04 mmol) in THF (2 ml) was added dropwise to a strirred
and ice-cooled suspension of LiAlH.sub.4 (0.20 g, 5.27 mmol) in THF
(10 ml), and the mixture was stirred at ambient temperature for 3
h. The excess of LiAlH.sub.4 was decomposed with a mixture of
H.sub.2O (0.4 ml) and THF (10 ml), the resulting precipitate was
filtered off and washed with EtOAc (4.times.15 ml). The combined
filtrate and washings were dried (sicc. Na.sub.2SO.sub.4) and
evaporated under reduced pressure. The crystalline residue was
filtered and washed with Et.sub.2O.
[0123] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 2.66 (3H,
s, NCH.sub.3), 2.84-3.07 (3H, om, CHCH.sub.2 NCH), 3.20 (3H, br s,
OH, NH.sub.2), 5.04 (1H, d, J=5.1 Hz, OCH), 7.25 (3H, m,
C.sub.6H.sub.4), 7.46 (1H, m, C.sub.6H.sub.4).
EXAMPLE B/2
(1R,2S)-2-(1-methylhydrazino)-1-indanol hydrogenmaleate (SZE
5302)
[0124] (1R,2S)-2-methylamino-1-indanol (0.2 g, 1.23 mmol) was
converted to the corresponding hydrazino alcohol according to the
procedure described in Example B/1. The crystalline residue was
treated with an equivalent amount of maleic acid in a mixture of
MeOH and Et.sub.2O to give crystalline hydrogenmaleate salt, which
was filtered off and recrystallized.
[0125] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 3.19 (3H, s,
NCH.sub.3), 3.28 (1H, dd, J=15.6, 9.0 Hz, CHCH.sub.2), 3.37 (1H,
dd, J=15.6, 7.7 Hz, CHCH.sub.2), 4.06 (1H, m, NCH), 5.32 (1H, d,
J=5.4 Hz, OCH), 6.29 (2H, s, CHCOOH), 7.32-7.52 (4H, om,
C.sub.6H.sub.4).
EXAMPLE C
(1R*,2S*)-2-(1-methylhydrazino)-1-indanol hydrogenmaleate (SZE
5303)
[0126] (1R*,2S*)-2-Methylamino-1-indanol (0.2 g, 1.23 mmol) was
converted to the corresponding hydrazino alcohol hydrogenmaleate
according to the procedure described in Example B/2.
[0127] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): identical
with the spectrum of the (1R,2S) analogue.
EXAMPLE D
(1R*,2R*)-5-methyl-2-(1-methylhydrazino)-1-indanol hydrogenmaleate
(SZE 5283)
[0128] A solution of NaNO.sub.2 (1.38 g, 20 mmol) in H.sub.2O (10
ml) was added dropwise to a suspension of
(1R*,2R*)-5-methyl-2-methylamino-1-inda- nol (1.77 g, 10 mmol) in
H.sub.2O (25 ml) with vigorous stirring on an ice-cold bath, and
then AcOH (0.90 g, 15 mmol) was added dropwise. The mixture was
stirred at room temperature for 12 h, then was extracted with EtOAc
(4.times.40 ml). The combined organic phases were dried (sicc.
Na.sub.2SO.sub.4) and evaporated under reduced pressure to give
1.58 g N-nitroso derivative as an oil which was used in the next
step without further purification.
[0129] A solution of
(1S,2S)-5-methyl-2-methylamino-N-nitroso-1-indanol (1.58 g, 7.7
mmol) in THF (25 ml) was added dropwise to a strirred and
ice-cooled suspension of LiAlH4 (0.60 g, 15.8 mmol) in THF (40 ml),
and the mixture was stirred at ambient temperature for 3 h. The
excess of LiAlH4 was decomposed with a mixture of H.sub.2O (1.2 ml)
and THF (20 ml), the resulting precipitate was filtered off and
washed with EtOAc (4.times.50 ml). The combined filtrate and
washings were dried (sicc. Na.sub.2SO.sub.4) and evaporated under
reduced pressure. The oily residue was treated with an equivalent
amount of maleic acid in a mixture of EtOH and Et.sub.2O to give
crystalline hydrogenmaleate salt, which was filtered off and
recrystallized.
[0130] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 2.34 (3H, s,
CCH.sub.3), 2.96-3.13 (4H, om, CHCH.sub.2, NCH.sub.3), 3.39 (1H,
dd, J=16.1, 8.1 Hz, CHCH.sub.2), 3.85 (1H, m, NCH), 5.43 (1H, d,
J=6.3 Hz, OCH), 6.29 (2H, s, CHCOOH), 7.16 (1H, s, C.sub.6H.sub.3),
7.21 (1H, d, J=7.8 Hz, C.sub.6H.sub.3), 7.30 (1H, d, J=7.7 Hz,
C.sub.6H.sub.3).
EXAMPLE E
(1R*,2R*)-6-methyl-2-(1-methylhydrazino)-1-indanol hydrogenmaleate
(SZE 5272)
[0131] (1R*,2S*)-6-Methyl-2-methylamino-1-indanol (1.77 g, 10 mmol)
was converted to the corresponding hydrazino alcohol
hydrogenmaleate according to the procedure described in Example
D.
[0132] .sup.1H-NMR (500 MHz, D.sub.2O) .delta. (ppm): 2.35 (3H, s,
CCH.sub.3), 3.00 (1H, dd, J=15.8, 8.4 Hz CHCH.sub.2), 3.08 (3H, s,
NCH.sub.3), 3.38 (1H, dd, J=15.8, 8.3 Hz, CHCH.sub.2), 3.83 (1H, m,
NCH), 5.42 (1H, d, J=6.5 Hz, OCH), 6.30 (2H, s, CHCOOH), 7.24 (3H,
m, C.sub.6H.sub.3).
EXAMPLE F
(1R*,2R*)-6-methoxy-2-(1-methylhydrazino)-1-indanol hydrogenmaleate
(SZE 5282)
[0133] (1R*,2S*)-6-Methoxy-2-methylamino-1-indanol (0.77 g, 4 mmol)
was converted to the corresponding hydrazino alcohol
hydrogenmaleate according to the procedure described in Example
D.
[0134] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. (ppm): 2.99-3.12
(4H, om, CHCH.sub.2, NCH.sub.3), 3.40 (1H, dd, J=16.3, 8.4 Hz,
CHCH.sub.2), 3.78-3.89 (4H, om, NCH, OCH.sub.3), 5.41 (1H, d, J=6.1
Hz, OCH), 6.26 (2H, s, CHCOOH), 6.94 (2H, m, C.sub.6H.sub.3) 7.33
(1H, d, J=8.4 Hz, C.sub.6H.sub.3).
3TABLE 1 Physical data of the synthesized racemic compounds
Elemental analysis M.p. Yield Formula Calcd./Found (%) Synthetic
Number Structure (.degree. C.) (%) (M.w.) C H N method SZE 5303 18
122-124 62 C.sub.14H.sub.18N.sub.2O.sub.5(294.30) 57.14 57.03 6.16
5.87 9.52 9.40 Example C SZE 5272 19 128-132 55
C.sub.15H.sub.20N.sub.2O- .sub.5(308.33) 58.43 58.62 6.54 6.48 9.09
9.03 Example E SZE 5283 20 98-107 58
C.sub.15H.sub.20N.sub.2O.sub.5(308.33) 58.43 58.19 6.54 6.20 9.09
8.86 Example D SZE 5282 21 121-123 72
C.sub.15H.sub.20N.sub.2O.sub.6(324.33) 55.55 55.27 6.22 6.08 8.64
8.54 Example F
[0135]
4TABLE 2 Physical data of the synthesized enantiomeric compounds
Elemental analysis M.p. Yield Formula Calcd./Found (%) Synthetic
Number Structure (.degree. C.) [.alpha.].sub.D.sup.20 (%) (M.w.) C
H N method SZE 5298 22 99-100 +29 (MeOH, c = 0.5) 75
C.sub.10H.sub.14N.sub.2O (178.23) 67.39 67.16 7.92 7.69 15.72 15.45
Example A SZE 0000 23 Slowly cryst. oil 68 C.sub.10H.sub.14N.sub.2O
(178.23) 67.39 67.16 7.92 7.69 15.72 15.45 Example B/1 SZE 5302 24
111-114 -4 (H.sub.2O, c = 0.5) 72
C.sub.14H.sub.18N.sub.2O.sub.5(294.30) 57.14 56.93 6.16 5.99 9.52
9.38 Example B/2
EXAMPLE 15
In Vitro Inhibition of VAP-1 SSAO Activity
[0136] VAP-1 SSAO activity was measured using the coupled
colourimetric method essentially as described for monoamine oxidase
and related enzimes (Holt, A, et al., Anal. Biochem. 244:384-392
(1997)). Recombinant human VAP-1 SSAO expressed in Chinese Hamster
Ovary (CHO) cells was used as a source of VAP-1 SSAO for activity
measurements. Native CHO cells have negligible SSAO activity. These
cells and their culture have previously been described (Smith, D.
J., et al., J. Exp. Med. 188:17-27 (1998)). A cell lysate was
prepared by suspending approximately 3.6.times.10.sup.8 cells in 25
ml lysis buffer (150 mM NaCl, 10 mM Tris-Base pH 7.2, 1.5 mM
MgCl.sub.2, 1% NP40) and incubating at 4.degree. C. overnight on a
rotating table. The lysate was clarified by centrifugation at 18000
g for 5 min at room temperature and the supernatant used directly
in the assay. The VAP-1 SSAO assay was performed in 96 well
microtitre plates as follows. To each well was added a
predetermined amount of inhibitor if required. The amount of
inhibitor varied in each assay but was generally at a final
concentration of between 1 nM and 50 .mu.M. Controls lacked
inhibitor. The inhibitor was in a total volume of20:1 in water. The
following reagents were then added. 0.2M potassium phosphate buffer
pH 7.6 to a total reaction volume of 200 .mu.l, 45 .mu.l of freshly
made chromogenic solution containing 1 mM 2,4-dichlorophenol, 500
.mu.M 4-aminoantipyrine and 4 U/ml horseradish peroxidase and an
amount of CHO cell lysate containing VAP-1 SSAO that caused a
change of 0.6 A.sub.490 per h. This was within the linear response
range of the assay. The plates were incubated for 30 min at
37.degree. C. and the background absorbance measured at 490 nm
using a Wallac Victor II multilabel counter. To initiate the enzyme
reaction 20 .mu.l 10 mM benzylamine (final concentration=1 mM) was
added and the plate incubated for 1 h at 37.degree. C. The increase
in absorbance, reflecting VAP-1 SSAO activity, was measured at 490
nm. Inhibition was presented as percent inhibition compared to
control after correcting for background absorbance and IC.sub.50
values calculated using GraphPad Prism.
EXAMPLE 16
Comparison of VAP-1 SSAO Activity Versus Total Rat MAO Activity
[0137] Rat MAO was prepared from rat liver by rinsing the 1 g liver
sample several times in 14 ml KCl-EDTA-solution to remove all
blood. Then 1 g liver sample was homogenised in 4 ml ice-cold
potassium phosphate buffer (0.1 M, pH 7.4) with an Ultra-Turrax
homogeniser (setting 11 000 rpm, 4.times.10 s). After
centrifugation at 500 g for 10 min at 4.degree. C. the supernatant
was carefully withdrawn and was centrifuged at 12 300 g for 15 min
at 4.degree. C. The supernatant was discharged and sedimented
mitochondria were resuspended in 4 ml fresh phosphate buffer and
centrifuged as previously. The mitochondria were suspended in 4 ml
phosphate buffer and homogenized with an Ultra-Turrax homogeniser
(setting 11000 rpm, 2.times.10 s). Mitochondrial preparate was
aliquoted and stored at -70.degree. C. Total MAO activity was
measured in a similar way as for VAP-1 SSAO except that
2,4-dichlorophenol was replaced by 1 mM vanillic acid. To each well
was added a predetermined amount of inhibitor if required. The
amount of inhibitor varied in each assay but was generally at a
final concentration of between 10 nM and 800 .mu.M. Controls lacked
inhibitor. The inhibitor was in a total volume of 20:1 in water.
The following reagents were then added. 0.2 M potassium phosphate
buffer pH 7.6 for a total reaction volume of 300 .mu.l, 50 .mu.l of
freshly made chromogenic solution (as above) and 50 .mu.l of MAO
preparation. The plates were incubated for 30 min at 37.degree. C.
and the background absorbance measured at 490 nm using a Wallac
Victor II multilabel counter. To initiate the enzyme reaction 20
.mu.l of 5 mM tyramine (final concentration 0.5 mM) was added and
the plate incubated for 1 h at 37.degree. C. The increase in
absorbance, reflecting MAO activity, was measured at 490 nm.
Inhibition was presented as percent inhibition compared to control
after correcting for background absorbance and IC.sub.50 values
calculated using GraphPad Prism. Clorgyline and pargyline
(inhibitors of MAO-A and -B respectively) at 0.5 .mu.M were added
to some wells as positive controls for MAO inhibition.
[0138] The ability of compounds of Examples 1 to 14 to inhibit
VAP-1 SSAO activity with specificity for VAP-1 SSAO over rat MAO is
shown in Table 3. The results indicate that the compounds of the
invention are specific inhibitors of human VAP-1 SSAO activity. The
compounds of the present invention are therefore expected to have
therapeutic utility in the treatment of diseases and conditions in
which the SSAO activity of the human adhesion molecule VAP-1 plays
a role.
5TABLE 3 Potency and specificity of Examples 1 to 14 VAP-1 SSAO
Total MAO Selectivity for Example inhibitory activity inhibitory
activity VAP-1 SSAO over Compound IC.sub.50 uM IC.sub.50 uM MAO 4
0.66 21 32 2 5.30 19 4 1 0.70 22 31 6 0.65 19 29 7 0.47 13 28 8
0.56 12 21 9 0.62 16 26 10 0.66 15 23 12 0.66 20 30 14 0.71 20 28
11 0.71 22 31 13 0.66 19 29 19 4.32 14 3
EXAMPLE 17
Inhibition of Carrageenan-evoked Rat Paw Oedema
[0139] The Model in the Literature:
[0140] Carrageenan-induced rat paw oedema has been extensively used
in the evaluation of anti-inflammatory effects of various compounds
and it is useful in assessing the efficacy of compounds to
alleviate acute inflammation (Whiteley P E and Dalrymple S A (1998)
Models of inflammation: carrageenan-induced paw edema in the rat,
in Current Protocols in Pharmacology (Enna S J, Williams M, Ferkany
J W, Kenakin T, Porsolt R E and Sullivan J P eds) pp 5.4.1-5.4.3,
John Wiley & Sons, New York.). The oedema is biphasic (Vinegar
et al., J. Pharmacol. Exp. Ther. 166:96-103 (1969)). The first
phase is not readily inhibited by cyclooxygenase inhibitors while
the later phase is (Seibert et al., Proc. Natl Acad. Sc (USA).
91:12013-12017 (1994)). The full development of the oedema has also
been demonstrated to be neutrophil-dependent (Salvemini et al, Br.
J. Pharmacol. 118:829-838. (1996)).
[0141] Description of Time Model Used:
[0142] Female Sprague Dawley rats were used and compound 4 was
injected at 3 different does of 10, 32 and 100 mg kg.sup.-1
intraperitoneally 15 min prior to carrageenan exposure. Oedema in
the paws was induced as previously described (Whiteley P E and
Dalrymple S A (1998) Models of inflammation: carrageenan-induced
paw edema in the rat, in Current Protocols in Pharmacology (Enna S
J, Williams M, Ferkany J W, Kenakin T, Porsolt R E and Sullivan J P
eds) pp 5.4.1-5.4.3, John Wiley & Sons, New York.).) by
injecting 0.05 ml of a 0.5% solution of carrageenan (Type IV
Lambda, Sigma) in saline with a 27-G needle subcutaneously in the
right hind foot pad. The size of the tested foot of each animal was
measured volumetrically using a plethysmometer (Ugo Basile, Cat.
No. 1750) before induction of oedema, and at 60 and 180 min after
carrageenan injection. Three hours after injection of carrageenan
the animals were killed in a CO.sub.2 atmosphere. Both hind-paws
were removed by severing them at the tarso-tibial joint and they
were weighed immediately using a scale accurate to 0.0001 g.
[0143] Outcome:
[0144] The 100 mg kg.sup.-1 dose clearly and significantly reduced
the paw swelling at 60 min (p<0.05 by Dunnett's test following
analysis of variance) and 180 min (FIG. 1) in which the oedema was
nearly totally inhibited (p<0.001 by Dunnett's test following
analysis of variance).
EXAMPLE 18
Inhibition of Collagen-Induced Arthritis in Mouse
[0145] The Model in the Literature:
[0146] Mouse collagen-induced arthritis (CIA) is a frequently used
model both for studying the basic mechanisms of autoimmune
arthritis and in assessing the efficacy of potential antiarthritic
agents (van den Berg and Joosten, 1999 in In Vivo Models of
Inflammation (Morgan D W and Marshall L A eds) pp 51-75, Birkhauser
Verlag, Basel). Compounds acting through various mechanisms have
been demonstratd to be effective in the model and they include
cyclooxygenase inhibitors, interleukins 4 and 10, leukotriene
synthesis inbitors and anti-TNF antibodies (Joosten et al, J.
Immunol. 159:4094-4102. 1997; van den Berg and Joosten, 1999 in In
Vivo Models of Inflammation (Morgan D W and Marshall L A eds) pp
51-75, Birkhauser Verlag, Basel)).
[0147] Description of the Model Used.
[0148] The study was conducted with groups of 14 mice to obtain
statistically valid results. For arthritis induction DBA/1 mice
(male, aged 10-12 weeks, approximate weight 25 g) were immunized
with bovine type II collagen (100 .mu.g) emulsified in Freund's
complete adjuvant by four subcutaneous injections in the back. At
day 21, animals were boosted with an i.p. injection of 100 .mu.g
collagen type II diluted in PBS. This strain is highly susceptible
to CIA induced with bovine type II collagen. After the second
immunization, polyarthritis starts to develop in 1 to 2 weeks, with
a disease incidence of approx. 80% at day 38 (Joosten et al., J.
Immunol. 159:4094-4102. 1997). Arthritis development was scored
from day 21 onwards. Animals were treated for 2.5 weeks starting
after the second booster but before the arthritis onset (day 23).
Intraperitoneal medication with compound 4 (10 or 50 mg kg.sup.-1
twice daily) was initiated at day 23 and continued until day
37.
[0149] Outcome:
[0150] A reduction in the final arthritis score (p<0.05 for
either dose by Dunn's test following Kruskal-Wallis test) and
cumulative score (p<0.05 for 10 mg kg.sup.-1 and p<0.01 for
50 mg kg.sup.-1 dose by Dunn's test following Kruskal-Wallis test)
was detected (FIG. 2). There was no statistically significant
effect on the lag time preceding the first signs of arthritis.
[0151] Having now fully described this invention, it will be
understood to those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations, and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *