U.S. patent application number 11/955460 was filed with the patent office on 2008-06-26 for spiropiperidine derivatives.
Invention is credited to Caterina Bissantz, Christophe Grundschober, Raffaello Masciadri, Hasane Ratni, Mark Rogers-Evans, Patrick Schnider.
Application Number | 20080153862 11/955460 |
Document ID | / |
Family ID | 39209551 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080153862 |
Kind Code |
A1 |
Bissantz; Caterina ; et
al. |
June 26, 2008 |
SPIROPIPERIDINE DERIVATIVES
Abstract
The present invention is concerned with novel spiro-piperidine
derivatives as V1a receptor antagonists, their manufacture,
pharmaceutical compositions containing them and their use for the
treatment of anxiety and depressive disorders and other diseases.
The compounds of present invention are described with formula (I)
##STR00001## wherein R.sup.1 to R.sup.5, R.sup.5', R.sup.7 to
R.sup.9, R.sup.7', R.sup.8', X and Y are as defined in the
specification.
Inventors: |
Bissantz; Caterina; (Village
Neuf, FR) ; Grundschober; Christophe; (Rodersdorf,
CH) ; Masciadri; Raffaello; (Basel, CH) ;
Ratni; Hasane; (Habsheim, FR) ; Rogers-Evans;
Mark; (Oberwil, CH) ; Schnider; Patrick;
(Bottmingen, CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
39209551 |
Appl. No.: |
11/955460 |
Filed: |
December 13, 2007 |
Current U.S.
Class: |
514/278 ;
546/17 |
Current CPC
Class: |
A61P 15/08 20180101;
A61P 25/22 20180101; A61P 25/24 20180101; C07D 401/06 20130101;
C07D 471/10 20130101; A61P 1/16 20180101; A61P 9/00 20180101; C07D
221/20 20130101; C07D 491/107 20130101; A61P 9/12 20180101; A61P
13/12 20180101; C07D 211/16 20130101; A61P 9/04 20180101; C07D
405/06 20130101 |
Class at
Publication: |
514/278 ;
546/17 |
International
Class: |
A61K 31/438 20060101
A61K031/438; A61P 25/22 20060101 A61P025/22; A61P 25/24 20060101
A61P025/24; C07D 491/107 20060101 C07D491/107; C07D 221/20 20060101
C07D221/20; C07D 471/10 20060101 C07D471/10 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 2006 |
EP |
06127086.4 |
Claims
1. A compound of formula (I) ##STR00067## wherein X is C.dbd.O and
Y is NR.sup.6, or X is CH.sub.2 and Y is NR.sup.6; R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are each independently hydrogen, halo,
C.sub.1-6-alkyl, optionally substituted by OH,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, optionally substituted by
OH, or halo-C.sub.1-6-alkoxy; R.sup.5 and R.sup.5' are each
independently hydrogen or methyl; R.sup.6 is hydrogen or
C.sub.1-6-alkyl; R.sup.7, R.sup.7' R.sup.8, R.sup.8', and R.sup.9
are each independently selected from hydrogen, halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, and cyano, or R.sup.7 and R.sup.8,
R.sup.7' and R.sup.8', R.sup.8 and R.sup.9, or R.sup.8' and R.sup.9
are bound together to form a ring with the phenyl moiety, wherein
--R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is
--N(R.sup.10)--N.dbd.CH--, or --CH.dbd.N--N(R.sup.10)--, wherein
R.sup.10 is hydrogen or C.sub.1-6-alkyl,
--N(R.sup.11)--CH.dbd.CH--, or --CH.dbd.CH--N(R.sup.12)--, wherein
R.sup.11 is hydrogen or C.sub.1-6-alkyl,
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, --O--(CR.sup.16R.sup.16').sub.n--O--, wherein n is 1 or
2, and R.sup.16 and R.sup.16' are each independently hydrogen, halo
or C.sub.1-6-alkyl, --N(R.sup.17)--CH.dbd.N--, or
--N.dbd.CH--N(R.sup.17)--, wherein R.sup.17 is hydrogen or
C.sub.1-6-alkyl, or --N(R.sup.18)--C(O)--CH.sub.2--, or
--CH.sub.2--C(O)--N(R.sup.18)--, wherein R.sup.18 is hydrogen or
C.sub.1-6-alkyl, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 having formula I-c ##STR00068##
3. The compound of claim 1 having formula I-h ##STR00069##
4. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each independently hydrogen, halo, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, optionally substituted by OH.
5. The compound of claim 1 wherein R.sup.1 is hydrogen or halo.
6. The compound of claim 1, wherein R.sup.2 is hydrogen, halo, or
C.sub.1-6-alkoxy.
7. The compound of claim 1, wherein R.sup.3 is hydrogen, halo, or
C.sub.1-6-alkoxy, optionally substituted by OH.
8. The compound of claim 1, wherein R.sup.4 is hydrogen or
C.sub.1-6-alkyl.
9. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are hydrogen.
10. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3, and
R.sup.4, are each independently C.sub.1-6-alkyl or
C.sub.1-6-alkoxy, optionally substituted by OH.
11. The compound of claim 1, wherein R.sup.5 and R.sup.5' are both
hydrogen or wherein R.sup.5 and R.sup.5' are both
C.sub.1-6-alkyl.
12. The compound of claim 1, wherein R.sup.6 is hydrogen or
C.sub.1-6-alkyl.
13. The compound of claim 1, wherein R.sup.7 and R.sup.7' are both
hydrogen.
14. The compound of claim 1, wherein R.sup.7 and R.sup.7' are each
independently hydrogen or halo.
15. The compound of claim 1, wherein one of R.sup.7 and R.sup.7' is
hydrogen and the other is halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano.
16. The compound of claim 1, wherein R.sup.8 and R.sup.8' are each
independently hydrogen, halo, or C.sub.1-6-alkoxy.
17. The compound of claim 1, wherein R.sup.7 and R.sup.8 or
R.sup.7' and R.sup.8' are bound together to form a ring with the
phenyl moiety, wherein --R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'--
is --N(R.sup.10)--N.dbd.CH-- or --CH.dbd.N--N(R.sup.10)--, wherein
R.sup.10 is hydrogen or C.sub.1-6-alkyl, --N(R.sup.11)--CH.dbd.CH--
or --CH.dbd.CH--N(R.sup.12)--, wherein R.sup.11 is hydrogen or
C.sub.1-6-alkyl,
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, --O--(CR.sup.16R.sup.16').sub.n--O--, wherein n is 1 or
2, and R.sup.16 and R.sup.16' are each independently hydrogen, halo
or C.sub.1-6-alkyl, or --N(R.sup.17)--CH.dbd.N-- or
--N.dbd.CH--N(R.sup.17)--, wherein R.sup.17 is hydrogen or
C.sub.1-6-alkyl.
18. The compound of claim 1, wherein R.sup.9 is hydrogen, halo, or
C.sub.1-6-alkyl.
19. The compound of claim 1, wherein R.sup.8 and R.sup.9 or
R.sup.8' and R.sup.9' are bound together to form a ring with the
phenyl moiety, wherein --R.sup.8-R.sup.9-- or --R.sup.8'-R.sup.9--
is --C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, --N(R.sup.18)--C(O)--CH.sub.2--, or
--CH.sub.2--C(O)--N(R.sup.18)--, wherein R.sup.18 is hydrogen or
C.sub.1-6-alkyl.
20. The compound of claim 1, wherein R.sup.7 and R.sup.8 are bond
together to form a ring with the phenyl moiety.
21. The compound of claim 1, wherein R.sup.7' and R.sup.8' are
bound together to form a ring with the phenyl moiety.
22. The compound of claim 24, selected from the group consisting of
5-Bromo-1'-(4-tert-butylbenzoyl)spiro[indole-3,4'-piperidin]-2(1H)-one;
5-Bromo-1'-(2-naphthoyl)spiro[indole-3,4'-piperidin]-2(1H)-one; and
1'-(4-Chlorobenzoyl)-4-methylspiro[indole-3,4'-piperidin]-2(1H)-one.
23. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula I ##STR00070## wherein X
is C.dbd.O and Y is NR.sup.6, or X is CH.sub.2 and Y is NR.sup.6;
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
hydrogen, halo, C.sub.1-6-alkyl, optionally substituted by OH,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, optionally substituted by
OH, or halo-C.sub.1-6-alkoxy; R.sup.5 and R.sup.5' are each
independently hydrogen or methyl; R.sup.6 is hydrogen or
C.sub.1-6-alkyl; R.sup.7, R.sup.7', R.sup.8, R.sup.8', and R.sup.9
are each independently selected from hydrogen, halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, and cyano, or R.sup.7 and R.sup.8,
R.sup.7' and R.sup.8', R.sup.8 and R.sup.9, or R.sup.8' and R.sup.9
are bound together to form a ring with the phenyl moiety, wherein
--R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is
--N(R.sup.10)--N.dbd.CH--, or --CH.dbd.N--N(R.sup.10)--, wherein
R.sup.10 is hydrogen or C.sub.1-6-alkyl,
--N(R.sup.11)--CH.dbd.CH--, or --CH.dbd.CH--N(R.sup.12)--, wherein
R.sup.11 is hydrogen or C.sub.1-6-alkyl,
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, --O--(CR.sup.16R.sup.16').sub.n--O--, wherein n is 1 or
2, and R.sup.16 and R.sup.16' are each independently hydrogen, halo
or C.sub.1-6-alkyl, --N(R.sup.17)--CH.dbd.N--, or
--N.dbd.CH--N(R.sup.17)--, wherein R.sup.17 is hydrogen or
C.sub.1-6-alkyl, or --N(R.sup.18)--C(O)--CH.sub.2--, or
--CH.sub.2--C(O)--N(R.sup.18)--, wherein R.sup.18 is hydrogen or
C.sub.1-6-alkyl, or a pharmaceutically acceptable salt thereof and
a pharmaceutically acceptable carrier.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 06127086.4, filed Dec. 22, 2006, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Vasopressin is a 9 amino acid peptide mainly produced by the
paraventricular nucleus of the hypothalamus. Three vasopressin
receptors, all belonging to the class I G-protein coupled
receptors, are known. The V1a receptor is expressed in the brain,
liver, vascular smooth muscle, lung, uterus and testis, the V1b or
V3 receptor is expressed in the brain and pituitary gland, the V2
receptor is expressed in the kidney where it regulates water
excretion and mediates the antidiuretic effects of vasopressin.
[0003] In the periphery vasopressin acts as a neurohormone and
stimulates vasoconstriction, glycogenolysis and antidiuresis. In
the brain vasopressin acts as a neuromodulator and is elevated in
the amygdala during stress (Ebner, K., C. T. Wotjak, et al. (2002).
"Forced swimming triggers vasopressin release within the amygdala
to modulate stress-coping strategies in rats." Eur J Neurosci
15(2): 384-8). The V1a receptor is extensively expressed in the
brain and particularly in limbic areas like the amygdala, lateral
septum and hippocampus which are playing an important role in the
regulation of anxiety. Indeed V1a knock-out mouse show a reduction
in anxious behavior in the plus-maze, open field and light-dark box
(Bielsky, I. F., S. B. Hu, et al. (2003). "Profound Impairment in
Social Recognition and Reduction in Anxiety-Like Behavior in
Vasopressin V1a Receptor Knockout Mice." Neuropsychopharmacology).
The downregulation of the V1a receptor using antisense
oligonucleotide injection in the septum also causes a reduction in
anxious behavior (Landgraf, R., R. Gerstberger, et al. (1995). "V1
vasopressin receptor antisense oligodeoxynucleotide into septum
reduces vasopressin binding, social discrimination abilities, and
anxiety-related behavior in rats." Regul Pept 59(2): 229-39).
[0004] The V1a receptor is also mediating the cardiovascular
effects of vasopressin in the brain by centrally regulating blood
pressure and heart rate in the solitary tract nucleus (Michelini,
L. C. and M. Morris (1999). "Endogenous vasopressin modulates the
cardiovascular responses to exercise." Ann N Y Acad Sci 897:
198-211). In the periphery it induces the contraction of vascular
smooth muscles and chronic inhibition of the V1a receptor improves
hemodynamic parameters in myocardial infarcted rats (Van
Kerckhoven, R., I. Lankhuizen, et al. (2002). "Chronic vasopressin
V(1A) but not V(2) receptor antagonism prevents heart failure in
chronically infarcted rats." Eur J Pharmacol 449(1-2): 135-41).
SUMMARY OF THE INVENTION
[0005] The present invention provides novel spiro-piperidine
derivatives as V1a receptor antagonists, their manufacture,
pharmaceutical compositions containing them and their use for the
treatment of anxiety and depressive disorders and other
diseases.
[0006] In particular, the present invention provides compounds of
formula (I)
##STR00002##
wherein [0007] X is O and Y is C.dbd.O, [0008] X is O and Y is
CH.sub.2, [0009] X is C.dbd.O and Y is NR.sup.6, [0010] X is
CH.sub.2 and Y is O, [0011] X-Y is CH.dbd.CH, [0012] X-Y is
CH.sub.2--CH.sub.2, [0013] X is C.dbd.O and Y is O, or [0014] X is
CH.sub.2 and Y is NR.sup.6; R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each independently
[0015] hydrogen,
[0016] halo,
[0017] C.sub.1-6-alkyl, optionally substituted by OH,
[0018] halo-C.sub.1-6-alkyl,
[0019] C.sub.1-6-alkoxy, optionally substituted by OH, or
[0020] halo-C.sub.1-6-alkoxy;
R.sup.5 and R.sup.5' are each independently hydrogen or methyl;
R.sup.6 is hydrogen or C.sub.1-6-alkyl; R.sup.7, R.sup.7', R.sup.8,
R.sup.8' and R.sup.9 are each independently selected from
[0021] hydrogen,
[0022] halo,
[0023] halo-C.sub.1-6-alkyl,
[0024] C.sub.1-6-alkyl,
[0025] C.sub.1-6-alkoxy,
[0026] halo-C.sub.1-6-alkoxy,
[0027] nitro, and
[0028] cyano,
[0029] or R.sup.7 and R.sup.8, R.sup.7' and R.sup.8', R.sup.8 and
R.sup.9, or R.sup.8' and R.sup.9 are bound together to form a ring
with the phenyl moiety, wherein
[0030] --R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is [0031]
--N(R.sup.10)--N.dbd.CH-- or --CH.dbd.N--N(R.sup.10)--, [0032]
wherein R.sup.10 is hydrogen or C.sub.1-6-alkyl, [0033]
--N(R.sup.11)--CH.dbd.CH-- or --CH.dbd.CH--N(R.sup.11)--, [0034]
wherein R.sup.11 is hydrogen or C.sub.1-6-alkyl, [0035]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0036] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0037] --O--(CR.sup.16R.sup.16').sub.n--O--, [0038]
wherein n is 1 or 2, and R.sup.16 and R.sup.16' are each
independently hydrogen, halo or C.sub.1-6-alkyl, [0039]
--N(R.sup.17)--CH.dbd.N-- or --N.dbd.CH--N(R.sup.17)--, [0040]
wherein R.sup.17 is hydrogen or C.sub.1-6-alkyl, or [0041]
--N(R.sup.18)--C(O)--CH.sub.2-- or --CH.sub.2--C(O)--N(R.sup.18)--,
[0042] wherein R.sup.18 is hydrogen or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof.
[0043] The compounds of formula (I) can be manufactured by the
methods given below, by the methods given in the examples or by
analogous methods. Appropriate reaction conditions for the
individual reaction steps are known to a person skilled in the art.
Starting materials are either commercially available or can be
prepared by methods analogous to the methods given below, by
methods described in references cited in the text or in the
examples, or by methods known in the art.
[0044] The compounds of formula (I) possess pharmaceutical
activity, in particular they are modulators of V1a receptor
activity. More particular, the compounds are antagonists of the V1a
receptor. Such antagonists are useful as therapeutics in the
conditions of dysmenorrhea, hypertension, chronic heart failure,
inappropriate secretion of vasopressin, liver cirrhosis, nephrotic
syndrome, obsessive compulsive disorder, anxiety and depressive
disorders. The preferred indications with regard to the present
invention are the treatment of anxiety and depressive
disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The following definitions of the general terms used in the
present description apply irrespective of whether the terms in
question appear alone or in combination. It must be noted that, as
used in the specification and the appended claims, the singular
forms "a", "an," and "the" include plural forms unless the context
clearly dictates otherwise.
[0046] In the present description, the term "alkyl", alone or in
combination with other groups, refers to a branched or
straight-chain monovalent saturated hydrocarbon radical. The term
"C.sub.1-6-alkyl" denotes a saturated straight- or branched-chain
hydrocarbon group containing from 1 to 6 carbon atoms, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
the isomeric pentyls and the like. A preferred sub-group of
C.sub.1-6-alkyl is C.sub.1-4-alkyl, i.e. with 1-4 carbon atoms.
[0047] In the present invention, the term "alkylene" refers to a
linear or branched saturated divalent hydrocarbon radical. In
particular, "C.sub.1-6-alkylene" means a linear saturated divalent
hydrocarbon radical of one to six carbon atoms or a branched
saturated divalent hydrocarbon radical of three to six carbon
atoms, e.g. methylene, ethylene, 2,2-dimethylethylene, n-propylene,
2-methylpropylene, and the like.
[0048] In the present description, the term "alkoxy" and
"C.sub.1-6-alkoxy" refers to the group R'--O--, wherein R' is alkyl
or C.sub.1-6-alkyl as defined above. Examples of alkoxy groups are
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,
sec-butoxy and the like. A preferred sub-group of C.sub.1-6-alkoxy,
and still more preferred alkoxy groups are methoxy and/or
ethoxy.
[0049] In the present description, the term "thioalkyl" and
"C.sub.1-6-thioalkyl" refers to the group R'--S--, wherein R' is
alkyl or C.sub.1-6-alkyl as defined above.
[0050] The term "C.sub.1-6-hydroxyalkyl" or "C.sub.1-6-alkyl
substituted by OH" denotes a C.sub.1-6-alkyl group as defined above
wherein at least one of the hydrogen atoms of the alkyl group is
replaced by a hydroxyl group.
[0051] The term "C.sub.1-6-cyanoalkyl" or "C.sub.1-6-alkyl
substituted by CN" denotes a C.sub.1-6-alkyl group as defined above
wherein at least one of the hydrogen atoms of the alkyl group is
replaced by a CN group.
[0052] The term "halo" or "halogen" refers to fluorine (F),
chlorine (Cl), bromine (Br) and iodine (I) with fluorine, chlorine
and bromine being preferred.
[0053] The term "halo-C.sub.1-6-alkyl"" is synonymous with
"C.sub.1-6-haloalkyl" or "C.sub.1-6-alkyl substituted by halo" and
means a C.sub.1-6-alkyl group as defined above wherein at least one
of the hydrogen atoms of the alkyl group is replaced by a halogen
atom, preferably fluoro or chloro, most preferably fluoro. Examples
of halo-C.sub.1-6-alkyl include but are not limited to methyl,
ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl
or n-hexyl substituted by one or more Cl, F, Br or I atom(s) as
well as those groups specifically illustrated by the examples
herein below. Among the preferred halo-C.sub.1-6-alkyl groups are
difluoro- or trifluoro-methyl or -ethyl.
[0054] The term "halo-C.sub.1-6-alkoxy" is synonymous with
"C.sub.1-6-haloalkoxy" or "C.sub.1-6-alkoxy substituted by halo"
and means a C.sub.1-6-alkoxy group as defined above wherein at
least one of the hydrogen atoms of the alkyl group is replaced by a
halogen atom, preferably fluoro or chloro, most preferably fluoro.
Among the preferred halogenated alkoxy groups are difluoro- or
trifluoro-methoxy or -ethoxy.
[0055] The term "C.sub.2-12-alkenyl", alone or in combination,
denotes a straight-chain or branched hydrocarbon residue of 2 to 12
carbon atoms comprising at least one double bond. A preferred
sub-group of C.sub.2-12-alkenyl is C.sub.2-6-alkyenyl. Examples of
the preferred alkenyl groups are ethenyl, propen-1-yl, propen-2-yl
(allyl), buten-1-yl, buten-2-yl, buten-3-yl, penten-1-yl,
penten-2-yl, penten-3-yl, penten-4-yl, hexen-1-yl, hexen-2-yl,
hexen-3-yl, hexen-4-yl and hexen-5-yl, as well as those
specifically illustrated by the examples herein below.
[0056] The term "one or more" substituents preferably means one,
two or three optional substituents per ring.
[0057] "Pharmaceutically acceptable," such as pharmaceutically
acceptable carrier, excipient, etc., means pharmacologically
acceptable and substantially non-toxic to the subject to which the
particular compound is administered.
[0058] The term "pharmaceutically acceptable acid addition salts"
embraces salts with inorganic and organic acids, such as
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methane-sulfonic acid,
p-toluenesulfonic acid and the like.
[0059] "Therapeutically effective amount" means an amount that is
effective to prevent, alleviate or ameliorate symptoms of disease
or prolong the survival of the subject being treated.
[0060] The term "bound together to form a ring with the phenyl
moiety" means that the residues of the phenyl ring, which are
located in ortho-position to each other, may form an anellated ring
to the phenyl moiety.
[0061] The invention further comprises individual optical isomers
of the compounds herein as well as racemic and non-racemic mixtures
thereof.
[0062] In detail, the present invention relates to compounds of
formula (I)
##STR00003##
wherein [0063] X is O and Y is C.dbd.O, [0064] X is O and Y is
CH.sub.2, [0065] X is C.dbd.O and Y is NR.sup.6, [0066] X is
CH.sub.2 and Y is O, [0067] X-Y is CH.dbd.CH, [0068] X-Y is
CH.sub.2--CH.sub.2, [0069] X is C.dbd.O and Y is O, or [0070] X is
CH.sub.2 and Y is NR.sup.6; R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each independently
[0071] hydrogen,
[0072] halo,
[0073] C.sub.1-6-alkyl, optionally substituted by OH,
[0074] halo-C.sub.1-6-alkyl,
[0075] C.sub.1-6-alkoxy, optionally substituted by OH, or
[0076] halo-C.sub.1-6-alkoxy;
R.sup.5 and R.sup.5' are each independently hydrogen or methyl;
R.sup.6 is hydrogen or C.sub.1-6-alkyl; R.sup.7, R.sup.7', R.sup.8,
R.sup.8', and R.sup.9 are each independently selected from
[0077] hydrogen,
[0078] halo,
[0079] halo-C.sub.1-6-alkyl,
[0080] C.sub.1-6-alkyl,
[0081] C.sub.1-6-alkoxy,
[0082] halo-C.sub.1-6-alkoxy,
[0083] nitro, and
[0084] cyano,
[0085] or R.sup.7 and R.sup.8, R.sup.7' and R.sup.8', R.sup.8 and
R.sup.9, or R.sup.8' and R.sup.9 are bound together to form a ring
with the phenyl moiety, wherein
[0086] --R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is [0087]
--N(R.sup.10)--N.dbd.CH-- or --CH.dbd.N--N(R.sup.10)--, [0088]
wherein R.sup.10 is hydrogen or C.sub.1-6-alkyl, [0089]
--N(R.sup.11)--CH.dbd.CH-- or --CH.dbd.CH--N(R.sup.12)--, [0090]
wherein R.sup.11 is hydrogen or C.sub.1-6-alkyl, [0091]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0092] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0093] --O--(CR.sup.16R.sup.16').sub.n--O--, [0094]
wherein n is 1 or 2, and R.sup.16 and R.sup.16' are each
independently hydrogen, halo or C.sub.1-6-alkyl, [0095]
--N(R.sup.17)--CH.dbd.N-- or --N.dbd.CH--N(R.sup.17)--, [0096]
wherein R.sup.17 is hydrogen or C.sub.1-6-alkyl, or [0097]
--N(R.sup.18)--C(O)--CH.sub.2-- or --CH.sub.2--C(O)--N(R.sup.18)--,
[0098] wherein R.sup.18 is hydrogen or C.sub.1-6-alkyl, or a
pharmaceutically acceptable salt thereof.
[0099] In certain embodiments of the invention, R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently hydrogen, halo,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy, optionally substituted by
OH.
[0100] In certain embodiments of the invention, R.sup.1 is hydrogen
or halo, preferably hydrogen or fluoro.
[0101] In certain embodiments of the invention, R.sup.2 is
hydrogen, halo or C.sub.1-6-alkoxy; preferably hydrogen, fluoro,
bromo or methoxy.
[0102] In certain embodiments of the invention, R.sup.3 is
hydrogen, halo, or C.sub.1-6-alkoxy, optionally substituted by OH;
preferably hydrogen, chloro, bromo, methoxy or
--O(CH.sub.2).sub.2OH.
[0103] In certain embodiments of the invention, R.sup.4 is hydrogen
or C.sub.1-6-alkyl; preferably hydrogen or methyl.
[0104] In certain embodiments all R.sup.1 to R.sup.4 are
hydrogen.
[0105] In certain embodiments, one residue of R.sup.1 to R.sup.4 is
halo and the others are hydrogen.
[0106] In certain embodiments, one residue of R.sup.1 to R.sup.4 is
C.sub.1-6-alkyl, preferably methyl, and the others are
hydrogen.
[0107] In certain embodiments, one residue of R.sup.1 to R.sup.4 is
C.sub.1-6-alkoxy, optionally substituted by OH, preferably methoxy
or --O(CH.sub.2).sub.2OH, and the others are hydrogen.
[0108] In certain embodiments of the invention, R.sup.5 and
R.sup.5' are both hydrogen, in other embodiments of the invention,
R.sup.5 and R.sup.5' are both methyl, in other embodiments of the
invention, R.sup.5 is hydrogen and R.sup.5' is methyl.
[0109] In certain embodiments of the invention, R.sup.5 is
hydrogen, R.sup.5' is methyl, X is O and Y is C.dbd.O.
[0110] In certain embodiments of the invention, R.sup.6 is hydrogen
or C.sub.1-6-alkyl, preferably hydrogen.
[0111] In certain embodiments of the invention, both R.sup.7 and
R.sup.7' are hydrogen.
[0112] In certain embodiments of the invention, one of R.sup.7 and
R.sup.7' is hydrogen and the other is halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano. In certain embodiments of the invention, R.sup.7 and
R.sup.7' are each independently hydrogen or halo.
[0113] In certain embodiments of the invention, one of R.sup.7 and
R.sup.7' is hydrogen and the other is halo, preferably chloro.
[0114] In certain embodiments of the invention, each of R.sup.8 and
R.sup.8' are independently hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano.
[0115] In certain embodiments of the invention, R.sup.8 and
R.sup.8' are each independently hydrogen, halo, or
C.sub.1-6-alkoxy, preferably hydrogen, chloro, ethoxy or
methoxy.
[0116] In certain embodiments of the invention, R.sup.7 and R.sup.8
or R.sup.7' and R.sup.8' are bound together to form a ring with the
phenyl moiety, wherein
[0117] --R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is [0118]
--N(R.sup.10)--N.dbd.CH-- or --CH.dbd.N--N(R.sup.10)--, [0119]
wherein R.sup.10 is hydrogen or C.sub.1-6-alkyl, [0120]
--N(R.sup.11)--CH.dbd.CH-- or --CH.dbd.CH--N(R.sup.12)--, [0121]
wherein R.sup.11 is hydrogen or C.sub.1-6-alkyl, [0122]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0123] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0124] --O--(CR.sup.16R.sup.16').sub.n--O--, [0125]
wherein n is 1 or 2, and R.sup.16 and R.sup.16' are each
independently hydrogen, halo or C.sub.1-6-alkyl, or [0126]
--N(R.sup.17)--CH.dbd.N-- or --N.dbd.CH--N(R.sup.17)--, [0127]
wherein R.sup.17 is hydrogen or C.sub.1-6-alkyl.
[0128] In certain embodiments of the invention, R.sup.7 and R.sup.8
are bound together to form a ring with the phenyl moiety as
described above, and
[0129] R.sup.9, R.sup.8' and R.sup.7' are hydrogen,
[0130] R.sup.9 and R.sup.7' are hydrogen, and R.sup.8' is halo,
preferably chloro, or
[0131] R.sup.9 and R.sup.7' are hydrogen, and R.sup.8' is
C.sub.1-6-alkoxy, preferably ethoxy or methoxy.
[0132] In certain embodiments of the invention, R.sup.7' and
R.sup.8' are bound together to form a ring with the phenyl moiety
as described above, and
[0133] R.sup.9, R.sup.8 and R.sup.7 are hydrogen,
[0134] R.sup.9 and R.sup.7 are hydrogen, and R.sup.8 is halo,
preferably chloro, or
[0135] R.sup.9 and R.sup.7 are hydrogen, and R.sup.8 is
C.sub.1-6-alkoxy, preferably ethoxy or methoxy.
[0136] In certain embodiments of the invention, R.sup.7 and R.sup.8
are halo, preferably chloro, and R.sup.9, R.sup.7' and R.sup.8' are
hydrogen.
[0137] In certain embodiments of the invention, R.sup.9 is
hydrogen, halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano.
[0138] In certain embodiments of the invention, R.sup.9 is
hydrogen, halo, or C.sub.1-6-alkyl, preferably hydrogen, chloro or
tert-butyl.
[0139] In certain embodiments of the invention,
R.sup.8 and R.sup.9 or R.sup.8' and R.sup.9 are bound together to
form a ring with the phenyl moiety, wherein
[0140] --R.sup.8-R.sup.9-- or --R.sup.8'-R.sup.9'-- is [0141]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0142] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0143] --N(R.sup.18)--C(O)--CH.sub.2-- or
--CH.sub.2--C(O)--N(R.sup.18)--, [0144] wherein R.sup.18 is
hydrogen or C.sub.1-6-alkyl.
[0145] In certain embodiments of the invention, R.sup.8 and R.sup.9
are bound together to form a ring with the phenyl moiety as
described above, and R.sup.7, R.sup.8' and R.sup.7' are
hydrogen.
[0146] In certain embodiments of the invention, R.sup.8' and
R.sup.9 are bound together to form a ring with the phenyl moiety as
described above, and R.sup.7, R.sup.8 and R.sup.7' are
hydrogen.
[0147] In certain embodiments of the invention, R.sup.8 and R.sup.9
are halo, preferably chloro, and R.sup.7, R.sup.7' and R.sup.8' are
hydrogen.
[0148] In certain embodiments of the invention, R.sup.8' and
R.sup.9 are halo, preferably chloro, and R.sup.7, R.sup.7' and
R.sup.8'' are hydrogen.
[0149] In certain embodiments of the invention, R.sup.9 is
C.sub.1-6-alkyl or halo, preferably tert-butyl or chloro, and
R.sup.7, R.sup.7', R.sup.8, and R.sup.8' are hydrogen.
[0150] Preferred compounds of the invention are those of formula
(I) wherein
R.sup.8 and R.sup.9 are halo, or wherein R.sup.8 and R.sup.9 are
bound together to form a ring with the phenyl moiety, wherein
[0151] --R.sup.8-R.sup.9-- is [0152]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0153] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, and R.sup.7, R.sup.7' and R.sup.8' are hydrogen.
[0154] Preferred compounds of the invention are those of formula
(I) wherein
R.sup.8' and R.sup.9 are halo, or wherein R.sup.8' and R.sup.9 are
bound together to form a ring with the phenyl moiety, wherein
[0155] --R.sup.8'-R.sup.9-- is [0156]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0157] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, and R.sup.7, R.sup.7' and R.sup.8 are hydrogen.
[0158] Preferably, R.sup.7, R.sup.7', R.sup.8, R.sup.8' and R.sup.9
are not simultaneously hydrogen.
[0159] A certain embodiment of the invention relates to a compound
of formula (I)
##STR00004##
wherein [0160] X is O and Y is C.dbd.O, [0161] X is O and Y is
CH.sub.2, [0162] X is C.dbd.O and Y is NR.sup.6, [0163] X is
CH.sub.2 and Y is O; or [0164] X-Y is CH.dbd.CH, or [0165] X-Y is
CH.sub.2--CH.sub.2, or [0166] X is C.dbd.O and Y is O, or [0167] X
is CH.sub.2 and Y is NR.sup.6; R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each independently
[0168] hydrogen,
[0169] halo,
[0170] C.sub.1-6-alkyl, optionally substituted by OH,
[0171] halo-C.sub.1-6-alkyl,
[0172] C.sub.1-6-alkoxy, optionally substituted by OH, or
[0173] halo-C.sub.1-6-alkoxy;
R.sup.5 and R.sup.5' are each independently hydrogen or methyl;
R.sup.6 is hydrogen or C.sub.1-6-alkyl; R.sup.7 and R.sup.7' are
each independently selected from
[0174] hydrogen,
[0175] halo,
[0176] halo-C.sub.1-6-alkyl,
[0177] C.sub.1-6-alkyl,
[0178] C.sub.1-6-alkoxy,
[0179] halo-C.sub.1-6-alkoxy,
[0180] nitro, and
[0181] cyano;
R.sup.8 and R.sup.8' are each independently selected from
[0182] hydrogen,
[0183] halo,
[0184] C.sub.1-6-alkoxy,
[0185] halo-C.sub.1-6-alkyl,
[0186] C.sub.1-6-alkyl,
[0187] halo-C.sub.1-6-alkoxy,
[0188] nitro, and
[0189] cyano;
R.sup.7 and R.sup.8 or R.sup.7' and R.sup.8' are bound together to
form a ring with the phenyl moiety, wherein
[0190] --R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is [0191]
--N(R.sup.10)--N.dbd.CH--, or --CH.dbd.N--N(R.sup.10)--, [0192]
wherein R.sup.10 is hydrogen or C.sub.1-6-alkyl, [0193]
--N(R.sup.11)--CH.dbd.CH--, or --CH.dbd.CH--N(R.sup.11)--, [0194]
wherein R.sup.11 is hydrogen or C.sub.1-6-alkyl, [0195]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0196] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0197] --O--(CR.sup.16R.sup.16).sub.n--O--, [0198]
wherein n is 1 or 2, and R.sup.16 and R.sup.16' are each
independently hydrogen, halo or C.sub.1-6-alkyl, [0199]
--N(R.sup.17)--CH.dbd.N--, or --N.dbd.CH--N(R.sup.17)--, [0200]
wherein R.sup.17 is hydrogen or C.sub.1-6-alkyl, R.sup.9 is
hydrogen,
[0201] halo,
[0202] C.sub.1-6-alkyl,
[0203] halo-C.sub.1-6-alkyl,
[0204] C.sub.1-6-alkoxy,
[0205] halo-C.sub.1-6-alkoxy,
[0206] nitro, or
[0207] cyano;
R.sup.8 and R.sup.9 or R.sup.8' and R.sup.9 are bound together to
form a ring with the phenyl moiety, wherein
[0208] --R.sup.8-R.sup.9-- or --R.sup.8'-R.sup.9-- is [0209]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0210] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0211] --N(R.sup.18)--C(O)--CH.sub.2--, or
--CH.sub.2--C(O)--N(R.sup.18)--, [0212] wherein R.sup.18 is
hydrogen or C.sub.1-6-alkyl, or a pharmaceutically acceptable salt
thereof.
[0213] A certain embodiment of the invention relates to compounds
of formula (I)
##STR00005##
wherein [0214] X is O and Y is C.dbd.O, [0215] X is O and Y is
CH.sub.2, [0216] X is C.dbd.O and Y is NR.sup.6, [0217] X is
CH.sub.2 and Y is O, [0218] X-Y is CH.dbd.CH, [0219] X-Y is
CH.sub.2--CH.sub.2, [0220] X is C.dbd.O and Y is O, or [0221] X is
CH.sub.2 and Y is NR.sup.6; R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each independently
[0222] hydrogen,
[0223] halo, or
[0224] C.sub.1-6-alkoxy, optionally substituted by OH,
R.sup.5 and R.sup.5' are each independently hydrogen or methyl;
R.sup.6 is hydrogen or C.sub.1-6-alkyl; R.sup.7 and R.sup.7' are
each independently hydrogen or halo; R.sup.8 and R.sup.8' are each
independently hydrogen, halo, or C.sub.1-6-alkoxy; R.sup.7 and
R.sup.8 or R.sup.7' and R.sup.8' are bound together to form a ring
with the phenyl moiety, wherein
[0225] --R.sup.7-R.sup.8-- or --R.sup.7'-R.sup.8'-- is [0226]
--N(R.sup.10)--N.dbd.CH-- or --CH.dbd.N--N(R.sup.10)--, [0227]
wherein R.sup.10 is hydrogen or C.sub.1-6-alkyl, [0228]
--N(R.sup.11)--CH.dbd.CH-- or --CH.dbd.CH--N(R.sup.11)--, [0229]
wherein R.sup.11 is hydrogen or C.sub.1-6-alkyl, [0230]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0231] wherein R.sup.12, R.sup.13 R.sup.14 and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0232] --O--(CR.sup.16R.sup.16').sub.n--O--, [0233]
wherein n is 1 or 2, and R.sup.16 and R.sup.16' are each
independently hydrogen, halo or C.sub.1-6-alkyl, [0234]
--N(R.sup.17)--CH.dbd.N-- or --N.dbd.CH--N(R.sup.17)--, [0235]
wherein R.sup.17 is hydrogen or C.sub.1-6-alkyl, R.sup.9 is
hydrogen, halo, or C.sub.1-6-alkyl; R.sup.8 and R.sup.9 or R.sup.8'
and R.sup.9 are bound together to form a ring with the phenyl
moiety, wherein
[0236] --R.sup.8-R.sup.9-- or --R.sup.8'-R.sup.9-- is [0237]
--C(R.sup.12).dbd.C(R.sup.13)--C(R.sup.14).dbd.C(R.sup.15)--,
[0238] wherein R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
independently selected from hydrogen, halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano, [0239] --N(R.sup.18)--C(O)--CH.sub.2-- or
--CH.sub.2--C(O)--N(R.sup.18)--, [0240] wherein R.sup.18 is
hydrogen or C.sub.1-6-alkyl, or a pharmaceutically acceptable salt
thereof.
[0241] In one embodiment, the invention provides compounds of
formula I wherein [0242] X is O and Y is C.dbd.O, [0243] X is O and
Y is CH.sub.2, [0244] X is CH.sub.2 and Y is O, or [0245] X is
C.dbd.O and Y is O.
[0246] In one embodiment, the invention provides compounds of
formula I wherein [0247] X is C.dbd.O and Y is NR.sup.6, or [0248]
X is CH.sub.2 and Y is NR.sup.6.
[0249] In one embodiment, the invention provides compounds of
formula I wherein [0250] X is C.dbd.O and Y is NR.sup.6, or [0251]
X is CH.sub.2 and Y is NR.sup.6.
[0252] An embodiment of the invention relates to compounds of
formula (I-a)
##STR00006##
wherein R.sup.1 to R.sup.5' and R.sup.7 to R.sup.9 are as defined
in any combination as described above.
[0253] An embodiment of the invention relates to compounds of
formula (I-b)
##STR00007##
wherein R.sup.1 to R.sup.5' and R.sup.7 to R.sup.9 are as defined
in any combination as described above.
[0254] An embodiment of the invention relates to compounds of
formula (I-c)
##STR00008##
wherein R.sup.1 to R.sup.9 are as defined in any combination as
described above.
[0255] An embodiment of the invention relates to compounds of
formula (I-d)
##STR00009##
wherein R.sup.1 to R.sup.5' and R.sup.7 to R.sup.9 are as defined
in any combination as described above.
[0256] An embodiment of the invention relates to compounds of
formula (I-e)
##STR00010##
wherein R.sup.1 to R.sup.5' and R.sup.7 to R.sup.9 are as defined
in any combination as described above.
[0257] An embodiment of the invention relates to compounds of
formula (I-f)
##STR00011##
wherein R.sup.1 to R.sup.5' and R.sup.7 to R.sup.9 are as defined
in any combination as described above.
[0258] An embodiment of the invention relates to compounds of
formula (I-g)
##STR00012##
wherein R.sup.1 to R.sup.5' and R.sup.7 to R.sup.9 are as defined
in any combination as described above.
[0259] An embodiment of the invention relates to compounds of
formula (I-h)
##STR00013##
wherein R.sup.1 to R.sup.9 are as defined in any combination as
described above.
[0260] Any compound of formula (I-a) to (I-h) may be combined with
any residue or combination of residues R.sup.1 to R.sup.9 as
defined above.
[0261] Preferred compounds are those of formula (I-a) to (I-f).
[0262] Preferred compounds of the invention are those of the
examples. More preferred are the following compounds: [0263]
6-Methoxy-1'-(2-naphthoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one,
[0264]
1'-(3,4-Dichlorobenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-o-
ne, [0265]
1'-(3,4-Dichlorobenzoyl)-6-methoxy-3H-spiro[2-benzofuran-1,4'-p-
iperidin]-3-one, [0266]
1'-(3,4-Dichlorobenzoyl)-5-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]--
3-one, [0267]
1'-(3,4-Dichlorobenzoyl)-5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-
-one, [0268]
1'-(3,4-Dichlorobenzoyl)-6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-p-
iperidin]-3-one, [0269]
1'-(4-tert-Butylbenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidine],
[0270]
1'-[(5-Methoxy-1H-indol-7-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperid-
ine], [0271]
5-Bromo-1'-(2-naphthoyl)spiro[indole-3,4'-piperidin]-2(1H)-one,
[0272] 1'-(2-Naphthoyl)spiro[indene-1,4'-piperidine], and [0273]
1'-(3,4-Dichlorobenzoyl)-2,3-dihydrospiro[indene-1,4'-piperidine].
[0274] The invention also encompasses methods for the treatment of
dysmenorrhea, hypertension, chronic heart failure, inappropriate
secretion of vasopressin, liver cirrhosis, nephrotic syndrome,
obsessive compulsive disorder, anxiety and depressive disorders
which comprises administering an effective amount of a compound of
formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or
(I-h).
[0275] The invention also encompasses a pharmaceutical composition
comprising a compound of formula (I), (I-a), (I-b), (I-c), (I-d),
(I-e), (I-f), (I-g) or (I-h) and a pharmaceutically acceptable
carrier. The pharmaceutical composition may further comprise at
least one pharmaceutically acceptable excipient.
[0276] In a certain embodiment, the compound of the invention can
be manufactured according to a process comprising reacting a
compound of formula (II):
##STR00014##
with an acid chloride of formula (III-b)
##STR00015##
to obtain the compound according to formula (I) wherein R.sup.1 to
R.sup.10 and X and Y are as defined above.
[0277] In a certain embodiment, the compound of the invention can
be manufactured according to a process comprising reacting a
compound of formula (II):
##STR00016##
with an acid of formula (III-a)
##STR00017##
to obtain the compound of formula (I) wherein R.sup.1 to R.sup.10
and X and Y are as defined above.
[0278] The synthesis of compounds of general formula (I) will be
described in more detail below and in the examples.
[0279] The compounds of the present invention exhibit V1a activity,
which may be detected as described below:
V1a Activity
Material & Method:
[0280] The human V1a receptor was cloned by RT-PCR from total human
liver RNA. The coding sequence was subcloned in an expression
vector after sequencing to confirm the identity of the amplified
sequence. To demonstrate the affinity of the compounds from the
present invention to the human V1a receptor binding studies were
performed. Cell membranes were prepared from HEK293 cells
transiently transfected with the expression vector and grown in 20
liter fermenters with the following protocol.
[0281] 50 g of cells were resuspended in 30 ml freshly prepared ice
cold Lysis buffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to
pH=7.4+complete cocktail of protease inhibitor (Roche
Diagnostics)); homogenized with Polytron for 1 min; and sonicated
on ice for 2.times.2 minutes at 80% intensity (Vibracell
sonicator). The preparation was centrifuged 20 min at 500 g at
4.degree. C., the pellet was discarded and the supernatant
centrifuged 1 hour at 43'000 g at 4.degree. C. (19'000 rpm). The
pellet was resuspended in 12.5 ml Lysis buffer+12.5 ml Sucrose 20%
and homogenized using a Polytron for 1-2 min. The protein
concentration was determined by the Bradford method, and aliquots
were stored at -80.degree. C. until use. For binding studies 60 mg
Yttrium silicate SPA beads (Amersham) were mixed with an aliquot of
membrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM
CaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50 ul of
bead/membrane mixture was then added to each well of a 96 well
plate, followed by 50 ul of 4 nM 3H-Vasopressin (American
Radiolabeled Chemicals). For total binding measurement 100 ul of
binding buffer were added to the respective wells, for non-specific
binding 100 ul of 8.4 mM cold vasopressin and for compound testing
100 ul of a serial dilution of each compound in 2% DMSO. The plate
was incubated 1 h at room temperature, centrifuged 1 min at 1000 g
and counted on a Packard Top-Count. Non-specific binding counts
were subtracted from each well and data was normalized to the
maximum specific binding set at 100%. To calculate an IC 50 the
curve was fitted using a non-linear regression model (XLfit), and
the Ki was calculated using the Cheng-Prussoff equation.
TABLE-US-00001 Ex pKi hV1a 1 8.08 6 7.72 7 7.54 9 7.32 11 7.53 12
7.66 25 7.2 27 7.3 33 6.96 36 7.05 42 6.95
[0282] The present invention also provides pharmaceutical
compositions containing compounds of the invention, such as
compounds of formula (I), and (Ia) to (If), or pharmaceutically
acceptable salts thereof and a pharmaceutically acceptable carrier.
Such pharmaceutical compositions can be in the form of tablets,
coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or suspensions. The pharmaceutical
compositions also can be in the form of suppositories or injectable
solutions.
[0283] The pharmaceutical compositions of the invention, in
addition to one or more compounds of the invention, contain a
pharmaceutically acceptable carrier. Suitable pharmaceutically
acceptable carriers include pharmaceutically inert, inorganic or
organic carriers.
[0284] Lactose, corn starch or derivatives thereof, talc, stearic
acid or its salts etc can be used as such excipients e.g. for
tablets, dragees and hard gelatine capsules. Suitable excipients
for soft gelatine capsules are e.g. vegetable oils, waxes, fats,
semi-solid and liquid polyols etc. Suitable excipients for the
manufacture of solutions and syrups are e.g. water, polyols,
saccharose, invert sugar, glucose etc. Suitable excipients for
injection solutions are e.g. water, alcohols, polyols, glycerol,
vegetable oils etc. Suitable excipients for suppositories are e.g.
natural or hardened oils, waxes, fats, semi-liquid or liquid
polyols etc.
[0285] Moreover, the pharmaceutical compositions can contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0286] The dosage at which a compound of the invention can be
administered can vary within wide limits and will, of course, be
fitted to the individual requirements in each particular case. In
general, in the case of oral administration a daily dosage of about
10 to 1000 mg per person of a compound of general formula (I)
should be appropriate, although the above upper limit can also be
exceeded when necessary.
[0287] The following Examples illustrate the present invention
without limiting it. All temperatures are given in degrees
Celsius.
Example A
[0288] Tablets of the following composition can be manufactured in
the usual manner:
TABLE-US-00002 mg/tablet Active substance 5 Lactose 45 Corn starch
15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight
100
Example B
[0289] Capsules of the following composition are manufactured:
TABLE-US-00003 mg/capsule Active substance 10 Lactose 155 Corn
starch 30 Talc 5 Capsule fill weight 200
[0290] The active substance, lactose and corn starch can be firstly
mixed in a mixer and then in a comminuting machine. The mixture the
can be returned to the mixer, the talc can be added thereto and
mixed thoroughly. The mixture can be filled by machine into hard
gelatine capsules.
Example C
[0291] Suppositories of the following composition can be
manufactured:
TABLE-US-00004 mg/supp. Active substance 15 Suppository mass 1285
Total 1300
[0292] The suppository mass can be melted in a glass or steel
vessel, mixed thoroughly and cooled to 45.degree. C.
[0293] Thereupon, the finely powdered active substance can be added
thereto and stirred until it has dispersed completely. The mixture
the can be poured into suppository moulds of suitable size, left to
cool; the suppositories then can be removed from the moulds and
packed individually in wax paper or metal foil.
[0294] In the following, the synthesis of compounds of formula (I)
is further exemplified: The following general scheme A is an
example of the preparation of the compounds of the invention
according to general procedure 1:
##STR00018##
General Procedure 1--Amide Coupling with Acid Chlorides:
[0295] A solution of the amine (1 eq), the acid chloride (1 eq) and
DIPEA (1.5 eq) in DMF is stirred at RT for 14 h. The mixture is
concentrated and purified by preparative HPLC to yield the desired
product.
[0296] The following general scheme B is an example of the
preparation of the compounds of the invention according to general
procedure 2:
##STR00019##
General Procedure 2--Amide Coupling with Carboxylic Acids:
[0297] A solution of the acid (1 eq) and HATU (1 eq) in DMF is
shaken for 30 min at RT and then a solution of the amine (1 eq) and
DIPEA (2 eq) in DMF is added and the mixture shaken at RT for 2 h.
The mixture is concentrated and purified by preparative HPLC to
yield the desired product.
EXAMPLES
Example 1
6-Methoxy-1'-(2-naphthoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
##STR00020##
[0299] Amide coupling according to general procedure I:
[0300] Amine: 6-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0301] Acid chloride: Naphthalene-2-carbonyl chloride
[0302] ES-MS m/e (%): 388.4 (M+H.sup.+).
Example 2
1'-(4-tert-Butylbenzoyl)-6-chloro-3H-spiro[2-benzofuran-1,4'-piperidin]-3--
one
##STR00021##
[0304] Amide coupling according to general procedure I:
[0305] Amine: 6-chloro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0306] Acid chloride: 4-tert-Butyl-benzoyl chloride
[0307] ES-MS m/e (%): 398.4 (M+H.sup.+).
Example 3
Rac-(1R,3'S)-1'-(4-tert-butylbenzoyl)-3'-methyl-3H-spiro[2-benzofuran-1,4'-
-piperidin]-3-one
##STR00022##
[0309] Amide coupling according to general procedure I:
[0310] Amine:
rac-(1R,3'S)-3'-methyl-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in WO 9929696)
[0311] Acid chloride: 4-tert-Butyl-benzoyl chloride
[0312] ES-MS m/e (%): 378.5 (M+H.sup.+).
Example 4
1'-(4-tert-Butylbenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
##STR00023##
[0314] Amide coupling according to general procedure I:
[0315] Amine: 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in Journal of Organic Chemistry (1976), 41(15),
2628-33)
[0316] Acid chloride: 4-tert-Butyl-benzoyl chloride
[0317] ES-MS m/e (%): 364.5 (M+H.sup.+).
Example 5
5-Methoxy-1'-(2-naphthoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
##STR00024##
[0319] Amide coupling according to general procedure I:
[0320] Amine: 5-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0321] Acid chloride: Naphthalene-2-carbonyl chloride
[0322] ES-MS m/e (%): 388.5 (M+H.sup.+).
Example 6
1'-(3,4-Dichlorobenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
##STR00025##
[0324] Amide coupling according to general procedure 2:
[0325] Amine: 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in Journal of Organic Chemistry (1976), 41(15),
2628-33)
[0326] Acid: 3,4-Dichloro-benzoic acid
[0327] ES-MS m/e (%): 376.4 (M+H.sup.+).
Example 7
1'-(3,4-Dichlorobenzoyl)-6-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-
-one
##STR00026##
[0329] Amide coupling according to general procedure 2:
[0330] Amine: 6-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0331] Acid: 3,4-Dichloro-benzoic acid
[0332] ES-MS m/e (%): 406.4 (M+H.sup.+).
Example 8
6-Chloro-1'-(3,4-dichlorobenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3--
one
##STR00027##
[0334] Amide coupling according to general procedure 2:
[0335] Amine: 6-chloro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0336] Acid: 3,4-Dichloro-benzoic acid
[0337] ES-MS m/e (%): 410.3 (M+H.sup.+).
Example 9
1'-(3,4-Dichlorobenzoyl)-5-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-
-one
##STR00028##
[0339] Amide coupling according to general procedure 2:
[0340] Amine: 5-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0341] Acid: 3,4-Dichloro-benzoic acid
[0342] ES-MS m/e (%): 406.4 (M+H.sup.+).
Example 10
5-Bromo-1'-(3,4-dichlorobenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-o-
ne
##STR00029##
[0344] Amide coupling according to general procedure 2:
[0345] Amine: 5-bromo-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described herein)
[0346] Acid: 3,4-Dichloro-benzoic acid
[0347] ES-MS m/e (%): 456.3 (M+H.sup.+).
[0348] The synthesis of
5-bromo-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one is described
below (3):
##STR00030##
Preparation of 1
1'-methyl-(5-bromo-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one)
[0349] Butyllithium (97.2 ml of 1.47 M solution in hexane, 143
mmol) was added dropwise to a solution of 2,5-Dibromo-benzoic acid
(20 g, 72 mmol) in dry THF (300 ml) at -78.degree. C. over a period
of 3.5 h under a nitrogen atmosphere. The reaction mixture was
stirred at -78.degree. C. for 2 h. A solution of N-methyl
piperidone (11.31 g, 99 mmol) in hexane (40 mL) was added dropwise
during 30 min to the reaction mixture at 78.degree. C. The reaction
mixture was allowed to come to room temperature and stirring was
continued for overnight. The reaction mixture was added to a
mixture of water (500 ml) and ether (300 mL). The aqueous layer was
extracted with ether (5.times.150 mL) and acidified with
concentrated HCl (to pH 2-3) and extracted with ether (2.times.150
ml).
[0350] The acidic solution was boiled for 1 h and then cooled to
0-5.degree. C. and made alkaline (to pH 9-10) with aqueous NaOH.
The cold solution was rapidly extracted with chloroform
(5.times.300 mL). The combined chloroform extracts were washed with
water (150 ml), dried over sodium sulfate and evaporated under
reduced pressure. The residue was purified was purified by silica
gel (100-200) column chromatography eluting with methanol in
dichloromethane (0.5% to 2.5%) to afford 1 (4.2 g, 20%). 1H-NMR
(400 MHz, CDCl3): .delta. 1.71 (d, J=14.2 Hz, 2H), 2.15-2.24 (m,
2H), 2.37 (s, 3H), 2.45-2.52 (m, 2H), 2.83-2.87 (m, 2H), 7.26 (d,
J=8.25 Hz, 1H), 7.75 (dd, J=7.8, 1.7 Hz, 1H). 13C-NMR (100 MHz,
CDCl3): .delta. 35.95, 46.05, 51.42, 84.00, 122.54, 122.97, 127.52,
128.64, 137.06, 152.24, 167.77.
Preparation of 2
1'-cyano-(5-bromo-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one)
[0351] A solution of 1 (3.0 g, 10 mmol) in chloroform (50 ml) was
added dropwise to a stirred boiling solution of cyanogens bromide
(12.16 g, 120 mmol) in chloroform (100 ml) under a nitrogen
atmosphere and the resulting solution was refluxed for overnight.
The reaction mixture was cooled and washed with 25 mL of 5% HCl and
then with 20 ml of water. The organic layer was dried over sodium
sulfate and evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (100-200) eluting with
methanol in dichloromethane (0.5% to 1.0%) to get the pure product
(1.6 g, 51%). 1H-NMR (400 MHz, CDCl3): .delta. 1.72 (d, J=14.2 Hz,
2H), 2.24-2.32 (m, 2H), 3.37-3.59 (m, 4H), 7.32 (d, J=8.2 Hz, 1H),
7.83 (dd, J=8.0, 1.7 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H).
Preparation of 3
5-bromo-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
[0352] A mixture of 2 (1.0 g, 3.2 mmol) and 20% HCl (12 ml) was
heated under reflux under a nitrogen atmosphere for 6 h. The
reaction mixture was cooled to 0-5.degree. C. and pH was adjusted
to 9-10 with aqueous NaOH solution and rapidly extracted with
chloroform (3.times.50 ml). The combined extracts were washed with
water, the organic layer was dried over sodium sulfate and
evaporated under reduced pressure. The residue was washed with
distilled hexane and dried under high vacuum to get the pure
product (0.64 g, 70%). IR (KBr) 3333.84, 290.53, 283525, 2811.07,
2749.38, 1756.04, 1470.28, 1415.14, 1271.03, 1196.28, 1083.84,
929.07, 831.50, 792.35, 734.78, 691.24, 548.46, 534.50 cm-1. 1H-NMR
(400 MHz, CDCl3): .delta. 1.66-1.72 (m, 2H), 2.02-2.09 (m, 2H),
3.07-3.18 (m, 4H), 7.29 (d, J=7.8 Hz, 1H), 7.77 (dd, J=7.8, 1.7 Hz,
1H), 7.99 (d, J=1.7 Hz, 1H). 13C-NMR (100 MHz, CDCl3): .delta.
6.33, 42.49, 85.23, 122.61, 122.93, 127.39, 128.64, 137.07, 152.44,
167.91. FIA-MS: 282.1 and 284.1; C12H1279BrNO2 [MH+] requires
282.1. mp: 162-163.degree. C.
Example 11
1'-(3,4-Dichlorobenzoyl)-5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3--
one
##STR00031##
[0354] Amide coupling according to general procedure 2:
[0355] Amine: 5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in WO 2001014376)
[0356] Acid: 3,4-Dichloro-benzoic acid
[0357] ES-MS m/e (%): 394.3 (M+H.sup.+).
Example 12
1'-(3,4-Dichlorobenzoyl)-6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-pi-
peridin]-3-one
##STR00032##
[0359] Amide coupling according to general procedure 2:
[0360] Amine:
6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in WO 2001014376)
[0361] Acid: 3,4-Dichloro-benzoic acid
[0362] ES-MS m/e (%): 436.4 (M+H.sup.+).
Preparation of
(6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one):
6
##STR00033##
[0363] Preparation of 4
1'-methyl-6-(2-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
[0364] To a solution of the substituted 2-bromo-4-fluoro-benzoic
acid (10.9 g, 50 mmol) in dry THF (200 ml) at -78.degree. C.
n-butyllithium (1.6 M in hexanes) (100 mmol) was added drop wise (3
h) and the resulting solution was stirred for an additional 2 h at
the same temperature. Freshly distilled N-methyl 4-piperidone 6
(7.91 g, 70 mmol) in dry hexane (25 ml) was added over 30 min at
the same temperature. The mixture was then allowed to stir at rt
and was finally added to ether (200 ml) and water (300 ml). The
basic (aqueous) layer was extracted with ether (5.times.100 ml) and
the aqueous layer was acidified with concentrated hydrochloric acid
(pH 2-3) and extracted with ether. The aqueous solution was boiled
for 1 h and was then cooled to 0-5.degree. C. and made alkaline (pH
9-10) with cold aqueous sodium hydroxide. The cold solution was
rapidly extracted with chloroform (5.times.200 ml). The combined
chloroform extracts were washed with water, dried, concentrated to
give light yellow solid which was purified over neutral alumina
eluting with a gradient of 30-50% ethyl acetate-hexane to obtain
1.75 g (15%) of 9 as white solid. 1H-NMR (CDCl.sub.3, 400 MHz):
1.68-1.75 (m, 2H), 2.18-2.19 (m, 1H), 2.38 (s, 3H), 2.44-2.52 (m,
2H), 2.68-2.84 (m, 2H), 2.84-2.85 (m, 1H), 7.02-7.05 (m, 1H),
7.19-7.22 (m, 1H), 7.84-7.87 (m, 1H); FIA-MS: 236 (M+1).
Preparation of 5
1'-cyano-6-(2-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
[0365] To a solution of the N-methylated lactone 9 (1.17 g, 5 mmol)
in dry chloroform (10 ml) was added cyanogenbromide (60 mnol) and
the resulting solution was refluxed for 36 h. The reaction mixture
was extracted with 5% HCl (5 ml) and then with water (2.5 ml). The
chloroform solution was dried (anhydrous MgSO4) and concentrated to
give a pale yellow solid which was chromatographed over SiO2
eluting with 1% MeOH--CH2Cl2 to give 858 mg (70%) 5 as white solid.
1H-NMR (CDCl.sub.3, 400 MHz): 1.72-1.76 (m, 2H), 2.22-2.30 (m, 1H),
3.48-3.60 (m, 4H), 7.09-7.11 (m, 1H), 7.11-7.28 (m, 1H), 7.89-7.92
(m, 1H); IR (KBr): 3492, 3043, 2216, 1760, 1602, 1478 cm-1.
Preparation of 6
6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one)
[0366] N-cyano lactone 5 (1.23 g, 5 mmol) was heated with ethylene
glycol (5 ml) and sodium hydroxide (0.82 g, 20.5 mmol) for 15-20
min at 130.degree. C. Most of the ethylene glycol was removed by
distillation under high vacuum. The residual reaction mixture was
diluted with water and extracted repeatedly with chloroform. The
combined organics was dried and concentrated to give a semi solid
material which was purified over Al2O3 column upon elution with
5-7% MeOH/CH.sub.2Cl.sub.2 containing NH3 (aqueous) to yield 789 mg
(60%) of CRI 1072 as pale yellow solid. 1H-NMR (d6-DMSO, 400 MHz):
1.47-1.50 (m, 2H), 2.03-2.10 (m, 2H0, 2.79-2.85 (m, 2H), 2.95-2.97
(m, 2H), 3.73-3.76 (m, 2H), 4.12-4.14 (m, 2H), 7.09 (d, J=8.4 Hz,
1H), 7.20 (s, 1H), 7.69 (d, J=8.4 Hz, 1H); 13C-NMR (d6-DMSO, 100
MHz): 35.9, 42.3, 59.3, 70.4, 84.6, 106.4, 116.6, 117.0, 126.8,
156.9, 163.9, 168.5; FIA-MS: 264.3 (M+1).
Example 13
1'-(2,3-Dichlorobenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
##STR00034##
[0368] Amide coupling according to general procedure 2:
[0369] Amine: 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in Journal of Organic Chemistry (1976), 41(15),
2628-33)
[0370] Acid: 2,3-Dichloro-benzoic acid
[0371] ES-MS m/e (%): 376.4 (M+H.sup.+).
Example 14
1'-(2,3-Dichlorobenzoyl)-6-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-
-one
##STR00035##
[0373] Amide coupling according to general procedure 2:
[0374] Amine: 6-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0375] Acid: 2,3-Dichloro-benzoic acid
[0376] ES-MS m/e (%): 406.4 (M+H.sup.+).
Example 15
6-Chloro-1'-(2,3-dichlorobenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidin]-3--
one
##STR00036##
[0378] Amide coupling according to general procedure 2:
[0379] Amine: 6-chloro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0380] Acid: 2,3-Dichloro-benzoic acid
[0381] ES-MS m/e (%): 410.2 (M+H.sup.+).
Example 16
1'-(2,3-Dichlorobenzoyl)-5-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-
-one
##STR00037##
[0383] Amide coupling according to general procedure 2:
[0384] Amine: 5-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0385] Acid: 2,3-Dichloro-benzoic acid
[0386] ES-MS m/e (%): 406.4 (M+H.sup.+).
Example 17
1'-(2,3-Dichlorobenzoyl)-5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3--
one
##STR00038##
[0388] Amide coupling according to general procedure 2:
[0389] Amine: 5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in WO 2001014376)
[0390] Acid: 2,3-Dichloro-benzoic acid
[0391] ES-MS m/e (%): 394.3 (M+H.sup.+).
Example 18
1'-(2,3-Dichlorobenzoyl)-6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-pi-
peridin]-3-one
##STR00039##
[0393] Amide coupling according to general procedure 2:
[0394] Amine:
6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described herein)
[0395] Acid: 2,3-Dichloro-benzoic acid
[0396] ES-MS m/e (%): 436.4 (M+H.sup.+).
Example 19
1'-[(5-Chloro-1H-indazol-7-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperid-
in]-3-one
##STR00040##
[0398] Amide coupling according to general procedure 2:
[0399] Amine: 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in Journal of Organic Chemistry (1976), 41(15),
2628-33)
[0400] Acid: 5-Chloro-1H-indazole-7-carboxylic acid (described in
WO 2006013048)
[0401] ES-MS m/e (%): 382.4 (M+H.sup.+).
Example 20
1'-[(5-Chloro-1H-indazol-7-yl)carbonyl]-6-methoxy-3H-spiro[2-benzofuran-1,-
4'-piperidin]-3-one
##STR00041##
[0403] Amide coupling according to general procedure 2:
[0404] Amine: 6-methoxy-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in EP 722941)
[0405] Acid: 5-Chloro-1H-indazole-7-carboxylic acid (described in
WO 2006013048)
[0406] ES-MS m/e (%): 412.4 (M+H.sup.+).
Example 21
1'-(1-Naphthoyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00042##
[0408] Amide coupling according to general procedure 2:
[0409] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0410] Acid: Naphthalene-1-carboxylic acid
[0411] ES-MS m/e (%): 344.4 (M+H.sup.+).
Example 22
4-Fluoro-1'-(1-naphthoyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00043##
[0413] Amide coupling according to general procedure 2:
[0414] Amine: 4-fluoro-3H-spiro[2-benzofuran-1,4'-piperidine]
[0415] (prepared according to Journal of Medicinal Chemistry
(1995), 38(11), 2009-17)
[0416] Acid: Naphthalene-1-carboxylic acid
[0417] ES-MS m/e (%): 362.3 (M+H.sup.+).
Example 23
1'-(2-Ethoxy-1-naphthoyl)-4-fluoro-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00044##
[0419] Amide coupling according to general procedure 2:
[0420] Amine: 4-fluoro-3H-spiro[2-benzofuran-1,4'-piperidine]
(prepared according to Journal of Medicinal Chemistry (1995),
38(11), 2009-17)
[0421] Acid: 2-Ethoxynaphthalene-1-carboxylic acid (CAS
2224-00-2)
[0422] ES-MS m/e (%): 406.5 (M+H.sup.+).
Example 24
1'-(2-Ethoxy-1-naphthoyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00045##
[0424] Amide coupling according to general procedure 2:
[0425] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0426] Acid: 2-Ethoxynaphthalene-1-carboxylic acid (CA
2224-00-2)
[0427] ES-MS m/e (%): 388.3 (M+H.sup.+).
Example 25
1'-(4-tert-Butylbenzoyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00046##
[0429] Amide coupling according to general procedure 1:
[0430] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0431] Acid: 4-tert-Butyl-benzoyl chloride
[0432] ES-MS m/e (%): 350.5 (M+H.sup.+).
Example 26
1'-[(2,2-Difluoro-1,3-benzodioxol-4-yl)carbonyl]-3H-spiro[2-benzofuran-1,4-
'-piperidine]
##STR00047##
[0434] Amide coupling according to general procedure 1:
[0435] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0436] Acid: 2,2-Difluoro-benzo[1,3]dioxole-4-carbonyl chloride
(CAS 143096-86-0)
[0437] ES-MS m/e (%): 374.4 (M+H.sup.+).
Example 27
1'-[(5-Methoxy-1H-indol-7-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidi-
ne]
##STR00048##
[0439] Amide coupling according to general procedure 2:
[0440] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0441] Acid: 5-Methoxy-1H-indole-7-carboxylic acid (prepared
herein)
[0442] ES-MS m/e (%): 363.5 (M+H.sup.+).
Preparation of 5-Methoxy-1H-indole-7-carboxylic acid
##STR00049##
[0444] A solution of 7-Bromo-5-methoxy-1H-indole (described in WO
2002028861) in THF was treated with 2 eq. of a solution of n-BuLi
in n-hexane (1.6M) at 5.degree. and after 30 min at this
temperature was cooled to -75.degree.. Dry ice (excess) was added
and after 15 mins the mixture was quenched with H.sub.2O and washed
with EtOAc. After acidification of the aqueous layer and extraction
into CH.sub.2Cl.sub.2, evaporation gave the desired product.
[0445] ES-MS m/e (%): 192.1 (M+H.sup.+).
Example 28
1'-(1H-Benzimidazol-7-ylcarbonyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00050##
[0447] Amide coupling according to general procedure 2:
[0448] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0449] Acid: 3H-Benzoimidazole-4-carboxylic acid (CAS
46006-36-4)
[0450] ES-MS m/e (%): 334.4 (M+H.sup.+).
Example 29
1'-(1H-Indol-7-ylcarbonyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00051##
[0452] Amide coupling according to general procedure 2:
[0453] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0454] Acid: 1H-Indole-7-carboxylic acid (CAS 1670-83-3)
[0455] ES-MS m/e (%): 333.5 (M+H.sup.+).
Example 30
1'-(1,3-Benzodioxol-4-ylcarbonyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00052##
[0457] Amide coupling according to general procedure 2:
[0458] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0459] Acid: Benzo[1,3]dioxole-4-carboxylic acid (CAS
5768-39-8)
[0460] ES-MS m/e (%): 338.4 (M+H.sup.+).
Example 31
3,3-Dimethyl-6-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1-
,3-dihydro-2H-indol-2-one
##STR00053##
[0462] Amide coupling according to general procedure 2:
[0463] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (CAS
38309-60-3)
[0464] Acid: 3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic
acid (described in EP 344634)
[0465] ES-MS m/e (%): 377.5 (M+H.sup.+).
Example 32
5-Bromo-1'-(4-tert-butylbenzoyl)spiro[indole-3,4'-piperidin]-2(1H)-one
##STR00054##
[0467] Amide coupling according to general procedure 2:
[0468] Amine: 5-bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(preparation described herein)
[0469] Acid: 4-tert-Butyl-benzoic acid
[0470] ES-MS m/e (%): 441.5 (M+H.sup.+).
5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
##STR00055##
[0471] 1,5-Dichloro-3-methyl-3-azapentane, hydrochloride 8
[0472] Formic acid (10.0 g; 0.2 mol) and 37% formaldehyde (20 ml)
were mixed in a 250 ml round-bottom flask equipped with reflux
condenser. 1,5-Dichloro-3-azapentane, hydrochloride (17.0 g; 0.1
mol) was added and the solution was heated with magnetic stirring
at 100.degree. C. After 3 h the temperature was increased to
120.degree. C. for 20 min and finally allowed to cool to room
temperature before the solvent was evaporated in vacuo to afford 8
as white solid in quantitative yield. .sup.1HNMR (CD.sub.3OD, 400
MHz) .delta. 3.0 (s, 3H); 3.45 (br s, 2H); 3.62 (br s, 2H); 4.07
(br s, 4H).
1'-(Methyl)spiro[indole-3,4'-piperidin]-2(1H)-one 10
[0473] A solution of oxindole 9 (6.25 g, 47 mmol) in THF (500 ml)
was cooled to -78.degree. C. and to it a solution of sodium
hexamethyldisilazide (43 g, 235 mmol) in THF (300 ml) was added
drop wise under N.sub.2 atmosphere. After stirring at -78.degree.
C. for 45 min, N-methylbis (2-chloromethyl) amine hydrochloride (9
g, 47 mmol) was added, as a solid. The reaction mixture was stirred
at -78.degree. C. for 1 h and at room temperature for 24 h. After
quenching with H.sub.2O (90 ml), the mixture was extracted with
ethyl acetate (3.times.100 ml). The organic extracts were washed
with brine (25 ml), dried and the solvent removed in vacuo. Silica
gel chromatography (5-50% MeOH/CH.sub.2Cl.sub.2, gradient) gave 6 g
(57%) of 10 as a solid. .sup.1HNMR (CD.sub.3OD, 400 MHz) .delta.
1.84 (m, 2H); 2.51 (m, 2H); 2.62 (s, 3H); 3.02 (m, 2H); 3.37 (m,
2H); 6.82 (d, 1H, J=7.68 Hz); 6.94 (t, 1H, J=7.58 Hz); 7.12 (t, 1H,
J=7.7 Hz); 7.26 (d, 1H, J=9 Hz); 9.27 (br s, 1H).
5-bromo-1'-(methyl)spiro[indole-3,4'-piperidin]-2(1H)-one (11)
[0474] A solution of
1'-(methyl)spiro[indole-3,4'-piperidin]-2(1H)-one (6.3 g, 29.1
mmol) in CH.sub.3CN (100 ml) and MeOH (5 ml) was cooled to
-5.degree. C. and NBS (7.8 g, 44 mmol) was slowly added with
stirring. The reaction mixture was stirred for 3.5 h at 0.degree.
C. Solvent was removed by vacuo. The residue was purified by silica
gel chromatography (2-20% MeOH/CH.sub.2Cl.sub.2) to give 6 g as a
solid. The solid compound was dissolved in ethyl acetate (600 ml)
and washed with saturated aqueous NaHCO.sub.3 solution, dried
(Na.sub.2SO.sub.4). Evaporation of the solvent in vacuo gave 4.2 g
(47%) of 11. .sup.1HNMR (CD.sub.3OD, 400 MHz) .delta. 7.51 (d,
J=1.8 Hz, 1H), 7.35 (dd, J=1.9 and 8.2 Hz, 1H), 6.81 (d, J=8.2 Hz,
1H), 2.93 (m, 2H), 2.67 (m, 2H), 2.41 (s, 3H), 1.86 (m, 4H).
5-bromo-1'-(cyano)spiro[indole-3,4'-piperidin]-2(1H)-one (12)
[0475] 5-bromo-1'-(methyl)spiro[indole-3,4'-piperidin]-2(1H)-one 11
(4.6 g, 15.6 mmol) was dissolved in chloroform (700 ml) and treated
with CNBr (22 g, 209.5 mmol) at room temperature. The mixture was
heated to reflux for 24 h. The reaction mixture was cooled, diluted
with methylene chloride (300 ml) and washed with 10% aqueous
K.sub.2CO.sub.3 solution (2.times.100 ml). After the mixture was
dried (Na.sub.2SO.sub.4) and concentrated, the residue was purified
by silica gel chromatography (0-5% MeOH/CH.sub.2Cl.sub.2) to gave 7
as a solid 3.9 g (82%). .sup.1HNMR (CDCl.sub.3, 400 MHz) .delta.
7.52 (d, J=1.8 Hz, 1H), 7.37 (dd, J=1.8 and 8.2 Hz, 1H), 6.82 (d,
J=8.2 Hz, 1H), 3.83 (m, 2H), 3.41 (m, 2H), 2.00 (m, 2H), 1.86 (m,
2H).
5-bromo-spiro[indole-3,4'-piperidin]-2(1H)-one (13)
[0476]
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4'-piperidine]-1'-cyano
12 (3.3 g, 10.8 mmol) was suspended in ethylene glycol (10 ml). The
mixture was treated in NaOH (1.8 g, 45 mmol) and heated to
130.degree. C. for 15 min. It was diluted with methylene chloride
(500 ml) and washed with 10% aqueous K.sub.2CO.sub.3 (2.times.100
m). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated
and residue purified by silica gel chromatography (30%
MeOH/CH.sub.2Cl.sub.2) to gave 13 as a light ceramic white solid
1.8 g (60%), mp 256-258.degree. C. .sup.1HNMR (DMSO-d.sub.6, 400
MHz) .delta. 10.6 (br s, 1H, NH), 7.57 (d, J=1.84 Hz, 1H), 7.36 (d,
J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.05 (br s, 1H, NH), 3.06
(m, 2H), 2.84 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H), .sup.13C NMR
(DMSO-d.sub.6, 100 MHz) .delta. 180.93, 140.64, 137.98, 130.42,
126.75, 113.20, 111.45, 46.24, 40.92, 32.94. Anal. Calcd for
C.sub.12H.sub.13BrN.sub.2O: C, 51.26; H, 4.66; N, 9.9. Found: C,
50.87; H, 4.91; N, 9.67.
Example 33
5-Bromo-1'-(2-naphthoyl)spiro[indole-3,4'-piperidin]-2(1H)-one
##STR00056##
[0478] Amide coupling according to general procedure 2:
[0479] Amine: 5-bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(preparation described herein)
[0480] Acid: Naphthalene-2-carboxylic acid
[0481] ES-MS m/e (%): 435.4 (M+H.sup.+).
Example 34
1'-(4-Chlorobenzoyl)-4-methylspiro[indole-3,4'-piperidin]-2(1H)-one
##STR00057##
[0483] Amide coupling according to general procedure 2:
[0484] Amine: 4-methylspiro[indole-3,4'-piperidin]-2(1H)-one
(preparation in analogy to
5-bromospiro[indole-3,4'-piperidin]-2(1H)-one starting from
1,5-Dichloro-3-methyl-3-azapentane, hydrochloride
[0485] Acid: 4-Chloro-benzoic acid
[0486] ES-MS m/e (%): 355.4 (M+H.sup.+).
Example 35
1'-(3,4-Dichlorobenzoyl)spiro[1-benzofuran-3,4'-piperidine]
##STR00058##
[0488] Amide coupling according to general procedure 2:
[0489] Amine: Spiro[1-benzofuran-3,4'-piperidine] (CAS
38309-60-3)
[0490] Acid: 3,4-Dichloro-benzoic acid
[0491] ES-MS m/e (%): 362.4 (M+H.sup.+).
Example 36
1'-(2-Naphthoyl)spiro[indene-1,4'-piperidine]
##STR00059##
[0493] Amide coupling according to general procedure 2:
[0494] Amine: Spiro[indene-1,4'-piperidine] (CAS 33042-66-9)
[0495] Acid: Naphthalene-2-carboxylic acid
[0496] ES-MS m/e (%): 340.5 (M+H.sup.+).
Example 37
1'-(4-tert-Butylbenzoyl)spiro[indene-1,4'-piperidine]
##STR00060##
[0498] Amide coupling according to general procedure 2:
[0499] Amine: Spiro[indene-1,4'-piperidine] (CAS 33042-66-9)
[0500] Acid: 4-tert-Butyl-benzoic acid
[0501] ES-MS m/e (%): 346.5 (M+H.sup.+).
Example 38
1'-[(2,2-Difluoro-1,3-benzodioxol-4-yl)carbonyl]spiro[indene-1,4'-piperidi-
ne]
##STR00061##
[0503] Amide coupling according to general procedure 2:
[0504] Amine: Spiro[indene-1,4'-piperidine] (CAS 33042-66-9)
[0505] Acid: 2,2-Difluoro-benzo[1,3]dioxole-4-carbonyl chloride
(CAS 143096-86-0)
[0506] ES-MS m/e (%): 370.4 (M+H.sup.+).
Example 39
1'-(3,4-Dichlorobenzoyl)spiro[indene-1,4'-piperidine]
##STR00062##
[0508] Amide coupling according to general procedure 2:
[0509] Amine: Spiro[indene-1,4'-piperidine] (CAS 33042-66-9)
[0510] Acid: 3,4-Dichloro-benzoic acid
[0511] ES-MS m/e (%): 358.4 (M+H.sup.+).
Example 40
1'-(2,3-Dichlorobenzoyl) spiro[indene-1,4'-piperidine]
##STR00063##
[0513] Amide coupling according to general procedure 2:
[0514] Amine: Spiro[indene-1,4'-piperidine] (CAS 33042-66-9)
[0515] Acid: 2,3-Dichloro-benzoic acid
[0516] ES-MS m/e (%): 358.4 (M+H.sup.+).
Example 41
1'-[(5-Chloro-1H-indazol-7-yl)carbonyl]spiro[indene-1,4'-piperidine]
##STR00064##
[0518] Amide coupling according to general procedure 2:
[0519] Amine: Spiro[indene-1,4'-piperidine] (CAS 33042-66-9)
[0520] Acid: 5-Chloro-1H-indazole-7-carboxylic acid (described in
WO 2006013048)
[0521] ES-MS m/e (%): 364.4 (M+H.sup.+).
Example 42
1'-(3,4-Dichlorobenzoyl)-2,3-dihydrospiro[indene-1,4'-piperidine]
##STR00065##
[0523] Amide coupling according to general procedure 2:
[0524] Amine: 2,3-Dihydrospiro[indene-1,4'-piperidine] (CAS
428-38-6)
[0525] Acid: 3,4-Dichloro-benzoic acid
[0526] ES-MS m/e (%): 360.4 (M+H.sup.+).
Example 43
1'-(2,3-Dichlorobenzoyl)-2,3-dihydrospiro[indene-1,4'-piperidine]
##STR00066##
[0528] Amide coupling according to general procedure 2:
[0529] Amine: 2,3-Dihydrospiro[indene-1,4'-piperidine] (CAS
428-38-6)
[0530] Acid: 2,3-Dichloro-benzoic acid
[0531] ES-MS m/e (%): 360.4 (M+H.sup.+).
* * * * *