Back to EveryPatent.com
| United States Patent |
6,172,075
|
|
Adam
, et al.
|
January 9, 2001
|
Di-or triaza-spiro [4,5] decane derivatives
Abstract
The present invention relates to compounds of the general formula
##STR1##
wherein
R.sup.1 is C.sub.6 -.sub.10 -cycloalkyl, optionally substituted by lower
alkyl or --C(O)O-lower alkyl; decahydro-naphthalen-1-yl;
decahydro-naphthalen-2-yl; indan-1-yl or indan-2-yl, optionally
substituted by lower alkyl; decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl;
acenaphthen-1-yl; 2,3-dihydro-1H-phenalen-1-yl;
2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or octahydro-inden-2-yl;
R.sup.2 is hydrogen; lower alkyl; .dbd.O or phenyl, optionally substituted
by lower alkyl, halogen or alkoxy;
.sup.A is cyclohexyl or phenyl, optionally substituted by lower alkyl,
halogen or alkoxy;
X is --CH(OH)--; --C(O)--; --CHR.sup.3 --; --CR.sup.3.dbd.; --O--; --S--;
--CH(COOR.sup.4)-- or --C(COOR.sup.4)--;
Y is --CH.sub.2 --; --CH.dbd.; --CH(COOR.sup.4)--, --C(COOR.sup.4).dbd.; or
--C(CN)--;
R.sup.3 is hydrogen or lower alkoxy;
R.sup.4 is lower alkyl, cycloalkyl, phenyl, or benzyl and
either a or b is optionally an additional bond,
and to pharmaceutically acceptable acid addition salts thereof.
The compounds are agonists of the orphanin FQ (QFQ) receptor and therefore
useful in the treatment of diseases, related to this receptor.
| Inventors:
|
Adam; Geo (Schopfheim, DE);
Cesura; Andrea (Basel, CH);
Jenck; Fran.cedilla.ois (Riedisheim, FR);
Kolczewski; Sabine (Lorrach, DE);
Rover; Stephan (Inzlingen, DE);
Wichmann; Jurgen (Steinen, DE)
|
| Assignee:
|
Hoffman-La Roche Inc. (Nutley, NJ)
|
| Appl. No.:
|
330724 |
| Filed:
|
June 11, 1999 |
Foreign Application Priority Data
| Intern'l Class: |
A61K 031/438; C07D 471/10 |
| Field of Search: |
514/278
546/16,19
|
References Cited
| Foreign Patent Documents |
| 63-208844 | Aug., 1988 | JP.
| |
Other References
U.S. application No. 09/009,457, filed Jan. 20, 1998, pending.
U.S. application No. 09/204,184, filed Dec. 3, 1998, pending.
U.S. application No. 09/330,851, filed Jun. 11, 1999, pending.
Julius, Nature 377:476(1995).
Meunier, Eur. J. Pharmacol., 340:1-15 (1997).
Henderson et al., Trends Pharmacol. Sci., 18:293-300 (1997).
Mogil, et al., Neuroscience, 75:333-337 (1996).
Vanderah et al., Eur. J. Pain, 2:267-280 (1998).
Jenck et al., Proc. Natl. Acad. Sci., USA, 94:14854-14858 (1997).
Pomonis et al., Neuroreport, 8:369-371 (1996).
Manabe et al., Nature, 394:577-581 (1998).
Peluso et al., J. Neuroimmmuno, 81:184-192 (1998).
Porro et al., Prog. Clin. Biol Res. 397:315-325 (1998).
Ito et al., Heterocycles 36:21-24 (1993).
Bunzow et al., Febs Lett. 347:284-288 (1994).
Cheng et al., Biochem. Pharmacol.22:309-3108 (1973).
Doepp et al., Chem. Ber. 121:1651-1655 (1998).
Isuge et al., Chem. Lett. pp. 923-976 (1986).
|
Primary Examiner: Aulakh; Charanjit S.
Attorney, Agent or Firm: Johnston; George W., Tramaloni; Dennis P.
Parent Case Text
This application is based on EP Patent Application No. 98110803.8 filed on
Jun. 12, 1998 and claims priority thereto under 35 U.S.C. .sctn.119(a)-(d)
or 35 U.S.C. .sctn.365(a)-(b).
Claims
What is claimed is:
1. Compounds of the general formula I
##STR92##
wherein
R.sup.1 is C.sub.6 -cycloalkyl which is substituted by lower alkyl or
--C(O)O-lower alkyl; C.sub.7-10 -cycloalkyl, which is unsubstituted or
substituted by lower alkyl or --C(O)O-lower alkyl;
decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or
indan-2-yl, which is unsubstituted or substituted by lower alkyl;
decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl;
2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or
octahydro-inden-2-yl;
R.sup.2 is hydrogen; lower alkyl; .dbd.O or phenyl, which is unsubstituted
or substituted by lower alkyl, halogen or alkoxy;
.sup.A is cyclohexyl or phenyl, which is unsubstituted or substituted by
lower alkyl, halogen or alkoxy;
X is --CH(OH)--; --C(O)--; --CHR.sup.3 --; --CR.sup.3.dbd.; --O--; --S--;
--CH(COOR.sup.4)-- or --C(COOR.sup.4).dbd.;
Y is --CH.sub.2 --; --CH.dbd.; --CH(COOR.sup.4)--, --C(COOR.sup.4).dbd.; or
--C(CN)--;
R.sup.3 is hydrogen or lower alkoxy;
R.sup.4 is lower alkyl, cycloalkyl, phenyl, or benzyl and
either a or b is optionally an additional bond,
racemic mixtures and their corresponding enantiomers and pharmaceutically
acceptable acid addition salts thereof.
2. A compound according to claim 1, wherein R.sup.1 is C.sub.6-10
-cycloalkyl, optionally substituted by lower alkyl, R.sup.2 is hydrogen, X
is --CH(OH)--, --C(O)-- or --CHOCH.sub.3 and Y is --CH.sub.2 --.
3. A compound according to claim 2,
(RS)-8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
4. A compound according to claim 2,
(R)-8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
5. A compound according to claim 2,
(S)-8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
6. A compound according to claim 2,
8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one.
7. A compound according to claim 2,
(RS)-8-(cis-4-isopropyl-cyclohexyl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.
5]decane.
8. A compound according to claim 2,
(RS)-8-cyclononyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
9. A compound according to claim 1, wherein R.sup.1 is selected from the
group consisting of decahydro-naphthalen-2-yl,
2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl, 4-methyl-indan-2-yl,
octahydro-inden-2-yl and decahydro-azulen-2-yl; R.sup.2 is hydrogen; X is
--CH(OH)-- or --CHOCH.sub.3 ; and Y is --CH.sub.2 --.
10. A compound according to claim 9, (RS)- and
(SR)-8-[(2RS,4aSR,8aRS)-decahydro-naphthalen-2-yl]-1-phenyl-1,8-diaza-spir
o[4.5]decan-4-ol .
11. A compound according to claim 9,
8-(decahydro-naphthalen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
12. A compound according to claim 9,
8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
13. A compound according to claim 9, (RS)- and
(SR)-8-[(RS)-(4-methyl-indan-2-yl)]-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
14. A compound according to claim 9,
8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
15. A compound according to claim 9,
8-(octahydro-inden-2-yl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane
(mixture of diastereoisomers).
16. A pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula I
##STR93##
wherein
R.sup.1 is C.sub.6 -cycloalkyl which is substituted by lower alkyl or
--C(O)O-lower alkyl; C.sub.7-10 -cycloalkyl, which is unsubstituted or
substituted by lower alkyl or --C(O)O-lower alkyl;
decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or
indan-2-yl, which is unsubstituted or substituted by lower alkyl;
decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl;
2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or
octahydro-inden-2-yl;
R.sup.2 is hydrogen; lower alkyl; .dbd.O or phenyl, which is unsubstituted
or substituted by lower alkyl, halogen or alkoxy;
.sup.A is cyclohexyl or phenyl, which is unsubstituted or substituted by
lower alkyl, halogen or alkoxy;
X is --CH(OH)--; --C(O)--; --CHR.sup.3 --; --CR.sup.3.dbd.; --O--; --S--;
--CH(COOR.sup.4)-- or --C(COOR.sup.4).dbd.;
Y is --CH.sub.2 --; --CH.dbd.; --CH(COOR.sup.4)--, --C(COOR.sup.4).dbd.; or
--C(CN)--;
R.sup.3 is hydrogen or lower alkoxy;
R.sup.4 is lower alkyl, cycloalkyl, phenyl, or benzyl and
either a or b is optionally an additional bond,
as well as pharmaceutically acceptable salts thereof and a pharmaceutically
acceptable carrier.
17. A method of treating disorders in mammals related to the orphanin FQ
receptor selected from the group consisting of anxiety, stress,
depression, trauma, Alzheimer's mediated memory loss, epilepsy, arterial
blood pressure disorders, obesity, acute pain, chronic pain, Na+
excretion, control of water balance, and symptoms associated with drug
withdrawal comprising administering to said mammal a therapeutically
effective amount for treating said disorder of a compound of formula I
##STR94##
wherein
R.sup.1 is C.sub.6-10 -cycloalkyl, which is unsubstituted or substituted by
lower alkyl or --C(O)O-lower alkyl; decahydro-naphthalen-1-yl;
decahydro-naphthalen-2-yl; indan-1-yl or indan-2-yl, which is
unsubstituted or substituted by lower alkyl; decahydro-azulen-2-yl;
bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl; 2,3-dihydro-1H-phenalen-1-yl;
2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or octahydro-inden-2-yl;
R.sup.2 is hydrogen; lower alkyl; .dbd.O or phenyl, which is unsubstituted
or substituted by lower alkyl, halogen or alkoxy;
.sup.A is cyclohexyl or phenyl, which is unsubstituted or substituted by
lower alkyl, halogen or alkoxy;
X is --CH(OH)--; --C(O)--; --CHR.sup.3 --; --CR.sup.3.dbd.; --O--; --S--;
--CH(COOR.sup.4)-- or --C(COOR.sup.4).dbd.;
Y is --CH.sub.2 --; --CH.dbd.; --CH(COOR.sup.4)--, --C(COOR.sup.4).dbd.; or
--C(CN)--;
R.sup.3 is hydrogen or lower alkoxy;
R.sup.4 is lower alkyl, cycloalkyl, phenyl, or benzyl and
either a or b is optionally an additional bond,
as well as pharmaceutically acceptable salts thereof and a pharmaceutically
acceptable carrier.
18. A process for preparing a compound of formula I as defined in claim 1,
comprising reductively aminating a compound of formula
##STR95##
with a compound of formula
##STR96##
wherein
R.sup.1 is C.sub.6 -.sub.10 -cycloalkyl, which is unsubstituted or
substituted by lower alkyl or --C(O)O-lower alkyl;
decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or
indan-2-yl, which is unsubstituted or substituted by lower alkyl;
decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl;
2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or
octahydro-inden-2-yl;
R.sup.2 is hydrogen; lower alkyl; .dbd.O or phenyl, which is unsubstituted
or substituted by lower alkyl, halogen or alkoxy;
.sup.A is cyclohexyl or phenyl, which is unsubstituted or substituted by
lower alkyl, halogen or alkoxy;
X is --CH(OH)--; --C(O)--; --CHR.sup.3 --; --CR.sup.3.dbd.; --O--; --S--;
--CH(COOR.sup.4)-- or --C(COOR.sup.4).dbd.;
Y is --CH.sub.2 --; --CH.dbd.; --CH(COOR.sup.4)--, --C(COOR.sup.4).dbd.; or
--C(CN)--;
R.sup.3 is hydrogen or lower alkoxy;
R.sup.4 is lower alkyl, cycloalkyl, phenyl, or benzyl and
either a or b may be an additional bond.
19. The process of claim 18 further comprising converting a racemic mixture
of a compound of formula I into its enantomeric components thus obtaining
substantially optically pure compounds.
20. The process of claim 18 further comprising converting a compound of
formula I into a pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
This invention relates to di-or triaza-spiro [4,5] decane derivatives
particularly wherein R.sup.1 is C.sub.6-10 cycloalkyl which may be
substituted or unsubstituted or wherein R.sup.1 is
decahydro-naphthalen-2-yl and compositions thereof.
BACKGROUND OF THE INVENTION
OFQ, a heptadeca peptide, has been isolated from rat brain and is a natural
ligand to a G-protein coupled receptor (OFQ-R), found at high levels in
brain tissue. OFQ exhibits agonistic activity at the OFQ-R both in vitro
and in vivo.
Julius (Nature 377,476, [1995]) discusses the discovery of OFQ noting that
this peptide shares greatest sequence homology with dynorphin A, an
established endogenous ligand for opioid receptors. OFQ inhibits adenylate
cyclase in CHO(LC 132.sup.+) cells in culture and induces hyperalgesia
when administered intra-cerebroventricularly to mice. The pattern of
results indicate that this heptadecapeptide is an endogenous agonist of
the LC 132 receptor and it appears to have pro-nociceptive properties. It
has been described that when injected intra-cerebroventricularly in mice,
OFQ slowes down locomotive activity and induces hyperalgesia and it has
been concluded that OFQ may act as a brain neurotransmitter to modulate
nociceptive and locomotive behavior.
It has been found that the compounds of the present invention interact with
the orphanin FQ (OFQ) receptor and consequently are useful in the
treatment of a variety of psychiatric, neurological and physiological
disorders.
In the following references some of these indications have been described:
Nociceptin/orphanin FQ and the opioid receptor-like ORL1receptor, Eur. J.
Pharmacol., 340: 1-15, 1997;
The orphan opioid receptor and its endofenous ligand ociceptin/orphanin FQ,
Trends Pharmacol. Sci., 18:293-300,1997;
Orphanin FQ is a functional anti-opioid peptide, Neuroscience, 75:333-337,
1996;
Orphanin FQ/nociceptin-lack of antinociceptive, hyperalgesic or allodynic
effects in acute thermal or mechanical tests, following
intracerebroventricular or intrathecal administration to mice or rats,
Eur. J. pain, 2: 267-280, 1998;
Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to
stress, Proc. Natl. Acad. Sci., USA, 94: 14854-14858, 1997;
Orphanin FQ, an agonist of orphan opioid receptor ORL1, stimulates feeding
in rats, Neuroreport, 8: 369-371, 1996;
Facilitation of long-term potentiation and memory in mice lacking
nociceptin receptors, Nature, 394: 577-581, 1998;
Distribution of nociceptin/orphanin FQ receptor transcript in human central
nervous system and immune cells, J. Neuroimmuno, 81: 184-192, 1998;
Orphanin FQ plays a role in sepsis, Prog. Clin. Biol. Res. (1998), 397,
315-325.
Objects of the present invention are the compounds of formula I and
pharmaceutically acceptable addition salts thereof, racemic mixtures and
their corresponding enantiomers, the preparation of the above-mentioned
compounds, medicaments containing them and their manufacture as well as
the use of the above-mentioned compounds in the control or prevention of
illnesses, especially of illnesses and disorders of the kind referred
above, or in the manufacture of corresponding medicaments.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula
##STR2##
wherein
R.sup.1 is C.sub.6-10 -cycloalkyl, optionally substituted by lower alkyl or
--C(O)O-lower alkyl; decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl;
indan-1-yl or indan-2-yl, optionally substituted by lower alkyl;
decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl;
2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or
octahydro-inden-2-yl;
R.sup.2 is hydrogen; lower alkyl; .dbd.O or phenyl, optionally substituted
by lower alkyl, halogen or alkoxy;
.sup.A is cyclohexyl or phenyl, optionally substituted by lower alkyl,
halogen or alkoxy;
X is --CH(OH)--; --C(O)--; --CHR.sup.3 --; --CR.sup.3.dbd.; --O--; --S--;
--CH(COOR.sup.4)-- or --C(COOR.sup.4).dbd.;
Y is --CH.sub.2 --; --CH.dbd.; --CH(COOR.sup.4)--, --C(COOR.sup.4).dbd.; or
--C(CN)--;
R.sup.3 is hydrogen or lower alkoxy;
R.sup.4 is lower alkyl, cycloalkyl, phenyl, or benzyl; and
either a or b is optionally an additional bond,
and to pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I and their salts are characterized by valuable
therapeutic properties. It has surprisingly been found that the compounds
of the present invention are agonists of the orphanin FQ (OFQ) receptor.
Consequently they are useful in the treatment of psychiatric, neurological
and physiological disorders, especially, but not limited to, amelioration
of symptoms of anxiety and stress disorders, depression, trauma, memory
loss due to Alzheimer's disease or other dementias, epilepsy and
convulsions, acute and/or chronic pain conditions, symptoms of addictive
drug withdrawal, control of water balance, Na.sup.+ excretion, arterial
blood pressure disorders and metabolic disorders such as obesity.
DETAILED DESCRIPTION OF THE INVENTION
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, such as lower alkyl and lower alkoxy.
The term "lower alkyl" denotes a straight- or branched-chain alkyl group
containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl,
isopropyl, n-butyl, i-butyl, 2-butyl, butyl, t-butyl and the like.
Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term "cycloalkyl" denotes a saturated carbocyclic group containing from
5-15 carbon atoms, preferred are cyclohexyl, cyclooctyl, cyclononyl and
cyclodecyl.
The term "halogen" denotes chlorine, iodine, fluorine and bromine.
The term "pharmaceutically acceptable acid addition salts" embraces salts
with inorganic and organic acids well-known in the art for pharmaceutic
purposes, 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.
Preferred compounds of the present invention are those of formula I, in
which R.sup.1 is C.sub.6-10 -cycloalkyl, optionally substituted by lower
alkyl, R.sup.2 is hydrogen, X is --CH(OH)--, --C(O)-- or --CHOCH.sub.3 and
Y is --CH.sub.2 --, for example the following compounds:
(RS)-8-(cis4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol,
(R)-8-(cis-4-Isopropyl-cyclohexy)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol,
(S)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol,
8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro [4.5]decan-4-one,
(RS)-8-(cis-4-Isopropyl-cyclohexyl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.
5]decane, and
(RS)-8-Cyclononyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
Further preferred are compounds of formula I, in which R.sup.1 is
decahydro-naphthalen-2-yl, 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl,
4-methyl-indan-2-yl, octahydro-inden-2-yl and decahydro-azulen-2-yl,
R.sup.2 is hydrogen, X is --CH(OH)-- or --CHOCH.sub.3 and Y is --CH.sub.2
--,
Examples of such compounds are
(RS)- and
(SR)-8-[(2RS,4aSR,8aRS)-decahydro-naphthalen-2-yl]-1-phenyl-1,8-diaza-spir
o[4.5]decan-4-ol,
8-(decahydro-naphthalen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol,
8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol,
(RS)- and
(SR)-8-[(RS)-(4-methyl-indan-2-yl)]-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol,
8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol or
8-(octahydro-inden-2-yl)-4-methoxy-1-phenyl-1,8-diaza-spiro [4.5]decane
(mixture of diastereoisomers).
The present compounds of formula I and their pharmaceutically acceptable
salts can be prepared by methods known in the art, for example, by the
processes described below, which comprise
a) reductively aminating a compound of formula
##STR3##
with a compound of formula
##STR4##
wherein R.sup.1, R.sup.2, a, b, .sup.A, X and Y have the significances
given above, or
b) reducing a compound of formula
##STR5##
to a compound of formula
##STR6##
wherein R.sup.1, R.sup.2, b, .sup.A and Y have the significances given
above, or
c) oxidizing a compound of formula
##STR7##
to a compound of formula
##STR8##
wherein R.sup.1, R.sup.2, b, .sup.A and Y have the significances given
above, or
d) reducing a compound of formula I-3 to a compound of formula
##STR9##
wherein R.sup.1, R.sup.2, b, .sup.A and Y have the significances above, or
e) alkylating a compound of formula I-1 to a compound of formula I, wherein
X is --CH(lower alkoxy)--, or
f) hydrogenating a compound of formula I, wherein .sup.A is phenyl, to a
compound of formula I, wherein .sup.A is cyclohexyl, or
g) treating a compound of formula
##STR10##
with an amino thiol of the formula
##STR11##
to give a compound of formula
##STR12##
wherein R.sup.1 and .sup.A have the significances given above and R.sup.2
is hydrogen or phenyl, or
h) treating a compound of formula
##STR13##
with a compound of formula
##STR14##
to give a compound of formula
##STR15##
wherein R.sup.1 and .sup.A have the significances given above, and R.sup.2
is phenyl, optionally substituted by lower alkyl, halogen or alkoxy, and
if desired
converting a racemic mixture into its enantiomeric components thus
obtaining optically pure compounds, and
converting a compound of formula I obtained into a pharmaceutically
acceptable acid addition salt.
In accordance with process variant a) the reductive amination of a keto
compound of formula II with an amine of formula III is carried out by
stirring with a dehydrating agent in the presence of molecular sieves (4
.ANG.), in an inert solvent, such as toluene or tetrahydrofuran (THF), at
reflux temperature. An alternative method is the dehydration in the
presence of an acidic catalyst with removal of water, e.g. with azeotropic
removal of water, or with tetraisopropyl-orthotitanate in THF.
The obtained intermediate enamine or imine is then reduced with a reducing
agent, such as metal hydrides or hydrogen in the presence of a
hydrogenating catalyst, preferably with sodium cyanoborohydride in a
protic solvent, for example in a mixture of THF and ethanol at acidic pH.
Examples for corresponding keto compounds of formula II are the following:
cis-octahydro-2(1H)-naphthalenone, 4-(1-methylethyl)-cyclohexanone,
2-indanone, 4-ethyl-cyclohexanone, 1,3-dihydro-4-methyl-2H-inden-2-one,
4-oxo-cyclohexanecarboxilic acid ethyl ester, cyclodecanone,
(3a,RS,8aRS)-decahydro-azulen-2-on, cis-octahydro-inden-2-one,
cyclooctanone or cis-bicyclo[6.2.0]dec-9-one.
In accordance with process variant b) a compound of formula I-1 or I-3 is
reduced to a compound of formula I-2. This process is carried out in
conventional manner with a reducing agent, preferably a metal hydride,
such as lithium aluminium hydride in an aprotic solvent, for example in
diethylether.
In accordance with process variant c) a compound of formula I-1 is oxidized
in an inert solvent, such as in acetic anhydride in DMSO at room
temperature or with 4-methyl-morpholine-4-oxide in the presence of
tetra-n-propylammonium-perruthenate and molecular sieves in
dichloromethane at room temperature.
The reduction of a compound of formula I-3 to a compound of formula I-1-1
and/or to I-1-2 is carried out with an inert solvent, for example in the
presence of an enantioselective (enantiopure) reagent or catalyst to
achieve an enantiospecific formation of one enantiomer. Preferred
enantioselective reagents are chiral oxazaborolidines. The reaction is
carried out in the presence of borane-dimethylsulfide in THF at about room
temperature. The chiral oxazaborolidines are formed in situ from chiral
1-amino-2-indanols and borane-dimethylsulfide.
In accordance with process variant e) a compound of formula I-1 is
alkylated. The preferred alkylating agent is dimethylsulfate. The process
is carried out in conventional manner in an inert solvent with sodium
hydride in dimethylformamide.
In process variant f) is described the hydrogenation of a compound of
formula I, wherein .sup.A is phenyl. The desired cyclohexyl ring is
yielded in a protic solvent, such as methanol and in the presence of a
hydrogenating catalyst, for example in the presence of platinum oxide. The
reaction is carried out under hydrogen pressure between 1 and 50 bar.
The formation of a 1,3-thiazolidine derivative is described in process
variant g). The reaction is carried out by treating a mixture of a ketone
and an amino thiol with a Lewis acid, such as boron trifluoride diethyl
ether complex, in a chlorinated solvent, for example in dichloromethane.
The process step h) describes the cycloaddition of an imine of formula VII
with a nitrile oxide of formula IX to give a compound of formula I-6. The
process is carried out by treating an imine with a slight excess of a
corresponding hydroximinoyl chloride and a base, such as triethylamine, in
an inert solvent, for example in THF, described in general in Heterocycles
36, 21-24, 1993.
Racemic mixtures can be converted into its enantiomeric components in
conventional manner, for example by preparative HPLC.
The salt formation is effected at room temperatures in accordance with
methods which are known per se and which are familiar to any person
skilled in the art. Not only salts with inorganic acids, but also salts
with organic acids come into consideration. Hydrochlorides, hydrobromides,
sulphates, nitrates, citrates, acetates, maleates, succinates,
methanesulphonates, p-toluenesulfonates and the like are examples of such
salts.
The compounds of formula II, III, IV, V, VII, VIII, IX and XII which are
used as starting materials are known compounds or can be prepared by
methods known per se.
The following scheme 1 describes the cyclization of compounds of formulae
IX and XII to yield compounds of formulae I-7 and I-1-3. Scheme 2
describes possible reaction variants to yield compounds of formulae I-5
and I-6 and scheme 3 describes the preparation of compounds of formula I,
wherein X is S.
##STR16##
wherein R.sup.1 and .sup.A have the significances given above.
##STR17##
wherein R.sup.1 and .sup.A have the significances given above.
##STR18##
wherein R.sup.1, R.sup.2 and .sup.A have the significances given above.
As mentioned earlier, the compounds of formula I and their pharmaceutically
usuable addition salts possess valuable pharmacodynamic properties. It has
been found that the compounds of the present invention are agonists of the
OFQ receptor and have effects in animal models of psychiatric,
neurological and physiological disorders, such as anxiety, stress
disorders, depression, trauma, memory loss due to Alzheimer's disease or
other dementias, epilepsy and convulsions, acute and/or chronic pain
conditions, symptoms of addictive drug withdrawal, control of water
balance, Na.sup.+ excretion, arterial blood pressure disorders and
metabolic disorders such as obesity.
The compounds were tested for pharmacologic activity in accordance with the
methods given hereinafter:
Methods of OFQ-R Binding Assay
Cell Culture
HEK-293 cells adapted to suspension growth (293s) were cultured in HL
medium plus 2% FBS. The cells were transfected with the rat OFQ receptor
cDNA (LC132), FEBS Lett. 347, 284-288, 1994, cloned in the expression
vector pCEP4 (Invitrogen, SanDiego, Calif., USA) using lipofectin (Life
Technologies, Bethesda, Md., USA). Transfected cells were selected in the
presence of hygromycin (1000 U/ml) (Calbiochem, SanDiego, Calif., USA). A
pool of resistant cells was tested for OFQ-R expression by binding of
[.sup.3 H]-OFQ (Amersham PLC, Buckinghamshire, England). These cells
(293s-OFQ-R) were expanded for large scale culture and membrane
preparation.
Membrane preparation
293s-OFQ-R cells were harvested by centrifugation, washed 3 times with
phosphate buffered saline (PBS) before resuspension in buffer A (50 mM
Tris-HCl, pH 7.8, 5 mM MgCl.sub.2, 1 mM EGTA) and disruption with a tissue
homogenizer (30 seconds, setting 4, Pt 20, Kinematica, Kriens-Lucern,
Switzerland). A total membrane fraction was obtained by centrifugation at
49,000.times.g at 4.degree. C. This procedure was repeated twice and the
pellet was resuspended in buffer A. Aliquots were stored at -70.degree. C.
and protein concentrations were determined using the BCA.TM. Protein Assay
Reagent (Pierce, Rockford, Ill.) following the manufacturer's
recommendations.
Binding Assays
[.sup.3 H]-OFQ competition studies were carried out with 77 .mu.g membrane
protein in a final assay volume of 0.5 ml buffer A plus 0.1% BSA and 0.01%
bacitracin (Boehringer-Mannheim, Mannheim, Germany) for one hour at room
temperature. 50 nM unlabeled OFQ was used to define the non-specific
binding. The assays were terminated by filtration through Whatman GF/C
filters (Unifilter-96, Canberra Packard S.A., Zurich, Switzerland)
pretreated with 0.3% polyethylenimine (Sigma, St. Louis, Mo., USA) and
0.1% BSA (Sigma) for 1 hour. The filters were washed 6 times with 1 ml of
ice bold 50 mM Tris-HCl pH 7.5. The retained radioactivity was counted on
a Packard Top-Count microplate scintillation counter after addition of 40
.mu.l of Microscint 40 (Canberra Packard). The effects of compounds were
determined using at least 6 concentrations in triplicate, and determined
twice. IC.sub.50 values were determined by curve fitting and these calues
were converted to K.sub.i values by the method of Cheng and Prusoff,
Biochem. Pharmacol., 22, 3099, 1973.
The affinity to the OFQ-receptor, given as pK.sub.i, is in the range of 7,1
to 9,8. For example, the pK.sub.i -values
of.8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
(Exl.6) and (RS)-8-Acenaphthalen-1-yl-1-phenyl-1,8-diaza-spiro[4.5]decane
(Exl.19) are 9,4 and 8,6, respectively.
GTP.gamma.S Binding Assay
This assay was used to define whether the compounds of this invention are
agonists or antagonists of the OFQ receptor.
Agonist-mediated binding of GTP.gamma.S was investigated in 96-well plates
using a Scintillation Proximity Assay (SPA) using either hOFQR membranes
or membranes prepared from cells transfected with the various human opiate
receptors (.mu., .delta. and .kappa.). Binding was performed in 200 .mu.l
20 mM HEPES-buffer (pH 7.4, plus 6 mM MgCl.sub.2 and 100 mM NaCl),
supplemented with 20 .mu.M GDP, 10 .mu.m cold GTP.gamma.S and 0.3 nM
GTP[.gamma..sup.35 ]S (1130 Ci/mmol). Twenty .mu.g membranes, 1 mg
wheatgerm agglutinin SPA beads (Amersham, Little Chalfont, UK) and either
OFQ (10.sup.-5 M to 10.sup.-10 M) or synthetic compounds (10.sup.-4 M to
10.sup.-9 M) were added.
The reaction mixture was incubated on a shaker for 60 min at 22.degree. C.
and then centrifuged for 5 min at 1500 rpm in an Eppendorf 5403
centrifuge. Finally the plates were read in a Top counter (Packard).
Compounds of this invention have been shown to be agonists of the OFQ
receptor having PEC.sub.50 ranges from about 5.6 to about 7.2.
The preparation of the following compounds is described in Examples 1-53:
##STR19##
OptionalBond
A R.sup.1 R.sup.2 X Y
a/b Ex.
phenyl
##STR20##
H.sub.2 CHOH CH.sub.2 no 1
phenyl
##STR21##
H.sub.2 CHOH CH.sub.2 no 2
phenyl
##STR22##
H.sub.2 CHOH CH.sub.2 no 3
phenyl
##STR23##
H.sub.2 CHOH CH.sub.2 no 4
phenyl
##STR24##
H.sub.2 CO CH.sub.2 no 5
phenyl
##STR25##
H.sub.2 CO CH.sub.2 no 6
phenyl
##STR26##
H.sub.2 CHOH CH.sub.2 no 7
phenyl
##STR27##
H.sub.2 CHOH CH.sub.2 no 8
phenyl
##STR28##
H.sub.2 CHOH CH.sub.2 no 9
phenyl
##STR29##
H.sub.2 CHOH CH.sub.2 no 10
phenyl
##STR30##
H.sub.2 CHOH CH.sub.2 no 11
phenyl
##STR31##
H.sub.2 CHOH CH.sub.2 no 12
phenyl
##STR32##
H.sub.2 CHOH CH.sub.2 no 13
phenyl
##STR33##
H.sub.2 CHOH CH.sub.2 no 14
phenyl
##STR34##
H.sub.2 CHOH CH.sub.2 no 15
phenyl
##STR35##
H.sub.2 CHOH CH.sub.2 no 16
phenyl
##STR36##
H.sub.2 CHOH CH.sub.2 no 17
phenyl
##STR37##
H.sub.2 CHOH CH.sub.2 no 18
phenyl
##STR38##
H.sub.2 CH.sub.2 CH.sub.2 no 19
phenyl
##STR39##
H.sub.2 CO CH.sub.2 no 20
phenyl
##STR40##
.dbd.O CHOH CH.sub.2 no 21
phenyl
##STR41##
H.sub.2 CO CH.sub.2 no 22
phenyl
##STR42##
H.sub.2 CO CH.sub.2 no 23
phenyl
##STR43##
H.sub.2 CO CH.sub.2 no 24
phenyl
##STR44##
H.sub.2 CO CH.sub.2 no 25
phenyl
##STR45##
H.sub.2 CO CH.sub.2 no 26
phenyl
##STR46##
H.sub.2 CO CH.sub.2 no 27
phenyl
##STR47##
H.sub.2 CO CH.sub.2 no 28
phenyl
##STR48##
H.sub.2 CH.sub.2 CH.sub.2 no 29
phenyl
##STR49##
H.sub.2 CH.sub.2 CH.sub.2 no 30
phenyl
##STR50##
H.sub.2
##STR51##
CH.sub.2 no 31
phenyl
##STR52##
H.sub.2 CO CH.sub.2 no 32
phenyl
##STR53##
H.sub.2
##STR54##
CH.sub.2 no 33
phenyl
##STR55##
H.sub.2
##STR56##
CH.sub.2 no 34
phenyl
##STR57##
H.sub.2 CO CH.sub.2 no 35
phenyl
##STR58##
H.sub.2
##STR59##
CH.sub.2 no 36
phenyl
##STR60##
H.sub.2 CHOH CH.sub.2 no 37
phenyl
##STR61##
H.sub.2 S CH.sub.2 no 38
phenyl
##STR62##
H --C(COOCH.sub.3) --C(COOCH.sub.3) a 39
phenyl
##STR63##
O
##STR64##
CH.sub.2 no 40
phenyl
##STR65##
H.sub.2
##STR66##
CH.sub.2 no 41
phenyl
##STR67##
H.sub.2 --CO-- CH.sub.2 no 42
phenyl
##STR68##
H.sub.2
##STR69##
CH.sub.2 no 43
phenyl
##STR70##
H.sub.2
##STR71##
CH.sub.2 no 44
phenyl
##STR72##
H.sub.2
##STR73##
CH.sub.2 no 45
phenyl
##STR74##
H.sub.2
##STR75##
CH.sub.2 no 46
phenyl
##STR76##
H.sub.2
##STR77##
CH.sub.2 no 47
phenyl
##STR78##
H.sub.2
##STR79##
CH.sub.2 no 48
phenyl
##STR80##
H.sub.2
##STR81##
CH.sub.2 no 49
phenyl
##STR82##
H.sub.2
##STR83##
CH.sub.2 no 50
phenyl
##STR84##
H.sub.2
##STR85##
##STR86##
no 51
phenyl
##STR87##
H.sub.2
##STR88##
##STR89##
no 52
phenyl
##STR90##
##STR91##
--O-- --N.dbd. b 53
The compounds of formula I as well as their pharmaceutically usable acid
addition salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations. The pharmaceutical preparations can be
administered orally, e.g. in the form of tablets, coated tablets, dragees,
hard and soft gelatine capsules, solutions, emulsions or suspensions. The
administration can, however, also be effected rectally, e.g. in the form
of suppositories, or parenterally, e.g. in the form of injection
solutions.
The compounds of formula I and their pharmaceutically usable acid addition
salts can be processed with pharmaceutically inert, inorganic or organic
excipients for the production of tablets, coated tablets, dragees and hard
gelatine capsules. 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.
Moreover, the pharmaceutical preparations 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.
The dosage can vary within wide limits and will, of course, be fitted to
the individual requirements in each particular case. In general, the
effective dosage for oral or parenteral administration is 0,01-20
mg/kg/day, preferred as a dosage of 0,1-10 mg/kg/day for all described
indications. The dayly dosage for an adult of 70 kg weight is therefore
between 0,7-1400 mg/day, preferred is 7-700 mg/day, although the above
upper limit can also be exceeded when necessary.
The following Examples illustrate the present invention without limiting
it. All temperatures are given in degrees Celsius.
EXAMPLE 1
8-(Decahydro-naphthalen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1) Mixture of isomers, configuration at (4a,8a) is cis
cis-Octahydro-2(1H)-naphthalenone (1.1 mmol) was dissolved in toluene,
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (1.1 mmol) and molecular
sieves (4 .ANG., 1.0 g) were added. The mixture was refluxed with stirring
for 16 h, filtered and the filtrate was evaporated. The residue was
dissolved in THF/ethanol (10 ml, 9:1), sodium cyanoborohydride (1.1 mmol)
was added and the pH was adjusted to 4. The mixture was stirred for 3 h at
room temperature. Ice-water (30 ml) and potassium carbonate solution (50%,
10 ml) were added. The mixture was extracted twice with dichloromethane,
organic phases were pooled, dried with MgSO4 and concentrated.
Chromatography on silica gel (methylenchloride/methanol, 98:2) yielded the
desired product which was crystallized as its HCl-salt from ethanol. 65 mg
(16%)
8-(decahydro-naphthalen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1) as a colorless solid, m.p.>250.degree. C. and MS:
m/e=369.3 (M+H.sup.+).
EXAMPLE 2
(RS)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=357.3 (M+H.sup.+) was
prepared in accordance with the general method of example 1 from
4-(1-methylethyl)-cyclohexanone and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 3
(RS)-8-Indan-2-yl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride
(1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=349.4 (M+H.sup.+) was
prepared in accordance with the general method of example 1 from
2-indanone and (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 4
(RS)-8-(trans-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol hydrochloride (1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=357.3 (M+H.sup.+) was
prepared in accordance with the general method of example 1 from
4-(1-methylethyl)-cyclohexanone and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 5
8-Indan-2-yl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one hydrochloride (1:1)
(RS)-8-Indan-2-yl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (2.0 mmol) was
dissolved in DMSO (12 ml), acetic anhydride (0.6 ml) was added and the
mixture was stirred for 24 h at room temperature. The solvents were
removed in vacuo. Chromatography on silica gel (methylenchloride/methanol,
98:2) yielded the desired product which was crystallized as its HCl-salt
from ethyl acetate. 0.37 g (48%)
8-indan-2-yl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one hydrochloride (1:1)
as a colorless solid, m.p.>250.degree. C. and MS: m/e=347.4 (M+H.sup.+).
EXAMPLE 6
8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
hydrochloride (1:1)
The title compound, m.p. 226-228.degree. C. and MS: m/e=355.4 (M+H.sup.+)
was prepared in accordance with the general method of example 5 from
(RS)-8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
EXAMPLE 7
Mixture of (RS)-8-cis and
-trans-4-ethyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=343.4 (M+H.sup.+) was
prepared in accordance with the general method of example 1 from
4-ethyl-cyclohexanone and (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 8
Mixture of (RS)- and
(SR)-8[(RS)-(4-Methyl-indan-2-yl)]-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=363.2 (M+H.sup.+) was
prepared in accordance with the general method of example 1 from
1,3-dihydro-4-methyl-2H-inden-2-one and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 9
(RS)-4-cis-(4-Hydroxy-1-phenyl-1,8-diaza-spiro[4.
5]dec-8-yl)-cyclohexanecarboxylic acid ethyl ester hydrochloride (1:1)
The title compound, m.p.>225.degree. C. dec. and MS: m/e=387.3 (M+H.sup.+)
was prepared in accordance with the general method of example 1 from
4-oxo-cyclohexanecarboxylic acid ethyl ester and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 10
(RS)-8-Cyclononyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride
(1:2)
The title compound, white solid, m.p. 170.degree. C. (dec.) and MS:
m/e=357.3 (M+H.sup.+) was prepared in accordance with the general method
of example 1 from cyclononanone and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 11
(RS)-8-Cyclodecyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride
(1:2)
The title compound, white solid, m.p. 170.degree. C. (dec.) and MS:
m/e=371.3 (M+H.sup.+) was prepared in accordance with the general method
of example 1 from cyclodecanone and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 12
8-(Decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1) (mixture of diastereoisomers)
The title compound, white solid, m.p. 265.degree. C. (dec.) and MS:
m/e=369.4 (M+H.sup.+) was prepared in accordance with the general method
of example 1 from (3aRS, 8aRS)-decahydro-azulen-2-on and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 13
8-(Octahydro-inden-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:2) (mixture of diastereoisomers)
The title compound, white solid, m.p. 236.degree. C. (dec.) and MS: m/e=354
(M.sup.+) was prepared in accordance with the general method of example 1
from cis-octahydro-inden-2-one and
(RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 14
(RS)-8-Cyclooctyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride
(1:2)
The title compound, white solid, m.p. 173.degree. C. (dec.) and MS: m/e=342
(M.sup.+) was prepared in accordance with the general method of example 1
from cyclooctanone and (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol.
EXAMPLE 15
8-(Bicyclo[6.2.0]dec-9-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:2) (mixture of diastereoisomers)
To a stirred solution of cis-bicyclo[6.2.0]dec-9-one (0.79 g, 5.2 mmol) in
THF (10 ml) were added at RT tetraisopropyl-orthotitanate (1.9 ml, 6.5
mmol) and (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (1.2 g, 5.2 mmol).
The mixture was stirred at RT for 20 h and evaporated. The residue was
dissolved in THF (4 ml)-ethanol (14 ml), sodium cyanoborohydride (0.25 g,
4.0 mmol) was added and the mixture was stirred at RT for 20 h. Water was
added, the suspension was filtered and the filtrate was evaporated. Column
chromatography on silica gel (dichloromethane-methanol-ammonia 26:1.0.1)
and crystallization from 3N MeOH-HCl/diethyl ether yielded the title
compound (0.86 g, 38%) as a white solid, m.p. 174.degree. C. (dec.) and
MS: m/e=369.4 (M+H.sup.+).
EXAMPLE 16
8-(Acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride
(1:2) (mixture of diastereoisomers)
To a stirred solution of
(RS)-8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decane-2,4-dione
(0.67 g, 1.7 mmol) in THF (35 ml) was added at RT lithium aluminiumhydride
(128 mg, 3.4 mmol) and the reaction mixture was boiled under reflux for 7
h. Water (20 drops) was added slowly at RT to the stirred solution and
afterwards the reaction mixture was dried (Na.sub.2 SO.sub.4) and
filtered. The filtrate was evaporated and the crude product purified by
column chromatography on silica gel (ethyl acetate/hexane 9:1) to yield
(RS)-8-acenaphthen-1-yl-1-phenyl-1,8-diaza-spiro[4.5]decane (50 mg/see
example 20) as a pale yellow oil and
8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (127 mg) as a
pale brown foam, which while stirring was dissolved in 3N MeOH-HCl (0.5
ml) and treated with diethyl ether (15 ml). After 1 h the solid was
filtered off to yield the desired product (128 mg, 55%) as a pale brown
solid, m.p. 196.degree. C. and MS: m/e=385.3 (M+H.sup.+).
Better yields are observed by first reducing
(RS)-8-(acenaphten-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decane-2,4-dione
with sodium borohydride (see example 21) and afterwards with lithium
aluminiumhydride as described in this example.
EXAMPLE 17
8-(2,3-Dihydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:2) (mixture of diastereoisomers)
The title compound, pale brown solid, m.p. 197.degree. C. (dec.) and MS:
m/e=399.4 (M+H.sup.+) was prepared in accordance with the general method
of examples ag and 16 from
(RS)-N-[4-Cyano-1-(2,3-dihydro-1H-phenalen-1-yl)-piperidin-4-yl]-N-phenyl-
acetamide.
EXAMPLE 18
8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol hydrochloride (1:2) (mixture of diastereoisomers)
The title compound, white solid, m.p. 195.degree. C. and MS: m/e=403.4
(M+H.sup.+) was prepared in accordance with the general method of example
16 from
(1RS,3aRS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-
spiro[4.5]decane-2,4-dione.
EXAMPLE 19
(RS)-8-Acenaphthen-1-yl-1-phenyl-1,8-diaza-spiro[4.5]decane hydrochloride
(1:1)
A stirred solution of
(RS)-8-acenaphthen-1-yl-1-phenyl-1,8-diaza-spiro[4.5]decane (50 mg/see
example 16) in 3N MeOH-HCl (0.2 ml) was treated with diethyl ether (5 ml).
After 1 h the solid was filtered off to yield the desired product (50 mg,
91%) as a pale brown solid, m.p. 195.degree. C. and MS: m/e=369.4
(M+H.sup.+).
EXAMPLE 20
(RS)-8-Acenaphthen-1-yl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
hydrochloride (1:1.4)
A mixture of 8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
(0.25 g, 0.65 mmol; as a mixture of diastereoisomers),
4-methylmorpholine-4-oxide (176 mg, 1.3 mmol),
tetra-n-propylammonium-perruthenate (22.8 g, 0.065 mmol) and powdered
sieves (4A, 0.5 g) in dichloromethane (10 ml) was stirred at RT for 1 h.
The reaction mixture was filtered, evaporated and purified by column
chromatography on silica gel (ethyl acetate) to give an oil (150 mg) which
while stirring was dissolved in 3N MeOH-HCl (1 ml) and treated with
diethyl ether (50 ml). After 2 h the solid was filtered off to yield the
desired product (150 mg, 53%) as a pale brown solid, m.p. 174.degree. C.
and MS: m/e=383.3 (M+H.sup.+).
EXAMPLE 21
(RS)-8-(Acenaphthen-1-yl)-4-hydroxy-1-phenyl-1,8-diaza-spiro[4.
5]decan-2-one hydrochloride (1:1) (mixture of diastereoisomers)
To a stirred solution of
(RS)-8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decane-2,4-dione
(0.17 g, 0.43 mmol) in MeOH (5 ml) was added at RT sodium borohydride (19
mg, 0.5 mmol) and stirring was continued for 1.5 h. The reaction mixture
was poured in brine (20 ml) and extracted with dichloromethane (2.times.40
ml. The combined organic layers were dried (MgSO.sub.4) and evaporated.
The crude product was purified by column chromatography on silica gel
(dichloromethane/methanol 97.3) to give 170 mg of a pale yellow foam which
while stirring was dissolved in 3N MeOH-HCl (0.5 ml) and treated with
diethyl ether (15 ml). After 3 h the solid was filtered off to yield the
desired product (103 mg, 55%) as a pale brown solid, m.p. 221.degree. C.
and MS: m/e=399.4 (M+H.sup.+).
EXAMPLE 22
8-Bicyclo[6.2.0]dec-9-yl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
hydrochloride (1:1) (mixture of diastereoisomers)
The title compound, pale brown solid, m.p. 140.degree. C. (dec.) and MS:
m/e=367.2 (M+H.sup.+) was prepared in accordance with the general method
of example 20 from
8-(bicyclo[6.2.0]dec-9-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (mixture of diastereoisomers).
EXAMPLE 23
8-(Decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one fumarate
(1:1) (mixture of diastereoisomers)
Oxidation of
8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture
of diastereoisomers) according to the general method of example 20 and
formation of the fumarate with fumaric acid in diethyl ether yielded the
title compound, pale brown solid, m.p. 219.degree. C. and MS: m/e=367.3
(M+H.sup.+).
EXAMPLE 24
8-Cyclooctyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one fumarate (1:1)
Oxidation of (RS)-8-cyclooctyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 20 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
pale brown solid, m.p. 197.degree. C. and MS: m/e=341.3 (M+H.sup.+).
EXAMPLE 25
(3aRS,7aSR)-8-(Octahydro-inden-2-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-one fumarate
Oxidation of
8-(octahydro-inden-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture
of diastereoisomers) according to the general method of example 20 and
formation of the fumarate with fumaric acid in diethyl ether yielded the
title compound, pale brown solid, m.p. 225.degree. C. and MS: m/e=353.4
(M+H.sup.+).
EXAMPLE 26
(1RS,3aRS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-s
piro[4.5]decan-4-one fumarate (1:1)
Oxidation of
8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol (mixture of diastereoisomers) according to the general method
of example 20 and formation of the fumarate with fumaric acid in diethyl
ether yielded the title compound, pale brown solid, m.p. 144.degree. C.
and MS: m/e=401.5 (M+H.sup.+).
EXAMPLE 27
8-Cyclodecyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one fumarate (1:1)
Oxidation of (RS)-8-cyclodecyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 20 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
pale brown solid, m.p. 177.degree. C. and MS: m/e=369.4 (M+H.sup.+).
EXAMPLE 28
8-Cyclononyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one fumarate (1:1)
Oxidation of (RS)-8-cyclononyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 20 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
pale brown solid, m.p. 185.degree. C. and MS: m/e=355.3 (M+H.sup.+).
EXAMPLE 29
(3aRS,7aSR)-8-(Octahydro-inden-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decane
fumarate (1:0.5)
The title compound, pale yellow solid, m.p. 264.degree. C. and MS:
m/e=339.4 (M+H.sup.+) was prepared in accordance with the general method
of example 1 from cis-octahydro-inden-2-one and
1-phenyl-1,8-diaza-spiro[4.5]decane.
EXAMPLE 30
8--Cyclodecyl-1-phenyl-1,8-diaza-spiro[4.5]decane fumarate (1:0.5)
The title compound, white solid, m.p. 167.degree. C. and MS: m/e=355.5.4
(M+H.sup.+) was prepared in accordance with the general method of example
1 from cyclodecanone and 1-phenyl-1,8-diaza-spiro[4.5]decane.
EXAMPLE 31
(RS)-8-(cis-4-Isopropyl-cyclohexyl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.
5]decane hydrochloride (1:1)
RS)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (0.3 mmol) was dissolved in dimethylformamide (15 ml),
sodium hydride (1.2 mmol) was added and the mixture stirred for 1 h at
room temperature. Dimethylsulfate (0.9 mmol) was added and stirring
continued for 5 h. The mixture was quenched with ice-water (10 ml) and
saturated sodiumbicarbonate solution (10 ml) and extracted three times
with dichloromethane. The organic phases were pooled, dried with Na.sub.2
SO.sub.4 and concentrated. Chromatography on silica gel (ethyl acetate)
yielded the desired product which was crystallized as its HCl-salt from
ethanol. 55 mg (44%)
(RS)-8-(cis-4-isopropyl-cyclohexyl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.
5]decane hydrochloride (1:1) as a colorless solid, m.p. 214-215.degree. C.
and MS: m/e=371.4 (M+H.sup.+).
EXAMPLE 32
8-(trans-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
hydrochloride (1:1)
The title compound, m.p. 237-238.degree. C. and MS: m/e=355.4 (M+H.sup.+)
was prepared in accordance with the general method of example 5 from
(RS)-8-(trans-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
EXAMPLE 33
(R)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1)
(1S,2R)-1-Amino-2-indanol (0.05 mmol) was dissolved in tetrahydrofurane (2
ml), borane-dimethylsulfide (0.34 mmol) was added and the mixture was
stirred for 16 h at room temperature. A solution of
8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
(0.5 mmol) dissolved in tetrahydrofurane (4 ml) was then added slowly to
this mixture. The reaction was quenched with methanol (1 ml) and water (20
ml) and extracted three times with methylene chloride. The organic phases
were pooled, dried with Na.sub.2 SO.sub.4 and concentrated. Chromatography
on silica gel (ethyl acetate) yielded the desired product which was
crystallized as its HCl-salt from ethyl acetate. 20 mg (10%)
(R)-8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1)as a colorless solid, m.p.>250.degree. C. and MS:
m/e=357.3 (M+H.sup.+).
EXAMPLE 34
(S)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=357.3 (M+H.sup.+) was
prepared in accordance with the general method of example 33 from
8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
and (1R,2S)-1-amino-2-indanol.
EXAMPLE 35
(RS)-8-(4-Methyl-indan-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-one
hydrochloride (1:1)
The title compound, m.p.>250.degree. C. and MS: m/e=361.3 (M+H.sup.+) was
prepared in accordance with the general method of example 5 from the
mixture of (RS)- and
(SR)-8[(RS)-(4-Methyl-indan-2-yl)]-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-ol.
EXAMPLE 36
8-(Octahydro-inden-2-yl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane
hydrochloride (1:2) (mixture of diastereoisomers)
The product of example 13 (130 mg) was dissolved in 10 ml dry DMF and 75 mg
of sodium hydride (50% in mineral oil) was added at room temperature. The
reaction mixture was stirred for one hour after which 100 ml of
dimethyl-sulfate were added. Stirring was continued for 24 h, then the
reaction mixture was quenched by the addition of ice cold 1N hydrochloric
acid. The aqueous layer was extracted two times with ether and the
extracts were discarded. The aqueous layer was then basified with 2N
sodium hydroxide solution and extracted three times with ethyl acetate.
The combined organic extracts were washed with water and brine,
concentrated and subjected to preparative thin layer-chromatography to
yield the free base (60 mg) as a clear oil that crystallized on standing.
Formation of the hydrochloride under standard conditions furnished the
title compound, m/z=369 [M+H].
EXAMPLE 37
8-(Octahydro-inden-2-yl)-1-cyclohexyl-1,8-diaza-spiro[4.5]decan-4-ol
hydrochloride (1:2) (mixture of diastereoisomers)
The product of example 13 (50 mg) was dissolved in 150 ml methanol and 50
mg of platinium oxide were added. The mixture was hydrogenated for 38 h
under 20 atmospheres hydrogen gas at room temperature. Then the reaction
mixture was filtered and the solvent evaporated. The residue purified by
preparative thin layer chromatography to yield the free base as a slightly
yellow solid (15 mg). Formation of the hydrochloride under standard
conditions furnished the title compound, m/z=361 [M+H].
EXAMPLE 38
(RS)-8-(cis-4-Isopropyl-cyclohexyl)-4-phenyl-1-thia-4,8-diaza-spiro[4.
5]decane fumarate (1:2)
cis-(4-isopropyl-cyclohexyl)-piperidine-4-one (224 mg ) was dissolved in 15
ml dichloromethane and 139 ml of N-phenyl-2-amino ethanethiol were added
under argon. The reaction mixture was cooled to 0.degree. C. and 630 ml
borontriflouride-diethyl ether-complex (freshly distilled) was added.
After 1 hour, the reaction was quenched with one ml of aqueous ammonium
hydrochloride solution. The aqueous layer was extracted two times with
dichloromethane and ether and the extract s dried over sodium sulfate.
Evaporation of the solvent gave a yellow oil, which was purified by
preparative thin layer chromatography to yield the title compound (72 mg)
which was converted to the fumarate salt using standard conditions. m.p.
175-176.degree. C.; m/z=359 [M+H].sup.+..
EXAMPLE 39
8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro [4,5]dec-3
-ene-3,4-dicarboxylic acid dimethylester hydrochloride (1:1.33)
[1-(cis-4-Isopropyl-cyclohexyl)-piperidin-4-ylidene]phenyl-amine (1.00 g,
3.35 mmol) was treated at 0.degree. C. with (trimethylsilyl)methyl
trifluoromethane sulfonate (792 mg, 3.35 mmol). 1,2-Dimethoxy ethane (35
ml) and dimethyl acetylenedicarboxylate (2.38 g, 16.8 mmol) followed by
caesium fluoride (509 mg, 3.35 mmol) were added and the reaction mixture
was stirred at room temperature for 40 h. The solvent was evaporated, the
residue taken up in ethyl acetate and extracted with water. The organic
phase was dried with MgSO.sub.4 and concentrated. Chromatography on silica
gel (hexane/ethyl acetate 8:1) followed by thin layer chromatography
(toluene/ethyl acetate 10:1) gave the desired product which was
precipitated as its HCl-salt from ether. 46 mg (2.7%)
(8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4,5]dec-3-ene-3,4
-dicarboxylic acid dimethylester hydrochloride (1:1.33) as a white solid,
dec.>200.degree. C., MS: m/e=455.5 (M+H.sup.+).
EXAMPLE 40
Mixture of (RS)- and
(SR)-(2RS,4aSR,8aRS)-8-Decahydro-naphthalen-2-yl)-4-hydroxy-1-phenyl-1,8-d
iaza-spiro[4.5]decan-2-one hydrochloride (1:1)
The title compound, m.p.>166.degree. C. dec. and MS: m/e=383.3 (M+H.sup.+)
was prepared in accordance with the general method of example 21 from
(2RS,4aSR,8aRS)-8-(decahydronaphthalen-2-yl)-4-hydroxy-1-phenyl-1,8-diaza-
spiro[4.5]decan-2,4-dione.
EXAMPLE 41
Mixture of (RS)- and
(SR)-8-[(2RS,4aSR,8aRS)-decahydro-naphthalen-2-yl]-1-phenyl-1,8-diaza-spir
o[4.5]decan-4-ol hydrochloride (1:1)
The title compound, m.p.>250.degree. C. dec. and MS: m/e=369.4 (M+H.sup.+)
was prepared in accordance with the general method of example 16 from
(RS)- and
(SR)-(2RS,4aSR,8aRS)-8-(decahydro-naphthalen-2-yl)-4-hydroxy-1-phenyl-1,8-
diaza-spiro[4.5]decan-2-one.
EXAMPLE 42
(2RS,4aSR,8aRS)-8-(Decahydro-naphthalen-2-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decan-4-one hydrochloride (1:1)
The title compound, m.p. 250-251.degree. C. dec. and MS: m/e=367.3
(M+H.sup.+) was prepared in accordance with the general method of example
5 from (RS)- and
(SR)-8-[(2RS,4aSR,8aRS)-decahydro-naphthalen-2-yl]-1-phenyl-1,8-diaza-spir
o[4.5]decan-4-ol.
EXAMPLE 43
Mixture of (RS)- and
(SR)-8-[(1RS,3aSR)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,8-d
iaza-spiro[4.5]decan-4-ol fumarate (1:1)
The title compound, light brown solid, m.p. 205.degree. C. and MS:
m/e=403.5 (M+H.sup.+) was prepared in accordance with the general method
of example 17 from
(1RS,3aSR)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-
spiro[4.5]decane-2,4-dione and subsequent formation of the fumarate.
(1RS,3aSR)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-s
piro[4.5]decane-2,4-dione was prepared from
(1RS,3aSR)-1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-piperidin-4-one as
described for
(1RS,3aRS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-
spiro[4.5]decane-2,4-dione.
EXAMPLE 44
Mixture of (RS)- and
(SR)-8-[(1RS,3aRS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-4-methoxy-1-ph
enyl-1,8-diaza-spiro[4.5]decane fumarate (1:1)
Methylation of a mixture of (RS)- and
(SR)-8-(1RS,3aRS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-di
aza-spiro[4.5]decan-4-ol according to the general method of example 31 and
formation of the fumarate with fumaric acid in diethyl ether yielded the
title compound, pale brown solid, m.p. 206.degree. C. and MS: m/e=417.3
(M+H.sup.+).
EXAMPLE 45
Mixture of (RS)- and
(SR)-8-[(RS)-acenaphthen-1-yl]-4-methoxy-1-phenyl-1,8-diaza-spiro[4.
5]decane fumarate (1:1)
Methylation of a mixture of (RS)- and
(SR)-8-(acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 31 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
pale brown solid, m.p. 208.degree. C. and MS: m/e=399.4 (M+H.sup.+).
EXAMPLE 46
(RS)-8-Cyclodecyl-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane
hydrochloride (1:2)
Methylation of (RS)-8-cyclodecyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 31 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
white solid, m.p. 170.degree. C. (dec.) and MS: m/e=385.4 (M+H.sup.+).
EXAMPLE 47
(RS)-8-Cyclooctyl-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane
hydrochloride (1:1.5)
Methylation of (RS)-8-cyclooctyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 31 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
white solid, m.p. 160.degree. C. (dec.) and MS: m/e=357.3 (M+H.sup.+).
EXAMPLE 48
8-Bicyclo[6.2.0]dec-9-yl-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane
hydrochloride (1:1) (mixture of distereoisomers; config. in bicyclodecane
moiety at C1 and C8 cis)
Methylation of
8-(bicyclo[6.2.0]dec-9-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
(mixture of distereoisomers; config. in bicyclodecane moiety at C1 and C8
cis) according to the general method of example 31 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
white solid, m.p. 170.degree. C. (dec.) and MS: m/e=383.3 (M+H.sup.+).
EXAMPLE 49
(RS)-8-Cyclononyl-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane fumarate
(1:1)
Methylation of (RS)-8-cyclononyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
according to the general method of example 31 and formation of the
fumarate with fumaric acid in diethyl ether yielded the title compound,
pale brown solid, m.p. 196.degree. C. (dec.) and MS: m/e=371.3
(M+H.sup.+).
EXAMPLE 50
8-(Decahydro-azulen-2-yl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane
fumarate (1:1) (mixture of the diastereoisomers)
Methylation of
8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture
of diastereoisomers) according to the general method of example 31 and
formation of the fumarate with fumaric acid in diethyl ether yielded the
title compound, white solid, m.p. 260.degree. C. (dec.) and MS: m/e=383.3
(M+H.sup.+).
EXAMPLE 51
(3RS,
4SR)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4,5]decane-3,
4-dicarboxylic acid dimethylester hydrochloride (1:1)
The title compound, MS: m/e=457.5 (M+H.sup.+) was prepared in accordance
with the general method of example 39 from
[1-(cis-4-isopropyl-cyclohexyl)-piperidin-4-ylidene]phenyl-amine and
dimethyl maleate.
EXAMPLE 52
(3RS,
4RS)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4,5]decane-3,
4-dicarboxylic acid dimethylester hydrochloride (1:1)
The title compound, dec.>200.degree. C. and MS: m/e=457.5 (M+H.sup.+) was
prepared in accordance with the general method of example 39 from
[1-(cis-4-isopropyl-cyclohexyl)-piperidin-4-ylidene]phenyl-amine and
dimethyl fumarate.
EXAMPLE 53
8-(cis-4-Isopropyl-cyclohexyl)-3,4-diphenyl-1-oxa-2,4,8-triaza-spiro[4,5]de
c-2-ene hydrochloride (1:1)
[1-(cis-4-Isopropyl-cyclohexyl)-piperidin-4-ylidene]phenyl-amine (1.20 g,
4.00 mmol), benzohydroximioyl chloride (2.25 g, 8.00 mmol) and triethyl
amine (810 mg, 8.00 mmol) were stirred at room temperature in 70 ml
tetrahydrofuran for 24 h. The solvent was evaporated, the residue taken up
in methylene chloride and extracted with water. The organic phase was
dried with MgSO.sub.4 and concentrated. Chromatography on silica gel
(hexane/ethyl acetate 9:1) followed by recrystallization from diisopropyl
ether gave 40 mg (2.4%) of the desired product as colourless crystalls,
m.p.=131.degree. C. and MS: m/e=418.4 (M+H.sup.+). It was precipitated as
its HCl-salt from ether/dioxane.
SYNTHESES OF INTERMEDIATES
Example aa
(RS)-1-Phenyl-1,8-diaza-spiro[4.5]decan-4-ol
(RS)-8-Benzyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (7.8 mmol) was
dissolved in methanol (100 ml) and ethylacetate (100 ml). Palladium on
carbon (10%, 0.2 g) was added and the mixture was hydrogenated at room
temperature and normal pressure. Filtration and evaporation yielded the
desired product. 1.8 g (99%) (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol
as a beige solid, m.p. 141-144.degree. C. and MS: m/e=232 (M.sup.+).
Example ab
(RS)-N-(1-Acenaphthen-1-yl)-4-cyano-piperidin-4-yl)-N-phenyl-acetamide
To a stirred mixture of pyridine (4.5 ml, 55.5 mmol), acetyl chloride (2
ml, 27.7 mmol) and DMAP (20 mg) in dichloromethane (150 ml) was added
dropwise at RT a solution of
(RS)-4-phenylamino-1-(acenaphthen-1-yl)-piperidine-4-carbonitrile (4.9 g,
13.9 mmol) in dichloromethane (100 ml). After 21 h the reaction mixture
was poured in sat. NaHCO.sub.3 (100 ml) and the layers were separated. The
aqueous phase was extracted with dichloromethane (150 ml), the combined
organic layers were washed with sat. NaHCO.sub.3 (100 ml), brine (100 ml),
dried (MgSO.sub.4) and evaporated. The crude product was purified by
column chromatography on silica gel (ethyl acetate/hexane 4:1) to give
beside 1.49 g
(RS)-4-phenylamino-1-(acenaphthen-1-yl)-piperidine-4-carbonitrile (1.49,
30%) the desired product (2.9 g, 53%) as a pale brown foam, MS: m/e=396.2
(M+H.sup.+).
Example ac
(RS)-N-[4-Cyano-1-(2,3-dihydro-1H-phenalen-1-yl)-piperidin-4-yl]-N-phenyl-a
cetamide
The title compound, pale brown foam, MS: m/e=410.4 (M+H.sup.+) was prepared
in accordance with the general method of example ab from
(RS)-4-phenylamino-1-(2,3-dihydro-1H-phenalen-1-yl)-piperidine-4-carbonitr
ile.
Example ad
(1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-piperidin-4-one and
(1RS,3aSR)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-piperidin-4-one
To a stirred mixture of (RS)-2,3,3a,4,5,6-hexahydro-phenalen-1-one (3.53 g,
19.0 mmol), hydroxylamine hydrochloride (2.2 g, 32.0 mmol) and water (14
ml) was added dropwise at 75.degree. C. MeOH (18 ml) and afterwards a
solution of sodium acetate (6.7 g, 49.9 mmol) in water (13 ml). Stirring
was continued over a period of 1.5 h, water (40 ml) was added and after
cooling (ice bath) the solid was collected by filtration. After drying in
vacuo the crude product was dissolved in 3.5 N NH.sub.3 /MeOH (160 ml) and
hydrogenated over Raney-Nickel (2.9 g, washed with MeOH) at RT for 65 h.
The catalyst was filtered off, the solution evaporated in vacuo to give a
green oil (3.52 g), which was dissolved in ethanol (36.5 ml). Potassium
carbonate (0.26 g, 1.9 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium
iodide (7.0 g, 26.2 mmol) dissolved in water (13 ml) were added and the
mixture was refluxed for 45 min. The reaction mixture was poured into 3N
sodium hydroxide solution (160 ml) and extracted with ethylacetate
(2.times.300 ml). The combined organic layers were dried (MgSO.sub.4) and
evaporated. Intensive column chromatography on silica gel
(toluene/ethylacetate 9:1) yielded
(1RS,3aSR)-1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-piperidin-4-one
(2.37 g, 47%) and
(1RS,3aRS)-1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-piperidin-4-one
(1.97 g, 39%). Both compounds are pale yellow oils, MS: m/e=269 (M.sup.+).
Example ae
(1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-4-phenylamino-piperi
dine-4-carbonitrile
(1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-piperidin-4-one
(2.62 g, 9.7 mmol) was dissolved in acetic acid (12 ml). Aniline (0.97 ml,
10.6 mmol) and trimethylsilylcyanide (1.2 ml, 9.7 mmol) were added and the
mixture was stirred for 3 h at RT. The reaction mixture was poured into
cold ammonia solution (40 ml), extracted with methylene chloride
(2.times.200 ml) and brine (150 ml). The combined organic layers were
combined, dried with magnesium sulfate and concentrated. Crystallization
from diethylether/hexane yielded
(1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-4-phenylamino-piper
idine-4-carbonitrile (3.1 g, 86%) as a pale yellow solid, m.p. 142.degree.
C. and MS: m/e=372.4 (M+H.sup.+).
Example af
(1RS,3aRS)-N-[4-Cyano-1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-piperidin
-4-yl]-N-phenyl-acetamide
The title compound, pale brown foam, MS: m/e=410.4 (M+H.sup.+) was prepared
in accordance with the general method of example ab from
(1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-4-phenylamino-piper
idine-4-carbonitrile.
Example ag
(RS)-8-(Acenaphthen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decane -2,4-dione
To a stirred solution of
(RS)-N-(1-acenaphthen-1-yl-4-cyano-piperidin-4-yl)-N-phenyl-acetamide
(1.47 g, 3.7 mmol) in THF (75 ml) was added dropwise at -78.degree. C. a
freshly prepared solution of LDA (4.6 mmol) in THF (25 ml). Stirring was
continued for 1 h at -78.degree. C. and for additional 2 h at RT, the
reaction mixture was poured in cooled brine (100 ml) and extracted with
ethyl acetate (2.times.200 ml). The combined organic layers were washed
with brine (100 ml), dried (MgSO.sub.4) and evaporated to give a yellow
foam (1.49 g). A stirred solution of the intermediate in MeOH (100 ml) and
1N HCl (30 ml) was boiled under reflux for 1 h and evaporated. To the
residue was added 1 N NaOH (30 ml) and sat. NaHCO.sub.3 (30 ml). The
aqueous solution was extracted with dichloromethane (2.times.100 ml),
washed with brine (70 ml), dried (MgSO.sub.4) and evaporated. The crude
product was purified by column chromatography on silica gel
(dichloromethane/methanol 30:1) to yield the desired product (0.68 g, 46%)
as a pale brown foam, MS: m/e=397.3 (M+H.sup.+).
Example ah
(1RS,3aRS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-s
piro[4.5]decane-2,4-dione
The title compound, pale yellow foam, MS: m/e=415.4 (M+H.sup.+) was
prepared in accordance with the general method of example ag from
(1RS,3aRS)-N-[4-Cyano-1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-piperidi
n-4-yl]-N-phenyl-acetamide.
Example ai
1-Phenyl-1,8-diaza-spiro[4.5]decane
The title compound, yellow oil, MS: m/e=217.3 (M+H.sup.+) was prepared in
accordance with the general method of example aa from
8-benzyl-1-phenyl-1,8-diaza-spiro[4.5]decane.
Example aj
cis-(4-(2-methyl-ethyl)-cyclohexyl)-piperidine-4-one
cis-4-(2-methyl-ethyl)-cyclohexyl-amine hydrochloride(60.7 g) was dissolved
in ethanol (725 ml). Potassium carbonate (51.8 g) and
1-ethyl-1-methyl-4-oxo-piperidinium iodide (126.6 g) dissolved in water
(240 ml) were added and the mixture was refluxed for 1 hour. The reaction
mixture was concentrated and extracted three times with dichloromethane.
The combined organic layers were washed with aqueous bicarbonate and
water, dried (MgSO.sub.4) and evaporated. Filtration over silica gel
(cyclohexane/ethylacetate 17:3) yielded 69.7 g of a yellow oil which was
distilled to yield the title compound (75%) as a slightly yellow oil. b.p.
111.degree. C./0.45 mbar; m/z=223 [M.sup.+. ].
Example ak
cis-[1-(4-Isopropyl-cyclohexyl)-piperidin-4-ylidene]phenyl-amine
cis-1-(4-Isopropyl-cyclohexyl)-piperidine-4-one (5.0 g, 23.4 mmol), aniline
(3.3 g, 35.3 mmol) and molecular sieves (20 g, 4A) were stirred in 100 ml
pentane at room temperature for 6 days. The molecular sieves were filtered
off and the solvent was evaporated. The crude product was used without any
further purification.
Example al
(2RS,4aSR,8aRS)-8-(Decahydro-naphthalen-2-yl)-1-phenyl-1,8-diaza-spiro[4.
5]decane-2,4-dione hydrochloride (1:1)
The title compound, m.p.>250.degree. C. dec. and MS: m/e=381.3 (M+H.sup.+)
was prepared in accordance with the general method described in Van Parys,
Marc et al., Bull. Soc. Chim. Belg. (1981), 90(7), 749-55 from
(2RS,4aSR,8aRS)-decahydro-naphthalen-2-ylamine.
EXAMPLE A
Tablets of the following composition are manufactured in the usual manner:
mg/tablet
Active substance 5
Lactose 45
Corn starch 15
Microcrystalline cellulose 34
Magnesium stearate 1
Tablet weight 100
EXAMPLE B
Capsules of the following composition are manufactured:
mg/capsule
Active substance 10
Lactose 155
Corn starch 30
Talc 5
Capsule fill weight 200
The active substance, lactose and corn starch are firstly mixed in a mixer
and then in a comminuting machine. The mixture is returned to the mixer,
the talc is added thereto and mixed thoroughly. The mixture is filled by
machine into hard gelatine capsules.
EXAMPLE C
Suppositories of the following composition are manufactured:
mg/supp.
Active substance 15
Suppository mass 1285
Total 1300
The suppository mass is melted in a glass or steel vessel, mixed thoroughly
and cooled to 45.degree. C. Thereupon, the finely powdered active
substance is added thereto and stirred until it has dispersed completely.
The mixture is poured into suppository moulds of suitable size, left to
cool, the suppositories are then removed from the moulds and packed
individually in wax paper or metal foil.
Top