Di-or triaza-spiro [4,5] decane derivatives

Details Di-or triaza-spiro [4,5] decane derivatives Di-or triaza-spiro [4,5] decane derivatives

1999-06-11

2003-11-04

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S016000, C546S019000

Reexamination Certificate

active

06642247

ABSTRACT:

FOREIGN PRIORITY CLAIMED
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. §119(a)-(d) or 35 U.S.C. §365(a)-(b).
FIELD OF THE INVENTION
This invention relates to di- or triaza-spiro [4,5] decane derivatives particularly wherein R
1
is C
6-10
cycloalkyl which may be substituted or unsubstituted or wherein R
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
+
) 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 ORL1 receptor,
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
ociceptin-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
wherein
R
1
is C
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
2
is hydrogen; lower alkyl; ═O or phenyl, optionally substituted by lower alkyl, halogen or alkoxy;
 is cyclohexyl or phenyl, optionally substituted by lower alkyl, halogen or alkoxy;
X is —CH(OH)—; —C(O)—; —CHR
3
—; —CR
3
═; —O—; —S—; —CH(COOR
4
)— or —C(COOR
4
)═;
Y is —CH
2
—; —CH═; —CH(COOR
4
)—, —C(COOR
4
)═; or —C(CN)—;
R
3
is hydrogen or lower alkoxy;
R
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
+
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, 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
1
is C
6-10
-cycloalkyl, optionally substituted by lower alkyl, R
2
is hydrogen, X is —CH(OH)—, —C(O)— or —CHOCH
3
and Y is —CH
2
—, for example the following compounds:
(RS)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol,
(R)-8-(cis-4-Isopropyl-cyclohexyl)-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)-4methoxy-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
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
2
is hydrogen, X is —CH(OH)— or —CHOCH
3
and Y is —CH
2
—.
Examples of such compounds are
(RS)- and (SR)-8-[(2RS,4aSR,8aRS)-decahydro-naphthalen-2-yl]-1-phenyl-1,8-diaza-spiro[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

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