Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-13
2001-08-21
Rotman, Alan L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S019300, C514S020800, C514S002600, C514S247000, C514S303000, C514S506000, C514S018700, C546S018000, C546S020000
Reexamination Certificate
active
06277991
ABSTRACT:
FIELD OF INVENTION
The present invention relates to use of small organic compounds acting as opioid receptor ligands for the treatment of vasomotor disturbances. In particular the present invention relates to the compounds of formula Ia or Ib for the treatment of migraine, non-insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence and/or vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
BACKGROUND OF THE INVENTION
A “hot flush” is a sudden transient sensation ranging from warmth to intense heat and typically accompanied by flushing and perspiration. It is the classic sign of the menopause and the predominant complaint of menopausal women. A positive correlation between plasma levels of calcitonin gene-related peptide (CGRP) and frequency of hot flushes in women has recently been reported (Chen et al., 1993, Lancet (342) 49), in accordance with the potent vasodilatory effect of CGRP (Brain et al., 1985, Nature, (313) 54-56). Also, a positive correlation between CGRP antagonists and diabetes, septic shock and inflammation has been described (Feurstein, G, Willette, R and Aiyar, N., 1995, Can. J. Physiol. Pharmacol. 73:1070-1074).
Recently, a novel heptadecapeptide, nociceptin, was discovered (Meunier et al., 1995, Nature (377) 532-535, Reinscheid et al., 1995, Science (270) 792-794). Nociceptin and analogues thereof have been disclosed in WO 97/07212, EP 813065 and in WO 97/07208. These peptides and inhibitors thereof are said to be useful for antagonizing physiologic effects of an opioid in an animal, and for treating/preventing a disease related to: hyperalgesia, neuroendocrine secretion, stress, locomotor activity, anxiety etc. Jenck, F et. al. also found, that Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress (PNAS Vol. 94,1997). It is well known that triaza-spiro compounds are vasodilating agents and morphine-like analgesics as disclosed in U.S. Pat. Nos. 3,238,216 and 3,155,670 by Janssen.
SUMMARY OF THE INVENTION
It has been found that members of a novel group of triaza-spiro compounds have high affinity for nociceptin receptors which make them useful as regulators of peripheral vasomotor effects known as hot flushes. The present invention provides a compound of the formula Ia or Ib as disclosed below or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of Type II diabetes, septic shock, inflammation, incontinence and vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes.
Further objects will become apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to use of a small organic compound acting as an opioid receptor ligand for the preparation of a pharmaceutical composition for the treatment of a disease selected from migraine, non-insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence, vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes and/or for alleviating symptoms of drug withdrawal, in particular abstinence symptoms occurring during withdrawal from abusive drugs.
In another aspect the invention relates to use of a small organic compound acting as a Nociceptin receptor ligand with a molecular weight of less than 1000 or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
In still another aspect the invention relates to use of small organic compounds acting as Nociceptin receptor ligand with a molecular weight less than 600 or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
In yet another aspect the invention relates to use of a small organic compound acting as a Nociceptin receptor ligand with less than 5 amide bonds or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
In a further aspect the invention relates to use of a small organic compound acting as a Nociceptin receptor ligand wherein said compound has no amide bonds or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
In still another aspect the invention relates to use of a compound wherein said compound comprises a triaza-spiro compound acting as a Nociceptin receptor ligand or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
In yet another aspect the invention relates to use of a small organic compound acting as a Nociceptin receptor ligand with an IC
50
less than 1 &mgr;M or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
In a second aspect the invention relates to a compound of formula
wherein
R
1
is phenyl, arylalkyl or thienyl, optionally substituted with one or more of halogene, cyano, nitro, trifluoromethyl, C
1-6
-alkyl, hydroxy, C
1-6
-alkoxy or NR
6
R
8
wherein R
6
and R
8
independently are hydrogen or C
1-6
-alkyl, or R
1
is C
1-6
-alkyl;
R
2
is aminophenyl, C
1-6
-monoalkylaminophenyl, C
1-6
-dialkylaminophenyl, cyanophenyl, C
2-6
-alkylphenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, coumarinyl, said groups may be substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C
1-6
-alkyl, hydroxy, C
1-6
-alkoxy, C(O)R
7
, wherein R
7
is —OH, C
1-6
-alkoxy or —NR
12
R
13
, wherein R
12
and R
13
independently are hydrogen or C
1-6
-alkyl or
R
2
is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl, any of which may be substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C
1-6
-alkyl, hydroxy, C
1-6
-alkoxy, C(O)R
7
, wherein R
7
is —OH, C
1
-alkoxy or —NR
12
R
13
, wherein R
12
and R
13
independently are hydrogen or C
1-6
alkyl, provided that R
1
is not phenyl, R
3
is not methyl or hydrogen or R
4
is not hydrogen, acetyl, methyl, hydroxymethyl, ethyl, 2-cyanoethyl, propionyl or methoxymethyl;
R
3
is hydrogen, C
1-6
-alkyl, phenyl, benzyl or acetyl;
R
4
is hydrogen or (CH
2
)
m
—(CHR
9
)—(CH
2
)
p
-AR
11
, wherein m and p independently are 0-4 and R
9
is hydrogen, C
1-6
-alkyl, phenyl or arylalkyl, R
11
is C
1-6
-alkyl, hydroxy, C
1-6
-alkoxy, guanidino, an amino acid residue or a 2-4 peptidyl residue with a C-terminal group consisting of either OCH
3
, or NH
2
; R
11
can also be a group NR
14
R
15
wherein R
14
and R
15
independently are hydrogen, C
1-6
alkyl, (CH
2
)qR
16
where q can be 0 to 6 and R
16
can be a C3-C7 membered cycloalkyl ring, an optionally substituted aromatic or heteroaromatic ring, an aliphatic ring containing one or more heteroatoms, an alkoxy or aryloxy group, an amino or a guanidino group; A is —CH
2
or —C═O; provided that when R
11
is an amino acid or peptidyl residue, then A is a —C═O group;
R
5
is hydrogen or C
1-4
-alkyl;
z is CHR
10
wherein R
10
is hydrogen, C
1-6
-alkyl, phenyl or arylalkyl—or z is C
2-8
-alkylene, C
2-8
-alkenylene or C
2-8
-alkynylene;
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.
In another aspect of the invention R
1
is phenyl, arylalkyl or thienyl, optionally substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C
1-6
-alkyl, hydroxy, C
1-6
-alkoxy or NR
6
R
8
wherein R
6
and R
8
independently are hydrogen or C
1-6
-alkyl, or R
1
is C
1-6
-alkyl;
R
2
is aminophenyl, C
1-6
-monoalkylaminophenyl, C
1-6
-dialkylaminophenyl, cyanophenyl, C
2-6
-alkylphenyl, naphthyl, tetrahydronaphthyl, furanyl, in
Hohlweg Rolf
Thomsen Christain
Watson Brett
Desai Rita
Green, Esq. Reza
Gregg, Esq. Valeta A.
Novo Nordisk A S
Rotman Alan L.
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