Kappa agonist compounds and pharmaceutical formulations thereof

Details Kappa agonist compounds and pharmaceutical formulations thereof Kappa agonist compounds and pharmaceutical formulations thereof

2000-01-06

2002-05-21

Higel, Floyd D. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S091000, C548S413000, C548S578000

Reexamination Certificate

active

06391910

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compounds, to processes of their preparation, to pharmaceutical compositions containing them and to their medical use as agonists at kappa opioid receptors.
2. Reported Developments
Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.
It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (&mgr;), delta (&dgr;) and kappa (&kgr;), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L., Neuropharmacology, 21, 487-497, 1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al, J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The &dgr; receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The &mgr; receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects.
The &kgr; receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, gut motility, temperature control and various endocrine functions. They also produce analgesia. [See, for example: Leander et al, J. Pharmacol. Exp. Ther. 234, 463-469, 1985; Morley et al, Peptides 4, 797-800, 1983; Manzanares et al, Neuroendocrinology 52, 200-205, 1990; and Iyengar et al, J. Pharmacol. Exp. Ther, 238, 429-436, 1986.]
Most clinically used opioid analgesics such as morphine and codeine act as &mgr; receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds which are &kgr;-receptor agonists act as analgesics through interaction with &kgr; opioid receptors. The advantage of these agonists over the classical &mgr; receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
A large number of classes of compounds which act as agonists at &kgr; opioid receptors have been described in the art including the following illustrative classes of compounds.
U.S. Pat. No. 4,065,573 discloses 4-amino-4-phenylcyclohexane ketal compounds having analgesic activity.
U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives having analgesic properties and reduced physical dependence liability properties, relative to morphine and methadone.
U.S. Pat. No. 4,145,435 discloses N-(2-amino-cycloaliphatic)-phenylacetamide compounds having analgesic activity and narcotic antagonist activity.
U.S. Pat. No. 4,098,904 discloses N-(2-amino-cycloaliphatic)-benzoamides and naphthamides useful for relieving pain.
U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides useful as analgesic and having low abuse liability.
U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and thia-spirocyclic compounds having analgesic activity, low physical dependence and abuse liability properties and little dysphoric inducing properties.
U.S. Pat. No. 4,663,343 discloses substituted naphthalenyloxy-1,2-diaminocyclohexyl amides as analgesics.
U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides having high kappa-opioid affinity, selectivity and potency and useful as analgesics, diuretics, anti-inflammatory and psychotherapeutic agents.
SUMMARY OF THE INVENTION
Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.
In its compound aspect, the present invention provides a compound of the formulae I, II, IIA, III, IIIA, IV and IVA, or a pharmaceutically acceptable salt thereof
The compounds of formula (I) have the following structure:
wherein
n−1-3, where n=1 is preferred
R
1
and R
2
are independently ═CH
3
; —(CH
2
)
m
, where m=4-8, m=4 is most preferred; —CH
2
CH(OH)(CH
2
)
2
—; CH
2
CH(F)(CH
2
)
2
—; —(CH
2
)
2
O(CH
2
)
2
—; or —(CH
2
)
2
CH═CHCH
2
—;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH
3
, SO
2
CH
3
, CF
3
, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
Z is
—P(O)(OBn)
2
; —P(O)(OH)
2
; —(CH
2
)
p
C(O)NHOH; —(CH
2
)
p
CO
2
H; —SO
2
CH
3
; —SO
2
NH
2
; —CO(CH
2
)
p
CH(NH
2
)(CO
2
H); —COCH(NH
2
)(CH
2
)
p
CO
2
H; —CO
2
CH
3
; —CONH
2
; —(CH
2
)
p
O(CH
2
)
p
CO
2
H; —(CH
2
)
p
O(CH
2
)
p
CONHOH; —(CH
2
)
p
NHSO
2
CH
3
; —(CH
2
)
p
NCH(S)NHCH(CO
2
H)(CH
2
)
p
CO
2
H; —(CH
2
)
p
SO
3
H; or
or Z is
 wherein
p=0-20;
R
3
=—H or —Ac;
X
2
=—CO
2
H; —NHSO
2
CH
3
; NHP(O)(OBn)
2
, NHP(O)(OH)
2
,
—OP(O)(OBn)
2
; or OP(O)(OH)
2
;
X and Y are independently
—CH
2
NHSO
2
CH
3
, —CH
2
NHP(O)(OBn)
2
, —CH
2
NHP(O)(OH)
2
, —CH
2
OP(O)(OBn)
2
, —CH
2
OP(O)(OH)
2
, —(CH
2
)
q
O(CH
2
)
q
CO
2
H, —(CH
2
)
q
O(CH
2
)
q
SO
3
H, —(CH
2
)
q
O(CH
2
)
q
CHNHOH, —CH
2
NHC(S)NHCH(CO
2
H)(CH
2
)
q
CO
2
H or
 wherein
r=1-20
R
4
=—H or —Ac
X
3
=—CO
2
H; —NHSO
2
CH
3
; —NHP(O)(OBn)
2
; —NHP(O)(OH)
2
; —OP(O)(OBn)
2
; or —OP(O)(OH)
2
.
The compounds of formula II have the following structure:
wherein
n=1-3, where n=1 is preferred
R
1
and R
2
are independently ═CH
3
; —(CH
2
)
m
, where m=4-8, m=4 is most preferred; —CH
2
CH(OH)(CH
2
)
2
—; CH
2
CH(F)(CH
2
)
2
—; —(CH
2
)
2
O(CH
2
)
2
—; or —(CH
2
)
2
CH═CHCH
2
—;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH
3
, SO
2
CH
3
, CF
3
, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
X
4
and X
5
are independently
—OP(O)(OBn)
2
; —OP(O)(OH); —CO
2
H; —SO
3
H; —SO
3
H; —O(CH
2
)
n
CO
2
H; —NHSO
2
CH
3
; —CONH(CH
2
)
s
CO
2
H; or —SO
2
NH(CH
2
)
s
CO
2
H; wherein
s=1-5
or X
4
and X
5
are independently
 wherein
t=1-20
R
5
=—H or —Ac
X
6
—CO
2
H; —NHSO
2
CH
3
; —NHP(O)(OBn)
2
; —NHP(O)(OH)
2
; —OP(O)(OBn)
2
; or —OP(O)(OH)
2
.
The compounds of formula IIA have the following structure:
wherein
n=1-3, where n=1 is preferred
R
1
and R
2
are independently ═CH
3
; —(CH
2
)
m
, where m=4-8, m=4 is most preferred; —CH
2
CH(OR)(CH
2
)
2
— wherein R is H, alkyl, acyl or aroyl; CH
2
CH(F)(CH
2
)
2
—; —(CH
2
)
2
O(CH
2
)
2
—; or —(CH
2
)
2
CH═CHCH
2
—;
Ar=mono- or di-substituted phenyl; wherein said substituents are selected from the group consisting of halogen, OCH
3
, OH, SO
2
CH
3
, CF
3
, NH
2
, alkyl, CN, unsubstituted and substituted sulfamoyl groups;
Ar may also be substituted with
—NH(CH
2
)
u
CO
2
R′; —NH(CH
2
)
u
(CH═CH)
u
(CH
2
)CO
2
R′; —NHCO(CH
2
)
u
(CH═CH)
u
(CH
2
)
u
CO
2
R′; —NHP(O)(OBn)
2
; —NHP(O)(OR′)
2
; —(CH
2
)
u
NHSO
2
CH
3
; —(CH
2
)NHC(S)NHCH(CO
2
R′)(CH
2
)CO
2
R′; —CONHOH; or —(CH
2
)
u
CONHOH;
 wherein
u=0-5;
R′=H or lower alkyl;
or Ar is
R
6
=—H or —Ac
R
7
=—NH(CH
2
)
v
CO
2
H; —NH(CH
2
)
v
CH(NH
2
)(CO
2
H); —NHCH(CO
2
H)(CH
2
)
v
NH
2
; —NH(CH
2
)
v
SO
3
H; —NH(CH
2
)
v
PO
3
H
2
; —NH(CH
2
)
v
NHC(NH)NH
2
; or —NHCH(CO
2
H)(CH
2
H)
v
CO
2
H; and
X
8
=—CO
2
H; —NHSO
2
CH
3
; —NHP(O)(OBn)
2
; —NHP(O)(OH)
2
; —OP(0)(OBn)
2
; or —OP(O)(OH)
2
;
v=1-20.
X
4
and X
5
are independently H; halogen; OH; OCH
3
; CF
3
; NO
2
; NH
2
; amino substituted with acyl, carbamate, alkyl or aryl sulfonates; COR′ where R′ is OH, amide, alkoxy, aryloxy or heteroaryloxy.
Compounds of formula (IIA) have at least one chiral center and may exist in more tha

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