Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa...

Details Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa... Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa...

2001-01-26

2001-11-06

Oswecki, Jane C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S245000, C546S247000, C546S304000, C546S309000, C546S310000, C549S068000, C549S070000, C549S072000, C549S073000, C564S163000, C564S183000, C585S024000

Reexamination Certificate

active

06313302

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel pyrrolidinyl and pyrrolinyl ethylamine compounds and their pharmaceutically acceptable salts, and to pharmaceutical compositions containing them. The pharmaceutically active compounds of this invention can be used as a selective kappa-receptor agonist.
BACKGROUND ART
Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency and abuse. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the discovery of the subtype of opioid receptor such as mu (&mgr;), delta (&dgr;), kappa (&kgr;) in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a mu-receptor agonist, separating the action based on a kappa-receptor agonist from the action based on mu-receptor agonist has been investigated. Recently kappa-selective agonists (kappa-agonists) have been reported from the above viewpoint for example, EMD-61753: A. Barber et al.,
Br. J. Pharmacol.
, Vol. 113, pp. 1317-1327, 1994. Some of them actually have been studied in clinical trials (
Med. Res. Rev.
, Vol. 12, p. 525, 1992).
European Patent No. EP 0254545 B1 discloses a variety of ethylenediamine compounds. European Patent No. EP 0483580 A2 discloses a variety of pyrrolidine compounds as analgesics. International Publication WO 96/30339 discloses a wide variety of pyrrolidinyl hydroxamic acid compounds as selective kappa-receptor agonists
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
and the salts thereof, wherein
A is hydrogen, halo, hydroxy, C
1
-C
6
(preferably C
1
-C
4
) alkyl, halo C
1
-C
6
(preferably C
1
-C
4
) alkyl, C
1
-C
6
(preferably C
1
C
4
) alkoxy, halo C
1
-C
6
(preferably C
1
-C
4
) alkoxy, oxo, OY wherein Y is a hydroxy protecting group, or absent;
the broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent;
Ar
1
is phenyl optionally substituted by one or more (preferably one to two) substituents selected from halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkoxy-C
1
-C
4
alkoxy, CF
3
, carboxy-C
1
-C
4
alkoxy and C
1
-C
4
alkoxy-carbonyl-C
1
-C
4
alkoxy;
Ar
2
is aryl or heteroaryl selected from phenyl, naphthyl, pyridyl, thienyl furyl, pyrrolyl and pyrimidyl the aryl or heteroaryl being optionally substituted by one or more (preferably one to two) substituents selected from halo, hydroxy, amino, nitro, carboxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylamino, di C
1
-C
4
alkylamino, halo C
1
-C
4
alkyl, C
1
-C
4
alkylthio and sulfonyl methyl;
R
1
is hydrogen, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or OY wherein Y is a hydroxy protecting group; and
R
2
and R
3
are independently selected from hydrogen, hydroxy, C
1
-C
7
alkyl optionally substituted by or more (preferably one to five) hydroxy or halo, C
3
-C
6
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
7
(preferably C
1
-C
5
) alkoxy, phenyl optionally substituted by halo (preferably substituted by one or two halogen atoms), phenyl C
1
-C
7
(preferably C
1
-C
5
) alkyl, halo substituted phenyl C
1
-C
7
alkyl, and (CH
2
)nX—R
4
wherein n is one or two, X is O, NH or S and R
4
is C
1
-C
3
alkyl, or when Ar
2
is phenyl, —Ar
2
—C(═O)—N(R
2
)— is a pride group and R
3
is C
1
-C
7
alkyl, or
R
2
and R
3
, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C
1
-C
3
alkyl or halo.
When Ar
2
is phenyl, R
2
R
3
N—C(═O)— is preferably at the meta or para position on the phenyl ring with respect to 2-(A-pyrrolydinyl)-1-Ar
1
-ethyl-N(R
1
)—. When oxo is selected as “A” group, it is apparent that the oxygen atom should be attached to the pyrrolidinyl group through a double bond.
The pyrrolidinyl and pyrrolynyl ethylaiine compounds of the present invention of formula (I) exhibit good kappa-receptor agonist activity, and thus are useful as an analgesic, anesthetic, anti-inflammatory or neuroprotective agent, and also useful in the treatment of arthritis, stroke or functional bowel disease such as abdominal pain, for the treatment of a mammalian subject, especially a human subject. Specifically, these compounds are useful as an analgesic for acute and chronic pain. Especially, these compounds are useful as an analgesic at central nervous system in the mammalian subject. Also, these compounds are useful as an analgesic for peripheral mediated inflammatory pain caused, for example by burns (induced by a contact with heat, acid or the other agents), scald (induced by a contact by hot liquid or steam), rheumatism or the like, in the said subject.
Accordingly, the present invention provides a pharmaceutical composition, which is useful as an analgesic, anesthetic, anti-inflammatory or neuroprotect:ve agent, and also useful in the treatment of the above-mentioned diseases, which comprises a therapeutically effective amount of the compound of the formula (I), and a pharmaceutically inert carrier.
The present invention also provides a method for the treatment of a medical condition for which agonist activity toward opioid kappa-receptor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of the compound of the formula (I).
DETAILED DESCRIPTION OF THE INVENTION
In this specification, the term “hydroxy protecting group” means a functional group to protect a hydroxy group against undesirable reactions during synthetic procedures, including, but not limited to benzyl, benzoyl, methoxymethyl, tetrahydropyranyl and trialkylsilyl.
The term “C
1
-C
6
alkyl” is used herein means a straight or branched alkyl including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like.
The term “C
1
-C
6
alkoxy” is used herein to mean a straight or branched —OR(R is C
1
-C
6
alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy and the like.
The term “halo” means F, Cl, Br or I, preferably F or Cl.
The term “halo C
1
-C
6
alkyl” means a straight or branched, halo-substitued alkyl of 1 to 6 carbon atoms including, but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl, substituted by 1 to 13 (preferably one to five) halogen atoms.
The term “halo C
1
-C
6
alkoxy” means C
1
-C
6
alkoxy substituted by 1 to 13 (preferably one to three) halogen atoms.
The term “halo substituted phenyl C
1
-C
7
alkyl” means C
1
-C
7
alkyl having a phenyl group attached to its terminal carbon atom, the phenyl group being substituted by one to five (preferably one to two) halogen atoms.
A preferred group of compounds of this invention includes the compounds of the formula (I) wherein
A is hydrogen, halo, hydroxy, oxo, or OY, or if the broken line is a double bond then A is absent;
Ar
1
is phenyl optionally substituted by one to three substituents selected from halo, hydroxy, C
1
-C
4
alkoxy, carboxy C
1
-C
4
alkoxy and C
1
-C
4
alkoxy-carbonyl-C
1
-C
4
alkoxy;
Ar
2
is phenyl, pyidyl or thienyl, optionally substituted by one to two halo or C
1
-C
4
alkoxy;
R
1
is hydrogen, hydroxy or C
1
-C
4
alkyl; and
R
2
and R
3
are independently selected from hydrogen, C
1
-C
7
alkyl optionally substituted by one or more hydroxy or halo, C
3
-C
6
(preferably C
3
-C
4
) cylcloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
(preferably C
2
-C
3
) alkynyl, C
1
-C
4
alkoxy phenyl and halo substituted phenyyl C
1
-C
7
alkyl, when Ar
2
is phenyl, —Ar
2
—C(═O)—N(R
2
)— is a phthalimide group and R
3
is C
1
-C
7
alkyl, or
R
2
and R
3
, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.
A more preferred gro

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