Substituted heterocyclic siprodecane compound active as an...

Details Substituted heterocyclic siprodecane compound active as an... Substituted heterocyclic siprodecane compound active as an...

2001-05-21

2002-11-19

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S252010, C514S235500, C514S235800, C514S236800, C514S249000, C514S253090, C514S245000, C514S273000, C544S129000, C544S211000, C544S219000, C544S298000, C544S332000, C544S336000, C544S360000, C546S016000, C546S020000

Reexamination Certificate

active

06482829

ABSTRACT:

FIELD OF INVENTION
The present invention is generally a heterocyclic spirodecane and more particularly a substituted heterocyclic spiro[4.5]decane with activity at the NK-1, substance P receptor.
BACKGROUND
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases reviewed in “Tachykinin Receptor and Tachykinin Receptor Antagonists”, J. Auton. Pharmacol., 13, 23-93, 1993.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in “Neuropeptides, 32(1), 1-49, (1998)” and “Eur. J. Pharmacol., 383(3), 297-303, (1999)”.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title “Neurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injury” (Authors: A. J. Nimmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).”
SUMMARY
A compound of the present invention has the formula
wherein
R
1
is hydrogen, lower alkyl, lower alkenyl, phenyl or the following groups
—(CH
2
)
m
-non aromatic heterocyclyl, which is unsubstituted or substituted by lower alkyl, or is
—(CH
2
)
m
-heteroaryl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, CF
3
, benzyl or cyano, or is
—(CH
2
)
m
—C(O)—NRR′,
—(CH
2
)
m
—C(O)-lower alkyl,
—(CH
2
)
m
—C(O)—O-lower alkyl,
—(CH
2
)
m
—O-lower alkyl,
—(CH
2
)
m
—CH[C(O)—O-lower alkyl]
2
,
—(CH
2
)
m
CH(OH)—CH
2
—O-phenyl,
—(CH
2
)
m
—CH(CF
3
)OH,
—(CH
2
)
m
—OH,
—(CH
2
)
m
—CN,
—(CH
2
)
m
—NRR′,
—(CH
2
)
m
-cycloalkyl or
—(CH
2
)
m
—CHF
2
;
R
2
is hydrogen, lower alkyl, halogen or lower alkoxy;
R
3
is lower alkyl, lower alkoxy, halogen or CF
3
;
R,R′ are the same or different and are hydrogen or lower alkyl;
X is >N—, or >CH—;
X
1
/X
2
are independently from each other hydrogen, hydroxy or lower alkoxy or may be together an oxo group;
Y
1
/Y
2
are independently from each other hydrogen, lower alkyl, —(CH
2
)
m
-phenyl or may be together an oxo group;
Z is a —(CH
2
)
q
— or —C(O)—;
m is 0, 1, 2, 3 or 4;
n is 2 or 3;
n′ 0, 1 or 2;
q is 0 or 1;
or pharmaceutically acceptable acid addition salts thereof.
A compound of formula I or its salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compound of the present invention is an antagonist of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
Preferred compounds of the present invention include, but are not limited to:
The compound having the formula
wherein R
1
, R
2
and R
3
are as defined above and wherein n=2 and one of R
3
is F and the other of R
3
is CF
3
.
Another preferred compound based on formula I-a has the formula I-c with R
1
being hydrogen, lower alkyl, —(CH
2
)
m
-cycloalkyl, —(CH
2
)
m
—NRR′ or —(CH
2
)
m
-unsubstituted non-aromatic; and m=0, 1, 2, 3, 4.
wherein R
1
and R
2
are as defined above; or further including R
1
being hydrogen and R
2
being hydrogen; and wherein R
1
is phenyl or —(CH
2
)
m
-unsubstituted heteroaromatic alkyl. A further preferred embodiment based on structure I-c includes R
1
being —(CH
2
)
m
-substituted heteroaryl and R
2
being hydrogen; R
1
being substituted or unsubstituted-(CH
2
)
m
-non aromatic heterocyclic or, —(CH
2
)
m
—NRR′ and R
2
being hydrogen; R
1
being a —(CH
2
)
m
—O—O-lower alkyl, —(CH
2
)
m
—O-lower alkyl or —(CH
2
)
m
—CH(OH)—CH
2
—O-phenyl and R
2
being hydrogen; R
1
being —(CH
2
)
m
—CF
3
, —(CH
2
)
m
CN or —(CH
2
)
m
OH; R
1
being unsubstituted or substituted-(CH
2
)
m
-heteroaryl, m is 0, 1, 2, 3 or 4; and R
2
is halogen and n′ is 1 or 2; R
1
is —(CH
2
)m—OH, unsubstituted or substituted-(CH
2
)m-heteroaryl, m is 0, 1, 2, 3 or 4; and R
2
is lower alkyl or lower alkoxy; R
1
is hydrogen, R
2
is lower alkyl, lower alkoxy or halogen and wherein n′ is 1 or 2; or R
1
being —(CH
2
)
m
—C(O)—NRR′, —(CH
2
)
m
—CH—(CF3)OH or unsubstituted or substituted-(CH
2
)
m
-non-aromatic heterocyclic wherein m is 1, 2, 3 or 4 and R
2
is hydrogen or halogen.
Another preferred embodiment has the formula
wherein R
1
and R
2
are as defined above. Yet another preferred embodiment based on formula I-d includes R
1
being hydrogen, lower alkyl, phenyl or —(CH
2
)
m
-unsubstituted or substituted heterocyclic non-aromatic heterocyclic; and R
2
being hydrogen or lower alkyl, m is 1, 2, 3, 4; or further includes R
1
being lower alkyl, —(CH
2
)
m
-unsubstituted and substituted heteroaromatic, m=0, 1, 2, 3, 4; or R
1
being —(CH2)
m
-unsubstituted or substituted heteroaromatic and R
2
being halogen.
A further preferred embodiment includes the structure
wherein R
1
is hydrogen.
Yet another preferred embodiment has the structure
wherein R
1
, R
2
, X
1
and X
2
are as defined above. A further preferred embodiment based on the structure I-f includes X
1
or X
2
being hydrogen, hydroxy or lower alkoxy, R
1
being hydrogen, phenyl or —(CH
2
)
m
-unsubstituted or substituted non-aromatic heterocyclic; and R
2
being hydrogen or lower alkyl.
A further preferred embodiment has the structure I-g
wherein Y
1
or Y
2
, R
1
, R
2
and R
3
are as above or R
1
being —(CH
2
)
m
-substituted or unsubstituted heteroaryl. Another preferred embodiment based on the structure I-g includes R
1
being hydrogen, R
2
being lower alkyl and R
3
being halogen, OCF
3
or CF
3
.
A further embodi

Affiliated with

Also associated with

Rating

Substituted heterocyclic siprodecane compound active as an... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted heterocyclic siprodecane compound active as an..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted heterocyclic siprodecane compound active as an... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2944944