Diazapane derivatives useful as antagonists of neurokinin 1...

Details Diazapane derivatives useful as antagonists of neurokinin 1... Diazapane derivatives useful as antagonists of neurokinin 1...

2001-05-14

2002-09-17

Kifle, Bruck (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S501000, C540S524000, C540S526000, C540S527000

Reexamination Certificate

active

06452001

ABSTRACT:

FIELD OF INVENTION
The present invention is generally related to diazapane compounds and more particularly to substituted diazapane compounds showing utility as antagonists of Neurokinin 1 Receptors.
BACKGROUND
The neuropeptide receptors for substance P (NK-1) are 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) and anxiety (Can., J. Phys., 1997, 75, 612-621).
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.
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)”.
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. Cemak, R. Vink).”
SUMMARY
The present invention provides a compound of the formula
wherein
R
1
, R
2
are independently from each other aryl or heteroaryl, wherein the heteroaryl group contains one or two heteroatoms, selected from N, O or S, and wherein the aryl or heteroaryl groups are unsubstituted or substituted by 1 to 3 substituents, which are independently from each other halogen, CF
3
, lower alkoxy or lower alkyl;
R
3
is hydrogen, lower alkyl, —(CH
2
)
n
N(R)
2
, —(CH
2
)
n
-heteroaryl or is a —(CH
2
)
n
-non aromatic heterocycle, the heterocycles are unsubstituted, or substituted by halogen, CF
3
, lower alkoxy or lower alkyl;
R
4
is ═O, ═N(CH
2
)
n
CH
3
or ═N(CH
2
)
n
N(R)
2
, or wherein R
3
and R
4
together with the N and C atoms to which they are attached, form the group —CR
5
═N—N═;
R
5
is hydrogen, —(CH
2
)
n
N(R)
2
, —(CH
2
)
n
-heteroaryl or is a —(CH
2
)
n
-non aromatic heterocycle, which heterocycles are unsubstituted, or, substituted by halogen, CF
3
, lower alkoxy or lower alkyl;
R is hydrogen or lower alkyl;
n is 0, 1, 2 or 3;
and pharmaceutically acceptable acid addition salts and their enantiomers.
The compound of formula I and pharmaceutically acceptable salts thereof are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists 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.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts and their enatiomeric forms thereof, the preparation of the above-mentioned compounds, pharmaceutical compositions 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 to earlier or in the manufacture of corresponding medicaments.
DETAILED DESCRIPTION
The present invention is a compound of the stucture
wherein
R
1
and R
2
, are a substituted or unsubstituted aryl ring structure having six to twelve carbon ring atoms, or a substituted or unsubstituted heteroaryl ring structure having five to twelve ring members with one or two of the ring members being a heteroatom selected from the group consisting of nitrogen, oxygen or sulfur. The substituted aryl or heteroaryl ring structure is substituted with one to three substituents selected from the group consisting of halogen, CF
3
, lower alkoxy, and lower alkyl.
R
3
is independently hydrogen, lower alkyl, —(CH
2
)
n
N(R)
2
, —(CH
2
)
n
—X—;
R
4
is independently ═O, ═N(CH
2
)
n
CH
3
or ═N(CH
2
)
n
NR
2
, or taken together with R
3
and with their respective attached N and C atoms form —CR
5
═N═N—;
R
5
is hydrogen, —(CH
2
)
n
N(R)
2
or is a substituted or unsubstituted —(CH
2
)
n
—X;
X is a substituted or unsubstituted heterocyclic ring structure having five to twelve ring members, with one or two of the ring members being a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen. The substituted heterocyclic ring structure being substituted with one to three substituents selected from the group consisting of halogen, CF
3
, lower alkoxy, and lower alkyl;
R is hydrogen or lower alkyl; and
n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt and enantiomeric forms thereof.
Preferred embodiments of compound I include a compound of structure of I-a
In one preferred embodiment of compound 1-a, R
3
is hydrogen, R
1
is an aryl ring structure, such as a substituted phenyl ring structure, and R
2
is a substituted ring structure. In another preferred embodiment, R
3
and R
1
are as above, and R
2
is a substituted napthyl ring structure. In yet another preferred embodiment of compound 1-a, R
1
is a heteroaromatic ring structure, R
2
is a substituted phenyl ring structure and R
3
is hydrogen. A further preferred embodiment of compound 1-a includes R
1
and R
2
as substituted or unsubstituted aromatic ring structures and R
3
is a non-aromatic heterocyclic ring structure. Yet another preferred embodi

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