Cyclic compounds, their production and use

Details Cyclic compounds, their production and use Cyclic compounds, their production and use

2000-08-23

2002-12-03

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S460000, C540S461000, C540S485000, C544S346000

Reexamination Certificate

active

06489315

ABSTRACT:

The present invention relates to novel cyclic compounds having an excellent tachykinin receptor antagonistic effect, and a method for producing them, as well as a composition containing the foregoing cyclic compounds.
Capsaicine is a stimulative essential component to be in a capsicum, and this is known as a substance which selectively stimulates C-fibers comprising substance P (hereinafter simply referred to as SP), neurokinin A (NKA), calcitonin gene-related peptides (CGRP), etc. of the primary sensory nerve to thereby liberate such intrinsic neuropeptides.
Tachykinin is a generic term for a group of neuropeptides. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are known in mammals, and it is known that these peptides bind to the corresponding receptors (neurokinin-1, neurokinin-2, neurokinin-3) that exist in living body to thereby exhibit various biological activities.
Of such neuropeptides, substance P has the longest history and has been studied in detail. In 1931, the existence of substance P in the extract from equine intestines was confirmed, and its structure was determined in 1971. Substance P is a peptide consisting of 11 amino acids. It is known that substance P plays an important role in the peripheral and central nervous systems as an information transmitter substance or the like. In addition, it is considered that substance P participates in various disorders (for example, pain, inflammation, allergy, pollakisuria, urinary incontinence, respiratory tract disorders, psycosis, etc.)
Substance P is broadly distributed over the central and peripheral nervous systems, while having, in addition to the function as a transmitter substance for primary sensory neurons, various physiological activities for vasodilation, promotion of vascular extravasation, contraction of smooth muscles, neuronal excitatory activity, salivation, promotion of diuresis, immunological enhancement, etc. In particular, it is known that SP liberated from the terminal of the spinal (dorsal) horn due to a pain impulse transmits the pain to secondary neurons and that SP liberated from the peripheral terminal induces an inflammatory response in the nociceptive field. In addition, it is considered that SP is involved in Alzheimer type dementia [see review article: Physiological Reviews, Vol. 73, pp. 229-308, (1993); Journal of Autonomic Pharmacology, Vol. 13, pp. 23-93, (1993)].
At present, the following compounds have been known as those having a substance P receptor antagonistic effect.
(1) In Japanese Patent Laid-Open No. 1-287095, disclosed are compounds of a formula:
R
1
-A-D-Trp(R
2
)-Phe-R
3
wherein R
1
represents a hydrogen atom or an amino-protecting group; R
2
represents a hydrogen atom, an amino-protecting group, a carbamoyl-(lower)alkyl group, a carboxy-(lower)alkyl group, or a protected carboxy-(lower)alkyl group; R
3
represents an ar-(lower)alkyl group, a group of a formula:
wherein R
4
and R
5
represent, independently, a hydrogen atom, an aryl group or an optionally substituted lower alkyl group, or R
4
and R
5
are bonded to each other to form a benzene-condensed lower alkylene group, or a group of a formula:
—OR
6
wherein R
6
represents a hydrogen atom, an aryl group or an optionally substituted lower alkyl group; A represents a single bond or one or two amino acid residues, provided that when A is one amino acid residue of -D-Trp-, R
4
is not be a hydrogen atom, and a salt thereof.
(2) In EP-A-436,334, disclosed are compounds of a formula:
(3) In EP-A-429,366, disclosed are compounds of a formula:
(4) In Journal of Medicinal Chemistry, Vol. 34, p. 1751 (1991), disclosed are compounds of a formula:
(5) In WO91/09844, disclosed are compounds of a formula:
(6) In EP-A-522,808, disclosed are compounds of a formula:
(7) In WO93/01169, disclosed are compounds of a formula:
(8) In EP-A-532,456, disclosed are compounds of a formula:
(9) In Bioorganic & Medicinal Chemistry Letters, Vol. 4, p. 1903 (1994), disclosed is a compound of a formula:
(10) In European Journal of Pharmacology, Vol. 250, p. 403 (1993), disclosed is a compound of a formula:
(11) In EP-A-585,913, disclosed are compounds of a formula:
 wherein
Ring A may be optionally substituted;
Ring B represents an optionally substituted benzene ring;
one of X and Y represents —NR
1
— (where R
1
represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), —O— or —S—, while the other represents —CO—, —CS— or —C(R
2
)R
2a
— (where R
2
and R
2a
represent, independently, a hydrogen atom or an optionally substituted hydrocarbon group); or one of these represents —N═, while the other represents ═CR
3
— (where R
3
represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, a substituted hydroxyl group, or a mercapto group optionally substituted by an optionally substituted hydrocarbon group);
— — — — — — — — —
represents a single bond or a double bond;
Z represents ═CR
4
— (where R
4
represents a hydrogen atom, a hydroxyl group or an optionally substituted hydrocarbon group) or a nitrogen atom, when
— — — — — — — — —
adjacent to Z is a single bond, and represents a carbon atom when
— — — — — — — — —
adjacent to Z is a double bond;
D represents a C
1-3
alkylene group optionally substituted by oxo or thioxo group(s), or D and Y may together form a 5- to 7-membered ring optionally substituted by oxo or thioxo group(s);
E represents —NR
5
— (where R
5
represents a hydrogen atom, or an optionally substituted hydrocarbon group, or R
5
and Y may together form a 5- to 7-membered ring optionally substituted by oxo or thioxo group(s)), —O— or —S(O)
n
— (where n represents 0, 1 or 2);
G represents a bond or a C
1-3
alkylene group;
Ar represents an optionally substituted aryl group or an optionally substituted heterocyclic group;
provided that (i) when —X—Y— is —O—CO— or —CO—O—, D is —CO— and E is —NR
5
—, then (a) G is a C
1-3
alkylene group, and Ar is a substituted aryl group or a substituted heterocyclic group, or (b) G is a bond, and
R
5
is an optionally substituted hydrocarbon group, and (ii) when —X—Y— is —NH—CO—, then D is —CO—, or a salt thereof, etc.
On the other hand, the following compounds have been known as those having a neurokinin-A receptor antagonistic effect.
(1) In Life Sciences, Vol. 50, PL101 (1992), disclosed are compounds of a formula:
(2) In Bioorganic & Medicinal Chemistry Letters, Vol. 10 4, P.1951 (1994), disclosed are compounds of a formula:
(3) In AFMC International Medicinal Chemistry Symposium (Tokyo), P6M139 (1995.9), disclosed are compounds of a formula:
(4) In Tachykinins (Florence), P.21 (1995.10), disclosed are compounds of a formula:
(5) In Journal of Medicinal Chemistry, Vol. 38, P.3772 (1995), disclosed are compounds of a formula:
(6) In Bioorganic & Medicinal Chemistry Letters, Vol. 5, P.2879 (1995), disclosed are compounds of a formula:
However, these references do not disclose condensed heterocyclic compounds having a basic skeleton of a formula:
wherein
Ring M is a heterocyclic ring having —N═C<, —CO—N< or —CS—N< as the partial structure —X{overscore (— — — — — — — — —)} Y<;
R
a
and R
b
are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M;
Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of them is an optionally substituted heterocyclic ring; and
Ring Z is an optionally substituted nitrogen-containing heterocyclic ring. Nor do these references disclose the properties of such compounds.
At present, compounds which have excellent tachykinin receptor antagonistic effects (especially, substance P and NKA receptor antagonistic effects) and are sufficiently satisfactory as medicines for the above-mentioned various disorders (especially, pollakisuria, urinary incontinence, etc.) from the v

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