Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-03
2001-03-13
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S359000, C544S365000, C544S366000, C544S367000, C544S369000, C544S236000, C514S249000, C514S254030
Reexamination Certificate
active
06200978
ABSTRACT:
This application claims priority from U.K. application serial no. 9804734.3 which was filed on Mar. 5, 1998.
The present invention relates to compounds, including inter alia pharmaceutical compositions comprising the same and methods for making the same.
In particular, the present invention relates to compounds that are capable of treating gastrointestinal disorders such as irritable bowel syndrome and diarrhoea, urinary urge incontinence, and pain.
More particularly, this invention relates to cyclic compounds and compositions comprising the same—as well as their preparation—and their use as selective agonists for the delta (&dgr;) receptor.
In particular, the present invention provides compounds that are suitable for use as &dgr; opioid agonists.
Agonists and antagonists are agents that recognise and bind to receptors thereby affecting biochemical and/or physiological pathways. Agonists inhibit or suppress neurotransmitter outputs in tissues containing receptors—e.g. they can inhibit pain responses—or they can affect other output-related phenomena. Antagonists also bind to receptors but they do not inhibit neurotransmitter outputs. Thus, antagonists are capable of binding to the receptor sites and thereby block the binding of agonist species which are selective for the same species.
At least four subtypes of opioid receptors—namely &dgr;, mu (&mgr;) and kappa (&kgr;)—are described and documented in the scientific literature. At least the &dgr;, &mgr; and &kgr; receptors are present in the central and peripheral nervous systems of many species including man. A brief introduction to opioid receptors may also be found in WO 95/04051, WO 97/23467, WO 93/15062, and WO 97/23466.
For example, it is known that &mgr; receptors mediate analgesia, respiratory depression and inhibition of gastrointestinal transit.
According to WO 95/04051, the existence of the opioid &dgr; receptor is a fairly recent discovery. &dgr; receptors mediate analgesia, but do not appear to inhibit intestinal transit as do the &mgr; receptors. Activation of &dgr; receptors is known to produce antinociception in rodents and can induce analgesia in man, in addition to influencing motility of the gastrointestinal tract [see Burks, T.F. (1995) in “The pharmacology of opioid peptides”, Tseng L. F. ed. Harwood Academic Publishers].
WO 97/23467 states that the &dgr; receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Hence, ligands for the &dgr; receptor may therefore find potential use as analgesics and/or antihypertensive agents. In addition, ligands for the &dgr; receptor have also been shown to possess immunomodulatory activities.
WO 97/23467 further states that with few exceptions, currently selective opioid &dgr; ligands are peptidic in nature and are unsuitable for administration by systemic routes. Moreover, some non-peptidic &dgr; antagonists are available but these compounds (e.g. naltrindole) suffer from poor selectivity for the &dgr; receptor vs the &mgr; receptor binding and exhibit no analgesic activity—a fact which highlights the need for the development of selective &dgr; ligands.
WO 95/04051 also states that opioid receptors are characterised as either agonists or antagonists. WO 95/04051 further states that &dgr; receptor agonists and antagonists can be distinguished by their activity in the electrically stimulated mouse vas deferens assay. Further details on this assay are presented in this document.
In more detail, WO 95/04051 discloses diarylmethyl piperazine compounds that are said to bind to the &mgr;, &dgr; and &kgr; receptors. These diarylmethyl piperazine compounds have the general formula:
One of the underlined R groups (i.e. R) can be a phenyl group that may be optionally substituted. For the definitions of the other R groups see WO 95/040501.
WO 93/15062 discloses diarylmethyl piperazine compounds and diarylmethyl piperidine compounds that are said to bind to the &mgr;, &dgr;, &sgr; and &kgr; receptors.
WO 97/23466 discloses substituted 7 membered N ring compounds for the treatment of pain. In particular, Examples 14 and 15 of WO 97/23466 disclose a compound of the formula:
For ease of reference this compound will be called the '466 compound.
WO 97/23467 discloses substituted 7 membered N ring compounds for the treatment of pain.
EP-A-0133 323 discloses antihistaminic benzhydrylpiperazines.
WO 98/52929 (published Nov. 26, 1998; filed Apr. 17, 1998) discloses anti-inflammatory piperazinyl-benzyl-tetrazole derivatives.
According to WO 95/0401, there is a continuing need in the art for improved opioid compounds, particularly compounds which are free of adverse side effects of conventional opiates such as morphine (which is selective for the &mgr; receptor).
The present invention seeks to provide novel compounds and compositions comprising the same that are capable of treating inter alia gastro-intestinal disorders.
Aspects of the present invention are presented in the accompanying claims and in the following text.
According to the present invention there is provided a compound of the formula (I)
wherein:
A is N or C-X
wherein X is H or C
1-4
alkyl;
G is C-Y
wherein Y is H or C
1-4
alkyl;
B is an optional C
1-6
hydrocarbyl group, optionally substituted;
L is an optional C
1-6
hydrocarbyl group, optionally substituted;
and wherein A, B, and L in combination with the N constitute a first ring structure which has from 5-7 atoms in the ring;
further wherein:
either D is H or a C
1-10
hydrocarbyl group,
or D is a C
1-10
hydrocarbyl group linked to B or L to form a second ring structure which includes the N of the first ring structure, which second ring structure is fused to the first ring structure and which second ring structure has from 5-7 atoms in the ring;
E is a phenyl group substituted by at least one or more of hydroxy, C
1-4
alkoxy, or NH
2
SO
2
—C
1-4
alkylene;
F represents a combination of a phenyl group and a heterocyclic group, wherein
(i) the heterocyclic group is not a tetrazole,
(ii) the phenyl group is positioned intermediate (in between) G and the heterocyclic group,
(iii) the phenyl group is fused to the heterocyclic group or is linked directly to the heterocyclic group or is attached via a spacer group to the heterocyclic group, wherein the spacer group is any one of C
1-4
alkylene, carbonyl or SO
2
, and
(iv) the heterocyclic group is substituted by at least one or more of: a —COOH group, a bio-isostere of a —COOH group, a biolabile ester derivative of a —COOH group, a C
1-10
hydrocarbyl group comprising one or more —COOH groups, a C
1-10
hydrocarbyl group comprising one or more bio-isosteres of a —COOH group, or a C
1-10
hydrocarbyl group comprising one or more biolabile ester derivatives of a —COOH group,
or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or salt.
It will be appreciated that what is to be claimed includes the following:
(i) a compound of the formula (I) or a pharmaceutically acceptable salt thereof;
(ii) one or more processes for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof;
(iii) novel intermediates for use in those processes;
(iv) a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable diluent, carrier or excipient;
(v) a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament;
(vi) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of a gastro-intestinal disease or disorder;
(vii) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for use as an agonist for &dgr; preceptor;
(viii) a method for the treatment of a gastro-intestinal disease or disorder which method comprises administering to a subject an ef
Maw Graham Nigel
Middleton Donald Stuart
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Stockton Laura L.
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