Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-06-25
2001-12-11
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S872000, C514S619000, C514S318000, C514S319000, C514S323000, C514S324000, C514S326000
Reexamination Certificate
active
06329394
ABSTRACT:
The present invention relates to the use of certain tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, in the treatment of emesis.
Tachykinin antagonists are known to be useful in the treatment of a variety of disorders including pain, inflammatory diseases, allergic disorders, CNS disorders, skin disorders, cough and gastrointestinal disorders such as ulcerative colitis and Crohn's disease.
It has now been found that tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, are useful in the treatment of emesis. Our co-pending European Patent Application No. 92202831 (Publication No. 0533280) relates to the use of tachykinin antagonists in the treatment of emesis.
The use of the tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, specifically disclosed in co-pending European Patent Application No. 92202831 in the treatment of emesis is not included within the scope of the present invention.
The invention accordingly provides, in a first aspect, the novel use of the tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, generically and specifically disclosed in published European Patent Application Nos. 512901, 512902, 514273, 514275, 517589, 520555, 522808, 528495, 532456 and published PCT Patent Application Nos. 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92122569, 93/00331, 93/01159, 93/01160, 93/01165, 93/01169 and 93/01170, which disclosures are incorporated herein by reference, in the treatment of emesis.
There is also provided as a further aspect of the invention the use of the tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, generically and specifically disclosed in the above referenced patent specifications in the preparation of a medicament for use in the treatment of emesis.
In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, suffering from or susceptible to emesis, comprising administration of an effective amount of a tachykinin antagonist, including substance P antagonists and other neurokinin antagonists, generically or specifically disclosed in the above referenced patent specifications.
It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
Tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, disclosed in the above referenced patent specifications have been shown to have anti-emetic activity as indicated by for example their ability to inhibit cisplatin- or radiation-induced emesis in the ferret.
The treatment of emesis mentioned hereinbefore includes the treatment of nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. Tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, are useful in the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis; pregnancy; vestibular disorders, such as motion sickness and vertigo; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); and opioid analgesics, such as morphine.
Tachykinin antagonists acting at NK
1
receptors have been found to be particularly useful in the treatment of emesis.
In a preferred aspect therefore the invention provides the use of an NK
1
receptor antagonist generically or specifically disclosed in the above referenced patent specifications in the treatment of emesis.
Particularly preferred tachykinin antagonists for use in the present invention include those generically and specifically disclosed in:
EP512901, i.e. compounds of the formula
wherein
Y represents a group Cy-N or Cy-CH
2
—N wherein
Cy represents phenyl optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, C
1-4
alkoxy, C
1-4
alkyl, trifluoromethyl; C
3-7
cycloalkyl; pyrimidinyl; or pyridyl;
or Y represents a group Ar—(CH
2
)
x
C(X)— wherein
Ar represents phenyl optionally substituted by one or more groups, which may be the same or different, selected from hydrogen, halogen, hydroxy, C
1-4
alkoxy, trifluoromethyl, C
1-4
alkyl; pyridyl; or thienyl; x is zero or 1;
X represents hydrogen, hydroxy, C
1-4
alkoxy, C
1-4
acyloxy, carboxy, C
1-4
alkoxycarbonyl, cyano, a group N(X
1
)
2
wherein X
1
represents independently hydrogen, C
1-4
alkyl, hydroxy C
1-4
alkyl, C
1-4
acyl or -(X
1
)
2
represents, together with the nitrogen atom to which it is attached, a heterocycle selected from pyrrolidine, piperidine or morpholine; a group —S—X
2
wherein X
2
represents hydrogen or C
1-4
alkyl; or X forms a double bond with an adjacent carbon atom;
m is 2 or 3;
Ar
1
represents phenyl optionally substituted by one or more groups, which may be the same or different, selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C
1-4
alkoxy, C
1-4
alkly; thienyl; benzothienyl; naphthyl; or indolyl;
n is zero 1, 2 or 3;
p is 1 or 2 provided that p is 2 when n is 1 and Q represents two hydrogen atoms;
Q represents oxygen or two hydrogen atoms;
T represents a group selected from C(O) and —CH
2
—;
q is zero, 1, 2 or 3;
Z represents phenyl optionally substituted by one or more groups selected from halogen, more particularly chlorine or fluorine, trifluoromethyl, C
14
alkyl, hydroxyl, C
1-4
alkoxy; naphthyl optionally substituted by one or more groups selected from halogen, trifluoromethyl, C
1-4
alkyl, hydroxyl; pyridyl; thienyl; indolyl; quinolyl; benzothienyl; imidazolyl; or in addition when T represents C(O), —(CH
2
)
q
—Z may also represent a benzyl group substituted on the —CH — by hydroxy, C
1-4
alkoxy or C
1-4
alkyl group and optionally substituted on the aromatic ring by halogen, more particularly chlorine or fluorine, trifluoromethyl, C
1-4
alkyl, hydroxy, C
1-4
alkoxy; or an optionally substituted mono-, bi- or tricyclic aromatic or heteroaromatic group; and salts thereof with mineral or organic acids, or, where Y represents Ar—(CH
2
)
x
—C(X)—, quarternary ammonium salts or N-oxides formed with the piperidine nitrogen atom (b).
EP 512902, i.e. compounds of the formula
wherein
Ar
1
represents phenyl optionally substituted by halogen, C
1-3
alkyl, trifluoromethyl, C
1-3
alkoxy or hydroxy; thienyl, pyridyl or naphthyl optionally substituted by halogen; indolyl; or benzothienyl;
R represents hydrogen, methyl or (CH
2
)
n
L;
n represents 2 to 6;
L represents hydrogen or amino;
Z and Z
1
represent hydrogen, M or OM;
M represents hydrogen, C
1-6
alkyl, a-hydroxybenzyl, a-(C
1-3
alkyl) benzyl, phenylC
1-3
alkyl (optionally ring substituted by halogen, hydroxy, C
1-4
alkoxy or C
1-4
alkyl), pyridylC
1-3
alkyl, naphthylC
1-3
alkyl, pyridylthioC
1-3
alkyl, styryl, 1-methyl-2-imidiazolylthioC
1-3
alkyl, 1-oxo-3-phenyl-2-indanyl, or optionally substituted aryl or heteroaryl;
T
1
=a bond, CH
2
or CO;
T=CO or C(W)NH;
W=O or S;
with the proviso that (a) T
1
is not a bond when Z
1
is hydrogen or OM; and (b) T is not C(W)NH when Z is hydrogen or OM;
and acid addition and quarternary ammonium salts thereof.
EP 514273, i.e. compounds of the formula
wher
Bunce Keith Thomas
Hagan Russell Michael
Bacon & Thomas
Glaxo Group Limited
Travers Russell
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