GB2242628A - Asthma prophylactic use of K+ channel activators - Google Patents
Asthma prophylactic use of K+ channel activators Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Abstract
Use of specified K<+>channel activators in particular benzopyran derivatives, in the prophylactic treatment of obstructive or inflammatory airways disease, for example asthma, as well as pharmaceutical compositions comprising said K<+> channel activators suitable for such use.
Description
ASTHMA PROPEYLACTIC USE OF K+ CHANNEL ACTIVATORS
The present invention relates to a new use, in particular a new pharmaceutical use for known compounds.
More particularly the present invention relates to a new pharmaceutical use for compounds selected from the group consisting of:
I: Compounds of formula I
wherein either:
A) V denotes R1-C, T denotes R2-C and W denotes H-C, wherein R1 signi
fies hydrogen, halogen, ethynyl, hydroxy, cyano or the groups of
formulae -NR6R8, -CO2R6 or -CONR6R7 and R2 signifies hydrogen, halo
gen, C1~4alkoxy, hydroxy or the group of formula -NR6R8, whereby R6
and R7 independently of one another respectively denote hydrogen or
a C1-4alkyl group and R8 signifies hydrogen, a C14alkyl group, a
formyl, an acetyl or a trifluoroacetyl group, or one of R1 and R2
signifies nitro and the other of R1 and R2 is defined as above; or
B) V denotes N, T denotes R2-C wherein R2 has the significance given
above and W denotes HC; or
C) V denotes R1'-C, T denotes H-C and W denotes N wherein R1, signifies
hydrogen, a cyano or a nitro group; or
D) V denotes N, T denotes H-C and W denotes N,
R3 and R4 independently of one another, denote hydrogen or a C1-4- alkyl group or R3 and R4 together signify a group -(CH2)n- wherein n
is 2, 3, 4 or 5
R5 signifies hydrogen or OR8 wherein R8 is as defined above
Rg and Rlo respectively denote hydrogen or methyl or together signi
fy an oxo- or a thio-group
m is 1, 2 or 3
X signifies 0 or Nor11 wherein R11 signifies hydrogen, a C14alkyl-, formyl-, acetyl- or hydroxymethyl- group
Y is CH, C-halogen, N, C-formyl or C-hydroxymethyl and
Z is CH2, O, S, CH-halogen or NR6 wherein R6 is as defined above
and their N-oxides,
as well as the pharmaceutically acceptable acid addition and quaternary ammonium salts thereof;
II: Compounds of formula II
wherein X is halogen and R is C14alkyl; III: The compound of formula III
and its pharmaceutically acceptable acid addition salts;
IV:Compounds of formula IV
wherein R1 is a group of the formula
wherein R3 and R4 are hydrogen, C1alkyl, C2-8alkenyl, C14 aralkyl, C3-10cycloalkyl or
C3-10alkylcycloalkyl, with the proviso that both R3 and R4 are not hydrogen, or an aziridinyl, azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino or 4-lower-alkylpiperazinyl group, each of said heterocyclic groups having optionally attached as substituents on carbon atoms thereof one to three
C1-8alkyl groups inclusive, a nitrogen atom of each of said heterocyclic groups being the point of attachment of R1 to the ring in said formula, and wherein R2 is hydrogen, C18alkyl, C2-8 alkenyl, C3~10alkoxyalkyl, C3~l0cycloalkyl or C3-10alkylcycloalkyl, a phenyl or naphthyl radical, C,14aralkyl, C7-14alkaryl, C815alkaralkyl, C815alkoxyaralkyl or C1 4haloaralkyl.
as well as the pharmaceutically acceptable acid addition salts thereof;
V: Compounds of formula I as illustrated and defined in claim 1 of UK patent specification No 1,489,879 as well as the pharmaceutically acceptable acid addition salts thereof;
VI: Compounds of formula I as illustrated and defined in claim 1 of
European patent publication No 314,446, as well as the pharmaceutically acceptable acid addition salts thereof;
VII: Compounds of formula I as illustrated and defined in claim 1 of
European Patent publication No 273,262, as well as the pharmaceutically acceptable salts thereof;
VIII: Compounds of formula I as illustrated and defined in claim 1 of
European patent publication No 298,452, as well as the pharmaceutically acceptable acid addition salts thereof;
IX:Compounds of formula I as illustrated and defined in claim 1 of
European Patent publication No 339,562, as well as the pharmaceutically acceptable salts thereof;
X: Compounds as illustrated and defined in claim 1 of European Patent publication No 344,747, as well as the pharmaceutically acceptable salts thereof;
XI: Compounds of formula I as illustrated and defined in claim 1 of
European Patent publication No 296,975 or of European Patent publication
No 312,432, as well as the pharmaceutically acceptable salts thereof;
XII: Compounds of formula I as illustrated and defined in claim 1 of
European Patent publication No 327,127, as well as the pharmaceutically acceptable salts thereof;
XIII: Compounds of formula I as illustrated and defined in claim 1 of
European Patent publication No 277,612.
The compounds of said group, and pharmaceutically acceptable forms thereof, e.g. pharmaceutically acceptable salts thereof, are hereinafter collectively referred to as COMPOUNDS OF THE INVENTION.
COMPOUNDS OF THE INVENTION as defined under I above are known, e.g.
from UK patent specification No 2,204,868A. COMPOUNDS OF THE INVENTION as defined under II are known, e.g. from US patent No 2,986,573,
COMPOUNDS OF THE INVENTION as defined under III are known, e.g. from US patent No 4,200,640, COMPOUNDS OF THE INVENTION as defined under IV are known, e.g. from UK patent specification No 1,167,735.
Where the aforementioned UK patent specification Nos 2,204,868A, 1,489,879 and 1,167,735, US patent numbers 2,986,573 and 4,200,640,
European patent publication numbers 314,446, 273,262, 296,975, 312,432, 298,452, 339,562, 344,747, 327,127 and 277,612 (hereinafter collectively referred to as BASIC TEXTS) identify preferred sub-groups for the compounds defined, preferred substituent groupings for compounds defined or preferred isomeric forms for the compounds defined, these are also preferred in relation to the present invention, and the contents of the
BASIC TEXTS are, for the purposes of defining such preferences, incorporated herein by reference.
The present invention is also to be understood as embracing any additional pharmaceutically acceptable forms of he compounds and salts defined above as may occur/be identified in BASIC TEXTS, for example solvates, as identified e.g. in European patent publication No 314,446 or tautomeric forms, e.g. as identified in UK patent specification No 1,489,879, such additional pharmaceutically acceptable forms also being encompassed by the term COMPOUNDS OF THE INVENTION.
COMPOUNDS OF THE INVENTION may be prepared in accordance with the methods known in the art, for example as described in BASIC TEXTS.
Individual COMPOUNDS OF THE INVENTION suitable for use in accordance with the present invention include any of those specifically named or exemplified in BASIC TEXTS, the contents of which are, for the purposes of identifying such individual compounds incorporated herein by refet- ence.
A particularly interesting sub-group of COMPOUNDS OF THE INVENTION for use in accordance with the present invention comprises those defined under I above.
For use in accordance with the present invention the following
COMPOUNDS OF THE INVENTION are preferred: 1. (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oXo-1-cyclopent- 1-enyloxy)-2H-1-benzopyran-6-carbonitrile (cf. UK patent specification
No 2,204,868A, example 7), this being the compound of formula Ia
referred to hereinafter as PCO 400; 2. 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine-1,1-dioxide of formula
IIa
also known and referred to hereinafter as DIAZOXIDE; 3. N-[2-(nitrooxy)ethyl]-3-pyridinecarboxamide of formula III above, also known and referred to hereinafter as NICORANDIL; 4. 6-amino-1 , 2-dihydro-1-hydroxy-2-imino-4-piperidinopyrmidine of formula IVa
also known and referred to hereinafter as MINOXIDIL; 5.N-cyano-N'-4-pyridinyl-N'-(1,2,2-trimethyl-propyl)guanidine of formula Va
also known and referred to hereinafter as PINACIDIL. For use in accordance with the present invention PINACIDIL is suitably employed in (+) form and as its mono-hydrate; 6. Trans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H- 1-benzopyran-4-yl] -2, 3-dihydro-1H-isoindol-1-one of formula VIa
referred to hereinafter as AHC, (for use in the present invention, the (-)-3S,4R form of AHC is preferred); 7. 2,2-dimethyl-4-(lH-2-pyridon-1-yl)-6-cyano-2H-chromen of formula
VIIa
also known and referred to hereinafter as EMD 52 692; 8. 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine-N-oxide of formula VIIIa
also known and referred to hereinafter as Ro 31-690; 9. The following compound of formula IXa
10. The following compound of formula Xa
and pharmaceutically acceptable salt forms thereof, e.g. as hereinbefore set forth, in particular acid addition and quaternary ammonium salts.
COMPOUNDS OF THE INVENTION are known to have K+ channel opening activity and have been proposed for use in various medical indications, notably in the cardiovascular field, e.g. as vasodilators. It has also been proposed that certain of these compounds may find utility as bronchodilator drugs, e.g. for the symptomatic treatment of asthma.
In accordance with the present invention it has now surprisingly and unexpectedly been found that COMPOUNDS OF THE INVENTION are capable of suppressing, diminishing or abrogating basal pathology of obstructive or inflammatory airways disease, e.g. of suppressing, diminishing or abrogating airways hyperreactivity or pulmonary eosinophil accumulation causal to or inherent in the aetiology of such disease. COMPOUNDS OF
THE INVENTION are thus now found to be useful for the prophylaxis of obstructive or inflammatory airways disease, i.e. they are capable, following advance administration, of preventing or reducing the occurrence or frequency of disease symptoms, e.g. acute bronchoconstriction.
This is in marked contrast to drugs employed symptomatically, i.e. to alleviate disease symptoms as and when they occur and which may have no influence on essential disease pathology.
With respect to their prophylactic utility in the treatment of inflammatory airways disease it has, in accordance with the invention, in particular been found that COMPOUNDS OF THE INVENTION: a) inhibit acute response in hypersensitive subjects following allergen or other challenge eliciting hypersensitivity reaction (e.g. following induction of hyperreactivity and airways obstruction via PAF challenge); b) suppress development of airways hyperreactivity subsequent to challenge as under a); c) reverse recently established exacerbation of airways hyperreactivity; and d) diminish basal, or on-going, airways hyperreactivity, as evidenced in test methods as described hereinafter.
[For further discussion of the relevance of a), b) and c) above and their relationship to prophylactic utility in treating inflammatory airways disease, see e.g.: Altounyan, Clin. Allergy (supp) 10 481 (1980); Morley et al; Lancet ii, 1142 (1984); Mazoni et al; J Physiol 365 107P (1985); Traietti et al,; Respiration 46 62 (1984); Taytard et al; Am Rev Respiratory Disease 134 983 (1986); Szezeklik et al;
Thrombosis and Haematosis 56 283 (1986); Basran et al; Clin Allergy 14 75 (1984); Karlsson et al; Brit J Clin Pharmacol 27 371 (1985); and
Mazzoni et al; Brit J Pharmacol 86 571P (1985)1.
COMPOUNDS OF THE INVENTION may thus be used for the prophylactic treatment of obstructive or inflammatory airways disease, e.g. asthma.
In particular, by continued administration they may be used to provide advance protection against bronchoconstrictor attack consequential to obstructive or inflammatory airways disease, in particular asthma, or for the control, restriction or reversal of basal pathology of such disease, e.g. for the control, restriction or reversal of basal causes of asthma and asthma attack, e.g. airways hyperreactivity.
In accordance with the foregoing the present invention provides in a series of embodiments:
A. A method for the prophylactic treatment of obstructive or inflamma
tory airways disease in a subject in need thereof, which method
comprises administering to said subject an effective amount of a
COMPOUND OF THE INVENTION.
B. A method for the treatment (e.g. control, restriction or reversal)
of basal pathology of inflammatory or obstructive airways disease
(e.g. of airways-hyperreactivity) in a subject in need thereof,
which method comprises administering to said subject an effective
amount of COMPOUND OF THE INVENTION.
C. A method for the prophylactic treatment of obstructive or inflamma
tory airways disease (e.g. for advance protective treatment against
acute airways obstruction, for example bronchospasm, e.g. as
occurring in the symptomatology of diseases, disorders or conditions
as herein set forth) in a subject in need thereof, which method
comprises administering to said subject a prophylactically effective
amount of COMPOUND OF THE INVENTION.
The method of the present invention as defined under A to C above is, in particular, applicable to the treatment of asthma of whatever type or genesis. It is applicable to both intrinsic and, especially, extrinsic asthma. It is especially applicable to the treatment of allergic asthma, whether atopic, (i.e. IgE-mediated) or non-atopic, as well as e.g. bronchitic asthma, exercise induced asthma, occupational asthma, asthma induced following bacterial infection and other nonallergic asthmas.Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms, in particular at night, and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now more correctly identified as incipient or early-phase asthmatics. (For convenience of definition this particular asthmatic condition is referred to hereinafter as "wheezy-infant syndrome".)
The method of the present invention as defined under A to C above is also applicable to the treatment of pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and, in particular, byssinosis.
Prophylactic efficacy of COMPOUNDS OF THE INVENTION when employed in accordance with the methods of the invention, e.g. for the treatment of specific diseases or conditions as set forth above, will be evidenced by reduced frequency or severity of symptomatic attack, e.g. acute asthmatic or bronchoconstrictor attack in the subject treated. It will fur ther be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory (e.g. 62 adrenergic) therapy.
Prophylactic benefit of COMPOUNDS OF THE INVENTION employed in accordance with the methods of the invention will in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by an asthma attack, usually in the early hours of the morning, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously administered symptomatic asthma therapy, and by which any drug previously taken may be anticipated to have been rendered inactive by metabolic or other procedures of elimination from the body. This nocturnal asthma is harder to control than other forms of asthma and carries with it a higher risk of death.Since COMPOUNDS OF THE INVENTION exert prophylactic rather than symptomatic effect and by their action on basal pathology (e.g. airways hyperreactivity) exert advance protective action against future attack, appropriate administration on the day preceding will act to abrogate "morning dipping" on the day following.
Accordingly the present invention further provides:
D. A method for reducing requirement for symptomatic drug therapy, e.g.
anti-inflammatory or bronchodilator drug therapy, in a subject re
ceiving such therapy, for the treatment, e.g. for the alleviation of
symptoms of obstructive or inflammatory airways disease, e.g.
asthma, which method comprises administering to said subject a pro
phylactically effective amount of a COMPOUND OF THE INVENTION; as
well as
E. A method for the treatment of "morning dipping" in a subject in need
thereof which method comprises administering to said subject a pro
phylactically effective amount of a COMPOUND OF THE INVENTION.
The present invention also provides:
F. A COMPOUND OF THE INVENTION for use in a method of treatment as
defined under any one of A to E above;
G. A COMPOUND OF THE INVENTION for use in the preparation of a pharma
ceutical composition, for use in a method of treatment as defined
under any one of A to E above;
As will be appreciated, in practicing the present invention
COMPOUNDS OF THE INVENTION are administered in advance of asthma attack and appropriately in accordance with a suitable prophylactic regimen, e.g. on a continuing or regular basis, e.g. daily, e.g. at daily dosage rates as hereinafter discussed.
Utility of COMPOUNDS OF THE INVENTION in accordance with the present invention may be demonstrated, for example, in test models and in clinical trials, e.g. performed as follows:
EXAMPLE A: SUPPRESSION OF AIRWAYS HYPERREACTIVITY - PAF TREATED ANIHALS Naive (i.e. non-presensitised) guinea-pigs are anaethetised with phenobarbital (lOOmg/kg i.p.) and pentobarbital (30mg/kg i.p.) and paralysed with gallamine (lOmg/kg i.m.). Animals are ventilated via a tracheal cannula (8ml/kg, 1Hz). Ventilation is monitored by a Fleisch flow transducor in line with the inspiratory circuit. When making measurements of flow, coincident pressure changes in the thorax are monitored directly via an intrathoracic trochar, permitting display of differential pressure relative to the trachea. From this information, resistance and compliance are calculated at each inspiration.Intra venous injection of low dose bombesin (240ng/kg) established airways sensitivity to spasmogens. Following infusion of PAF (platelet activating factor) over 1 hour (total dose = 600ng/kg), repeated injection of low dose bombesin or histamine reveals development of airways hyperreactivity, which can conveniently be expressed as the paired difference between the response amplitude before and after PAF exposure.
Administration of COMPOUNDS OF THE INVENTION (e.g. compounds as defined under I above, for example PCO 400) as a bolus or as a sustained infusion during PAF exposure at dosages of from about 0.06 to about 1 mg/kg diminishes the incremental increase of responses to bombesin/histamine.
CLINICAL TRIALS 1. Utility in obstructive inflammatory airways disease, e.g. asthma
Prophylactic efficacy of COMPOUNDS OF THE INVENTION (e.g. compounds as defined under I above, for example PCO 400) may be determined in clinical trials of classic design, e.g. involving subjects exhibiting allergic (atopic) bronchoconstrictor response, by administration of test medication or placebo 1 to 2 hours prior to allergen challenge, or by administration of test medication at regular dosage rates (e.g. 2 or 3 times daily) or placebo over a period of 1 to 7 days prior to allergen challenge.
Suitable individual dosages in such clinical trials are as hereinafter indicated, e.g. for compounds as defined under I above, for example PCO 400 comprise e.g. ca. 0.5 to 1.0 mg (for single administration or administration 2 to 3x daily).
Both acute (0 to 1 hour) and long-term (up to 12 hour) change in lung function is determined post-medication by measurement of lung function parameters, e.g. as follows:
a) FVC; FEV 0.5; FEV 1.0; FEV 3.0;
b) FEV 0.5/FVC; FEV 1/FVC; FEV 3/FVC;
c) PEF; FEF 25-75%; FEF 75-85%; FEF 25%; FEF 50%; FEF 75%; FEF 0.2-2.2;
d) Flow expiratory curve and flow inspiratory curve.
Tolerance of medication and possible occurrence of side effects are also reported.
In addition to monitoring of lung function, blood eosinophil levels are also monitored and the incidence of activated eosinophils and eosinophil secretory proteins is determined. In individual studies, subjects are also subjected to lung lavage and the presence of eosinophils and platelets and their respective secretory products determined before and after exposure to allergen.
In clinical trials designed in accordance with the above principles, compounds as defined under 1 above, for example PCO 400, provide advance protection against bronchoconstrictor response to allergen compared with control subjects receiving placebo only, on administration at dosages indicated. Similar results are obtained with other COMPOUNDS OF THE
INVENTION at the same or equivalent dosage rates.
2. Prophylactic efficacy in asthma
Prophylactic efficacy of COMPOUNDS OF THE INVENTION may also be demonstrated in clinical trials involving administration to groups of asthmatic subjects on a regular daily basis over periods from at least 2, preferably 3 months, up to 6 months and more. Initial dosaging for a compound as described under I above, for example PCO 400, is of the order of from 0.5 to 1.0 mg administered once or in divided dosages 2 or 3x daily, for oral administration, with subsequent reduction in appropriate cases to a maintenance dosage of 0.25 to 0.5 mg per day orally.
During the course of the trial subjects are monitored continually and all relevant parameters recorded, including lung function, alterations in the incidence of activated eosinophils or the release of eosinophil products into the blood or bronchial fluids and/or changes in the function of platelets ex vivo and, in particular, frequency and severity of asthma exacerbation or attack. Additional bronchodilator therapy is provided on the occasion of any such attack.
Subjects receiving therapy comprising a compound as defined under I above, e.g. PCO 400, at dosages indicated above or other COMPOUNDS OF
THE INVENTION at the same or equivalent dosage rates, show marked reduction in frequency of asthma exacerbation or attack, tending with duration of the trial, to lead to freedom from attack as compared with subjects receiving alternative, non-prophylactic therapy. Where participating subjects are initially dependent on concomitant, bronchodilator e.g. methyl-xanthine or 62-agonist therapy, increasingly reduced need for concomitant therapy is also observed.
3. Utility in the treatment of pneumoconiosis
The trial is performed analogously to 2 above but with groups of subjects having a history of pneumoconiosis, e.g. characterised by events of restricted lung function, for example including difficulty in breathing, wheezing, dyspnea or occasional bronchoconstrictor attack and a record of pneumoconiosis-related work absenteeism. Suitable subjects include cotton-mill workers exhibiting severe byssinosis.
COMPOUND OF THE INVENTION is administered daily at dosage rates as set forth in 2 above, over periods in excess of 2, preferably in excess of 3 months.
During the course of the trial, subjects are monitored continually and all relevant parameters are recorded, including basal lung-function, frequency of attack with impairment of lung-function, requirement for other medication and frequency of absenteeism attributable to pneumoconiosis.
Subjects receiving therapy in accordance with the invention exhibit overall improvement in basal lung-function during the course of the trial accompanied by reduced frequency of attack and absenteeism as well, in cases where frequent use of alternative medication is recorded at trial entry, reduced need for concomitant medication.
In the above clinical trials, COMPOUNDS OF THE INVENTION, e.g. compounds as defined under I above, for example PCO 400, are found to be well tolerated both in terms of reported and observed occurrence of side effects.
4. Utility in the treatment of morning dipping
Prophylactic efficacy of COMPOUNDS OF THE INVENTION may further be demonstrated in clinical trials involving administration to subjects specifically prone to morning dipping. The trial is performed analogously to 2. above.
COMPOUND OF THE INVENTION is administered to groups of subjects daily over periods of, for example, 2 weeks to at least 3 months at dosage rates as set forth in 2. above.
During the course of the trial, subjects are monitored continually and all relevant parameters, in particular lung function parameters such as PEF and FEV1, are recorded.
Subjects receiving therapy in accordance with the invention, e.g. receiving a COMPOUND OF THE INVENTION, e.g. compounds as defined under I above, e.g. PCO 400, exhibit a continuous improvement in lung function parameters with time, in particular shown by a diminished diurnal variation in PEF rates measured morning and evening.
Reduction in asthma symptoms such as wheezing, tightness of the chest, cough etc., and the frequency and severity of asthma attacks is also observed and the exaggerated response to various bronchoconstrictor stimuli, e.g. histamine, methacholine etc., over time is reduced in subjects undergoing treatment.
Dosages of COMPOUNDS OF THE INVENTION employed in practicing the method of the invention will of course vary depending, e.g. on the particular compound selected, the mode of administration (for example whether oral or by inhalation), the particular condition to be treated, the severity of the condition and the therapy desired.
In general however, COMPOUNDS OF THE INVENTION will produce satisfactory results in the method of the present invention, as hereinabove described, at dosages substantially equivalent to, or, preferably less than, those dosages employed in indications described for the individual
COMPOUNDS OF THE INVENTION in the art, e.g. in the BASIC TEXTS. Suitable dosages will thus be at the lower end of dosage ranges indicated in
BASIC TEXTS or down to ca. 5% below these.
With regard to compounds as defined uner I above, and in particular
PCO 400, satisfactory results are obtained on oral administration at dosage rates of the order of from about 0.1 to about 2 mg/day, more suitably of from about 0.2 to about lmg/day, e.g. of ca 1 mg/day e.g.
administered once or in divided dosages 2 to 3x daily or in sustained release form. Suitable unit dosage forms thus contain, e.g. 0.03, 0.1, 0.25, 0.5, 0.75 or lmg of active agent per unit dosage.
Where administration by inhalation is practiced dosaging will generally be lower, e.g. of the order of from ca. 50 to 500 ug/day, more suitably of from ca. 50 to 200 ug/day.
For the purposes of prophylactic therapy COMPOUNDS OF THE INVENTION, in particular compounds as defined under I above, e.g. PCO 400, will suitably be administered on a regular daily basis over prolonged periods of time, e.g. with multiple administration, for example 2 or 3x daily or with administration in sustained release form. For the prophylactic treatment of "morning dipping" an appropriate daily regimen will suitably incorporate at least one administration, e.g. of the order of from ca. 0.2 mg to 2.0 mg e.g. of ca. 0.5 mg in the evening, suitably shortly prior to sleep.
COMPOUNDS OF THE INVENTION as defined under II to XIII above, and in particular the individually preferred compounds of II to XIII, may be employed in the method of the present invention at dosages similar to those described above for compounds as defined under I above.
Pharmaceutical compositions comprising a COMPOUND OF THE INVENTION may be prepared in conventional manner, e.g. by admixture with conventional pharmaceutically acceptable diluents and carriers and encapsulation.
Such compositions conveniently contain more than 1% by weight of
COMPOUND OF THE INVENTION and my be prepared by conventional techniques to be in conventional forms, for example capsules, tablets, dispersible powders, suspensions, solutions and the like. Suitable pharmaceutical diluents or carriers include, for example, water, alcohols, natural or hardened oils or waxes, calcium and sodium carbonates, calcium phosphate, kaolin, talc and lactose, as well as suitable preserving agents, such as ethyl-p-hydroxy-benzoate, suspending agents such as methyl cellulose, tragacanth and sodium alginate, wetting agents, such as leci thin, polyoxyethlene stearate and polyoxyethylene sorbitan mono-oleate, granulating and disintegrating agents such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc, in order to provide an elegant and palatable pharmaceutical preparation. Compositions in tablet form may be coated by conventional techniques to delay disintegration of the tablet and absorption of the active ingredient in the gastrointestinal tract and thereby provide sustained action over a long period.
Dosages of compounds as defined under I above, e.g. PCO 400, employed in practicing the methods of the present invention, as well as the active ingredient content of dosage forms, in particular unit dosage forms, for use in practicing the methods of the present invention are determined by the particular and novel utility taught. Moreover, specific dosage forms are neither known from nor suggested by the teachings of the art. Such compositions also form an integral part of the present invention.
Accordingly, in a further series of specific embodiments, the present invention also provides:
H. A pharmaceutical composition (e.g. for use in any method as defined
under A to E, above) in unit dosage form and comprising a compound
as defined under I above, e.g. PCO 400, as active ingredient in an
amount of from 0.1 to 2 mg/unit dosage, together with one or more
pharmaceutically acceptable diluents or carriers therefor;
I. A pharmaceutical composition according to H for oral administration.
J. A pharmaceutical composition according to H or I comprising a com
pound as defined under I above, e.g. PCO 400, as active ingredient
in an amount of from 0.03 to 1 mg/unit dosage, suitably 0.1, 0.25,
0.5 or 0.75 mg/unit dosage.
K. A pharmaceutical composition in liquid form and suitable or adapted
for administration in spray or other liquid particulate form to the
internal surfaces of the lung and comprising a compound as defined
under I above, e.g. PCO 400, as active ingredient, together with one
or more pharmaceutically acceptable liquid diluents or carriers
therefor.
L. A process for the preparation of a pharmaceutical composition as
defined in any one of H to L above which process comprises intima
tely admixing a compound as defined under I above, e.g. PCO 400,
together with one or more pharmaceutically acceptable diluents or
carriers therefor.
Compositions as defined under L above may be prepared in essentially conventional manner. Such compositions include, e.g. solutions or fine dispersions of a compound as defined under I above, e.g. PCO 400, in particular aqueous solutions or dispersions. Such solutions or dispersions will also suitably comprise one or more surfactive agents, e.g. to promote or assist nebulisation or distribution upon adsorption at the lung surface following inhalation. Such compositions will suitably be contained in an appropriate delivery device, e.g. aerosol, nebuliser or atomiser. Such device will preferably be adapted to administer a fixed spray volume on single or multiple, e.g. double or triple, activation, the total amount of COMPOUND OF THE INVENTION delivered in said fixed spray volume being as hereinbefore indicated.
Such device will also suitably be provided with means to facilitate administration of contained composition by inhalation, e.g. as known in the art for other medication applied by inhalation to the internal surfaces of the lungs. Such means may, for example, include provision of an outlet (e.g. nozzle) to said container, shaped or adapted for appli cation of composition exiting through said outlet on actuation of the device.
COMPOUNDS OF THE INVENTION are well tolerated at dosages required for use in accordance with the present invention. Thus, compounds as defined under I, above, for example PCO 400, are observed to have minimal central side effects and are substantially non-toxic at dosages up to 318 mg/kg/day in the rat and in dogs have been shown to be well tolerated up to a dosage level of 1 mg/kg/day.
Claims (12)
1. (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oXo-1-cy- clopent-1-enyloxy)-2H-1-benzopyran-6-carbonitrile;
2. 7-chloro-3-methyl-2H-112,4-benzothiadiazine-1,1-dioxide;
3. N-[2-(nitrooxy)ethyl]-3-pyridinecarboxamide; 4. 6-amino-1 , 2-dihydro-1-hydroxy-2-imino-4-piperidinopyrmidine; 5. N-cyano-N'-4-pyridinyl-N'-(1,2,2-trimethyl-propyl)guanidine; 6.Trans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluorometh oxy)-4H-1-benzopyran-4-yl]-2, 3-dihydro-lH-isoindol-1-one; 7. 2, 2-dimethyl-4-( 1H-2-pyridon-l-yl)-6-cyano-2H-chromen; 8. 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine-N
oxide; 9. The following compound of formula IXa;
and; 10. The following compound of formula Xa;
3. A method according to claim 2 wherein the compound administered is (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oXo-1-cyclopent- 1-enyloxy)-2H-1-benzopyran-6-carbonitrile.
4. A method according to any one of claims 1, 2 or 3 for the inhibition
of acute response in hypersensitive subjects following allergen or
other challenge eliciting hypersensitivity reaction.
5. A method according to any one of claims 1, 2 or 3 for the suppress
ion of development of airways hyperreactivity subsequent to allergen
or other challenge eliciting hypersensitivity reaction.
6. A method according to any one of claims 1, 2 or 3 for the reversal
of recently established exacerbation of airways hyperreactivity.
7. A method according to any one of claims 1, 2 or 3 for diminishing
basal airways hyperreactivity.
8. A method for the treatment of morning dipping in a subject in need
thereof which comprises administering to said subject a prophylac
tically effective amount of a compound as defined in claims 1 to 3.
9. A pharmaceutical composition: in unit dosage form and comprising a
compound as defined under I above in claim 1, as active ingredient
in an amount of from 0.1 to 2 mg/unit dosage, together with one or
more pharmaceutically acceptable diluents or carriers therefor; or
in liquid form and suitable or adapted for administration in spray
or other liquid particulate form and comprising a compound as de
fined under I above, in claim 1, as active ingredient, together with
one or more pharmaceutically acceptable diluents or carriers there
for.
10. A composition according to claim 9 comprising (-)-(3S,4R)-3,4-di hydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-cyclopent-1-enyloxy)-2H- l-benzopyran-6-carbonitrile as active ingredient.
11. A composition according to claim 9 or 10 in oral unit dosage form.
12. A composition according to claim 9, 10 or 11 comprising (-)-(3S,4R) 3, 4-dihydro-3-hydroxy-2, 2-dimethyl-4-(2-oxo-1-cyclopent-1-enyloxy)- 2H-1-benzopyran-6-carbonitrile as active ingredient in an amount of
from 0.1 to 1 mg/unit dosage.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9007908A GB2242628A (en) | 1990-04-06 | 1990-04-06 | Asthma prophylactic use of K+ channel activators |
| FR9006293A FR2662080A1 (en) | 1990-04-06 | 1990-05-17 | Use of potassium channel activators for the prophylaxis of asthma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9007908A GB2242628A (en) | 1990-04-06 | 1990-04-06 | Asthma prophylactic use of K+ channel activators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9007908D0 GB9007908D0 (en) | 1990-06-06 |
| GB2242628A true GB2242628A (en) | 1991-10-09 |
Family
ID=10674066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9007908A Withdrawn GB2242628A (en) | 1990-04-06 | 1990-04-06 | Asthma prophylactic use of K+ channel activators |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2662080A1 (en) |
| GB (1) | GB2242628A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019755A1 (en) * | 1992-04-02 | 1993-10-14 | Smithkline Beecham Plc | Medicament for the treatment of airways inflammation and airways hyperresponsiveness |
| WO1994006770A1 (en) * | 1992-09-15 | 1994-03-31 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | N-cyano-n'-pyridylguanidines as serotonin antagonists |
| EP0747374A1 (en) * | 1995-06-07 | 1996-12-11 | Bristol-Myers Squibb Company | Sulfonamido substituted benzopyran potassium channel activators |
| US5912244A (en) * | 1993-08-04 | 1999-06-15 | Pfizer Inc. | Benzopyrans |
| WO2007027780A2 (en) * | 2005-09-01 | 2007-03-08 | Janssen Pharmaceutica N.V. | Benzopyran and pyranopyridine derivatives as potassium channel openers |
| US7576094B2 (en) | 2004-12-13 | 2009-08-18 | Eli Lilly And Company | Spiro derivatives as lipoxygenase inhibitors |
| US7838553B2 (en) | 2005-09-01 | 2010-11-23 | Janssen Pharmaceutica Nv | Benzopyran derivatives as potassium channel openers |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2204868A (en) * | 1987-05-16 | 1988-11-23 | Sandoz Ltd | Benzo(6)pyrans and pyranopyridines |
-
1990
- 1990-04-06 GB GB9007908A patent/GB2242628A/en not_active Withdrawn
- 1990-05-17 FR FR9006293A patent/FR2662080A1/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2204868A (en) * | 1987-05-16 | 1988-11-23 | Sandoz Ltd | Benzo(6)pyrans and pyranopyridines |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019755A1 (en) * | 1992-04-02 | 1993-10-14 | Smithkline Beecham Plc | Medicament for the treatment of airways inflammation and airways hyperresponsiveness |
| WO1994006770A1 (en) * | 1992-09-15 | 1994-03-31 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | N-cyano-n'-pyridylguanidines as serotonin antagonists |
| US5563160A (en) * | 1992-09-15 | 1996-10-08 | Leo Pharmaceutical Products Ltd. A/S (L.o slashed.vens Kemiske Fabrik Produktionsaktieselskab) | N-cyano-N'-pyridylguanidines as serotonin antagonists |
| US5912244A (en) * | 1993-08-04 | 1999-06-15 | Pfizer Inc. | Benzopyrans |
| US6071938A (en) * | 1993-08-04 | 2000-06-06 | Pfizer Inc. | Benzopyrans |
| EP0747374A1 (en) * | 1995-06-07 | 1996-12-11 | Bristol-Myers Squibb Company | Sulfonamido substituted benzopyran potassium channel activators |
| US7576094B2 (en) | 2004-12-13 | 2009-08-18 | Eli Lilly And Company | Spiro derivatives as lipoxygenase inhibitors |
| WO2007027780A2 (en) * | 2005-09-01 | 2007-03-08 | Janssen Pharmaceutica N.V. | Benzopyran and pyranopyridine derivatives as potassium channel openers |
| WO2007027780A3 (en) * | 2005-09-01 | 2007-07-12 | Janssen Pharmaceutica Nv | Benzopyran and pyranopyridine derivatives as potassium channel openers |
| US7812183B2 (en) | 2005-09-01 | 2010-10-12 | Janssen Pharmaceutica Nv | Benzopyran derivatives as potassium channel openers |
| US7838553B2 (en) | 2005-09-01 | 2010-11-23 | Janssen Pharmaceutica Nv | Benzopyran derivatives as potassium channel openers |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9007908D0 (en) | 1990-06-06 |
| FR2662080A1 (en) | 1991-11-22 |
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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |
