U.S. patent application number 10/641506 was filed with the patent office on 2004-04-22 for medical treatment.
Invention is credited to Bailey, Clifford James, Jackson, Helen Christine, Jones, Robert Brian.
Application Number | 20040077730 10/641506 |
Document ID | / |
Family ID | 10800326 |
Filed Date | 2004-04-22 |
United States Patent
Application |
20040077730 |
Kind Code |
A1 |
Bailey, Clifford James ; et
al. |
April 22, 2004 |
Medical treatment
Abstract
A compound of formula I 1 or a pharmaceutically acceptable salt
thereof in which R.sub.1 and R.sub.2 are independently H or methyl
(for example N,N-dimethyl-1-[1-(4-chlorophe-
nyl)cyclobutyl]-3-methylbutyl amine hydrochloride optionally in the
form of its monohydrate) is used for reducing insulin resistance in
humans in whom Impaired Glucose Tolerance and Non-Insulin Dependent
Diabetes Mellitus have not presented.
Inventors: |
Bailey, Clifford James;
(Birmingham, GB) ; Jones, Robert Brian;
(Nottingham, GB) ; Jackson, Helen Christine;
(Nottingham, GB) |
Correspondence
Address: |
ABBOTT BIORESEARCH
100 RESEARCH DRIVE
WORCESTER
MA
01605-4314
US
|
Family ID: |
10800326 |
Appl. No.: |
10/641506 |
Filed: |
August 15, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10641506 |
Aug 15, 2003 |
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09702125 |
Oct 30, 2000 |
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6617360 |
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09702125 |
Oct 30, 2000 |
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09254924 |
Mar 17, 1999 |
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6174925 |
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09254924 |
Mar 17, 1999 |
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PCT/EP97/05039 |
Sep 15, 1997 |
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Current U.S.
Class: |
514/650 |
Current CPC
Class: |
A61K 31/135 20130101;
Y10S 514/866 20130101; A61P 5/50 20180101; A61P 3/10 20180101 |
Class at
Publication: |
514/650 |
International
Class: |
A61K 031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 21, 1996 |
GB |
9619757.9 |
Claims
1. A method of reducing insulin resistance in humans in whom
Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes
Mellitus have not presented but in whom there is an increased risk
of developing such conditions, said method comprising administering
to a human in need thereof a therapeutically effective amount of a
compound of formula I 3including enantiomers and pharmaceutically
acceptable salts thereof in which R.sub.1 and R.sub.2 are
independently H or methyl, in conjunction with a pharmaceutically
acceptable diluent or carrier.
2. A method as claimed in claim 1 in which the human is not
obese.
3. A method as claimed in claim 1 in which the human is obese.
4. A method as claimed in any preceding claim wherein the compound
of formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyla- mine
hydrochloride.
5. A method as claimed in any preceding claim wherein the compound
of formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyla- mine
hydrochloride in the form of its monohydrate.
6. Use of a compound of formula I 4including enantiomers and
pharmaceutically acceptable salts thereof in which R.sub.1 and
R.sub.2 are independently H or methyl, in the manufacture of a
medicament for reducing insulin resistance in humans in whom
Impaired Glucose Tolerance and Non-Insulin Dependent Diabetes
Mellitus have not presented but in whom there is an increased risk
of developing such conditions.
7. The use as claimed in claim 6 in which the human is not
obese.
8. The use as claimed in claim 6 in which the human is obese.
9. The use as claimed in claim 6, 7 or 8 in which the compound of
formula I is
N,N-dimethyl-1-[1-(4-chorophenyl)cyclobutyl]-3-methylbutylamine
hydrochloride.
10. The use as claimed in claim 6, 7 or 8 in which the compound of
formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
hydrochloride mono-hydrate.
11. A pharmaceutical composition for reducing insulin resistance in
humans in whom Impaired Glucose Tolerance and Non-Insulin Dependent
Diabetes Mellitus have not presented but in whom there is an
increased risk of developing such conditions, comprising a
therapeutically effective amount of a compound of formula I
5including enantiomers and pharmaceutically acceptable salts
thereof in which R.sub.1 and R.sub.2 are independently H or methyl,
in conjunction with a pharmaceutically acceptable diluent or
carrier.
12. A pharmaceutical composition as claimed in claim 11 in which
the compound of formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-- methylbutylamine
hydrochloride.
13. A pharmaceutical composition as claimed in claim 11 in which
the compound of formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-- methylbutylamine
hydrochlorid monohydrate.
14. Use of a compound of formula I in the manufacture of a
medicament which is an insulin sensitiser.
15. Use of a compound of formula I in the manufacture of a
medicament for reducing the amount of insulin required daily by a
human having Insulin Dependent Diabetes Mellitus or NIDDM.
16. Use of a compound of formula I in the manufacture of a
medicament for the prophylaxis of long-term detrimental effects
caused by prolonged high doses of insulin in humans having Insulin
Dependent Diabetes Mellitus or NIDDM.
17. Use of a compound of formula I in the manufacture of a
medicament for the prophylaxis of Impaired Glucose Tolerance and
Non-Insulin Dependent Diabetes Mellitus in humans having a high
risk of developing the same.
18. Use as claimed in claim 17 in which the human is not obese.
19. Use of a compound for formula I in the manufacture of a
medicament for reducing insulin resistance in humans having
acanthosis nigricans, leprechaunism, lipoatrophy or polycystic
ovary syndrome or other conditions in which insulin resistance is
present.
20. Use of a compound of formula I in the manufacture of a
medicament for combination therapy of NIDDM patients to improve
their weight and diabetic control, comprising a compound of formula
I and an oral insulin secretagogue or insulin sensitising
agent.
21. A method of improving the weight and diabetic control of NIDDM
patients comprising the administration of a compound of formula I
in combination with an oral insulin secretagogue or insulin
sensitising agent in conjunction with a pharmaceutically acceptable
diluent or carrier to a human in need thereof.
22. A product containing a compound of formula I and an oral
insulin secretagogue or insulin sensitising agent as a combined
preparation for simultaneous, separate or sequential use for the
improvement of weight and diabetic control in NIDDM patients.
23. A product comprising a pharmaceutical composition which
comprises a compound of formula I and an oral insulin secretagogue
or insulin sensitising agent together with a pharmaceutically
acceptable diluent or carrier.
24. A product as claimed in claim 22 or 23 in which the oral
insulin secretagogue is
1,1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate (BTS67582) or
a sulfonylurea selected from tolbutamide, tolazamide,
chlorpropamide, glibenclamide, glimepiride, glipizide and
gliclazide.
25. A product as claimed in claim 22 or 23 in which the insulin
sensitising agent is selected from metformin, ciglitazone,
troglitazone and pioglitazone.
26. A method for reducing the amount of insulin required daily by a
human having Insulin Dependent Diabetes Mellitus or NIDDM
comprising the administration of a compound of formula I in
conjunction with a pharmaceutically acceptable diluent or carrier
to a human in need thereof.
27. A method for the prophylaxis of long-term detrimental effects
caused by prolonged high doses of insulin in humans having Insulin
Dependent Diabetes Mellitus or NIDDM comprising the administration
of a compound of formula I in conjunction with a pharmaceutically
acceptable diluent or carrier to a human in need thereof.
28. A method for the prophylaxis of Impaired Glucose Tolerance and
Non-Insulin Dependent Diabetes Mellitus in humans having a high
risk of developing the same comprising the administration of a
compound of formula I in conjunction with a pharmaceutically
acceptable diluent or carrier to a human in need thereof.
29. A method as claimed in claim 27 in which the human is not
obese.
30. A method of reducing insulin resistance in humans having
acanthosis nigricans, leprechaunism, lipoatrophy or polycystic
ovary syndrome or other conditions in which insulin resistance is
present comprising the administration of a compound of formula I in
conjunction with a pharmaceutically acceptable diluent or carrier
to a human in need thereof.
Description
[0001] This invention relates to a method of reducing insulin
resistance in humans in whom Impaired Glucose Tolerance (IGT) and
Non-Insulin Dependent Diabetes Mellitus (NIDDM) have not
presented.
[0002] At present, a person who has a fasting plasma glucose level
of greater then 7.8 mmol/l is classified as being diabetic
(although this value is currently under review and may soon be set
at a lower level, between 6 and 7 mmol/l). However, there is a
standard means of classifying whether or not a person is diabetic,
and this is important when a person has a fasting blood glucose
level just below the above stated level. This means is called the
Oral Glucose Tolerance Test (OGTT).
[0003] The OGTT is conducted in the following manner. After an
overnight fast of 10-16 hours, a fasting blood glucose reading is
taken. Glucose (75 g) is administered orally in water (250-300 ml).
A further blood glucose reading is taken after 2 hours. Diabetes is
diagnosed if the fasting glucose level is greater than 7.8 mmol/l
or if the 2 hour level is greater than 11.1 mmol/l. Impaired
Glucose Tolerance (IGT) is diagnosed if the fasting glucose level
is less than 7.8 mmol/l and the 2 hour value is in the range
7.81-11.1 mmol/l. Normal glucose tolerance is declared if both the
fasting glucose level and the 2 hour level are less than 7.8
mmol/l.
[0004] The majority of people are non-diabetic and have normal
glucose tolerance. A proportion of these people will be at risk of
developing Impaired Glucose Tolerance and/or diabetes in the
future. One well-documented risk-factor is obesity, in which mild
insulin resistance is a common phenomenon. This is often
compensated for in the obese body by an increase in the plasma
insulin level. However, the body can only increase its insulin
secretion to a certain level, so if the insulin resistance
continues to worsen in an obese person, eventually the body will
not be able to compensate by providing extra insulin. At this time
the plasma glucose levels will start to become elevated, presenting
IGT or Non-Insulin Dependent Diabetes Mellitus (NIDDM).
[0005] Clearly, this gradual decline towards IGT and NIDDM is
undesirable both for the individual and in terms of the cost of
healthcare. It would, therefore, b advantageous to restrict insulin
resistance for as long as possible in these people.
[0006] The term "glucose tolerance" includes glucose disposal in
muscle tissue, and hepatic glucose output.
[0007] The term "Insulin resistance" means a reduced biological
response to insulin. Insulin resistance can involve effects on both
hepatic glucose output and peripheral glucose uptake, and may be
due to reduced insulin receptor numbers, reduced tyrosine kinase
activity of the insulin receptor and/or abnormalities distal to the
receptor.
[0008] Surprisingly, it has now been found that the administration
of certain arylcyclobutylalkylamines has efficacy in reducing
insulin resistance.
[0009] According to the present invention there is provided a
method for reducing insulin resistance in humans in whom Impaired
Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus have
not presented but in whom there is an increased risk of developing
such conditions, said method comprising administering to a human in
need thereof a therapeutically effective amount of a compound of
formula I 2
[0010] including enantiomers and pharmaceutically acceptable salts
thereof, in which R.sub.1 and R.sub.2 are independently H or
methyl, in conjunction with a pharmaceutically acceptable diluent
or carrier. The human may be obese or may be not obese.
[0011] The preparation and use of compounds of formula I, such as
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
(or
N-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N,N-dimethylamine)
and salts thereof, in the treatment of depression is described in
British Patent Specification 2098602. The use of compounds of
formula I such as
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
and salts thereof in the treatment of Parkinson's disease is
described in European Patent Number 282206. The use of
N,N-dimethyl-1-[1-(4-chlorophen- yl)cyclobutyl]-3-methylbutylamine
and salts thereof in the treatment of cerebral function disorders
is described in U.S. Pat. No. 4,939,175. The use of
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
hydrochloride in the treatment of obesity is described in European
Patent Number 397831. A particularly preferred form of this
compound is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
hydrochloride monohydrate (sibutramine hydrochloride monohydrate)
which is described in European Patent Number 230742. The use of
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
and salts thereof for improving the glucose tolerance of humans
having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes
Mellitus is described in published PCT application WO95/20949. It
does not disclose or suggest that the compounds of the present
invention possess an insulin sensitising activity, nor does it
disclose or suggest that the compounds of the present invention
would be able to reduce insulin resistance in humans in whom IGT
and NIDDM have not presented.
[0012] It may be appreciated by those skilled in the art that
compounds of formula I may exist as salts with pharmaceutically
acceptable acids. Examples of such salts include hydrochlorides,
hydrobromides, sulphates, methanesulphonates, nitrates, maleates,
acetates, citrates, fumarates, tartrates [eg (+)-tartrates,
(-)-tartrates or mixtures thereof including racemic mixtures],
succinates, benzoates and salts with amino acids such as glutamic
acid. Compounds of formula I and their salts may exist in the form
of solvates (for example hydrates).
[0013] It will be appreciated by those skilled in the art that
compounds of formula I contain a chiral centre. When a compound of
formula I contains a single chiral centre it may exist in two
enantiomeric forms. The present invention includes the use of the
individual enantiomers and mixtures of the enantiomers. The
enantomers may be resolved by methods known to those skilled in the
art, for example by formation of diastereoisomeric salts or
complexes which may be separated, for example, by crystallisation;
via formation of diastereoisomeric derivatives which may be
separated, for example, by crystallisation, gas-liquid or liquid
chromatography; selective reaction of one enantiomer with an
enantiomer-specific reagent, for example enzymatic oxidation or
reduction, followed by separation of the modified and unmodified
enantiomers; or gas-liquid or liquid chromatography in a chiral
environment, for example on a chiral support, for example silica
with a bound chiral ligand or in the presence of a chiral solvent.
It will be appreciated that where the desired enantiomer is
converted into another chemical entity by one of the separation
procedures described above, a further step is required to liberate
the desired enantiomeric form. Alternatively, specific enantiomers
may be synthesised by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer to the other by asymmetric transformation.
[0014] Specific compounds of formula I are
N,N-dimethyl-1-[1-(4-chlorophen-
yl)-cyclobutyl]-3-methylbutylamine,
N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-- methylbutyl}-N-methylamine,
and 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylb- utylamine including
racemates, individual enantiomers and mixtures thereof, and
pharmaceutically acceptable salts thereof. A preferred compound of
formula I is N,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-
-methylbutylamine or a salt thereof, for example the hydrochloride
salt. A preferred form of this hydrochloride is its
monohydrate.
[0015] The compound of formula I may be administered in any of the
known pharmaceutical dosage forms. The amount of the compound to be
administered will depend on a number of factors including the age
of the patient, the severity of the condition and the past medical
history of the patient and always lies within the sound discretion
of the administering physician but it is generally envisaged that
the dosage of the compound to be administered will be in the range
0.1 to 50 mg preferably 1 to 30 mg per day given in one or more
doses.
[0016] Oral dosage forms are the preferred compositions for use in
the present invention and these are the known pharmaceutical forms
for such administration, for example tablets, capsules, granules,
syrups and aqueous or oil suspensions. The excipients used in the
preparation of these compositions are the excipients known in the
pharmacist's art Tablets may be prepared from a mixture of the
active compound with fillers, for example calcium phosphate;
disintegrating agents, for example maize starch; lubricating
agents, for example magnesium stearate; binders, for example
microcrystalline cellulose or polyvinylpyrrolidone and other
optional ingredients known in the art to permit tableting the
mixture by known methods. The tablets may, if desired, be coated
using known methods and excipients which may include enteric
coating using for example hydroxypropylmethylcellulose phthalate.
The tablets may be formulated in a manner known to those skilled in
the art so as to give a sustained release of the compounds of the
present invention. Such tablets may, if desired, b provided with
enteric coatings by known methods, for example by the use of
cellulose acetat phthalat. Similarly, capsules, for example hard or
soft gelatin capsules, containing the active compound with or
without added excipients, may be prepared by known methods and, if
desired, provided with enteric coatings in a known manner. The
contents of the capsule may be formulated using known methods so as
to give sustained release of the active compound. The tablets and
capsules may conveniently each contain 1 to 50 mg of the active
compound.
[0017] Other dosage forms for oral administration include, for
example, aqueous suspensions containing the active compound in an
aqueous medium in the presence of a non-toxic suspending agent such
as sodium carboxy-methylcellulose, and oily suspensions containing
a compound of the present invention in a suitable vegetable oil,
for example arachis oil. The active compound may be formulated into
granules with or without additional excipients. The granules may be
ingested directly by the patient or they may be added to a suitable
liquid carrier (for example, water) before ingestion. The granules
may contain disintegrants, eg an effervescent couple formed from an
acid and a carbonate or bicarbonate salt to facilitate dispersion
in the liquid medium.
[0018] The therapeutically active compounds of formula I may be
formulated into a composition which the patient retains in his
mouth so that the active compound is administered through the
mucosa of the mouth.
[0019] Dosage forms suitable for rectal administration are the
known pharmaceutical forms for such administration, for example,
suppositories with cocoa butter or polyethylene glycol bases.
[0020] Dosage forms suitable for parenteral administration are the
known pharmaceutical forms for such administration, for example
sterile suspensions or sterile solutions in a suitable solvent.
[0021] Dosage forms for topical administration may comprise a
matrix in which the pharmacologically active compounds of the
present invention are dispersed so that the compounds are held in
contact with the skin in order to administer the compounds
transdermally. A suitable transdermal composition may be prepared
by mixing the pharmaceutically active compound with a topical
vehicle, such as a mineral oil, petrolatum and/or a wax, e.g.
paraffin wax or beeswax, together with a potential transdermal
accelerant such as dimethyl sulphoxide or propylene glycol.
Alternatively the active compounds may be dispersed in a
pharmaceutically acceptable cream, gel or ointment base. The amount
of active compound contained in a topical formulation should be
such that a therapeutically effective amount of the compound is
delivered during the period of time for which the topical
formulation is intended to be on the skin.
[0022] The therapeutically active compound of formula I may be
formulated into a composition which is dispersed as an aerosol into
the patients oral or nasal cavity. Such aerosols may be
administered from a pump pack or from a pressurised pack containing
a volatile propellant.
[0023] The therapeutically active compounds of formula I used in
the method of the present invention may also be administered by
continuous infusion either from an external source, for example by
intravenous infusion or from a source of the compound placed within
the body. Internal sources include implanted reservoirs containing
the compound to be infused which is continuously released for
example by osmosis and implants which may be (a) liquid such as an
oily suspension of the compound to be infused for example in the
form of a very sparingly water-soluble derivative such as a
dodecanoate salt or a lipophilic ester or (b) solid in the form of
an implanted support, for example of a synthetic resin or waxy
material, for the compound to be infused. The support may be a
single body containing all the compound or a series of several
bodies each containing part of the compound to be delivered. The
amount of active compound present in an internal source should be
such that a therapeutically effective amount of the compound is
delivered over a long period of time.
[0024] In some formulations it may be beneficial to use the
compounds of the present invention in the form of particles of very
small size, for example as obtained by fluid energy milling.
[0025] In the compositions of the present invention the active
compound may, if desired, be associated with other compatible
pharmacologically active ingredients.
[0026] The following in vitro and in vivo tests support the finding
that compounds of formula I have efficacy in reducing insulin
resistance, and may have an insulin sensitising action. It will be
appreciated by those skilled in the art that 10 mg of sibutramine
in the form of the hydrochloride monohydrate is equivalent to 8.37
mg of sibutramine as free base.
Study 1 In vitro L6 Muscle Cells
[0027] L6 Muscle cells were obtained from the European Culture
Collection (Porton Down) and were used at passages 7-11. Cells were
maintained in standard tissue culture medium DMEM, and glucose
uptake was assessed using [.sup.3H]-2-deoxyglucose (2DG) with and
without the presence of added insulin (10.sup.-8 M) as has been
previously described (Walker P S et al, Glucose transport activity
in L6 muscle cells is regulated by the coordinate control of
subcellular glucose transporter distribution, biosynthesis, and
mRNA transcription, JBC, 1990;265(3),1516-1523, and Kilp A et al,
Stimulation of hexose transport by metformin in L6 muscle cells in
culture, Endocrinology,1992;130(5), 2535-2544).
[0028] Uptake of 2DG was expressed as the percentage change
compared with control. Values are presented as mean .+-.SEM of sets
of 4 wells per experiment. Differences between sets of wells were
evaluated by Student's t test, probability values p<0.05 were
considered to be significant. In the absence of added insulin, L6
cells incubated for 24 hours with the compound of formula I in
which R.sub.1 and R.sub.2 are both H, showed a significant increase
in 2DG uptake (from 100.+-.2.1 in controls to 116.9.+-.3.8,
123.9.+-.4.3 and 134.+-.7.3 at 10.sup.-8, 10.sup.-7 and 10.sup.-6 M
respectively). In the presence of added insulin (10.sup.-8 M),
significant increases in 2DG uptake were observed following 24 hour
incubation with the compound of formula I in which R.sub.1 and
R.sub.2 are both methyl (sibutramine hydrochloride monohydrate) at
10.sup.-8 M (from 149.9.+-.4.3 to165.3.+-.2.6), the compound of
formula I in which R.sub.1 is methyl and R.sub.2 is H at 10.sup.-7
M (from 147.3.+-.3.0 to 160.7.+-.4.5), and the compound of formula
I in which R.sub.1 and R.sub.2 are both H, at 10.sup.-7 M and
10.sup.-6 M (from 149.1.+-.3.9 to 161.8.+-.3.3 and 165.2.+-.3.6
respectively).
[0029] This study shows that in the presence or absence of added
insulin, compounds of formula I increase glucose uptake in L6
muscle cells.
Study 2--In vivo ob/ob Mice
[0030] Studies were performed in obese ob/ob mice (Aston Strain)
which are a model of severe insulin resistance and are also
hyperglycaemic. The derivation and characteristics of this animal
model have been previously described (Flatt P R, Bailey C J,
Development of glucose intolerance and impaired plasma insulin
response to glucose in obese hyperglycaemic (ob/ob) mice, Horm
Metab Res 1981;13:556-560, and Bailey C J et al, Influence of
genetic background and age on the expression of the obese
hyperglycaemic syndrome in Aston ob/ob mice, Int J Obesity,
1982;6:11-21).
[0031] The ob/ob mice were individually housed in polypropylene
cages at a temperature of 21.+-.1.degree. C. and 55% humidity. The
mice had free access to a standard rat and mouse pelleted diet
(Compound Rat and Mouse Diet, Special Diet Services, Witham, Essex)
and tap water at all times. Animals were maintained on a reverse
phase light-dark cycle. Lights were off between 09.00 h and 17.00 h
in the acute experiment and between 10.00 h and 18.00 h in the
chronic experiment. During this time the laboratory was illuminated
by red lamps. Animals were acclimatised to these conditions for at
least two weeks before experimentation.
[0032] All animals were given deionised water (at the start of the
dark period) for 7 days. Body weight and food intake were measured
daily. Blood samples were taken immediately before daily
administration of vehicle (deionised water 10 ml/kg po) or compound
of formula I in which R.sub.1 and R.sub.2 are both methyl
(sibutramine hydrochloride monohydrate; 10 mg/kg po) on day 1
(baseline) and after 14 and 28 days of treatment (on day 15 and day
29 respectively). Blood samples were also taken 14 days following
withdrawal of the sibutramine hydrochloride monohydrate (on day 43
of the study). Plasma glucose was determined by a glucose oxidase
procedure (Analox GM7) and plasma insulin determined by
radioimmunoassay (Amerlex, Amersham).
[0033] No significant changes in body weight or food intake were
observed between vehicle and sibutramine hydrochloride monohydrate.
Plasma glucose in sibutramine hydrochloride monohydrate-treated
ob/ob fell after 14 and 28 days of treatment, with a significant
difference from control at day 28 (P<0.01, Table 1). After 14
days of drug withdrawal, plasma glucose was unaffected in the
vehicle dosed group but rose significantly in the sibutramine
hydrochloride monohydrate treated group to control values. No
significant changes in plasma insulin were observed though plasma
insulin tended to fall in the sibutramine hydrochloride monohydrate
treated group and increased on compound withdrawal.
Study 3--In vivo ob/ob Mice
[0034] Young ob/ob mice (Aston Strain) were randomised into 3
groups as follows: control, receiving placebo treatment (phosphate
buffered saline 2.5 ml/kg/day po); sibutramine hydrochloride
monohydrate-treated (5 mg/kg/day po); and pair-fed control,
supplied with the same daily food intake as that consumed by the
sibutramine hydrochloride monohydrate-treated group on the previous
day. There was a 1 week run-in period followed by 6 weeks of
treatment. Body weight and food intake were monitored every 1 to 2
days, and blood samples for plasma glucose and insulin were taken
from the tail vein at weekly intervals in the non-fasted state at
11 a.m. An ip glucose tolerance test (D-glucose, 2 g/kg in 40% w/v
solution in distilled water) and an insulin hypoglycaemia test
(Actrapid, Novo-Nordisk, 2.5 u/kg ip) were conducted after 5 weeks
of treatment. Food was withheld only for the duration of these
tests (approx. 4 hours). The basal blood samples and the test
procedures were undertaken 18 hours after the last treatment
administration.
[0035] Treatment was stopped after 6 weeks, and the mice were
monitored for the next 6 weeks. The pair-fed mice continued to be
pair-fed with respect to the sibutramine hydrochloride monohydrate
withdrawal group. A second insulin hypoglycaemia test was conducted
4 weeks after treatment was stopped. Plasma glucose was determined
by an automated glucose oxidase procedure (Beckman) and plasma
insulin determined by radioimmunnoassay (Amerlex, Amersham).
[0036] During sibutramine hydrochloride monohydrate treatment,
significant reduction in body weight and plasma insulin compared to
vehicle were observed. In an ip glucose tolerance test significant
reductions in plasma insulin (P<0.05; see FIG. 1) and in plasma
glucose (P<0.05; see FIG. 2) were observed with sibutramine
hydrochloride monohydrate treatment compared to the vehicle treated
group. Significant improvements in insulin hypoglycaemia
(P<0.05; see FIG. 3; at 5 weeks) with sibutramine hydrochloride
monohydrate treatment compared to the vehicle treated group were
also observed. These results indicate that compounds of formula I,
at a relatively low dose, are able to provide an improvement in
insulin sensitivity because there is better glucose utilisation
with less insulin. The pair-fed group showed a similar weight
reduction to the sibutramine hydrochloride monohydrate treated
group, but no improvement was observed in the oral glucose
tolerance test. Therefore the pair-fed group do not show an
improvement in insulin sensitivity.
[0037] During the sibutramine hydrochloride monohydrate withdrawal
period, body weight and plasma insulin remained significantly lower
than the vehicle treated group for almost all of the 6 week
withdrawal period.
[0038] In Table 1 and FIGS. 1-3, "sibutramine" indicates
"sibutramine hydrochloride monohydrate".
1TABLE 1 Effect of chronic administration of the compound of
formula I in which R.sub.1 and R.sub.2 are both methyl (10 mg/ka
po) and its withdrawal on plasma glucose and plasma insulin in
ob/ob mice. Day of Treatment Vehicle Compound Plasma glucose
(mmol/l) Plasma insulin (ng/ml) Treatment. Study Days (n) (n)
Vehicle Compound Vehicle Compound Prior to 1 0 22 32 24.3 .+-. 0.6
24.3 .+-. 0.6 92.0 .+-. 4.5 92.0 .+-. 4.5 treatment Sibutramine 15
14 22 32 21.7 .+-. 0.9 19.0 .+-. 0.6 49.7 .+-. 3.5 45.1 .+-. 2.6
Sibutramine 29 28 14 21 26.0 .+-. 1.4 15.8 .+-. 0.7** 46.2 .+-. 4.5
35.1 .+-. 2.7 Drug 43 14 6 12 22.9 .+-. 1.7 23.6 .+-. 1.2 40.6 .+-.
8.6 77.1 .+-. 11.3 Withdrawal Values are back-transformed means
.+-. SEM adjusted for differences between the treatment groups at
baseline. Significant differences from the vehicle-treated control
group are denoted by **P < 0.01. (n) is the number of animals
involved.
[0039] The data from the three studies indicate that compounds of
formula I can enhance both basal and insulin stimulated glucose
uptake into the L6 muscle cells and that in the absence of changes
in either body weight or food intake, the compound of formula I in
which R.sub.1 and R.sub.2 are both methyl can reduce plasma glucose
levels in ob/ob mice. These data taken together suggest an insulin
sensitising action of compounds of formula I. The data also
indicate the ability of compounds of formula I to decrease insulin
resistance.
[0040] There are a several syndromes, such as acanthosis nigricans,
leprechaunism, lipoatrophy and polycystic ovary syndrome, which
exhibit insulin resistance as part of their profile. The above data
suggest that a compound of formula I may have utility in
alleviating the insulin resistance in humans having such
conditions. Therefore the present invention further provides the
use of a compound of formula I in the manufacture of a medicament
for reducing insulin resistance in humans having acanthosis
nigricans, leprechaunism, lipoatrophy or polycystic ovary syndrome
or other conditions in which insulin resistance is present.
[0041] The present invention also provides a method of treatment
for acanthosis nigricans, leprechaunism, lipoatrophy or polycystic
ovary syndrome or other conditions in which insulin resistance is
present, comprising administration of a compound of formula I to a
patient in need thereof in conjunction with a pharmaceutically
acceptable diluent or carrier.
[0042] NIDDM patients are often treated with oral insulin
secretagogues, such as 1,1-dimethyl-2-(2-morpholinophenyl)guanidine
fumarate (BTS67582) or sulfonylureas including tolbutamide,
tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide
and gliclazide, or with insulin sensitising agents including
metformin, ciglitazone, troglitazone and pioglitazone. A further
use of a compound of formula I is in the manufacture of a
medicament, for combination therapy of NIDDM patients to improve
their weight and diabetic control, comprising a compound of formula
I and an oral insulin secretagogue or an insulin sensitising
agent.
[0043] The present invention further provides a method of improving
the weight and diabetic control of NIDDM patients comprising the
administration of a compound of formula I in combination with an
oral insulin secretagogue or an insulin sensitising agent in
conjunction with a pharmaceutically acceptable diluent or carrier
to a human in need thereof.
[0044] Preferably, the oral insulin secretagogue is
1,1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582)
or a sulphonylurea selected from tolbutamide, tolazamide,
chlorpropamide, glibenclamide, glimepiride, glipizide and
gliclazide. Preferably, the insulin sensitising agent is selected
from metformin, ciglitazone, troglitazone and pioglitazone.
[0045] The compound of formula I and the oral insulin secretagogue
or insulin sensitising agent may be administered either
concomitantly or concurrently, for example in the form of separate
dosage units to be used simultaneously, separately or sequentially.
Accordingly, the present invention further provides a product
containing a compound of formula I and an oral insulin secretagogue
or insulin sensitising agent as a combined preparation for
simultaneous, separate or sequential use for the improvement of
weight and diabetic control in NIDDM patients. The ratio of the
compound of formula I to the oral insulin secretagogue or insulin
sensitising agent is such that the quantity of each active
ingredient employed will be such as to provide a therapeutically
effective level, but will not be larger than the quantity
recommended as safe for administration.
[0046] The action of reducing insulin resistance shown by compounds
of formula I indicates that compounds of formula I may be useful in
the manufacture of a medicament which can be used as an insulin
sensitiser. Accordingly, the present invention further provides the
use of a compound of formula I in the manufacture of a medicament
which is an insulin sensitiser.
[0047] Some patients who are diagnosed as being Insulin Dependent
Diabetics can also show a certain amount of insulin resistance.
Therefore, there may be benefits in treating these patients with a
compound of formula I in order to reduce their insulin resistance.
This would mean that these patients would require a lower dosage of
insulin in order to maintain similar or better control of their
diabetes since the insulin dose would be associated with a greater
blood glucose lowering efficacy. Such therapy would provide
long-term benefits in terms of reducing the detrimental effects
which can be caused by prolonged high-dosage of insulin treatment
Additionally, some NIDDM patients are also treated with insulin and
have insulin resistance. Accordingly the present invention further
provides a method for, and the use of a compound of formula I in
the manufacture of the medicament for, reducing the amount of
insulin required daily by a human having Insulin Dependent Diabetes
Mellitus or NIDDM. The present invention also provides a method
for, and the use of a compound of formula I in the manufacture of a
medicament for, the prophylaxis of long-term detrimental effects
caused by prolonged high dosage of insulin in humans having Insulin
Dependent Diabetes Mellitus or NIDDM.
* * * * *