Title of Invention

NOVEL COMPOUNDS AS BETA-3-ADRENORECEPTOR AGONIST"

Abstract The present invention discloses compounds of Formula 1. The present invention also discloses beta-3 agonists of formula I and methods for treating beta 3 mediated diseases and condition using the compounds of formula I, in particular methods for treating diabetes or obesity.
Full Text "NOVEL COMPOUNDS AS BETA-3-ADRENORECEPTOR AGONIST"
Field of the invention
This invention relates to a new class of chemical compounds and to their use
in medicine. In particular, the invention concerns novel phenethanolamine
derivatives, methods for their preparation, pharmaceutical compositions
containing them and their use as agonists at atypical beta-adrenoceptors (also
known as beta-3-adrenoceptors).
Background of the Invention
Atypical beta-adrenoceptors belong to the family of adrenoceptors that
mediate the physiological actions of the hormones adrenaline and noradrenaline.
Such receptors have been described for example by J R S Arch et al., Nature,
309, 163-165 (1984); C Wilson et a/., Eur. J. Pharmacol., 100, 309-319 (1984); L
J Emorine et al., Science, 245, 1118-1121 (1989); and A. Biancherti et al. Br. J.
Pharmacol., 100, 831-839 (1990).
Phenethanolamine derivatives having activity at atypical beta-adrenoceptors
are disclosed in, for example, European Patent Applications EP-A-0455006 and
EP-A-0543662.
Sub-types of the adrenoceptors, ar, a2-, ßr, ß2- and ß3-(atypica!) can be
identified on the basis of their pharmacological properties and physiological
effects. Chemical agents that stimulate or block these receptors (but not ß3) are
widely used in clinical medicine. More recently, emphasis has been placed
upon specific receptor selectivity in order to reduce side effects caused, in part,
by interactions with other receptors.
Atypical beta-adrenoceptors are known to occur in adipose tissue and the
gastrointestinal tract. Atypical beta-adrenoceptor agonists have been found to be
particularly useful as thermogenic anti-obesity agents and as anti-diabetic
agents. Compounds having atypical beta-adrenoceptor agonist activity have also
been described as being useful in the treatment of hyperglycaemia, as animal
growth promoters, as blood platelet aggregation inhibitors, as positive inotropic
agents and as antiatherosclerotic agents, and as being useful in the treatment of
glaucoma.
Summary of the Invention
The invention therefore provides, in a first aspect, compounds of formula
(I) and pharmaceutically acceptable derivatives thereof:

wherein X is oxygen or sulfur, optionally substituted by one or more groups
selected from C1-4 alkyl and halogen, and where the heterocycle containing X is
substituted meta or para to the depicted NH;
R1 is hydrogen or C1-6alky!;
R represents substituents selected from C1-6 alkyl, halogen, trifluoromethyl and
C1-6alkoxy; and
n represents an integer from 0-4.
Preferably the compounds of this invention are agonists for human beta-3
adrenoceptor ("ß3"). More preferably, the compounds of this invention are
selective agonists for ß3.
In another aspect, the present invention provides a pharmaceutical
formulation comprising a compound of the invention. Preferred pharmaceutical
compositions further comprise a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method for the prevention
or treatment of clinical conditions or diseases susceptible to amelioration by
administration of an atypical beta-adrenoceptor agonist, comprising
administration of an effective amount of a compound or composition of this
invention.
in a further aspect, the present invention provides the use of a compound of
formula (I), or a pharmaceutically acceptable derivative thereof, in the
manufacture of a medicament for the treatment of conditions or diseases
susceptible to amelioration by administration of an atypical beta-adrenoceptor
agonist.
Detailed Description of the Invention
As used herein, the terms "alkyl" and "alkoxy" mean a straight or branched
alkyl group or alkoxy group respectively, containing the indicated number of
carbon atoms. For example, C1-6alky! means a straight or branched alkyl
containing at least 1 and at most 6 carbon atoms.
Preferably the heterocycle containing X is substituted meta to the depicted
NH.
Preferably R1 is hydrogen or methyl. When R1 is other than hydrogen, then
preferably the stereochemisty around the carbon to which R1 is bonded is R.
Preferably R is chlorine, fluorine, or CF3.
Preferably n is 0, 1, or 2. Most preferably n is 0.
Preferably the stereochemisty around the carbon to which the depicted OH is
bonded is JR.,............
It will be appreciated that the above compounds of Formula (I) may contain
optically active centers. The individual, isolated isomers and mixtures thereof,
including racemates, are all within the scope of the present invention. Typically,
where R1 is methyl, mixtures of diastereomers of compounds of Formula (I) may
be obtained, which are enriched with greater than or equal to 80% by weight of
one diastereomer.
Suitable compounds of formula (I) of the invention include:
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-
3-carboxylic acid;
2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-
carboxylic acid;
2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-
3-carboxylic acid;
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid;
2-(3-{[2-(3-Chiorophenyl)-2R-hydroxyl-ethylamino]ethy!amino}phenyi)thiophene-
3-carboxylic acid;
2-(4-{2R-[2-(3-Chloropheny!)-2R-hydroxyl-
ethy!amino]propylamino}phenyl)thiophene-3-carboxylic acid; and
pharmaceutically acceptable derivatives thereof.
Particularly preferred compounds of the invention include:
2-(3-{[2~(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-
carboxylic acid;
2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-
3-carboxylic acid; and pharmaceutically acceptable derivatives thereof.
By "a pharmaceutically acceptable derivative" is meant any pharmaceutically
acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any
other compound which, upon administration to the recipient, is capable of
providing (directly or indirectly) a compound of formula (I) or an active metabolite
or residue thereof.
It will be appreciated by those skilled in the art that the compounds of formula
(I) may be modified to provide pharmaceutically acceptable derivatives thereof at
any of the functional groups in the compounds of formula (I). Of particular
interest as such derivatives are compounds modified at the carboxyl function,
hydroxyl functions or at amino groups.
It will be appreciated by those skilled in the art that the pharmaceutically
acceptable derivatives of the compounds of formula (I) may be derivatised at
more than one position.
Preferred pharmaceuticaliy acceptable derivatives of the compounds of
formula (I) are pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of the compounds of formula (I) include
those derived from pharmaceutically acceptable inorganic and organic acids and
bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric,
nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic,
toluene- p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic,
malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Other acids
such as oxalic, while not in themselves pharmaceutically acceptable may be
useful in the preparation of salts useful as intermediates in obtaining compounds
of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium),
alkaline earth metal (e.g. magnesium), ammonium and NR4+ (where R is C1-
4alkyl) salts.
The compounds of formula (I) and their pharmaceutically acceptable
derivatives act as agonists at atypical beta-adrenoceptors and as such are useful
in the treatment of clinical conditions susceptible to amelioration by
administration of an atypical beta-adrenoceptor agonist. Such conditions include
hyperglycaemia, obesity, hyperlipemia, irritable bowel syndrome and its
associated pain, motility dysfunction, excessive gastrointestinal secretion, non-
specific diarrhoea, neurogenic inflammation, regulation of intraocular pressure,
triglyceridemia, diabetes, e.g. non-insulin-dependent diabetes mellitus (NIDDM or
Type 2), such as obese NIDDM and non-obese NIDDM, diabetic complications
such as retinopathy, nephropathy, neuropathy, cataracts, coronary heart
diseases and arteriosclerosis, osteoporosis; and gastrointestinal disorders,
particularly inflammatory gastrointestinal disorders. They are also of use in
increasing the high-density-lipoprotein (HDL) cholesterol concentration and
decreasing the triglyceride concentration in blood serum, especially human blood
serum, and are therefore of potential use in the treatment and/or prophylaxis of
atherosclerosis. They also may be useful for the treatment of hyperinsulinaemia,
depression, muscle wasting, and urinary incontinence. References in this
specification to treatment include prophylactic treatment as well as the alleviation
of symptoms.
In a further aspect, the invention provides the use of a compound of general
Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for the
manufacture of a medicament for the treatment of a condition susceptible of
amelioration by an atypical beta-adrenoceptor agonist.
While it is possible that, for use in therapy, a compound of the invention may
be adnninistered as the raw chemical it is preferable to present the active
ingredient as a pharmaceutical formulation. The invention thus further provides a
pharmaceutical formulation comprising a compound of Formula (I) or a
pharmaceutically acceptable derivative thereof together with one or more
pharmaceutically acceptable carriers thereof and, optionally, other therapeutic
and/or prophylactic ingredients. The carrier(s) or excipient(s) must be
"acceptable" in the sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
The compounds for use according to the present invention may be formulated
for oral, buccal, parenteral, rectal or transdermal administration or in a form
suitable for administration by inhalation or insufflation (either through the mouth
or the nose).
For oral administration, the pharmaceutical compositions may take the form
of, for example, tablets or capsules prepared by corventional means with
pharmaceutically acceptable excipients such as binding agents (e.g.
pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl
methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica);
disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents
(e.g. sodium lauryl sulphate). The tablets may be coated by methods well known
in the art. Liquid preparations for oral administration may take the form of, for
example, solutions, syrups or suspensions, or they may be presented as a dry
product for constitution with water or other suitable vehicle before use. Such
liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol
syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g.
lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl
alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-
hydroxybenzoates or sorbic acid). The preparations may also contain buffer
salts, flavoring, coloring and sweetening agents as appropriate. Preparations for
oral administration may be suitably formulated to give controlled release of the
active compound.
For buccal administration the compositions may take the form of tablets or
lozenges formulated in conventional manner.
The compounds according to the present invention may be formulated for
parenteral administration by injection e.g. by bolus injection or continuous
infusion. Formulations for injection may be presented in unit dosage form e.g. in
ampoules or in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in
powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free
water, before use.
The compounds according to the present invention may also be formulated in
rectal compositions such as suppositories or retention enemas, e.g. containing
conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also
be formulated as a depot preparation. Such long acting formulations may be
administered by implantation (for example subcutaneously, transcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example, the compounds
according to the present invention may be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable oil) or ion
exchange resins, or as sparingly soluble derivatives, for example, as a sparingly
soluble salt.
Suitable therapeutic ingredients which may be formulated with compounds of
the invention, together with one or more pharmaceutical carriers or excipients,
include ingredients which may be used in the same clinical conditions as those
listed herein for atypical beta-adrenoceptor agonists. Such ingredients may
include, for example, PPAR-gamma agonists.
A proposed dose of the compounds according to the present invention for
administration to a human (of approximately 70 kg body weight) is 0.1 mg to 1 g,
preferably to 1 mg to 100 mg of the active ingredient per unit dose, expressed as
the weight of free base. The unit dose may be administered, for example, 1 to 4
times per day. The dose will depend on the route of administration. It will be
appreciated that it may be necessary to make routine variations to the dosage
depending on the age and weight of the patient as well as the severity of the
condition to be treated. The precise dose and route of administration will
ultimately be at the discretion of the attendant physician or veterinarian.
The compounds of the invention may be prepared by any of the processes
known in the art for the preparation of similar compounds. For example,
according to a first process wherein X, R1, and R are as defined as for formula (I),
compounds of formula (I) may be prepared by reaction of compounds of formula
(II) and (III)
where P1 and P2 are suitable protecting groups for oxygen and nitrogen groups
respectively and R2 is lower alkyl or H, in the presence of a reducing agent,
followed by deprotection of any protecting groups present.
Compounds of formula (II) are described in PCT publication number
WO95/33724 or may be prepared by standard methods.
In an alternative process, a compound of formula (I) may be prepared by
hydrolysis of a compound of formula (IV) or a pharmaceutically acceptable
version thereof:
wherein R and R1 are as defined in formulas (II) and (III), R2 is lower alkyl and R3
represents C1-6 alkyl or aryl optionally substituted by hydrogen, C1-6 alkyl or
halogen; followed by the step of hydrolysing the ester group -CO2R2 to produce a
compound of formula (I), wherein the furan ring is substituted by a -CO2H group.
Preferably, hydrolysis of a compound of formula (IV) to form a compound
of Formula (I) is carried out by reflux in the presence of an aqueous solution of a
group 1 or group 2 metal hydroxide, e.g. NaOH or KOH, and preferably an
alkanol, e.g. MeOH, for at least 4h. The step of hydrolysing the ester group -
CO2R2 to produce a compound of formula (IA), wherein R4 is substituted by a -
CO2H group can be carried out by a further hydrolysis step under standard
hydrolysis conditions as would be apparent to a skilled person.
A compound of formula (IV) may be prepared by reacting a compound of
formula (V) with a compound of formula (VI):

at elevated temperature and pressure, optionally in the presence of one or more
of: C3-6alkanols, acetonitrile, N-methyl-pyrrolidinone (NMP), isobutylacetate,
isopropylacetate, dimethylformamide (DMF), toluene, xylene or
dimethylacetamide (DMA); preferably toluene and/or xylene. The temperature for
the reaction is suitably 100°C or greater, preferably 100-150°C, more preferably
100-120°C.
The reaction of a compound of formula (V) with a compound of formula
(VI) to form a compound of formula (IV) and the subsequent conversion of a
compound of formula (IV) to a compound of formula (I) may be carried out
separately or in situ. The reaction is preferably carried out in situ.
A compound of formula (VI) may be prepared from a compound of
formula.(VII):

wherein L represents a leaving group such as a halogen atom (e.g. chlorine), by
5 cyclisation in the presence of a solvent selected from: dichloromethane (DCM),
EtOAc, toluene and/or xylene, and a base selected from: Na2CO3, NaOH,
anhydrous Et3N and/or an amine, e.g. aqueous NH3. Preferably the solvent is
DCM. Preferably the base is aqueous NH3.
Compounds of Formula (VII) may be prepared from compounds of
10 Formula (III) using any suitable method for the preparation of amidines. For
example, by condensation of a compound of Formula (VIII) wherein L represents
a leaving group
as previously defined, in the presence of a solvent selected from: DCM, toluene,
15 EtOAc, or CH3CN, and PCI5 or POCI3. Preferably the solvent is EtOAc.
Preferably PCI5 is present.
A compound of formula (III) may be prepared by reaction of a compound of
formula (IX)

where Y represents the diazonium salt N2+, with a suitable 5-membered
heterocyclic ring of formula (X), followed by reduction of the nitro group using
standard methods. Suitable compounds of formula (X) are known or are
prepared by standard methods. For example, where X is oxygen, thus forming a
furan group, a compound of formula (III) may be prepared directly by reaction of
a compound of formula (IX) where Y represents the diazonium salt N2+ with a
furan of formula (X), followed by reduction with standard methods. A compound
of formula (IX) where Y represents the diazonium salt N2+ may in turn be
prepared from a compound of formula (IX) where Y = NH? by standard methods
known in the literature. Alternatively, a compound of formula (III) may be
prepared from the reaction of a compound of formula (IX) where Y = Br, I or
triflate with a furan of formula (X) in the presence of a suitable palladium catalyst
and a suitable base followed by reduction of the nitro grcup under standard
conditions. Suitable palladium catalysts include, but are not limited to,
tetrakiis(triphenylphosphine)palladium(0). Suitable bases include, but are not
limited to KOAc. Use of the palladium catalyst Pd(PPh3)4 in the presence of the
base KOAc is preferred.
Compounds of formula (IX) are known compounds or may be prepared by
processes well known in the art.
Suitable reducing agents of use in the reactions include hydrogen in the
presence of a catalyst, such as a noble metal catalyst, for examplepalladium,
platinum or platinum oxide, Raney-nickel or hydride reducing agents such as
borohydrides, for example sodium borohydride sodium triacetoxyborohydride or
sodium cyanoborohydride. Suitable reaction conditions will be readily apparent
to those skilled in the art and are further illustrated by the accompanying
examples.
The protecting groups used in the preparation of compounds of formula (I)
may be used in conventional manner. See for example "Protective Groups in
Organic Chemistry" Ed. J. F. W. McOmie (Plenum Press 1973) or "Protective
Groups in Organic Synthesis" by Theodora W Greene and P M G Wuts (John
Wiley and Sons 1991).
Conventional amino protecting groups may include for example araikyl
groups,-such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl
groups such as N-benzyloxycarbony! ort-butoxycarbonyl.
Conventional oxygen protecting groups may include for example alky silyl
groups, such as tri methyl silyl, or tert-butyldimethyisilyl; alkyl ethers such as
tetrahydropyranyl, or tert-butyl; or esters such as acetate.
Removal of any protecting groups present may be achieved by conventional
procedures.
Atypical beta-adrenoceptor agonists are compounds, which demonstrate a
pharmacological response mediated at atypical beta-adrenoceptors. This
activity has been measured as the ability to stimulate lipolysis by rat adipocytes
at sub-micromolar concentrations, in a response that is resistant to blockade by
standard beta-adrenoceptor blocking drugs such as propranolol.
Another useful means of identifying an atypical beta-adrenoceptor agonist
involves the measurement of agonist activity at atypical beta-adrenoceptors in
the rat isolated lower oesophagus. Typically in this assay, a compound of general
Formula (I) for use according to the present invention has an equipotent molar
ratio (E:PMR) relevant to isoprenaline of less than 30. The rat oesophagus assay
is based upon that described by Ford et. al., Br. J. Pharmacol., 105(suppl.),
235P, 1992. The relative potency of each test compound (EPMR) is compared to
isoprenaline as follows:
wherein EC50 is the molar concentration of agonist which produces 50% of the
maximum possible response for that agonist.
A particularly useful method for determining agonist activity at human atypical
beta-adrenoceptors involves the use of Chinese hamster ovarian (CHO) cells
i transfected with the human beta-3-adrenoceptor according to Method 1. The
cell lines may also be transfected with human beta-1- and beta-2- adrenoceptor
in a similar manner to provide a method of determining the selectivity of the
compounds of the invention at the three receptors.
Method 1 - Cell culture
General cell culture guidelines are observed (Fershney, R.A. (1987) Culture
of animal cells: A manual of basic technique. Wiley-Liss, Inc., N.Y.). A standard
cell culture incubator is used (37°C, 5% CO2 in air, 95% relative humidity). H
p3CHO cells are grown in DMEM/F12 (with pyroxidineHCI, 15 mM HEPES, L-
glutamine), supplanted with 10% heat-inactivated FBS, 500 µg/ml G418, 2 mM L-
glutamine, 100 units penicillin G and 100 µg streptomycin sulfate. One confluent
flask of cells is trypsinised and resuspended in the above medium at a
concentration of 30-40,000 cells/100 ul and plated into 96-well flat bottom plates.
The cells are then used for assay within 18-24 hours.
The medium is aspirated from each well, and replaced with 180 µl DMEM/F12
with 500 mM IBMX. Antagonists, if required, are added at this stage. The plate
is then placed back in the incubator for 30 min. Drugs are then added to the
wells (20 (il, 100x required final concentration) for 60 min. Responses were
determined by measuring cAMP levels of a 20 ul sample of extracellular media
using a scintillation proximity based radio-immunoassay (NEN Flashplates).
CHO-6CRE-luciferase cell lines which stably express hp3 receptors are
seeded at 30,000 cells/well for 24 hr in DMEM/F12 containing 10% FBS. Media is
removed from the cells and replaced with DMEM/F12 buffer (180 µl) containing
300 mM IBMX and 1 mM ascorbic acid for 30 min prior to addition of compound.
Vehicle or agonist (20 ^il) is added and incubated at 37°C for 60 minutes. At the
1 end of the incubation period, samples of extracellular media are removed for
direct assay in cAMP Flashplates (NEN).
As used herein, a compound is considered to be an agonist for hß3 if the
compound stimulates the accumulation of extracellular cAMP with CHO-6CRE-
luciferase cells expressing hp3. The compounds of this invention have an EC50 of
at most 10 nM at hp3. The relative potency of a hp3 agonist may be compared to
its potency for stimulating the accumulation of extracellular cAMP with CHO-
6CRE-luciferase cells expressing hß2 and hß1. The compounds of this invention
are at least 100 times more potent at hp3 than at hß2 or hß1
The invention is further illustrated by the following intermediates and
examples. All temperatures are in degrees centigrade. Chromatography was
carried out on silica (Merck 9385) unless otherwise stated. HPLC
characterization systems are labeled as follows:
System 1: (C18), using a 30-80% acetonitrile-water with 0.1% trifluoroacetic
acid gradient mobile phase with detection by absorbance at 254 nM.
System 2: (C18), using 1:4 acetonitrile-water containing trifluoroacetic acid
(0.1 %) and triethylamine (0.1%) mobile phase with detection by absorbance at
254 nM.
System 3: (C18), using 30-100% acetonitrile-water containing trifluoroacetic
acid (0.1%) and triethylamine (0.1%) mobile phase with detection by absorbance
at 254 nM.
System 4: (C18), using 1:1 acetonitrile-water containing trifluoroacetic acid
(0.1 %) mobile phase with detection by absorbance at 254 nM
HPLC retention times are expressed in minutes as tR
Intermediate 1
2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylic acid methyl
ester.
A solution of 2-(3-aminophenyl)furan-3-carboxylic acid methyl ester (0.31 g) and
{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethyisilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propionaldehyde (0.63 g) in dichloromethane (9 mL)
containing acetic acid (0.03 mL) was stirred at room temperature for 30 min. The
reaction mixture was cooled to 0° C and sodium triacetoxyborohydride (0.30 g)
was added. The mixture was stirred at room temperature for 18 h, washed with
) aqueous sodium bicarbonate solution, dried over magnesium sulfate, and
concentrated under reduced pressure. The residue was chromatographed on
silica eluting with hexanes: ethyl acetate (9:1) to give the title compound as a
yellow solid (0.523 g). c34H47N2O6CISi: M+Na 665
Similarly prepared were:
Intermediate 2
2-[3-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]-amino}ethylamino)phenyl]furan-3-carboxylic acid methyl ester
as a colorless gum (1.15 g), C33H45N2O6CISi: MH+ 629. from 2-(3-
aminophenyl)furan-3-carboxylic acid methyl ester (742 mg) and {(tert-
butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanyloxy)-2-(3-chloro-phenyl)-ethyl]-
amino}-acetaldehyde (1.17 g).
Intermediate 3
2-[4-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]-amino}propylamino)phenyllfuran-3-carboxylic acid methyl
ester as a brown oil (0.45 g), TLC hexane:ethyl acetate (1:1) Rf =0.65, from 2-(4-
aminophenyl)furan-3-carboxylic acid methyl ester (0.22 g) and {2R-(tert-
butoxyoarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propionaldehyde (0.45 g).
Intermediate 4
2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylic acid methyl
; ester as a yellow oil (0.383 g), TLC hexane:ethyl acetate (1:1) Rf =0.66, from 2-
(3-aminophenyl)thiophene-3-carboxylic acid methyl ester (0.30g) and {2R-(tert-
butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propionaldehyde (0.56 g).
) Intermediate 5
2-[3-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylic acjd methyl
ester as a colorless gum (1.15 g), C33H45N2O5CISSi: MH+ 646, from 2-(3-
aminophenyl)thiophene-3-carboxylic acid methyl ester (795 mg) and {(tert-
butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanyloxy)-2-(3-chloro-phenyl)-ethyl]-
amino}-acetaldehyde (1.17 g).
Intermediate 6
2-[4-(2IR-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylic acid methyl
ester as a yellow oil (0.155 g), C34H47N2O5CISSi: MH+ 659, from 2-(4-
aminophenyl)thiophene-3-carboxylic acid methyl ester (0.17 g) and {2R-(tert-
butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propionaldehyde (0.32 g).
Intermediate 7
2-(3-Nitrophenyl)furan-3-carboxylicacid
A solution of 3-nitroaniline (8.28 g) in concentrated hydrochloric acid (20 ml_) was
treated with sodium nitrite (4.2 g) in water (20 mL) at 0° C. The mixture was
stirred for 10 min, and then filtered. To the filtrate was added 3-furancarboxylic
acid (6.05 g) in acetone (10 mL), followed by a solution of cupric chloride (2.4 g)
in water (8 mL). The mixture was left to stand at room temperature for two days,
poured into water (200 mL), and stirred for two hours. The resulting solid was
dissolved in 10% sodium bicarbonate solution, and triturated with ethyl aceate.
The resulting aqueous solution was acidified with 1N hydrochloric acid to
precipitate a solid. Recrystallization of the solid from benzene gave the title
compound as a brown solid (3.57 g). C11H7NO5: MH+232
Similarly prepared were:
Intermediate 8
2-(4-Nitrophenyl)furan-3-carboxylicacid as a tan solid (1.52 g), n.m.r. (DMSO-d6)
5 values include 6.91 (s, 1H),7.96 (s, 1H), 8.27 (dd, 4H), 13.09 (bs, 1H), from 4-
nitroaniline (4.14 g) and 3-furancarboxylic acid (3.03 g).
Intermediate 9
2-(3-Nitrophenyl)thiophene-3-carboxylic acid as a tan solid (0.45 g),
C11H7NO4S: MH- 248, from 3-nitroaniline (4.14 g) and 3-thiophenecarboxylic
acid (3.46 g).
Intermediate 10
2-(4-Nitrophenyl)thiophene-3-carboxylic acid as a tan solid (2.83 g),
C11H7NO4S: MH- 248, from 4-nitroaniline (4.14 g) and 3-thiophenecarboxylic
acid (3.46 g).
Intermediate 11
2-(3-Nitrophenyl)furan-3-carboxylic acid methyl ester
A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid (1.2 g) in methanol (200
mL) containing concentrated sulfuric acid (5 drops) was heated under reflux for
18 h. The reaction solution was evaporated to dryness under reduced pressure to
give the title compound as a yellow solid (0.66 g). m.p.=93-94°C
Similarly prepared were:
Intermediate 12
2-(4-Nitrophenyl)furan-3-carboxylic acid methyl ester as a yellow solid (1.15 g),
m.p.=113-114° C, from 2-(4-nitrophenyl)furan-3-carboxylic acid (0.52 g).
intermediate 13
2-(3-Nitrophenyl)thiophene-3-carboxylic acid methyl ester as a white solid (0.31
9).
C12H9NO4S: MH- 262, from 2-(3-nitrophenyl)thiophene-3-carboxylic acid (0.45
9).
Intermediate 14
2-(4-Nitrophenyl)thiophene-3-carboxylic acid methyl ester as a white solid (1.0 g),
n.m.r. (DMSO-d6) d values include 3.78 (s, 3H), 7.43 (d, 1H), 7.64 (m, 1H). 7.72
(m, 2H), 8.21 (d, 1H), 8.33 (m, 1H), from 2-(4-nitrophenyl)thiophene-3-carboxylic
acid (1.5 g).
Intermediate 15
2-(3-Aminophenyl)furan-3-carboxylic acid methyl ester
A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid methyl ester (1.0 g) in
methanol (60 mL) containing 10% palladium on carbon (2.9 g) was stirred under
1 atmosphere of hydrogen for 1 h. The reaction mixture was then filtered through
Celite. Removal of the solvent at reduced pressure gave the title compound as a
yellow solid (0.75 g). C12H11NO3: M+Na+ 240
) Similarly prepared were:
Intermediate 16
2-(4-Aminophenyl)furan-3-carboxylic acid methyl ester as a yellow solid (1.0 g),
Assay Found: C 66.19; H 5.17; N 6.33%, C12H11NO3 requires C 66.35; H 5.10;
5 N 6.45%, from 2-(4-nitrophenyl)furan-3-carboxylic acid methyl ester (1.0 g).
Intermediate 17
2-(3-Aminophenyl)thiophene-3-carboxylic acid methyl ester as a brown oil (0.30
9).
C12H11NO2S: M+Na+ 255, from 2-(3-nitrophenyl)thiophene-3-carboxylic acid
methyl ester (0.30 g).
Intermediate 18
2-(4-Aminophenyl)thiophene:3=carboxylic acid methyl ester as a brown oil (0.17
g).
C12H11NO2S: MH+234, from 2-(4-nitrophenyl)thiophene-3-carboxylic acid
methyl ester (0.70 g).
Intermediate 19
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-
3-carboxylic acid methyl ester
2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-buty!dimethylsilanoxy)-2-(3-
chlorophenyl)ethyl)amino}propylamino)phenyl]furan-3-carboxylic acid methyl
ester (0.523 g) was dissolved in 4N hydrochloric acid in dioxane (5.0 mL), stirred
at room temperature for 1h and then diluted with diethyi ether (10 mL) to
separate an oil. The oil was chromatographed on silica and eluting with ethyl
acetate: methanol (9:1) to give the title compound as a red oil (0.19 g).
C23H25N2O4CI: MH+ 429
Intermediate 20
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylaminolpropylamino}phenyl)furan-
3-carboxylic acid methyl ester hydrochloride as a white solid (613 mg),
C22H23N2O4CI: MH+ 415, from 2-[3-{tert-butoxycarbonyi-[2R-(tert-
butyidimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-
amino}ethylamino)phenyl]thiophene-3-carboxylic acid methyl ester (1.15 g).
Similarly prepared were:
Intermediate 21
2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-
3-carboxylic acid methyl ester as a brown oil (0.19 g), TLC ethyl acetate:
) methanol (8:2) Rf =0.27, from 2-[4-(2R-{tert-butoxycarbonyI-[2R-(tert-
butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-
3-carboxylic acid methy! ester (0.45 g).
Intermediate 22
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid methyl ester as an
orange oil (0.086 g), C23H25N2O3CIS: MH+ 445, from 2-[3-(2R-{tert-
butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}
propylamino)phenyl]thiophene-3-carboxylic acid methyl ester (0.383 g).
Intermediate 23
2-(3-{2R-[2-(3-Chloropheny[)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid methyl ester
hydrochloride as a tan foam (1.15 g), C22H23N2O3CIS: MH+ 431, from 2-[3-
{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-
amino}ethylamino)phenyl]thiophene-3-carboxylic acid methyl ester (1.65 g).
Intermediate 24
2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid methyl ester as an
orange oil (0.060 g), C23H25N2O3CIS: MH+ 445, from 2-[4-(2R-{tert-
butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-
chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylic acid methyl
ester (0.155 g).
Intermediate 25
Methyl 2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-
ethylarnino]propylamino}phenyl)furan-3-carboxylate as a white foam (992 mg),
C34H47N2O6SiCI: [MH+] 643, from 2-(3-aminophenyl)furan-3-carboxylic acid
methyl ester (700 mg) and {2R-(tert-butoxycarbonyl)-[2R-(tert-
butyldimethylsi!anoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde (1.26 g).

Intermediate 26
Methyl 2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]-N-
ethylpropylamino}phenyl)-furan-3-carboxylate as a white foam (331 mg),
C36H51N2O6SiCI: [MH+] 671, from methyl 2-(3-{2R-[2-(3-chlorophenyl)-2R-
hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylate (429 mg) and
acetaldehyde (47 mg).
Intermediate 27
Ethyl 2-(3-aminophenyl)-3-furoate hydrochloride
To a stirred solution of 1-bromo-3-nitrobenzene (50 g) and ethyl 3-furoate (48.6
g) in toluene (500 mL) were added potassium acetate (36.4 g) and
tetrakis(triphenylphosphine)palladium(0) (14.3 g). The mixture was heated at
reflux for 66 hours, cooled to room temperature, and filtered through Celite (50
g). The filtercake was rinsed with ethyl acetate (2 x 200 mL). The combined
filtrate/rinse was concentrated to an oil. Methanol (500 mL) and 10% palladium
on carbon (50% wet paste, 3.2 g) were added. The mixture was stirred under an
atmosphere of hydrogen until uptake ceased. The mixture was filtered through
Celite (50 g), and the filtercake was rinsed with ethyl acetate (200 mL). The
combined filtrate/rinse was concentrated to an oil, and ethyl acetate (250 mL)
was added. The solution was washed with water (100 mL). The organic phase
was dried over sodium sulfate, filtered, and concentrated to an oil.
Dichloromethane (50 mL) was added, and the resulting solution was filtered
through a silica gel plug (100 g). The plug was rinsed with dichloromethane
(2500 mL) to extract all ethyl 2-(3-aminophenyl)-3-furoate hydrochloride. The
combined filtrate/rinse was concentrated to an oil, and methyl tert-butyl ether
(250 mL) was added. To this stirred solution was slowly added 4.0 M HCI in
dioxane (93 mL). After aging for 15 minutes at 0 - 5 °C, the precipitate was
collected by filtration, washed with methyl tert-butyl ether (2 x 100 mL), and dried
in vacuo at 45 - 50 °C to yield 46.8 g (71% th) of the title compound as a beige
solid. 1H NMR (300 MHz, d6-DMSO) d:7.90 (d, 1H), 7.78 (m, 2H), 7.51 (t, 1H),
7.30 (d, 1H), 4.25 (q, 2H), 1.26 (t, 3H).
Intermediate 28
Ethyl 2-[3-(2-fnethyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]-3-furoate
A/-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10
min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate
(2 mL) at 0°C under nitrogen to give a clear pale straw solution. After 45 min at
0°C toluene (12 mL) was added, and ethyl 2-(3-aminophenyl)-3-furoate
hydrochloride (1.78 g) was added in one portion into the above solution at 0-5°C.
The mixture was stirred at 0-5°C for 10 min and then allowed to warm up to 20°C.
After 2 h formation of the amidine is essentially complete (HPLC ethyl 2-(3-
aminophenyl)-3-furoate hydrochloride cooled to 0-5°C, crushed ice (18 g) was added over 20 min to destroy
phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a
rate that the internal temperature was kept below 25oC (ca. 15 min). After 1h at
20°C additional ethyl acetate (12 mL) added to the above mixture, the organic
layer was separated, washed with deionized water (2x12 mL), and concentrated
under reduced pressure. The residue was dissolved in acetone (5 mL) and ethyl
acetate (5 mL), and treated with oxalic acid (0.72 g) at 40°C for 30 min. After
aging at washed with acetone (2x0.5vol), and dried in vacuo at 45-50°C to yield 1.9 g
(73%) of white solid. 1H NMR (400, d6-DMSO) d: 8.00 (s, 1H), 7.92-7.90 (m, 2H),
7.64-7.55 (m, 2H), 6.90 (d, 1H), 4.32 (t, 2H), 4.22 (q, 2H), 3.93 (t, 2H), 2.22 (s,
3H), 1.24 (t, 3H).
Example 1
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylaminolpropylamino}phenyl)furan-
3-carboxylic acid
To a solution of 2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)furan-3-carboxylic acid methyl ester (0.19 g) in
3:1 methanol: water (5.5 mL) was added solid lithium hydroxide monohydrate
(0.185 g). The solution was stirred at room temperature for 18 h and
concentrated at reduced pressure. The residue was chromatographed on silica
eluting with chloroform: methanol: cone, ammonium hydroxide (10:5:1) to give
the title compound as a tan solid (0.067 g). m.p.=184-186°C, HPLC system 1: tR
11.19 min.
Similarly prepared were:
Example 2
2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-
carboxylic acid as a white solid (317 mg), m.p.=250 °C (dec), C21H21N2O4CI:
[MH+] 402. Assay Found C 62.65; H 5.21; N 6.91%, C21H21N2O4CI1 requires C
62.92; H 5.28; N 6.99%, from 2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)furan-3-carboxylic acid methyl ester
hydrochloride (613 mg).
In an alternative preparation, ammonium hydroxide (28%, 13 mL) was added
over 10 min to a mixture of ethyl 2-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-
yl)phenyl]-3-furoate (13.0 g), deionized water (104 mL), and toluene (104 mL).
After 30 min stirring, the organic layer was collected, washed with deionized
water (26 mL), and concentrated to ca. 30 mL to remove traces of water
azetropically. (R)-3-Chlorostyrene oxide (5.17 g) was added, and the resultant
was heated under nitrogen at 110°C for at least 14h. The mixture was cooled to
ca. 50°C. 1M Sodium hydroxide aqueous solution (77.8 mL) and methanol (39
mL) were added, and the apparatus was configured for distillation. After ca. 1h,
the homogeneous solution obtained was heated at reflux (ca. 4h) until the
hydrolysis was complete (HPLC acetate cooled to -Methanol (26 mL) and 1M hydrochloric acid (78 mL) were heated to ca. 50°C.
The reaction mixture from above was added over 20 min, and the resultant slurry
was cooled to by filtration, washed with deionized water (2x26 mL), and dried in vacuo at 50°C
to yield 12.7 g (95%) of the title compound as an off-white solid.
Example 3
2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxylethylamino]propylannino}phenyl)furan-3-
carboxylic acid as a tan solid (0.059 g), HRMS C22H23N2O4CI: MH+ calc
415.1425, found 415.1412 a =1.3 mmu, HPLC system 1: tR 11.06 mm., from 2-
(4-{2R-[2-(3-chlorophenyl)-2R-hydroxylethylamino]propylamino}phenyl)furan-3-
carboxylic acid methyl ester (0.19 g).
Example 4
2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-
ethylarnino]propylamino}phenyl)thiophene-3-carboxylic acid as a tan solid (0.088
g), HRMS C22H23N2O3CIS MH+ calc 431.1196, found 431.1180 a =1.6 mmu,
HPLC system 1: tR 12.38 min., from 2-(3-{2R[2-(3-chlorophenyi)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid methyl ester (0.086
g).
Example 5
2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino1ethylamino}phenyl)thiophene-
3-carboxylic acid as a cream colored solid (296.8 mg), m.p =275 °C (dec)
C21H21N2O3CIS : [MH*] 417. Assay Found C 60.47; H 5.04; N 6.67%,
C21H21N2O4CI1 requires C 60.50; H 5.08; N 6.72%, from 2-(3-{2R-[2-(3-
chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-
carboxylic acid methyl ester hydrochloride (1.15 g).
Example 6
2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid as a tan solid (0.010
g), HRMS C22H23N2O3CIS MH+ calc 431.1196, found 431.1183 a =1.3 mmu,
HPLC system 1: tR 12.03 min., from 2-(4-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-
ethylamino]propylamino}phenyl)thiophene-3-carboxylic acid methyl ester (0.060
g)-
WE CLAIM:
1. A compound of formula (I), or a pharmaceutically acceptable derivative
thereof.

wherein X is oxygen or sulfur, optionally substituted by one or more groups
selected from C1-4 alkyl and halogen, and where the heterocycle containing X is
substituted meta or para to the depicted NH;
R1 is hydrogen or C1-6-alkyl;
R represents substituents selected from C1-6 alkyl, halogen, trifiuoromethyl, and
C1-6alkoxy; and
n represents an integer from 0-4.
2. A compound as claimed in claim 1, which is an agonist for human beta-3
adrenoceptor.
3. A compound as claimed in claim 1, which is a selective agonist for human beta-3
adrenoceptor.
4. A compound as claimed in claim 1, wherein the heterocycle containing X is
substituted meta to the depicted NH.
5. A compound as claimed in claim 1, wherein R1 is hydrogen or methyl.
6. A compound as claimed in claim 1, wherein when R1 is other than hydrogen, the
stereochemisty around the carbon to which R1 is bonded, is R, as defined in claim 1.
7. A compound as claimed in claim 1, wherein R is chlorine, fluorine, or CF3.
8. A compound as claimed in claim 1, wherein n is 0, 1, or 2.
9. A compound as claimed in claim 1, wherein n is 0.
10. A compound as claimed in claim 1, wherein the stereochemisty around the carbon
to which the depicted OH is bonded, is R, as defined in claim 1.
11. A compound as claimed in claim 1, which is selected from the group consisting of:
2-(3--{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propyIarhino}phenyl)furan-
3-carboxy!ic acid;
2-(3-{[2-(3-ChiorophenyI)-2R-hydroxyl-ethylamino]ethy!amino}phenyI)furan-3-
carboxylic acid;
2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxy!ethylamino]propylamino}phenyl)furan-3-
carboxylic acid;
2-(3-{2R-[2-(3-ChlorophenyI)-2R-hydroxyl-
ethyiamino]propyiamino}phenyl)thiophene-3-carboxyiic acid;
2-(3-{[2-(3-Ch!oropheny!)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-
3-carboxyiic acid;
2-(4-{2R-[2-(3-Chlorophenyi)-2R-hydroxyl-
ethylamino]propyIamino}phenyl)thiophene-3-carboxylicacid;
and pharmaceutically acceptable derivatives thereof.
12. A compound as claimed in claim 1, which is selected from the group consisting of:
2-(3-{[2-(3-Chlorophenyi)-2R-hydroxyi-ethylamino]ethyIamino}phenyi)furan-3-
carboxylic acid;
2-(3-{[2-(3-Ch!orophenyi)-2R-hydroxyl-ethylamino]ethyiamino}phenyl)thiophene-
3-carboxylic acid;
and pharmaceutically acceptable derivatives thereof.
13. A pharmaceutical formulation comprising a compound as claimed in claim 1, and
pharmaceutically acceptable carrier, such as herein described.
14. A compound as claimed in any one of claims 1 to 12, which is capable of being
used in the manufacture of a medicament for the treatment of a mammal, including man,
of conditions or diseases susceptible of amelioration by an atypical beta-adrenoceptor
agonist, which are, for example, obesity and urinary incontinence.
15. A pharmaceutical formulation as claimed in claim 13, which is capable of being
used for the prevention or treatment of clinical conditions or diseases susceptible to
amelioration by administration of an atypical beta-adrenoceptor agonist, which are, for
example, obesity and urinary incontinence.
The present invention discloses compounds of Formula I. The present invention also discloses beta-3 agonists of
formula I and methods for treating beta-3 mediated diseases and condition using the compounds of formula I, in particular methods
for treating diabetes or obesity.

Documents:

874-kolnp-2003-granted-abstract.pdf

874-kolnp-2003-granted-assignment.pdf

874-kolnp-2003-granted-claims.pdf

874-kolnp-2003-granted-correspondence.pdf

874-kolnp-2003-granted-description (complete).pdf

874-kolnp-2003-granted-examination report.pdf

874-kolnp-2003-granted-form 1.pdf

874-kolnp-2003-granted-form 18.pdf

874-kolnp-2003-granted-form 3.pdf

874-kolnp-2003-granted-form 5.pdf

874-kolnp-2003-granted-gpa.pdf

874-kolnp-2003-granted-letter patent.pdf

874-kolnp-2003-granted-reply to examination report.pdf

874-kolnp-2003-granted-specification.pdf


Patent Number 214242
Indian Patent Application Number 00874/KOLNP/2003
PG Journal Number 06/2008
Publication Date 08-Feb-2008
Grant Date 07-Feb-2008
Date of Filing 08-Jul-2003
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GRFEENFORD MIDDLESEX UB6 ONN GREAT BRITAIN.
Inventors:
# Inventor's Name Inventor's Address
1 DEATON DAVID N GLAXOSMITHKLINE FIVE MOORE DRIVE USA
2 SHEARER BARRY GEORGE GLAXOSMITHKLINE FIVE MOORE DRIVE USA
3 UEHLING DAVID EDWARD GLAXOSMITHKLINE FIVE MOORE DRIVE USA
PCT International Classification Number C07D 307/68
PCT International Application Number PCT/US01/49299
PCT International Filing date 2001-12-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0102408.2 2001-01-31 U.S.A.