peT
`
`WORLD INTELLECI1JAL PROPERTY ORGANIZATION
`International Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER TIIE PATENT COOPERATION TREATY (pCT)
`WO 97n6189
`
`(51) International Patent Classification 6 :
`A61K 31144, 38118, 38117
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`9 May 1997 (09.05.97)
`
`(21) International Application Number:
`
`PCf/US96/17444
`
`(22) International Filing Date:
`
`31 October 1996 (31.10.96)
`
`(30) Priority Data:
`60/007,138
`9603724.7
`
`1 November 1995 (01.11.95)
`22 February 1996 (22.02.96)
`
`US
`GB
`
`(81) Designated States: AL, AM, AU, AZ, BA, BB, BG, BR, BY,
`CA, CN, CU, CZ, EE, GE, HU, IL, IS, JP, KG, KR, KZ,
`LC, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ,
`PL, RO, RU, SG, SI, SK, TJ, TM, TR, TT, UA, US, UZ,
`VN, ARIPO patent (KE, LS, MW, SO, SZ, UG), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, n, TM), European
`patent (AT, BE, CH, DE, OK, ES, FI, FR, GB, GR, IE, IT,
`LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI,
`CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (for all designated States except US): MERCK &
`CO., INC. [USIUS]; 126 East Lin::oln Avenue, Rahw:>y, NJ
`07065 (US).
`
`Published
`With international search report.
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): SMITH, Roy, G. [GBIUS];
`126 East Lincoln Avenue, Rahway, NJ 07065 (US).
`
`(74) Common Representative: MERCK & CO., INC.; 126 East
`Lincoln Avenue, Rahway, NJ 07065 (US).
`
`(54) Title: COMBINATION THERAPY FOR TIIE TREATMENT OF DIABETES AND OBESITY
`
`(57) Abstract
`
`The combination of the /33 adrenergic receptor agonist Compound A and a compound which modifies feeding behavior (e.g., the
`OB protein) is useful in the treatment of obesity and diabetes, either as compounds, pharmaceutically acceptable salts, pharmaceutical
`compoisition ingredients. Methods of treating obesity and diabetes are also described.
`
`ASTELLAS 2005
`Sawai v. Astellas
`IPR2018-00079
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the per on the front pages of pamphlets publishing international
`applications under the per.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`OE
`OK
`EE
`ES
`FI
`FR
`GA
`
`Annenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Gennany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LR
`LT
`LV
`LV
`MC
`MO
`MG
`ML
`MN
`MR
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People' 5 Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lilhuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SO
`SE
`SG
`SI
`SK
`SN
`SZ
`TO
`TG
`TJ
`17
`UA
`UG
`US
`UZ
`VN
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
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`WO 97/16189
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`TITLE OF THE INVENTION
`COMBINA TION THERAPY FOR THE TREATMENT OF DIABETES
`AND OBESITY
`
`5 FJELD OF THE INVENTION
`The present invention provides a combination useful in
`the treatment of obesity and diabetes, either as compounds,
`phannaceutically acceptable salts or phannaceutical composition
`ingredients. Methods of treating obesity and diabetes are also
`disclosed. More particularly, the combination of the present
`invention comprises a ~3 agonist and a compound which modifies
`feeding behavior (e.g., Ob protein, also known as leptin).
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`BACKGROUND OF THE INVENTION
`Obesity, which can be defined as a body weight more than
`20% above the ideal body weight, is a major health concern in Western
`societies, since it is accompanied by numerous complications such as
`hypertension, non-insulin dependent diabetes mellitus and
`arteriosclerosis, which in tum cause heart disease, stroke and premature
`death. Obesity is the result of a positive energy balance, as a
`consequence of increased ratio of caloric intake to energy expenditure.
`The molecular factors regulating food intake and body weight balance
`are incompletely understood. [B. Staels et aI., J. BioI. Chem. 270(27),
`15958 (1995); F. Lonnquist et aI., Nature Medicine 1(9), 950 (1995)].
`25 Although the genetic and/or environmental factors leading to obesity are
`poorly understood, several genetic factors have recently been identified.
`~-Adrenoceptors have been subclassified as P I and P2 since
`1967. Increased heart rate is the primary consequence of (31-receptor
`stimulation, while bronchodilation and smooth muscle relaxation
`typically result from ~2 stimulation. Adipocyte lipolysis was initially
`thought to be solely a PI -mediated process. However, more recent
`results indicate that the receptor-mediating lipolysis is atypical in
`nature. These atypical receptors, later called P3-adrenoceptors, are
`found on the cell surface of both white and brown adipocytes where
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`their stimulation promotes both lipolysis (breakdown of fat) and energy
`expenditure.
`Early developments in this area produced compounds with
`greater agonist activity for the stimulation of lipolysis (P3 activity) than
`for stimulation of atrial rate (P 1) and tracheal relaxation (P2). These
`early developments disclosed in Ainsworth et ru., U.S. Patents 4,478,849
`and 4,396,627, were derivatives of phenylethanolamines.
`Such selectivity for P3-adrenoceptors could make
`compounds of this type potentially useful as antiobesity agents. In
`addition, these compounds have been reported to show
`antihyperglycemic effects in animal models of non-insulin-dependent
`diabetes mellitus.
`A major drawback in treatment of chronic diseases with ~3
`agonists is the potential for stimulation of other p-receptors and
`subsequent side effects. The most likely of these include muscle tremor
`(~2) and increased heart rate (P 1). Although these phenylethanolamine
`derivatives do possess some P3 selectivity, side effects of this type have
`been observed in human volunteers. It is reasonable to expect that these
`side effects resulted from partial PI and/or P2 agonism.
`More recent developments in this area are disclosed in
`Ainsworth ~al., U.S. Patent 5,153,210, Caulkett ~ru., U.S. Patent
`4,999,377, Alig ~al., U.S. Patent 5,017,619, Lecount ~.al., European
`Patent 427480 and Bloom ~ M., European Patent 455006.
`Even though these more recent developments purport to
`describe compounds with greater P3 selectivity over the PI and P2
`activities, this selectivity was determined using rodents, in particular,
`rats as the test animal. Because even the most highly selective
`compounds, as determined by these assays, still show signs of side
`effects due to residual PI and P2 agonist activity when the compounds
`are tested in humans, it has become apparent that the rodent is not a
`good model for predicting human P3 selectivity.
`Recently, assays have been developed which more
`accurately predict the effects that can be expected in humans. These
`assays utilize cloned human P3 receptors which have been expressed in
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`Chinese hamster ovary cells. See Emorine et aI, Science, 1989,
`245:1118-1121; and Liggett, Mol. Phaonacol., 1992,42:634-637. The
`agonist and antagonist effects of the various compounds on the
`cultivated cells provide an indication of the antiobesity and antidiabetic
`effects of the compounds in humans.
`These developments have recently led to the discovery of
`potent and selective ~3 agonists useful for treating obesity and diabetes.
`For example, U.S. Patent No. 5,451,677, issued September 19, 1995,
`hereby incorporated by reference, describes substituted phenyl
`sulfonamides which are selective ~3 agonists useful for treating obesity
`and diabetes. These phenyl sulfonamide compounds have been found to
`be useful in the composition and methods of the instant invention.
`More recently, a potent and selective ~3 agonist, (R)-N-[4-
`[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]-phenyl]-4-[4-(3-
`cycIopentylpropyJ)-5-tetrazolon-l-yl]benzenesulfonamide, hereinafter
`referred to as Compound A, has been identified.
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`Compound A
`
`The synthesis of Compound A and its utility for treating obesity and
`diabetes is described in more detail below, and in PCT International
`application publication number WO 95{29159, published November 2,
`1995, and in U.S. Patent No. 5,561,142, issued October 1,1996.·
`In addition to ~3 agonists which act on obesity and diabetes
`by increasing metabolic rate, researchers have recently cloned the
`mouse OB gene and its human homologue. [Yo Zhang et al., Nature
`372, 425 (1994)] The DB gene product, i.e., the DB protein (also
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`known as leptin), a 167 amino acid polypeptide, has been shown to
`result in a dose- and time-dependent weight loss when administered to
`mice via intraperitoneal (IP) injection. [M.A. Pelleymounter et aI.,
`Science 269, 540 (1995)]. This weight loss effect is attributable to both
`a reduction in food intake and an increase in energy expenditure.
`Moreover, since both the mouse and human OB protein have this same
`effect when administered to mice, the possibility exists that similar
`effects would also occur in humans. [J .L. Halaas et al., Science 269, 543
`(1995)].
`
`It has now been found that a combination of a ~3 selective
`agonist compound and a compound which modifies feeding behavior,
`for example, by reducing total food intake or by reducing caloric intake
`or selectively reducing intake of specific components of the diet such as
`carbohydrates or fats, provides effective therapy for treating obesity
`and diabetes. More specifically, a combination of Compound A and the
`OB protein or a derivative thereof is particularly preferred for the
`treatment of obesity and diabetes.
`
`SUMMARY OF THE INVENTION
`The present invention provides a composition comprising a
`selective ~3 agonist and a compound which modifies feeding behavior
`(e.g., reduces food intake); and the pharmaceutically acceptable salts and
`esters thereof.
`In one embodiment of the invention is the composition
`comprising a selective ~3 agonist and Ob protein or a derivative of the
`Ob protein; and the pharmaceutically acceptable salts and esters thereof.
`Preferably, the human Ob protein, or a derivative thereof, is used in
`combination with a selective ~3 agonist.
`In a class of the invention is the composition wherein the
`selective ~3 agonist is Compound A, i.e., (R)-N-[4-[2-[[2-hydroxy-2-
`(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropy1)-5-
`tetrazolon-l-yl]benzenesulfonamide; and the pharmaceutically
`acceptable salts and esters thereof. Preferably, the selective ~3 agonist
`is the dihydrochloride salt of Compound A, i.e., (R)-N,-[4-[2-[[2-
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`hydroxy-2-(pyridin-3-yl)ethyl]amino ]-ethyl]phenyl]-4-[ 4-(3-
`cycIopentylpropyl)-5-tetrazolon-l-yl]benzenesulfonamide
`dihydrochloride.
`Illustrative of the invention is a method of treating obesity
`in a subject in need thereof which comprises administering to the subject
`a therapeutically effective amount of any of the compositions described
`above.
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`Exemplifying the invention is a method of treating diabetes
`in a subject in need thereof which comprises administering to the subject
`lOa therapeutically effective amount of any of the compositions described
`above.
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`An illustration of the invention is a phannaceutical
`composition comprising a therapeutically effective amount of any of the
`compositions described above and a phannaceutically acceptable carrier.
`Further illustrating the invention is the phannaceutica] composition
`made by combining a selective ~3 agonist, a compound which modifies
`feeding behavior and a pharmaceutica]]y acceptable carrier. Further
`exemplifying the invention is a process for making a pharmaceutical
`composition which comprises combining a selective ~3 agonist, a
`compound which modifies feeding behavior and a pharmaceutically
`acceptable carrier.
`An example of the invention is the use of a selective ~3
`agonist and Ob protein, or a derivative thereof, in the preparation of a
`medicament for the treatment of obesity.
`Another example of the invention is the use of a selective
`~3 agonist and Ob protein, or a derivative of the Ob protein, in the
`preparation of a medicament for the treatment of diabetes.
`Further illustrating the invention is a drug which is useful
`for treating obesity, the effective ingredients of the said drug being a
`selective ~3 agonist and Ob protein, or a derivative of the Ob protein.
`Further exemplifying the invention is a drug which is
`useful for treating diabetes, the effective ingredients of the said drug
`being a selective ~3 agonist and Ob protein, or a derivative of Ob
`protein.
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`DET AD..ED DESCRIPTION OF THE INVENTION
`This invention is concerned with the combination of
`certain compounds, or pharmaceutically acceptable salts thereof, for
`the treatment of obesity and diabetes. Obesity and diabetes mellitus
`are often treated by encouraging patients to lose weight by reducing
`their food intake and by increasing their metabolic rate. The ob
`protein reduces food intake. A ~3 selective agonist is targeted to fat
`and causes increases in metabolic rate. Thus, it has now been found
`that combination treatment with Ob protein, or a compound that
`causes increased expression of ob protein, with a P3 selective agonist
`is advantageous over treatment with either a P3 selective agonist or
`Db protein alone in the treatment of obesity and diabetes. Moreover,
`in addition to its effects on reducing food intake, the ob protein has
`broad affects. For example, ob protein increases metabolic rate by
`unknown pathways and lowers glucose and insulin in diabetic mice.
`As discussed above, P3 selective agonists also increase metabolic rate
`by specifically targeting fat cells. Thus, when P3 selective agonists
`are used in combination with the ob gene product, additional
`beneficial affects on metabolism occur in very obese people.
`As used herein, the terms "selective P3 agonist" and "P3
`selective agonists" are synonymous and refer to agonists which are
`selective for the P3 adrenergic receptor SUbtype over the ~ 1 and ~2
`adrenergic receptor SUbtypes in humans. Examples of selective ~3
`adrenergic agonists are Compound A and the compounds described
`in u.S. Patent No. 5,541,677. Compound A and additional selective
`~3 adrenergic agonists which are useful in the compositions and
`methods of the present invention are described in U.S. Patent No.
`5,561,142, issued October 1, 1996 and PCI' International patent
`application Publication No. WO 95/29159, published November 2,
`1995.
`
`The term "subject," as used herein refers to an animal,
`preferably a manunal, most preferably a human, who has been the
`object of treatment, observation or experiment.
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`The tenn "therapeutically effective amount" as used
`herein means that amount of active compound(s) or phannaceutical
`agent(s) that elicits the biological or medicinal response in a tissue,
`system, animal or human that is being sought by a researcher,
`veterinarian, medical doctor or other clinician, which includes
`alleviation of the symptoms of the disease being treated.
`The term "diabetes," as used herein, incJudes both
`insulin-dependent diabetes mellitus (i.e., IDDM, also known as type I
`diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM,
`also known as Type II diabetes).
`As used herein, the tenn "composition" is intended to
`encompass a product comprising the specified ingredients in the
`specified amounts, as well as any product which results, directly or
`indirectly, from combination of the specified ingredients in the specified
`amounts.
`
`The combination of the present invention is defined as
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`follows:
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`Compound A and a compound which acts by reducing
`food intake when administered to a subject, or pharmaceutically
`acceptable salts thereof. Preferably, the combination comprises
`Compound A and Ob protein. Most preferably, the combination
`comprises Compound A and human Ob protein.
`The ~3 agonist, Compound A, is synthesized as shown in
`Example I, below, and as shown in Example 70 of U.S. Patent No.
`5,561,142, issued October 1, 1996, hereby incorporated by
`reference .. Compound A is (R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-
`y I )ethyl] amino ]ethy I ]-pheny I] -4-[ 4-(3-cyclopentylpropyl)-5-
`tetrazolon-l-yl]benzenesulfonamide, or a phannaceutically
`acceptable salt thereof. Preferably, the dihydrochloride salt of
`30 Compound A is utilized in the combination.
`Compounds which reduce food intake include the Ob
`protein (Le., leptin). As used herein, the tenns "Ob protein," "OB
`protein" and "ob protein" all refer to the same protein and are also
`synonymous with the protein referred to as "Ieptin." Preferably, the
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`combination of the present invention comprises Compound A and the
`Ob protein, or phannaceutically acceptable salts thereof.
`The Ob protein is obtained by expression of the recently
`discovered Ob gene. Expression of mouse Ob gene product in
`5 Drosophila Schneider 2 (S2) cells is described in Example 13, below.
`Based on the published sequence of the human Ob cDNA [Yo Zhang
`et a1.. Nature 372.425-432 (1994); R.V. Considine et aI., J. Clin.
`Invest. 95, 2986-2988 (1995)], one of ordinary skill in the art could
`isolate human cDNA and obtain human Ob protein by expression of
`the human Ob cDNA in Drosophila S2 cells according to the
`protocol of Example 13. Similarly, the Ob protein may also be
`expressed in a bacterial expression system such as E. coli or a yeast
`system and purified by one of ordinary skill in the art.
`In addition to the combination comprising Compound A
`and the Ob protein, compounds which cause increased expression of
`the Ob protein (for example, glucocorticoids, see P. De Vos, J. Bioi.
`Chern. 270(27), 15958-15961 (1995» are also useful in combination
`with Compound A for treating obesity and diabetes. Further
`included within the invention are derivatives of Ob protein in which
`the protein is truncated to produce a small peptide and/or one or·
`more amino acids are deleted, added, substituted or modified but
`which derivatives maintain the biological effect on feeding behavior
`and food intake. Examples of leptin derivatives (e.g., truncated
`forms of leptin) which are useful in the present invention include
`25 U.S. Patent Nos. 5,552,524; 5,552,523; 5,552,522; 5,521,283; and
`PCT International application publication nos. WO 96/23513; WO
`96/23514; WO 96/23515; WO 96/23516; WO 96/23517; WO
`96/23518; WO 96/23519; WO 96/23520, all published on August 8,
`1996.
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`The phannaceutically acceptable salts of the present
`invention (in the form of water- or oil-soluble or dispersible products)
`include the conventional non-toxic salts or the quaternary ammonium
`salts which are formed, e.g., from inorganic or organic acids or bases.
`Examples of such acid addition salts include acetate, adipate, alginate,
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`aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,
`camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,
`dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
`glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,
`hydro bromi de , hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
`methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,
`pectinate. persulfate, 3-phenylpropionate, picrate, pivalate, propiona.te,
`succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts
`include ammonium salts, alkali metal salts such as sodium and potassium
`salts, alkaline earth metal salts such as calcium and magnesium salts,
`salts with organic bases such as dicyclohexylamine salts, N-methyl-D(cid:173)
`glucamine, and salts with amino acids such as arginine, lysine, and so
`forth. Also, the basic nitrogen-containing groups may be quatemized
`with such agents as lower alkyl halides, such as methyl, ethyl, propyl,
`and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl,
`diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl,
`lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl
`halides like benzyl and phenethyl bromides and others. Other
`pharmaceutically acceptable salts include the sulfate salt ethanolate and
`sulfate salts.
`The pharmaceutically acceptable salts of the composition of
`the instant invention include the composition wherein one of the
`individual components of the combination is in the form of a
`pharmaceutically acceptable salt, or the composition wherein all of the
`individual components are in the form of pharmaceutically acceptable
`salts (wherein the salts for each of the components can be the same or
`different), or a pharmaceutically acceptable salt of the combined
`components (Le., a salt of the composition). In one embodiment of the
`present invention, the hydrochloride salt of the composition is utilized.
`The pharmaceutically acceptable esters in the present
`invention refer to non-toxic esters, preferably the alkyl esters such as
`methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, of
`which the methyl ester is preferred. However, other esters such as
`phenyl-CI-5 alkyl may be employed if desired.
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`Esterification of alcohols, such as Compound A of the
`present invention, is performed by a variety of conventional
`procedures, including reacting the alcohol group with the appropriate
`anhydride, carboxylic acid or acid chloride. These reactions, as well as
`other methods of esterification of alcohols, are readily apparent to the
`skilled artisan.
`Reaction of the alcohol with the appropriate anhydride is
`carried out in the presence of an acylation catalyst, such as 4-DMAP (4-
`dimethylaminopyridine, also known as N,N-dimethylaminopyridine),
`pyridine, or 1 ,8-bis [dimethy lamino ]napthalene.
`Reaction of the alcohol with the appropriate carboxylic acid
`is carried out in the presence of a dehydrating agent and, optionally, an
`acylation catalyst. The dehydrating agent, which serves to drive the
`reaction by the removal of water is selected from dicyclohexylcarbo-
`diimide (DCC), 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide (EDC)
`or other water soluble dehydrating agents.
`Alternatively, reaction of the alcohol with appropriate
`carboxylic acid can also result in esterification, if performed instead in
`the presence of trifluoroacetic anhydride, and, optionally, pyridine. A
`further variant is reacting the alcohol with appropriate carboxylic acid
`in the presence of N,N-carbonyldiimidazole with pyridine.
`Reaction of the alcohol with the acid chloride is carried out
`with an acylation catalyst, such as 4-DMAP or pyridine.
`During any of the above methods for forming esters, it
`25 may be necessary and/or desirable to protect sensitive or reactive
`groups on any of the molecules concerned. This may be achieved by
`means of conventional protecting groups, such as those described in
`Protective Groups in Or&anic Chemist[)', ed. J.F.W. McOmie, Plenum
`Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in
`30 Or&anic Synthesis, John Wiley & Sons, 1991. The protecting groups
`may be removed at a convenient subsequent stage using methods known
`from the art.
`In one aspect, the present invention provides a combination
`of compounds or a pharmaceutically acceptable ester thereof: or a
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`pharmaceutically acceptable salt thereof for use in the treatment of
`obesity in human or non-human animals.
`The present invention further provides a combination of
`compounds, or a pharmaceutically acceptable ester thereof; or
`pharmaceutically acceptable salt thereof, for use in the treatment of
`hyperglycemia (diabetes) in human or non-human animals.
`The disease diabetes mellitus is characterized by metabolic
`defects in production and utilization of glucose which result in the
`failure to maintain appropriate blood sugar levels. The result of these
`defects is elevated blood glucose or hyperglycemia. Research on the
`treatment of diabetes has centered on attempts to normalize fasting and
`postprandial blood glucose levels. Treatments have included parenteral
`administration of exogenous insulin, oral administration of drugs and
`dietary therapies.
`Two major forms of diabetes mellitus are now recognized.
`Type I diabetes, or insulin-dependent diabetes, is the result of an
`absolute deficiency of insulin, the hormone which regulates glucose
`utilization. Type II diabetes, or insulin-independent diabetes (i.e., non(cid:173)
`insulin-dependent diabetes mellitus), often occurs in the face of normal,
`or even elevated levels of insulin and appears to be the result of the
`inability of tissues to respond appropriately to insulin. Most of the
`Type II diabetics are also obese. The combination of the present
`invention is useful for treating both Type I and Type II diabetes. The
`combination is especially effective for treating Type n diabetes.
`The combination of compounds of the present invention is
`useful in the treatment of obesity and diabetes. For these pwposes, the
`combinations of the present invention may be administered orally,
`parenterally (including subcutaneous injections, intravenous,
`intramuscular, intrasternal injection or infusion techniques), by
`inhalation spray, or rectally, in dosage unit formulations containing
`conventional non-toxic pharmaceutically acceptable carriers, adjuvants
`and vehicles.
`Thus, in accordance with the combination of the present
`invention there is further provided a method of treating and a
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`phannaceutical composition for treating obesity and diabetes. The
`treatment involves administering to a patient in need of such
`treatment a phannaceutical composition comprising a phannaceutical
`carrier and a therapeutically effective amount of each compound in
`the combination of the present invention.
`These phannaceutical compositions may be in the form
`of orally-administrable suspensions or tablets; nasal sprays; sterile
`injectable preparations, for example, as sterile injectable aqueous or
`oleaginous suspensions or suppositories.
`In accordance with the methods of the present invention,
`the individual components of the combination can be administered
`separately at different times during the course of therapy or
`concurrently in divided or single combination forms. For example,
`in a two-component combination which is the P3 agonist, Compound
`15 A, and the Ob protein, treatment with Ob protein can commence
`prior to, subsequent to or concurrent with commencement of
`treatment with Compound A. Furthermore, the term administering
`also encompasses the use of prodrugs of the P3 agonist and/or Ob
`protein which convert in vivo to a selective P3 agonist or Ob protein
`or derivative thereof. The instant invention is therefore to be
`understood as embracing all such regimes of simultaneous or
`alternating treatment and the term "administering" is to be
`interpreted accordingly.
`When any of the active ingredients (e.g. Compound A)
`are administered orally as a suspension, these compositions are
`prepared according to techniques well-known in the art of
`phannaceutical formulation and may contain microcrystalline
`cellulose for imparting bulk, alginic acid or sodium alginate as a
`suspending agent, methyl cellulose as a viscosity enhancer, and
`sweeteners/flavoring agents known in the art. As immediate release
`tablets, these compositions may contain microcrystalline cellulose,
`dicalcium phosphate, starch, magnesium stearate and lactose and/or
`other excipients, binders, extenders, disintegrants, diluents and
`lubricants known in the art.
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`When administered by nasal aerosol or inhalation, these
`compositions are prepared according to techniques well-known in the
`art of phannaceutical fonnulation and may be prepared as solutions
`in saline, employing benzyl alcohol or other suitable preservatives,
`absorption promoters to enhance bioavailability, fluorocarbons,
`and/or other solubilizing or dispersing agents known in the art.
`The compounds utilized in the combination may also be
`administered in intravenous (both bolus and infusion),
`intraperitoneal, subcutaneous, topical with or without occlusion, or
`intramuscular fonn, all using fonns well known to those of ordinary
`skill in the phannaceutical arts. When administered by injection, the
`injectable solutions or suspensions may be fonnulated according to
`known art, using suitable non-toxic, parenterally-acceptable diluents
`or solvents, such as mannitol, 1,3-butanediol, water, Ringer's
`solution or isotonic sodium chloride solution, or suitable dispersing
`or wetting and suspending agents, such as sterile, bland, fixed oils,
`including synthetic mono- or diglycerides, and fatty acids, including
`oleic acid.
`
`When rectally administered in the fonn of suppositories,
`these compositions may be prepared by mixing the drug with a
`suitable non-irritating excipient, such as cocoa butter, synthetic
`glyceride esters or polyethylene glycols, which are solid at ordinary
`temperatures, but liquidify and/or dissolve in the rectal cavity to
`release the drug.
`The active ingredients of the combination (e.g., Compound
`A) of the present invention may be administered as a phannaceutical
`composition, for example, with an inert diluent, or with an assimilable
`edible carrier, or they may be enclosed in hard or soft shell capsules, or
`they may be compressed into tablets, or they may be incorporated
`directly with the food of the diet. For oral therapeutic administration,
`which includes sublingual administration, these active compounds may
`be incorporated with excipients and used in the fonn of tablets, pills,
`capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
`Such compositions and preparations should contain at least 0.1 percent
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`of the active ingredients. The percentage of active ingredients in these
`compositions may, of course, be varied and may conveniently be
`between about 2 percent to about 60 percent of the weight of the unit.
`The amount of active ingredients in such therapeutically useful
`compositions is such that an effective dosage will be obtained. The
`active compounds can also be administered intranasally as, for example,
`liquid drops or spray.
`The effective dosage of each of the active ingredients
`employed in the combination may vary depending on the particular
`compound employed, the mode of administration, the condition being
`treated and the severity of the condition being treated. Thus, the dosage
`regimen utilizing the compounds of the present invention is selected in
`accordance with a variety of factors including type, species, age, weight,
`sex and medical condition of the patient; the severity of the condition to
`be treated; the route of administration; the renal and hepatic function of
`the patient; and the particular compound thereof employed. A physician
`or veterinarian of ordinary skill can readily determine and prescribe the
`effective amount of the drug required to prevent, counter or arrest the
`progress of the condition. Optimal precision in achieving concentration
`20 of drug within the range that yields efficacy without toxicity requires a
`regimen based on the kinetics of the drug's availability to target sites.
`This involves a consideration of the distribution, equilibrium, and
`elimination of a drug.
`The compounds of this invention can be administered to
`humans