PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`lntemational Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`
`(11) International Publication Number:
`
`WO 96/29074
`
`A61K 31/42, 31/445, 31/405, 31/495,
`31/50, 31/415, 31/44, 31/40, 31/135,
`31/435, 31/15, 31/34
`
`(43) International Publication Date:
`
`26 September 1996 (2609.96)
`
`(21) International Application Number:
`
`PCT/US96/04198
`
`(22) International Filing Date:
`
`20 March 1996 (20.03.96)
`
`(30) Priority Data:
`08/408,238
`
`22 March 1995 (22.03.95)
`
`US
`
`(71) Applicant: ELI LILLY AND COMPANY [US/US]; Lilly
`Corporate Center, Indianapolis, IN 46285 (US).
`
`JOHNSON, Kirk, W.; 31 Triple Crown Lane,
`(72) Inventors:
`Camby, IN 46113 (US). PHEBUS, Lee, A.; 1744 West
`1000 North, Fountaintown, IN 46130 (US).
`
`(74) Agents: GAYDO, Paul, J. et al.; Eli Lilly and Company, Lilly
`Corporate Center, Indianapolis, IN 46285 (US).
`
`AZ, BB, BG, BR, BY,
`, FI, GE, GE, I-IU, IS,
`,
`L , LS. LT, LU, LV, MD,
`PL, PT, RO, RU, SD.
`UG. U2, VN, ARIPO
`SE, SG, SI, SK, TI, TM,
`G), Eurasian patent (AM,
`patent (KE, LS, MW, S
`AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT,
`BE, CH, DE, DK, 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).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: METHODS OF TREATING OR PREVENTING PAIN OR NOCICEPTION
`
`(57) Abstract
`
`This invention provides methods for the treatment or prevention of pain or nociception which comprises administering to a mammal
`in need thereof a combination of a tachykinin receptor antagonist and either a serotonin agonist or a selective serotonin reuptake inhibitor.
`This administration may be concurrent or sequential, with either of the two activities being administered fitst.
`
`   
`


`
`Lannett Holdings, Inc. LAN 1018
`
`

`
`
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PC!‘ on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`31
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`EE
`ES
`FI
`FR
`GA
`
`Armenia
`Austria
`Australia
`Barbados _
`Belgium
`Burkina Faao
`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
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`T080
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`
`

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`
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`WO 96/29074
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`PCT/US96/04198
`
`METHODS OF TREATING OR PREVENTING
`
`PAIN OR NOCICEPTION
`
`5
`
`Since the discovery of serotonin (5-hydroxytryptamine, 5-
`
`HT) over four decades ago, the cumulative results of many diverse
`
`studies have indicated that serotonin plays a significant role in the
`
`10
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`15
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`20
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`2 5
`
`functioning of the mammalian body, both in the central nervous system
`and in peripheral systems as well. Morphological studies of the central
`nervous system have shown that serotonergic neurons, which originate
`
`in the brain stem, form a very diffuse system that projects to most areas
`
`of the brain and spinal cord. R.A. O'Brien, &_mfl
`
` , 1:41 (1978); H.W.M. Steinbusch, HANDBOOK OF
`CHEMICAL NEUROANATOMY, Volume 3, Part II, 68 (1984); N.E. Anden,
`
`g_t_a_l_,, , 672313 (1966). These studies have
`been complemented by biochemical evidence that indicates large
`concentrations of 5-HT exist in the brain and spinal cord. H.W.M.
`
`Steinbusch, §_unr_g.
`With such a diffuse system, it is not surprising that 5-HT
`
`has been implicated as being involved in the expression of a number of
`behaviors, physiological responses, and diseases which originate in the
`central nervous system. These include such diverse areas as sleeping,
`eating, perceiving pain, controlling body temperature, controlling blood
`pressure, depression, schizophrenia, and other bodily states. R.W.
`Fuller, BIOLOGY OF SEROTONERGIC TRANSMISSION, 221 (1982); D.J.
`
`Boullin, SEROTONIN IN MENTAL ABNORMALITIES 12316 (1973); J.
`
`Barchas, 94.31,, ,(1973).
`
`Serotonin plays an important role in peripheral systems as
`
`well. For example, approximately 90% of the body's serotonin is
`
`3 0
`
`synthesized in the gastrointestinal system, and serotonin has been
`
`found to mediate a variety of contractile, secretory, and
`
`electrophysiologic effects in this system. Serotonin may be taken up by
`the platelets and, upon platelet aggregation, be released such that the
`cardiovascular system provides another example of a peripheral
`network that is very sensitive to serotonin. Given the broad distribution
`
`3 5
`
`of serotonin within the body, it is understandable that tremendous
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`WO 96/29074
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`PCT/US96/04198
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`
`In particular,
`interest in drugs that affect serotonergic systems exists.
`receptor-specific agonists and antagonists are of interest for the
`treatment of a wide range of disorders, including anxiety, depression,
`hypertension, migraine, compulsive disorders, schizophhrenia, autism,
`neurodegenerative disorders, such as Alzheimer's disease,
`Parkinsonism, and Huntington's chorea, and cancer chemotherapy-
`
`induced vomiting. M.D. Gershon, etaln THE PERIPHERAL ACTIONS OF
`5-HYDROXYTRYPTAMINE, 246 (1989); P.R. Saxena, gLa,L_, ,km[n_a1__o_f
`
` , 15:Supplement 7 (1990).
`Serotonin produces its effects on cellular physiology by
`binding to specialized receptors on the cell surface. It is now recognized
`that multiple types of receptors exist for many neurotransmitters and
`hormones, including serotonin. The existence of multiple, structurally
`distinct serotonin receptors has provided the possibility that subtype-
`selective pharmacologic agents can be produced. The development of
`such compounds could result in new and increasingly selective
`therapeutic agents with fewer side effects, since activation of individual
`receptor subtypes may function to affect specific actions of the different
`parts of the central and/or peripheral serotonergic systems.
`An example of such specificity can be demonstrated by
`using the vascular system as an example.
`In certain blood vessels,
`stimulation of 5-HT1-like receptors on the endothelial cells produces
`vasodilation while stimulation of 5-HT2 receptors on the smooth muscle
`
`cells produces vasoconstriction.
`Currently, the major classes of serotonin receptors (5-HT1,
`5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT5, and 5-HT7) contain some fourteen to
`eighteen separate receptors that have been formally classified based on
`their pharmacological or structural differences.
`[For an excellent
`review of the pharmacological effects and clinical implications of the
`various 5-HT receptor types, 53 Glennon, QLQL, N_e_ums_ci_e_n_c5La,nd
`
`14:35 (199o).]
`Tachykinins are a family of peptides which share a
`common amidated carboxy terminal sequence. Substance P was the
`first peptide of this family to be isolated, although its purification and the
`determination of its primary sequence did not occur until the early
`
`1970's.
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`5
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`10
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`WO 96/29074
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`Between 1983 and 1984 several groups reported the isolation
`
`of two novel mammalian tachykinins, now termed neurokinin A (also
`known as substance K, neuromedin L, and neurokinin cc), and
`neurokinin B (also known as neuromedin K and neurokinin B). S_@_, J .E.
`
`Maggio, , 6 (Supplement 3):237-243 (1985) for a review of these
`discoveries.
`'
`Tachykinins are widely distributed in both the central and
`peripheral nervous systems, are released from nerves, and exert a
`variety of biological actions, which, in most cases, depend upon
`activation of specific receptors expressed on the membrane of target
`cells. Tachykinins are also produced by a number of non-neural tissues.
`The mammalian tachykinins substance P, neurokinin A,
`and neurokinin B act through three major receptor subtypes, denoted as
`NK-1, NK-2, and NK-3, respectively. These receptors are present in a
`
`variety of organs.
`Substance P is believed _ig_tgr_a1ia to be involved in the
`
`neurotransmission of pain sensations, including the pain associated
`with migraine headaches and with arthritis. These peptides have also
`been implicated in gastrointestinal disorders and diseases of the
`gastrointestinal tract such as inflammatory bowel disease. Tachykinins
`have also been implicated as playing a role in numerous other maladies,
`
`as discussed infra.
`Tachykinins play a major role in mediating the sensation
`and transmission of pain or nociception, especially migraine
`headaches.
`s_e_e_,__e_,_g_, S.L. Shepheard, gLaL, fi
` , 108:11-20 (1993); S.M. Moussaoui, gt_aL, E_um_p_ean
` , 238:421-424 (1993); and W.S. Lee, §_t_a.L, British
`
` , 112:920-924 (1994).
`In view of the wide number of clinical maladies associated
`
`with an excess of tachykinins, the development of tachykinin receptor
`antagonists will serve to control these clinical conditions. The earliest
`tachykinin receptor antagonists were peptide derivatives. These
`antagonists proved to be of limited pharmaceutical utility because of
`
`their metabolic instability.
`Recent publications have described novel classes of non-
`peptidyl tachykinin receptor antagonists which generally have greater
`
`10
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`35
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`PCT/U S9610-4198
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`oral bioavailability and metabolic stability than the earlier classes of
`
`tachykinin receptor antagonists. Examples of such newer non-peptidyl
`
`tachykinin receptor antagonists are found in United States Patent
`
`5,328,927, issued July 12, 1994; United States Patent 5,360,820, issued
`
`5 November 1, 1994; United States Patent 5,344,830, issued September 6,
`
`1994; United States Patent 5,331,089, issued July 19, 1994; European
`
`Patent Publication 591,040 A1, published April 6, 1994; Patent
`
`Cooperation Treaty publication WO 94/01402, published January 20, 1994;
`
`Patent Cooperation Treaty publication WO 94/04494, published March 3,
`
`10
`
`1994; and Patent Cooperation Treaty publication W0 93/011609, published
`
`January 21, 1993.
`
`Because of the current dissatisfaction of the currently
`
`marketed treatments for pain or nociception within the affected
`
`population, there exists a need for a more efficacious and safe
`treatment.
`
`15
`
`This invention provides methods for the treatment or
`
`prevention of pain or nociception in a mammal which comprise
`
`administering to a mammal in need thereof an effective amount of a
`
`composition having both tachykinin receptor antagonist activity and
`
`2 0
`
`either serotonin agonist activity or activity as a selective serotonin
`
`reuptake inhibitor.
`
`In particular, the present invention provides methods for
`
`treating persons afilicted with, or with a heightened risk of contracting,
`
`one or more disorders selected from the group consisting of chronic
`
`25
`
`pain, such as neuropathic pain, and post-operative pain, pain associated
`
`with arthritis, cancer-associated pain, chronic lower back pain, cluster
`
`headaches, herpes neuralgia, phantom limb pain, central pain, dental
`
`pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical
`
`pain, bone injury pain, pain during labor and delivery, pain resulting
`
`30
`
`from burns, including sunburn, post partum pain, angina pain, and
`
`genitourinary tract-related pain including cystitis.
`
`This invention further provides methods for the treatment
`
`or prevention of pain or nociception in a mammal which comprise the
`
`sequential administration to a mammal in need thereof a composition
`
`3 5
`
`having serotonin agonist activity (or selective serotonin reuptake
`
`

`
`
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`W0 96/29074
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`PCI‘lUS96/04198
`
`-5-
`
`inhibitor activity) followed by the administration of a composition having
`
`tachykinin receptor antagonist activity.
`This invention also provides methods for the treatment or
`prevention of pain or nociception in a mammal which comprise the
`sequential administration to a mammal in need thereof a composition
`having tachykinin receptor antagonist activity followed by the
`administration of a composition having serotonin agonist activity (or
`
`selective serotonin reuptake inhibitor activity).
`
`The terms and abbreviations used in the instant
`
`5
`
`10
`
`preparations and examples have their normal meanings unless
`otherwise designated. For example "°C" refers to degrees Celsius; "N"
`refers to normal or normality; "mmol" refers to millimole or millimoles;
`"g" refers to gram or grams;
`means milliliter or milliliters; "L"
`15 means liter or liters;
`refers to molar or molarity; "MS" refers to
`mass spectrometry; "IR" refers to infrared spectroscopy; and "NMR"
`
`refers to nuclear magnetic resonance spectroscopy.
`Many serotonin binding receptors have been identified.
`These receptors are generally grouped into seven classes on the basis of
`their structure and the pharmacology of the receptor as determined by
`
`20
`
`the binding efficiency and drug-related characteristics of numerous
`serotonin receptor-binding compounds.
`In some of the groups several
`subtypes have been identified. [For a relatively recent review of 5-
`hydroxytryptamine receptors, see, E. Zifa and G. Fillion,
`2 S , 44:401-458 (1992); D. Hoyer, et_a.L,
` , 46:157-203 (1994).] Table I, infi-_a, lists the
`seven classes of serotonin receptors as well as several known subtypes.
`
`3 0
`
`This table also provides the physiological distribution of these receptors
`as well as biological responses mediated by the receptor class or subtype,
`if any such response is known. This table is derived from D. Hoyer, e_t
`QL, "VII. International Union of Pharmacology Classification of
`Receptors for 5-Hydroxytryptamine (Serotonin)", Elmngmgolqgigal
` , 46:157-203 (1994), a publication of the Serotonin Club Receptor
`Nomenclature Committee of the IUPHAR Committee for Receptor
`
`35 Nomenclature.
`
`

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`-3-
`
`The Hoyer, gLgL, reference describes for each class or
`
`subtype one or more compounds which have efficacy as antagonists or
`
`agonists for the receptor.
`The 5-HT1 family includes subtypes which can be grouped
`
`together based on the absence of introns in the cloned genes, a common
`G-coupled protein transduction system (inhibition of adenylate cyclase),
`and similar operational characteristics. The 5-HT1 family of inhibitory
`
`receptors includes subtypes A, B, D, E, and F. The 5-HT1 G protein-
`
`linked receptors general inhibit the production of cyclic adenosine
`monophosphate (cAMP), while the 5-HT2 G protein linked receptors
`
`10
`
`stimulate phosphoinosytol hydrolysis.
`The 5-HT1A receptor was the first cloned human serotonin
`
`receptor. Activated 5-HT1A receptors expressed in HeLa cells inhibit
`forskolin-stimulated adenylate cyclase activity. The 5-HT11) receptor
`
`15
`
`was originally idenfified in bovine brain membrane by Heuring and
`Peroutka. R.E. Heuring and S.J. Peroutka, ,
`7:894-903 (1987). The 5-HT113 receptors are the most common 5-HT
`
`receptor subtype in the human brain and may be identical to the 5-HT1-
`mm receptor in the cranial vasculature. S.D. Silberstein, ,
`
`20
`
`34:408-417 (1994). Sumatriptan and the ergot alkaloids have high affinity
`
`for both the human 5-HT11) and the 5-HT113 receptors. M.
`
`The 5-HT1p subtype of receptor has low aflinity for 5-
`
`carboxamidotryptamine (5-CT) unlike the other 5-HT receptors, except
`for the 5-HT1E subtype. Unlike the 5-HT1E receptors, however, the 5-
`
`25
`
`HT11: receptors do show affinity for sumatriptan.
`
`
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`Table I
`
`
`Receptor
`Type
`5-HT 1
`
`Response
`Neuronal
`
`hyperpolarisation,
`hypotension
`
`Subtype
`5-HT1A
`
`Location
`
`Neuronal, mainly in
`CNS
`
`5-HT]_B
`
`CNS and some
`
`peripheral nerves
`
`Inhibition of
`neurotransmitter release
`
`5-HT1D
`
`Mainly CNS
`
`Inhibition of
`neurotransmitter release
`
`5-HT1E
`
`Only CNS
`
`5-HT1F
`
`Mainly CNS
`
`Inhibition of adenylyl
`cyclase
`
`Inhibition of adenylyl
`cyclase
`
`5-HT1-like
`
`Intracranial
`vasculature
`
`Smooth muscle contraction
`
`5-HT2
`
`5—HT2A
`
`5-HT213
`
`5-HT2c
`
`5-HT3
`
`5-HT4
`
`Vascular smooth
`
`muscle, platelets,
`lung, CNS,
`gastrointestinal tract
`
`Vasoconstriction, platelet
`aggregation,
`bronchoconstriction
`
`Mainly peripheral,
`some CNS
`
`Rat stomach fundic muscle
`contraction
`
`CNS (high density in
`choroid plexus)
`
`upregulates
`phosphoinositide turnover
`
`Peripheral and
`central neurones
`
`Depolarization
`
`Gastrointestinal tract,
`CNS, heart, urinary
`bladder
`
`Activation of
`
`acetylchloline release in
`gut, tachycardia,
`upregulates cAMP in CNS
`neurones
`
`5-HT5
`
`5-HT5A
`
`5-HT5B
`
`5-HT5
`
`CNS
`
`CNS
`
`CNS
`
`Not known
`
`Not known
`
`Activation of adenylyl
`cyclase
`
`CNS
`Activation of adenylyl
`5-HT7
` ..:j
`cyclase
`
`
`
`
`
`

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`The biological efficacy of a compound believed to be effective
`
`as a serotonin agonist may be confirmed by first employing an initial
`screening assay which rapidly and accurately measures the binding of
`the test compound to one or more serotonin receptors. Once the binding
`of the test compound to one or more serotonin receptors is established,
`
`5
`
`the in viyg activity of the test compound on the receptor is established.
`Assays useful for evaluating serotonin agonists are well known in the
`art. S_@_,3_,g., E. Zifa and G. Fillion, supra; D. Hoyer, g=_1'._&, supra, and
`
`10
`
`the references cited therein.
`
`r
`
`n'n
`
`rB'n i
`
`i
`
`'
`
`Binding to the 5-HT1F receptor.
`
`1 5
`
`The ability of a compound to bind to a serotonin receptor
`
`was measured using standard procedures. For example, the ability of a
`compound to bind to the 5-HT1F receptor substype was performed
`
`essentially as described in N. Adham, §LLa_L,
`
` , 90:40:;-412 (1993).
`The cloned 5-HT1p receptor was expressed in stably
`
`20
`
`transfected LM(tk') cells. Membrane preparations were made by
`
`growing these transfected cell lines to confluency. The cells were
`
`washed twice with phosphate-buffered saline, scraped into 5 ml of ice-
`
`cold phosphate-buffered saline, and centrifuged at 200 x g for about five
`25 minutes at 4°C. The pellet was resuspended in 2.5 ml of cold Tris buffer
`(20 mM Tris-HCl, pH 7.4 at 23°C, 5 mM EDTA) and homogenized. The
`
`lysate was centrifuged at 200 x g for about five minutes at 4°C to pellet
`
`large fragments. The supernatant was then centrifuged at 40,000 x g for
`about 20 minutes at 4°C. The membranes were washed once in the
`
`30
`
`homogenization bufi'er and resuspended in 25 mM glycylclycine buffer,
`
`pH 7.6 at 23°C.
`Radioligand binding studies were performed using [3H]5-
`
`HT (20-30 Ci/mmol). Competition experiments were done by using
`
`various concentrations of drug and 4.5-5.5 nM [3H]5-HT. Nonspecific
`
`3 5
`
`binding was defined by 10 LLM 5-HT. Binding data were analyzed by
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`nonlinear-regression analysis.
`
`IC5o values were converted to K; values
`
`using the Cheng-Prusoff equation.
`
`For comparison purposes, the binding affinities of
`
`5
`
`compounds for various serotonin receptors may be determined
`
`essentially as described above except that different cloned receptors are
`employed in place of the 5-HT1F receptor clone employed therein.
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`10
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`15
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`5
`
`.n E
`
`.
`
`g
`
`.
`
`.
`
`Adenylate Cyclase Activity.
`
`Adenylate cyclase activity was determined in initial
`
`experiments in LM(tk-) cells, using standard techniques. S_gq-_,3_,_g‘, N.
`
`Adham, et_aL, suD_I:a.; R.L. Weinshank. e.LaL. Br.o£9.e.din2.u2f_th.e
`
`8923630-3634 (1992), and the
`
`references cited therein.
`
`Intracellular levels of cAMP were measured using the
`
`clonally derived cell line described above. Cells were preincubated for
`
`about 20 minutes at 37°C in 5% carbon dioxide, in Dulbecco's modified
`
`20
`
`Eagle's medium containing 10 mM HEPES, 5 mM theophylline, and 10
`
`[AM pargyline. Varying concentrations of the test compounds were
`
`added to ths medium to determine inhibition of forskolin-stimulated
`
`adenylate cyclase.
`
`25
`
`Some compounds that bind serotonin receptors show no
`
`receptor selectively, i.e. they bind different receptor subtypes with
`
`comparable affinity. One example of such a non-selective serotonin
`
`receptor binding compound is dihydroergotamine, a compound having
`
`the structure
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`3 O
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`NH
`
`and the chemical name, 9,1O-dihydro-12'-hydroxy-2'-methyl-55
`
`(phenylmethyl)ergotaman-3',6‘,18'-trione. This compound is
`
`5
`
`commercially available [as the mesylate salt] or may be prepared as
`
`described in Stoll and Hofmann, , 2622070 (1943).
`
`A compound having a high affinity for one (or a few)
`
`receptor subtype and low afiinity for other receptor subtypes using
`
`studies analogous to the binding assays supra, is considered to be
`
`10
`
`subtype-selective. Such compounds are especially preferred in the
`
`methods of the present invention.
`
`One example of such a compound is sumatriptan, a
`
`compound having the structure
`
`CH3
`
`CH3
`
`\
`
`312
`
`CH2
`
`H N
`
`H3C/ \ /
`
`O//s\\0
`
`15
`
`and the chemical name, 3-[2-(dimethylamino)ethy1]-N-methy1-1H-
`
`indole-5-methanesulfonamide. This compound is commercially
`
`available or may be prepared as described in United States Patent
`
`2 0
`
`5,037,845, issued August 6, 1991, which is herein incorporated by
`
`reference. Sumatriptan is selective for the 5-HT1 receptor subtypes.
`
`An additional serotonin agonist which is specific for the 5-
`
`HT1 class of receptors is a compound of the structure
`
`
`
`

`
`WO 96/29074
`
`PCT/U S96/04] 98
`
`-11-
`
`
`
`having the designation 311C90 and the chemical name (S)-4-[[3-[2-
`(dimethy1amino)ethyl]-1H-indol-5-yllmethyl]-2-oxazolidinone. This
`compound may be synthesized as described in Patent Cooperation Treaty
`Publication WO 91/18897, published December 12, 1991. Unlike
`
`sumatriptan, 311C90 is believed capable of crossing the blood-brain
`
`barrier. Sgjp, September 7, 1994.
`Especially preferred serotonin agonists employed in the
`methods of this invention are those compounds with a high aflinity for
`the 5-HT1F subtype of receptor. One such class of compounds is typified
`
`10
`
`by the compound
`
`,N /
`
`H
`
`- HCl
`
`15
`
`20
`
`having the chemical name 5-fluoro-3-[1-[2-[1-methyl-1H-pyrazol-4-
`yl]ethyl]-4-piperid1'nyl]-1H-indole hydrochloride. This compound may be
`prepared as described in co-pending United States patent application
`
`08/318,329, filed October 5, 1994.
`
`Essentially, to a solution of 2.0 g (9.2 mmol) 5-fluoro-3-(4-
`
`piperidinyl)-1H-indole in 50 ml dimethylformamide were added 2.65 g
`(0.025 mole) sodium carbonate followed by 1.87 g (9.2 mmol) 1-methyl-4-
`
`(2-methanesulfonyloxyethyl)-1H-pyrazole. The resulting mixture was
`
`heated at 100°C for 18 hours under nitrogen. The dimethylformamide
`
`25
`
`was distilled under reduced pressure and the resulting residue was
`
`
`
`
`
`

`
`
`
`W0 96/29074
`
`PCT/U S96/04 198
`
`-12-
`
`partitioned between water and dichloromethane. The dichloromethane
`phase was separated, washed sequentially with water and saturated
`aqueous sodium chloride solution and then dried over sodium sulfate to
`give 4.0 g of a brown oil. The brown oil was chromatographed over silica
`gel, eluting with 95:5 dichloromethanezmethanol. Fractions shown to
`contain product were combined and concentrated under reduced
`pressure to give 5-fluoro-3-[1-[2-[1-methyl-1H-pyrazol-4-yl]ethyl]-4-
`piperidinyl]-1H-indole as a yellow oil. The oil was dissolved in a
`minimal volume of methanol and to it were added 1.21 ml (0.006 mole)
`
`5N hydrochloric acid. To the resulting solution was added ethyl acetate
`to the point of incipient precipitation. The solid recovered was
`recrystallized from methanol/ethyl acetate to give 1.61 g (51.1%) of the
`
`title compound as an off-white solid.
`
`5
`
`10
`
`The starting materials described herein are either
`
`15
`
`commercially available or may be synthesized from commercially
`
`available materials using known methods.
`
`Also especially preferred compounds employed in the
`
`methods of the present invention are those compounds which have a
`high aflinity for the 5-HT2 subtypes of receptors. Such compounds are
`
`20
`
`well known to those skilled in the art. S_e_e__e_.g;, Hoyer, e_t_a_1__, supra, at
`
`174-179.
`
`Some additional classical serotonin agonists which are
`
`25
`
`frequently employed are:
`
`(a) Rauwolscine -- a compound of the formula
`
`
`
`

`
`
`
`wo 95/29074
`
`PCTIUS96/04198
`
`-13-
`
`having the chemical name 17oL-hydroxy-20a-yohimban-16]}-carboxylic
`
`acid methyl ester. This compound, also known as oz-yohimbine, can be
`
`prepared as described in Tfike, e.La.l., ,
`
`5
`
`3822496 (1973) or can be purchased commercially from many sources.
`
`(b) Yohimbine -- a compound also known as allo-yohimbine
`
`having the formula
`
`
`
`with the chemical name 17-hydroxyyohimban-16-carboxylic acid methyl
`
`ester. This compound, which is available from commercial sources,
`
`can also be synthesized as described in Toke, g;t_a_1_., sgmna.
`
`(c) on-Methyl-5-hydroxytryptamine —- a compound of the
`
`formula
`
`NH2
`
`c1-:3
`
`\
`
`NH
`
`I-IO
`
`having the chemical name 3-(2-aminopropyl)-1H-indo1—5-ol, which is
`
`available from commercial sources.
`
`(cl) 1—(1-Naphthyl)piperazine -- a compound of the formula
`
`10
`
`15
`
`20
`
`25
`
`

`
`
`
`WO 96/29074
`
`PCTlUS96/04198
`
`.14.
`
`if:
`CD
`
`which is described in U.S. Patent 4,520,024, issued May 28, 1985, which
`
`is herein incorporated by reference.
`
`(e) Metoclopramide -- a compound of the formula
`
`H
`O§C’N\/\N/CHQCH3
`
`OCH3
`
`CH2CH3
`
`Cl
`
`NH2
`
`10
`
`15
`
`20
`
`having the chemical name 4-amino-5-chloro-N-[(2-diethylamino)ethyl]-
`2-methoxybenzamide, which is described in United States Patent
`3,177,252, which is herein incorporated by reference.
`
`The above groups of compounds are only illustrative of the
`serotonin receptor agonists which are currently under development or
`are frequently employed in serotonin receptor studies. This listing of
`groups of compounds is not meant to be comprehensive, the methods of
`the present invention may employ any serotonin receptor agonist and is
`not limited to any particular class of compound.
`
`In addition to the methods supra employing serotonin
`
`agonists, this invention also encompasses methods for the treatment or
`prevention of pain or nociception in a mammal which comprise
`administering to a mammal in need thereof an effective amount of a
`
`

`
`WO 96/29074
`
`PCT/US96/04198
`
`-15-
`
`composition having both tachykinin receptor antagonist activity and
`selective serotonin reuptake inhibition activity.
`
`This invention further provides methods for the treatment
`or prevention of pain or nociception in a mammal which comprise the
`sequential administration to a mammal in need thereof a composition
`having selective serotonin reuptake inhibition activity followed by the
`administration of a composition having tachykinin receptor antagonist
`
`activity.
`
`This invention also provides methods for the treatment or
`prevention of pain or nociception in a mammal which comprise the
`sequential administration to a mammal in need thereof a composition
`having tachykinin receptor antagonist activity followed by the
`administration of a composition having selective serotonin reuptake
`
`inhibition activity.
`
`The selective serotonin reuptake inhibitors (SSRI’s) are a
`
`series of compounds which selectively inhibit the serotonin transporter
`on membranes of serotonin neurons. These uptake inhibitors increase
`
`the concentration of serotonin within the synaptic cleft by blocking its
`
`removal via the membrane transporter. Inhibitors of serotonin uptake
`
`increase serotonin action on postsynaptic receptors on target neuron,
`and increase serotonergic neurotransmission, resulting in functional
`
`consequences that are mostly subtle, i.e., not detectable by gross
`observation, but are detectable by various specific techniques.
`For instance, serotonin uptake inhibitors reduce aggressive
`
`behavior, decrease food uptake, decrease alcohol drinking in reats,
`decrease rapid-eye-movememt sleep, potentiate morphine analgesia,
`and the like. R.W. Fuller, , 53:35-45 (1992).
`
`Serotonin uptake inhibitors are used clinically in the treatment of
`mental depression, bulimia, and obsessive-compulsinve disorder. They
`are also reported to be effective as appetite suppressant drugs in the
`treatment of obesity, in borderline personality disorder,
`
`trichotillomania, panic disorder, and attention deficit hyperactivity
`disorder. Se_e_,_e,g,, R.W. Fuller, , 852255-270
`(1992).
`In addition, serotonin uptake inhibitors have been reported to
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`have therapeutic benefit in premenstrual syndrome, diabetic
`
`
`
`
`
`

`
`WO 96/29074
`
`PCT/US96/04198
`
`-16.
`
`neuropathy, certain non-cognitive symptoms of Alzheimer’s Disease,
`chronic pain, and in postanoxic intention myoclonus. 151.
`One such compound is fluoxetine, a compound having the
`
`structure
`
`O
`
`Zifl
`
`and the chemical name N-methyl-3-(4-trifluoromethylphenoxy}3-
`phenylpropylamine. This compound is prepared as described in United
`States Patent 4,314,081 which is herein incorporated by reference.
`
`10
`
`Another selective serotonin reuptake inhibitor which may
`
`be employed in the methods of the present invention is citalopram, a
`
`compound having the structure
`
`NC
`
`00
`
`O
`
`F
`
`CH2CH3CH2N (CH3 ) 2
`
`and the chemical name 1-[3-(dimethylamino)propy1]-1-4-fluorophenyl)-
`
`1,3-dihydro-5-isobenzofurancarbonitrile. This compound may be
`prepared as described in United States Patent 4,136,193, the entire
`contents of which are herein incorporated by reference.
`
`Another compound belonging to this class of therapeutics is
`
`femoxetine, a compound having the structure
`
`15
`
`20
`
`
`
`
`
`

`
`WO 96/29074
`
`PCTIUS96/04 198
`
`-17-
`
`‘CH3 OCH3
`
`are
`
`N F
`
`and the chemical name 2-(1,3,4-oxadiazol-2-y1)pheno1. This compound
`
`may be prepared as described in United States Patent 3,912,743, the
`entire contents of which are herein incorporated by reference.
`
`5
`
`Another SSRI which may be employed in the methods of the
`
`present invention is fluvoxamine, a compound having the structure
`
`F3C i:|Z\/\/O\CH3
`
`N“‘ O" CHQCHQNHQ
`
`1 O
`
`and the chemical name 5-methoxy- 1-[4-(trifluoromethy1)phenyl]-1-
`pentanone O-(2—aminoethyl)0xime. This compound may be prepared as
`described in United States Patent 4,085,225, the entire contents of which
`
`are herein incorporated by reference.
`Another compound belonging to this class of therapeutics is
`
`15
`
`indalpine, a compound having the structure
`
`NH
`
`HN /
`
`20
`
`and the chemical name 3-[2-(4-piperidinyl)ethyl]-1H-indole. This
`
`compound may be prepared as described in United States Patent
`
`
`
`

`
`WO 96/29074
`
`PCT/US96/04198
`
`-18-
`
`4,064,255, the entire contents of which are herein incorporated by
`reference.
`
`Another such compound is paroxetine, a compound having
`
`the structure
`
`Z211
`
`and the chemical name trans-(-)-3-[(1,3-benzodioxo1-5-yloxy)methy1]-4-(4-
`
`fluorophenyl)piperidine. This compound is prepared as described in
`
`10 United States Patents 3,912,743 and 4,007,196, the entire contents of
`
`which are herein incorporated by reference.
`
`Sertraline is another SSRI which may be employed in the
`
`methods of the present invention. This compound, having the chemical
`
`name (1S-cis)-4—(3,4—dichlorophenyl)—1,2,3,4-tetrahydro-N-methyl- 1-
`
`15
`
`naphthalenamine, has the following structure.
`
`Hs
`
`NHCH3
`
`
`
`Sertraline may be prepared as described in United States Patent
`
`20
`
`4,536,518, the entire contents of which are herein incorporated by
`reference.
`
`An additional SSRI which may be employed in the methods
`
`of the present invention is zimeldine, a compound of the structure
`
`
`
`
`
`

`
`
`
`W0 96/291174
`
`PCT/US96/04198
`
`-19-
`
`Br
`
`N
`
`having the chemical name (Z)-3-(4-bromophenyl)-N,N—dimethyl-3-(3-
`pyridinyl)-2-propen-1-amine. This compound may be prepared as
`described in United States Patent 3,928,369, the entire contents of which
`
`are herein incorporated by reference.
`The above groups of compounds are only illustrative of the
`
`selective serotonin reuptake inhibitors which are currently under
`development or are frequently employed in serotonin receptor studies.
`This listing of groups of compounds is not meant to be comprehensive,
`the methods of the present invention may employ any selective serotonin
`reuptake inhibitors and is not limited to any particular class of
`
`compound.
`
`10
`
`15
`
`The methods of the present invention, in addition to the
`
`serotonin agonists and selective serotonin reuptake inhibitors, examples
`of which are described above, also employ various tachykinin receptors.
`
`In recent publications many different groups of non-peptidyl tachykinin
`
`20
`
`receptor antagonists have been described.
`
`Patent Cooperation Treaty publication WO 94/01402,
`published January 20, 1994, describes a series of compounds best typified
`
`by the following compound.
`
`
`
`25
`
`
`
`

`
`WO 96/29074
`
`PCT/US96/04198
`
`-20-
`
`European Patent Publication 591,040 A1, pub