United States Patent (l9J
`Berger et al.
`
`[54) TRICYCUC S.HT3 RECEPTOR
`ANT AGONJSTS
`
`[75]
`
`Inventors: JaC()b Berger, Los Altos Hills; Robin
`D. Clark, Palo Alto; Richard M .
`Eglen, Mountain View; William L.
`Smith,· Sunnyvale; Klaus K.
`Weinbardt, San Francisco, all of
`Calif.
`(73] Assignee: Syntex (U.S.A.) Inc., Palo Alto, Calif.
`(21) Appl. No.: 704,565
`(22] Filed:
`May 22,1991
`
`(63)
`
`(51]
`
`(52)
`
`(58]
`
`[56)
`
`Related U.S. APJ)Iication Data
`Continuation-in-pan of Ser. No. 442,082, Nov. 28,
`1989, abandoned.
`Int. Cl.S ................... C07D 471/ 08; A61K 31/SS;
`A61K 31/ 455
`u.s. Cl ..................................... 514/ 296; 514/211;
`514/872; 540/520; 546/99; 546/100
`Field or Search .................. 546/99, 100; 540/520;
`514/211, 296
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,341,528 9/1967 Shave), Jr ............................. 546/ 98
`3,896,132 7/ 1975 Bernauer ......................... 260/289 R
`4,309,543 1/1982 Keeley .................................. 546/98
`4,571,396 1/1986 Hutt .................................... 546/156
`4,959,367 9/1990 King et al. .......................... 514/243
`
`FOREIGN PATENT DOCUMENTS
`0093488 11/ 1983 European Pat. OfT ..
`430190 6/ 1991 European Pat. OfT • .
`88-04292 6/1988 World Int. Prop. 0 ..
`
`OTHER PUBLICATIONS
`
`Reynolds, J. C. 1989, Prokinetic Agents: A Key in the
`Future of Gastroenterology, Gastroenterology Clinics
`of North America, 18:437-457.
`1989, Drugs Acting on 5-Hydroxytryptamine Recep·
`tors, The Lancet, pp. 717-719.
`Scholtysik, G. 1988, 5-Hydroxytryptamine Antagonist
`ICS 205-930 Blocks Cardiac Potassium, Sodi.um and
`Calcium Channels, J. of Pharrnacol. Exp. Ther. 245,
`3:773-778.
`King et al. 1990, Benzotriazinones as "Vinual Ring"
`Mimics of o-Methoxybenzamides: Novel and Potent
`S-HTJ Receptor Antagonists, J. Med. Chem.
`33:2942-2944.
`Peatfield, R. 1988, Drugs and the treatment of Mi-
`graine, Trends Pharmacal. Sci. 9:141- 145.
`Komatsu et al. 1978, Chern. Abs. 89:100352x.
`Hibert et al. 1988, Preparation and testing of 4-(·
`2-pyrimidinyl)-1-piperazinepyrimidinediones and -ox·
`azinones
`as minor
`tranquilizers, Chern. Abs.
`108:221716p.
`
`Primary Examiner- Mark L. Berch
`Attorney, Agent, or Firm-Wayne W. Montgomery;
`Derek P. Freyberg; Tom M. Moran
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`5,202,333
`Apr. 13, 1993
`
`US005202333A
`(II] Patent Number:
`[45] Date of Patent:
`
`ABSTRACT
`[57)
`The present invention is directed to 5-HT 3 receptor
`antagonist compounds of formula 1:
`0 II
`R3
`~l)p-(Y;/
`y (r.
`
`(Rl)f
`
`in which
`the dashed line denotes an optional double bond;
`n is I, 2 or 3;
`p is 0, 1, 2 or 3;
`·
`q is 0, 1 or 2;
`each R t is independently selected from halogen, hy·
`droxy, lower alkoxy, lower alkyl, nitro, amino, a~o
`carbonyl, (lower alkyl)amino, di(lower alkyl)arruno,
`·
`and (lower alkanoyl)amino;
`each R2 is lower alky1; and
`R3 is a group selected from Formulae (a), (b), (c) and
`(d):
`
`(0)" t N B
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`in which
`u is 0 or 1;
`z is 1, 2 or 3; and
`R' is C t., alkyl, Cl-8 cycloalkyl, C3-s cycloalkyl-Ct-2
`alkyl, or a group (CH2)1RS where t is I or 2 and RS is
`thienyl, pyrrolyl, or fury!, each optionally further
`substituted by one or two substituents selected from
`Ct~alkyl, Ct-6alkoxy, trifluoromethyl or halogen, or
`is phenyl optionally substituted by one or two substit-
`uents selected from Ct-4 alkoxy, trifluoromethyl,
`halogen, nitro, carboxy, esterified carboxy, and Ct-4
`.alkyl optionally substituted by hydroxy, C1-4 alkoxy,
`carboxy, esterified carbox or in vivo h dr I za I
`acyloxy; and the p
`Dr. Reddy's Laboratories, Ltd., et al.
`individual isomers,
`v.
`Helsinn Healthcare S .A., et al.
`preparation, comp
`thereof.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1010
`
`50
`
`

`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`USOOS202333A
`5,202,333
`[II) Patent Number:
`[45) Date of Patent: Apr. 13, 1993
`ABSTRACT
`
`(57)
`
`United States Patent £191
`Berger et al.
`[54) TRICYCLIC S-HT3 RECEPTOR
`ANTAGONISTS
`
`(75)
`
`Inventors: Jacob Berger, Los Altos Hills; RobiD
`D. Oark, Palo Al to; Richard M.
`Eglen, Mountain View; William L.
`Smltb, Sunnyvale; Klaus K.
`Welnbardt, San Francisco, all of
`Calif.
`(73) Assignee: S)'lltex (U.S.A.) IDe:., Palo Alto, Calif.
`[21) Appl. No.: 704,565
`May 22, 1991
`(22) Filed:
`
`[63)
`
`[51)
`
`(52)
`
`(58)
`
`Related U.S. Application Data
`Continualion·in·pan of Se~. No. 442,082, Nov. 28,
`1989, abandoned.
`Int. a .s ................... C07D 47V08; A61K 31/ 55;
`A61K 31/ 455
`u.s. Cl. .................................... 514/ 296; 514/211;
`514/ 872; 540/520; 546/ 99; 546/ 100
`Field of Surc:b .................. 546/99, 100; 540/ 520;
`514/ 211, 296
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,341,528 9/1967 Shave), Jr ............................. 546/98
`3,896,132 7/1975 Bernauer ......................... 260/289 R
`4,309,543 1/1982 Keeley .................................. 546/98
`4,571,396 1/1986 Hull .................................... 546/ 156
`4,959,367 9/1990 King et al. .......................... 514/243
`
`FOREIGN PATENT DOCUMENTS
`0093488 1111983 European Pat. Off .
`.
`430190 6/ 1991 European Pat. OIT ..
`88-04292 6/ 1988 World Int. Prop. 0 ..
`
`OTHER PUBLICA TlONS
`
`Reynolds, J. C. 1989, P rokinetic Agents: A Key in the
`Future of Gastroenterology, Gastroenterology Clinics
`of North America, 18:437-457.
`1989, D rugs Acting on 5-Hydroxy1ryptamine Recep·
`tors, The Lancet, pp. 717-719.
`Scholtysik, G. 1988, 5- Hydroxytryptamine Antagonist
`ICS 205-930 Blocks Cardiac Potassium, Sodium and
`Calcium Channels, J. of Pharmacol. Exp. Ther. 245,
`3:773-778.
`King et al. 1990, Benzotriazinones as "Virtual Ring"
`Mimics of o-Methoxybenzamides: Novel and Potent
`.Med. Chem.
`J.
`S-HT3 Receptor Antagonists,
`33:2942-2944.
`Peatfield, R. 1988, Drugs and the treatment of Mi·
`graine, Trends Pnarmacol. Sci. 9:141-145.
`Komatsu et al. 1978, Chern. Abs. 89:100352x.
`Hibert et al. 1988, Preparation and testing of 4-(·
`2-pyrirnidinyl)-1- piperazinepyrirnidinediones and -ox-
`azinones as minor
`tranquilizers, Chern. Abs.
`108:221716p.
`
`Primary Examiner-Mark L. Berch
`Auomey, Agent,, or Firm- Wayne W. Montgomery;
`Derek P. Freyberg; Tom M. Moran
`
`in which
`the dashed line denotes an optional double bond;
`n is I, 2 or 3;
`p is (), I, 2 or 3;
`q is (), I or 2;
`·
`each R l is independently selected from halogen, hy·
`droxy, lower alkoxy,lower alkyl, nitro, amino, ~ino
`carbonyl, Oower alkyl)amino, diOower alkyl)anuno,
`and Oower alkanoyl)amino;
`each R2 is lower alkyi; and
`R 3 is a group selected from Formulae (a), (b), (c) and
`(d):
`
`(0).
`
`-GL·
`(O). t N
`~
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`in which
`u is 0 or I;
`t is I, 2 or 3; and
`R4 is C l-7 alkyl, C3-8 cycloalkyl, C3.g cycl'oalkyl-CI·2
`alkyl, or a group (CH2)1R5 where t is I or 2 and R 5 is
`thienyl, pyrrolyl, or fury!, each optionally further
`substituted by one or two substituents selected from
`C1-6alkyl, C 1·6alkoxy, trilluoromethyl or halogen, or
`is phenyl optionally substituted by one or two substit·
`uents selected from C1-4 alkoxy, trifluoromethyl,
`halogen, nitro, carboxy, este.rified carboxy, and c,_.
`alkyl optionally substituted by hydroxy, C 1-4 alkoxy,
`carboxy, esterified carboxy or in vivo hydrolyzable
`acyloxy; and the pharmaceutically acceptable salts,
`individual isomers, rni11tures of isomers, processes for
`preparation, compositions, and methods of use
`thereof.
`
`50 Claims, No Drawings
`
`Exh. 1010
`
`

`
`1
`TRICYCLIC S-HT3 RECEPTOR ANTAGONISTS
`
`N
`
`(0). t
`~
`(0). t -())-
`
`5,202,333
`2
`Drugs and the Treatment of Migraine. Trt11ds. Phar-
`macol. &i. 1988, 9, 141).
`The S-HT3 receptor anta.gonist ICS 205-930 inhibits
`This application is a continuation-in-part of copcnd·
`arrhythmias in a variety of animal models and exerts
`maed class III and class I antiarrhythmic properties in
`ing application, Ser. No. 07/442,082, filed Nov. 28, 1989 ~
`ventricular myocytes (see Scboltysik, G .; lmoto, Y.;
`and now abandoned.
`Yata.ni, A ; Brown, A.M. J. PharmacoL Exp. Th~r. 1988,
`FIELD OF THE INVENTION
`245, 773 and references therein). 5-HTJ antagon.ists may
`1bis invention relates to novel compounds which are
`therefore be of use in treating or preventing arrhytb-
`5-HT3 receptor antagonists, pharmaceutical composi- 10 m.ias.
`tions containing them and methods for their use and
`The disclosures of these and other documents re-
`ferred to throughout this ap plication, e.g., in the Phar·
`metbods for preparing these compounds. In particular,
`it relates to tricyclic 5-HTJ receptor antagonists con-
`macology section of the Detailed Description of the
`taining a bridged bicyclic amine substituent. The inven-
`Invention, are incorporated here.in by reference.
`tion also relates to novel intermediates for making the IS
`SUMMARY OF THE INVENTION
`S-HT3 receptor antagonists.
`The f_ust aspect of this invention is the compounds of
`BACKGROUND OF THE INVENTION
`Formula I:
`Serotonin, a neurotransmitter with maed and com·
`plex pharmacological characteristics, was fllSt discov- lO
`ered in 1948 and subsequently bas been the subject of
`substantial research. Serotonin, also referred to as 5·
`hydroxytryptamine (5-HT), acts both centrally and
`peripherally on discrete 5-HT receptors. 5-HT Recep-
`tors are presently d elineated into three major subclas- 25
`silications - 5-HT" 5-HT2 and 5-HT3- each of which
`may also be heterogeneous. Receptors of the 5-HTJ
`subclass pervade autonomic neurons and appear to re&·
`ulate the release of a variety of neurotransmitters in the 30
`gastrointestinal, cardiovascular and central nervous
`systems.
`5-HTJ receptors are located in high densities on neu-
`rons associated with the emetic reflex and drugs which
`block the interactions of serotonin at the 5-HT 3 receptor lS
`level, i.e., 5-HT3 receptor antagonists, possess potent
`antiemetic properties. Such antagonists demonstrate
`utility for counteracting the emetic effects of cancer
`chemotherapy and radiotherapy (see Drugs Acting on
`5-Hydroxytrypt.a.mine Receptors: The LA11cet Sep. 23, 40
`1989 and refs. cited therein).
`Functional bowel disorders are prevalent in much of
`the industrialized world. Chronic gastroesophageal
`reflux disease alone may be present in as much as 15%
`of the population. Use of pro kinetic agents is one of the 4S
`most effective methods known for treating such disor-
`ders. Because many 5-HT J antagonists possess proki·
`netic properties and are relatively free from side effects
`they are particularly useful in the treatment of gastroin-
`testinal diseases (see Reynolds R. C. Prokinetic Agents: so
`A Key in the Futu.re of Gastroenterology. Gastroellter-
`ology Clinics of North Am~rica 1989, 18, 437 ... 57).
`S.HT3receptors are present in those areas of the brain
`which control mood, emotion, reward and memory.
`S-HT3 receptor antagonists reduce mesolimbic dopa- 55
`mine levels, a necessary property for antipsychotic
`activity. Such antagonists also increase cholinergic tone
`in the limbic-cortical region, which may explain their
`cognitive enhancing effects. In addition, 5-HTJ antago-
`nists possess anxiolytic properties, demonstrate poten· 60
`tial for use in the treatment of dependency disorders and
`are under investigation in patients with schizophrenia
`(see article from Tile Lancet previously cited).
`There is evidence that 5·HT 3 receptors mediate noci-
`ceptive input to afferent neurons (see Glaum, S.; Proud- 6S
`fit, H. K.; Anderson, E . G. Neurosci. utt. 1988, 95, 313).
`5·HTJ antagonists may therefore be of value in the
`control of pain, particularly migraine (~ Peatfield R.;
`
`in which
`the dashed line denotes a.n optional double boud;
`n is t. 2 or 3;
`p is o. 1, 2 or 3;
`qisO.tor2;
`each R ' is independently selected from halogen, hy-
`droxy. Lower alkoxy, lower alkyl, nitro, amino, amino
`carbonyl, (lower alkyl)amino, di(lower alkyl)amioo.
`and (lower alkanoyl)amino;
`each R2 is lower alkyl; and
`Rl is a group selected from F ormulae (a), (b). (c) and
`(d):
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`Exh. 1010
`
`

`
`3
`
`(RI)p
`
`•
`
`(Rl)q
`
`w NH/R3
`
`5,202,333
`4
`"Lower" modifies alkyl, alkoxy and alkonyl and re-
`in which
`fers to those alkyl radicals or Jt groups in allkoxy and
`u is 0 or 1;
`alkonyl radicals containing 1 to 6 carbon atoms.
`z is 1, 2 or 3; and
`R4 is Ct.? alkyl, C3.s cycloalkyl, C 3•8 cycloalkyl-C1_2
`"Halogen" means fluorine, chlorine, bromine, or
`alkyl, or a group (CH2)rRS where t is I or 2 and JtS is S iodine.
`thienyl, pyrrolyl, or fury], each optionally substituted
`"Esterified carboxy" means the ester group -COOR
`by one or two substituents selected from C1-6 alkyl, C1-6
`wherein R is Ct-8 alkyl.
`alkoxy, trifluoromethyl or halogen, or is phenyl option-
`"In vivo hydrolyzable acyloxy" means a group
`ally substituted by one or two substituents selected from
`-OC(O)R, wherein R is CJ.aalkyl, capable ofundergo-
`Ct-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, 10 ing enzymatic hydrolysis within a living organism.
`"~ving .gr~up" has ~e meanfng co~venti?nally
`esterified carbox.y, and C1-4 alkyl optionally further
`substituted by hydroxy, c1_. alkoxy, carboxy, esterified
`assoctated Wlth 1~ m synthenc orgaruc ch~try, ':~·· an
`carboxy or in vivo hydrolyzable acy1oxy; and the phar-
`ato~ or group diSplaceable under alkylating condittons,
`maceutically acceptable salts, individual isomers and
`and mcludes halogen and alkane- or arenesulfonyloxy
`mixtures of isomers thereof.
`15 such as mesyloxy, ethanesulfonyloxy, benzenesui-
`A second aspect of this invention is a pharmaceutical
`fonyloxy, tosyloxy and the like.
`composition containing a compound of Formula I in
`"Animal" includes _humans, non-human mammals
`admixture with one or more suitable excipients.
`(e.~., dogs, cats, rabb1ts, cattle, horses, s~eep, goats,
`A third aspect of this invention is a method of treating
`s~e, and deer) and non-mammals (e.g., buds and the
`diseases involving emesis, gastrointestinal disorders, 20 lik~).
`.
`,
`.
`.
`.
`CNS disorders, cardiovascular disorders or pain by
`CytotoXIc agents . mc~ude ~la~um . an~-cancer
`administering a therapeutically effective amount of a
`age~ts such as CISplatm
`. (CJs-<b~edJchloro-
`platmum), as well as non~platmum ~t1-can~r -~gs
`compound of Formula I to a subject afllicted with such
`a condition
`such as cyclophosphanude (cytoXJn), vmcnstrme
`A fourth .aspect of this invention is the compounds of 25 (leurocristine)! procarbazine (N:(l-methyletbyl)-4-[(2-
`Form 1a II·
`methy!lhydrazmo)methyl)benzamJde), methotrexate,
`u
`·
`fluorouracil, mechlorethamine hydrochloride
`(2-
`chloro-N-(2-chloroethyl)-N-methylethanamine hydro-
`chloride), doxorubicin, adriamycin, dactinomycin (ac-
`30 tinomycin·D) cytarabine, ,carmustine, dacarbazine, and
`others listed at page 1143 ofthe Journal ofCIU.icol On-
`cology 1989; 7(8): 1143.
`"Disease" specifically includes any unhealthy condi-
`tion of an animal or part thereof and includes an Wl-
`35 healthy condition which may be caused by, or incident
`to, medical or veterinary therapy applied to that animal,
`i.e., the "side effects" of such therapy. Thus, "disease"
`in which n, p, q, Rl, Rland Rl are as dermed for For-
`here includes the emesis caused by therapy with agents
`mula I. which are useful intermediates in preparing
`having emetogenic side effects, in particular by therapy
`for cancer, such as chemotherapy with cytotoxic agents
`compounds of Formula I.
`and radiotherapy.
`A fifth aspect of this invention are the processes for
`"Emesis", for the purposes of this application, will
`preparing compounds of Formula I and is set forth in
`have a meaning that is broader than the normal, dictio-
`the "Detailed Description Of The Invention."
`nary defmition and includes not only vomiting, but also
`45 nausea and retching.
`DETAILED DESCRIPTION OF THE
`"Optional" or "optionally" means that the subse-
`INVENTION
`quently described event or circumstance may or may
`Definitions
`not occur, and that the description includes instances
`.
`.
`.
`Unles~ oth~rWlse state~, the followmg te~ ~ m
`where the event or circumstance occurs and instances
`the specdicat1on and cla.uns have the meanmgs g~ven ~ in which it does not. For egmpJe, "optional bond"
`be~?w: ,
`.
`.
`means that the bond may or may not be present and that
`Alkyl means a str:1ught, ~ranched, or cychc satu-
`the description includes both single bonds and double
`rated hydrocarbon radJ<:aJ havmg from one to the num-
`bonds; "optionally converting 8 compound of Formula
`~r of carbo? atoms des1gnated. For example C1.7 alkyl
`I to a corresponding pharmaceutically acceptable salt"
`JS alkyl havmg at least one but n~ more than seven ss means that the conversion may or may not be carried
`out in order for the process described to fall within the
`carbon atoms, e.g., methyl, ethyl, 1-propyl, n-propyl,
`n-butyl, ~yclopropylmethyl, pentyl, cyclohexyl, heptyl
`invention, and the invention includes those processes
`and the like.
`wherein the compound of Formula I is converted to the
`salt and those processes in which it is not.
`"Alkoxy" means the radical -OR wherein R is alkyl
`having from one to the number of carbon atoms desig· 60
`"Pharmaceutically acceptable" means that which is
`useful in preparing a pharmaceutical composition that is
`~ted, e.g., Ct.7 aiJc.oxy includes, e.g., methoxy, ethoxy,
`l·pro_poxy, n-propoxy, n-butoxy, pentoxy, hexoxy and
`generally safe, non-toxic and neither biologically nor
`the like.
`otherwise undesirable and includes that which is ac-
`"Alkonyl" means the radical -C(O)R wherein R is
`ceptable for veterinary use as well as human pbarma-
`alkyl having from one to the number of carbon atoms 6S ceutical use.
`designated, e.g., c l·7alkonyl includes ethanoy], propan-
`"Pharmaceutically acceptable salts" means salts
`oyl, i-butanoyl, n-butanoyl, pentanoyl, hexanoyl and the
`which are pharmaceutically acceptable, as defined
`like.
`above, and which possess the desired pharmacological
`
`11
`
`40
`
`Exh. 1010
`
`

`
`5,202,333
`5
`6
`activity. Such salts include acid addition salts formed
`described as the (RS)· or (±)-mixture thereof. Unless
`with inorganic acids such as hydrochloric acid, hydro-
`indicated otherwise, the description or naming of a
`bromic acid, sulfuric acid, nitric acid, phosphoric acid,
`particular compound in the :specification and claims is
`and the like; or with organic acids such as acetic acid,
`intended to include: both individual enantiomers and
`propionic acid, he·xanoic acid, hc:ptanoic acid, cy· -s mixtures, racemic or otherwise, thereof. Conventions
`for stereochemical nomenclature, methods for the de·
`clopentanepropionic acid, glycolic acid, pyruvic acid,
`lactic acid, malonic acid, succinic acid, ma1ic acid, ma·
`termination of stereochemistry and the scparatioD of
`Jeic acid, fumaric acid, tanaric acid, citric acid, benzoic
`stereoisomers are well-known in the art (see discussion
`acid, o-(4-hydroxybenzoyl)benzoic acid, cinnam.ic acid,
`iD Chapter -4 of "Advanced Organic Chemistry", 3rd
`mandelic acid, methanesulfonic acid, ethanesulfonic 10 edition March, Jerry, John Wiley and Sons, New York,
`1985).
`acid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesul-
`fonic acid, benzenesulfonic acid p-<:hlorobenzenesul-
`Certain compounds of Formulae 1 and 11 can exist as
`fo~c a~id, 2-naphthalen~ulf~nic acid, p-!oluenesul-
`stereoisomc:rs. For example, certain compounds possess
`lforuc ac1d, camphorsulforuc ac1d, 4-mc:thylblcyclo[2.2.-
`a chiral center at the ring carbon of the R3 substituent
`l)oct-2-ene-_l-carboxylic acid, glucohepto~c ac~d, 4,4'· 15 which is bonded to the amide nitrogen and, when ·the
`d the "o
`methylenebls(3-hydroxy-2-ene-1-carboxylic ac1d), 3-
`t, t th 3
`·t·
`1. naJ bo d · b
`b
`·
`·
`·
`·
`.
`.
`.
`op 10
`n 1s a sen a
`e a-pos1 10n an
`re,, re
`h 1
`p enylpr<;>pto~c ac1d, tnmet .Y a~tlc actd, _tertli:'"Y
`can exist as (R)· or (S)-isomers. In addition certain
`butylacettc ac1d, Iaury! sulfunc ac1d, glucoruc ac1d,
`'.
`.
`compounds can fXJst ~ the ~endo)- ~r (exo)-lSOlmers,
`sJutamic acid, hydroxynaphthoic acid, salicylic acid,
`stearic acid, muconic acid, and the like.
`20 e.g., when the R substituent JS 1-azabtcyclo[J.3,. )Don-
`In addition, pharmaceutically acceptable salts may be
`4-yl.
`formed when an acidic proton present is capable of
`~en a compo~d of Fo~ula I or ~I possesses one
`reacting with inorganic or organic bases. Acceptable
`c~ral center, a pa~r of e~anllomeno eXIsts. When two
`inorganic bases include sodium hydroxide, sodium car·
`chiral centers are ~resent m ~ co~pound of Formula. I,
`bonate, potassium hydroxide, aluminum hydroxide and 2S four sep~ate ster01somers eJUst (1.e., two separate piW'S
`of enantlomers). When a compound of Formula I pos-
`calcium hydroxide. Acceptable organic bases include
`ethanolaminc: diethanolaminc: triethanolamine trome-
`sesses two chiral centers and can exist as endo or exo,
`thamiDc:, N-~ethylglucaminc: ~d the like.
`'
`eight separate stereoisomers are possible (i.e., two sepa-
`that
`"Therapc:utically effective amount" means
`rate pairs of c:nantiomc:rs in the c:ndo or exo form).
`amount which, when administered to an animal for 30
`It is to be understood that when referring to Formula
`treating a disease, is sufficient to effect such treatment
`I, ll, (a), (b), (c) or (d) iD this application, a straight line
`:for the disease.
`depicting the covalent bond between the R3substituent
`"Treating" or "treatment" of a disease includes:
`and the amide nitrogen represents the possible geomet-
`(1) preventing the disease from occurring in an animal
`ric isomers and enantiomers or the mixtures, racemic or
`which may be: predisposed to the: disease but does not 35 otherwise, thereof. Similarly, when referring to For-
`yet experience or display symptoms of the disease,
`mula I iD which the optionally bond is absent, a straight
`{2) inhibiting the disease, i.e., arresting its development,
`line depicting the covalent bond between carbons 3a
`or
`and 4 represents either the R or S configurations or a
`{3) relieving the: disease, i.e., causing regression of the mixture racemic, or otherwise, thereof. For purposes of
`disease.
`40· the present application when referring to a compound
`Compounds that have identical molecular formulae
`by name or by formula and the configuration is not
`designated, it is to be understood that the reference is to
`'but differ in the nature or sequence of bonding of their
`atoms or in the arrangement of their atoms in space are
`all possible forms.
`tc:nned "isomers". Isomers that differ iD the nature or
`Certain R3 substituents descnl>ed in this application
`sequence of bonding of their atoms arc: termed "consti- 4S are of particular interest and are therefore defined spe·
`tutional isomers". Isomers that differ only in the ar-
`cifically as the following:
`(1) Formula (b) where z is 2 and u is 0 having the
`rangc:ment of their atoms in space are termed "stereo-
`isomers". Stereoiso·mc:rs that are not mirror images of
`specific formula
`one· another are termed "diasteromers" and stereoiso-
`mers that are mirror images arc: termed "enantiomers" so
`or sometimes "optical isomers". Stereoisomers that are
`superimposable upon their mirror images are termed
`"achiral" and those not superimposable are termed
`"chrial". A carbon atom bonded to four different
`groups is termed a "chiral center" or alternatively an SS
`"asymmetric carbon".
`·
`When a compound has a chira1 center, a pair of enan-
`tiomers of opposite chirality is possible. An enantiomer
`can be characterized by the absolute configuration of its
`chiral center and described by the R- and S-sequencing 60
`rules of Cahn and Prelog (i.e., as (R)- and (S)-isomers)
`or by the manner in which the molecule: rotates the
`plane of polarized light and designated as dextrorota-
`tory or levorotatory (i.e., as ( + )- and (-)-isomers,
`respectively). A chiral compound can exist as either 6S
`iDdividua1 enantiomer or as a mixture thereof. A mix·
`ture containing equal proportions of the enantiomers is
`termed a "racemic mixture" or "racemate" and may be
`
`is referred to as l-azabicyclo[2.2.2]oct-4yl;
`(3) Formula (a) where z is 3, u is 0 and R• is methyl
`having tlhe specific formula
`
`is referred to as 1-azabicyclo[2.2.2)oct-3-yl;
`(2) Formula (b) where z is 2 and u is 0 having the
`specific formula
`
`Exh. 1010
`
`

`
`7
`
`5,202,333
`
`8
`
`H
`
`is referred to as (endo)-9-methyl-9-azabicyclo[3.3.1]-
`non·3·yl;
`(4) Formula (a) ·where z is 3, u is 0 and R• is methyl
`having the specific formula
`
`CH3
`
`/
`N
`
`s
`
`10
`
`IS
`
`20
`
`is referred to as (endo)-1-azabicyclo(3.3.1)non4yl.
`(8) Formula (c) wherein z is 2 and u is 0 having the
`specific formula
`
`25 is referred to as (exo)-1-azabicyclo[3.3.1)non+yl.
`Compounds of Formulae I and II are named in accor-
`dance with generally acceptable nomenclature rules
`established by "Chemical Abstracts." For example, the
`compound of Formula I in which the optional bond is
`30 present, p, q and u are 0 and R3 is l-117.11!bicyclo-
`(2.2.2]oct-4-yl:
`
`3S
`
`0 .r:N
`
`Ill ~~
`
`3
`
`(CHz).,
`
`is referred to as (exo)-9-methyl-9-azabicyclo(J.J.l)non-
`3-yl;
`(S) Formula (a) where z is 2, u is 0 and R4 is methyl
`having the specific formula
`
`CH!
`
`/
`N
`
`.-F1?
`
`is named
`2-(1-azabicyclo[2.2.2Joct-4-yl)-1,2,4,5·tetrahydrocy·
`45 clopent(de]isoquinolin-1-one when n is I;
`2-(l-azabicyclo[2.2.2Joct+yl)·2,4,5,6-tetrahydro-IH-
`benz[de]isoquinolin-1-one when n is 2: and
`is refered to as (endo)-8-methyl-8-azabicyclo[3.2.l]oct-
`2-(azabiyclo[2.2.2Joct-4-y1)·1,2,4,S,6,7-hexahydrocy·
`3-yl;
`clohept[de]isoquinolin-1-one when n is 3.
`(6) Formula (a) where z is 2 u is 0 and R• is methyl 50 The compound of Formula II in which the optional
`bond is present, p, q and u are 0 and R3 is 1-aza.bicyclo-
`having the specific formula
`[2.2.2]oct-4-yl:
`
`55
`
`60
`
`r=: N
`~w
`
`0
`II~
`
`is referred to as (exo)-8-methyl-8-azabicyclo[3.2.1)oct-
`3-yl;
`
`(7) Formula (c) wherein z is 2 and u is 0 having the
`specific formula
`
`is named
`65 N-(1-azabioyclo[2.2.2]oct-4-yl)-4-indancarboxamide
`when nisI;
`N-(l~azabicyclo[2.2.2)oct-4-yl)-5,6,7,8-tetrahydro-l-
`naphthalenecarboxamide when n is 2; and
`
`Exh. 1010
`
`

`
`5,202,333
`10
`9
`N-(1-azabicyclo(2.2.2]oct-4-yl)·5,6,7 ,8·tetrahydro-
`parathyroidism and Addison's disease. Emesis may also
`be caused by ingested toxins, e.g., enterotoxins in sta-
`9H-benzocyclohepten-1-carboxamide when n is 3.
`phylococcus-contaminated foods, or by drugs adminis-
`PRESENTLY PREFERRED EMBODIMENTS
`tered fo.r therapeutic purposes, e.g., digitalis, emetine
`While the broadest defmition of this invention is set
`5 and chemotherapeutic agents.
`Compounds of Formula I are of particular value in
`forth in the Summary of the Invention, certain com·
`pounds of Formulae I and II are preferred. For exam-
`treating (especially preventing) the emesis induced by
`ple, preferred compounds of Formula I are those in
`radiation poisoning, treatment for cancer with radio-
`which both q and u are 0, pis I, or 2, each R I is indepen-
`therapy or chemotherapy with cytotoxic agents or drug
`-dently selected from halogen, lower alkoxy or amino,
`10 therapy in general wherein a significant side effect is
`and R4 is lower alkyl.
`emesis, e.g., amphotericin B in treating immunosup-
`0£ particular interest are those compounds of For·
`pressed ·patients, zidovudine (AZ1) in the treatment of
`mula I in which each p, q and u are 0, R 4 is methyl, ~d
`AIDS and interleukin in treating cancer.
`R3 is one of the following groups:
`Compounds of Formula I are useful as prokinetic
`IS agents in the treatment of gastrointestinal diseases, i.e.,
`1-azabicyclo[2.2.2]oct-3-yl;
`l-azabicyclo-[2.2.2)oct-4-yl;
`diseases of the stomach, esophagus and of both the large
`endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl;
`and small intestines. Examples of specific diseases in-
`exo-9-methyl-9-aza bicyclo[3.3.1 ]non-3-yl;
`clude, but are not limited to, dyspepsia (e.g., non-ulcer
`dyspepsja), gastric stasis, peptic ulcer, renux esophagi-
`endo·8-methyl·8-azabicyclo[3.2.1]oct-3-yl;
`20 tis, flatulence, bile renux gastritis, pseudo-obstruction
`~o-8-methyl-8-azabicyclo(3.2.1 ]oct-3-yl;
`syndrome, irritable colon syndrome (which may result
`endo-1-azabicyclo[ 3.3.1 ]non-4-yl; or
`in chronic constipation and diarrhea), diverticular dis-
`exo-J.azabicyclo[3.3.J)non~yl.
`ease, bil:iary dysmotility (which may result in sphincter
`Of most interest are the compounds of Formula I in
`which each p, q and u are 0, and R3 is l-azabicyclo(2.2.-
`of Oddi dysfunction and "sludge" or microscopic crys·
`tals in the gall bladder), gastroparesis (e.g., diabetic,
`l]oct-3-yl, in particular wherein one or, when present, 25
`postsurgical or idiopathic), irritable bowel syndrome
`both chiral centers, possess S configurations.
`Preferred compounds of Formula II are those in
`amd retarded gastric emptying. The compounds of
`which both p and q are 0, p is 0, I, or 2, each Rl is
`Formula I are also useful as short-term prokinetics to
`independently selected from halogen, lower alkoxy or
`facilitate diagnostic radiology and intestinal intubation.
`amino, and R4 is lower alkyl.
`In addition, the compounds. are Useful for treating diar-
`rhea, particularly diarrhea induced by cholera and car-
`Of particular interest are those COmpOunds of For-
`cinoid syndrome.
`mula II in which each p, q, and u are 0, R4is methyl, and
`R3 is one of the foJJowing groups:
`Compounds of Formula I are useful in treating dis-
`1-azabicyclo(2.2.2)oct·3-yl;
`eases of the central nervous system. Categories of such
`35 diseases include cognitive disorders, psychoses, obses-
`1-azabicyclo-[2.2.2]oct-4-yl;
`endo-9-methyl-9-az.abicyclo[3.3.1]non·3-yl;
`sive/compulsive and anxiety/depression behavior.
`exo·9·methyl-9-azabicyclo[3.3.1 )non-3-yl;
`Cognitive disorders include attentional or memory defl·
`cit, dementia states (including senile dementia of the
`en do-8-methyl-8 -az.abicyclo(3.2.1]oct-3-yl;
`Alzheimer's type and aging), cerebral vascular defi-
`exo-8-methyl-8-azabicyclo(3.2.1]oct-3-yl;
`40 ciency and Parkinson's disease. Psychoses that are treat-
`endo-l-az.abicyclo[3.3.1)non-4-yl; or
`able using the compounds of Formula I include para-
`exo·l-azabicyclo[3.3.1)non-4-yl.
`noia, schlzophrenia and autism. Obsessive/compulsive
`Of most interest are compounds of Formula II in
`behavior that is treatable using compounds of Formula
`which each p, q, and u are 0, and Rlis l -azabicyclo(2.2.-
`l]oct-3-yl, in particular the S-isomers thereof.
`I includes eating disorders, e.g., bulimia, a condition in
`It is unde.rstood that these compounds of Formula II 4S
`which an abnormal and constant craving for food is
`of special interest are particularly useful in the synthesis
`present.
`of preferred compounds of Formula I.
`Representative, treatable anxiety/depressive states
`include anticipatory anxiety (e.g., prior to surgery, den·
`UTILITY
`tal work, etc.), depression, mania, seasonal affective
`Compounds of Formula I exhibit utility in treating a .50 disorder (SAD), and the convulsions and anxiety
`broad range of diseases in animals, particularly humans.
`caused by withdrawal from addictive substances such as
`Examples of diseases that may be treated using the com·
`opiates, benzodiazapines, nicotine, alcohol, cocaine and
`pounds of Formuh I include emesis, gastrointestinal
`other drugs of abuse.
`Compounds of Formula I are useful in the treatment
`disorders, central nervous system (CNS) disorders, car-
`diovascular disorders or pain.
`55 of cardiovascular diseases. Such diseases include ·ar·
`Compounds of Formula I are useful in the prevention
`rhythmias and hypertension.
`It is thought that S-HTJ antagonists prevent certain
`and treatment of emesis. causes of such emesis include
`surgical anesthesia, psychological stress, pregnancy,
`adverse nervous transmissions and/or prevent vasodila-
`certain disease states, radiotherapy, radiation poisoning
`tion and are therefore of value for reducing perceived
`and toxic substances. Disease states which are known to 60 levels of pain. Compounds of Formula I are, therefore,
`useful in treating pain such as that associated with clus-
`induce emesis inc~ude conditions such as gut obstruc-
`tion, raised intracranial pressure, acute myocardial in-
`ter headaches, migraines, trigeminal neuralgia and vis-
`farction, migraine headaches and adrenal crisis. Toxic
`cera! pain (e.g., that caused by abnormal distension of
`substances which induce emesis include toxins in the
`hollow visceral organs).
`form of abnormal metabolites or abnormal accumula- 65
`ln summary, an aspect of this invention is a method
`tion of natural occurring substances associated with
`for treating an animal, pa