United States Patent [191
`Berger et al.
`
`[54] TRICYCLIC 5-HT3 RECEPTOR
`ANTAGONISTS
`
`[75]
`
`Inventors: Jacob Berger, Los Altos Hills; Robin
`D. Clark, Palo Alto; Richard M.
`Eglen, Mountain View; William L.
`Smith,· Sunnyvale; Klaus K.
`Weinhardt, San Francisco, all of
`Calif.
`[73] Assignee: Syntex (U.S.A.) Inc., Palo Alto, Calif.
`[21] Appl. No.: 704,565
`Filed:
`May 22,1991
`[22]
`
`[63]
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 442,082, Nov. 28,
`1989, abandoned.
`Int. Cl.s ................... C07D 471/08; A61K 31/55;
`A61K 31/455
`u.s. Cl ..................................... 514/296; 514/211;
`514/872; 540/520; 546/99; 546/100
`Field of 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. Off ..
`430190 6/1991 European Pat. Off ..
`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, Sodium and
`Calcium Channels, J. of Pharmacal. Exp. Ther. 245,
`3:773-778.
`King et al. 1990, Benzotriazinones as "Virtual Ring"
`Mimics of o-Methoxybenzamides: Novel and Potent
`J. Med. Chern.
`5-HT3 Receptor Antagonists,
`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
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005202333A
`5,202,333
`[11] Patent Number:
`[45] Date of Patent: Apr. 13, 1993
`
`ABSTRACT
`[57]
`The present invention is directed to 5-HT3 receptor
`antagonist compounds of formula I:
`0
`II
`
`in which
`the dashed line denotes an optional double bond;
`n is I, 2 or 3;
`pis 0, 1, 2 or 3;
`q is 0, 1 or 2;
`.
`each R I is independently selected from halogen, hy-
`droxy, lower alkoxy, lower alkyl, nitro, amino, a~ino
`carbonyl, (lower alkyl)amino, di(lower alkyl)ammo,
`and (lower alkanoyl)amino;
`each R2 is lower alkyi; and
`R3 is a group selected from Formulae (a), (b), (c) and
`(d):
`
`(O)u
`
`-GL·
`(O)u t N B
`(O)u t
`-0)""·
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`in which
`u is 0 or 1;
`z is 1, 2 or 3; and
`R4 is C!-7 alkyl, CJ-8 cycloalkyl, CJ-8 cycloalkyl-C!-2
`alkyl, or a group (CH2)1R5 where t is I or 2 and R5 is
`thienyl, pyrrolyl, or furyl, each optionally further
`substituted by one or two substituents selected from
`C1-6alkyl, C1-6alkoxy, trifluoromethyl or halogen, or
`is phenyl optionally substituted by one or two substit-
`uents selected from C1-4 alkoxy, trifluoromethyl,
`halogen, nitro, carboxy, esterified carboxy, and C1-4
`alkyl optionally substituted by hydroxy, C1-4 alkoxy,
`carboxy, esterified carboxy or in vivo hydrolyzable
`acyloxy; and the pharmaceutically acceptable salts,
`Dr. Reddy’s Laboratories, Ltd., et al.
`individual isomers, mixtures of isomers, processes for
`v.
`preparation, compositions, and methods of use
`thereof.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1006
`
`SO Claims, No Drawings
`
`

`
`United States Patent [191
`Berger et al.
`
`[54] TRICYCLIC 5-HT3 RECEPTOR
`ANTAGONISTS
`
`[75]
`
`Inventors: Jacob Berger, Los Altos Hills; Robin
`D. Clark, Palo Alto; Richard M.
`Eglen, Mountain View; William L.
`Smith,· Sunnyvale; Klaus K.
`Weinhardt, San Francisco, all of
`Calif.
`[73] Assignee: Syntex (U.S.A.) Inc., Palo Alto, Calif.
`[21] Appl. No.: 704,565
`Filed:
`May 22,1991
`[22]
`
`[63]
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 442,082, Nov. 28,
`1989, abandoned.
`Int. Cl.s ................... C07D 471/08; A61K 31/55;
`A61K 31/455
`u.s. Cl ..................................... 514/296; 514/211;
`514/872; 540/520; 546/99; 546/100
`Field of 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. Off ..
`430190 6/1991 European Pat. Off ..
`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, Sodium and
`Calcium Channels, J. of Pharmacal. Exp. Ther. 245,
`3:773-778.
`King et al. 1990, Benzotriazinones as "Virtual Ring"
`Mimics of o-Methoxybenzamides: Novel and Potent
`J. Med. Chern.
`5-HT3 Receptor Antagonists,
`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
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005202333A
`5,202,333
`[11] Patent Number:
`[45] Date of Patent: Apr. 13, 1993
`
`ABSTRACT
`[57]
`The present invention is directed to 5-HT3 receptor
`antagonist compounds of formula I:
`0
`II
`
`in which
`the dashed line denotes an optional double bond;
`n is I, 2 or 3;
`pis 0, 1, 2 or 3;
`q is 0, 1 or 2;
`.
`each R I is independently selected from halogen, hy-
`droxy, lower alkoxy, lower alkyl, nitro, amino, a~ino
`carbonyl, (lower alkyl)amino, di(lower alkyl)ammo,
`and (lower alkanoyl)amino;
`each R2 is lower alkyi; and
`R3 is a group selected from Formulae (a), (b), (c) and
`(d):
`
`(O)u
`
`-GL·
`(O)u t N B
`(O)u t
`-0)""·
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`in which
`u is 0 or 1;
`z is 1, 2 or 3; and
`R4 is C!-7 alkyl, CJ-8 cycloalkyl, CJ-8 cycloalkyl-C!-2
`alkyl, or a group (CH2)1R5 where t is I or 2 and R5 is
`thienyl, pyrrolyl, or furyl, each optionally further
`substituted by one or two substituents selected from
`C1-6alkyl, C1-6alkoxy, trifluoromethyl or halogen, or
`is phenyl optionally substituted by one or two substit-
`uents selected from C1-4 alkoxy, trifluoromethyl,
`halogen, nitro, carboxy, esterified carboxy, and C1-4
`alkyl optionally substituted by hydroxy, C1-4 alkoxy,
`carboxy, esterified carboxy or in vivo hydrolyzable
`acyloxy; and the pharmaceutically acceptable salts,
`individual isomers, mixtures of isomers, processes for
`preparation, compositions, and methods of use
`thereof.
`
`SO Claims, No Drawings
`
`Exh. 1006
`
`

`
`5,202,333
`2
`Drugs and the Treatment of Migraine. Trends. Phar-
`macal. Sci 1988, 9, 141).
`The 5-HT3 receptor antagonist ICS 205-930 inhibits
`arrhythmias in a variety of animal models and exerts
`mixed class III and class I antiarrhythmic properties in
`ventricular myocytes (see Scholtysik, G.; Imoto, Y.;
`Yatani, A; Brown, A.M. J. Pharmacal Exp. Ther. 1988,
`245, 773 and references therein). 5-HT3 antagonists may
`therefore be of use in treating or preventing arrhyth-
`mias.
`The disclosures of these and other documents re-
`ferred to throughout this application, e.g., in the Phar-
`macology section of the Detailed Description of the
`Invention, are incorporated herein by reference.
`SUMMARY OF THE INVENTION
`The f_rrst aspect of this invention is the compounds of
`Formula 1:
`
`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 I is independently selected from halogen, hy-
`droxy, lower alkoxy, lower alkyl, nitro, amino, amino
`carbonyl, (lower alkyl)amino, di(lower alkyl)amino,
`and (lower alkanoyl)amino;
`each R2 is lower alkyl; and
`R3 is a group selected from Formulae (a), (b), (c) and
`(d):
`
`(O)u
`
`-GL·
`(0)" t
`N B
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`1
`TRICYCLIC S-HT3 RECEPTOR ANTAGONISTS
`
`This application is a continuation-in-part of copend-
`ing application, Ser. No. 07/442,082, filed Nov. 28, 1989 5
`and now abandoned.
`FIELD OF THE INVENTION
`This invention relates to novel compounds which are
`5-HT3 receptor antagonists, pharmaceutical composi- 10
`tions containing them and methods for their use and
`methods for preparing these compounds. In particular,
`it relates to tricyclic 5-HT3 receptor antagonists con-
`taining a bridged bicyclic amine substituent. The inven-
`tion also relates to novel intermediates for making the 15
`5-HT3 receptor antagonists.
`BACKGROUND OF THE INVENTION
`Serotonin, a neurotransmitter with mixed and com-
`plex pharmacological characteristics, was first discov- 20
`ered in 1948 and subsequently has been the subject of
`substantial research. Serotonin, also referred to as 5-
`hydroxytryptam.ine (5-HT), acts both centrally and
`peripherally on discrete 5-HT receptors. 5-HT Recep-
`tors are presently delineated into three major subclas- 25
`siflcations - 5-HTt, 5-HT2 and 5-HT3- each of which
`may also be heterogeneous. Receptors of the 5-HT3
`subclass pervade autonomic neurons and appear to reg-
`ulate the release of a variety of neurotransmitters in the 30
`gastrointestinal, cardiovascular and central nervous
`systems.
`5-HT3 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 35
`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-Hydroxytryptamine Receptors: The Lancet 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 prokinetic agents is one of the 45
`most effective methods known for treating such disor-
`ders. Because many 5-HT3 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: 50
`A Key in the Future of Gastroenterology. Gastroenter-
`ology Clinics of North America 1989, 18, 437-457).
`5-HT3 receptors are present in those areas of the brain
`which control mood, emotion, reward and memory.
`5-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-HT3 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 The Lancet previously cited).
`There is evidence that 5-HT3 receptors mediate noci-
`ceptive input to afferent neurons (see Glaum, S.; Proud- 65
`flt, H. K.; Anderson, E. G. Neurosci Lett. 1988,95, 313).
`5-HT3 antagonists may therefore be of value in the
`control of pain, particularly migraine (~ Peatfleld R.;
`
`Exh. 1006
`
`

`
`3
`
`11
`
`40
`
`w NH/R3
`
`5,202,333
`4
`"Lower" modifies alkyl, alkoxy and alkonyl and re-
`in which
`fers to those alkyl radicals or R groups in alkoxy and
`u is 0 or 1;
`z is 1, 2 or 3; and
`alkonyl radicals containing 1 to 6 carbon atoms.
`R4 is Ct-7 alkyl, C3-8 cycloalkyl, c3•8 cycloalkyi-C1•2
`"Halogen" means fluorine, chlorine, bromine, or
`alkyl, or a group (CH2)1R5 where t is 1 or 2 and R5 is 5 iodine.
`thienyl, pyrrolyl, or fury I, each optionally substituted
`"Esterified carboxy" means the ester group -COOR
`by one or two substituents selected from Ct-6alkyl, Ct-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 Ct-8 alkyl, capable of un'dergo-
`c14 alkoxy, trifluoromethyl, halogen, nitro, carboxy, 10 ing enzymatic hydrolysis within a living organism.
`"Leaving group" has the meaning conventionally
`esterified carboxy, and c 14 alkyl optionally further
`substituted by hydroxy, c14 alkoxy, carboxy, esterified
`associated with it in synthetic organic chemistry, i.e., an
`carboxy or in vivo hydrolyzable acyloxy; and the phar-
`atom or group displaceable under alkylating conditions,
`and includes halogen and alkane- or arenesulfonyloxy
`maceutically acceptable salts, individual isomers and
`mixtures of isomers thereof.
`15 such as mesyloxy, ethanesulfonyloxy, benzenesul-
`A second aspect of this invention is a pharmaceutical
`fonyloxy, tosyloxy and the like.
`composition containing a compound of Formula 1 in
`"Animal" includes humans, non-human mammals
`admixture with one or more suitable excipients.
`(e.~-· dogs, cats, rabbits, 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., brrds and the
`diseases involving emesis, gastrointestinal disorders, 20 lik~Cyt).
`.
`,
`.
`. 1
`1 .
`CNS disorders, cardiovascular disorders or pain by
`otoxtc agents. mc_ude ~ a~um. an~-cancer
`agl e~ts )such
`administering a therapeutically effective amount of a
`asll C1Splatml t" (cls-dlammmt_ edlchldruoro-
`am· d
`b.
`p atmum , as we as non-p a mum an 1-cancer
`· h
`h
`gs
`I I
`d f F
`compoun o ormu a
`to a su ~ect
`Jete w1t sue
`h
`h
`·d
`(
`· )
`·
`· t ·
`1 h
`d"f
`sue
`as eye op osp ann e
`cytoxtn, vmcns nne
`a coA~ 1 rtlohn.
`t fthi .
`.
`. th
`d
`f 25 Oeurocristine), procarbazine (N-(1-methylethyl)-4-((2-
`· )
`th 1h d
`th l]be
`·d )
`th tr
`te
`aspec o
`s mvenuon 1s
`e compoun s o
`me y y razmo me y
`nzann e , me o exa
`,
`F
`•0U
`1 11
`(2-
`ormu a
`:
`fluorouracil, mechlorethamine hydrochloride
`chloro-N-(2-chloroethyl)-N-methylethanamine hydro-
`chloride), doxorubicin, adriamycin, dactinomycin (ac-
`30 tinomycin-D) cytarabine, carmustine, dacarbazine, and
`others listed at page 1143 of the Jou17Ull of Clinical On-
`cology 1989"; 7(8): 1143.
`"Disease" specifically includes any unhealthy condi-
`tion of an animal or part thereof and includes an un-
`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"
`here includes the emesis caused by therapy with agents
`in which n, p, q, Rl, R2 and R3 are as defmed for For-
`having emetogenic side effects, in particular by therapy
`mula I, which are useful intermediates in preparing
`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
`.
`.
`.
`where the event or circumstance occurs and instances
`Unless otherwtse stated, the followmg terms used m
`the specification and claims have the meanings given 50 in which it does not. For example, "optional bond"
`below:
`means that the bond may or may not be present and that
`"Alkyl" means a straight, branched, or cyclic satu-
`the description includes both single bonds and double
`bonds; "optionally converting a compound of Formula
`rated hydrocarbon radical having from one to the num-
`ber of carbon atoms designated. For example Ct-7 alkyl
`1 to a corresponding pharmaceutically acceptable salt"
`is alkyl having at least one but no more than seven 55 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, i-propyl, n-propyl,
`n-butyl, cyclopropylmethyl, pentyl, cyclohexyl, heptyl
`invention, and the invention includes those processes
`and the like.
`wherein the compound of Formula I is converted to the
`"Alkoxy" means the radical -OR wherein R is alkyl
`salt and those processes in which it is not.
`having from one to the number of carbon atoms desig- 60
`"Pharmaceutically acceptable" means that which is
`nated, e.g., Ct-7 alkoxy includes, e.g., methoxy, ethoxy,
`useful in preparing a pharmaceutical composition that is
`i-propoxy, 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-
`"Aikonyl" means the radical -C(O)R wherein R is
`ceptable for veterinary use as well as human pharma-
`alkyl having from one to the number of carbon atoms 65 ceutical use.
`designated, e.g., Ct-7 alkonyl includes ethanoyl, propan-
`"Pharmaceutically acceptable salts" means salts
`which are pharmaceutically acceptable, as defined
`oyl, i-butanoyl, n-butanoyl, pentanoyl, hexanoyl and the
`like.
`above, and which possess the desired pharmacological
`
`(RI)p
`
`(R2)q
`
`"
`
`Exh. 1006
`
`

`
`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
`particular compound in the specification and claims is
`bromic acid, sulfuric acid, nitric acid, phosphoric acid,
`and the like; or with organic acids such as acetic acid,
`intended to include both individual enantiomers and
`propionic acid, hexanoic acid, heptanoic acid, cy- -s mixtures, racemic or otherwise, thereof. Conventions
`clopentanepropionic acid, glycolic acid, pyruvic acid,
`for stereochemical nomenclature, methods for the de-
`termination of stereochemistry and the separation of
`lactic acid, malonic acid, succinic acid, malic acid, ma-
`leic acid, fumaric acid, tartaric acid, citric acid, benzoic
`stereoisomers are well-known in the art (see discussion
`in Chapter 4 of "Advanced Organic Chemistry", 3rd
`acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,
`mandelic acid, methanesulfonic acid, ethanesulfonic 10 edition March, Jerry, John Wiley and Sons, New York,
`acid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesul-
`1985).
`fonic acid, benzenesulfonic acid p-chlorobenzenesul-
`Certain compounds of Formulae 1 and 11 can exist as
`fonic acid, 2-naphthalenesulfonic acid, p-toluenesul-
`stereoisomers. For example, certain compounds possess
`a chiral center at the ring carbon of the R3 substituent
`fonic acid, camphorsu1fonic acid, 4-methylbicyclo[2.2.-
`l]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'- 15 which is bonded to the amide nitrogen and, when the
`methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-
`optional bond is absent, at the 3a-position and therefore
`phenylpropionic acid, trimethylacetic acid, tertiary
`. t
`(R)
`(S) ·
`dd"t"
`rtam"
`1
`·
`"d 1
`1
`lfi ·
`"d
`·
`"d
`can eXIs as
`- or
`-tsomers. n a
`1 ton, ce
`b
`I
`1
`uty acetic act , aury su unc ac1 , g ucomc ac1 ,
`d
`· t
`th
`( d )-
`(
`)-"
`·
`"d h d
`h h ·
`"d sali
`li
`"d
`compoun s can eXIs as
`e en o or exo ISOmers,
`I
`g utamtc act , y roxynap t mc ac1 ,
`cy c ac1 ,
`,
`1]
`1 [
`.
`.
`•
`3
`stearic acid, muconic acid, and the like.
`20 e.g., when the R substituent IS 1-azab1cyc o 3.3. non-
`In addition, pharmaceutically acceptable salts may be
`4-yl.
`~en a compo~d of Fo~ula I or I_I possesses one
`formed when an acidic proton present is capable of
`reacting with inorganic or organic bases. Acceptable
`c~ral center, a parr of e~ant1omers eXISts. When two
`chiral centers are ~resent m ~ co~pound of Formula. I,
`inorganic bases include sodium hydroxide, sodium car-
`bonate, potassium hydroxide, aluminum hydroxide and 25 four sep~ate stermsomers eXIst (1.e., two separate parrs
`calcium hydroxide. Acceptable organic bases include
`of enant10mer:s). When a compound _of Formula I pes-
`ethanolamine, diethanolamine, triethanolamine trome-
`sesses two chiral centers and can eXIst as endo or exo,
`thamine, N-methylglucamine and the like.
`'
`eight separate stereoisomers are possible (i.e., two sepa-
`that
`"Therapeutically effective amount" means
`rate pairs of enantiomers in the endo 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, II, (a), (b), (c) or (d) in this application, a straight line
`depicting the covalent bond between the R3 substituent
`for the disease.
`"Treating" or "treatment" of a disease includes:
`and the amide nitrogen represents the possible geomet-
`ric isomers and enantiomers or the mixtures, racemic or
`(1) preventing the disease from occurring in an animal
`which may be predisposed to the disease but does not 35 otherwise, thereof. Similarly, when referring to For-
`mula I in which the optionally bond is absent, a straight
`yet experience or display symptoms of the disease,
`(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
`by name or by formula and the configuration is not
`Compounds that have identical molecular formulae
`but differ in the nature or sequence of bonding of their
`designated, it is to be understood that the reference is to
`atoms or in the arrangement of their atoms in space are
`all possible forms.
`termed "isomers". Isomers that differ in the nature or
`Certain R3 substituents described in this application
`sequence of bonding of their atoms are termed "consti- 45 are of particular interest and are therefore defmed spe-
`tutional isomers". Isomers that differ only in the ar-
`cifically as the following:
`rangement of their atoms in space are termed "stereo-
`(1) Formula (b) where z is 2 and u is 0 having the
`isomers". Stereoisomers that are not mirror images of
`specific formula
`one another are termed "diasteromers" and stereoiso-
`mers that are mirror images are termed "enantiomers" 50
`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 55
`"asymmetric carbon".
`When a compound has a chiral 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 65
`individual 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 1-azabicyclo[2.2.2]oct-4yl;
`(3) Formula (a) where z is 3, u is 0 and R4 is methyl
`having the 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. 1006
`
`

`
`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 R4 is methyl
`having the specific formula
`
`CH3
`
`/
`N
`
`5
`
`10
`
`15
`
`20
`
`is referred to as (endo)-1-azabicyclo(3.3.1]non-4-yl.
`(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-4-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 1-azabicyclo-
`(2.2.2]oct-4-yl:
`
`35
`
`40
`
`o-0
`
`ill ~
`
`3
`
`(CH2)n
`
`is referred to as (exo)-9-methyl-9-azabicyclo[3.3.1]non-
`3-yl;
`(5) Formula (a) where z is 2, u is 0 and R4 is methyl
`having the specific formula
`
`H
`
`is refered to as (endo)-8-methyl-8-azabicyclo[3.2.1]oct-
`3-yl;
`(6) Formula (a) where z is 2 u is 0 and R4 is methyl 50
`having the specific formula
`
`is named
`2-(1-azabicyclo[2.2.2]oct-4-yl)-1 ,2,4,5-tetrahydrocy-
`45 clopent[de]isoquinolin-1-one when n is 1;
`2-( l-azabicyclo[2.2.2]oct-4-yl)-2,4,5,6-tetrahydro-1H-
`benz[de]isoquinolin-1-one when n is 2; and
`2-(azabiyclo[2.2.2]oct-4-yl)-1,2,4,5,6,7-hexahydrocy-
`clohept[de]isoquinolin-1-one when n is 3.
`The compound of Formula II in which the optional
`bond is present, p, q and u are 0 and R3 is 1-azabicyclo-
`(2.2.2]oct-4-yl:
`
`55
`
`60
`
`65
`
`is named
`N-(1-azabioyclo[2.2.2]oct-4-yl)-4-indancarboxamide
`when n is 1;
`N-(1-azabicyclo[2.2.2]oct-4-yl)-5,6,7,8-tetrahydro-1-
`naphthalenecarboxamide when n is 2; and
`
`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
`
`Exh. 1006
`
`

`
`5,202,333
`10
`9
`parathyroidism and Addison's disease. Emesis may also
`N-(1-azabicyclo[2.2.2]oct-4-yl)-5,6,7,8-tetrahydro-
`9H-benzocyclohepten-l-carboxamide when n is 3.
`be caused by ingested toxins, e.g., enterotoxins in sta-
`phylococcus-contaminated foods, or by drugs adminis-
`PRESENTLY PREFERRED EMBODIMENTS
`tered for therapeutic purposes, e.g., digitalis, emetine
`While the broadest definition of this invention is set
`5 and chemotherapeutic agents.
`forth in the Summary of the Invention, certain com-
`Compounds of Formula I are of particular value in
`treating (especially preventing) the emesis induced by
`pounds of Formulae I and II are preferred. For exam-
`radiation poisoning, treatment for cancer with radio-
`ple, preferred compounds of Formula I are those in
`which both q and u are 0, pis 1, or 2, each Rl is indepen-
`therapy or chemotherapy with cytotoxic agents or drug
`10 therapy in general wherein a significant side effect is
`dently selected from halogen, lower alkoxy or amino,
`and R4 is lower alkyl.
`emesis, e.g., amphotericin B in treating immunosup-
`Of particular interest are those compounds of For-
`pressed patients, zidovudine (AZn in the treatment of
`mula I in which each p, q and u are 0, R4is methyl, ~ptd
`AIDS and interleukin in treating cancer.
`R3 is one of the following groups:
`Compounds of Formula I are useful as prokinetic
`15 agents in the treatment of gastrointestinal diseases, i.e.,
`1-azabicyclo[2.2.2]oct-3-yl;
`diseases ofthe stomach, esophagus and of both the large
`1-azabicyclo-[2.2.2]oct-4-yl;
`and small intestines. Examples of specific diseases in-
`endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl;
`clude, but are not limited to, dyspepsia (e.g., non-ulcer
`exo-9-methyl-9-azabicyclo[3.3.1 ]non-3-yl;
`dyspepsia), gastric stasis, peptic ulcer, reflux esophagi-
`endo-8-methyl-8-azabicyclo[3.2.1 ]oct-3-yl;
`20 tis, flatulence, bile reflux gastritis, pseudCK>bstruction
`exo-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-1-azabicyclo[3.3.l)non-4-yl.
`ease, biliary dysmotility (which may result in sphincter
`Of most interest are the compounds of Formula I in
`of Oddi dysfunction and "sludge" or microscopic crys-
`which each p, q and u are 0, and R 3 is 1-azabicyclo[2.2.-
`2]oct-3-yl, in particular wherein one or, when present, 25
`tals in the gall bladder), gastroparesis (e.g., diabetic,
`both chiral centers possess S configurations.
`postsurgical or idiopathic), irritable bowel syndrome
`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, 1, 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-
`mula II in which each p, q, and u are 0, R4is methyl, and
`cinoid syndrome.
`R3 is one of the following groups:
`Compounds of Formula I are useful in treating dis-
`eases of the central nervous system. Categories of such
`1-azabicyclo[2.2.2)oct-3-yl;
`35 diseases include cognitive disorders, psychoses, obses-
`l-azabicyclo-[2.2.2]oct-4-yl;
`sive/compulsive and anxiety/depression behavior.
`endo-9-methyl-9-azabicyclo[3.3.l]non-3-yl;
`Cognitive disorders include attentional or memory defi-
`exo-9-methy l-9-azabicyclo[3.3.1 ]non-3-yl;
`cit, dementia states (including senile dementia of the
`endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl;
`Alzheimer's type and aging), cerebral vascular defi-
`exo-8-methyl-8-azabicyclo[3.2.1 ]oct-3-y I;
`40 ciency and Parkinson's disease. Psychoses that are treat-
`endo-l-azabicyclo[3.3.1]non-4-yl; or
`able using the compounds of Formula I include para-
`exo-l-azabicyclo[3.3.l)non-4-yl.
`noia, schizophrenia 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 R3is 1-azabicyclo[2.2.-
`I includes eating disorders, e.g., bulimia, a condition in
`2]oct-3-yl, in particular the S-isomers thereof.
`which an abnormal and constant craving for food is
`It is understood that these compounds of Formula II 45
`present.
`of special interest are particularly useful in the synthesis
`Representative, treatable anxiety/depressive states
`of preferred compounds of Formula I.
`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 so disorder (SAD), and the convulsions and anxiety
`caused by withdrawal from addictive substances such as
`broad range of diseases in animals, particularly humans.
`opiates, benzodiazapines, nicotine, alcohol, cocaine and
`Examples of diseases that may be treated using the com-
`pounds of Formula 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-HT3 antagonists prevent certain
`and treatment of emesis. Causes of such emesis include
`adverse nervous transmissions and/or prevent vasodila-
`surgical anesthesia, psychological stress, pregnancy,
`tion and are therefore of value for reducing perceived
`certain disease states, radiotherapy, radiation poisoning
`and toxic substances. Disease states which are known to 60 levels of pain. Compounds of Formula I are, therefore,
`induce emesis include conditions such as gut obstruc-
`useful in treating pain such as that associated with clus-
`tion, raised intracranial pressure, acute myocardial in-
`ter headaches, migraines, trigeminal neuralgia and vis-
`farction, migraine headaches and adrenal crisis. Toxic
`ceral pain (e.g., that