United States Patent (19)
`Berger et al.
`(54) TRICYCLIC 5-HT3 RECEPTOR ANTAGONSTS
`(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
`22 Filed: May 22, 1991
`Related U.S. Application Data
`63 Continuation-in-part of Ser. No. 442,082, Nov. 28, 1989, abandoned.
`51 Int. Cl. ................... CO7D 471/08; A61K 31/55;
`A61K 31/455
`52 U.S. Cl. .................................... 514/296; 514/211; 514/872; 540/520; 546/99; 54.6/100 58 Field of Search .................. 546/99, 100; 540/520;
`514/211, 296
`(56) References Cited
`U.S. PATENT DOCUMENTS
`3,341,528 9/1967 Shavel, Jr. ............................ 54.6/98
`3,896,132 7/1975 Bernauer.... 260/289 R
`4,309,543 l/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. O. .
`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 Pharmacol. Exp. Ther. 245, 3:773-778.
`King et al. 1990, Benzotriazinones as "Virtual Ring" Mimics of o-Methoxybenzanides: Novel and Potent 5-HT3 Receptor Antagonists, J. Med. Chen.
`33:2942-2944.
`Peatfield, R. 1988, Drugs and the treatment of Mi graine, Trends Pharmacol. Sci. 9:141-145.
`Komatsu et al. 1978, Chen, Abs. 89:1.00352x.
`Hibert et al. 1988, Preparation and testing of 4-(- 2-pyrimidinyl)-1-piperazinepyrimidinediones and -ox
`azinones as minor tranquilizers, Chen. Abs. 108:221716p.
`Primary Examiner-Mark L. Berch Attorney, Agent, or Firm-Wayne W. Montgomery; Derek P. Freyberg; Tom M. Moran
`|||||||||||||||
`USO05202333A
`11 Patent Number:
`(45) Date of Patent:
`5,202,333
`Apr. 13, 1993
`(57) ABSTRACT
`The present invention is directed to 5-HT3 receptor antagonist compounds of formula I:
`O I
`I
`(R)
`in which
`the dashed line denotes an optional double bond;
`n is 1, 2 or 3;
`p is 0, 1, 2 or 3; q is 0, 1 or 2; each R1 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):
`* (a)
`(O), (b)
`N
`/
`(CH2)
`(O) (c)
`(O) (d)
`in which
`u is 0 or l;
`z is 1, 2 or 3; and R is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C-2 alkyl, or a group (CH2).R.5 where t is 1 or 2 and R5 is thienyl, pyrrolyl, or furyl, each optionally further
`substituted by one or two substituents selected from C1-6 alkyl, C1-6 alkoxy, 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 C-4 alkyl optionally substituted by hydroxy, C14 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.
`50 Claims, No Drawings
`
`HELSINN EXHIBIT 2032
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00945
`Page 1 of 22
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`5,202,333 1
`TRICYCLIC 5-HT3 RECEPTOR ANTAGONSTS
`This application is a continuation-in-part of copend
`ing application, Ser. No. 07/442,082, filed Nov. 28, 1989
`and now abandoned.
`FIELD OF THE INVENTION
`This invention relates to novel compounds which are 5-HT3 receptor antagonists, pharmaceutical composi
`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 5-HT3 receptor antagonists.
`BACKGROUND OF THE INVENTION
`Serotonin, a neurotransmitter with mixed and com
`plex pharmacological characteristics, was first discov ered in 1948 and subsequently has 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 delineated into three major subclas
`sifications - 5-HT1, 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 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-HT3 receptor 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
`10
`15
`2
`Drugs and the Treatment of Migraine. Trends. Phar macol, 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. Pharmaco. Exp. Ther. 1988, 245,773 and references therein). 5-HT3 antagonists may therefore be of use in treating or preventing arrhyth
`18S.
`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 first aspect of this invention is the compounds of
`- Formula I:
`25
`30
`35
`(R)
`in which
`the dashed line denotes an optional double bond; n is 1, 2 or 3;
`p is 0, 1, 2 or 3; q is 0, 1 or 2; each R1 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 5-Hydroxytryptamine Receptors: The Lancet Sep. 23, 40 R3 is a group selected from Formulae (a), (b), (c) and 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
`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: 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 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
`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 fit, 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 (see Peatfield R.;
`45
`55
`65
`(d):
`(Q), (a)
`(b)
`(c)
`(d)
`(CH2)
`
`Page 2 of 22
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`
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`5,202,333
`in which
`u is 0 or l;
`z is 1, 2 or 3; and R" is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C-2 alkyl, or a group (CH2)R where t is 1 or 2 and R5 is thienyl, pyrrolyl, or furyl, each optionally substituted
`by one or two substituents selected from C-6 alkyl, C1-6 alkoxy, trifluoromethyl or halogen, or is phenyl option
`ally substituted by one or two substituents selected from C1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy,
`esterified carboxy, and C1-4 alkyl optionally further substituted by hydroxy, C14 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the phar
`maceutically acceptable salts, individual isomers and
`mixtures of isomers thereof.
`A second aspect of this invention is a pharmaceutical composition containing a compound of Formula I in
`admixture with one or more suitable excipients. A third aspect of this invention is a method of treating diseases involving emesis, gastrointestinal disorders, CNS disorders, cardiovascular disorders or pain by administering a therapeutically effective amount of a
`compound of Formula I to a subject afflicted with such
`a condition.
`10
`15
`20
`A fourth aspect of this invention is the compounds of 25
`Formula II:
`I
`(CH2)
`(R)
`in which n, p, q, R, R2 and R3 are as defined for For mula I, which are useful intermediates in preparing compounds of Formula I. A fifth aspect of this invention are the processes for preparing compounds of Formula I and is set forth in the "Detailed Description Of The Invention.”
`DETALED DESCRIPTION OF THE
`INVENTION
`Definitions
`Unless otherwise stated, the following terms used in the specification and claims have the meanings given
`below:
`"Alkyl' means a straight, branched, or cyclic satu rated hydrocarbon radical having from one to the num ber of carbon atoms designated. For example C1-7 alkyl is alkyl having at least one but no more than seven carbon atoms, e.g., methyl, ethyl, i-propyl, n-propyl, n-butyl, cyclopropylmethyl, pentyl, cyclohexyl, heptyl
`and the like.
`"Alkoxy' means the radical -OR wherein R is alkyl
`having from one to the number of carbon atoms desig nated, e.g., C1-7 alkoxy includes, e.g., methoxy, ethoxy, i-propoxy, n-propoxy, n-butoxy, pentoxy, hexoxy and
`the like.
`"Alkonyl' means the radical -C(O)R wherein R is alkyl having from one to the number of carbon atoms designated, e.g., C1-7 alkonyl includes ethanoyl, propan oyl, i-butanoyl, n-butanoyl, pentanoyl, hexanoyl and the
`like.
`30
`35
`45
`55
`65
`4.
`"Lower” modifies alkyl, alkoxy and alkonyl and re fers to those alkyl radicals or R groups in alkoxy and alkonyl radicals containing 1 to 6 carbon atoms. "Halogen" means fluorine, chlorine, bromine, or iodine.
`"Esterified carboxy" means the ester group -COOR wherein R is C-8 alkyl. "In vivo hydrolyzable acyloxy' means a group -OC(O)R, wherein R is C1-8 alkyl, capable of undergo ing enzymatic hydrolysis within a living organism. "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes halogen and alkane- or arenesulfonyloxy such as mesyloxy, ethanesulfonyloxy, benzenesul fonyloxy, tosyloxy and the like.
`"Animal' includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, and deer) and non-mammals (e.g., birds and the like). "Cytotoxic agents' include platinum anti-cancer agents such as cisplatin (cis-diamminedichloro platinum), as well as non-platinum anti-cancer drugs such as cyclophosphamide (cytoxin), vincristrine (leurocristine), procarbazine (N-(1-methylethyl)-4-(2- methylhydrazino)methylbenzamide), methotrexate,
`fluorouracil, mechlorethamine hydrochloride (2- chloro-N-(2-chloroethyl)-N-methylethanamine hydro
`chloride), doxorubicin, adriamycin, dactinomycin (ac tinomycin-D) cytarabine, carmustine, dacarbazine, and
`others listed at page 1143 of the Journal 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 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 having emetogenic side effects, in particular by therapy for cancer, such as chemotherapy with cytotoxic agents and radiotherapy. "Emesis', for the purposes of this application, will have a meaning that is broader than the normal, dictio nary definition and includes not only vomiting, but also nausea and retching.
`"Optional" or "optionally" means that the subse quently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances
`in which it does not. For example, "optional bond' means that the bond may or may not be present and that the description includes both single bonds and double bonds; "optionally converting a compound of Formula I to a corresponding pharmaceutically acceptable salt"
`means that the conversion may or may not be carried out in order for the process described to fall within the
`invention, and the invention includes those processes wherein the compound of Formula I is converted to the salt and those processes in which it is not. "Pharmaceutically acceptable' means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor
`otherwise undesirable and includes that which is ac
`ceptable for veterinary use as well as human pharma
`ceutical use.
`"Pharmaceutically acceptable salts' means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological
`Page 3 of 22
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`5,202,333 5
`activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydro
`bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cy clopentanepropionic acid, glycolic acid, pyruvic acid,
`lactic acid, malonic acid, succinic acid, malic acid, ma
`leic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,
`mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesul
`fonic acid, benzenesulfonic acid p-chlorobenzenesul fonic acid, 2-naphthalenesulfonic acid, p-toluenesul fonic acid, camphorsulfonic acid, 4-methylbicyclo2.2.- 2oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'- methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3
`phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid,
`stearic acid, muconic acid, and the like. In addition, pharmaceutically acceptable salts may be formed when an acidic proton present is capable of reacting with inorganic or organic bases. Acceptable
`inorganic bases include sodium hydroxide, sodium car bonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include
`ethanolamine, diethanolamine, triethanolamine, trome thamine, N-methylglucamine and the like. "Therapeutically effective amount" means that
`annount which, when administered to an animal for
`treating a disease, is sufficient to effect such treatment
`for the disease.
`"Treating” or "treatment' of a disease includes: (1) preventing the disease from occurring in an animal
`which may be predisposed to the disease but does not yet experience or display symptons of the disease,
`(2) inhibiting the disease, i.e., arresting its development,
`Or
`(3) relieving the disease, i.e., causing regression of the
`disease.
`Compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are
`termed "isomers'. Isomers that differ in the nature or
`sequence of bonding of their atoms are termed "consti tutional isomers'. Isomers that differ only in the ar rangement of their atoms in space are termed "stereo isomers'. Stereoisomers that are not mirror images of
`one another are termed "diasteromers' and stereoiso
`mers that are mirror images are termed "enantiomers' 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 "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 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
`individual enantioner or as a mixture thereof. A mix
`ture containing equal proportions of the enantiomers is
`termed a "racemic mixture' or "racemate' and may be
`O
`15
`20
`25
`35
`45
`50
`55
`65
`6
`described as the (RS)- or (-)-mixture thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is
`intended to include both individual enantiomers and
`mixtures, racemic or otherwise, thereof. Conventions
`for stereochemical nomenclature, methods for the de termination of stereochemistry and the separation of
`stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry', 3rd
`edition March, Jerry, John Wiley and Sons, New York,
`1985). Certain compounds of Formulae I and II can exist as stereoisomers. For example, certain compounds possess
`a chiral center at the ring carbon of the R3 substituent which is bonded to the amide nitrogen and, when the optional bond is absent, at the 3a-position and therefore
`can exist as (R)- or (S)-isoners. In addition, certain compounds can exist as the (endo)- or (exo)-isomers, e.g., when the R substituent is 1-azabicyclo[3.3.1non 4-yl.
`When a compound of Formula I or II possesses one
`chiral center, a pair of enantiomers exists. When two chiral centers are present in a compound of Formula I, four separate steroisomers exist (i.e., two separate pairs of enantiomers). When a compound of Formula I pos
`sesses two chiral centers and can exist as endo or exo,
`eight separate stereoisomers are possible (i.e., two sepa
`rate pairs of enantiomers in the endo or exo form). It is to be understood that when referring to Formula I, II, (a), (b), (c) or (d) in this application, a straight line depicting the covalent bond between the R3substituent and the amide nitrogen represents the possible geomet
`ric isomers and enantiomers or the mixtures, racemic or
`otherwise, thereof. Similarly, when referring to For mula I in which the optionally bond is absent, a straight
`line depicting the covalent bond between carbons 3a and 4 represents either the R or S configurations or a
`mixture racemic, or otherwise, thereof. For purposes of the present application when referring to a compound
`by name or by formula and the configuration is not
`designated, it is to be understood that the reference is to all possible forms. Certain R3 substituents described in this application are of particular interest and are therefore defined spe cifically as the following:
`(1) Formula (b) where z is 2 and u is 0 having the specific formula
`N
`1-2)
`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
`is referred to as 1-azabicyclo2.2.2]oct-4yl;
`(3) Formula (a) where z is 3, u is 0 and R is methyl having the specific formula
`Page 4 of 22
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`5,202,333
`CH3 H
`N
`f 5
`N
`H
`10
`is referred to as (endo)-1-azabicycloS.3.1non-4-yl.
`(8) Formula (c) wherein z is 2 and u is 0 having the is referred to as (endo)-9-methyl-9-azabicyclo[3.3.1 specific formula
`non-3-yl; 15
`(4) Formula (a) where z is 3, u is 0 and R is methyl H
`having the specific formula
`N
`20 CH3 / N
`25 is referred to as (exo)-1-azabicyclo3.3.1non-4-yl.
`Compounds of Formulae I and II are named in accor dance with generally acceptable nomenclature rules
`H 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 is referred to as (exo)-9-methyl-9-azabicyclo[3.3.1)non- 2.2.2]oct-4-yl:
`3-yl;
`(5) Formula (a) where z is 2, u is 0 and R is methyl
`having the specific formula 35
`O p N
`> 1 2
`N
`-- eHs 2 3
`N 40 3a
`(CH2)
`is named
`H 2-(1-azabicyclo[2.2.2]oct-4-yl)-1,2,4,5-tetrahydrocy
`45 clopent deisoquinolin-1-one when n is l; 2-(1-azabicyclo2.2.2]oct-4-yl)-2,4,5,6-tetrahydro-1H
`benzdeisoquinolin-1-one when n is 2; and f t -8-methvi-8- A is refered to as (endo)-8-methyl-8-azabicyclo3.2.1]oct 2-(azabiyclo[2.2.2]oct-4-yl)-1,2,4,5,6,7-hexahydrocy
`3-yl; cloheptidelisoquinolin-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 having the specific formula bond is present, p, q and u are 0 and R is 1-azabicyclo 2.2.2]oct-4-yl:
`oHs 55 N O N
`NH
`60
`H (CH2)
`is referred to as (exo)-8-methyl-8-azabicyclo[3.2.1]oct- is named 3-yl; 65 N-(1-azabioyclo[2.2.2]oct-4-yl)-4-indancarboxamide
`9 s when n is 1;
`(7) Formula (c) wherein z is 2 and u is 0 having the N-(1-azabicyclo[2.2.2]oct-4-yl)-5,6,7,8-tetrahydro-1-
`specific formula naphthalenecarboxamide when n is 2; and
`Page 5 of 22
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`5,202,333 9 N-(1-azabicyclo2.2.2Oct-4-yl)-5,6,7,8-tetrahydro 9H-benzocyclohepten-1-carboxamide when n is 3.
`PRESENTLY PREFERRED EMBODIMENTS
`While the broadest definition of this invention is set
`forth in the Summary of the Invention, certain com pounds of Formulae I and II are preferred. For exam ple, preferred compounds of Formula I are those in which both q and u are 0, p is 1, or 2, each R is indepen dently selected from halogen, lower alkoxy or amino, and R is lower alkyl. Of particular interest are those compounds of For mula I in which each p, q and u are 0, Ris methyl, and R is one of the following groups: 1-azabicyclo2.2.2]oct-3-yl; 1-azabicyclo-2.2.2]oct-4-yl; endo-9-methyl-9-azabicyclo3.3.1 non-3-yl; exo-9-methyl-9-azabicyclo3.3.1 non-3-yl; endo-8-methyl-8-azabicyclo3.2.1]oct-3-yl; exo-8-methyl-8-azabicycloS.2.1]oct-3-yl; endo-1-azabicyclo3.3.1non-4-yl; or exo-1-azabicyclo3.3.1non-4-yl.
`Of most interest are the compounds of Formula I in which each p, q and u are 0, and R3 is 1-azabicyclo[2.2.- 2oct-3-yl, in particular wherein one or, when present, both chiral centers possess S configurations. Preferred compounds of Formula II are those in which both p and q are 0, p is 0, 1, or 2, each R is independently selected from halogen, lower alkoxy or amino, and R is lower alkyl. Of particular interest are those compounds of For mula II in which each p, q, and u are 0, Ris methyl, and R3 is one of the following groups: 1-azabicyclo[2.2.2]oct-3-yl; i-azabicyclo-2.2.2]oct-4-yl; endo-9-methyl-9-azabicyclo[3.3.1)non-3-yl; exo-9-methyl-9-azabicyclo3.3.1non-3-yl; endo-8-methyl-8-azabicyclo3.2.1]oct-3-yl; exo-8-methyl-8-azabicyclo3.2.1]oct-3-yl; endo-1-azabicyclo3.3.1non-4-yl; or exo-1-azabicyclo[3.3.1 non-4-yl.
`Of most interest are compounds of Formula II in which each p, q, and u are 0, and R is 1-azabicyclo[2.2.- 2oct-3-yl, in particular the S-isomers thereof. It is understood that these compounds of Formula II of special interest are particularly useful in the synthesis of preferred compounds of Formula I.
`UTILITY
`Compounds of Formula I exhibit utility in treating a broad range of diseases in animals, particularly humans. Examples of diseases that may be treated using the com pounds of Formula I include emesis, gastrointestinal
`disorders, central nervous system (CNS) disorders, car diovascular disorders or pain. Compounds of Formula I are useful in the prevention
`and treatment of emesis. Causes of such emesis include
`surgical anesthesia, psychological stress, pregnancy, certain disease states, radiotherapy, radiation poisoning
`and toxic substances. Disease states which are known to
`induce emesis include conditions such as gut obstruc tion, raised intracranial pressure, acute myocardial in farction, migraine headaches and adrenal crisis. Toxic substances which induce emesis include toxins in the
`form of abnormal metabolites or abnormal accumula
`tion of natural occurring substances associated with such conditions as hepatic coma, renal failure, diabetic ketoacidosis, hyperthyroid crisis, both hypo- and hyper
`O
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`65
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`parathyroidism and Addison's disease. Emesis may also be caused by ingested toxins, e.g., enterotoxins in sta phylococcus-contaminated foods, or by drugs adminis tered for therapeutic purposes, e.g., digitalis, emetine and chemotherapeutic agents. Compounds of Formula I are of particular value in treating (especially preventing) the emesis induced by radiation poisoning, treatment for cancer with radio therapy or chemotherapy with cytotoxic agents or drug therapy in general wherein a significant side effect is emesis, e.g., amphotericin B in treating immunosup
`pressed patients, zidovudine (AZT) in the treatment of AIDS and interleukin in treating cancer. Compounds of Formula I are useful as prokinetic agents in the treatment of gastrointestinal diseases, i.e., diseases of the stomach, esophagus and of both the large and small intestines. Examples of specific diseases in clude, but are not limited to, dyspepsia (e.g., non-ulcer dyspepsia), gastric stasis, peptic ulcer, reflux esophagi tis, flatulence, bile reflux gastritis, pseudo-obstruction syndrome, irritable colon syndrome (which may result in chronic constipation and diarrhea), diverticular dis ease, biliary dysmotility (which may result in sphincter of Oddi dysfunction and "sludge' or microscopic crys tals in the gall bladder), gastroparesis (e.g., diabetic, postsurgical or idiopathic), irritable bowel syndrome amd retarded gastric emptying. The compounds of Formula I are also useful as short-term prokinetics to facilitate diagnostic radiology and intestinal intubation. In addition, the compounds are useful for treating diar rhea, particularly diarrhea induced by cholera and car cinoid syndrome.
`Compounds of Formula I are useful in treating dis eases of the central nervous system, Categories of such diseases include cognitive disorders, psychoses, obses sive/compulsive and anxiety/depression behavior. Cognitive disorders include attentional or memory defi cit, dementia states (including senile dementia of the Alzheimer's type and aging), cerebral vascular defi ciency and Parkinson's disease. Psychoses that are treat able using the compounds of Formula I include para noia, schizophrenia and autism. Obsessive/compulsive
`behavior that is treatable using compounds of Formula I includes eating disorders, e.g., bulimia, a condition in which an abnormal and constant craving for food is present.
`Representative, treatable anxiety/depressive states include anticipatory anxiety (e.g., prior to surgery, den
`tal work, etc.), depression, mania, seasonal affective disorder (SAD), and the convulsions and anxiety caused by withdrawal from addictive substances such as opiates, benzodiazapines, nicotine, alcohol, cocaine and other drugs of abuse. Compounds of Formula I are useful in the treatment of cardiovascular diseases. Such diseases include ar
`rhythmias and hypertension.
`It is thought that 5-HT3 antagonists prevent certain
`adverse nervous transmissions and/or prevent vasodila tion and are therefore of value for reducing perceived levels of pain. Compounds of Formula I are, therefore, useful in treating pain such as that associated with clus ter headaches, migraines, trigeminal neuralgia and vis
`ceral pain (e.g., that caused by abnormal distension of hollow visceral organs). In summary, an aspect of this invention is a method for treating an animal, particularly a human, exhibiting a disease involving emesis, a gastrointestinal disorder, a
`CNS disorders, a cardiovascular disorder or pain by
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`administering a therapeutically effective amount of a
`compound of Formula I to such animal.
`Pharmacology
`5-HT3 Receptor binding affinity is measured at 5-HT3 receptors in membranes prepared from the cere bral cortex of rat brains, an accepted in vitro assay (e.g., see Kilpatrick, G. J.; Jones, B. J.; Tyers, M. B. Nature 1987, 330, 24-31). The 5-HT3 receptor binding assay is described in Example 14. The compounds of Formula I exhibit affinity for the 5-HT3 receptor in this assay. 5-HT3 receptor antagonist activity is measured by the ability of compounds to inhibit the von Bezold-Jarisch reflex in anesthetized rats, an accepted in vivo assay (e.g., see Butler, A.; Hill, J. M.; Ireland, S.J.; Jordan, C. C.; Tylers, M. B. Brit. J. Pharmacol. 1988, 94,397-412; Cohen, M. L.; Bloomquist, W.; Gidda, J. S.; Lacefield, W. J. Pharmacol. Exp. Ther. 1989; 248, 197-201; Fo zard, J. R. Arch. Pharmacol. 1984, 326, 36-44). The 5-HT3 receptor antagonist assay is described in Exam ple 15. Anti-emetic activity is determined by measuring re duction of cisplatin-induced emesis in ferrets, an ac cepted assay (e.g., Costall, B.; Domeney, A. M.; Naylor, R. J.; Tattersall, F. D. Neuropharmacology 1986, 25(8), 959-961; Miner, W. D.; Sanger G. J. Brit. J. Pharmacol. 1986, 88, 497-499). The ferret, anti-emetic assay is de scribed in Example 16. Anti-enetic activity is also determined by measuring reduction of cisplatin-induced enesis in dogs, an ac cepted assay (e.g., see Smith, W. L.; Alphin, R. S.;
`Jackson, C. B.; Sancilio, L. F. J. Pharm. Pharmacol. 1989, 41, 101-105; Gylys, J. A. Res. Commun. Chen.
`Pathol. Pharmacol. 1979, 23(1), 61-68). The dog, anti emetic assay is described in Example 17. Prokinetic activity is determined by measuring the rate of gastric emptying after oral administration of test meal to rats, an accepted in vivo assay (e.g., see Drop pleman, D.; Gregory, R.; Alphin, R. S. J. Pharmacol. Methods 1980, 4(3), 227-30). The prokinetic assay is described in Example 18. Anxiolytic activity is determined by the art-recog nized Crawley and Goodwin two-compartment explor atory model (e.g., see Kilfoil, T.; Michel, A.; Montgom ery, D.; Whiting, R. L.; Neuropharmacology 1989, 28(9),
`901-905). In brief, the method involves determining whether a compound reduces the natural anxiety of mice in a novel, brightly lighted area. The anxiolytic behavior assay is described in Example 19. Anxiolytic activity during withdrawal from drugs of
`abuse is determined by the mouse, withdrawal anxiety test, an accepted assay (e.g., see Carboni, E.;, Acquas,
`E.; Leone, P.; Perezzani, L.; Di Chiara, G. Eur, J. Phar macol 1988, 151, 159-160). This procedure utilizes the exploratory model described above to test for anxiolytic activity after chronic administration and subsequent abrupt cessation of ethanol, diazepam, cocaine or nico tine treatments. The withdrawal anxiety assay is de scribed in Example 20. Cognition enhancing activity is determined by the mouse, habituation/cognitive enhancement test (e.g., see Barnes, J. M.; Costall, B.; Kelly, M. E.; Naylor, F. J.; Onaivi, E. S.; Tomkins, D. M.; Tyers, M. B. Br. J. Pharmacol. 1989, 98,693P). This procedure utilizes the exploratory model described above to test for improve ments in the impaired cognitive performance of aged mice. The cognitive enhancement assay is described in Example 21.
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`Administration and Pharmaceutical Composition
`In general, compounds of Formula I will be adminis tered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another compound of Formula I or with another therapeutic agent. A thera peutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. Therapeutically effective amounts of compounds of Formula I may range from approxi mately 1.0 nanogram per Kg (ng/Kg) body weight per day to 1.0 mg/Kg body weight per day. Preferably the amount will be approxim