11111111111111111111111111fRO!1,171111111111111111111111111111111
`
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`US005817671A
`[n] Patent Number: (cid:9)
`[11] Patent Number:
`[45] Date of Patent:
`[45] Date of Patent: (cid:9)
`
`5,817,671
`5, 817, 671
`Oct. 6, 1998
`Oct. 6, 1998
`
`United States Patent [19]
`United States Patent
`[19]
`Filla et al.
`Filla et al.
`
`[54] 5-HT, F AGONISTS
`[54] 5-HT„ AGONISTS
`
`Inventors: Sandra Ann Filla, Indianapolis; Kirk
`[75] Inventors: Sandra Ann Filla, Indianapolis; Kirk
`[75]
`W. Johnson, Carmel; Lee A. Phebus,
`W. Johnson, Carmel; Lee A. Phebus,
`Fountaintown; John Mehnert Schaus,
`John Mehnert Schaus,
`Fountaintown;
`Zionsville, all of Ind.
`Zionsville, all of Ind.
`
`[73] Assignee: Eli Lilly and Company, Indianapolis,
`[73] Assignee: Eli Lilly and Company,
`Indianapolis,
`Ind.
`Ind.
`
`[21] Appl. No. : 969, 851
`[21] Appl. No.: 969,851
`Nov. 14, 1997
`Nov. 14, 1997
`[22] Filed: (cid:9)
`[22] Filed:
`
`Related U. S. Application Data
`Related U.S. Application Data
`
`[60] Provisional application No. 60/030,950 Nov. 15, 1996.
`[60] Provisional application No. 60/030, 950 Nov. 15, 1996.
`[51] Int. Cl. ' . . . . . . . . . . . . . . . . . . . . . . . . . A61K 31/44; C07D 471/04
`[51] Int. C1.6
` A61K 31/44; C07D 471/04
`[52] U. S. Cl. . . . . . . . . . . . . . . . . . . . . . . . . . 514/300; 544/58. 4; 544/127;
`[52] U.S. Cl. (cid:9)
` 514/300; 544/58.4; 544/127;
`546/113
`546/113
`[58] Field of Search
`[58] Field of Search (cid:9)
` 546/113; 514/300
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546/113; 514/300
`
`[56]
`[56]
`
`References Cited
`References Cited
`U. S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`5,051,412 9/1991 Macor (cid:9)
`5, 051, 412
`. . . . . . . . . . . . . . . .
`9/1991
`Macor
`5,169,947 12/1992 Macor .
`Macor .
`5, 169, 947
`12/1992
`5,521,196 5/1996 Audia et al. .
`Audia et al. .
`5, 521, 196
`5/1996
`5,521,197 5/1996 Audia .
`5, 521, 197
`.
`5/1996
`Audia
`5,604,240 2/1997 Chambers et al. .
`Chambers et al. .
`2/1997
`5, 604, 240
`5,708,008 1/1998 Audia et al. .
`Audia et al. .
`5, 708, 008
`1/1998
`
`
`
`546/113 (cid:9)
`546/113
`
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`
`0379314
`0379314
`2295615
`2295615
`WO 96/29075
`WO 96/29075
`
`7/1990 European Pat. Off. .
`7/1990 European Pat. OII. .
`6/1996 United Kingdom .
`.
`6/1996 United Kingdom
`9/1996 WIPO .
`9/1996 WIPO .
`
`Primary Examiner~obert W. Ramsuer
`Primary Examiner—Robert W. Ramsuer
`Attorney, Agent, or Firm~obert D. Titus; David E. Boone
`Attorney, Agent, or Firm—Robert D. Titus; David E. Boone
`
`ABSTRACT
`ABSTRACT
`[57] (cid:9)
`[57]
`This invention provides 5-HT, r agonists of Formula I:
`This invention provides 5-HT1, agonists of Formula I:
`
`A
`
`N — R
`N—R
`
`/
`
`/
`H
`H
`
`where A — B, X, and R are as defined
`
`where A—B, X, and R are as defined in the specification.
`in the specification.
`The invention also encompasses pharmaceutical formula-
`formula-
`The invention
`also encompasses pharmaceutical
`tions employing compounds of Formula I as well as methods
`tions employing compounds of Formula I as well as methods
`associated with 5-HT, r activation
`of treating conditions
`of treating conditions associated with 5-HTiF activation
`employing these compounds or compositions. The invention
`these compounds or compositions. The invention
`employing
`intermediates useful for the preparation of the
`also provides intermediates useful for the preparation of the
`also provides
`compounds of Formula I.
`compounds of Formula I.
`
`13 Claims, No Drawings
`13 Claims, No Drawings
`
`MYLAN - EXHIBIT 1013
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`1
`1
`5-HT~ AGONISTS
`5-HT,, AGONISTS
`
`5, 817, 671
`5,817,671
`
`CROSS-REFERENCE
`CROSS-REFERENCE
`This application claims the benefit of U.S. Provisional 5
`5
`the benefit of U. S. Provisional
`This application claims
`application Ser. No. 60/030, 950, filed Nov. 15, 1996.
`application Ser. No. 60/030,950, filed Nov. 15, 1996.
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`2
`substituted)C, — C4 alkyl)phenyl,
`alkoxycarbonyl substituted)C1—C4 alkyl)phenyl,
`alkoxycarbonyl
`with C, — C4
`C, — C4 alkyl u-substituted
`C1—C 4 alkyl a-substituted with C1—C4
`alkoxycarbonyl, heteroaryl; or
`heteroaryl; or
`alkoxycarbonyl,
`R3 and R4 taken together with the nitrogen atom to
`R and R
`taken
`the nitrogen atom
`to
`together with
`which they are attached form a pyrrolidine,
`they are attached
`which
`form
`a pyrrolidine,
`piperidine, piperazine, 4-substituted piperazine,
`4-substituted
`piperazine,
`piperidine,
`piperazine,
`morpholine or thiomorpholine ring;
`morpholine or thiomorpholine
`ring;
`is C, — Cp alkyl, Ca — Cp alkenyl, phenyl, substituted
`R5 is C„—C6 alkyl, C3—C6 alkenyl, phenyl, substituted
`R
`phenyl, Ca — Ca cycloalkyl, C, — C4 alkyl pp-substituted
`phenyl, C3—C8 cycloalkyl, Cl—C4 alkyl w-substituted
`with C, — C4 alkoxy;
`Serotonin (5-HT) exhibits diverse physiological activity 10
`Serotonin (5-HT) exhibits diverse physiological
`with Cl—C4 alkoxy;
`activity
`is C, — C, p alkyl, substituted Cy Cyp alkyl, Cp Cyp
`mediated by at least seven receptor classes, the most het-
`mediated by at least seven receptor classes, the most het-
`R6 is C1—C10 alkyl, substituted C1—C10 alkyl, C2—C10
`R
`alkenyl, Cp Cypalkynyl, Ca — Ca cycloalkyl, phenyl,
`erogeneous of which appears
`to be 5-HT, . A human gene
`erogeneous of which appears to be 5-HT1. A human gene
`alkenyl, C2—Cloalkynyl, C3—C8 cycloalkyl, phenyl,
`phenyl(C, — C4
`which expresses one of these 5-HT, receptor
`which expresses one of these 5-HT1 receptor subtypes,
`substituted phenyl, naphthyl, phenyl(C1—C4
`substituted
`subtypes,
`naphthyl,
`phenyl,
`alkylene), phenyl(C, — C4 alkylene) substituted on the
`named 5-HT, e, was isolated by Kao and coworkers (Proc.
`named 5-HT1,, was isolated by Kao and coworkers (Proc.
`alkylene), phenyl(C1—C4 alkylene) substituted on the
`Natl. Acad. Sci. USA, 90, 408 — 412 (1993)). This 5-HT, e
`Natl. Acad. Sci. USA, 90, 408-412 (1993)). This 5-HT1F 15
`phenyl ring, 2-phenylethylen-l-yl, diphenylmethyl,
`ring, 2-phenylethylen-l-yl,
`diphenylmethyl,
`phenyl
`15
`benzofused C4 — Ca cycloalkyl, C, — C4 alkylene
`receptor exhibits a pharmacological profile distinct from any
`receptor exhibits a pharmacological profile distinct from any
`benzofused C4—C8 cycloalkyl, Cl—C4 alkylene
`pp-substituted with Ca — Cp cycloalkyl, or a hetero-
`serotonergic receptor yet described.
`receptor yet described.
`serotonergic
`w-substituted with C3—C6 cycloalkyl, or a hetero-
`cycle; and pharmaceutically acceptable acid addition
`acceptable acid addition
`cycle; and pharmaceutically
`Moskowitz has proposed that currently unknown triggers
`Moskowitz has proposed
`that currently unknown
`triggers
`salts and solvates thereof.
`salts and solvates thereof.
`for pain stimulate trigeminal ganglia which innervate vas-
`innervate vas-
`for pain stimulate
`trigeminal ganglia which
`This invention also provides a pharmaceutical formula-
`the cephalic tissue, giving rise to release of
`formula-
`This invention also provides a pharmaceutical
`culature within the cephalic tissue, giving rise to release of 20
`culature within
`20
`tion which comprises, in association with a pharmaceuti-
`in association with a pharmaceuti-
`tion which comprises,
`vasoactive neuropeptides from axons on the vasculature.
`vasoactive neuropeptides
`from axons on the vasculature.
`cally acceptable carrier, diluent or excipient, a compound of
`cally acceptable carrier, diluent or excipient, a compound of
`a series of
`These released neuropeptides then activate a series of
`These
`released neuropeptides
`then activate
`Formula I.
`Formula I.
`events, a consequence of which
`events, a consequence of which is pain. This neurogenic
`is pain. This neurogenic
`A further embodiment of this invention
`A further embodiment of this invention is a method for
`for
`is a method
`inflammation is blocked by sumatriptan and ergot alkaloids
`is blocked by sumatriptan
`and ergot alkaloids
`inflammation
`25 increasing activation of the 5-HT, e receptor for treating a
`increasing activation of the 5-HT1F receptor for treating a
`involving 5-HT receptors, believed
`by mechanisms involving 5-HT receptors, believed to be 25
`to be
`by mechanisms
`variety of disorders which have been linked
`variety of disorders which have been linked to decreased
`to decreased
`the 5-HT, o subtype,
`closely related to the 5-HT1, subtype, located on the
`located on
`to
`closely
`related
`the
`fibers (Neurology, 43(suppl. 3), S16 — S20
`of serotonin
`neurotransmission of serotonin in mammals. Included
`Included
`neurotransmission
`in mammals.
`trigeminovascular fibers (Neurology, 43(suppl. 3), S16—S20
`trigeminovascular
`among these disorders are depression, migraine pain,
`that agonists of the
`these disorders
`are depression, migraine
`(1993)). It has been demonstrated
`(1993)). It has been demonstrated that agonists of the
`pain,
`among
`bulimia, premenstrual syndrome or late luteal phase
`or
`bulimia,
`late
`luteal phase
`premenstrual
`5-HT1F receptor inhibit peptide extravasation due to stimu-
`syndrome
`5 HTye receptor inhibit peptide extravasation due to stimu-
`syndrome, alcoholism, tobacco abuse, panic disorder,
`lation of the trigeminal ganglia (Audia and Nissen, U. S. Pat.
`tobacco abuse, panic disorder,
`alcoholism,
`30 syndrome,
`lation of the trigeminal ganglia (Audia and Nissen, U.S. Pat. 30
`anxiety, general pain, chronic pain, post-traumatic
`anxiety, general pain, chronic pain, post-traumatic
`No. 5, 521, 196).
`No. 5,521,196).
`loss, dementia of aging, social phobia,
`syndrome, memory loss, dementia of aging, social phobia,
`syndrome, memory
`Compounds which exhibit afflnity for the 5-HT, e receptor
`Compounds which exhibit affinity for the 5-HT1F receptor
`attention deficit hyperactivity disorder, disruptive behavior
`attention deficit hyperactivity
`disorder, disruptive behavior
`provide a new approach for the treatment of diseases linked
`provide a new approach for the treatment of diseases linked
`disorders, impulse control disorders, borderline personality
`impulse control disorders, borderline personality
`disorders,
`to abnormal serotonergic neurotransmission. Furthermore,
`serotonergic neurotransmission.
`Furthermore,
`to abnormal
`disorder, obsessive compulsive disorder, chronic fatigue
`disorder, chronic
`3s disorder, obsessive compulsive
`fatigue
`compounds selective for the 5-HT1F receptor subtype are 35
`selective for the 5-HT, e receptor subtype are
`compounds
`syndrome, premature ejaculation, erectile difficulty, anor-
`anor-
`ejaculation, erectile difflculty,
`syndrome, premature
`potentially useful for treating such diseases while causing
`potentially useful for treating such diseases while causing
`exia nervosa, disorders of sleep, autism, mutism, allergic
`exia nervosa, disorders of sleep, autism, mutism, allergic
`fewer undesired side effects.
`side elfects.
`fewer undesired
`rhinitis, trichotillomania, trigeminal neuralgia, dental pain or
`trigeminal neuralgia, dental pain or
`rhinitis, trichotillomania,
`temperomandibular joint dysfunction pain. The compounds
`joint dysfunction pain. The compounds
`temperomandibular
`40 of this invention are also useful as a prophylactic
`of this invention are also useful as a prophylactic treatment
`treatment
`40
`for migraine. Any of these methods employ a compound of
`for migraine. Any of these methods employ a compound of
`Formula I.
`Formula I.
`The use of a compound of Formula I for the activation of
`The use of a compound of Formula I for the activation of
`the 5-HT, e receptor, for the inhibition of peptide extrava-
`the 5-HT1F receptor, for the inhibition of peptide extrava-
`to stimulation of the trigeminal
`sation in general or due to stimulation of the trigeminal
`4s sation
`in general or due
`45
`treatment of any of the
`ganglia specifically, and for the treatment of any of the
`and for the
`specifically,
`ganglia
`of the
`disorders described supra, are all embodiments of the
`disorders described
`are all embodiments
`supra,
`present invention.
`invention.
`present
`The present invention also includes intermediates useful
`The present
`invention also includes
`intermediates useful
`so for the preparation of compounds of Formula I.
`for the preparation of compounds of Formula I.
`50
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`provides 5-substituted-3-
`The present invention provides 5-substituted-3-
`invention
`The present
`and 5-substituted-3-(1, 2, 3, 6-
`(piperidin-4-yl)-
`(piperidin-4-yl)- and 5-substituted-3-(1,2,3,6-
`2-b]pyridines of Formula
`tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridines of Formula
`tetrahydropyridin-4-yl)pyrrolo[3,
`I:
`
`A (cid:9)
`A
`
`N — R
`N-R
`
`/
`
`/
`H
`
`in which
`in which
`A — B is — C=CH — or — CH — CH~ —;
`A—B is —C=CH— or —CH—CH2—;
`R is H, C1—C6 alkyl, benzyl, or phenylethyl;
`R is H, Cy Cp alkyl, benzyl, or phenylethyl;
`X is — NR'SO~R, — NHC(Q)NR R, — NHC(O)OR,
`or — NR'C(O)R where:
`X is —NR1S02R2, —NHC(Q)NR3R4, —NHC(0)0R5,
`or —NR1C(0)R6 where:
`Q is 0, or S;
`Q is 0, or S;
`R' is H or C, — C4 alkyl;
`R1 is H or C1—C4 alkyl;
`is C, — C4 alkyl, phenyl or substituted phenyl;
`R2 is C1—C4 alkyl, phenyl or substituted phenyl;
`R
`R3 and R4 are independently selected from the group
`R and R are independently
`selected from the group
`consisting of H, Cy Cp alkyl, Ca — Cp alkenyl, Ca — C,
`consisting of H, C1—C6 alkyl, C3—C6 alkenyl, C3—C8
`cycloalkyl, phenyl, substituted phenyl, phenyl
`substituted
`cycloalkyl,
`phenyl
`phenyl,
`phenyl,
`(C, — C4 alkylene), phenyl(C, — C4 alkylenyl)
`(C1—C4 alkylene), phenyl(C1—C4 alkylenyl) substi-
`substi-
`ring, ((C, — C4 alkyl or C, — C4
`tuted in the phenyl ring, ((C1—C4 alkyl or Cl—C4
`in the phenyl
`tuted
`
`DETAILED DESCRIPTION OF THE
`DETAILED DESCRIPTION OF THE
`INVENTION
`INVENTION
`The general chemical terms used in the formulae above
`The general chemical
`terms used in the formulae above
`the term "alkyl"
`55 have their usual meanings. For example, the term "alkyl"
`their usual meanings. For example,
`55 have
`includes such groups as methyl, ethyl, n-propyl, isopropyl,
`includes such groups as methyl, ethyl, n-propyl,
`isopropyl,
`n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pent-yl-,
`pentyl, 2-pent-yl-,
`sec-butyl,
`tert-butyl,
`n-butyl,
`isobutyl,
`3-pentyl-, neopentyl, hexyl, heptyl, octyl and the like. The
`3-pentyl-, neopentyl, hexyl, heptyl, octyl and the like. The
`term "alkoxy" includes
`term "alkoxy" includes such groups as methoxy, ethoxy,
`such groups as methoxy, ethoxy,
`2-pentoxy-,
`sec-butoxy,
`tert-butoxy,
`60 isopropoxy, sec-butoxy, tert-butoxy, 2-pentoxy-,
`60 isopropoxy,
`3-hexyloxy, heptyloxy, octyloxy, and the like. The term
`like. The term
`3-hexyloxy, heptyloxy, octyloxy, and
`the
`"alkylthio"
`"alkylthio" includes such groups as methylthio, ethylthio,
`includes such groups as methylthio,
`ethylthio,
`isopropylthio, sec-butylthio, tert-butylthio, and the like. The
`and the like. The
`sec-butylthio,
`tert-butylthio,
`isopropylthio,
`term "alkenyl" includes vinyl, allyl, 1-buten-4-yl, 2-buten-
`term "alkenyl" includes vinyl, allyl, 1-buten-4-yl, 2-buten-
`65 4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-
`6s 4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-
`6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like.
`6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like.
`The term "alkynyl" includes acetylenyl, propynyl, 2-butyn-
`The term "alkynyl" includes acetylenyl, propynyl, 2-butyn-
`
`

`
`5,817,671
`
`3
`4-yl, 1-butyn-4-yl, 1-pentyn-5-yl, 2-pentyn-5-yl and the
`1-pentyn-5-yl,
`4-yl, 1-butyn-4-yl,
`2-pentyn-5-yl
`the
`and
`like. The term "acyl" includes, for example, formyl, acetyl,
`like. The term "acyl" includes, for example, formyl, acetyl,
`propanoyl, butanoyl, and 2-methylpropanoyl. The term
`The
`term
`and 2-methylpropanoyl.
`butanoyl,
`propanoyl,
`"cycloalkyl"
`"cycloalkyl" includes such groups as cyclopropyl,
`includes
`as cyclopropyl,
`such groups
`cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
`cyclohexyl,
`cyclobutyl,
`cyclopentyl,
`cycloheptyl
`and
`term "phenyl(C, — C4 alkylene)"
`cyclooctyl. The term "phenyl(Ci—C, alkylene)" includes
`cyclooctyl. The
`includes
`such groups as benzyl, phenethyl, phenpropyl and phen-
`such groups as benzyl, phenethyl,
`and phen-
`phenpropyl
`term "(C, — C4 alkyl)sulfonyl"
`butyl. The term "(C1—C4 alkyl)sulfonyl" includes
`includes
`butyl. The
`ethanesulfonyl
`methanesulfonyl,
`methanesulfonyl, ethanesulfonyl propanesulfonyl,
`propanesulfonyl,
`isopropanesulfonyl, butanesulfonyl and the like. The term
`and the like. The term
`butanesulfonyl
`isopropanesulfonyl,
`"halo" includes fluoro, chloro, bromo and iodo.
`"halo" includes fluoro, chloro, bromo and iodo.
`The term "substituted alkyl" is taken to mean an alkyl
`The term "substituted alkyl" is taken
`to mean an alkyl
`moiety substituted with up to three substituents selected
`selected
`moiety substituted with up
`to three substituents
`from the group consisting of hydroxy, C, — C4 alkoxy, halo,
`from the group consisting of hydroxy, C1—C, alkoxy, halo,
`aryloxy, C, — C4 alkoxycarbonyl
`aryloxy, C1—C, alkoxycarbonyl and heteroaryloxy.
`and heteroaryloxy.
`phenyl" or "phenyl(C, — C4
`term "substituted
`The term "substituted phenyl" or "phenyl(C1—C4
`The
`alkylene) substituted in the phenyl ring" is taken to mean the
`in the phenyl ring" is taken to mean the
`alkylene) substituted
`phenyl moiety may be substituted with one substituent
`phenyl moiety may be substituted with one substituent
`the group consisting of halo, C, — C4 alkyl,
`selected from the group consisting of halo, C1—C4 alkyl,
`selected from
`nitro, cyano, di(C, — C4
`Cy C8 alkoxy, C, — C4 alkylthio,
`C1—C8 alkoxy, C1—C4 alkylthio, nitro, cyano, di(C1—C4
`alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl,
`trifluoromethoxy,
`trifluoromethyl,
`alkyl)amino,
`phenyl,
`C, — C4 acyl, benzoyl or (C, — C4 alkyl)sulfonyl,
`C1—C4 acyl, benzoyl or (C1—C4 alkyl)sulfonyl, or two to
`or two to
`three substituents independently selected from the group
`selected from
`three substituents
`the group
`independently
`consisting of halo, nitro, C, — C4 alkyl, or C, — C4 alkoxy.
`consisting of halo, nitro, C1—C4 alkyl, or C1—C4 alkoxy.
`The term "heterocycle" is taken to mean stable aromatic
`The term "heterocycle" is taken to mean stable aromatic
`and non-aromatic 5- and 6-membered
`and non-aromatic 5- and 6-membered rings containing car-
`rings containing car-
`bon and from 1 to 3 heteroatoms
`bon and from 1 to 3 heteroatoms selected from the group
`selected from the group
`consisting of nitrogen, oxygen and sulfur, said rings being
`consisting of nitrogen, oxygen and sulfur, said rings being
`optionally monobenzofused. All of these
`optionally monobenzofused. All of these rings may be
`rings may be
`substituted with up to three substituents independently
`to
`substituents
`substituted with up
`three
`independently
`selected from the group consisting of halo, C, — C4 alkoxy,
`C, — C4 alkyl, cyano, nitro, hydroxy, — S(O)„-(C, — C4 alkyl)
`selected from the group consisting of halo, C1—C4 alkoxy,
`and — S(O)„-phenyl where n is 0, 1 or 2. Where tautomers
`C1—C4 alkyl, cyano, nitro, hydroxy, —S(0),-(C1—C4 alkyl)
`and —S(0),-phenyl where n is 0, 1 or 2. Where tautomers
`are possible, all tautomeric forms are contemplated by the
`forms are contemplated by the
`are possible, all tautomeric
`present invention. Non-aromatic rings include, for example,
`present invention. Non-aromatic
`rings include, for example,
`pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl,
`tetrahydrofuryl,
`piperazinyl,
`piperidinyl,
`pyrrolidinyl,
`oxazolidinyl, dioxanyl, pyranyl, and the like. Benzofused
`and the like. Benzofused
`oxazolidinyl, dioxanyl, pyranyl,
`1, 2, 3, 4-
`non-aromatic
`include
`indolinyl,
`rings
`non-aromatic rings include indolinyl, 1,2,3,4-
`tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and
`1, 2, 3, 4-tetrahydroisoquinolinyl
`tetrahydroquinolinyl,
`and
`the like. Aromatic rings include furyl, thienyl, pyridinyl,
`the like. Aromatic
`include
`rings
`thienyl, pyridinyl,
`furyl,
`pyridinyl-N-oxide, pyrrolyl, N-methylpyrrolyl, oxazolyl,
`pyridinyl-N-oxide,
`oxazolyl,
`pyrrolyl, N-methylpyrrolyl,
`isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl,
`isoxazolyl, pyrazolyl,
`triazolyl, oxadiazolyl,
`imidazolyl,
`thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,
`thiadiazolyl,
`thiazolyl, pyrimidinyl,
`pyrazinyl, pyridazinyl,
`like. Benzofused
`aromatic
`and the like. Benzofused aromatic rings include
`include
`rings
`the
`and
`isoquinolinyl-N-oxide,
`isoquinolinyl, isoquinolinyl-N-oxide, benzoxazolyl,
`benzoxazolyl,
`isoquinolinyl,
`quinolinyl-N-oxide,
`benzthiazolyl,
`quinolinyl,
`benzthiazolyl, quinolinyl, quinolinyl-N-oxide,
`benzofuranyl, thionaphthyl, indolyl and the like.
`indolyl and the like.
`benzofuranyl,
`thionaphthyl,
`The term "heteroaryl"
`The term "heteroaryl" is taken to mean an aromatic or
`is taken to mean an aromatic or
`benzofused aromatic heterocycle as defined in the previous
`benzofused aromatic heterocycle as defined
`in the previous
`paragraph. The term "substituted heteroaryl" is taken to
`paragraph. The term "substituted heteroaryl"
`to
`is taken
`mean an aromatic or benzofused aromatic heterocycle as
`aromatic heterocycle as
`mean an aromatic or benzofused
`defined in the previous paragraph substituted with up to
`substituted with up to
`defined
`in the previous paragraph
`three substituents independently selected from the group
`selected from
`three substituents
`the group
`independently
`consisting of halo, C, — C4 alkoxy, C, — C4 alkyl, cyano, nitro,
`hydroxy, — S(O)„-(C, — C4 alkyl) and — S(O)„-phenyl where
`consisting of halo, C1—C4 alkoxy, C1—C4 alkyl, cyano, nitro,
`hydroxy, —S(0),-(C1—C4 alkyl) and —S(0),-phenyl where
`n is 0, 1 or 2. Where tautomers are possible, all tautomeric
`n is 0, 1 or 2. Where tautomers are possible, all tautomeric
`forms are contemplated by the present invention. The term
`forms are contemplated by the present
`invention. The term
`"heteroaryl(C, — C4 alkyl)
`"heteroaryl(C4—C4 alkyl) is taken to mean a branched or
`to mean a branched or
`is taken
`linear alkyl chain of 1 to 4 carbon atoms substituted at some
`linear alkyl chain of 1 to 4 carbon atoms substituted at some
`point with an aromatic or benzofused aromatic heterocycle
`point with an aromatic or benzofused aromatic heterocycle
`moiety. The term "substituted heteroaryl(C, — C4 alkyl)" is
`moiety. The term "substituted heteroaryl(C1—C4 alkyl)" is
`to mean a branched or linear alkyl chain of 1 to 4
`taken to mean a branched or linear alkyl chain of 1 to 4
`taken
`carbon atoms substituted at some point with an aromatic or
`carbon atoms substituted at some point with an aromatic or
`benzofused aromatic heterocycle moiety which is substi-
`is substi-
`aromatic heterocycle moiety which
`benzofused
`tuted with up to three substituents independently selected
`selected
`tuted with up to three substituents
`independently
`the group consisting of halo, C, — C4 alkoxy, C, — C4
`alkyl, cyano, nitro, hydroxy, — S(O)„-(C, — C4 alkyl) and
`from the group consisting of halo, C1—C4 alkoxy, C1—C4
`from
`— S(O)„-phenyl where n is 0, 1 or 2.
`alkyl, cyano, nitro, hydroxy, —S(0),-(C1—C4 alkyl) and
`—S(0),-phenyl where n is 0, 1 or 2.
`
`5
`5
`
`25
`25 (cid:9)
`
`30
`3
`
`35
`35
`
`15
`15 (cid:9)
`
`4
`The term "heteroaryloxy" is taken to mean a heteroaryl or
`The term "heteroaryloxy"
`is taken to mean a heteroaryl or
`substituted heteroaryl group, as defined in the previous
`heteroaryl
`group, as defined
`substituted
`the previous
`in
`paragraph, bonded to an oxygen atom.
`to an oxygen atom.
`paragraph, bonded
`The term "aryloxy" is taken to mean a phenyl or substi-
`The term "aryloxy" is taken to mean a phenyl or substi-
`tuted phenyl group bonded to an oxygen atom.
`to an oxygen atom.
`tuted phenyl group bonded
`The term "4-substituted piperazine" is taken to mean a
`The term "4-substituted piperazine"
`is taken
`to mean a
`piperazine ring substituted at the 4-position with a substitu-
`at the 4-position with a substitu-
`ring substituted
`piperazine
`the group consisting of Cy C6 alkyl,
`ent selected from the group consisting of C1—C6 alkyl,
`ent selected
`from
`C, — C4 alkoxy substituted Cy C6 alkyl, phenyl, substituted
`C1—C4 alkoxy substituted C1—C6 alkyl, phenyl, substituted
`10
`phenyl, phenyl(C, — C4 alkylene), phenyl(C, — C4 alkylene)
`10 phenyl, phenyl(C1—C4 alkylene), phenyl(C1—C4 alkylene)
`substituted in the phenyl ring, heteroaryl, and heteroaryl
`and heteroaryl
`substituted
`ring, heteroaryl,
`in the phenyl
`(C, — C4 alkylene).
`(C1—C4 alkylene).
`The term "benzofused C4 — C8 cycloalkyl" is taken to mean
`The term "benzofused C4—C8 cycloalkyl" is taken to mean
`a C4 — C8 cycloalkyl group fused to a phenyl ring. Examples
`
`4—C a C, cycloalkyl group fused to a phenyl ring. Examples
`indanyl, 1, 2, 3, 4-
`of these groups
`of these groups include benzocyclobutyl, indanyl, 1,2,3,4-
`include benzocyclobutyl,
`tetrahydronaphthyl, and the like.
`and the like.
`tetrahydronaphthyl,
`While all of the compounds of this invention are useful as
`While all of the compounds of this invention are useful as
`5-HT1F agonists, certain classes are preferred. The follow-
`5 HTy~ agonists, certain classes are preferred. The follow-
`20 ing paragraphs describe such preferred classes.
`ing paragraphs describe such preferred classes.
`20
`aa) R is hydrogen;
`aa) R is hydrogen;
`ab) R is methyl;
`ab) R is methyl;
`ac) X is — NR'SO~R;
`ac) X is —NR1SO2R2;
`ad) X is — NHC(Q)NR R;
`ad) X is —NHC(Q)NR3R4;
`ae) X is — NHC(O)OR;
`ae) X is —NHC(0)0R5;
`af) X is — NR'C(O)R;
`at) X is —NR1C(0)R6;
`ag) Qis 0;
`ag) Q is 0;
`ah) R' is H;
`ah) R1 is H;
`ai) R2 is phenyl;
`ai) R
`is phenyl;
`aj)R isH;
`aj) R3 is H;
`is C, — C4 alkyl;
`ak) R4 is C1—C4 alkyl;
`ak) R
`al) R4 is methyl;
`al) R
`is methyl;
`am) R4 is phenyl;
`am) R
`is phenyl;
`is C~ — C8 alkenyl;
`an) R4 is C3—C8 alkenyl;
`an) R
`ao) R4 is allyl;
`ao) R
`is allyl;
`ap) R4 is phenyl monosubstituted with halo;
`ap) R
`is phenyl monosubstituted with halo;
`aq) R4 is 4-fluorophenyl;
`aq) R
`is 4-fluorophenyl;
`ar) R4 is heteroaryl;
`ar) R
`is heteroaryl;
`as) R4 is 4-pyridyl;
`as) R
`is 4-pyridyl;
`is C, — C4 alkyl;
`at) R5 is C1—C4 alkyl;
`at) R
`au) R5 is methyl;
`au) R
`is methyl;
`av) R5 is ethyl;
`av) R
`is ethyl;
`aw) R5 is propyl;
`aw) R
`is propyl;
`is C, — C, 0 alkyl;
`ax) R6 is C1—C10 alkyl;
`ax) R
`is C, — C4 alkyl;
`ay) R6 is C1—C4 alkyl;
`ay) R
`az) R6 is methyl;
`az) R
`is methyl;
`ba) R6 is ethyl;
`ba) R
`is ethyl;
`bb) R6 is propyl;
`bb) R
`is propyl;
`is C~ — C6 alkenyl;
`bc) R6 is C3—C6 alkenyl;
`bc) R
`bd) R6 is allyl;
`bd) R
`is allyl;
`is C~ — C6 cycloalkyl;
`be) R6 is C3—C6 cycloalkyl;
`be) R
`bf) R6 is cyclopropyl;
`bf) R
`is cyclopropyl;
`bg) R6 is cyclobutyl;
`bg) R
`is cyclobutyl;
`bd) R6 is phenyl;
`bd) R
`is phenyl;
`be) R6 is phenyl monosubstituted with halo;
`be) R
`is phenyl monosubstituted with halo;
`bf) R6 is phenyl monosubstituted with fluoro;
`bf) R
`is phenyl monosubstituted with fluoro;
`bg) R6 is 4-fluorophenyl;
`bg) R
`is 4-fluorophenyl;
`bh) R6 is phenyl monosubstituted with nitro;
`bh) R
`is phenyl monosubstituted with nitro;
`bi) R6 is phenyl monosubstituted with cyano;
`bi) R
`is phenyl monosubstituted with cyano;
`bj) R6 is 4-nitrophenyl;
`bj) R
`is 4-nitrophenyl;
`
`40
`40 (cid:9)
`
`45
`45 (cid:9)
`
`50
`50 (cid:9)
`
`55
`55
`
`60
`60 (cid:9)
`
`65
`65 (cid:9)
`
`

`
`5
`5
`
`10
`10
`
`15
`15
`
`20
`20
`
`bk) R6 is 4-cyanophenyl;
`bk) R
`is 4-cyanophenyl;
`bl) R6 is a heterocycle;
`bl) R is a heterocycle;
`substituted with C, — C4 alkyl,
`bm) R6 is furyl optionally substituted with C1-C, alkyl,
`bm) R
`is furyl optionally
`C, — C4 alkoxy, or halo;
`C1-C4 alkoxy, or halo;
`bn) R6 is 3-furyl;
`bn) R
`is 3-furyl;
`bo) R6 is thienyl optionally substituted with halo,
`bo) R
`is thienyl optionally
`substituted with halo,
`C, — C4alkyl or C, — C4 alkoxy;
`C1-C4alkyl or C1-C4 alkoxy;
`bp) R6 is 3-thienyl;
`bp) R
`is 3-thienyl;
`bq) R6 is pyridinyl optionally substituted with halo,
`bq) R
`is pyridinyl
`substituted with halo,
`optionally
`C, — C4 alkyl or C, — C4 alkoxy;
`C1-C4 alkyl or C1-C4 alkoxy;
`br) R6 is 4-pyridinyl;
`br) R
`bs) A — B is — C=CH —;
`is 4-pyridinyl;
`bs) A-B is -C=CH-;
`bt) A — B is — CH — CH~ —;
`bt) A-B is -CH-CH2-;
`bu) The compound is a free base;
`is a free base;
`bu) The compound
`by) The compound is a salt;
`is a salt;
`bv) The compound
`bw) The compound is the hydrochloride salt;
`bw) The compound
`is the hydrochloride
`salt;
`bx) The compound is the fumarate salt.
`is the fumarate salt.
`bx) The compound
`It will be understood that the above classes may be com-
`that the above classes may be com-
`It will be understood
`bined to form additional preferred classes. (cid:9)
`bined to form additional preferred classes.
`The compounds of the present
`The compounds of the present invention may, depending
`invention may, depending
`upon their structure and manner of synthesis and isolation,
`upon their structure and manner of synthesis and isolation,
`exist as a pharmaceutically acceptable solvate. These sol-
`acceptable solvate. These sol-
`exist as a pharmaceutically
`vates include water, methanol, and ethanol. Solvated forms
`vates include water, methanol, and ethanol. Solvated forms
`of the compounds of the present
`of the compounds of the present invention represent a 25
`represent
`invention
`a 25
`further embodiment of the present
`further embodiment of the present invention.
`invention.
`The compounds of this invention are useful in a method
`The compounds of this invention are useful in a method
`for increasing activation of the 5-HT, ~ receptor for treating
`for increasing activation of the 5-HTi, receptor for treating
`a variety of disorders which have been linked
`a variety of disorders which have been linked to decreased
`to decreased
`of serotonin
`neurotransmission of serotonin in mammals. It is preferred 30
`It is preferred
`in mammals.
`neurotransmission
`30
`of
`that the mammal to be treated by the administration of
`to be treated by the administration
`the mammal
`that
`compounds of this invention
`compounds of this invention is human.
`is human.
`Since the compounds of this invention are amines,
`Since the compounds of this invention are amines, they
`they
`react with any of a
`are basic in nature and accordingly react with any of a
`are basic in nature
`and accordingly
`number of inorganic and organic acids to form pharmaceu-
`number of inorganic and organic acids to form pharmaceu-
`35
`35
`tically acceptable acid addition salts. It is preferable to
`salts. It is preferable
`tically acceptable acid addition
`to
`convert the free amines to their pharmaceutically acceptable
`acceptable
`convert the free amines to their pharmaceutically
`acid addition salts for ease of handling
`acid addition salts for ease of handling and administration.
`and administration.
`Acids commonly employed to form such salts are inorganic
`Acids commonly employed
`to form such salts are inorganic
`acids such as hydrochloric acid, hydrobromic acid, 40
`acids such as hydrochloric
`acid, hydrobromic
`acid, 40
`hydroiodic acid, sulfuric acid, phosphoric acid, and the like,
`hydroiodic acid, sulfuric acid, phosphoric acid, and the like,
`and organic acids, such as p-toluenesulfonic acid, methane-
`acid, methane-
`and organic acids, such as p-toluenesulfonic
`sulfonic acid, oxalic acid, p-bromophenylsulfonic acid, car-
`acid, car-
`sulfonic acid, oxalic acid, p-bromophenylsulfonic
`bonic acid, succinic acid, citric acid, benzoic acid, acetic
`bonic acid, succinic acid, citric acid, benzoic acid, acetic
`like. Examples of such pharmaceutically
`acid and the like. Examples of such pharmaceutically 45
`acid and
`the
`45
`acceptable salts thus are the sulfate, pyrosulfate, bisulfate,
`acceptable salts thus are the sulfate, pyrosulfate, bisulfate,
`sulfite, bisulfite, phosphate, monohydrogenphosphate,
`sulfite, bisulfite, phosphate, monohydrogenphosphate,
`dihydrogenphosphate, metaphosphate, pyrophosphate,
`metaphosphate,
`dihydrogenphosphate,
`pyrophosphate,
`chloride, bromide, iodide, acetate, propionate, decanoate,
`iodide, acetate, propionate, decanoate,
`chloride, bromide,
`caprylate, acrylate, formate, isobutyrate, caproate, 50
`formate,
`caproate,
`acrylate,
`isobutyrate,
`caprylate,
`heptanoate, propiolate, oxalate, malonate, succinate,
`succinate,
`oxalate, malonate,
`heptanoate,
`propiolate