EP0749313A1 - Verfahren zur behandlung von mit dem 5-ht2b-rezeptor verbundenen zuständen - Google Patents

Verfahren zur behandlung von mit dem 5-ht2b-rezeptor verbundenen zuständen

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Publication number
EP0749313A1
EP0749313A1 EP95914014A EP95914014A EP0749313A1 EP 0749313 A1 EP0749313 A1 EP 0749313A1 EP 95914014 A EP95914014 A EP 95914014A EP 95914014 A EP95914014 A EP 95914014A EP 0749313 A1 EP0749313 A1 EP 0749313A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
compound
indole
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95914014A
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English (en)
French (fr)
Other versions
EP0749313A4 (de
Inventor
James Edmund Audia
Marlene Lois Cohen
Jaswant Singh Gidda
David Lloyd Garver Nelson
Stephen Richard Baker
Jesus Ezquerra-Carrera
Carlos Lamas-Peteira
Concepcion Pedregal-Tercero
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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Filing date
Publication date
Priority claimed from US08/380,566 external-priority patent/US5688807A/en
Priority claimed from US08/380,565 external-priority patent/US5663178A/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0749313A1 publication Critical patent/EP0749313A1/de
Publication of EP0749313A4 publication Critical patent/EP0749313A4/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
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    • A61P1/12—Antidiarrhoeals
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the present invention relates to a method for treating 5HT 2B receptor related conditions. Further, this application discloses new compounds of Formulas XI and XII infra .
  • This invention is directed to a method for treating a mammal suffering from or susceptible to a condition associated with modulation of a 5-HT 2B receptor.
  • Blocking serotonin receptors has been shown to result in a number of beneficial pharmacological effects, including reduction in disease states such as hypertension, depression, anxiety, and the like; see U.S. Patent No. 5,141,944.
  • Nelson et al . Psychopharmacolocrv and Biochemistry of Neurotransmitter Receptors, eds. H.I. Yamamura et al . , Elsevier/North Holland Inc., p 325, have confirmed that there are multiple serotonin recognition sites.
  • the general class of serotonin receptors are referred to as the 5-HT receptors.
  • 5-HT receptor sites include 5-HTI A , 5-HTI B , 5-HTID, 5-HT 2A 5-HT2B, 5-HT2C, 5-HT 3f and 5-HT4 sites.Each of these receptors mediates certain physiological effects. See Leonard, B.E., International Clinical Psvcho ⁇ harmacolo ⁇ y. 7:13-21 (1992) .
  • This invention provides a method for using compounds which are active at the 5-HT 2B receptor to treat or prevent 5-HT 2B related conditions. Further, this invention provides a method for selectively blocking the 5-HT 2B receptor. Additionally, this invention provides a method for blocking human 5-HT 2B receptors.
  • the 5-HT 2B receptor active compounds provide a useful tool for characterizing the 5-HT 2B receptor.
  • This invention provides a group of compounds which are 5HT 2B receptor antagonists. Applicants have discovered that such compounds are potent competitive inhibitors of serotonin-induced contraction of the colon. Thus, this invention provides compounds which can act to normalize gastrointestinal motility and be useful in the treatment of Functional Bowel Disorders.
  • 5-HT 2B receptor is localized in the rat lung, stomach fundus, uterus, bladder, and colon.
  • interesting areas of 5-HT 2B receptor localization in the human include but are not limited to the brain and blood vessels.
  • conditions which can be treated using a compound which modulates a 5-HT 2B receptor includes, for example, psychosis, depression, anxiety disorders, uterine diseases such as endometriosis, fibrosis, and other abnormal uterine contractivity, panic attack, migraine, eating disorders, seasonal affective disorder, consumption disorders, cardiovascular conditions, such as thrombosis, hypertension, angina, vasospasm, and other vascular occlusive diseases, incontinence, bladder dysfunction, respiratory/airway disorders including asthma, and the like.
  • This invention provides a method for treating a mammal suffering from or susceptible to a condition associated with dysfunctional or abnormal 5-HT 2B receptor stimulation, comprising administering an effective amount of a compound interacting with the 5HT 2B receptor as an agonist, partial agonist or antagonist selected from the group consisting of a compound of the Formula I
  • Q is hydrogen or (CHR 2 .R 4
  • R l is hydrogen or C 1 -C 3 alkyl
  • R 2 is hydrogen or C 1 -C 3 alkyl
  • R 3 is hydrogen or C 1 -C 3 alkyl
  • R 4 is C 5 -C8 cycloalkyl, substituted C 5 -C 8 cycloalkyl, C 5 - Cg cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, bicyclic or substituted bicyclic;
  • A is selected from the group consisting of
  • R ⁇ and R 7 are, independently, hydrogen, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 1 -C 6 ) alkyl, halo (C 2 -C 6 ) alkenyl, COR5, C1-C10 alkanoyl, CO2R5 ' , (Ci-C ⁇ alkyl) m amino, NO 2 , -SR 5 , or OR 5 ; m is 1 or 2;
  • R 5 is independently hydrogen or C 1 -C 4 alkyl
  • R 5' is C 1 -C 4 alkyl
  • R ⁇ is independently selected from the group consisting of an R ⁇ group, substituted C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl- (C ⁇ C 3 ) alkyl, C 7 -C 20 arylalkyl; or
  • R is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 2 -C 6 ) alkyl, halo (Ci-C ⁇ ) alkenyl, COR5, C 1 -C 10 alkanoyl, CO 2 R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR5, OR5, substituted C 3 -C 8 cycloalkyl, C 3 - Cs cycloalkyl, C3-C8 cycloalkyl- (C 1 -C 3 ) alkyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl, and C 7 -C 20 arylalkyl;
  • R 5 is independently hydrogen or C 1 -C 4 alkyl
  • R 5 - is C 1 -C 4 alkyl
  • Rg and Rio are independently selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C 8 cycloalkyl- (C 1 -C3)alkyl, C 5 -C 8 cycloalkenyl- (C 1 -C 3 )alkyl, C7-C 2 0 arylalkyl;
  • R ll is selected from the group consisting of C 1 -C 4 alkyl, OR 5' , fluoro, bromo, iodo, and chloro;
  • R 12 ⁇ is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; a compound of Formula III
  • R 12 is C 1 -C 4 alkyl or allyl ;
  • R 13 is -O- or -N (R 15 ) - ;
  • R 15 is hydrogen or C 1 -C 4 alkyl
  • R 14 is C 1 -C 4 alkyl, hydroxy C ⁇ -C alkyl, C 3 -C 7 cycloalkyl, and C3-C7 cycloalkyl substituted with hydroxy or methoxy; a compound of Formula IV
  • R 15 ' is C 1 -C 4 alkyl
  • R 16 is allyl or C 1 -C 4 straight chain alkyl
  • R 17 is hydrogen or C 1 -C 4 straight chain alkyl
  • R 18 is hydrogen, C 1 -C 4 alkyl, hydroxy, or C 1 -C 4 alkyloxy; m' is 0, 1, 2, or 3; a compound of Formula V
  • R 19 is C 1 -C 4 alkyl
  • R 20 is allyl or C 1 -C 4 straight chain alkyl ;
  • R 21 is hydrogen or C 1 -C 4 straight chain alkyl;
  • R 22 is pyridinyl or imidazolyl;
  • alk is a divalent organic radical derived from a straight or branched C 1 -C5 alkane; a compound of Formula VI
  • R 23 is C 1 -C3 alkyl or allyl
  • R 24 is C 1 -C3 hydroxyalkyl or C 1 -C 3 dihydroxyalkyl
  • R 25 is hydrogen or CH 3 ; a compound of Formula VII
  • R 25 ' is hydrogen or methoxy
  • Y b in combination with the carbon atom to which it is joined, defines a substituted or unsubtituted aromatic heterocyclic 5-membered ring selected from the group consisting of
  • R 26 is hydrogen, C 1 -C 3 alkyl, allyl, or ⁇ - ⁇ ] -CH 2 - ⁇ ]
  • R 27 is hydrogen, C 1 -C3 alkyl, allyl, , or
  • X" is an optionally substituted phenyl, C 1 -C 3 alkoxy, or C 1 -C 3 alkylthio;
  • R 28 and R 29 are independently hydrogen, C 1 -C 3 alkyl, Ci- C 3 alkoxy, hydroxy, C 1 -C3 alkylthio, halo, CN, phenyl; or together are -(CH 2 .p»-; p" is 3 to 6;
  • Y a is -CH 2 -, -0-, - ⁇ (0) m ..-; m" is 0, 1, or 2; and a compound of the Formula X
  • This invention provides a method for treating a mammal suffering from or susceptible to a condition associated with dysfunctional or abnormal 5-HT 2B receptor stimulation, comprising administering an effective amount of a compound interacting with the 5HT 2B receptor as an agonist, partial agonist or antagonist selected from the group consisting of a compound of the Formula XI
  • Q' is selected from the group consisting of hydrogen, R 34 , and
  • R 34 is selected from the group consisting of spiro- bicyclic, substituted spiro-bicyclic, bicyclic or substituted bicyclic;
  • R l is hydrogen or C 1 -C 3 alkyl
  • R 2 is hydrogen or C -C alkyl
  • R 3 is hydrogen or C 1 -C 3 alkyl
  • R 4 is C 5 -C 8 cycloalkyl, substituted C 5 -C 8 cycloalkyl, C 5 - C ⁇ cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, bicyclic or substituted bicyclic;
  • A is selected from the group consisting of
  • R ⁇ and R 7 are, independently, hydrogen, Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, halo, halo (Ci-C ⁇ )alkyl, halo(C 2 -C 6 ) alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5 ⁇ , (Ci-C ⁇ alkyl) m amino, N0 , -SR 5 , or OR 5 ; m is 1 or 2;
  • R 5 is independently hydrogen or C 1 -C 4 alkyl
  • R 5 is C 1 -C 4 alkyl
  • Rg is independently selected- from the group consisting of an Re group, substituted C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl- (C ⁇ C 3 )alkyl, C 7 -C2 0 arylalkyl; or
  • R ⁇ and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
  • R 30 and R 31 join to form a 3 to 8 member carbon ring
  • R 30 and R 31 are independently selected from the group consisting of C -C ⁇ alkyl and C 2 -C 6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • This invention provides a method for treating a mammal suffering from or susceptible to a condition associated with dysfunctional or abnormal 5-HT 2B receptor stimulation, comprising administering an effective amount of a compound interacting with the 5HT 2B receptor as an agonist, partial agonist or antagonist selected from the group consisting of a compound of the Formula XII
  • A is selected from the group consisting of
  • Rs and R 7 are, independently, hydrogen, Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, halo, halo (Ci-Cg) alkyl, halo(C 2 -C 6 ) alkenyl, COR 5 , C 1 -C 10 alkanoyl, C0 2 R 5 -, (Ci-C ⁇ alkyl) m amino, NO 2 , -SR 5 , or OR 5 ; m is 1 or 2 ;
  • R ⁇ is selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, halo, halo (C 2 -C 6 ) alkyl, halo (C -C ⁇ ) alkenyl, COR5, C 1 -C 10 alkanoyl, CO 2 R 5 ', (Ci-C ⁇ alkyl) m amino, NO 2 , -SR 5 , ORs, substituted C 3 -C cycloalkyl, C 3 - Cs cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl, Cs-Cg cycloalkenyl, substituted Cs-C cycloalkenyl, C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl, and C 7 -C 20 arylalkyl;
  • R 5 is independently hydrogen or C 1 -C 4 alkyl
  • R 5 - is C 1 -C 4 alkyl
  • R ⁇ and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
  • R 9 and Rio are independently selected from the group consisting of hydrogen, C -C ⁇ alkyl, substituted C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl, C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl, C 7 -C 20 arylalkyl;
  • R 11 is selected from the group consisting of C 1 -C 4 alkyl, OR 5 • , fluoro, bro o, iodo, and chloro;
  • R 30 and R 31 join to form a 3 to 8 member carbon ring
  • R 30 and R 31 are independently selected from the group consisting of C ⁇ Cs alkyl and C 2 -C 6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • this invention provides a method for blocking a 5HT 2B receptor in a mammal, comprising administering a 5H 2B receptor occupying dose of a compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra . ; or a pharmaceutically acceptable salt or solvate thereof.
  • This invention provides a method for blocking a 5HT 2B receptor in a mammal, comprising administering a 5H 2B receptor occupying dose of a compound selected from the group consisting of Formula XI, and XII supra . ; or a pharmaceutically acceptable salt or solvate thereof.
  • this invention provides a method for selectively interacting with the 5-HT 2B receptor in a mammal, comprising administering a 5-HT 2B selective compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra . ; or a pharmaceutically acceptable salt or solvate thereof to a mammal.
  • This invention provides a method for selectively interacting with the 5-HT 2B receptor in a mammal, comprising administering a 5-H 2B selective compound selected from the group consisting of of Formula XI and XII; or a pharmaceutically acceptable salt or solvate thereof to a mammal .
  • the present invention provides compounds of the Formula XI wherein Q' is selected from the group consisting of hydrogen, R 34 , and (CHR 2 )R 4 ;
  • R 34 is selected from the group consisting of spiro- bicyclic, substituted spiro-bicyclic, bicyclic or substituted bicyclic;
  • R is hydrogen or C 1 -C 3 alkyl
  • R 2 is hydrogen or Ci-C ⁇ alkyl
  • R 3 is hydrogen or C 1 -C 3 alkyl
  • R 4 is C 5 -C 8 cycloalkyl, substituted Cs-Cg cycloalkyl, C 5 - Cg cycloalkenyl, substituted Cs-Cg cycloalkenyl, bicyclic or substituted bicyclic;
  • A is selected from the group consisting of
  • R ⁇ and R 7 are, independently, hydrogen, C -C ⁇ alkyl, C 2 -C 6 alkenyl, halo, halo (Ci-C ⁇ ) alkyl, halo (C 2 -C 6 ) alkenyl, COR 5 , C 1 -C 10 alkanoyl, C ⁇ Rs-, (Ci-C ⁇ alkyl) m amino, NO 2 , -SR 5 , or OR 5 ; m is 1 or 2 ;
  • R 5 is independently hydrogen or C 1 -C 4 alkyl
  • R 5 - is C 1 -C 4 alkyl
  • Rg is independently selected from the group consisting of an R ⁇ group, substituted C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl- (C ⁇ C 3 ) alkyl, C 7 -C 20 arylalkyl; or
  • R ⁇ and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
  • R 30 and R 31 join to form a 3 to 8 member carbon ring
  • R 30 and R 31 are independently selected from the group consisting of Ci-C ⁇ alkyl and C 2 -C 6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • This invention provides compounds of Formula XII
  • A is selected from the group consisting of
  • R ⁇ _ and R 7 are, independently, hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (Ci-C ⁇ )alkyl, halo (C 2 -C 6 . alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R5 ' , (Ci-C ⁇ alkyl) ⁇ n amino, N0 , -SR 5 , or OR 5 ; m is 1 or 2;
  • Rg is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 2 -C 6 . alkyl, halo(Ci-C ⁇ ) alkenyl, CORs, C 1 -C 10 alkanoyl, CO 2 R 5 ⁇ , (C ⁇ -C6 alkylJm-amino, NO 2 , -SR 5 , ORs, substituted C 3 -C 8 cycloalkyl, C 3 - Cs cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 )alkyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl, and C 7 -C 20 arylalkyl;
  • R 5 is independently hydrogen or C 1 -C 4 alkyl
  • R 5 is C 1 -C 4 alkyl
  • R ⁇ and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
  • R 9 and Rio are independently selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, substituted C 3 -C 8 cycloalkyl., C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl, C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl, C 7 -C 20 arylalkyl;
  • R l i is selected from the group consisting of C 1 -C 4 alkyl, OR 5' , fluoro, bromo, iodo, and chloro; R 30 and R 31 join to form a 3 to 8 member carbon ring; or
  • R 30 and R 31 are independently selected from the group consisting of Ci-C ⁇ alkyl and C 2 -C 6 alkenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • this invention provides a method for interacting with a human 5-HT 2B receptor in a human, comprising administering a 5-HT 2B blocking dose of a compound selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceutically acceptable salt or solvate thereof to a human.
  • This invention provides a method for interacting with a human 5-HT 2B receptor in a human, comprising administering a 5-HT2B blocking dose of a compound selected from the group consisting of Formula XI and XII; or a pharmaceutically acceptable salt or solvate thereof.
  • a further embodiment of this invention is an article of manufacture comprising packaging material and one or more pharmaceutical agents contained within said packaging material, wherein said pharmaceutical agent is effective for the treatment of a condition requiring 5-HT 2B receptor occupation and is selected from the group consisting of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceutically acceptable salt or solvate thereof; and said packaging material comprises a label which indicates that said pharmaceutical agent can be used for the treatment of a condition requiring 5-HT 2B receptor modulation.
  • Another embodiment of this invention is an article of manufacture comprising packaging material and one or more pharmaceutical agents contained within said packaging material, wherein said pharmaceutical agent is effective for the treatment of a condition requiring 5-HT 2B receptor occupation and is selected from the group consisting of a compound of Formula XI, and XII supra . ; or a pharmaceutically acceptable salt or solvate thereof; and said packaging material comprises a label which indicates that said pharmaceutical agent can be used for the treatment of a condition requiring 5-H 2B receptor modulation.
  • treating includes prophylaxis of the named physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established.
  • Typical Ci-C ⁇ alkyl groups include methyl, ethyl, ⁇ -propyl, iso- propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • R 30 and R 31 join to form a 3 to 8 member carbon ring shall mean that R 30 and R 31 are most preferably independently selected from the group consisting of C 1 -C6 alkyl and C 2 -C 6 alkenyl.
  • the carbon ring thus formed may be saturated or unsaturated. As used herein, such ring may be illustrated as:
  • n 30 shall refer to the total number of carbon atoms in the ring thus formed.
  • Such carbon ring may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C 1 -C6 alkyl, NO 2 , halo, halo(Ci-C ⁇ )alkyl, halo(C 2 -C6. alkenyl, C 2 -C6 alkenyl, CO2R5, (Ci-C ⁇ alkyl) m amino, -SR5, and OR5.
  • a preferred embodiment is when R 30 and R 31 join to form a C 3 -C 6 member saturated carbon ring. It is another preferred embodiment that R 30 and R 31 join to form a C 3 -C 5 member saturated carbon ring.
  • R 30 and R 31 do not join to form a carbon ring, it is a preferred embodiment that R 30 and R 31 are independently selected from the group consisting of C 1 -C 3 alkyl.
  • halide include fluorine, chlorine, bromine, and iodine.
  • halogen include fluorine, chlorine, bromine, and iodine.
  • the preferred halogen is chlorine.
  • halo(C ⁇ C 6 )alkyl and “halo(C 2 - C ⁇ )alkenyl” refer to alkyl or alkenyl substituents having one or more independently selected halo atoms attached at one or more available carbon atoms.
  • halo- (Ci-C ⁇ )alkyl groups are trichloromethyl, trichloroethyl, and trifluoromethyl.
  • the most preferred halo- (Ci-Cg)alkyl is trifluoromethyl.
  • Ci-Cio alkanoyl represents a group of the formula C(O) (Ci-Cg) alkyl.
  • Typical Ci-Cio alkanoyl groups include acetyl, propanoyl, butanoyl, and the like.
  • Examples of such groups are methyla ino, dimethylamino, ethylamino, diethylamino, 2-propylamino, 1-propylamino, di(i_- propyl)amino, di (iso-propyl)a ino, methyl-n-propylamino, t- butylamino, and the like.
  • substituted(C 5 ⁇ C n ) cycloalkyl refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, N0 2 , halo, halo(C ⁇ -C 6 )alkyl, halo(C 2 -C ⁇ )alkenyl, C 2 -C6 alkenyl, CO 2 R5, (Ci-C ⁇ alkyl) m amino, -SR 5 , and OR 5 .
  • C3-C8 cycloalkyl- (C 1 -C 3 )alkyl represents a linear alkyl group substituted at a terminal carbon with a C 3 -C 8 cycloalkyl group.
  • Typical cycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl, 3- cyclopentylpropyl, and the like.
  • C5-C8 cycloalkenyl represents an olefinically unsaturated ring having five to eight carbon atoms, eg., phenyl, cyclohexadienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like.
  • substituted (C 5 -C 8 ) cycloalkenyl refers to a cycloalkenyl group as described supra wherein the cycloalkenyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, NO 2 , halo, halo(Ci-C ⁇ )alkyl, halo(C 2 -C6)alkenyl, C2-C6 alkenyl, COR 5 , C 1 -C 10 alkanoyl, C 7 - C20 arylalkyl, CO2R5. ( i-C ⁇ alkyl) m amino, -SR5, and OR5.
  • C5-C8 cycloalkenyl- (C 1 -C 3 )alkyl represents a linear C 1 -C3 alkyl group substituted at a terminal carbon with a C5-C8 cycloalkenyl group.
  • aryl represents phenyl or naphthyl.
  • the aryl group can be unsubstituted or can have one or two substituents independently selected from the group consisting of Ci-C ⁇ alkyl, C3-C8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, C 2 -C6 alkenyl, C3-C8 cycloalkyl- (C 1 -C 3 )alkyl, phenyl, C5-C8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C5-C 8 cycloalkenyl- (C1-C3)alkyl, COR5, C 1 -C 10 alkanoyl, OR5, and C 7 -C 1 6 arylalkyl.
  • the substituents may be located at any available position on the aryl ring.
  • C7-C20 arylalkyl represents an aryl-(C ⁇ - Cioalkyl substituent wherein the alkyl group is linear, such as benzyl, phenethyl, 3-phenylpropyl, or phenyl-t-butyl; or branched.
  • bicyclic represents either an unsaturated or saturated stable 7- to 12-membered bridged or fused bicyclic carbon ring.
  • the bicyclic ring may be attached at any carbon atom which affords a stable structure.
  • the term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
  • the term "unsaturated bicyclic” represents a stable bicyclic ring of 7 to 12 carbon atoms.
  • the unsaturated bicyclic ring may be attached at any carbon atom which affords a stable structure.
  • the unsaturated bicyclic ring may be substituted with from one to four substituents as defined for "substituted bicyclic" infra .
  • substituted bicyclic refers to a bicyclic ring system with up to 4 substituents attached at any desired positions on the bicyclic ring system.
  • the bicyclic substituents may be independently selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, NO 2 , halo, halo(C ⁇ C ⁇ )alkyl, halo(C 2 -C 6 )alkenyl, C 2 -C 6 alkenyl, COR 5 , C 1 -C 10 alkanoyl, C7-C 2 0 arylalkyl, CO 2 R 5 , (C 1 -C 5 alkyl) m amino, -SR 5 , and OR 5 ; wherein R 5 is defined supra .
  • substituted bicyclic substituent may bond to the CHR 2 group through any available carbon atom in the bicyclic ring system.
  • the term includes, but is not limited to compounds such as, 2-methyldicyclohexyl, 3-hydroxydicyclohexyl, benzocyclohexyl, benzocyclohexenyl, 2-methoxybenzocyclohexyl, 6-chlorobenzocyclohexenyl, 8-ethenylbenzocyclohexyl, and the like.
  • spiro-bicyclic and "substituted spiro- bicyclic” refer to a bicyclic or substituted bicyclic (as defined supra.) directly attached to the carbon of the parent ring at substituent Q'.
  • a spiro- bicyclic is attached as shown:
  • naphthyl refers to a naphthalene ring system substituent, as commonly used in organic chemistry.
  • the naphthyl substituent may bond to the CHR 2 group through any available carbon atom in the naphthyl ring system.
  • substituted naphthyl refers to a naphthyl ring system with up to 4 substituents attached at any desired positions on the naphthyl ring system.
  • the naphthyl substituents may be independently selected from the "substituted bicyclic" group supra .
  • phenyl refers to an unsubstituted benzene ring system.
  • substituted phenyl refers to a benzene ring system with from one to three substituents independently selected from the group of bicyclic substituents defined supra ; R 5 is defined supra .
  • C 1 -C 4 alkoxy represents a straight or branched alkoxy chain having from one to four carbon atoms.
  • C 1 -C 4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.
  • the ring attached to the amide nitrogen atom is cyclopentyl; when m is 1, the ring is cyclohexyl; when m 1 is 2, the ring is cycloheptyl; and when m 1 is 3, the ring is cyclooctyl. If the cycloalkyl ring is substituted, the substituent may be at an available position on the ring.
  • pyridinyl refers to 2-, 3-, or 4- pyridinyl.
  • imidazolyl refers to 1-, 2-, or 4- imidazolyl.
  • alk refers to a divalent organic radical derived from a straight or branched C 1 -C 5 alkane.
  • Such groups include but are not limited to -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 ⁇ , -CH(C 2 H 5 )-, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 )2-, -CH 2 CH(CH 3 )CH 2 -, -CH(CH 3 )CH(CH 3 ) -, -CH(CH 3 )CH 2 CH(CH 3 ) -, and the like.
  • phenyl refers to a phenyl ring which may contain one or two substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halo, NO 2 , and CN.
  • selective interaction with a 5-HT 2B receptor refers to a method of interacting with the 5-HT 2B receptor to a greater extent than the 5-HT 2A or" 5-HT 2C receptor.
  • protic acid refers to an acid having an acidic hydrogen.
  • Preferred protic acids include hydrochloric acid, formic acid, perchloric acid, sulfuric acid, and phosphoric acid in an aqueous medium.
  • the most preferred protic acids are hydrochloric acid, sulfuric acid, and formic acid.
  • organic solvent includes solvents containing carbon, such as halogenated hydrocarbons, ether, toluene, xylene, benzene, and tetrahydrofuran.
  • agitate includes such techniques as stirring, centrifugation, mixing, and other similar methods.
  • aprotic solvent refers to polar solvents of moderately high dielectric constant which do not contain an acidic hydrogen.
  • Examples of common aprotic solvents are dimethyl sulfoxide (DMSO) , dimethylformamide, sulfolane, tetrahydrofuran, diethylether, methyl-t-butyl ether, or 1,2- dimethoxyethane.
  • protic solvent refers to a solvent containing hydrogen that is attached to oxygen, and hence is appreciably acidic. Common protic solvents include such solvents as water, methanol, ethanol, 2-propanol, and 1- butanol.
  • inert atmosphere refers to reaction conditions in which the mixture is covered with a layer of inert gas such as nitrogen or argon.
  • ligand refers to compounds that are bound by the indicated receptor. Compounds useful as selective ligands may be used to selectively occupy the specific receptor site or may act as a selective agonist at the specific receptor site.
  • substantially pure is intended to mean at least about 90 mole percent, more preferably at least about 95 mole percent, and most preferably at least about 98 mole percent of the desired enantiomer or stereoisomer is present compared to other possible configurations.
  • Compounds which are contemplated for use in modulating -a 5-HT 2B receptor include, but are not limited to 7-bromo-8-methyl-l, 2,3, 4-tetrahydro-9H-pyrido [3, 4b] -indole, ⁇ -isopropyl-8-methoxy-l,2,3,4-tetrahydro-9H-pyrido[3, 4b] - indole, 5-chloro-8-ethoxy-l, 2,3, 4-tetrahydro-9H-pyrido[3 , 4b] - indole, 6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydro-9H- pyrido [3, 4b] -indole, 5-dimethylamino-8-hydroxy-l,2, 3 , 4- tetrahydro-9H-pyrido[3,4b] -indole, 6-nitro-8-butyl-l,2,3,4- te
  • Patents are herein incorporated by reference, 1,2-dimethyl-3-ethyl-5- (dimethylamino) -indole, 2- (di-n-propylamino) -8- (isothiazol-3- yl) -1,2,3,4-tetrahydronaphthalene, 2-ethylamino-8- (isoxazol- 3-yl) -1,2,3,4-tetrahydronaphthalene, 2-(N-methyl-N- benzylamino) -8- (5-n-propyl-l,2,3-oxadiazol-4-yl) -1,2,3,4- tetrahydronaphthalene, 2-diallylamino-8- (pyrazol-3-yl) - 1,2,3,4-tetrahydronaphthalene, 2-diethylamino-8- (1,3,4- oxadiazol-2-yl) -1,2,3,4-tetrahydronaphthalene, 2-
  • Especially preferred compounds for use in modulating a 5-HT 2B receptor include 7-bromo-8-methyl-l,2,3,4- tetrahydro-9H-pyrido[3,4b] -indole, 6-isopropyl-8-methoxy- 1,2,3,4-tetrahydro-9H-pyrido[3,4b] -indole, 5-chloro-8-ethoxy- 1,2,3,4-tetrahydro-9H-pyrido[3,4b] -indole, 6-chloro-7-methyl- 8-fluoro-1,2,3,4-tetrahydro-9H-pyrido[3,4b] -indole, 5- dimethylamino-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b] - indole, 6-nitro-8-butyl-l,2,3, 4-tetrahydro-9H-pyrido[3,4b] - indo
  • a preferred compound of Formula IX has the following structure:
  • R 6 is selected from the group consisting of C 1 -C 4 alkyl, ORs-, fluoro, bromo, and chloro;
  • R 5' is C 1 -C 4 alkyl
  • R l , R7, and Re are as defined supra .
  • the 5-HT 2B receptor has been identified in various tissues and organs in the rat.
  • the primary areas of 5-HT 2B receptor localization in the rat include lung, uterus, bladder, stomach, and colon. Further, the 5-HT 2B receptor has been identified in various tissues and organs in the human. Interesting areas of 5-HT 2B receptor localization in the human include but are not limited to the brain and blood vessels.
  • physiological conditions which can be mediated by the 5-HT 2B receptor include incontinence, bladder dysfunction, Functional Bowel Disorders, stomach emptying disorders, respiratory disorders including asthma, uterine dysfunction including endometriosis, fibrosis, and motility disorders such as but not limited to induction of labor, sleeping disorders, eating disorders, including bulimia and obesity, consumption disorders, thermoregulation, sexual disorders, hyperactivity, excessive aggression, alcoholism, anxiety, obsessive-compulsive disorders, depression, psychosis, schizophrenia and schizophreniform disorders, panic disorders, Gilles de la Tourette syndrome, and Alzheimer's disease and cardiovascular diseases such as thrombosis, hypertension, vasospasm (peripheral and/or central) such as stroke, angina, and other vascular occlusive diseases.
  • migraine headaches can be treated using 5-HT 2B receptor stimulating compounds of this invention.
  • Preferred examples of such conditions which may be treated using 5-HT 2B modulators include cardiovascular disorders, uterine dysfunction, sleep disorders, hallucinogenic activity, psychosis, anxiety, depression, thermoregulation, feeding disorders, and hypotension. See Leonard, B.E., International Clinical Psvchopharmacolo ⁇ v, 7, 13-21 (1992) . It is particularly preferred to use a 5-HT 2B antagonist for treating a Functional Bowel Disorder.
  • the present invention also provides methods for treating or preventing the above-named conditions.
  • psychosis or psychotic conditions are characterized by hallucinations, delusions, or grossly disorganized behavior which indicate that the patient suffers from gross impairment in reality testing. Therefore, drugs having antipsychotic activity can be useful for treating a variety of important psychotic conditions.
  • the term “Functional Bowel Disorder” refers to a functional gastrointestinal disorder manifested by (1) abdominal pain and/or (2) symptoms of disturbed defecation (urgency, straining, feeling of incomplete evacuation, altered stool form [consistency] and altered bowel frequency/timing) and/or (3) bloating (distention) .
  • the term “Functional Bowel Disorder” includes but is not limited to irritable bowel syndrome, hypermotility, ichlasia, hypertonic lower esophogeal sphinctor, tachygastria, constipation, hypermotility associated with irritable bowel syndrome.
  • Abnormal bowel function includes diarrhea, constipation, mucorrhea, and pain or discomfort over the course of the sigmoid colon. Such disorders are influenced by psychological factors and stressful life situations.
  • IBS Irritable Bowel Syndrome
  • Functional Bowel Disorder includes conditions such as Irritable Bowel Syndrome, ichlasia, hypertonic lower esophogeal sphincter, tachygastria, hypermotility associated with irritable bowel syndrome, and constipation.
  • the compounds described herein can form acid addition salts with a wide variety of inorganic and organic acids.
  • Typical acids which can be used include sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric, hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic, p- toluenesulfonic, benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and the like.
  • the pharmaceutically acceptable acid addition salts are especially preferred for the treatment of 5-HT 2B receptor related conditions.
  • Certain compounds are preferred for use in treating conditions related to the modulation of a 5-HT 2B receptor.
  • the following invention embodiments and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and embodiments of the invention.
  • the following list of embodiments of this invention is in no way intended to limit the scope of this invention in any way:
  • A) Ri is hydrogen
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl
  • R 4 is C 5 -C8 cycloalkenyl or substituted C 5 -C 8 cycloalkenyl, bicyclic or substituted bicyclic, wherein the substituents are selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, NO 2 , halo, halo (Ci-C ⁇ ) alkyl, C 2 -C 6 alkenyl, COR 5 , (Ci-C ⁇ alkyl) m amino, -SR 5 , and OR 5 .
  • A is a group of formula III
  • A is a group of formula IV wherein R ⁇ and R 7 are Ci-C ⁇ alkyl or halo, and Rs is hydrogen, C 1 -C 5 alkyl, halo, C 5 -C 8 cycloalkyl, phenyl or substituted-phenyl;
  • the compound interacting with the 5-HT 2B receptor is a 5-HT 2B receptor antagonist
  • the compound interacting witht he 5-HT 2B receptor is a 5-HT2 B receptor partial agonist;
  • R 4 is substituted C 5 -C 8 cycloalkenyl; wherein the substituents are selected from the group consisting of hydrogen, NO 2 , halo, (Ci-C ⁇ alkyl) m amino, and OR5;
  • A is a group of formula IV wherein R ⁇ is hydrogen, R7 and Re are independently selected from the group consisting of halo and C 1 -C 4 alkyl;
  • R 4 is naphthyl or substituted naphthyl wherein the naphthyl substituents are selected from the group consisting of (C 1 -C 6 alkyl) m amino and OR5;
  • Y a is CH 2 , R 26 and R 27 are each C 2 -C3 alkyl; and R 28 and R 29 are each hydrogen;
  • the 5-HT 2B modulated condtion is a Functional Bowel Disorder.
  • the Functional Bowel Disorder is irritable bowel syndrome.
  • the 5-HT 2B modulated condition is psychosis.
  • the 5-HT 2B selective compound has a greater affinity for 5-HT 2 B receptors than it has for 5-HT 2A receptors.
  • the 5-HT 2B selective compound has a greater affinity for 5-HT 2 B receptors than it has for 5-HT 2 c receptors.
  • the 5-HT 2B modulated condtion is selected from the group consisting of urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, and respiratory disorder.
  • the compound is administered in a unit dosage form.
  • the label on the article of manufacture states that the compound is useful for treating a condition selected from the group consisting of urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, respiratory disorder, and Functional Bowel Disorder.
  • a pharmaceutical formulation comprising one or more pharmaceutically acceptable exipients and a 5-HT2 B receptor modulating compound
  • Certain compounds of Formula II are useful for modulating 5HT 2B receptors. Certain compounds of Formula II within the scope of this invention are preferred for that use.
  • the following invention embodiments and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and embodiments of the invention. The following list of embodiments of this invention is in no way intended to limit the scope of this invention in any way.
  • Rg -and R o are each hydrogen.
  • R 11 is C 1 -C 3 alkyl.
  • R 11 is chloro, fluoro, or bromo.
  • Rn is -OCH 3 .
  • R ⁇ is C 1 -C 4 alkyl.
  • R ⁇ is methyl
  • the compounds of the present invention are useful for modulating or blocking the 5-HT 2 receptor. Certain of the present compounds of Formula XI and XII are preferred for that use.
  • the following invention embodiments and compound characteristics listed in tabular form may be independently selected or combined to produce a variety of preferred compounds and embodiments of the invention. The following list of embodiments of this invention is in no way intended to limit the scope of this invention in any way.
  • A) Ri is hydrogen
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl
  • R 4 is Cs-C cycloalkenyl or substituted Cs-C ⁇ cycloalkenyl, wherein the substituents are selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, O 2 , halo, halo(C ⁇ C ⁇ )alkyl, C 2 -C 6 alkenyl, CORs, ⁇ C ⁇ C ⁇ alkyl) m amino, -SR 5 , and OR 5;
  • A is a group of formula III
  • A is a group of formula IV wherein R ⁇ and R 7 are Ci-C ⁇ alkyl or halo, and R % is hydrogen, C 1 -C 5 alkyl, halo, Cs-C ⁇ cycloalkyl, phenyl or substituted-phenyl;
  • R2 is hydrogen
  • H is hydrogen
  • R 4 is substituted Cs-C ⁇ cycloalkenyl; wherein the substituents are selected from the group consisting of hydrogen, NO 2 , halo, (Ci-Cg alkyl) m amino, and OR 5 ;
  • A is a group of formula IV wherein R ⁇ is hydrogen, R 7 and R ⁇ are independently selected from the group consisting of halo and C 1 -C 4 alkyl.
  • R 30 and R 31 join to form a 3 to 6 member carbon ring
  • R 30 and R 31 join to form a 3 to 5 member carbon ring
  • R 30 and R 31 are each methyl
  • R 4 is naphthyl;
  • P) R 4 is an optionally substituted bicyclic hydrocarbon ring system having 7 to 12 carbon atoms and 0, 1, 2, or 5 double bonds;
  • R 4 is a 6 to 10 carbon atom unsaturated bicyclic ring system
  • Q 1 is bicyclic or substituted bicyclic
  • R 34 is an optionally substituted bicyclic ring substituent
  • R 9 and Rio are each hydrogen;
  • Rg is selected from the group consisting of Ci-C ⁇ alkyl, substituted C3-C8 cycloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C 1 -C 3 )alkyl, C 5 -C8 cycloalkenyl-(C 1 -C 3 )alkyl, C7- C 2 0 arylalkyl;
  • R 4 is aromatic
  • R3 4 is spiro-bicyclic or substituted spiro- bicyclic
  • A-C, E or F I, L, N, P, R, and W.
  • the most preferred class of compounds has the following features:
  • the preferred classes of compounds for use as selective 5-HT 2B ligands have the following features:
  • the most preferred class of compounds for use as selective 5-HT 2B ligands has the following features:
  • Rg and Rio are each hydrogen
  • Rii is C 1 -C 3 alkyl
  • R 11 is chloro, fluoro, or bromo
  • R 11 is -OCH 3 ;
  • R 30 and R 31 join to form a 3 to 8 member carbon ring
  • R 30 and R 31 join to form a 3 to 6 member carbon ring;
  • a pharmaceutical formulation comprising a compound of Formula XI and/or XII and one or more pharmaceutically acceptable excipients.
  • Examples of compounds of Formula XI include but are not limited to:
  • Examples of compounds of Formula XII include but are not limited to:
  • the compounds which are useful for blocking 5-HT 2B receptors contemplates racemic mixtures as well as the substantially pure stereoisomers of the compounds of Formulas I through XII.
  • the term "enantiomer” is used herein as commonly used in organic chemistry to denote a compound which rotates the plane of polarization. Thus, the "- enantiomer” rotates the plane of polarized light to the left, and contemplates the levorotary compound of Formulas I through XII.
  • the + and - enantiomers can be isolated using well- known classical resolution techniques.
  • One particularly useful reference which describes such methods is JACQUES et. al . ENANTIOMERS, RACEMATES, AND RESOLUTIONS (John Wiley and Sons 1981) .
  • Appropriate resolution methods include direct crystallization, entrainment, and crystallization by optically active solvents. Chrisey, L.A. Heterocvcles, 267,
  • a preferred resolution method is crystallization with an optically active acid or by chiral synthesis as described in Example 46 using the method of A.I. Meyers. Loewe, M.F. et al . , Tetrahedron Letters. 3291, 26 (1985), Meyers, A.I. et al . , J. Am. Chem. Soc.. 4778, 110 (1988) .
  • Preferred optically active acids include camphorsulfonic and derivatives of tartaric acid.
  • the present invention encompasses both the R and the S configurations.
  • R and S are used herein as commonly used in organic chemistry to denote the specific configuration of a chiral center. See, R.T. Morrison and R.N. Boyd, Organic Chemistry, pp 138-139 (4th Ed. Allyn & Bacon, Inc., Boston) and Orchin, et al. The Vocabulary of Organic Chemistry, p. 126, (John Wiley and Sons, Inc.) .
  • the present invention includes, but is not limited to, the use of compounds such as (-)-(S)-7- methyl-8-bromo-l- [ (3 , 4-dimethoxyphenyl)methyl] -1,2,3,4- tetrahydro-9H-pyrido[3, 4-b] indole; (-) - (S) -5,7-dimethyl- 1,2, 3,4-tetrahydro-l- [ (3, 4-dimethoxyphenyl)methyl] -9H- pyrido[3,4-b] indole; (-) - (S) -5-fluoro-6-methyl-l- [ (2-chloro- 3, 4-dimethoxyphenyl)methyl] -1,2,3, 4-tetrahydro-9H-pyrido [3,4- b]indole; and (-) - (S) -6-methyl-l, 2, 3, 4-tetrahydro-l- [ (3, 4- dimethylphenyl)methyl
  • the invention also includes, but is not limited to, the use of (+)-(S)-7- methyl-8-bromo-l- [ (3, 4-dimethoxyphenyl)methyl] -1,2,3,4- tetrahydro-9H-pyrido [3 , 4-b] indole; (+) - (S) -5, 7-dimethyl- 1, 2,3,4-tetrahydro-l- [ (3, 4-dimethoxyphenyl)methyl] -9H- pyrido [3,4-b] indole; (+) -(S) -5-fluoro-6-methyl-l- [ (2-chloro- 3, 4-dimethoxyphenyl)methyl] -1,2,3, 4-tetrahydro-9H-pyrido[3 , 4- b] indole; (-) - (R) -7-methyl-8-bromo-l- [(3,4- dimethoxyphenyl)methyl] -1,2,3, 4-tetra
  • the compounds which are useful for interaction with 5-HT 2B receptors are known to form hydrates and solvates with appropriate solvents.
  • Preferred solvents for the preparation of solvate forms include water, alcohols, tetrahydrofuran, DMF, and DMSO.
  • Preferred alcohols are methanol and ethanol .
  • Other appropriate solvents may be selected based on the size of the solvent molecule. Small solvent molecules are preferred to facilitate the corresponding solvate formation.
  • the solvate or hydrate is typically formed in the course of recrystallization or in the course of salt formation.
  • One useful reference concerning solvates is Sykes, Peter, A Guidebook to Mechanism in Organic Chemistry, 6, 56, (1986, John Wiley & Sons, New York) .
  • the term "solvate” as used herein includes hydrate forms such as monohydrate and dihydrates.
  • compounds of Formula III can be prepared using the methods taught in Semonsky et al. , U.K. Patent No. 816,273 (July 8, 1959), U.S. Patent Nos. 2,736,728 and 2,774,763 which U.S. Patents are hereby incorporated by reference.
  • Compounds of Formula IV may be prepared as described in U.S. Patent Nos. 4,981,859 and 4,931,447 which are hereby incorporated by reference.
  • a process for preparing compounds of Formula V is described in U.S. Patent No. 4,902,691 which is hereby incorporated by reference.
  • a process for preparing compounds of Formula VI is described in U.S. Patent No. 4,563,461 which is hereby incorporated by reference.
  • a compound of Formula VII can be prepared as described in Forbes, I.T., J. Med. Chem.. 36:1104-1107 (1993).
  • a compound of Formula VIII is known in the art and may be purchased or prepared by recognized methods.
  • a process for preparing compounds of Formula IX is available to the artisan in the published European Patent application. The European Publication number is 0498590 Al (August 12, 1992; Bulliten 92/33) and is readily available to the United States artisan in the English language.
  • a compound of Formula X is known in the art and can be prepared by recognized methods.
  • the compounds of the present invention can be prepared using chemical processes that are understood in the art; however, the most preferred method for preparing the formula I compounds of this invention utilizes the process of Scheme V.
  • the most preferred method for preparing a compound of Formula II is using the general method illustrated in Scheme II infra .
  • Compounds of Formula II wherein Rg, R 12 , and/or Rio are not hydrogen can be prepared using accepted chemical methods such as reductive alkylation and direct alkylation of the corresponding tryptamine.
  • a compound of Formula I, wherein Q is hydrogen may be prepared by contacting glyoxylic compound of formula (i) with an amine of formula (h) . This Pictet-Spengler type reaction is generally applicable, provides desirable yields, and produces stable intermediates. Further, the product of the reaction typically may be directly isolated as the desired salt.
  • the compounds of formula (a) which may be used as starting materials for the compounds of the instant invention can be purchased from art-recognized vendors or may be prepared using well-known chemical techniques.
  • the compounds of formula (b) which are useful as starting materials for the compounds of this invention may be prepared as represented by Scheme I.
  • the R 4 group is as defined herein above.
  • the Scheme I reaction is begun by preparing a solution of compound (a) , acetylglycine and sodium acetate in acetic anhydride.
  • the reaction is commonly heated from about 90°C to about 110°C for a period of about 2- 15 hours .
  • the reaction mixture is cooled to about ambient temperature and stirred for a period of about 0-10 hours under inert conditions.
  • the reaction time will vary depending on the degree of substitution on the R 4 group and the completion of reaction desired.
  • the azalactone (b) may be isolated by standard isolation techniques such as filtration and may be dried under reduced pressure.
  • the chlorobutanal compound used in Scheme II may be prepared through the hydrogenation of chlorobutyryl chloride. The hydrogenation may be facilitated by the use of a catalyst such as Pd/C. Other halobutanal compounds may be suitable for the Scheme II process.
  • the starting compounds (c) in Scheme II may be purchased or prepared using known methods. March, J., Advanced Organic Chemistry Reactions, Mechanisms, and Structure. 3rd (John Wiley & Sons, New York, 1985) see especially page 1163.
  • the Fischer synthesis is commonly begun by adding a suitable saturated base like sodium carbonate to a stirred suspension of the hydrazine salt in an organic solvent like chloroform.
  • the hydrazine hydrochloride salt is one especially preferred hydrazine salt.
  • the desired hydrazine free base is extracted with the organic phase.
  • the oil is placed in an alcohol and water solution and treated with an appropriate base like sodium acetate.
  • the halobutanal is added and the tube purged with an inert gas like nitrogen.
  • the resulting mixture is placed in an oil bath which has been heated to about 90°C-110°C.
  • the mixture should be heated for about 17 to 19 hours.
  • the mixture is allowed to cool to ambient temperature and is concentrated under reduced pressure.
  • the residue is partitioned between a suitable organic and basic aqueous phase, such as chloroform/methanol and aqueous sodium carbonate.
  • a suitable organic and basic aqueous phase such as chloroform/methanol and aqueous sodium carbonate.
  • the organic phase may be concentrated and the resulting compound (d) purified by standard methods such as flash chromatography. If chromatography is used, fractions containing product may be combined and concentrated.
  • the oil is dissolved in an appropriate solvent, such as diethyl ether containing about 1% alcohol. A preferred alcohol is methanol.
  • the mixture may be treated with dry acid gas, such as dry HCl gas to produce the corresponding acid addition salt of the " desired compound (d) .
  • the Scheme III reaction is carried out by reacting compound (e) with the selected aldehyde in a suitable solvent such as ethanol or methanol for a period of about 1 to 50 hours depending on the desired product.
  • a suitable solvent such as ethanol or methanol
  • the reaction may be refluxed if necessary.
  • the precipitated reaction product is collected by common isolation methods, such as filtration and may be purified by recrystallization.
  • the reaction may be followed by a reductive alkylation.
  • the reductive alkylation is represented by Scheme IV.
  • a protic acid and aldehyde solution is commonly added to an aqueous solution of compound (f) .
  • the most preferred protic acid is formic acid.
  • the most preferred aldehyde is formaldehyde.
  • the artisan can readily choose other appropriate reagents to facilitate the reductive alkylation.
  • the resulting solution is refluxed for a period of about 4 to 80 hours. After reflux the solution should be made basic using an appropriate base such as potassium carbonate.
  • the desired product can then be extracted with an appropriate organic phase, such as chloroform.
  • the product can be dried, concentrated, and purified by known methods such as flash chromatography.
  • Compound (h) and compound (i) are contacted in a suitable protic aqueous acid solution.
  • glyoxylic acid may be used in place of (i) .
  • This step may be completed under inert conditions.
  • Compound (h) and compound (i) may be refluxed under atmospheric or inert conditions for a period of about 20 to about 30 hours.
  • Preferred protic acids include sulfuric acid and hydrochloric acid.
  • the most preferred acid solution is 1 N HCl.
  • the reaction mixture may be neutralized with an appropriate base, such as potassium carbonate, followed by extraction with an organic phase, such as chloroform.
  • the product can be isolated through solvent removal followed by chromatographic isolation, such as silica gel chromatography, or other common isolation techniques. Typically the product is isolated as the acid addition salt. Appropriate salt forms are discussed supra .
  • the compounds of the present invention can exist as resolved enantiomers.
  • (-)enantiomer may be prepared by the chemical resolution method of A.I. Meyers as represented by Scheme VI infra .
  • (+)enantiomer may be prepared using known resolution techniques described supra . All substituents are as defined hereinabove.
  • CSA represents camphorsulfonic acid.
  • Butylformadine (1) is prepared from the amino acid valine using known methods. Other formadine compounds will also work.
  • step 1 the compound (k) and butylformadine (1) solution is refluxed for a period of about 70 to 80 hours.
  • the product of the reflux reaction can be purified by standard isolation methods, such as flash chromatography. The isolated oil can be used without further purification.
  • Compound (m) prepared in step 1 can be added to a suspension of potassium hydride (KH) in tetrahydrofuran (THF) . Tetramethylethylenediamine (TMEDA) and then chloromethylmethyl ether (MOMC1) are added to the solution, as represented by step 2.
  • KH potassium hydride
  • THF tetrahydrofuran
  • MOMC1 chloromethylmethyl ether
  • the mixture is stirred for a period of about 1 hour.
  • the mixture can be treated with water and partitioned between an appropriate organic, such as diethyl ether, and water.
  • the product should be extracted with the organic phase, dried over potassium carbonate, and concentrated. The resulting oil may be used in subsequent steps without further purification.
  • step 3 n-BuLi is slowly added dropwise to a stirred, cooled (about -76°C to -80°C) solution of the formadine in dry THF.
  • the solution is stirred for a period of about 1 hour followed by addition of the chloro compound in dry THF.
  • the solution is stirred for an additional period of about 4-5 hours at the reduced temperature.
  • the mixture is allowed to cool to room temperature for a period of about 4 to 14 hours.
  • Wet THF is added and the solution concentrated.
  • the residue is dissolved in an appropriate organic solvent such as chloroform and washed with water.
  • the organic phase is dried over a suitable drying agent, such as sodium carbonate, and concentrated to facilitate purification of the desired product.
  • the product may be isolated by flash chromatography and concentrated. The resulting oil may be used in subsequent steps without further purification.
  • the deprotection reaction represented in step 4 is begun at reduced temperature (about 0°C) .
  • Water, acetic acid, and hydrazine hydrate are added to compound (o) .
  • the reaction temperature is decreased to about -10°C to -20°C for a period of about 60-120 hours.
  • the mixture is allowed to warm to ambient temperature and is concentrated.
  • the product is dissolved in an appropriate organic phase, such as chloroform, and washed with water.
  • the organic phase is dried over a suitable drying agent, such as sodium carbonate, and concentrated to a viscous oil.
  • the oil is dissolved in an appropriate solvent, such as diethyl ether and treated with a suitable organic or inorganic acid to afford the desired acid addition salt.
  • the salt can be isolated and purified by common chemical methods.
  • an appropriate saturated base solution such as sodium carbonate
  • the desired compound (q) salt may be prepared by the method of Scheme II, above.
  • the mixture is stirred at about ambient temperature for a period of about 1 hour.
  • the layers are separated, and the aqueous layer is extracted with an appropriate organic solvent, such as chloroform.
  • the organic layers are dried over an appropriate drying agent, such as sodium sulfate, and concentrated.
  • the residue is dissolved in a suitable solvent such as toluene and treated with phthalic anhydride.
  • the solution is refluxed for a period of about 12 to 20 hours with azeotropic drying.
  • the solution is cooled, concentrated, and recrystallized to give compound (r) .
  • compound (r) is mixed in THF.
  • the mixture is stirred for a period of about 1 hour.
  • Tetramethylethylenediamine (TMEDA) is added, followed by a haloalkyl such as methyl iodide (Mel) .
  • TMEDA Tetramethylethylenediamine
  • Mel haloalkyl
  • the reaction is quenched by the addition of water, followed by extraction with an appropriate organic phase, such as diethyl ether.
  • the organic phases are dried over an appropriate drying agent, such as magnesium sulfate and concentrated.
  • the solution of the concentrated compound (s) can be used directly in the next step. It is contacted with an appropriate solvent, such as methanol, and treated with hydrazine. The mixture is refluxed for a period of about 2 hours. The mixture is cooled to ambient temperature and treated with concentrated acid, such as HCl. The mixture is then treated with an alcohol and refluxed for a period of about 12 to- 20 hours. Preferred alcohols include methanol, ethanol, and butanol. After cooling to ambient temperature, the mixture is partitioned between a suitable organic and an aqueous phase. One suitable combination is chloroform and concentrated sodium carbonate solution. The aqueous layer may be further extracted, the organic phases combined, dried, and concentrated. The product may be purified by flash chromatography, concentrated, and converted to a desired salt. The resulting compound (t) may be used in Scheme III or Scheme V to produce the desired Formula I compound.
  • R 32 is independently selected from Ci-C ⁇ alkyl; A, and Q' are defined supra .
  • Optical rotations were obtained using methanol, pyridine, or other suitable solvent.
  • the hydrochloride salt of the particular compound was prepared by placing the free base into diethyl ether containing an alcohol such as methanol or other suitable solvent mixture. While stirring this ether solution, a solution of HCl in diethyl ether was added dropwise until the solution became acidic. Alternatively, the ether solution was treated with dry HCl gas.
  • the maleate salt of the particular compound was prepared by placing the free base in ethyl acetate or other suitable solvent and treating with maleic acid. The precipitate formed was filtered and dried to provide the corresponding hydrochloride or maleate salt of the free base.
  • Compounds of Formulas I through VI and VIII through XII are more preferred for treating a mammal suffering from or susceptible to a condition associated with abnormal or dysfunctional 5-HT 2B receptor stimulation. Additionally, compounds of Formulas I through VI and VIII through XII are more preferred for blocking a 5-HT 2B receptor in a mammal or in vi tro . Finally, compounds of Formulas I through VI and VIII through XII are more preferred for use in an article of manufacture.
  • hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptamine hydrochloride (3.6 g) as a pale solid, which was used without further purification.
  • hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford 7-bromo- tryptamine hydrochloride (1.5 g) as a pale solid, which was used without further purification.
  • 5-Methyl-7-bromotryptamine hydrochloride (4.95 g) was prepared as described in Example 3, except using 2-bromo-4-methylphenyl hydrazine hydrochloride (21 g) as starting material.
  • the solution was transferred to a sealable tube and purged with nitrogen for 10 minutes.
  • the tube was sealed and placed in an oilbath preheated to 95°C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure.
  • the residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated.
  • the residue was purified by flash chromatography on silica gel (15% methanol, 0.2% ⁇ H 4 OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure.
  • the mixture was placed in a sealable tube and purged with nitrogen for 10 minutes.
  • the tube was sealed and placed in an oil bath preheated to 95°C. Heating was continued for 15 hours.
  • the resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure.
  • the residue was partitioned between chloroform/methanol (75/25 by volume) and aqueous sodium carbonate solution.
  • the organic phase was concentrated and the crude indole ethanamine was purified by flash chromatography on silica gel (0-25% methanol gradient in chloroform as eluent) . Fractions containing product were combined and concentrated.
  • the oil was dissolved in diethyl ether (300 mL) containing 1% methanol and treated with dry HCl gas.
  • hydrochloride salt was isolated by filtration, washed with 2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford 7- bromotryptamine hydrochloride (6.3 g) as a pale solid, which was used without further purification.
  • 6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2-bromo-3- methylphenylhydrazine hydrochloride as starting material.
  • 5- (1, 1-dimethylethyl) -tryptamine hydrochloride was prepared (2.95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 4- (1,1- dimethylethyl) -phenylhydrazine hydrochloride (6.00 g) as starting material.
  • 4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3-fluoro-4- methylphenylhydrazine hydrochloride (6.00 g) as starting material.
  • 6,7-Benzotryptamine hydrochloride was prepared (2.85 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 1-naphthyl-hydrazine hydrochloride (6.00 g) as starting material.
  • a suspension of azalactone (prepared as described in Example 1) (1.51 g, 6.11 mmol.) and 6,7-benzotryptamine hydrochloride (1.50 g, 6.11 mmol.) in 1 N HCl (40 mL) was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform.
  • 5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 4- cyclohexylphenylhydrazine hydrochloride as starting material.
  • 4,7-dimethyltryptamine hydrochloride was prepared (0.94 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,5-dimethyl- phenylhydrazine hydrochloride (16.8 g) as starting material.
  • the mixture was placed in a sealable tube and purged with nitrogen for 10 minutes.
  • the tube was sealed and placed in an oil bath preheated to 100°C. Heating was continued for 18 hours.
  • the resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure.
  • the residue was partitioned between chloroform/methanol (75/25 by volume) and aqueous sodium carbonate solution.
  • the organic phase was concentrated and the crude indole ethanamine was purified by flash chromatography on silica gel (0-25% methanol gradient in chloroform as eluent) . Fractions containing product were combined and concentrated.
  • the oil was dissolved in diethyl ether (300 mL) containing 1% methanol and treated with dry HCl gas.
  • 5,7-Dimethyltryptamine hydrochloride was prepared (2.86 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,4- dimethylphenylhydrazine hydrochloride (15.0 g) as starting material.
  • 6-Dimethyltryptamine hydrochloride was prepared (1.06 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3,5- dimethylphenylhydrazine hydrochloride (7.65 g) as starting material.
  • 6,7-Dimethyltryptamine hydrochloride was prepared (2.26 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,2-dimethyl- phenylhydrazine hydrochloride (15.0 g) as starting material.
  • Azalactone (12.28 g) was prepared as in Example 21 except using 2,3,4-trimethoxybenzaldehyde (20.0 g) .
  • Azalactone (16.42 g) was prepared as in Example 21 except using 2-methoxybenzaldehyde (20.0 g) .
  • Azalactone (7.55 g) was prepared as in Example 21 except using 2 , 4-dimethoxybenzaldehyde (20.0 g) .
  • Azalactone (13.21 g) was prepared as in Example 21 except using 2 , 5-dimethoxybenzaldehyde (20.0 g) .
  • Azalactone (8.36 g) was prepared as in Example 21 except using 2,4,5-trimethoxybenzaldehyde (20.0 g) .
  • Azalactone (16.9 g) was prepared as in Example 21 except using 3,4-dimethoxy-5-nitrobenzaldehyde (23.5 g) .
  • Azalactone (11.1 g) was prepared as in Example 21 except using 3-iodo-4, 5-dimethoxybenzaldehyde (9.5 g) , and hippuric acid (6.41 g) instead of N-acetylglycine.
  • Azalactone (32.2 g) was prepared as in Example 21 except using 3-methoxy-4-allyloxybenzaldehyde (30.4 g) , and hippuric acid (28.3 g) instead of N-acetyl glycine.
  • Azalactone (0.330 g) was prepared as in Example 21 except using 3-fluoro-4-methoxybenzaldehyde (5.0 g) .
  • Azalactone (11.3 g) was prepared as in Example 21 except using 3,4-dimethylbenzaldehyde (25.0 g) .
  • Azalactone (5.26g) was prepared as in Example 21 except using 2-chloro-3,4-dimethoxybenzaldehyde (10.45 g) .
  • Azalactone (12.4 g) was prepared as in Example 21 except using 2-chloro-3-methoxy-4-hydroxybenzaldehyde (12.0 g ) .
  • n-Butyllithium (68.7 mL, 1.6 M in hexanes, 0.11 mol.) was added dropwise over 15 minutes and the orange solution stirred for 2 hours.
  • the mixture was poured into ice/water (500 mL) and was acidified to pH 2-3 with 5N HCl solution.
  • the mixture was extracted with diethyl ether (2 X 100 mL) and these extracts were discarded.
  • the aqueous phase was made basic with sodium hydroxide solution (50%) , cooling the mixture with ice when necessary.
  • reaction mixture was made basic with sodium hydroxide solution and extracted with diethyl ether (3 X 100 mL) .
  • the combined organic phases were washed with brine and dried over magnesium sulfate. Filtration and removal of solvent afforded crude product (11.3 g) as a viscous oil, which was used without further purification.
  • t-Butyllithium (68.4 mL, 1.7 M in pentane, 0.116 mol.) was added dropwise over 15 minutes and the orange solution stirred for 2 hours.
  • the mixture was poured into ice/water (500 mL) and was acidified to pH 2-3 with 5N HCl solution.
  • the mixture was extracted with diethyl ether (2 X 100 mL) and these extracts were discarded.
  • the aqueous phase was made basic with sodium hydroxide solution (50%) , cooling the mixture with ice when necessary.
  • reaction mixture was warmed to ambient temperature over about 2 hours.
  • the reaction mixture was made basic with sodium hydroxide solution and extracted with diethyl ether (3 X 100 mL) .
  • the combined organic phases were washed with brine and dried over magnesium sulfate. Filtration and removal of solvent afforded crude product (13.2 g) as a viscous oil, which was used without further purification.
  • the mixture was placed in a sealable tube and purged with nitrogen for 10 minutes.
  • the tube was sealed and placed in an oil bath preheated to 100°C. Heating was continued for 18 hours.
  • the resulting dark solution was cooled to ambient temperature and concentrated under reduced pressure.
  • the residue was partitioned between chloroform/methanol (75/25 by volume) and aqueous sodium carbonate solution.
  • the organic phase was concentrated and the crude indole ethanamine was purified by flash chromatography on silica gel (0-25% methanol gradient in chloroform as eluent) . Fractions containing product were combined and concentrated.
  • the oil was dissolved in diethyl ether (300 mL) containing 1% methanol and treated with dry HCl gas.
  • the solution was transferred to a sealable tube and purged with nitrogen for 10 minutes.
  • the tube was sealed and placed in an oilbath preheated to 95°C.
  • the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure.
  • the residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol.
  • the organic phase was dried over sodium sulfate and concentrated.
  • the residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH 4 OH, in chloroform as eluent) .
  • the fractions containing product were pooled and concentrated under reduced pressure.
  • the residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification.
  • 6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromo ⁇ tryptamme hydrochloride in Example 7, except using 2-bromo- 3-methyl phenylhydrazine hydrochloride as starting material.
  • 5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4- cyclohexylphenylhydrazine hydrochloride as starting material.
  • 3-fluoro-4-methyl-phenylhydrazme hydrochloride (21.4 g -) was prepared as described for 2-bromo-4 methyl- phenylhydrazine hydrochloride in Example 7, except using 3- fluoro-4-methyl aniline as starting material.
  • 4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromo- trypta ine hydrochloride in Example 7, except using 3-fluoro- 4-methyl-phenylhydrazine hydrochloride (6.00 g) as starting material.
  • 6,7-benzotryptamine hydrochloride was prepared (2.85 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 1-naphthyl-hydrazine hydrochloride (6.00 g) as starting material.
  • 5- (1,1-dimethylethyl) -tryptamine hydrochloride was prepared (2.95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-(1,1- dimethylethyl) -phenyl hydrazine hydrochloride (6.00 g) as starting material.
  • the crude product was purified by flash chromatography on silica gel (0-25% methanol in chloroform/0.2% NH 4 OH as eluent). The product containing fractions were pooled and concentrated under reduced pressure. The residue was dissolved in diethyl ether and treated with anhydrous HCl. The product 1, 5-dimethyl- tryptamine hydrochloride (6.08 g) was isolated by filtration as a tan solid and used without further purification.
  • the desired product was prepared using substantially the process of Example 66, except that the starting material was 7-methoxy-lH-indole-ethanamine. Melting Point: 207-209°C Elemental Analysis: C 60.17; H 5.56; N 8.60.
  • a sample of 8-methoxy-l,2,3,4-tetrahydro-9H- pyrido[3,4b] -indole was prepared substantially as described in Example 66.
  • a 0.36 g sample of the indole was contacted with 1 g K 2 CO3 and the mixture was purged with nitrogen.
  • a 40 mL sample of CH3CN was added to the resulting mixture.
  • a 0.12 mL sample of 1-iodopropane was added. The mixture was maintained under nitrogen and stirred in the dark. The resulting mixture was extracted. The organic phase was dried, evaporated, and chromatographed. The desired fractions were evaporated, taken up into methanol:ethyl acetate.
  • a sample of 8-methoxy-l,2,3,4-tetrahydro-9H- pyrido[3,4b] -indole was prepared substantially as described in Example 66.
  • the indole (1 g) , NaOAc (0.34 g) , NaBH 3 CN (0.53 g) , methanol (50 mL) , and HOAc (1.0 g) were stirred.
  • a 1.36 g (37% in 10 mL methanol) sample of CH 2 O was added to the indole mixture.
  • Example 70 8-methoxy-2(N)-eyelopropylmethy1-1,2,3,4-tetrahydro-9H- pyrido[3,4b]-indole
  • the desired product can be prepared using appropriate reagents and the process substantially as described in Example 69.
  • a 2.30 g sample of 6, 7-dimethyl-lH-indole- ethanamine was dissolved in a mixture of water and isopropanol with heating.
  • a 1.03 g sample of glyoxilic acid monohydrate in 10 mL of water was added to the flask. The solution was allowed to cool and made basic by the addition of potassium hydroxide. The reaction was stirred for 48 hours. The resulting solid was isolated by filtration and washed with water. The solid was dissolved in 50 mL of water and the solution was acidified by the slow addition of concentrated HCl. Heating was initiated and an additional 5 L of concentrated HCl was added. The resulting solid was isolated by decanting and dissolved in 10 mL of water.
  • the desired product was prepared using the process substantially as described in Example 1 except that the starting material was 6-methyl-7-chloro-lH-indole-3- ethanamine hydrochloride. Yield: 70 %
  • the oil was stirred in 100 mL of methanol while 4- chlorobutyraldehyde (12.3 g) was added. The resulting solution was transferred to a sealable tube and purged with nitrogen. _ The tube was sealed and the reaction mixture was heated in an oil bath maintained at 95°C for 14 hours. The resulting mixture was allowed to cool and concentrated to a residue which was partitioned between IN NaOH and chloroform. The combined organic extracts were dried and concentrated to an oil. The oil was chromatographed on silica gel using a gradient of 0-10% methanol in chloroform. Fractions containing product were concentrated to an oil which was taken up in a small amount of methanol and added to ethereal HCl. A solid was collected, washed with diethyl ether and vacuum dried at 50°C.
  • the desired 7-fluoro-lH-indole-3-ethanamine was prepared substantially as described in Example 81 infra . except that 2-fluorophenylhydrazme hydrochloride (25.5 g) was used. Additionally, reverse phase HPLC was required for final purification. Yield: 4 g
  • the resulting residue was dissolved in 750 mL ethanol and 15.5 g hydrazine hydrate was added. The mixture was heated at reflux for 14 hours. A 70 mL sample of 5N HCl was added and the mixture was allowed to cool. The cooled mixture was concentrated to a residue. The residue was partitioned between IN NaOH and chloroform. The organic portion was separated and the aqueous portion was extracted with chloroform. The combined organic extracts were dried (Na 2 S0 4 ) and concentrated to an oil. The oil was chromatographed on silica gel using a gradient of 0-10% methanol in chloroform.
  • the desired product was prepared substantially as described in Example 82.
  • 6-methyl-7-chloro-lH-indole-3-ethanamine was prepared using substantially the same process described in Example 82. Yield: 3.0 g (24%) Melting Point: 290°C Elemental Analysis: C 54.10; H 5.88; N 11.66.
  • 6-bromo-7-methyl-lH-indole-3-ethanamine was prepared substantially as described in Example 82 using appropriate starting materials. Yield: 1.6 g (56%) Melting Point: 251 °C Elemental Analysis: C 45.85; H 4.97; N 9.71.
  • a sample of 6, 7-dimethyl-lH-indole-3-ethanamine was prepared using appropriate starting materials and substantially the process described in Example 79.
  • the 6,7- dimethyl-lH-indole-3-ethanamine was purified by treating with K 2 CO 3 and extracting with 3:1 CHCl 3 /isopropanol .
  • the organic phase was dried, evaporated, and chromatographed.
  • the desired fractions were pooled, evaporated, and mixed with ethyl acetate.
  • the resulting material was diluted with ether and maleic acid in methanol. The solid was triturated in ether and dried.
  • indole starting materials (la, lb, and lc) infra , were purchased (la), prepared according to Bartoli 's procedure (lb) [Bartoli, G. et al. Tetrahedron Lett . , 1989,
  • the 2-Iodo-4, 6-dimethylaniline (5"') synthesis can be completed as follows: To a suspension of 5"' (24 mmol.), Cul (0.05 equiv.) and (PPh3)2PdCl2 (0.05 equiv.) in 30 ml of dry triethylamine under Ar atmosphere was added trimethylsilylacetylene (1.1 equiv.) and the resulting mixture was stirred for 3 hours. Then, the solvent was eliminated under vacuum and the residue purified by flash chromatography using hexane/ethyl acetate (3:1) as eluent to yield 6" in quantitative yield.
  • the title compound ( 3f ) was prepared using substantially the procedure of Example 90 ; however , the indole was lc and the aziridine was 2b .
  • Tr ⁇ «s-7-chloro-5-(3,4-dimethoxybenzyl)-l,2,3,4,4a,5,6,10c- octahydrocycloper_ta[a]pyrido [3,4-blindole, hydrochloride (4d)
  • the compounds of the present invention are useful in blocking the effect of serotonin or other agonists at 5-HT 2A , 5-HT 2B and/or 5-HT ⁇ c receptors .
  • the present invention also provides a method for blocking 5 -HT 2A - 5-HT 2 B or 5-HT ⁇ c receptors in mammals comprising administering to a mammal requiring blocking of a 5-HT 2A , 5-HT 2B . or 5-HT ⁇ c receptor, respectively, a receptor blocking dose of a compound of the invention.
  • One particularly useful embodiment of this invention is that it provides selective ligands for the 5-HT2B receptor.
  • Compounds with a high affinity for the 5-HT2B receptor generally are cross-reactive with the 5-HT 2 C receptor as well.
  • 5-HT 2B receptors can be selectively modulated using compounds of this invention at rates set forth above for blocking the effects of agonists at 5-HT 2B receptors.
  • the selective affinity may provide treatments with fewer side effects and will facilitate the development of additional therapeutic agents .
  • Compounds exhibiting activity at the 5HT 2B receptor are useful for treating disorders related to the modulation of the 5HT 2B receptor.
  • compounds having 5HT2B antagonist activity reduce the spasticity of the colon.
  • these compounds are useful for the treatment of functional bowel disorders including irritable bowel syndrome and irritable bowel syndrome-related symptoms .
  • the antispas odic effect of such compounds can reduce abdominal pain associated with functional bowel disorders.
  • the 5H 2B receptor is localized in other organs such as the brain, bladder, blood vessels, stomach, and uterus, indicating that additional conditions are 5HT 2B mediated.
  • Compounds demonstrating activity at the 5HT 2A receptor can be utilized in the treatment or prevention of conditions related to modulation of the 5HT 2 receptor. Examples of such conditions include hypertension, sleep disorders, hallucinogenic activity, psychosis, anxiety, depression, thermoregulation, feeding disorders, and hypotension. Leonard, B.E., International Clinical Psychopharmacolo ⁇ v, 7, 13-21 (1992) .
  • receptor blocking dose means an amount of compound necessary to block a targeted receptor, selected from the group consisting of 5-HT 2 A 5-HT 2B , and 5-HT ⁇ c receptor in a mammal.
  • the active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.05 to about 250 mg/kg of body weight. In the treatment of adult humans, the range of about 0.5 to 100 mg/kg, in single or divided doses, is preferred. The ranges of about 5 mg/kg to about 60 mg/kg and about 10 mg/kg to about 50 mg/kg are especially preferred.
  • the amount of the compound actually administered will be determined by a physician in light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • the compounds may be administered by a variety of routes such as oral, transdermal, subcutaneous, intranasal, intramuscular, and intravenous routes.
  • the compounds are preferably employed in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the invention.
  • a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the invention.
  • Such compositions contain from about 0.1 percent by weight to about 90.0 percent by weight of a present compound.
  • the present invention also provides pharmaceutical formulations comprising a compound of the invention and a pharmaceutically acceptable excipient therefor.
  • the active ingredient is usually mixed with an excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • an excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium), and soft and hard gelatin capsules.
  • the compounds of the invention may be delivered transdermally, if desired.
  • Transdermal permeation enhancers and delivery systems including patches and the like, are well known to the skilled artisan.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propylhydroxy- benzoates, talc, magnesium stearate, water, and mineral oil.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients.
  • a compound of this invention is admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system.
  • permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system.
  • Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired.
  • a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier.
  • the active compounds are effective over a wide dosage range.
  • dosages per day will normally fall within the range of about 0.05 to about 250 mg/kg of body weight.
  • the range of about 0.5 to 100 mg/kg, in single or divided doses is preferred.
  • the ranges of about 5 mg/kg to about 60 mg/kg and about 10 mg/kg to about 50 mg/kg are especially preferred.
  • the amount of the compound actually administered will be determined by a physician in light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • the compounds may be administered by a variety of routes such as oral, transdermal, subcutaneous, intranasal, intramuscular, rectally, and intravenous routes.
  • compositions of a compound of the present invention or its salts or solvates are most preferrably produced by formulating an active compound in unit dosage form with a pharmaceutical carrier.
  • unit dosage forms are tablets, pills, powders, aqueous and non-aqueous oral solutions and suspensions, transdermal delivery devices and patches, and parenteral solutions packaged in containers containing either one or more unit dosages and may be capable of being subdivided into individual doses.
  • suitable pharmaceutical carriers and/or diluents include gelatin capsules, sugars including lactose and sucrose, starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate, gelatin, talc, stearic acid, magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, propylene glycol, glycerin, sorbitol, polyethylene glycol, water, agar, alginic acid, isotonic saline, phosphate buffer solutions, lactic acid, glycolic acid, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, magnesium stearate, croscarmellose, alginic acid, sodium starch glycolate, lauryl sulfate.
  • gelatin capsules sugars
  • the active compound may be prepared as a microparticle using biodegradable polymers or other known methods.
  • the composition may be prepared using known formulation technology to provide a rapidly dissolving, sustained release, or targeted delivery compositions.
  • the compositions of this invnetion may contain other components such as coloring agents, flavoring, and/or preservatives.
  • the compositions may contain other therapeutic agents, for example an antacid or analgesic.
  • the article of manufacture will include packaging material.
  • Packaging material will preferably include a container.
  • the preferred container and packaging material can be selected using the characteristics of the compound to be packaged.
  • the preferred container may be glass, plastic, foil, sealed bubble packaging, clear, amber, and may incorporate other known pharmaceutical packaging technology.
  • the packaging may include features such as cotton, silica or other drying agents, and/or a measuring device.
  • the article of manufacture shall include a label indicating that the composition is useful for the treatment of an a condition associated with 5-HT2B receptor stimulation malfunction. Most preferably, the condition is selected from the group consisting of urinary incontinence, bladder dysfunction, uterine dysfunction, cardiovascular disorder, and respiratory disorder.
  • formulations may employ as active compounds any of the compounds of the present invention.
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve and filled into a hard gelatin capsule.
  • Formulation 4 Tablets containing 10 mg of active ingredient are made as follows:
  • microcrystalline cellulose 35 mg 35.0
  • polyvinylpyrrolidone (as 10% solution in water) 4 mg 4.0
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granule so produced is dried at 50°-60° C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granule which, after mixing, is compressed on a tablet machine to yield a tablet weighing 100 mg.
  • Formulation 5 A tablet formulation may be prepared using the ingredients below:

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EP95914014A 1994-03-11 1995-03-10 Verfahren zur behandlung von mit dem 5-ht2b-rezeptor verbundenen zuständen Withdrawn EP0749313A4 (de)

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US380566 1989-07-14
US380565 1989-07-14
US21262294A 1994-03-11 1994-03-11
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US08/380,566 US5688807A (en) 1994-03-11 1995-02-06 Method for treating 5HT2B receptor related conditions
US08/380,565 US5663178A (en) 1995-02-06 1995-02-06 Tetrahydro-beta carbolines
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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457101A (en) * 1994-06-03 1995-10-10 Eli Lilly And Company Thieno[1,5]benzoidiazepine use
CA2218143A1 (en) * 1995-04-18 1996-10-24 Eli Lilly And Company Method for using ergoline compounds to effect physiological and pathological functions at the 5-ht7 receptor
GB9523999D0 (en) 1995-11-23 1996-01-24 Lilly Co Eli Indolyl neuropeptide y receptor antagonists
JP2000507269A (ja) * 1996-03-15 2000-06-13 イーライ・リリー・アンド・カンパニー 一般かぜまたはアレルギー性鼻炎の処置方法
US5880134A (en) * 1996-03-20 1999-03-09 Eli Lilly And Company Method for using ergoline compounds to effect physiological and pathological functions at the 5-HT7 receptor
US5886003A (en) * 1996-03-25 1999-03-23 Eli Lilly And Company Methods of treating or ameliorating the symptoms of venomous bites and stings
IL126063A (en) * 1996-03-25 2002-04-21 Lilly Co Eli Medicinal products containing ulanzapine for the treatment of migraine pain
BR9708347A (pt) * 1996-03-25 1999-08-03 Lilly Co Eli Compostos de tetrahidorbeta-carbonila
WO2000069437A1 (en) 1999-05-18 2000-11-23 Synaptic Pharmaceutical Corporation Use of agonists or antagonists of the 5-ht7 receptor to treat disorders of the bladder
DK1188747T3 (da) 1999-05-24 2006-01-23 Mitsubishi Pharma Corp Phenoxypropylaminforbindelser
US6444477B1 (en) * 2000-11-28 2002-09-03 Pharmagene Laboratories Limited Assay method for detecting 5-HT2B antagonists
GB0203412D0 (en) 2002-02-13 2002-04-03 Pharmagene Lab Ltd 5-HT 2B receptor antagonists
EP1626715B1 (de) * 2003-05-09 2008-09-10 Laboratorios Del Dr. Esteve, S.A. Verwendung von sulfonamid-derivate zur herstellung eines medikaments für die vorbeugung oder behandlung von essstörungen
WO2006085510A1 (ja) * 2005-02-08 2006-08-17 Astellas Pharma Inc. 過敏性腸症候群の治療薬
CA2617473A1 (en) 2005-08-08 2007-02-15 Astellas Pharma Inc. Acylguanidine derivative or salt thereof
ATE542794T1 (de) 2006-02-20 2012-02-15 Astellas Pharma Inc Pyrrolderivat oder salz davon
TWI443098B (zh) 2008-03-24 2014-07-01 Medivation Technologies Inc 吡啶并〔３，４－ｂ〕吲哚及使用方法
WO2010058858A1 (ja) 2008-11-21 2010-05-27 ラクオリア創薬株式会社 ５－ｈｔ２ｂ受容体拮抗活性を有する新規ピラゾール－３－カルボキサミド誘導体
TW201038569A (en) * 2009-02-16 2010-11-01 Abbott Gmbh & Co Kg Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
WO2011038162A1 (en) * 2009-09-23 2011-03-31 Medivation Technologies, Inc. Pyrido(3,4-b)indoles and methods of use
CN102724875B (zh) * 2009-09-23 2015-05-27 梅迪维新技术公司 吡啶并[3,4-b]吲哚化合物及其使用方法
WO2017172957A1 (en) 2016-04-01 2017-10-05 Kalyra Pharmaceuticals, Inc. Estrogen receptor modulators
CA3130767A1 (en) * 2019-02-27 2020-09-03 The Regents Of The University Of California N-substituted indoles and other heterocycles for treating brain disorders
US11278532B2 (en) 2019-08-06 2022-03-22 Recurium Ip Holdings, Llc Estrogen receptor modulators for treating mutants
CN116514824A (zh) * 2022-01-29 2023-08-01 上海科技大学 三并环类化合物、其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3492304A (en) * 1968-06-24 1970-01-27 Warner Lambert Pharmaceutical 5,6,7,7a,8,8a,9,10,12,12a-decahydro-11h-benz(b)indolo(3,2,1-ij) 1,5 naphthyridin-11-ones
US4731358A (en) * 1982-10-29 1988-03-15 Schering Aktiengesellschaft β-carbolines and their use as tranquilizers
US5300645A (en) * 1993-04-14 1994-04-05 Eli Lilly And Company Tetrahydro-pyrido-indole
EP0620222A2 (de) * 1993-04-14 1994-10-19 Eli Lilly And Company Tetrahydro-betacarboline

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4520024A (en) * 1983-02-11 1985-05-28 Eli Lilly And Company Method of selectively blocking peripheral vascular serotonergic receptors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3492304A (en) * 1968-06-24 1970-01-27 Warner Lambert Pharmaceutical 5,6,7,7a,8,8a,9,10,12,12a-decahydro-11h-benz(b)indolo(3,2,1-ij) 1,5 naphthyridin-11-ones
US4731358A (en) * 1982-10-29 1988-03-15 Schering Aktiengesellschaft β-carbolines and their use as tranquilizers
US5300645A (en) * 1993-04-14 1994-04-05 Eli Lilly And Company Tetrahydro-pyrido-indole
EP0620222A2 (de) * 1993-04-14 1994-10-19 Eli Lilly And Company Tetrahydro-betacarboline

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
AUDIA, J. E. ET AL.: "Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B contractile receptor in the rat stomach fundus" J. MED. CHEM., vol. 39, 1996, pages 2773-2780, XP002167539 *
GLENNON, R. A.: "Central Serotonin Receptors as Targets for Drug Research" J. MED. CHEM., vol. 30, 1987, pages 1-12, XP002167538 *
MARTIN G R ET AL: "RECEPTORS FOR 5-HYDROXYTRYPTAMINE: CURRENT PERSPECTIVES ON CLASSIFICATION AND NOMENCLATURE" NEUROPHARMACOLOGY,GB,PERGAMON PRESS, OXFORD, vol. 33, no. 3/04, 1 March 1994 (1994-03-01), pages 261-273, XP002037183 ISSN: 0028-3908 *
ONDA, M.; KAWANISHI, M.: "Analogs of Rauwolfia Alkaloids" J. PHARM. SOC. JPN., vol. 76, 1956, pages 966-968, XP000985848 *
See also references of WO9524200A1 *
SP[TH, E. ET AL: "SYNTHESEN VON 4-CARBOLINEN" CHEMISCHE BERICHTE,XX,XX, vol. 120, 18 July 1930 (1930-07-18), pages 2102-2111, XP000917524 ISSN: 0009-2940 *

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