Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
• • 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
  • A61K31/40—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
  • 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
  • A61K31/41—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
• • 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
  • A61K31/4353—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
  • 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
  • A61K31/475—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
  • 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
  • A61K31/495—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
  • 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
  • A61K31/55—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
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/10—Laxatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
• 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-HT receptor sites include 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2A , 5-HT 2B , 5-HT2C, 5-HT 3f and 5-HT4 sites.Each of these receptors mediates certain physiological effects. See
• 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
• 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
• 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
• This invention provides a method for treating a mammal suffering from or susceptible to a condition
• Q is hydrogen or (CHR 2 )R 4
• R 1 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 -C 8 cycloalkyl, substituted C 5 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, bicyclic or substituted bicyclic;
• A is selected from the group consisting of
• R 6 and R 7 are, independently, hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 1 -C 6 )alkyl, halo (C 2 -C 6 )alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO2R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , or OR 5 ;
• n 1 or 2;
• R 5 is independently hydrogen or C 1 -C 4 alkyl
• R 5' is C 1 -C 4 alkyl
• R 8 is independently selected from the group consisting of an R 6 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 1 -C 3 )alkyl, C 7 -C 20 arylalkyl; or
• R 6 and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring
• R 8 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 (C 1 -C 6 )alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , OR 5 , 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
• R 5 is independently hydrogen or C 1 -C 4 alkyl
• R 5' is C 1 -C 4 alkyl
• R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1 -C 6 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, bromo, iodo, and chloro;
• R 12' is selected from the group consisting of hydrogen and C 1 -C 4 alkyl
• 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 1 -C 4 alkyl, C 3 -C 7
• 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;
• 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 -C 5 alkane
• R 23 is C 1 -C 3 alkyl or allyl
• R 24 is C 1 -C 3 hydroxyalkyl or C 1 -C 3 dihydroxyalkyl
• R 25 is hydrogen or CH 3 ;
• 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 R 27 is hydrogen, C 1 -C 3 alkyl, allyl, , or
• n' 1 to 5;
• 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, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 alkylthio, halo, CN, phenyl; or together are -(CH 2 ) p" -;
• p" is 3 to 6;
• Y a is -CH 2 -, -O-, -S(O) m" -;
• n 0, 1, or 2;
• This invention provides a method for treating a mammal suffering from or susceptible to a condition
• 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 1 is hydrogen or C 1 -C 3 alkyl
• R 2 is hydrogen or C 1 -C 6 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 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, bicyclic or substituted bicyclic;
• A is selected from the group consisting of
• R 6 and R 7 are, independently, hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 1 -C 6 ) alkyl, halo (C 2 -C 6 ) alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , or OR 5 ;
• n 1 or 2;
• R 5 is independently hydrogen or C 1 -C 4 alkyl
• R 5' is C 1 -C 4 alkyl
• R 8 is independently selected from the group consisting of an R 6 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 1 -C 3 )alkyl, C 7 -C 20 arylalkyl; or
• R 6 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 1 -C 6 alkyl and C 2 -C 6 alkenyl; or
• This invention provides a method for treating a mammal suffering from or susceptible to a condition
• A is selected from the group consisting of
• R 6 and R 7 are, independently, hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 1 -C 6 )alkyl, halo (C 2 -C 6 )alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5' or OR 5 ;
• n 1 or 2;
• R 8 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 (C 1 -C 6 ) alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5 ', (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , OR 5 , 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
• R 5 is independently hydrogen or C 1 -C 4 alkyl
• R 5' is C 1 -C 4 alkyl
• R 6 and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
• R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1 -C 6 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, bromo, 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 1 -C 6 alkyl and C 2 -C 6 alkenyl; or
• this invention provides a method for blocking a 5HT 2B receptor in a mammal, comprising
• This invention provides a method for blocking a 5HT 2B receptor in a mammal, comprising administering a 5HT 2B receptor occupying dose of a compound selected from the group consisting of Formula XI, and XII supra.; or a
• this invention provides a method for
• 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-HT 2B selective compound selected from the group consisting of of Formula XI and XII; or a
• the present invention provides compounds of the Formula XI
• 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 1 is hydrogen or C 1 -C 3 alkyl
• R 2 is hydrogen or C 1 -C 6 alkyl
• R 3 is hydrogen or C 1 -C 3 alkyl
• R 4 is C 5 -C 8 cycloalkyl, substitutedC 5 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, substitutedC 5 -C 8 cycloalkenyl, bicyclic or substituted bicyclic;
• A is selected from the group consisting of
• R 6 and R 7 are, independently, hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 1 -C 6 )alkyl, halo (C 2 -C 6 )alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5 -, (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , or OR 5 ;
• n 1 or 2;
• R 5 is independently hydrogen or C 1 -C 4 alkyl
• R 5' is C 1 -C 4 alkyl
• R 8 is independently selected from the group consisting of an R 6 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 1 -C 3 )alkyl, C 7 -C 20 arylalkyl; or
• R 6 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 1 -C 6 alkyl and C 2 -C 6 alkenyl; or
• This invention provides compounds of Formula XII
• A is selected from the group consisting of
• R 8 and R 7 are, independently, hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, halo (C 1 -C 6 ) alkyl, halo (C 2 -C 6 ) alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , or OR 5 ;
• n 1 or 2;
• R 8 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 (C 1 -C 6 )alkenyl, COR 5 , C 1 -C 10 alkanoyl, CO 2 R 5' , (C 1 -C 6 alkyl) m amino, NO 2 , -SR 5 , OR 5 , 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
• R 5 is independently hydrogen or C 1 -C 4 alkyl
• R 5' is C 1 -C 4 alkyl
• R 6 and R 7 together with the carbon atoms of group A form a 5- to 8-member carbon ring;
• R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1 -C 6 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, 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 C 1 -C 6 alkyl and C 2 -C 6 alkenyl; or
• 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
• 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
• 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.
• 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.
• 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 C 1 -C 6 alkyl groups include methyl, ethyl, n-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
• R 30 and R 31 are most preferably independently selected from the group
• the carbon ring thus formed may be saturated or unsaturated. As used herein, such ring may be illustrated as: ; wherein 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
• 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
• halide include fluorine, chlorine, bromine, and iodine.
• halogen include fluorine, chlorine, bromine, and iodine.
• the preferred halogen is chlorine.
• halo (C 1 -C 6 ) alkyl and “halo(C 2 -C 6 )alkenyl” refer to alkyl or alkenyl substituents having one or more independently selected halo atoms attached at one or more available carbon atoms. These terms include
• halo- (C 1 -C 6 )alkyl is trifluoromethyl.
• C 1 -C 10 alkanoyl represents a group of the formula C(O) (C 1 -C 9 ) alkyl.
• Typical C 1 -C 10 alkanoyl groups include acetyl, propanoyl, butanoyl, and the like.
• Examples of such groups are methylamino, dimethylamino, ethylamino, diethylamino, 2-propylamino, 1-propylamino, di(n-propyl)amino, di(iso-propyl) amino, 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, C 1 -C 6 alkyl, NO 2 , halo, halo (C 1 -C 6 )alkyl, halo (C 2 -C 6 )alkenyl, C 2 -C 6 alkenyl, CO 2 R 5 , (C 1 -C 6 alkyl) m amino, -SR 5 , and OR 5 .
• C 3 -C 8 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.
• C 5 -C 8 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, C 1 -C 6 alkyl, NO 2 , halo, halo (C 1 -C 6 )alkyl, halo (C 2 -C 6 )alkenyl, C 2 -C 6 alkenyl, COR 5 , C 1 -C 10 alkanoyl, C 7 -C 20 arylalkyl, CO 2 R 5 , (C 1 -C 6 alkyl) m amino, -SR 5 , and OR 5 .
• C 5 -C 8 cycloalkenyl-(C 1 -C 3 )alkyl represents a linear C 1 -C 3 alkyl group substituted at a terminal carbon with a C 5 -C 8 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 C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8
• cycloalkyl C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl-(C 1 -C 3 )alkyl, phenyl, C 5 -C 8 cycloalkenyl, substituted C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl-(C 1 -C 3 )alkyl, COR 5 , C 1 -C 10 alkanoyl, OR 5 , and C 7 -C 16 arylalkyl.
• the substituents may be located at any available position on the aryl ring.
• C 7 -C 20 arylalkyl represents an aryl-(C 1 -C 10 alkyl substituent wherein the alkyl group is linear, such as benzyl, phenethyl, 3-phenylpropyl, or phenyl- t-butyl; or branched.
• the bicyclic ring may be
• 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, C 1 -C 6 alkyl, NO 2 , halo, halo(C 1 -C 6 )alkyl, halo(C 2 -C 6 )alkenyl, C 2 -C 6 alkenyl, COR 5 , C 1 -C 10 alkanoyl, C 7 -C 20 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, benzocyclohexenyl, 2-methoxybenzocyclohexyl, 6-chlorobenzocyclohexenyl, 8-ethenylbenzocyclohexyl, and the like.
• spiro-bicyclic and "substituted spirobicyclic” refer to a bicyclic or substituted bicyclic (as defined supra.) directly attached to the carbon of the parent ring at substituent Q'.
• a spirobicyclic 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.
• cycloheptyl and when m' 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-,
• 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
• 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.
• 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.
• modulating -a 5-HT 2B receptor include, but are not limited to 7-bromo-8-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, ⁇ -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-1,2,3,4-tetrahydro-9H-pyrido[3,4b]-indole, 7-cyclo
• Patent 4,931,447 cycloalkylamides of (8 ⁇ )-1-alkyl-6-(substituted)ergolines described in U.S. Patent 4,981,859, compounds described in U.S. Patent 4,563,461, compounds described in U.S. Patent 4,902,691, wherein the four aforementioned U.S.
• 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-1,2,3-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-(di-n-propylamino)
• Especially preferred compounds for use in modulating a 5-HT 2B receptor include 7-bromo-8-methyl-1,2,3,4-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-1,2,3,4-tetrahydro-9H-pyrido[3,4b]- indole, 7-cyclohex
• a preferred compound of Formula IX has the following structure:
• R 6 is selected from the group consisting of C 1 -C 4 alkyl, OR 5' , fluoro, bromo, and chloro;
• R 5' is C 1 -C 4 alkyl
• R 1 , R 7 , and R 8 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,
• stomach emptylng 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
• 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.
• 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
• 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.
• Frctional 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
• Frctional Bowel Disorder includes but is not limited to irritable bowel syndrome, hypermotility, ichlasia, hypertonic lower esophogeal sphinctor, tachygastria,
• 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
• IBS Symptoms of IBS occur in approximately 14% of otherwise apparently healthy people. IBS is a complex condition, in part because it is not a disease but a syndrome composed of a number of conditions with similar manifestations.
• Histamine H2 receptor antagonists inhibit gastric acid secretion and my relieve some dyspeptic symptoms.
• the term Functional Bowel Disorder includes
• 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,
• 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.
• R 1 is hydrogen
• R 2 is hydrogen or methyl
• R 3 is hydrogen or methyl
• R 4 is C 5 -C 8 cycloalkenyl or substituted C 5 -C 8
• cycloalkenyl bicyclic or substituted bicyclic, wherein the substituents are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NO 2 , halo, halo (C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, COR 5 , (C 1 -C 6 alkyl) m amino, -SR 5 , and OR 5 .
• A is a group of formula III
• A is a group of formula IV wherein R 6 and R 7 are C 1 -C 6 alkyl or halo, and R 8 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, (C 1 -C 6 alkyl) m amino, and OR 5 ;
• A is a group of formula IV wherein R 6 is hydrogen, R 7 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 OR 5 ;
• Y a is CH 2 , R 26 and R 27 are each C 2 -C 3 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 2B receptors than it has for 5-HT 2A receptors.
• the 5-HT 2B selective compound has a greater affinity for 5-HT 2B 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
• 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
• 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
• R 9 and R 10 are each hydrogen.
• R 11 is C 1 -C 3 alkyl.
• R 11 is chloro, fluoro, or bromo.
• R 11 is -OCH 3 .
• R 6 is C 1 -C 4 alkyl.
• R 6 is methyl
• J) A method for using one or more compounds of Formula I and/or II for treating Irritable Bowel Syndrome.
• K) A pharmaceutical formulation comprising a compound of Formula I or II and one or more pharmaceutically acceptable excipients.
• 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.
• R 1 is hydrogen
• R 2 is hydrogen or methyl
• R 3 is hydrogen or methyl
• R 4 is C 5 -C 8 cycloalkenyl or substituted C 5 -C 8
• cycloalkenyl wherein the substituents are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NO 2 , halo, halo(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, COR 5 , (C 1 -C 6 alkyl) m amino, -SR 5 , and OR 5;
• A is a group of formula III
• A is a group of formula IV wherein R 6 and R 7 are C 1 -C 6 alkyl or halo, and R 8 is hydrogen, C 1 -C 5 alkyl, halo, C 5 -C 8 cycloalkyl, phenyl or substituted-phenyl;
• R 2 is hydrogen
• R 3 is hydrogen
• R 4 is substituted C 5 -C 8 cycloalkenyl; wherein the substituents are selected from the group consisting of hydrogen, NO 2 , halo, (C 1 -C 6 alkyl) m amino, and OR 5 ;
• A is a group of formula IV wherein R 6 is hydrogen, R 7 and R 8 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' is bicyclic or substituted bicyclic
• R 34 is an optionally substituted bicyclic ring substituent
• R 9 and R 10 are each hydrogen;
• R 9 is selected from the group consisting of C 1 -C 6 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 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:
• R 9 and R 10 are each hydrogen
• R 11 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
• 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.
• 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-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; (-)-(S)-5,7-dimethyl-1,2,3,4-tetrahydro-1-[(3,4-dimethoxyphenyl)methyl]-9H- pyrido[3,4-b]indole; (-)-(S)-5-fluoro-6-methyl-1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; and (-)-(S)-6-methyl-1,2,3,4-tetrahydro-1-[(3,4-dimethylphenyl)methyl]-9H-pyrido[3,4-
• the invention also includes, but is not limited to, the use of (+)-(S)-7-methyl-8-bromo-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; (+)-(S)-5,7-dimethyl-1,2,3,4-tetrahydro-1-[(3,4-dimethoxyphenyl)methyl]-9H-pyrido[3,4-b]indole; (+)-(S)-5-fluoro-6-methyl-1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; (-)-(R)-7-methyl-8-bromo-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]
• 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
• solvate as used herein includes hydrate forms such as monohydrate and
• 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.
• a compound of Formula VII can be prepared as described in
• 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
• 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 R 9 , R 12 , and/or R 10 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
• 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
• 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
• 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
• reaction mixture may be neutralized with an
• 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
• chloromethylmethyl ether (MOMC1) are added to the solution, as represented by step 2.
• 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
• the organic phase is dried over a suitable drying agent, such as sodium carbonate, and concentrated to facilitate
• the product may be isolated by flash chromatography and concentrated. The resulting oil may be used in subsequent steps without further purification.
• step 4 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
• the salt can be isolated and purified by common chemical methods.
• compound (r) is mixed in THF.
• TEDA Tetramethylethylenediamine
• Mel methyl iodide
• the reaction is quenched by the addition of water, followed by extraction with an appropriate organic phase, such as diethyl ether.
• organic phases are dried over an
• 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 C 1 -C 6 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.
• 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 .
• 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.
• 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
• 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)-try1tamine 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.
• Example 4 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,
• 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.
• Example 4 hydrochloride in Example 4, except using 3,5-dimethylphenylhydrazine hydrochloride (7.65 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.
• reaction mixture was gradually warmed to ambient temperature and stirred 14 H.
• Saturated ammonium chloride solution 100 mL was added and the mixture extracted with diethyl ether (3 X 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure.
• methoxymethyl-triphenylphosphonium chloride (8.81 g, 25.7 mmol.) in dry THF (150 mL) was added n-BuLi solution (16.1 mL. 1.6 M,- 25.7 mmol.) dropwise by syringe. The orange suspension was stirred at -78°C for 15 min. A solution of 4-dibutylaminobenzaldehyde (5.00 g, 2.14 mmol.) in THF (75 mL) was added to the ylide dropwise over 10 min. The
• reaction mixture was gradually warmed to ambient temperature and stirred 14 H.
• Saturated ammonium chloride solution 100 mL was added and the mixture extracted with diethyl ether (3 X 50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure.
• 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).
• methoxymethyltriphenylphosphonium chloride (118.9 g, 347 mmol.) in dry THF (2000 mL) was added potassium t-butoxide (39.3 g, 350 mmol.) in portions. The orange suspension was stirred at -20°C for 30 min. A solution of 3,4-dimethoxyacetophenone (50.0 g, 275 mmol.) in THF (500 mL) was added to the ylide dropwise over 30 min. The reaction mixture was gradually warmed to ambient temperature and stirred 2 H. Saturated ammonium chloride solution (500 mL) was added and the mixture extracted with diethyl ether (3 X 500 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure.
• Example 17 (2.0 g, 8.9 mmol.) was converted to its free base with aqueous potassium carbonate in chloroform. This solution was dried and treated with 1-methoxy-2-methyl-3',4'-dimethoxystyrene (prepared above in Example 40) (1.86 g, 8.9 mmol.) and trifluroracetic acid (2.03 g, 17.8 mmol) and was heated to reflux for 96 H. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The combined organic phases were concentrated under reduced pressure and the residue chromatographed on silica gel (2.5% MeOH/chloroform/0.2% NH 4 OH as eluent). The fractions
• 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.
• the aqueous phase was made basic with sodium hydroxide solution (50%), cooling the mixture with ice when necessary.
• the basic aqueous phase was extracted with diethyl ether (2 X 200 mL) and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to afford product as an oily solid (13.15 g), which was used without further purification.
• 6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromotryptamme hydrochloride in Example 7, except using 2-bromo-3-methyl phenylhydrazine 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-bromotryptamine hydrochloride in Example 7, except using 3-fluoro-4-methyl-phenylhydrazine hydrochloride (6.00 g) as starting material.
• Example 7 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.
• reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform.
• the desired product was prepared using
• Example 66 substantially the process of Example 66, except that the starting material was 7-methoxy-1H-indole-ethanamine.
• a sample of 8-methoxy-1,2,3,4-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 CO 3 and the mixture was purged with nitrogen.
• a 40 mL sample of CH 3 CN 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

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Pulmonology (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyridine Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Indole Compounds (AREA)
• Liquid Crystal Substances (AREA)
• Investigation Of Foundation Soil And Reinforcement Of Foundation Soil By Compacting Or Drainage (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (6)

Applications Claiming Priority (6)

Publications (1)

Family

ID=27395770

Family Applications (1)

Country Status (11)

Cited By (25)

Families Citing this family (7)

Citations (1)

Family Cites Families (4)

• 1995
  • 1995-03-10 CZ CZ962649A patent/CZ264996A3/cs unknown
  • 1995-03-10 AU AU21186/95A patent/AU679635B2/en not_active Ceased
  • 1995-03-10 WO PCT/US1995/003099 patent/WO1995024200A1/en not_active Ceased
  • 1995-03-10 HU HU9602482A patent/HUT75522A/hu unknown
  • 1995-03-10 CN CN95193029A patent/CN1148340A/zh active Pending
  • 1995-03-10 CA CA002185236A patent/CA2185236A1/en not_active Abandoned
  • 1995-03-10 EP EP95914014A patent/EP0749313A4/en not_active Withdrawn
  • 1995-03-10 IL IL11295895A patent/IL112958A0/xx unknown
  • 1995-03-10 FI FI963571A patent/FI963571A7/fi unknown
  • 1995-03-10 JP JP7523692A patent/JPH09510216A/ja active Pending
• 1996
  • 1996-09-10 NO NO963785A patent/NO963785L/no unknown

Patent Citations (1)

Also Published As

Similar Documents

Legal Events