WO1997023482A1 - 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives - Google Patents

2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives Download PDF

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Publication number
WO1997023482A1
WO1997023482A1 PCT/IB1996/001192 IB9601192W WO9723482A1 WO 1997023482 A1 WO1997023482 A1 WO 1997023482A1 IB 9601192 W IB9601192 W IB 9601192W WO 9723482 A1 WO9723482 A1 WO 9723482A1
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compound
treating
mammal
pharmaceutically acceptable
preventing
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PCT/IB1996/001192
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English (en)
French (fr)
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Mark A. Sanner
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Pfizer Inc.
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Priority to NZ320537A priority Critical patent/NZ320537A/xx
Priority to IL12445396A priority patent/IL124453A0/xx
Priority to DK96935226T priority patent/DK0874849T3/da
Priority to PL96327539A priority patent/PL327539A1/xx
Priority to SI9630343T priority patent/SI0874849T1/xx
Priority to JP52344697A priority patent/JP3204456B2/ja
Priority to AU73280/96A priority patent/AU704578B2/en
Priority to DE69615404T priority patent/DE69615404T2/de
Priority to CA002240594A priority patent/CA2240594C/en
Priority to BR9612246A priority patent/BR9612246A/pt
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to KR1019980704718A priority patent/KR100286786B1/ko
Priority to EP96935226A priority patent/EP0874849B1/en
Priority to AT96935226T priority patent/ATE205846T1/de
Publication of WO1997023482A1 publication Critical patent/WO1997023482A1/en
Priority to NO982843A priority patent/NO309936B1/no
Priority to GR20010401932T priority patent/GR3037060T3/el

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to novel pharmacologically active 2,7-substituted octahydro-1 H-pyrrolo[1 ,2-a]pyrazine derivatives, their acid addition salts, and certain precursors thereto.
  • the compounds of this invention are ligands for dopamine receptor subtypes, especially the dopamine D 4 receptor, and are therefore useful in the treatment of disorders of the dopamine system.
  • the dopamine D, receptor subtype has been shown to occur in the least two discrete forms. Two forms of the D 2 receptor subtype, and at least one form of the D 3 receptor subtype, have also been discovered. More recently, the D 4 (Van Tol et al., Nature (London), 1991 , 350, 610) and D 5 (Sunahara et al., Nature (London), 1991 , 350, 614) receptor subtypes have been described.
  • the compounds of the present invention being ligands for dopamine receptor subtypes, especially the dopamine D 4 receptor, are accordingly of use in the treatment or prevention of disorders of the dopamine system.
  • Dopamine D4 receptors are more prevalent in the brains of schizophrenic patients (Seeman, et al. Nature, 1993, 365. 441) relative to normal controls.
  • Dopamine receptor antagonists are useful for the treatment of psychotic disorders, such as schizophrenia, and the compounds of the present invention, being ligands for dopamine receptor subtypes, especially the dopamine D 4 receptor, are accordingly of use in the treatment or prevention of psychotic disorders, especially affective psychosis, schizophrenia, and schizoaffective disorders.
  • dopamine receptors control a great number of pharmacological events and, on the other hand, not all these events are presently known, there is a possibility that compounds that act on the dopamine D 4 receptor may exert a wide range of therapeutic effects in animals.
  • WO 94/10162 (published May 11 , 1994) and WO 94/10145 (published May 11 , 1994) report that dopamine ligands are of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, and disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea.
  • the compounds according to the present invention may thus be of use in the prevention and/or treatment of gastrointestinal disorders, and the facilitation of gastric emptying.
  • Dopamine is known to be a peripheral vasodilator, for example, it has been shown to exert a dilatory effect on the renal vascular bed This implies that the compounds of the present invention may be beneficial in controlling vascular blood flow.
  • dopamine receptor mRNA in rat heart and large vessels has been noted This suggests a role for dopamine receptor ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances
  • the compounds according to the present invention may therefore be of assistance in the prevention and/or treatment of such conditions as hypertension and congestive heart failure.
  • D4 receptor mRNA in mouse retina has been noted (Cohen, et al Proc Nat Acad Sci , 1992, 89 12093), suggesting that dopamine and D4 receptors play a role in ocular function.
  • the compounds of this invention may therefore be useful in the treatment of ocular disorders
  • D4 receptors influence melatonin biosynthesis in chick retina (Zawilska, Nowak, Neuroscience Lett , 1994, 166, 203), and since melatonin has been used for the treatment of sleep disorders, the compounds of this invention may be useful for the treatment of sleep disorders as well.
  • This invention relates to a compound of formula I
  • R 1 is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;
  • R 2 is H or (C 1 -C 6 )alkyl
  • R 3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl;
  • R 4 is H or (C 1 -C 6 )alkyl
  • R 5 is H or (C 1 -C 6 )alkyl
  • each group of R 1 and R 3 may be independently and optionally substituted with one to four substituents independently selected from the groups consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, -SR 4 , -SOR 4 , - SO 2 R 4 , -NHSO 2 R 4 , -(C 1 -C 6 )alkoxy, -NR 4 R 5 , -NR 4 COR 5 , -CONR 4 R 5 , phenyl, -COR 4 , -COOR 4 , -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, and trifluoromethoxy;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • this invention relates to compounds of formula I wherein
  • R 1 is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl;
  • R 1 and R 3 may be independently substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, -NR 4 R 5 , -(C 1 -C 6 )alkoxy, -COOR 4 , -CONR 4 R 5 , -(C 1 -C 6 )alkyl, - (C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, and trifluoromethoxy;
  • R 2 is H or CH 3 ;
  • n 0 or 1
  • n 0 or 1 ;
  • this invention relates to compounds of formula I wherein R 1 is phenyl or substituted phenyl;
  • R 3 is substituted or unsubstituted phenyl, pyridinyl, or pyrimidinyl
  • this invention relates to compounds of formula I wherein R 2 is H;
  • n 1 ;
  • this invention relates to compounds of formula I wherein R 2 is H,
  • n 1;
  • n 0;
  • this invention relates to compounds of formula I wherein
  • R 2 is H
  • n 0;
  • this invention relates to compounds of formula I wherein
  • R 1 is fluorophenyl, diflurophenyl, or cyanophenyl
  • R 3 is chloropyridinyl
  • this invention relates to compounds of formula I wherein
  • R 1 is fluorophenyl, diflurophenyl, or cyanophenyl
  • R 3 is fluoropyrimidinyl
  • this invention relates to compounds of formula I wherein R ⁇ is fluorophenyl, diflurophenyl, or cyanophenyl;
  • R 3 is chloropyridinyl
  • this invention relates to compounds of formula I wherein
  • R 1 is fluorophenyl, diflurophenyl, or cyanophenyl
  • R 3 is fluoropyrimidinyl
  • this invention relates to compounds of formula I wherein R 1 is fluorophenyl, diflurophenyl, or cyanophenyl;
  • R 3 is chloropyridinyl
  • this invention relates to compounds of formula I wherein
  • R 1 is fluorophenyl, diflurophenyl, or cyanophenyl
  • R 3 is fluoropyrimidinyl
  • this invention relates to compounds of formula I wherein
  • R 3 is 5-chloro-pyridin-2-yl-;
  • this invention relates to compounds of formula I wherein
  • R 3 is 5-fluoro-pyrimidin-2-yl-;
  • this invention relates to compounds of formula I wherein
  • R 3 is 5-chloro-pyridin-2-yl-;
  • this invention relates to compounds of formula I wherein
  • R 3 is 5-fluoro-pyrimidin-2-yl-;
  • this invention relates to compounds of formula I wherein
  • R 3 is 5-chloro-pyridin-2-yl-;
  • this invention relates to compounds of formula I wherein
  • R 3 is 5-fluoro-pyrimidin-2-yl-;
  • Preferred compounds of the invention are:
  • This invention also relates to a method for treating or preventing disorders of the dopamine system in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing psychotic disorders such as affective psychosis, schizophrenia, and schizoaffective disorders in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing movement disorders such as extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, or Gilles De La Tourette's syndrome in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • movement disorders such as extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, or Gilles De La Tourette's syndrome
  • This invention also relates to a method for treating or preventing movement disorders such as Parkinson's disease or Huntington's disease in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing
  • gastrointestinal disorders such as gastric acid secretion in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing
  • gastrointestinal disorders such as emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing chemical abuse, chemical dependencies or substance abuse in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing vascular and cardiovascular disorders such as congestive heart failure and hypertension in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing ocular disorders in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a method for treating or preventing sleep disorders in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing disorders of the dopamine system in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing psychotic disorders such as affective psychosis, schizophrenia, and schizoaffective disorders in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1, or a
  • This invention also relates to a pharmaceutical composition for treating or preventing movement disorders such as extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, or Gilles De La
  • Tourette's syndrome in a mammal comprising administering to said mammal an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing movement disorders such as Parkinson's disease or Huntington's disease in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing gastrointestinal disorders such as gastric acid secretion in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing gastrointestinal disorders such as emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing chemical abuse, chemical dependencies or substance abuse in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing vascular and cardiovascular disorders such as congestive heart failure and hypertension in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
  • This invention also relates to a pharmaceutical composition for treating or preventing ocular disorders in a mammal, including a human, comprising
  • This invention also relates to a pharmaceutical composition for treating or preventing sleep disorders in a mammal, including a human, comprising administering to said mammal an amount of a compound according to claim 1 , or a
  • this invention relates to compounds of formula IV
  • n 0 or 1 ;
  • Y is CH or N
  • Z is chloro or fluoro
  • Preferred compounds of formula IV which are useful intermediates for the preparation of compounds of formula I, are:
  • This invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I
  • the compounds of formula I are basic in nature and are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of those compounds of formula I are those that form non-toxic acid addition salts, i.e.
  • salts containing pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succmate, maleate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.
  • pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid cit
  • one or more substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkoxy refers to radicals having the formula -O-alkyl, wherein “alkyl” is defined as above.
  • the compounds of formula I contain chiral centers and therefore exist in different enantiomeric forms.
  • This invention relates to all stereoisomers of compounds of the formula I and mixtures thereof.
  • disorders of the dopamine system refers to disorders the treatment or prevention of which can be effected or facilitated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission.
  • the compounds in accordance with the present invention being ligands for dopamine receptor subtypes, especially the dopamine D4 receptor, within the body, are accordingly of use in the treatment or prevention of disorders of the dopamine system.
  • dopamine receptors are important for many functions in the animal body. For example, altered functions of these receptors participate in the genesis of psychosis, addiction, sleep, feeding, learning, memory, sexual behavior, and blood pressure.
  • This invention provides dopamine ligands that are of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, and disorders of hypothalamic-pituitary function such as
  • hyperprolactinaemia and amenorrhoea are hyperprolactinaemia and amenorrhoea.
  • the compounds according to the present invention are of use in the prevention or treatment of gastrointestinal disorders, and the facilitation of gastric emptying.
  • Dependence-inducing agents such as cocaine and amphetamine have been shown to interact with the dopamine system.
  • Compounds capable of counteracting this effect including the compounds in accordance with the present invention, are accordingly of value in the prevention or reduction of dependence on a dependence-inducing agent.
  • Dopamine is known to be a peripheral vasodilator; for example, it has been shown to exert a dilatory effect on the renal vascular bed. This shows that the compounds of the present invention are beneficial in controlling vascular blood flow.
  • dopamine receptor mRNA The localization of dopamine receptor mRNA in rat heart and large vessels has been noted. This suggests a role for dopamine receptor ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances.
  • the compounds according to the present invention are of assistance in the prevention or treatment of such conditions as hypertension and congestive heart failure.
  • D4 receptor mRNA in rat retina has been noted (Cohen, et al. Proc. Nat. Acad. Sci., 1992, 89, 12093), suggesting that dopamine and D4 receptors play a role in ocular function.
  • the compounds of this invention may therefore be useful in the treatment of ocular disorders.
  • D4 receptors influence melatonin biosynthesis in chick retina (Zawilska, Nowak, Neuroscience Lett., 1994, 166, 203), and since melatonin has been used for the treatment of sleep disorders, the compounds of this invention may be useful for the treatment of sleep disorders as well.
  • reaction inert solvent refers to a solvent system in which the components do not interact with starting materials, reagents, intermediates of products in a manner which adversely affects the yield of the desired product.
  • nitrogen protecting group means a moiety which when coupled with a basic nitrogen will remain inert while other reactions are carried out. The nitrogen protecting group may then be removed under mild conditions yielding the free amino group.
  • This invention contemplates two types of nitrogen protecting groups: those which may be removed by treatment with strong acid and those which may be removed by hydrogenation.
  • nitrogen protecting groups removed by strong acid are tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, diphenylmethoxycarbonyl, trityl, acetyl and benzoyl.
  • nitrogen protecting groups removed by hydrogenation are benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2-phenylethyloxycarbonyl, benzyl, p-methoxybenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl.
  • a preferred nitrogen protecting group is benzyl.
  • Compounds of formula VII are useful intermediates for the preparation of compounds of formula I.
  • Compounds of formula VII wherein n is 0 are known (Diafi, L; et al. J. Het. Chem., 1990, 27, 2181).
  • Compounds of formula VII wherein n is 1 may be prepared according to Scheme 1.
  • Compounds of formula VII wherein n is 2 may be prepared according to Scheme 2.
  • Scheme 1 summarizes methods suitable for preparing compounds VII wherein n is 1.
  • Compounds of the formulas V and VI wherein R 2 is hydrogen or methyl are known (Jones, R. C. F.; Howard, K. J. J. Chem. Soc. Perkin Trans. 1, 1993, 2391), and additional examples of VII wherein R 2 is a straight chain, branched or cyclic C 1 to C 6 alkyl may be prepared by this method using acrylate esters where the R 2 substituent is placed at the 2- position of the acrylate starting material.
  • Compounds VI may be converted into VII by the action of a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1,4-dioxane or 1 ,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1,4-dioxane or 1 ,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • THF tetrahydrofuran
  • 1,4-dioxane or 1 ,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about
  • Compound V wherein R 2 is hydrogen may be used to prepare VIII by the action of a base in a lower alcohol solvent such as methanol, ethanol or propanol with an amine base, wherein 1,8-diazbicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazbicyclo[4.3.0]non-5-ene (DBN) are preferred bases, at a temperature from about 0 °C to about 100 °C, where a preferred temperature is from about 20 °C to about 60 °C
  • Reduction of VIII to IX may be accomplished by exposing a mixture of VIII and a noble metal catalyst, wherein palladium is a preferred noble metal catalyst, wherein the metal may be conveniently suspended on an inert solid support such as charcoal, in a solvent such as ethyl acetate or hexane or a mixture thereof, to an atmosphere of hydrogen gas at a pressure of about 1 to 100 atmospheres, where a preferred pressure of hydrogen gas is about one to
  • Compound IX may be converted into VII by the action of a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1,4-dioxane or 1,2- dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1,4-dioxane or 1,2- dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2- dimethoxyethane
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2- dimethoxy
  • Compound IX may be converted into compound VI by treating a solution of IX in an ether solvent, preferably tetrahydrofuran (THF), with an alkali metal amide base, preferably lithium diisopropylamide or potassium hexamethyl disilazide, at a temperature from about 0 °C to about -100 °C, preferably from about -50 °C to about -80 °C, followed by addition of an appropriate alkylating agent, such as an alkyl halide, wherein alkyl halides of one to six carbon atoms and bromide or iodide are preferred.
  • an ether solvent preferably tetrahydrofuran (THF)
  • an alkali metal amide base preferably lithium diisopropylamide or potassium hexamethyl disilazide
  • an appropriate alkylating agent such as an alkyl halide, wherein alkyl halides of one to six carbon atoms and bromide or i
  • Compound IX prepared by this method may be converted into VII by the action of a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1,4-dioxane or 1,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1,4-dioxane or 1,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • a hydride reducing agent preferably diisobutyl aluminum hydride
  • THF tetrahydrofuran
  • a hydride reducing agent preferably diisobutyl aluminum hydride
  • a temperature from about 0 °C to about 80 °C, preferably from about 20 °C to about 60 °C.
  • a hydride of boron preferably sodium borohydride or sodium
  • cyanoborohydride in a lower alcohol solvent, preferably methanol or ethanol, at a temperature from about -10 °C to about 30 °C.
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with alcohol VII in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • a trialkyl amine preferably triethylamine
  • a reaction inert solvent preferably methylene chloride or chloroform
  • a suitable base such as an alkali metal hydride, preferably sodium hydride, or an alkali metal carbonate, preferably sodium carbonate or potassium carbonate
  • a polar reaction inert solvent preferably dimethyl formamide (DMF) or dimethylsulfoxide (DMSO)
  • compounds XII may be prepared from VII by combining approximately equimolar quantities of VII, an alcohol of formula
  • THF tetrahydrofuran
  • 1,4-dioxane or 1,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • compound XII may be prepared by combining VII with a compound of the formula R 1 (CH 2 ) m CO 2 H, a triarylphosphine, preferably triphenylphosphine (Ph 3 P), and dialkyl azodicarboxylate, preferably diethyl azodicarboxylate (DEAD), in a relatively polar ether solvent, preferably tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane, at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a compound of the formula R 1 (CH 2 ) m CO 2 H a triarylphosphine, preferably triphenylphosphine (Ph 3 P), and dialkyl azodicarboxylate, preferably diethyl azodicarboxylate (DEAD)
  • a relatively polar ether solvent
  • XII may be conveniently prepared by reacting VII with a compound of formula R 1 -(CH 2 ) m -L wherein L is a leaving group and a suitable base such as an alkali metal hydride, preferably sodium hydride, or an alkali metal carbonate, preferably sodium carbonate or potassium carbonate, in a reaction inert solvent, preferably a polar solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or acetonitrile, at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a suitable base such as an alkali metal hydride, preferably sodium hydride, or an alkali metal carbonate, preferably sodium carbonate or potassium carbonate
  • a reaction inert solvent preferably a polar solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or acetonitrile
  • leaving group refers to groups which may be replaced by other groups under suitable conditions, and includes, for example, halogen, lower-alkylsulfonyl and arylsulfonyl. Methanesulfonyl, bromo or iodo are preferred leaving groups.
  • a method of preparing compounds of formula XII wherein X is CHR 4 from VII involves conversion of the alcohol moiety of VII into a leaving group such as lower- alkylsulfonyl ester or arylsulfonyl ester as the first step of a two-step process.
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with VII in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • a trialkyl amine preferably triethylamine
  • a reaction inert solvent preferably methylene chloride or chloroform
  • the alkyl- or arylsulfonyl derivative is combined with a compound of the formula R 1 (CH 2 ) m CH(R 4 )MgY wherein Y is a halogen atom, preferably chloro, bromo, or iodo, and a salt of copper(l), preferably cuprous bromide or cuprous iodide, in an ether solvent, preferably tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane, at a temperature from about -100 °C to about 50 °C, preferably from about -80 °C to about 25 °C.
  • a compound of the formula R 1 (CH 2 ) m CH(R 4 )MgY wherein Y is a halogen atom, preferably chloro, bromo, or iodo, and a salt of copper(l), preferably cuprous bromide or cuprous io
  • Compounds of formula XII may be converted into compounds XIII by combining XII with a noble metal catalyst on an inert solid material, preferably palladium on charcoal, in a polar solvent such as a lower alcohol, preferably methanol or ethanol, to an atmosphere of hydrogen gas at a pressure of about one to twenty atmospheres and a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a noble metal catalyst on an inert solid material preferably palladium on charcoal
  • a polar solvent such as a lower alcohol, preferably methanol or ethanol
  • XIII may be conveniently prepared from XII by the action of ammonium formate and a noble metal catalyst, preferably palladium on charcoal, in a polar solvent such as water or a lower alcohol, preferably methanol or ethanol, or a mixture of water and a lower alcohol, at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a noble metal catalyst preferably palladium on charcoal
  • L is a leaving group.
  • the term "leaving group” (L) refers to groups which may be replaced by other groups under suitable conditions, and include, for example, halogen, lower-alkylsulfonyl and arylsulfonyl.
  • Activated forms of R 3 may also be derivatives of benzene bearing an electron withdrawing group (EWG) and a leaving group (L) in the ortho- or para- positions relative to one other:
  • R 3 is a derivative of benzene
  • halogens are the preferred leaving groups, especially fluoro, and nitro or cyano are examples of preferred electron withdrawing groups.
  • reaction inert solvents such as water, C 1 -C 6 alcohols, or dimethyl sulfoxide, wherein water, propanol, butanol, or pentanol are preferred, at a temperature from about 30 °C to about 170 °C, preferably from about 60 °C to about 110 °C.
  • an acid acceptor such as a trialkyl amine or an alkali carbonate may be useful, and sodium carbonate or potassium carbonate is preferred.
  • the formation of amino alcohols XIV from VII by this method may be conveniently carried out by combining VII with a noble metal catalyst on an inert solid material, preferably palladium on charcoal, in a polar solvent such as a lower alcohol, preferably methanol or ethanol, to an atmosphere of hydrogen gas at a pressure of about one to twenty atmospheres and a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • XIV may be conveniently prepared from VII by the action of ammonium formate and a noble metal catalyst, preferably palladium on charcoal, in a polar solvent such as water or a lower alcohol, preferably methanol or ethanol, or a mixture of water and a lower alcohol, at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a noble metal catalyst preferably palladium on charcoal
  • Compounds XV may be prepared by reacting XIV with an activated form of R 3 in a reaction inert solvent such as water, C 1 -C 6 alcohols, or dimethyl sulfoxide, wherein water, propanol, butanol, or pentanol are preferred, at a temperature from about 30 °C to about 170 °C, preferably from about 60 °C to about 110 °C.
  • a reaction inert solvent such as water, C 1 -C 6 alcohols, or dimethyl sulfoxide, wherein water, propanol, butanol, or pentanol are preferred, at a temperature from about 30 °C to about 170 °C, preferably from about 60 °C to about 110 °C.
  • an acid acceptor such as a trialkyl amine or an alkali carbonate may be useful, and sodium carbonate or potassium carbonate are preferred.
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with alcohol XV in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • a trialkyl amine preferably triethylamine
  • a reaction inert solvent preferably methylene chloride or chloroform
  • a suitable base such as an alkali metal hydride, preferably sodium hydride, or an alkali metal carbonate, preferably sodium carbonate or potassium carbonate
  • a polar reaction inert solvent preferably dimethyl formamide (DMF) or dimethylsulfoxide (DMSO)
  • compounds I may be prepared from XV by combining approximately equimolar quantities of XV, an alcohol of formula R 1 OH or a thiol of formula R 1 SH, triarylphosphine, preferably triphenylphosphine (Ph 3 P), and dialkyl azodicarboxylate, preferably diethyl azodicarboxylate (DEAD), in a relatively polar ether solvent such as tetrahydrofuran (THF), 1,4-dioxane or 1 ,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • THF tetrahydrofuran
  • 1,4-dioxane or 1 ,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • Compounds I wherein X is O and m is 1 or 2 may be conveniently prepared by reacting XV with a compound of formula R 1 -(CH 2 ) m -L wherein L is a leaving group and a suitable base such as an alkali metal hydride, preferably sodium hydride, or an alkali metal carbonate, preferably sodium carbonate or potassium carbonate, in a reaction inert solvent, preferably a polar solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or acetonitrile at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a suitable base such as an alkali metal hydride, preferably sodium hydride, or an alkali metal carbonate, preferably sodium carbonate or potassium carbonate
  • a reaction inert solvent preferably a polar solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or
  • leaving group refers to groups which may be replaced by other groups under suitable conditions, and include, for example, halogen, lower-alkylsulfonyl and arylsulfonyl. Methanesulfonyl, bromo or iodo are preferred leaving groups.
  • compound I may be prepared by combining XV with a compound of the formula R 1 (CH 2 ) m CO 2 H, a triarylphosphine, preferably triphenyl- phosphine (Ph 3 P), and dialkyl azodicarboxylate, preferably diethyl azodicarboxylate (DEAD), in a relatively polar ether solvent, preferably tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane, at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a compound of the formula R 1 (CH 2 ) m CO 2 H a triarylphosphine, preferably triphenyl- phosphine (Ph 3 P), and dialkyl azodicarboxylate, preferably diethyl azodicarboxylate (DEAD)
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with XV in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • a polar solvent preferably dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO)
  • R 4 is hydrogen
  • a polar reaction inert solvent preferably dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO)
  • a method of preparing compounds of formula I wherein X is CHR 4 from XV involves conversion of the alcohol moiety of XV into a leaving group such as lower- alkylsulfonyl ester or arylsulfonyl ester as the first step of a two-step process.
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with XV in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • the alkyl- or arylsulfonyl derivative is combined with a compound of the formula R 1 (CH 2 ) m CH(R 4 )MgY wherein Y is a halogen atom, preferably chloro, bromo, or iodo, and a salt of copper(l), preferably cuprous bromide or cuprous iodide, in an ether solvent, preferably tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane, at a temperature from about -100 °C to about 50 °C, preferably from about -80 °C to about 25 °C.
  • a compound of the formula R 1 (CH 2 ) m CH(R 4 )MgY wherein Y is a halogen atom, preferably chloro, bromo, or iodo, and a salt of copper(l), preferably cuprous bromide or cuprous io
  • a method for preparing compounds XVI from XV involves conversion of the alcohol moiety of XV into a leaving group such as lower-alkylsulfonyl ester or arylsulfonyl ester as the first step of a two-step process.
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with XV in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • the alkyl- or arylsulfonyl derivative is combined with an alkali metal cyanide, preferably sodium cyanide or potassium cyanide, in a polar, reaction inert solvent, preferably dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), at a temperature from about 25 °C to about 100 °C, preferably from about 35 °C to about 70 °C.
  • an alkali metal cyanide preferably sodium cyanide or potassium cyanide
  • a polar, reaction inert solvent preferably dimethylformamide (DMF) or dimethyl sulfoxide (DMSO)
  • a strong inorganic acid preferably hydrochloric acid or sulfunc acid
  • borohydride in a lower alcohol solvent, preferably methanol or ethanol, at a temperature from about -10 °C to about 30 °C.
  • a method for preparing compounds I wherein X is CH(R 4 ) from I wherein X is CH(OH) involves conversion of the alcohol moiety of I wherein X is CH(OH) into a leaving group such as lower-alkylsulfonyl ester or arylsulfonyl ester as the first step of a two-step process.
  • the alkyl- or arylsulfonyl ester is first prepared by the reaction of an alkyl- or arylsulfonyl chloride with I wherein X is CH(OH) in the presence of a trialkyl amine, preferably triethylamine, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10 °C to about 30 °C.
  • a trialkyl amine preferably triethylamine
  • a reaction inert solvent preferably methylene chloride or chloroform
  • the alkyl- or arylsulfonyl derivative is combined with a compound of the formula R 4 -MgY wherein Y is a halogen atom, preferably chloro, bromo, or iodo, and a salt of copper(l), preferably cuprous bromide or cuprous iodide, in an ether solvent, preferably tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane, at a temperature from about -100 °C to about 50 °C, preferably from about -80 °C to about 25 °C.
  • a compound of the formula R 4 -MgY wherein Y is a halogen atom, preferably chloro, bromo, or iodo, and a salt of copper(l), preferably cuprous bromide or cuprous iodide, in an ether solvent, preferably tetrahydrofuran (THF
  • Compounds XVII may be prepared by treating XVI with an aqueous solution of a strong inorganic acid, preferably hydrochloric acid or sulfunc acid, at a temperature from about 20 °C to about 120 °C, preferably from about 50 °C to about 100 °C.
  • a strong inorganic acid preferably hydrochloric acid or sulfunc acid
  • DEC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • a carboxylic acid of formula XVII, an amine of formula R 1 (CH 2 ) m -NHR 4 , a tertiary amine, preferably triethyl amine or diisopropyl ethyl amine, and 1-hydroxybenzotriazole hydrate (HOBT) dissolved in a reaction inert solvent, preferably methylene chloride or chloroform, is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC) at a temperature from about 0 °C to about 50 °C, preferably from about 10 °C to about 30 °C.
  • DEC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • R 4 is hydrogen
  • a polar reaction inert solvent preferably dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO)
  • Scheme 6 summarized methods for preparing compound XIV wherein n is 1 and R 2 is hydrogen.
  • amine XIX from XVIII may be conveniently carried out by combining XVIII with a noble metal catalyst on an inert solid material, preferably palladium on charcoal, in a polar solvent such as a lower alcohol, preferably methanol or ethanol, under an atmosphere of hydrogen gas at a pressure of about one to twenty atmospheres and a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • XIX may be conveniently prepared from XVIII by the action of ammonium formate and a noble metal catalyst, preferably palladium on charcoal, in a polar solvent such as water or a lower alcohol, preferably methanol or ethanol, or a mixture of water and a lower alcohol, at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 60 °C.
  • a noble metal catalyst preferably palladium on charcoal
  • a preferred method for preparing compound XX from compound XIX involves combining 2-(phthalimido)acetaldehyde with compound XIX, an alkali metal salt of a carboxylic acid, preferably sodium acetate or sodium propionate, and a boron hydride reducing agent, preferably sodium (triacetoxy)borohydride, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about 5 °C to about 30 oC in the first step of a two step process.
  • a reaction inert solvent preferably methylene chloride or chloroform
  • the 2-(phthalimido)ethyl derivative thus formed is combined with a primary amine capable of causing the removal of the phthalimido protecting group, preferably hydrazine hydrate or methyl amine, in water or a lower alcohol solvent, preferably water, methanol, or ethanol, or a mixture thereof, at a temperature from about 0 °C to about 60 °C, preferably from about 5 °C to about 30 °C.
  • a primary amine capable of causing the removal of the phthalimido protecting group, preferably hydrazine hydrate or methyl amine
  • n is 1 by the action of a strong hydride reducing agent in a reaction inert solvent, preferably an ether such as tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane at a temperature from about 0 °C to about 100 °C, preferably from about 25 °C to about 65 °C.
  • a strong hydride reducing agent preferably an ether such as tetrahydrofuran (THF), 1 ,4-dioxane or 1 ,2-dimethoxyethane
  • THF tetrahydrofuran
  • 1 ,4-dioxane 1 ,2-dimethoxyethane
  • suitable reducing agents are known, particularly hydrides of aluminum and boron, and lithium aluminum hydride or diborane are preferred reducing agents.
  • Compounds I wherein X is S may be converted into compounds I wherein X is SO by the action with an oxidizing agent, preferably about one molar equivalent of m-chloroperoxybenzoic acid, in a reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -100 °C to about 0 °C, preferably from about -80 °C to about -20 °C.
  • an oxidizing agent preferably about one molar equivalent of m-chloroperoxybenzoic acid
  • a reaction inert solvent preferably methylene chloride or chloroform
  • Compounds I where X is S or SO may be converted into compounds I where X is SO 2 by the action with an oxidizing agent, preferably m-chloroperoxybenzoic acid, in reaction inert solvent, preferably methylene chloride or chloroform, at a temperature from about -10°C to about 50 °C, preferably from about 0 °C to about 30°C.
  • an oxidizing agent preferably m-chloroperoxybenzoic acid
  • reaction inert solvent preferably methylene chloride or chloroform
  • novel compounds of the formula I and the pharmaceutically acceptable salts thereof are useful as dopaminergic agents, i.e., they possess the ability to alter dopamine mediated neurotransmission in mammals, including humans. They are therefore able to function as therapeutic agents in the treatment of a variety of conditions in mammals, the treatment or prevention of which can be effected or facilitated by an increase or decrease in dopamine mediated neurotransmission.
  • the compounds of the formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • the therapeutic compounds of this invention can be administered orally, transdermally (e.g. through the use of a patch), parenterally or topically. Oral administration is preferred. In general, these compounds are most desirably administered in dosages ranging from about 0.1 mg up to about 1000 mg per day, or 1 mg to 1000 mg per day in some cases, although variations may occur depending on the weight and condition of the person being treated and the particular route of administration chosen. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the therapeutic compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, for example. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Dopaminergic activity is related to the ability of compounds to bind to mammalian dopamine receptors, and the relative ability of compounds of this invention to inhibit [ 3 H]-spiperone binding to human dopamine D4 receptor subtypes expressed in clonal cell lines was measured using the following procedure.
  • D4 receptor binding ability has been described by Van Tol, et al. (Nature, 1991, 350, 610). Clonal cell lines expressing the human dopamine D4 receptor are harvested and homogenized (polytron) in a 50 mM Tris:HCl (pH 7.4 at 4 °C) buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCl 2 ), 5 mM magnesium chloride (MgCl 2 ), 5 mM potassium chloride (KCl) and 120 mM sodium chloride (NaCl). The homogenates are centrifugated for 10-15 min.
  • tissue homogenate 0.75 ml aliquots of tissue homogenate are incubated in triplicate with increasing concentrations of [ 3 H]-spiperone (70.3 Ci/mmol; 10-3000 pM final concentration) for 30-120 minutes at 22 °C in a total volume of 1 ml.
  • assays are initiated by the addition of 0.75 ml of membrane and incubated in duplicate with the indicated concentrations of competing ligands (10 -14 -10 -3 M) and/or [ 3 H]-spiperone (100-300 pM) for 60-120 min at 22°C. Assays are terminated by rapid filtration through a Brandell cell harvester and the filters subsequently monitored for tritium as described by Sunahara, R.K. et al.
  • a three-neck flask fitted with a reflux condenser and dropping funnel was charged with 100 mL of dry THF and 2.4 g (63 mmol) of lithium aluminum hydride (LAH), and a solution of 6.0 g (21 mmol) of (7SR,8aSR)-7-methoxycarbonyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1 ,2-a]pyrazin-1-one (Preparation 9) in 60 mL of dry THF was placed in the dropping funnel. The LAH suspension was heated to reflux and the ester solution was added over a 30-60 min period.
  • LAH lithium aluminum hydride

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PCT/IB1996/001192 1995-12-21 1996-11-06 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives WO1997023482A1 (en)

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CA002240594A CA2240594C (en) 1995-12-21 1996-11-06 2,7-substituted octahydro-pyrrolo¬1,2-a|pyrazine derivatives
DK96935226T DK0874849T3 (da) 1995-12-21 1996-11-06 2,7-substituerede octahydropyrrolo[1,2-a]pyrazinderivater
PL96327539A PL327539A1 (en) 1995-12-21 1996-11-06 2,7-substituted derivatives of octahydropyrrole[1,2-a]-pyrazine
SI9630343T SI0874849T1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1995-12-21 1996-11-06
JP52344697A JP3204456B2 (ja) 1995-12-21 1996-11-06 ２，７―置換オクタヒドロ―ピロロ［１，２―ａ］ピラジン誘導体
AU73280/96A AU704578B2 (en) 1995-12-21 1996-11-06 2,7-substituted octahydro-pyrrolo{1,2-a}pyrazine derivatives
DE69615404T DE69615404T2 (de) 1995-12-21 1996-11-06 2,7-SUBSTITUIERTE OCTAHYDROPYRROLO(1,2-a)PYRAZINDERIVATE
NZ320537A NZ320537A (en) 1995-12-21 1996-11-06 2,7-substituted octahydro-pyrrolo(1,2-a)pyrazine derivatives
IL12445396A IL124453A0 (en) 1995-12-21 1996-11-06 2,7-substituted octahydro-pyrrolo [1,2-A]pyrazine derivatives
BR9612246A BR9612246A (pt) 1995-12-21 1996-11-06 Derivados octaidro-pirrol(1,2-a)pirazinha 2,7-substituidos
KR1019980704718A KR100286786B1 (ko) 1995-12-21 1996-11-06 2,7-치환된옥타하이드로-피롤로[1,2-에이]피라진유도체
EP96935226A EP0874849B1 (en) 1995-12-21 1996-11-06 2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives
AT96935226T ATE205846T1 (de) 1995-12-21 1996-11-06 2,7-substituierte octahydropyrrolo(1,2- a)pyrazinderivate
NO982843A NO309936B1 (no) 1995-12-21 1998-06-19 2,7-Substituerte oktahydro-pyrrol[1,2-a]pyrazin-derivater, anvendelse derav, farmasøytisk preparat, samt mellomprodukter for fremstilling av derivatene
GR20010401932T GR3037060T3 (en) 1995-12-21 2001-10-30 2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives

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EP0982030A3 (en) * 1998-08-17 2000-05-10 Pfizer Products Inc. 2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives as 5ht 1a ligands
WO2001019821A1 (en) * 1999-09-14 2001-03-22 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl- and benzthienyl-phenoxy derivatives useful as d4 antagonists
US7091199B1 (en) 1999-09-14 2006-08-15 Aventis Pharmaceuticals Inc. Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists
US7125903B1 (en) 1999-09-14 2006-10-24 Aventis Pharmaceuticals Inc. Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists
WO2007021575A3 (en) * 2005-08-15 2007-04-05 Astrazeneca Ab Acetylenic piperazines as metabotropic glutamate receptor antagonists
US7253165B2 (en) 1999-09-14 2007-08-07 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl-and benzthienyl-phenoxy derivatives useful as D4 antagonists
US20130085142A1 (en) * 2011-09-29 2013-04-04 Abbvie Inc. SUBSTITUTED OCTAHYDROPYRROLO[1,2-a]PYRAZINES AS CALCIUM CHANNEL BLOCKERS
EP3846806A4 (en) * 2018-09-04 2022-06-08 Pipeline Therapeutics, Inc. Muscarinic acetylcholine m1 receptor antagonists
US11752149B2 (en) 2019-12-02 2023-09-12 Pipeline Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists

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US6281216B1 (en) * 1998-02-09 2001-08-28 Duphar International Research B.V. 2-aminoquinoline derivatives having d4-agonistic activity
PL349912A1 (en) * 1999-02-05 2002-10-07 Upjohn Co Process to prepare (5r)-(methylamino)-5,6-dihydro-4h-imidazo[4,5,1-ij]-quinolin-2(1h)-one
EP1083369B1 (en) 1999-09-10 2004-06-30 Mitsubishi Jidosha Kogyo Kabushiki Kaisha Continuously variable transmission
WO2003024960A1 (en) * 2001-09-19 2003-03-27 Merck Patent Gmbh Novel use of substituted aminomethyl chromans
US7728031B2 (en) * 2006-02-24 2010-06-01 Abbott Laboratories Octahydro-pyrrolo[3,4-b]pyrrole derivatives

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US6284757B1 (en) 1998-08-17 2001-09-04 Pfizer Inc. Pyrrolo[1,2-a]pyrazine derivatives as 5HT1A ligands
JP3356726B2 (ja) 1998-08-17 2002-12-16 ファイザー・プロダクツ・インク ５ＨＴ１Ａリガンドとしてのピロロ［１，２−ａ］ピラジン誘導体
EP0982030A3 (en) * 1998-08-17 2000-05-10 Pfizer Products Inc. 2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives as 5ht 1a ligands
US7253165B2 (en) 1999-09-14 2007-08-07 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl-and benzthienyl-phenoxy derivatives useful as D4 antagonists
WO2001019821A1 (en) * 1999-09-14 2001-03-22 Aventis Pharmaceuticals Inc. Benzisoxazolyl-, pyridoisoxazolyl- and benzthienyl-phenoxy derivatives useful as d4 antagonists
US7091199B1 (en) 1999-09-14 2006-08-15 Aventis Pharmaceuticals Inc. Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists
US7125903B1 (en) 1999-09-14 2006-10-24 Aventis Pharmaceuticals Inc. Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists
WO2007021575A3 (en) * 2005-08-15 2007-04-05 Astrazeneca Ab Acetylenic piperazines as metabotropic glutamate receptor antagonists
US20130085142A1 (en) * 2011-09-29 2013-04-04 Abbvie Inc. SUBSTITUTED OCTAHYDROPYRROLO[1,2-a]PYRAZINES AS CALCIUM CHANNEL BLOCKERS
US8669255B2 (en) * 2011-09-29 2014-03-11 Abbvie Inc. Substituted octahydropyrrolo[1,2-a]pyrazines as calcium channel blockers
EP3846806A4 (en) * 2018-09-04 2022-06-08 Pipeline Therapeutics, Inc. Muscarinic acetylcholine m1 receptor antagonists
US12054487B2 (en) 2018-09-04 2024-08-06 Contineum Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists
US11752149B2 (en) 2019-12-02 2023-09-12 Pipeline Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists
US12390462B2 (en) 2019-12-02 2025-08-19 Contineum Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists

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CO4480107A1 (es) 1997-07-09
CN1205704A (zh) 1999-01-20
AR005102A1 (es) 1999-04-14
GT199600101A (es) 1998-06-12
NO982843D0 (no) 1998-06-19
CA2240594A1 (en) 1997-07-03
DE69615404D1 (de) 2001-10-25
DK0874849T3 (da) 2001-11-19
EP0874849B1 (en) 2001-09-19
PE25998A1 (es) 1998-05-19
GR3037060T3 (en) 2002-01-31
MA26413A1 (fr) 2004-12-20
PT874849E (pt) 2002-01-30
CZ192998A3 (cs) 1999-05-12
RU2162470C2 (ru) 2001-01-27
TR199801161T2 (xx) 1998-10-21
JPH11508920A (ja) 1999-08-03
BR9612246A (pt) 1999-07-13
IL124453A0 (en) 1998-12-06
ATE205846T1 (de) 2001-10-15
JP3204456B2 (ja) 2001-09-04
NO309936B1 (no) 2001-04-23
TW479058B (en) 2002-03-11
HUP9900611A2 (hu) 1999-08-30
TNSN96164A1 (fr) 2005-03-15
ES2161377T3 (es) 2001-12-01
AU7328096A (en) 1997-07-17
CN1061350C (zh) 2001-01-31
ZA9610781B (en) 1998-06-22
MX9805088A (es) 1998-10-31
KR100286786B1 (ko) 2001-04-16
NZ320537A (en) 1999-03-29
US5714487A (en) 1998-02-03
CA2240594C (en) 2001-07-24
EP0874849A1 (en) 1998-11-04
KR19990076616A (ko) 1999-10-15
AU704578B2 (en) 1999-04-29
HUP9900611A3 (en) 2000-09-28
DE69615404T2 (de) 2002-06-06
SI0874849T1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2001-12-31
PL327539A1 (en) 1998-12-21
NO982843L (no) 1998-06-19

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